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Essais thérapeutiques

Liste relativement exhaustive des principaux essais observationnels ou thérapeutiques dans le domaine de HTA? mentionnés sur ce site

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AASK

AASK? : African American Study of Kidney Disease and Hypertension.

Abstract

CONTEXT :
Hypertension is a leading cause of end-stage renal disease (ESRD) in the United States, with no known treatment to prevent progressive declines leading to ESRD.

OBJECTIVE :
To compare the effects of 2 levels of blood pressure (BP) control and 3 antihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension.

DESIGN :
Randomized 3 x 2 factorial trial with enrollment from February 1995 to September 1998.

SETTING AND PARTICIPANTS :
A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years.

INTERVENTIONS :
Participants were randomly assigned to 1 of 2 mean arterial pressure goals, 102 to 107 mm Hg (usual ; n = 554) or 92 mm Hg or less (lower ; n = 540), and to initial treatment with either a beta-blocker (metoprolol 50-200 mg/d ; n = 441), an angiotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d ; n = 436) or a dihydropyridine calcium channel blocker, (amlodipine 5-10 mg/d ; n = 217). Open-label agents were added to achieve the assigned BP goals.

MAIN OUTCOME MEASURES :
Rate of change in GFR (GFR slope) ; clinical composite outcome of reduction in GFR by 50% or more (or > or =25 mL/min per 1.73 m2) from baseline, ESRD, or death. Three primary treatment comparisons were specified : lower vs? usual BP goal ; ramipril vs metoprolol ; and amlodipine vs metoprolol.

RESULTS :
Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP group and 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from baseline through 4 years did not differ significantly between the lower BP group (-2.21 [0.17] mL/min per 1.73 m2 per year) and the usual BP group (-1.95 [0.17] mL/min per 1.73 m2 per year ; P =.24), and the lower BP goal did not significantly reduce the rate of the clinical composite outcome (risk reduction for lower BP group = 2% ; 95% confidence interval [CI], -22% to 21% ; P =.85). None of the drug group comparisons showed consistent significant differences in the GFR slope. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in the clinical composite outcome of 22% (95% CI, 1%-38% ; P =.04) and 38% (95% CI, 14%-56% ; P =.004), respectively. There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups.

CONCLUSIONS :
No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal. Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline.
Comment in
Antihypertensive drugs and renal protection. [JAMA. 2003]
Long-term cardiovascular consequences of diuretics vs calcium channel blockers vs angiotensin-converting enzyme inhibitors. [JAMA. 2003]
Hypertension control and kidney disease : some questions answered, many remain. [JAMA. 2002]
pdf 11386927

Références

Wright JT Jr, Bakris G, Greene T, et al. ; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease : results from the AASK trial. JAMA. 2002 Nov 20 ; 288(19):2421-31. pdf 12435255

Agodoa LY, Appel L, Bakris GL, et al. ; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis : a randomized controlled trial. JAMA. 2001 Jun 6 ; 285(21):2719-28. pdf 11386927

Grams ME, Li L, Greene TH, Tin A, et al. Estimating time to ESRD using kidney failure risk equations : results from the African American Study of Kidney Disease and Hypertension (AASK). Am J Kidney Dis. 2015 Mar ; 65(3):394-402. pdf25441435

Bhalla M, Aziz H, Richard E, Lipkowitz MS, Bhatnagar V. Serum potassium predicts time to blood pressure response among African Americans with hypertensive nephrosclerosis. J Hum Hypertens. 2013 Jun ; 27(6):393-6. pdf 23151750

McMullan CJ, Bakris GL, Phillips RA?, Forman JP. Association of BP variability with mortality among African Americans with CKD. Clin J Am Soc Nephrol. 2013 May ; 8(5):731-8. pdf 23493382

Gabbai FB, Rahman M, Hu B, et al. ; African American Study of Kidney Disease and Hypertension (AASK) Study Group. Relationship between ambulatory BP and clinical outcomes in patients with hypertensive CKD. Clin J Am Soc Nephrol. 2012 Nov ; 7(11):1770-6. pdf 22935847

Li L, Astor BC, Lewis J, et al. Longitudinal progression trajectory of GFR among patients with CKD. Am J Kidney Dis. 2012 Apr ; 59(4):504-12. pdf 22284441

Toto RD, Greene T, Hebert LA, Hiremath L, Lea JP, Lewis JB, Pogue V, Sika M, Wang X ; AASK Collaborative Research Group. Relationship between body mass index and proteinuria in hypertensive nephrosclerosis : results from the African American Study of Kidney Disease and Hypertension (AASK) cohort. Am J Kidney Dis. 2010 Nov ; 56(5):896-906. pdf20801567

Appel LJ, Wright JT Jr, Greene T, et al. ; AASK Collaborative Research Group. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010 Sep 2 ; 363(10):918-29. pdf 20818902

Alves TP, Wang X, Wright JT Jr, Appel LJ, Greene T, Norris K, Lewis J ; AASK Collaborative Research Group. Rate of ESRD exceeds mortality among African Americans with hypertensive nephrosclerosis. J Am Soc Nephrol. 2010 Aug ; 21(8):1361-9. pdf 20651163

Onuigbo MA. RAAS blockade, renal failure, ESRD, and death among African Americans in the AASK Posttrial Cohort Study. Arch Intern Med. 2008 Nov 24 ; 168(21):2383-4. pdf 19029505

Taylor AL, Wright JT Jr. Should ethnicity serve as the basis for clinical trial design ? Importance of race/ethnicity in clinical trials : lessons from the African-American Heart Failure Trial (A-HeFT), the African-American Study of Kidney Disease and Hypertension (AASK), and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT?). Circulation. 2005 Dec 6 ; 112(23):3654-60 ; discussion 3666. pdf 16330707

Appel LJ, Middleton J, Miller ER 3rd, et al. The rationale and design of the AASK cohort study. J Am Soc Nephrol. 2003 Jul ; 14(7 Suppl 2):S166-72. pdf12819323

Fogo A, Breyer JA, Smith MC, Cleveland WH, Agodoa L, Kirk KA, Glassock R. AASK Pilot Study Investigators. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans : a report from the African American Study of Kidney Disease (AASK) Trial. Kidney Int.1997 Jan ;51(1):244-52 pdf 8995739

ABCD

ABCD? : Appropriate Blood Pressure Control in Diabetes.

Abstract

BACKGROUND :
It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence? of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study.

METHODS :
The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension.

RESULTS :
Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5 ; 95 percent confidence interval, 2.7 to 33.8).

CONCLUSIONS :
In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Références :

Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension.N Engl J Med. 1998 ;338:645-52. pdf9486993

Diabetes Care. 2000 ;23 Suppl 2:B54-64. pdf10860192
N Engl J Med. 2000 ;343:1969. pdf11186674
Nat Clin Pract Nephrol. 2007 ;3:428-38. pdf17653121

ACCESS

ACCESS? : Acute Candesartan Cilexetil Therapy in Stroke Survivals.

Abstract

BACKGROUND AND PURPOSE :
The Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study was designed to assess the safety of modest blood pressure reduction by candesartan cilexetil in the early treatment of stroke. The study was also designed to provide an estimate of the number of cases required to perform a larger phase III efficacy study.

METHODS :
Five hundred patients were recruited in a prospective, double-blind, placebo-controlled, randomized, multicenter phase II study.

RESULTS :
This safety trial was stopped prematurely when 342 patients (339 valid) had been randomized because of an imbalance in end points. Demographic data, cardiovascular risk factors, and blood pressure on admission, on study onset, and within the whole study period were not significantly different between the 2 groups. However, the cumulative 12-month mortality and the number of vascular events differed significantly in favor of the candesartan cilexetil group (odds ratio, 0.475 ; 95% CI, 0.252 to 0.895). There were no significant differences in concomitant medication and in number or type of side effects.

CONCLUSIONS :
Although the mechanisms by which angiotensin type 1 (AT1) receptor blockade affects cardiovascular morbidity and mortality are still unresolved, the present study shows that early neurohumoral inhibition has similar beneficial effects in cerebral and in myocardial ischemia. The fact that no cardiovascular or cerebrovascular event occurred as a result of hypotension is of significant clinical importance. When there is need for or no contraindication against early antihypertensive therapy, candesartan cilexetil is a safe therapeutic option according to the ACCESS results.

Référence

The ACCESS Study : evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Schrader J, Lüders S, Kulschewski A, Berger J, Zidek W, Treib J, Einhäupl K, Diener HC, Dominiak P ; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. Stroke. 2003 ;34:1699-703 pdf-12817109

ACCOMPLISH

ACCOMPLISH? : Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension.

Abstract

CONTEXTE :
La thérapie de combinaison optimale des médicaments pour l’hypertension n’est pas établie, bien que les directives actuelles des États-Unis recommande l’inclusion d’un diurétique. Nous émettons l’hypothèse que le traitement par la combinaison de l’angiotensine enzyme de conversion (IEC?) et une dihydropyridine calcium channel blocker serait plus efficace pour réduire le taux d’événements cardiovasculaires que le traitement avec un inhibiteur de l’ECA et un diurétique thiazidique.

MÉTHODES :
Dans une étude randomisée, en double aveugle, nous avons attribué 11 506 patients souffrant d’hypertension qui présentaient un risque? élevé d’événements cardiovasculaires pour recevoir un traitement à l’bénazépril ainsi que l’amlodipine ou bénazépril-hydrochlorothiazide. Le point final primaire était un critère composite de décès d’origine cardiovasculaire, infarctus du myocarde, accident vasculaire cérébral non fatal, l’hospitalisation pour angine de poitrine, la réanimation après arrêt cardiaque, et de revascularisation coronaire.
Résultats :
Les caractéristiques initiales des deux groupes étaient similaires. L’essai a été arrêté peu de temps après un suivi moyen de 36 mois, lorsque la limite de la règle d’arrêt prédéfini a été dépassé. Pression artérielle moyenne après ajustement de la dose étaient 131.6/73.3 mm Hg dans le groupe bénazépril-amlodipine et 132.5/74.4 mm Hg dans le groupe bénazépril-hydrochlorothiazide. Il y avait 552 résultats primaires des événements dans le groupe bénazépril-amlodipine (9,6%) et 679 dans le groupe bénazépril-hydrochlorothiazide (11,8%), soit une réduction du risque absolu de bénazépril-amlodipine thérapie de 2,2% et une réduction du risque relatif de 19,6 % (hazard ratio : 0,80, intervalle de confiance à 95% [IC], 0,72 à 0,90 ; P <0,001). Pour le critère secondaire de décès d’origine cardiovasculaire, infarctus du myocarde non fatal, AVC? non mortels et, le hazard ratio était de 0,79 (IC 95%, 0,67 à 0,92 ; P = 0,002). Les taux d’événements indésirables ont été semblables à ceux observés à partir de l’expérience clinique avec les médicaments de l’étude.
CONCLUSIONS :
La combinaison bénazépril-amlodipine était supérieure à la combinaison bénazépril-hydrochlorothiazide dans la réduction des événements cardiovasculaires chez les patients souffrant d’hypertension qui présentaient un risque élevé pour de tels événements.

Références

Jamerson K, Weber MA, Bakris GL, Dahlöf B, Pitt B, Shi V, Hester A, Gupte J, Gatlin M, Velazquez EJ ; ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 ;359:2417-28 pdf19052124

Lancet. 2010 ;375:1173-81 pdf20170948

J Am Coll Cardiol. 2010 ;56:77-85 pdf-20620720

Lancet. 2012 pii : S0140-6736(12)61343-9 pdf23219284

ACCORD

ACCORD? : Action to Control Cardiovascular Risk in Diabetes.

Abstract

Une cohorte de 4733 patients diabétiques de type 2 ont été randomisés pour un traitement intensif ciblant une PAS? <120 mmHg ou un traitement usuel ciblant une PAS < 140 mmHg. Le critère de jugement principal était un critère combiné, associant décès cardiovasculaire, IDM? et AVC? non fatals. Après 1 an, la PAS moyennée était 119,3 mmHg dans le groupe intensif et 133,5 mmHg dans le groupe usuel. L’incidence? annuelle du critère principal était 1,87% dans le groupe intensif et 2,09 dans le groupe usuel (HR? 0,88 [CI], 0.73 - 1.06 ; P=0.20). L’incidence annuelle de décès de toutes causes était de 1,28% et 1,19% (hazard ratio, 1.07 ; 95% CI, 0.85 - 1.35 ; P=0.55). L’incidence annuelle d’AVC, un critère pré-spécifié était de 0,32% et 0,53% (hazard ratio, 0.59 ; 95% CI, 0.39 - 0.89 ; P=0.01). Des effets indésirables graves sont survenus chez 3,3% des patients dans le groupe intensif et 1,3% dans le groupe usuel.
Chez les patients diabétiques de type 2, l’intensification du traitement antihypertenseur ne modifie pas la mortalité et la morbidité cardiovasculaire, à l’exception d’une réduction significative des AVC au prix d’une moins bonne tolérance.

Références :

ACCORD? Study Group, Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010 ;362:1575-85 pdf20228401

Action to Control Cardiovascular Risk in Diabetes Follow-On (ACCORDION) Eye Study Group and the Action to Control Cardiovascular Risk in Diabetes Follow-On
(ACCORDION) Study Group. Persistent Effects of Intensive Glycemic Control on Retinopathy in Type 2 Diabetes in the Action to Control Cardiovascular Risk in
Diabetes (ACCORD?) Follow-On Study. Diabetes Care. 2016 ;39(7):1089-100. pdf27289122

Nadkarni GN, Rao V, Ismail-Beigi F, et al.. Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline : The ACCORD? Trial. Clin J Am Soc Nephrol. 2016 May 17. pii : pdf27189318

Drake TC, Hsu FC, Hire D, et al. Factors associated with failure to achieve a glycated haemoglobin target of <8.0%> 26435375

Siraj ES, Rubin DJ, Riddle MC, et al. ; ACCORD? Investigators. Insulin Dose and Cardiovascular Mortality in the ACCORD? Trial. Diabetes Care. 2015 ;38(11):2000-8. pdf26464212

Chen LY, Bigger JT, Hickey KT, et al.. Effect of Intensive Blood Pressure Lowering on Incident Atrial Fibrillation and P-Wave Indices in the ACCORD? Blood Pressure Trial. Am J Hypertens. 2015 Oct 16. pii:hpv172. pdf26476086

Chow LS, Chen H, Miller ME, Marcovina SM, Seaquist ER. Biomarkers associated with severe hypoglycaemia and death in ACCORD?. Diabet Med. 2015 pdf-26261902

Hempe JM, Liu S, Myers L, McCarter RJ, Buse JB, Fonseca V. The hemoglobin glycation index identifies subpopulations with harms or benefits from intensive
treatment in the ACCORD? trial. Diabetes Care. 2015 ;38(6):1067-74. pdf25887355

Chow LS, Chen H, Miller ME, Marcovina SM, Seaquist ER. Biomarkers related to severe hypoglycaemia and lack of good glycaemic control in ACCORD?. Diabetologia. 2015 ;58(6):1160-6. pdf25652389

Buse JB. Glycemic Targets in Diabetes Care : Emerging Clarity after Accord. Trans Am Clin Climatol Assoc. 2015 ;126:62-76. Review. pdf26330660

Gerstein HC, Miller ME, Ismail-Beigi F, Largay J, McDonald C, Lochnan HA, Booth GL ; ACCORD? Study Group. Effects of intensive glycaemic control on ischaemic
heart disease : analysis of data from the randomised, controlled ACCORD? trial. Lancet. 2014 Nov 29 ;384(9958):1936-41

Mottl AK, Pajewski N, Fonseca V, et al. The degree of retinopathy is equally predictive for renal and macrovascular outcomes in the ACCORD? Trial. J Diabetes Complications. 2014 Nov-Dec ;28(6):874-9. pdf25123755

Punthakee Z, Miller ME, Simmons DL, et al. ; ACCORD? Group of Investigators. Durable change in glycaemic control following intensive
management of type 2 diabetes in the ACCORD? clinical trial. Diabetologia. 2014 Oct ;57(10):2030-7. pdf24985147

Margolis KL, O’Connor PJ, Morgan TM, et al. Outcomes of combined cardiovascular risk factor management
strategies in type 2 diabetes : the ACCORD? randomized trial. Diabetes Care. 2014 Jun ;37(6):1721-8. pdf24595629

Miller ME, Williamson JD, Gerstein HC, et al. ; ACCORD? Investigators. Effects of randomization to intensive glucose control on adverse events, cardiovascular disease, and mortality in older versus younger adults in the ACCORD? Trial. Diabetes Care. 2014 ;37(3):634-43. pdf24170759

Barzilay JI, Howard AG, Evans GW, Fleg JL, Cohen RM, Booth GL, Kimel AR, Pedley CF, Cushman WC. Intensive blood pressure treatment does not improve
cardiovascular outcomes in centrally obese hypertensive individuals with diabetes : the Action to Control Cardiovascular Risk in Diabetes (ACCORD?) Blood Pressure Trial. Diabetes Care. 2012 ;35(7):1401-5. pdf22723577

Bonds DE, Miller ME, Dudl J, et al. Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage : Secondary analysis of the ACCORD? clinical trial data. BMC Endocr Disord. 2012 ;12:5. pdf22646230

Punthakee Z, Miller ME, Launer LJ, et al. ; ACCORD? Group of Investigators ; ACCORD?-MIND Investigators. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes : post hoc epidemiologic analysis of the ACCORD? trial. Diabetes Care. 2012 Apr ;35(4):787-93. pdf22374637

Seaquist ER, Miller ME, Bonds DE, Feinglos M, Goff DC? Jr, Peterson K, Senior P ; ACCORD? Investigators. The impact of frequent and unrecognized hypoglycemia on
mortality in the ACCORD? study. Diabetes Care. 2012 Feb ;35(2):409-14. pdf22179956

Zoungas S, Woodward M. Diabetes. Insights from the extended follow-up of the ACCORD? trial. Nat Rev Cardiol. 2011 Jun ;8(6):308-10. pdf21502962

Ismail-Beigi F, Craven T, Banerji MA, et al. ; ACCORD? trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes : an analysis of the ACCORD? randomised trial. Lancet. 2010 ;376(9739):419-30. Epub 2010 Jun 30. Erratum in : Lancet. 2010 ;376(9751):1466. pdf20594588

Bonds DE, Miller ME, Bergenstal RM, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes : retrospective
epidemiological analysis of the ACCORD? study. BMJ. 2010 ;340:b4909. pdf20061358

Williamson JD, Miller ME, Bryan RN, et al. ; ACCORD? Study Group. The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD?-MIND) :
rationale, design, and methods. Am J Cardiol. 2007 ;99(12A):112i-122i. pdf17599421.

ADVANCE

ADVANCE? : Action in Diabetes and Vascular disease ; Preterax and Diamicron-MR Controlled Evaluation.

ADVANCE (Action in Diabetes and Vascular disease ; Preterax and Diamicron-MR Controlled Evaluation) Lancet. 2007 ;370:829.
Dans cette étude 11 140 patients avec un diabète de type 2 ont été randomisés pour recevoir une combinaison fixe de perindopril-indapamide ou un placebo en plus du traitement usuel. Le critère de jugement principal était un critère combiné (décès cardiovasculaire, IDM? ou AVC? non fatals, atteinte rétinienne ou rénale). Après un suivi moyen de 4,3 ans, les patients assignés au traitement actif ont baissé leur PAS?/PAD? de 5,6 /2,2 mmHg. Le risque? relatif d’événements micro- et macrovasculaires a été abaissé de 9 % (hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). Le risque relatif de décès cardiovasculaire a été réduit de 18% (HR? 0.82, 0.68-0.98, p=0.03) et les décès de toutes causes de 14% (HR 0.86, 0.75-0.98, p=0.03)

L’addition d’une combinaison perindopril-indapamide réduit donc les décès et les événements cardiovasculaires, un effet qui semble être attribuable à la réduction supplémentaire de la pression artérielle.

Lancet. 2007 Sep 8 ;370(9590):829-40 pdf17765963

ALLHAT

ALLHAT? : Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.

L’étude ALLHAT est un méga-essai thérapeutique randomisé contrôlé en double aveugle. Le but était de comparé les nouveaux antihypertenseurs IEC?, BCC?, alpha-bloqueur à un diurétique thiazidique (chlorthalidone) avec un suivi de 8 ans. Le critère principal d’évaluation comninait les événements coronariens d’issue fatale, les infarctus du myocarde d’issue fatale et non fatale. Il n’a pas été observé de différence entre les différents groupes à l’exception de l’alpha-bloqueur (doxasozine) bras d’essai thérapeutique interrompu prématurément en raison d’un excès de risque? coronarien, d’insuffisance cardiaque et d’AVC?.

Cette étude a fait conclure à l’absence de bénéfice supplémentaire apporté par les nouveaux antihypertenseurs comparé au diurétique thiazidique. Les limites méthodologiques ont été maintes fois débattues, dominées par l’utilisation d’associations thérapeutiques peu logiques, discréditant notamment l’IEC, l’existence d’une différence de pression artérielle sous traitement entre les trois groupes, l’arrêt des médicaments antérieurs sans période de lavage (wash-out). Ce résultat est à la base des recommandations américaines prônant l’utilisation du diurétique thiazidique en première intention.

Ref.

ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs? diuretic : The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 ;288(23):2981-97. pdf12479763

ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care : The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA. 2002 ;288(23):2998-3007. pdf12479764

Kronish IM, Lynch AI, Oparil S, Whittle J, Davis BR, Simpson LM, Krousel-Wood M, Cushman WC, Chang TI, Muntner P. The Association Between Antihypertensive Medication Nonadherence and Visit-to-Visit Variability of Blood Pressure : Findings From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Hypertension. 2016 Jul ;68(1):39-45. pdf27217410

Muntner P, Davis BR, Cushman WC, et al ; ALLHAT Collaborative Research Group. Treatment-resistant hypertension and the incidence? of cardiovascular disease and end-stage renal disease : results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2014 Nov ;64(5):1012-21. pdf25259745

Yamal JM, Oparil S, Davis BR, et al. ; ALLHAT Collaborative Research Group. Stroke outcomes among participants randomized to chlorthalidone, amlodipine or lisinopril in ALLHAT. J Am Soc Hypertens. 2014 Nov ;8(11):808-19. pdf25455006

Whittle J, Yamal JM, Williamson JD, et al. ; ALLHAT Collaborative Research Group.Clinical and demographic correlates of medication and visit adherence in a large randomized controlled trial. BMC Health Serv Res. 2016 Jul 8 ;16(1):236. pdf27391223

Whittle J, Lynch AI, Tanner RM, et al. Visit-to-Visit Variability of BP and CKD Outcomes : Results from the ALLHAT. Clin J Am Soc Nephrol. 2016 Mar 7 ;11(3):471-80. pdf26912544

Muntner P, Whittle J, Lynch AI, et al. Visit-to-Visit Variability of Blood Pressure and Coronary Heart Disease, Stroke, Heart Failure, and Mortality : A Cohort Study. Ann Intern Med. 2015 ;163(5):329-38. pdf26215765

Reisin E, Graves JW, Yamal JM, et al. ; ALLHAT Collaborative Research Group.Blood pressure control and cardiovascular outcomes in normal-weight, overweight, and obese hypertensive patients treated with three different antihypertensives in ALLHAT. J Hypertens. 2014 ;32(7):1503-13 ; discussion 1513. pdf24842697

Rahman M, Ford CE, Cutler JA, et al. ; ALLHAT Collaborative Research Group. Long-term renal and cardiovascular outcomes in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants by baseline estimated GFR. Clin J Am Soc Nephrol. 2012 (6):989-1002. pdf22490878

Barzilay JI, Davis BR, Pressel SL, et al. ; ALLHAT Collaborative Research Group. Long-term effects of incident diabetes mellitus on cardiovascular outcomes in people treated for hypertension : the ALLHAT Diabetes Extension Study. Circ Cardiovasc Qual Outcomes. 2012 ;5(2):153-62. pdf22396585

Onuigbo MA. ALLHAT findings revisited in the context of subsequent analyses, other trials, and meta-analyses. Arch Intern Med. 2009 Oct 26 ;169(19):1810 ; author reply 1810-1. pdf19858442

Cushman WC, Ford CE, Einhorn PT, et al. ; ALLHAT Collaborative Research Group.Blood pressure control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens. 2008 Oct ;10(10):751-60. pdf19090876

Davis BR, Piller LB, Cutler JA, et al. ; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group.Role of diuretics in the prevention of heart failure : the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006 May 9 ;113(18):2201-10. Epub 2006 May 1. pdf16651474

Rahman M, Pressel S, Davis BR, et al. ; ALLHAT Collaborative Research Group. Cardiovascular outcomes in high-risk hypertensive patients stratified by baseline glomerular filtration rate. Ann Intern Med. 2006 Feb 7 ;144(3):172-80. pdf16461961

Rahman M, Pressel S, Davis BR, et al. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic : a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005 Apr 25 ;165(8):936-46. pdf15851647

Rahman M, Brown CD, Coresh J, et al. ; Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. The prevalence of reduced glomerular filtration rate in older hypertensive patients and its association with cardiovascular disease : a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Arch Intern Med. 2004 May 10 ;164(9):969-76. pdf15136305

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Collaborative Research Group. Diuretic versus alpha-blocker as first-step antihypertensive therapy : final results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2003 Sep ;42(3):239-46. pdf12925554

Cushman WC, Ford CE, Cutler JA, et al. ; ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in diverse North American settings : the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). J Clin Hypertens (Greenwich). 2002 Nov-Dec ;4(6):393-404. pdf12461301

Piller LB, Davis BR, Cutler JA, et al. ; The ALLHAT Collaborative Research Group. Validation of Heart Failure Events in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Participants Assigned to Doxazosin and Chlorthalidone. Curr Control Trials Cardiovasc Med. 2002 Nov 14 ;3(1):10. pdf12459039

Davis BR, Cutler JA, Furberg CD, Wright JT, Farber MA, Felicetta JV, Stokes JD ; ALLHAT Collaborative Research Group. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone : further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann Intern Med. 2002 Sep 3 ;137(5 Part 1):313-20. pdf12204014

Grimm RH Jr, Margolis KL, Papademetriou V V, et al. Baseline Characteristics of Participants in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension. 2001 ;37(1):19-27. pdf11208751

ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone : the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2000 ;283(15):1967-75. Erratum in : JAMA 2002 ;288(23):2976. pdf10789664

ALTITUDE

ALTITUDE? : Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints.

Une cohorte de 8561 patients diabétiques de type à haut risque? cardiovasculaire et rénal, a été randomisée pour recevoir l’aliskiren 300 mg/j ou son placebo en plus d’un traitement usuel comportant un IEC? ou un ARA2?. Le critère de jugement principal était un critère combiné associant décès cardiovasculaire, arrêt cardiaque, IDM? ou AVC? non fatals, hospitalisation pour insuffisance cardiaque insuffisance rénale terminale ou doublement de la créatinine plasmatique. L’essai a été interrompu prématurément pour futilité et majoration des événements indésirables graves dans le groupe aliskiren. Après un suivi médian de 32,9 mois, le critère principal a été atteint chez 18,3% des patients sous aliskiren et 17,1% des patients sous placebo (hazard ratio, 1.08 ; 95% [CI], 0.98 - 1.20 ; P=0.12). La PA? systolique et diastolique était plus basse dans le groupe alikiren (–1,3/0,6 mmHg), ainsi que la réduction du rapport albumine/créatinine urinaire. La proportion de patients avec une hypokaliémie > 6,0 mmol/L était significativement plus élevée dans le groupe aliskiren (11,3 vs? 7,2%) de même que les hypotensions symptomatiques (12,1 vs 8,3%) (p< 0,001 pour les 2 comparaisons).
L’addition d’aliskiren en plus d’un traitement IEC ou ARA2 n’apporte donc pas de bénéfices sur le risque cardiovasculaire ou rénale et pourrait être délétère.

Parving HH, Brenner BM, McMurray JJ, et al. ; ALTITUDE Investigators.Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 ;367:2204 pdf23121378

Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) : rationale and study design. Nephrol Dial Transplant. 2009 May ; 24(5):1663-71. pdf19145003

Parving HH, Brenner BM, McMurray JJ, et al. ; ALTITUDE Investigators. Baseline characteristics in the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). J Renin Angiotensin Aldosterone Syst. 2012 Sep ; 13(3):387-93. pdf22333485

ASCOT

ASCOT? : Anglo-Scandinavian Cardiac Outcomes Trial.

CONTEXTE :
Le déficit apparent dans la prévention de la maladie coronarienne (CHD) a noté dans les essais hypertension précoce a été attribuée à des inconvénients des diurétiques et des bêta-bloquants utilisés. Pour une réduction donnée de la pression artérielle, certains ont suggéré que les nouveaux agents qui confèrent des avantages sur les diurétiques et les bêta-bloquants. Notre objectif était donc de comparer l’effet sur la non-fatal infarctus du myocarde et les maladies coronariennes mortelles de combinaisons de l’aténolol avec un thiazidique contre l’amlodipine avec le périndopril.
MÉTHODES :
Nous avons fait une étude multicentrique, prospective, randomisée et contrôlée chez 19 257 patients souffrant d’hypertension qui étaient âgés de 40 à 79 ans et a eu au moins trois autres facteurs de risque? cardiovasculaire. Les patients ont été assignés soit 10.5 mg d’amlodipine ajoutant 4-8 mg périndopril si nécessaire (à base d’amlodipine régime, n = 9639) ou l’aténolol 50-100 mg ajoutant bendrofluméthiazide 1,25-2,5 mg de potassium et, au besoin (aténolol régime ; n = 9618). Notre objectif principal était non fatal infarctus du myocarde (y compris l’infarctus du myocarde silencieux) et MC mortelles. L’analyse était en intention de traiter.
RÉSULTATS :
L’étude a été arrêtée prématurément après 5,5 ans de suivi médian et accumulé un total de 106 153 patients-années d’observation. Bien que non significative, par rapport à la posologie aténolol, moins de personnes sur le groupe amlodipine avaient un critère d’évaluation primaire (429 vs? 474 ; non ajusté HR? 0,90, IC 95% 0,79 à 1,02, p = 0,1052), mortels et non mortels course (327 vs 422 ; 0,77, 0.66 à 0.89, p = 0,0003), le total des événements cardiovasculaires et des procédures (1362 vs 1602, 0,84, 0,78 à 0,90, p <0,0001), et mortalité toutes causes confondues (738 vs 820 ; 0,89, de 0,81 à 0,99, p = 0,025). L’incidence? de développer un diabète était moins sur le traitement à base d’amlodipine (567 vs 799 ; 0,70, 0,63 à 0,78, p <0,0001).
Interprétation :
L’amlodipine empêche plus grands événements cardio-vasculaires et le diabète induit moins que le régime aténolol. Sur la base des données d’essais précédente, ces effets pourraient ne pas être entièrement expliqué par un meilleur contrôle de la pression artérielle, et cette question est abordée dans l’article ci-joint. Néanmoins, les résultats ont des implications en ce qui concerne les combinaisons optimales d’antihypertenseurs.

Dahlöf B1, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J ; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) : a multicentre randomised controlled trial.Lancet.2005 Sep 10-16 ;366(9489):895-906.. [PMID:16154016]

Lancet. 2005 ;366:895-906. pdf16154016
Lancet. 2005 ;366:907-13. pdf16154017

AUSTRALIAN TRIAL

AUSTRALIAN : Australian Therapeutic Trial in Mild Hypertension.

[No authors listed] Untreated mild hypertension. A report by the Management Committee of the Australian Therapeutic Trial in Mild Hypertension.Lancet.1982 Jan 23 ;1(8265):185-91 pdf6119558

Abstract
In all subjects of the Australian therapeutic trial in mild hypertension, mean pressures for the two screening visits were within the range 95-109 mm Hg for diastolic blood-pressure phase V(DBP) and less than 200 mm Hg for systolic blood-pressure (SBP). In the 1943 control (placebo) subjects mean blood-pressures fell from 158/102 mm Hg at the first screening visit to 144/91 mm Hg 3 years later. At that time pressures remained within the mild hypertension range in 32%, ahd risen above it in 12%, and had fallen below in 48%. Trial end-points (ischaemic heart disease or cerebrovascular accident) occurred in 8%. The outcome was related to the level of initial pressure but not to other characteristics measured at entry. The mean initial pressures of 22 subjects who experienced a cerebrovascular event were higher than those of a matched group with no hypertensive complications, but the 88 subjects who experienced ischaemic-heart-disease events had initial pressures similar to those in a matched control group. The trial end-point rate was related to the average DBP of subjects throughout the trial in those with average DBP greater than or equal to 95 mm Hg, and at those levels subjects on active treatment had a higher incidence? than subjects of the placebo group with the same DBP level. For those with average DBP below 95 mm Hg the incidence of trial end-points was not related to blood-pressure level or treatment. 16% of placebo subjects in this mild hypertensive population had a mean DBP of less than 95 mm Hg at the first three visits. If this were taken as an indication to withhold drug treatment, 3 years later one-quarter of them (4% of all subjects) would be found to be hypertensive or to have experienced a trial end-point, and thus inappropriately untreated, while the other 12% would have pressures below 95 mm Hg and have had no trial end-point.

BENEDICT

BENEDICT? : Bergamo Nephrologic Diabetic Complications Trial.

BACKGROUND :
The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion.
METHODS :
We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits).
RESULTS :
The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups.
CONCLUSIONS :
In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence? of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.

Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G ; Bergamo Nephrologic Diabetes Complications Trial ( BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004 ;351(19):1941-51. pdf15516697

CAFE

CAFE? : Conduit Artery Function Evaluation.

Etude ancillaire de ASCOT? avec évaluation de la pression centrale.

BACKGROUND :
Different blood pressure (BP)-lowering drugs could have different effects on central aortic pressures and thus cardiovascular outcome despite similar effects on brachial BP. The Conduit Artery Function Evaluation (CAFE?) study, a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), examined the impact of 2 different BP lowering-regimens (atenolol+/-thiazide-based versus amlodipine+/-perindopril-based therapy) on derived central aortic pressures and hemodynamics.
METHODS AND RESULTS :
The CAFE? study recruited 2199 patients in 5 ASCOT? centers. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressures and hemodynamic indexes on repeated visits for up to 4 years. Most patients received combination therapy throughout the study. Despite similar brachial systolic BPs between treatment groups (Delta0.7 mm Hg ; 95% CI, -0.4 to 1.7 ; P=0.2), there were substantial reductions in central aortic pressures with the amlodipine regimen (central aortic systolic BP, Delta4.3 mm Hg ; 95% CI, 3.3 to 5.4 ; P<0.0001 ;> 16476843

CAMELOT

CAMELOT? : Comparison of Amlodipine versus Enalapril to Limit Occurrences of Thrombosis.

CONTEXT :
The effect of antihypertensive drugs on cardiovascular events in patients with coronary artery disease (CAD) and normal blood pressure remains uncertain.
OBJECTIVE :
To compare the effects of amlodipine or enalapril vs? placebo on cardiovascular events in patients with CAD.
DESIGN, SETTING, AND PARTICIPANTS :
Double-blind, randomized, multicenter, 24-month trial (enrollment April 1999-April 2002) comparing amlodipine or enalapril with placebo in 1991 patients with angiographically documented CAD (>20% stenosis by coronary angiography) and diastolic blood pressure <100> 15536108

CANVAS

CANVAS?
Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes : results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018 ;6:691-704

Abstract
Background : In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, canagliflozin reduced the rates of major adverse cardiovascular events and the results suggested a renal benefit in patients with type 2 diabetes who were at high risk for cardiovascular events, compared with those treated with placebo. Here we report the results of a prespecified exploratory analysis of the long-term effects of canagliflozin on a range of sustained and adjudicated renal outcomes.

Methods : The CANVAS Program consists of two double-blind, randomised trials that assessed canagliflozin versus placebo in participants with type 2 diabetes who were at high risk of cardiovascular events, done at 667 centres in 30 countries. People with type 2 diabetes and an HbA1c of 7·0-10·5% (53-91 mmol/mol) who were aged at least 30 years and had a history of symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were eligible to participate. Participants in CANVAS were randomly assigned (1:1:1) to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomly assigned (1:1) to receive canagliflozin or matching placebo, at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. Participants and all study staff were masked to treatment allocations until study completion. Prespecified outcomes reported here include a composite of sustained and adjudicated doubling in serum creatinine, end-stage kidney disease, or death from renal causes ; the individual components of this composite outcome ; annual reductions in estimated glomerular filtration rate (eGFR) ; and changes in urinary albumin-to-creatinine ratio (UACR). The trials are registered with ClinicalTrials.gov, numbers NCT01032629 (CANVAS) and NCT01989754 (CANVAS-R).

Findings : Between Nov 17, 2009, and March 7, 2011 (CANVAS), and Jan 17, 2014, and May 29, 2015 (CANVAS-R), 15 494 people were screened, of whom 10 142 participants (with a baseline mean eGFR 76·5 mL/min per 1·73 m2, median UACR 12·3 mg/g, and 80% of whom were receiving renin-angiotensin system blockade) were randomly allocated to receive either canagliflozin or placebo. The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs? 2·8 per 1000 patient-years in the placebo group ; hazard ratio 0·53, 95% CI 0·33-0·84), with consistent findings across prespecified patient subgroups. Annual eGFR decline was slower (slope difference between groups 1·2 mL/min per 1·73 m2 per year, 95% CI 1·0-1·4) and mean UACR was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo. Total serious renal-related adverse events were similar between the canagliflozin and placebo groups (2·5 vs 3·3 per 1000 patient-years ; HR? 0·76, 95% CI 0·49-1·19).

Interpretation : In a prespecified exploratory analysis, canagliflozin treatment was associated with a reduced risk of sustained loss of kidney function, attenuated eGFR decline, and a reduction in albuminuria, which supports a possible renoprotective effect of this drug in people with type 2 diabetes.

CHARM

CHARM? : Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity.

Abstract
BACKGROUND :
Decreased renal function has been found to be an independent risk factor for cardiovascular outcomes in patients with chronic heart failure (CHF) with markedly reduced left ventricular ejection fraction (LVEF). The aim of this analysis was to evaluate the prognostic importance of renal function in a broader spectrum of patients with CHF.
METHODS AND RESULTS :
The Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity (CHARM?) program consisted of three component trials that enrolled patients with symptomatic CHF, based on use of ACE inhibitors and reduced (< or =40%) or preserved LVEF (>40%). Entry baseline creatinine was required to be below 3.0 mg/dL (265 micromol/L). Routine baseline serum creatinine assessments were done in 2680 North American patients. An analysis of the estimated glomerular filtration rate (eGFR), using the Modification of Diet in Renal Disease equation and LVEF on risk of cardiovascular death or hospitalization for heart failure, as well as on all-cause mortality, was conducted on these 2680 patients. The proportion of patients with eGFR <60 mL/min per 1.73 m2 was 36.0% ; 42.6% for CHARM?-Alternative, 33.0% for CHARM?-Added, and 34.7% for CHARM?-Preserved. During the median follow-up of 34.4 months (total 6493 person-years), the primary outcome of cardiovascular death or hospital admission for worsening CHF occurred in 950 of 2680 subjects. Both reduced eGFR and lower LVEF were found to be significant independent predictors of worse outcome after adjustment for major confounding baseline clinical characteristics. The risk for cardiovascular death or hospitalization for worsening CHF as well as the risk for all-cause mortality increased significantly below an eGFR of 60 mL/min per 1.73 m2 (adjusted hazard ratio, 1.54 for 45 to 60 mL/min per 1.73 m2 and 1.86 for <45 mL/min per 1.73 m2 for the primary outcome, both P<0.001,> 15466644

McMurray JJ1, Young JB, Dunlap ME, Granger CB, Hainer J, Michelson EL, Earle S, Olofsson B, Ostergren J, Yusuf S, Swedberg K, Pfeffer MA ; CHARM? Investigators. Relationship of dose of background angiotensin-converting enzyme inhibitor to the benefits of candesartan in the Candesartan in Heart failure : Assessment of Reduction in Mortality and morbidity (CHARM?)-Added trial. Am Heart J. 2006 May ;151(5):985-91.

CHHIPS

CHHIPS? : Controlling Hypertension and Hypothension Immediately Poststroke.

Abstract

BACKGROUND :
Raised blood pressure is common after acute stroke and is associated with an adverse prognosis. We sought to assess the feasibility, safety, and effects of two regimens for lowering blood pressure in patients who have had a stroke.

METHODS :
Patients who had cerebral infarction or cerebral haemorrhage and were hypertensive (systolic blood pressure [SBP] >160 mm Hg) were randomly assigned by secure internet central randomisation to receive oral labetalol, lisinopril, or placebo if they were non-dysphagic, or intravenous labetalol, sublingual lisinopril, or placebo if they had dysphagia, within 36 h of symptom onset in this double-blind pilot trial. The doses were titrated up if target blood pressure was not reached. Analysis was by intention to treat. This trial is registered with the National Research Register, number N0484128008.

FINDINGS :
179 patients (mean age 74 [SD 11] years ; SBP 181 [SD 16] mm Hg ; diastolic blood pressure [DBP] 95 [SD 13] mm Hg ; median National Institutes of Health stroke scale [NIHSS] score 9 [IQR 5-16] points) were randomly assigned to receive labetolol (n=58), lisinopril (n=58), or placebo (n=63) between January, 2005, and December, 2007. The primary outcome—death or dependency at 2 weeks—occurred in 61% (69) of the active and 59% (35) of the placebo group (relative risk [RR?] 1.03, 95% CI 0.80-1.33 ; p=0.82). There was no evidence of early neurological deterioration with active treatment (RR 1.22, 0.33-4.54 ; p=0.76) despite the significantly greater fall in SBP within the first 24 h in this group compared with placebo (21 [17-25] mm Hg vs? 11 [5-17] mm Hg ; p=0.004). No increase in serious adverse events was reported with active treatment (RR 0.91, 0.69-1.12 ; p=0.50) but 3-month mortality was halved (9.7%vs 20.3%, hazard ratio [HR?] 0.40, 95% CI 0.2-1.0 ; p=0.05).

INTERPRETATION :
Labetalol and lisinopril are effective antihypertensive drugs in acute stroke that do not increase serious adverse events. Early lowering of blood pressure with lisinopril and labetalol after acute stroke seems to be a promising approach to reduce mortality and potential disability. However, in view of the small sample size, care must be taken when these results are interpreted and further evaluation in larger trials is needed.

Référence :

Potter JF, Robinson TG, Ford GA, Mistri A, James M, Chernova J, Jagger C. Controlling hypertension and hypotension immediately post-stroke (CHHIPS) : a randomised, placebo-controlled, double-blind pilot trial.

Lancet Neurol. 2009 ;8:48-56 pdf19058760

CREDENCE

Credence?

Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 ;380:2295-2306

Abstract
Background : Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.

Methods : In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90> 300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.

Results : The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70 ; 95% confidence interval [CI], 0.59 to 0.82 ; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66 ; 95% CI, 0.53 to 0.81 ; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68 ; 95% CI, 0.54 to 0.86 ; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 ; 95% CI, 0.67 to 0.95 ; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61 ; 95% CI, 0.47 to 0.80 ; P<0.001). There were no significant differences in rates of amputation or fracture.

Conclusions : In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development ; CREDENCE? ClinicalTrials.gov number, NCT02065791.).

DAPA-CKD

Dapa-ckd

Background : Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.

Methods : We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.

Results : The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61 ; 95% confidence interval [CI], 0.51 to 0.72 ; P<0.001 ; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68 ; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92 ; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69 ; 95% CI, 0.53 to 0.88 ; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.

Conclusions : Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca ; DAPA-CKD? ClinicalTrials.gov number, NCT03036150.)

DAPA-HF

Dapa-HF

McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 ;381:1995-2008

Abstract
Background : In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

Methods : In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.

Results : Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74 ; 95% confidence interval [CI], 0.65 to 0.85 ; P<0.001).> 31535829

DASH / DASH-sodium

DASH : Dietary Approaches to Stop Hypertension

Akita S, Sacks FM, Svetkey LP, Conlin PR, Kimura G ; DASH-Sodium Trial Collaborative Research Group. Effects of the Dietary Approaches to Stop Hypertension (DASH) diet on the pressure-natriuresis relationship.Hypertension.2003 Jul ;42(1):8-13. 12756219

Vollmer WM1, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, Conlin PR, Svetkey LP, Erlinger TP, Moore TJ, Karanja N ; DASH-Sodium Trial Collaborative Research Group. Effects of diet and sodium intake on blood pressure : subgroup analysis of the DASH-sodium? trial.Ann Intern Med.2001 Dec 18 ;135(12):1019-28. 11747380

Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER 3rd, Simons-Morton DG, Karanja N, Lin PH ; DASH-Sodium Collaborative Research Group. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet.DASH-Sodium Collaborative Research Group.N Engl J Med.2001 Jan 4 ;344(1):3-10. 11136953

Moore TJ, Vollmer WM, Appel LJ, Sacks FM, Svetkey LP, Vogt TM, Conlin PR, Simons-Morton DG, Carter-Edwards L, Harsha DW. Effect of dietary patterns on ambulatory blood pressure : results from the Dietary Approaches to Stop Hypertension (DASH) Trial.DASH Collaborative Research Group.Hypertension.1999 Sep ;34(3):472-7. 10489396

Svetkey LP, Sacks FM, Obarzanek E, Vollmer WM, Appel LJ, Lin PH, Karanja NM, Harsha DW, Bray GA, Aickin M, Proschan MA, Windhauser MM, Swain JF, McCarron PB, Rhodes DG, Laws RL. The DASH Diet, Sodium Intake and Blood Pressure Trial (DASH-sodium) : rationale and design. DASH-Sodium Collaborative Research Group. J Am Diet Assoc.1999 Aug ;99(8 Suppl):S96-104. 10450301

DECLARE-TIMI 58

Declare-Timi58

BACKGROUND :
The cardiovascular safety profile of dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 that promotes glucosuria in patients with type 2 diabetes, is undefined.

METHODS :
We randomly assigned patients with type 2 diabetes who had or were at risk for atherosclerotic cardiovascular disease to receive either dapagliflozin or placebo. The primary safety outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. The primary efficacy outcomes were MACE and a composite of cardiovascular death or hospitalization for heart failure. Secondary efficacy outcomes were a renal composite (?40% decrease in estimated glomerular filtration rate to <60> 30415602

DIRECT

DIRECT? : Diabetic Retinopathy Candesartan Trials.

Abstract

BACKGROUND :
Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence? and progression of retinopathy in type 1 diabetes.

METHODS :
Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1.

FINDINGS :
1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18-55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR? for candesartan vs? placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups.

INTERPRETATION :
Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.

Références :

Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, Bilous R, Sjølie AK ; DIRECT Programme Study Group. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes : randomised, placebo-controlled trials. Lancet 2008 ;372:1394-402. pdf18823656

Ann Intern Med. 2009 ;151:11-20 pdf19451554

EMPA-kidney

Empa-kidney

Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain. Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight. In the kidney, increased sodium delivery to the macula densa mediated by SGLT-2 inhibition has the potential to reduce intraglomerular pressure, which may explain why SGLT-2 inhibitors reduce albuminuria and appear to slow kidney function decline in people with diabetes. Importantly, in the trials completed to date, these benefits appeared to be maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and did not appear to be dependent on ambient hyperglycaemia. There is therefore a rationale for studying the cardio-renal effects of SGLT-2 inhibition in people at risk of CV disease and hyperfiltration (i.e. those with substantially reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes.

EMPAREG

Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 ;373:2117-28

Abstract
Background : The effects of empagliflozin, an inhibitor of sodium-glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known.

Methods : We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina.

Results : A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86 ; 95.02% confidence interval, 0.74 to 0.99 ; P=0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs.? 5.9% in the placebo group ; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively ; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively ; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P=0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events.

Conclusions : Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly ; EMPA-REG? OUTCOME ClinicalTrials.gov number, NCT01131676.).

Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 ;375:323-34

Abstract
Background : Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG? OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.

Methods : We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria.

Results : Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61 ; 95% confidence interval, 0.53 to 0.70 ; P<0.001).> 26378978

EMPEROR-reduced

Emperor-reduced

Background : Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.

Methods : In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure.

Results : During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75 ; 95% confidence interval [CI], 0.65 to 0.86 ; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70 ; 95% CI, 0.58 to 0.85 ; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs.? -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin.

Conclusions : Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly ; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

EUROPA

EUROPA? : European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease.

Cette étude a évalué l’effet d’un IEC? le perindopril 8 mg comparé au placebo chez 12 218 patients coronariens stables ayant présenté un antécédent coronarien (infarctus du myocarde préalable, maladie coronarienne ou épreuve d’effort positive).
Sur le critère principal d’évaluation associant décès cardiovasculaire, infarctus du myocarde, arrêt cardiaque, la RRR? est de - 20 % et la réduction du risque? d’infarctus du myocarde de - 22 %. Seulement 12 % de la population était diabétique et le suivi est de 4.2 ans. Au cours de cet essai il n’a pas été montré de bénéfice parallèle sur la réduction du risque d’AVC?.

Fox KM ; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease : randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003 ;362:782-8. pdf13678872

EWPHE

EWPHE? : European Working Party on High Blood Pressure in the Elderly.

Abstract

A double-blind randomised placebo-controlled trial of antihypertensive treatment was conducted in patients over the age of 60. Entry criteria included both a sitting diastolic blood pressure on placebo treatment in the range 90-119 mm Hg and a systolic pressure in the range 160-239 mm Hg. 840 patients were randomised either to active treatment (hydrochlorothiazide + triamterene) or to matching placebo. If the blood pressure remained raised, methyldopa was added to the active regimen and matching placebo in the placebo group. An overall intention-to-treat analysis, combining the double-blind part of the trial and all subsequent follow-up, revealed a non-significant change in total mortality rate (-9%, p = 0.41) but a significant reduction in cardiovascular mortality rate (-27%, p = 0.037). The latter was due to a reduction in cardiac mortality (-38%, p = 0.036) and a non-significant decrease in cerebrovascular mortality (-32%, p = 0.16). In the double-blind part of the trial, total mortality rate was not significantly reduced (-26%, p = 0.077). Cardiovascular mortality was reduced in the actively treated group (-38%, p = 0.023), owing to a reduction in cardiac deaths (-47%, p = 0.048) and a non-significant decrease in cerebrovascular mortality (-43%, p = 0.15). Deaths from myocardial infarction were reduced (-60%, p = 0.043). Study-terminating morbid cardiovascular events were significantly reduced by active treatment (-60%, p = 0.0064). Non-terminating cerebrovascular events were reduced (-52%, p = 0.026), but the non-terminating cardiac events were not (+3%, p = 0.98). In the patients randomised to active treatment there were 29 fewer cardiovascular events and 14 fewer cardiovascular deaths per 1000 patient years during the double-blind part of the trial.

Amery A, Birkenhäger W, Brixko P, Bulpitt C, Clement D, Deruyttere M, De Schaepdryver A, Dollery C, Fagard R, Forette F, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet. 1985 Jun 15 ;1(8442):1349-54. pdf2861311

FEVER

FEVER? : Felodipine Event Reduction.

Abstract

OBJECTIVE :
To compare the incidence? of stroke and other cardiovascular events in hypertensive patients receiving a low-dose diuretic and low-dose calcium antagonist combination with those receiving low-dose diuretic monotherapy, and assess the effects of a small blood pressure difference at achieved levels lower than those achieved in previous placebo-controlled trials.

METHODS :
The Felodipine Event Reduction (FEVER) trial was an investigator-designed, prospective, multicentre, double-blind, randomized, placebo-controlled, parallel group trial. It enrolled 9800 Chinese patients, of either sex, aged 50-79 years, with one or two additional cardiovascular risk factors or disease, whose blood pressure, 6 weeks after switching from previous antihypertensive therapy to low-dose (12.5 mg a day) hydrochlorothiazide, was in the range 140-180 mmHg (systolic) or 90-100 mmHg (diastolic). These patients were randomly assigned either to low-dose felodipine extended release or placebo, and followed at 3-month intervals for an average of 40 months.

RESULTS :
The intention-to-treat analysis included 9711 randomly selected patients with only 30 (0.3%) lost to follow-up. A total of 31 842 patient-years of follow-up were accumulated, with 85.9% of patients remaining on blinded randomized treatment. Add-on therapy was given to 33.9% of the hydrochlorothiazide-felodipine patients and to 42.3% of the hydrochlorothiazide-placebo patients. In the felodipine group, systolic blood pressure (SBP)/diastolic blood pressure (DBP) decreased (from randomization to study end) from 154.2/91.0 to 137.3/82.5 mmHg, and in the placebo group from 154.4/91.3 to 142.5/85.0 mmHg, with an average difference throughout the trial of 4.2/2.1 mmHg. In the felodipine group, the primary endpoint (fatal and non-fatal stroke) was reduced by 27% (P = 0.001). Among secondary endpoints, all cardiovascular events were reduced by 27% (P < 0.001), all cardiac events by 35% (P = 0.012), death by any cause by 31% (P = 0.006), coronary events by 32% (P = 0.024), heart failure by 30% (P = 0.239), cardiovascular death by 33% (P = 0.019), cancer by 36% (P = 0.017) in the felodipine group. No significant differences were found in new-onset diabetes. Both treatments were very well tolerated.

CONCLUSIONS :
In moderately complicated hypertensive patients from China even a difference in SBP/DBP as small as 4/2 mmHg, such as that induced by adding low-dose felodipine to low-dose hydrochlorothiazide, is associated with very substantial reductions in the incidence of most types of cardiovascular events. As the SBP achieved in the felodipine group was below the recommended goal of less than 140 mmHg, and SBP in the placebo group was slightly above that level, FEVER provides the required evidence in support of the guidelines recommended goal, even for a hypertensive population not entirely consisting of patients with diabetes or previous cardiovascular events.

Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A ; FEVER Study Group. The Felodipine Event Reduction (FEVER) Study : a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005 ;23(12):2157-72. pdf16269957

GEMINI

GEMINI? : Glycemic Effect in Diabetes Mellitus : Carvedilol–Metoprolol Comparison in Hypertensives.

Abstract

CONTEXT :
Beta-blockers have been shown to decrease cardiovascular risk in patients with hypertension and type 2 diabetes mellitus (DM) ; however, some components of the metabolic syndrome are worsened by some beta-blockers.

OBJECTIVE :
To compare the effects of beta-blockers with different pharmacological profiles on glycemic and metabolic control in participants with DM and hypertension receiving renin-angiotensin system (RAS) blockade, in the context of cardiovascular risk factors.

DESIGN, SETTING, AND PARTICIPANTS :
A randomized, double-blind, parallel-group trial (The Glycemic Effects in Diabetes Mellitus : Carvedilol-Metoprolol Comparison in Hypertensives [GEMINI]) conducted between June 1, 2001, and April 6, 2004, at 205 US sites that compared the effects of carvedilol and metoprolol tartrate on glycemic control. The 1235 participants were aged 36 to 85 years with hypertension (>130/80 mm Hg) and type 2 DM (glycosylated hemoglobin [HbA1c], 6.5%-8.5%) and were receiving RAS blockers. Participants were followed up for 35 weeks.

INTERVENTIONS :
Participants were randomized to receive a 6.25- to 25-mg dose of carvedilol (n = 498) or 50- to 200-mg dose of metoprolol tartrate (n = 737), each twice daily. Open-label hydrochlorothiazide and a dihydropyridine calcium antagonist were added, if needed, to achieve blood pressure target.

MAIN OUTCOME MEASURES :
Difference between groups in mean change from baseline HbA1c following 5 months of maintenance therapy. Additional prespecified comparisons included change from baseline HbA1c in individual treatment groups, treatment effect on insulin sensitivity, and microalbuminuria.

RESULTS :
The 2 groups differed in mean change in HbA1c from baseline (0.13% ; 95% confidence interval [CI], -0.22% to -0.04% ; P = .004 ; modified intention-to-treat analysis). The mean (SD) HbA1c increased with metoprolol (0.15% [0.04%] ; P<.001) but not carvedilol (0.02% [0.04%] ; P = .65). Insulin sensitivity improved with carvedilol (-9.1% ; P = .004) but not metoprolol (-2.0% ; P = .48) ; the between-group difference was -7.2% (95% CI, -13.8% to -0.2% ; P = .004). Blood pressure was similar between groups. Progression to microalbuminuria was less frequent with carvedilol than with metoprolol (6.4% vs? 10.3% ; odds ratio, 0.60 ; 95% CI, 0.36-0.97 ; P = .04).

CONCLUSIONS :
Both beta-blockers were well tolerated ; use of carvedilol in the presence of RAS blockade did not affect glycemic control and improved some components of the metabolic syndrome relative to metoprolol in participants with DM and hypertension. The effects of the 2 beta-blockers on clinical outcomes need to be compared in long-term clinical trials.

Références :

Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension : a randomized controlled trial.
Bakris GL, Fonseca V, Katholi RE, McGill JB, Messerli FH, Phillips RA?, Raskin P, Wright JT Jr, Oakes R, Lukas MA, Anderson KM, Bell DS ; GEMINI Investigators.
JAMA. 2004 Nov 10 ;292(18):2227-36. pdf15536109

Am J Med. 2007 Jul ;120(7):610-5. pdf17602935

HDFP

HDFP? : Hypertension Detection and Follow-up Program.

Abstract
The Hypertension Detection and Follow-up Program (HDFP), in a community-based, randomized controlled trial involving 10,940 persons with high blood pressure (BP), compared the effects on five-year mortality of a systematic antihypertensive treatment program (Stepped Care [SC]) and referral to community medical therapy (Referred Care [RC]). Participants, recruited by population-based screening of 158,906 people aged 30 to 69 years in 14 communities througout the United States, were randomly assigned to SC or RC groups within each center and by entry diastolic blood pressure (DBP) (90 to 104, 105 to 114, and 115 + mm Hg). Over the five years of the study, more than two thirds of the SC participants continued to receive medication, and more than 50% achieved BP levels within the normotensive range, at or below the HDFP goal for DBP. Controls of BP was consistently better for the SC than for the RC group. Five-year mortality from all causes was 17% lower for the SC group compared to the RC group (6.4 vs? 7.7 per 100, P less than .01) and 20% lower for the SC subgroup with entry DBP of 90 to 104 mm Hg compared to the corresponding RC subgroup (5.9 vs 7.4 per 100, P less than .01). These findings of the HDFP indicate that the systematic effective management of hypertension has a great potential for reducing mortality for the large numbers of people with high BP in the population, including those with "mild" hypertension

Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the hypertension detection and follow-up program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension.
JAMA. 1979 Dec 7 ;242(23):2562-71.
pdf490882
JAMA. 1982 Feb 5 ;247(5):633-8.
pdf7033578
JAMA. 1988 Apr 8 ;259(14):2113-22.
pdf3346988

Five-year findings of the hypertension detection and follow-up program. III. Reduction in stroke incidence? among persons with high blood pressure. Hypertension Detection and Follow-up Program Cooperative Group.

Abstract
The Hypertension Detection and Follow-up Program (HDFP) previously reported a 16.9% reduction in all-cause mortality among its Stepped Care (SC) group, relative to the community-treated Referred Care (RC) group. The current report compares cerebrovascular disease (CV) morbidity and mortality in the SC and RC populations. The SC five-year stroke incidence (1.9 per 100 persons) is significantly lower than that found among the RC (2.9 per 100 persons). Reductions in stroke rates among SC were experienced for all race-sex groups, all diastolic blood pressure strata, all ages, and among those with or without evidence of long-standing hypertension. Comparisons of the CV death rates for SC (1.06 per 1,000 persons) and RC (1.91 per 1,000 persons) with those obtained for the general US population (0.83 per 1,000 persons) indicate that the CV death rate decreased in the SC hypertensive population to a level approaching that of the general US population.

Persistence of reduction in blood pressure and mortality of participants in the Hypertension Detection and Follow-up Program. Hypertension Detection and Follow-up Program Cooperative Group.

Abstract
The Hypertension Detection and Follow-up Program (HDFP) previously described a significant reduction in five-year, all-cause mortality in its intensively treated stepped care (SC) group relative to its referred care (RC) control group. At the time this finding was described, a proportion of the SC cohort had been treated for periods as long as 6.7 years, but comparable RC and SC mortality data beyond five years were not available. These data, which are described herein, indicate that the 6.7-year life-table mortality rates were 95.1/1000 participants for SC vs 116.3/1000 participants for RC, a larger mortality difference than was observed at five years. This favorable finding for SC extended to all major subgroups, including white women and those aged 30 to 49 years at trial entry. Six months after the close of the treatment trial, a two-year posttrial surveillance study, which extended mortality follow-up to 8.3 years, was conducted. The posttrial use of antihypertensive medication declined in SC and increased in RC participants so that by the end of the posttrial period, there was little difference in the percentages of SC and RC participants taking medication. Control of blood pressure, indicated by mean diastolic blood pressure and by percent of participants with a pressure of 90 mm Hg or less, was slightly better for SC than for RC participants (SC group, 86.5 mm Hg and 68% controlled ; RC group, 87.8 mm Hg and 62% controlled). The absolute mortality advantage found at 6.7 years persisted and increased throughout the posttrial period of follow-up despite discontinuation of the formal SC therapy program. It is postulated that regression of hypertensive end-organ changes brought about by the more effective SC treatment caused this favorable outcome.

JAMA. 1979 ;242:2562-71. pdf490882
JAMA. 1982 ;247:633-8. pdf7033578
JAMA. 1988 ;259:2113-22. pdf3346988

HOPE

HOPE? : Heart Outcomes Prevention Evaluation.

L’étude HOPE concerne les sujets à très haut risque? cardiovasculaire (70 % d’antécédants d’IDM?) qu’ils soient hypertendus ou non. 9 000 patients avec une pathologie vasculaire ou un diabète ou un autre facteur de risque cardiovasculaire sont inclus dans l’essai et reçoivent du ramipril à posologie progressivement adaptée jusqu’à 10 mg comparée au placebo. Le suivi est de 5 ans et l’étude inclut 38,5 % de diabètiques. L’étude a montré une réduction d’événements cardiovasculaires dans le groupe ramipril sur un critère composite d’évaluation incluant les décès cardiovasculaires par infarctus du myocarde et AVC? avec une RRR? de -22 %. La réduction du risque d’infarctus du myocarde est de -20 % et celui d’AVC de moins 32 %.

Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20 ;342(3):145-53. pdf10639539

HOT

HOT? : Hypertension Optimal Treatment Study.

BACKGROUND :
Despite treatment, there is often a higher incidence? of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.
METHODS :
18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.
FINDINGS :
Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg ; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001).
INTERPRETATION :
Intensive>
9635947

HYGIA

Hermida RC, Crespo JJ, Domínguez-Sardiña M, et al. Bedtime hypertension treatment improves cardiovascular risk reduction : the Hygia Chronotherapy Trial

Abstract
Aims : The Hygia Chronotherapy Trial, conducted within the clinical primary care setting, was designed to test whether bedtime in comparison to usual upon awakening hypertension therapy exerts better cardiovascular disease (CVD) risk reduction.

Methods and results : In this multicentre, controlled, prospective endpoint trial, 19 084 hypertensive patients (10 614 men/8470 women, 60.5 ± 13.7 years of age) were assigned (1:1) to ingest the entire daily dose of >1 hypertension medications at bedtime (n = 9552) or all of them upon awakening (n = 9532). At inclusion and at every scheduled clinic visit (at least annually) throughout follow-up, ambulatory blood pressure (ABP) monitoring was performed for 48 h. During the 6.3-year median patient follow-up, 1752 participants experienced the primary CVD outcome (CVD death, myocardial infarction, coronary revascularization, heart failure, or stroke). Patients of the bedtime, compared with the upon-waking, treatment-time regimen showed significantly lower hazard ratio-adjusted for significant influential characteristics of age, sex, type 2 diabetes, chronic kidney disease, smoking, HDL cholesterol, asleep systolic blood pressure (BP) mean, sleep-time relative systolic BP decline, and previous CVD event-of the primary CVD outcome [0.55 (95% CI 0.50-0.61), P < 0.001] and each of its single components (P < 0.001 in all cases), i.e. CVD death [0.44 (0.34-0.56)], myocardial infarction [0.66 (0.52-0.84)], coronary revascularization [0.60 (0.47-0.75)], heart failure [0.58 (0.49-0.70)], and stroke [0.51 (0.41-0.63)].

Conclusion : Routine ingestion by hypertensive patients of >1 prescribed BP-lowering medications at bedtime, as opposed to upon waking, results in improved ABP control (significantly enhanced decrease in asleep BP and increased sleep-time relative BP decline, i.e. BP dipping) and, most importantly, markedly diminished occurrence of major CVD events.
pdf31641769

HYVET

HYVET? : Hypertension in the Very Elderly Trial.

MÉTHODES :
Nous avons randomisé 3845 patients de 80 ans ou plus, originaires d’Europe, de Chine, d’Australasie et de Tunisie, et qui avaient une pression systolique artérielle de 160 mm Hg ou plus pour recevoir soit le diurétique indapamide (libération prolongée, 1,5 mg) ou un placebo. L’IEC? périndopril (2 ou 4 mg) ou un placebo, a été ajouté si nécessaire pour atteindre la pression artérielle cible de 150/80 mmHg. Le critère de jugement principal était l’AVC? fatal ou non fatal.
Résultats :
Le groupe de traitement actif (1933 patients) et le groupe placebo (1912 patients) ont été appariés (âge moyen, 83,6 ans ; pression artérielle moyenne en position assise, 173.0/90.8 mm Hg), 11,8% avaient des antécédents de maladie cardio-vasculaire. Le suivi médian était de 1,8 ans.
À 2 ans, la pression artérielle moyenne assise était de 15.0/6.1 mmHg, plus basse dans le groupe traitement actif que dans le groupe placebo.
En intention de traiter l’analyse, le traitement actif a été associé à une réduction de 30% du taux d’AVC fatal ou non fatal (intervalle de confiance à 95%, -1 à 51 ; P = 0,06), une réduction de 39% du taux de mortalité par accident vasculaire cérébral (IC à 95%, 1 à 62 ; P = 0,05), une réduction de 21% du taux de décès toutes causes confondues (95% CI, 4 à 35 ; P = 0,02), une réduction de 23% du taux de décès d’origine cardiovasculaire (95% CI, -1 à 40 ; P = 0,06), et une réduction de 64% du taux de l’insuffisance cardiaque (IC 95%, 42 à 78 ; P <0,001). Moins graves effets indésirables ont été rapportés dans le groupe traitement actif (358, contre 448 dans le groupe placebo, p = 0,001).
CONCLUSIONS :
Les résultats mettent en évidence que le traitement antihypertenseur avec l’indapamide (libération prolongée), avec ou sans périndopril, chez les personnes de 80 ans ou plus est bénéfique.

N Engl J Med. 2008 ;358(18):1887-98
pdf18378519

Autres publications HYVET

Rh Peters, N Beckett, R Fagard, et al. Increased pulse pressure linked to dementia : further results from the Hypertension in the Very Elderly Trial HYVET.J Hypertens. 2013,31:1868-1875.

CJ. Bulpitt, N Beckett, R Peters, et al. Does White Coat Hypertension Require Treatment Over Age 80 ? Results of the Hypertension in the Very Elderly Trial Ambulatory Blood Pressure Side Project. Hypertension. 2013 ;61:89-94.

N Beckett, R Peters, J Tuomilehto, et al. Immediate and late benefits of treating very elderly people with hypertension : results from active treatment extension to Hypertension in the Very Elderly randomized controlled trial. BMJ. 2012 ;344:1-10.

CJ Bulpitt, NS Beckett, R Peters, et al. Blood pressure control in the Hypertension in the Very Elderly Trial (HYVET). J Hum Hypertension. 2012 ;26:157-163.

R Peters, N Beckett, L Burch, et al. The effect of treatment based on a diuretic (indapamide) ±ACE inhibitor (perindopril) on fractures in the Hypertension in the Very Elderly Trial (HYVET). Age and Ageing. 2010 ;39:609-616.

M O’Rourke, M Namasivayam, A Adji. Treatment of hypertension in patients 80 years of age or older. Minerva Med. 2009 ;100:25-38.

R Peters, N Beckett, F Forette, et al. Vascular risk factors and cognitive function among 3763 participants in the Hypertension in the Very Elderly Trial (HYVET) : a cross-sectional analysis. Int Psychogeriatr. 2009,21:2,359-368.

N. Beckett, A. Fletcher, C. Bulpitt. The rationale for the Hypertension in the Very Elderly Trial (HYVET). European Heart Journal. 1999 ;1 (suppl P) : P13-P16.

E. Pinto, C. Bulpitt, N, Beckett, R. Peters, J.A. Staessen, C. Rajkumar. Rationale and methodology of monitoring ambulatory blood pressure and arterial compliance in the Hypertension in the Very Elderly Trial. Blood Pressure Monitoring. 2006 ;11:3-8.

R. Peters, N. Beckett, M. Nunes, A. Fletcher, F. Forette, C. Bulpitt. A substudy protocol of the Hypertension in the Very Elderly Trial assessing cognitive decline and dementia incidence? (HYVET-COG). Drugs Aging. 2006 ;23:83-92.

C. Bulpitt, R. Peters, J. A. Staessen, L. Thijs, M-C. De Vernejoul, A. Fletcher, N. Beckett. Fracture risk and the use of a diuretic (indapamide sr) ± perindopril : a substudy of the Hypertension in the Very Elderly Trial (HYVET). Trials. 2006 ;7:33.

N. Beckett, on behalf of the HYVET team. Progress report of the Hypertension in the Very Elderly Trial (HYVET). Journal of Hypertension. 2007 ;25 (suppl 2). Abstract S233.

F. Gueyffier, C. Bulpitt, J-P. Boissel, E. Schron, T. Ekbom, R. Fagard, E. Casiglia, K. Kerlikowske, J. Coope for the INDANA Group. Antihypertensive drugs in the very old people : a subgroup meta-analysis of randomized controlled trials. Lancet. 1999 ;353:793-796.

HYVET-cog

Peters R, Beckett N, Nunes M, Fletcher A, Forette F, Bulpitt C. A substudy protocol of the hypertension in the Very Elderly Trial assessing cognitive decline and dementia incidence (HYVET-COG) : An ongoing randomised, double-blind, placebo-controlled trial. Drugs Aging. 2006 ; 23(1):83-92. 16492072

Peters R, Beckett N, Forette F, et al. ; HYVET investigators. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG) : a double-blind, placebo controlled trial. Lancet Neurol.2008 Aug ;7(8):683-9. 18614402

HYVET pilot

Bulpitt CJ, Beckett NS, Cooke J, et al. Hypertension in the Very Elderly Trial Working Group. Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens. 2003 Dec ; 21(12):2409-17. 14654762

Beckett NS, Connor M, Sadler JD, Fletcher AE, Bulpitt CJ. Orthostatic fall in blood pressure in the very elderly hypertensive : results from the hypertension in the very elderly trial (HYVET) - pilot. J Hum Hypertens. 1999 Dec ; 13(12):839-40. 10618673

Bulpitt C, Fletcher A, Beckett N, et al. Hypertension in the Very Elderly Trial (HYVET) : protocol for the main trial. Drugs Aging. 2001 ; 18(3):151-64. 11302283

Bulpitt CJ, Fletcher AE, Amery A, et al. The Hypertension in the Very Elderly Trial (HYVET). Rationale, methodology and comparison with previous trials. Drugs Aging.1994 Sep ;5(3):171-83.Review. 7803945

IDNT

IDNT? : Irbesartan Diabetic Nephrophaty Trial.

Cette étude inclus a inclus 1715 patients hypertendus diabétiques de type II recevant un ARA2? (irbesartan) comparés à un groupe recevant un BCC?-DHP? (amlodipine), et à un groupe témoin (placebo). Le critère principal d’évaluation de l’étude est le temps de survenue d’un critère combiné associant décès, insuffisance rénale terminale et délai de doublement de la créatininémie. Sur ce critère, l’étude montre une RRR? de 20 % dans le groupe irbesartan comparé à placebo et de 23 % comparé à l’amlodipine. Le résultat est observé en l’absence de différence significative du niveau de la pression artérielle. Le résultat suggère un effet néphroprotecteur de l’ARA2 chez l’hypertendu diabétique de type 2 avec néphropathie.

Lewis EJ, Hunsicker LG, Clarke WR, et al. Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001 ;345:851-60. 11565517

Evans M, Bain SC, Hogan S, Bilous RW ; Collaborative Study Group participants. Irbesartan delays progression of nephropathy as measured by estimated glomerular filtration rate : post hoc analysis of the Irbesartan Diabetic Nephropathy Trial. Nephrol Dial Transplant. 2012 Jun ; 27(6):2255-63. 22172728

Pohl MA, Blumenthal S, Cordonnier DJ, et al. Independent and additive impact of blood pressure control and angiotensin II receptor blockade on renal outcomes in the irbesartan diabetic nephropathy trial : clinical implications and limitations. J Am Soc Nephrol. 2005 Oct ; 16(10):3027-37. 16120823

Berl T, Hunsicker LG, Lewis JB, et al. ; Collaborative Study Group. Impact of achieved blood pressure on cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial. J Am Soc Nephrol. 2005 Jul ; 16(7):2170-9. 15930097

Hunsicker LG, Atkins RC, Lewis JB, Braden G, de Crespigny PJ, DeFerrari G, Drury P, Locatelli F, Wiegmann TB, Lewis EJ ; Collaborative Study Group. Impact of irbesartan, blood pressure control, and proteinuria on renal outcomes in the Irbesartan Diabetic Nephropathy Trial. Kidney Int Suppl. 2004 Nov ; (92):S99-101. 15485429

Anavekar NS, Gans DJ, Berl T, Rohde RD, Cooper W, Bhaumik A, Hunsicker LG, Rouleau JL, Lewis JB, Rosendorff C, Porush JG, Drury PL, Esmatjes E, Raz I, Vanhille P, Locatelli F, Goldhaber S, Lewis EJ, Pfeffer MA. Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension : a case for albuminuria.Kidney Int Suppl. 2004 Nov ; (92):S50-5. 15485418

Rodby RA?, Rohde RD, Clarke WR, et al.. For the Collaborative Study Group.The Irbesartan type II diabetic nephropathy trial : study design and baseline patient characteristics. Nephrol Dial Transplant.2000 Apr ;15(4):487-97. 10727543

INSIGHT

INSIGHT? : International Nifedipine GITS Study : Intervention as a Goal in Hypertension Treatment.

Ont été inclus les patients hypertendus de 55 ans à 80 ans, à haut risque? cardiovasculaire recevant soit de la Nifédipine à libération prolongée 30 mg GITS soit un diurétique (hydrochlorothiazide 25 mg + amiloride 2,5 mg). Sur le critère principal composite il n’existe pas de différence significative en terme de morbi-mortalité entre les 2 groupes. Il faut remarquer un nombre important de sorties d’essai, et des effets indésirables fréquents sous inhibiteur calcique (œdème des membres inférieurs), et de distorsions hydroélectrolytiques prévisibles sous diurétique (posologie élévée). Parmi les critères secondaires on peut noter un excès de risque d’infarctus du myocarde fatal dans le groupe inhibiteur calcique (OR? = 3,2).

Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T, Ruilope LM. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study : Intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet. 2000 Jul 29 ;356(9227):366-72.
10972368

Mancia G, Brown M, Castaigne A, de Leeuw P, Palmer CR, Rosenthal T, Wagener G, Ruilope LM ; INSIGHT. Outcomes with nifedipine GITS or Co-amilozide in hypertensive diabetics and nondiabetics in Intervention as a Goal in Hypertension (INSIGHT). Hypertension. 2003 Mar ;41(3):431-6 12623939

INTERHEART

INTERHEART? study

Abstract

BACKGROUND :
Although more than 80% of the global burden of cardiovascular disease occurs in low-income and middle-income countries, knowledge of the importance of risk factors is largely derived from developed countries. Therefore, the effect of such factors on risk of coronary heart disease in most regions of the world is unknown.
METHODS :
We established a standardised case-control study of acute myocardial infarction in 52 countries, representing every inhabited continent. 15152 cases and 14820 controls were enrolled. The relation of smoking, history of hypertension or diabetes, waist/hip ratio, dietary patterns, physical activity, consumption of alcohol, blood apolipoproteins (Apo), and psychosocial factors to myocardial infarction are reported here. Odds ratios and their 99% CIs for the association of risk factors to myocardial infarction and their population attributable risks (PAR) were calculated.
FINDINGS :
Smoking (odds ratio 2.87 for current vs? never, PAR 35.7% for current and former vs never), raised ApoB/ApoA1 ratio (3.25 for top vs lowest quintile, PAR 49.2% for top four quintiles vs lowest quintile), history of hypertension (1.91, PAR 17.9%), diabetes (2.37, PAR 9.9%), abdominal obesity (1.12 for top vs lowest tertile and 1.62 for middle vs lowest tertile, PAR 20.1% for top two tertiles vs lowest tertile), psychosocial factors (2.67, PAR 32.5%), daily consumption of fruits and vegetables (0.70, PAR 13.7% for lack of daily consumption), regular alcohol consumption (0.91, PAR 6.7%), and regular physical activity (0.86, PAR 12.2%), were all significantly related to acute myocardial infarction (p<0.0001> 15364185

Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries : a case-control study.
Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L, Tanomsup S, Wangai P Jr, Razak F, Sharma AM, Anand SS ; INTERHEART? Study Investigators.
Lancet. 2005 Nov 5 ; 366(9497):1640-9. 16271645

Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART? study) : a case-control study.
McQueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, Steyn K, Sanderson JE, Hasani M, Volkova E, Kazmi K, Yusuf S ; INTERHEART? study investigators.
Lancet. 2008 Jul 19 ; 372(9634):224-33. 18640459

Risk factors for myocardial infarction in women and men : insights from the INTERHEART? study.
Anand SS, Islam S, Rosengren A, Franzosi MG, Steyn K, Yusufali AH, Keltai M, Diaz R, Rangarajan S, Yusuf S ; INTERHEART? Investigators.
Eur Heart J. 2008 Apr ; 29(7):932-40. 18334475

Parental history and myocardial infarction risk across the world : the INTERHEART? Study.
Chow CK, Islam S, Bautista L, Rumboldt Z, Yusufali A, Xie C, Anand SS, Engert JC, Rangarajan S, Yusuf S.
J Am Coll Cardiol. 2011 Feb 1 ; 57(5):619-27. 21272754

Estimating modifiable coronary heart disease risk in multiple regions of the world : the INTERHEART? Modifiable Risk Score.
McGorrian C, Yusuf S, Islam S, Jung H, Rangarajan S, Avezum A, Prabhakaran D, Almahmeed W, Rumboldt Z, Budaj A, Dans AL, Gerstein HC, Teo K, Anand SS ; INTERHEART? Investigators.
Eur Heart J. 2011 Mar ; 32(5):581-9. 21177699

Dysglycaemia and the risk of acute myocardial infarction in multiple ethnic groups : an analysis of 15,780 patients from the INTERHEART? study.
Gerstein HC, Islam S, Anand S, Almahmeed W, Damasceno A, Dans A, Lang CC, Luna MA, McQueen M, Rangarajan S, Rosengren A, Wang X, Yusuf S.
Diabetologia. 2010 Dec ; 53(12):2509-17. 20711717

Metabolic syndrome and risk of acute myocardial infarction a case-control study of 26,903 subjects from 52 countries.
Mente A, Yusuf S, Islam S, McQueen MJ, Tanomsup S, Onen CL, Rangarajan S, Gerstein HC, Anand SS ; INTERHEART? Investigators.
J Am Coll Cardiol. 2010 May 25 ; 55(21):2390-8. 20488312

Leong DP?, Smyth A, Teo KK, McKee M, Rangarajan S, Pais P, Liu L, Anand SS, Yusuf S ; INTERHEART? Investigators. Patterns of alcohol consumption and myocardial infarction risk : observations from 52 countries in the INTERHEART? case-control study. Circulation. 2014 Jul 29 ; 130(5):390-8. 24928682

INTERSALT

INTERSALT? study

Abstract

The relations between 24 hour urinary electrolyte excretion and blood pressure were studied in 10,079 men and women aged 20-59 sampled from 52 centres around the world based on a highly standardised protocol with central training of observers, a central laboratory, and extensive quality control. Relations between electrolyte excretion and blood pressure were studied in individual subjects within each centre and the results of these regression analyses pooled for all 52 centres. Relations between population median electrolyte values and population blood pressure values were also analysed across the 52 centres. Sodium excretion ranged from 0.2 mmol/24 h (Yanomamo Indians, Brazil) to 242 mmol/24 h (north China). In individual subjects (within centres) it was significantly related to blood pressure. Four centres found very low sodium excretion, low blood pressure, and little or no upward slope of blood pressure with age. Across the other 48 centres sodium was significantly related to the slope of blood pressure with age but not to median blood pressure or prevalence of high blood pressure. Potassium excretion was negatively correlated with blood pressure in individual subjects after adjustment for confounding variables. Across centres there was no consistent association. The relation of sodium to potassium ratio to blood pressure followed a pattern similar to that of sodium. Body mass index and heavy alcohol intake had strong, significant independent relations with blood pressure in individual subjects.

Références

Intersalt : an international study of electrolyte excretion and blood pressure.
Results for 24 hour urinary sodium and potassium excretion.
Intersalt Cooperative Research Group. [No authors listed]BMJ.1988 Jul 30 ;297(6644):319-28.PMID : 3416162 Copy PMIDFree PMC ArticleSimilar articles. 3416162

Rose G, Stamler J. INTERSALT Co-operative Research Group. The INTERSALT study : background, methods and main results. J Hum Hypertens.1989 Oct ;3(5):283-8.PMID : 2810325 Copy PMIDSimilar articles. 2810325

Elliott P. The INTERSALT study : an addition to the evidence on salt and blood pressure, and some implications. J Hum Hypertens. 1989 Oct ; 3(5):289-98. [PMID:2681780]

Elliott P, Dyer A, Stamler R, Stamler J. Correcting for regression dilution in INTERSALT. Lancet. 1993 Oct 30 ; 342(8879):1123. 8105352

Findings of the International Cooperative INTERSALT Study.
Stamler J, Rose G, Elliott P, Dyer A, Marmot M, Kesteloot H, Stamler R.
Hypertension. 1991 Jan ; 17(1 Suppl):I9-15. 1987018

Findings of the International Cooperative INTERSALT Study.
Stamler J, Rose G, Elliott P, Dyer A, Marmot M, Kesteloot H, Stamler R.
Hypertension. 1991 Jan ; 17(1 Suppl):I9-15. 1987018

Urinary biochemical markers of dietary intake in the INTERSALT study.
Dyer A, Elliott P, Chee D, Stamler J.
Am J Clin Nutr. 1997 Apr ; 65(4 Suppl):1246S-1253S. 9094929

The INTERSALT Study : background, methods, findings, and implications.
Stamler J.
Am J Clin Nutr. 1997 Feb ; 65(2 Suppl):626S-642S. 9022559

Inverse relation of dietary protein markers with blood pressure.
Findings for 1,020 men and women in the INTERSALT Study.
INTERSALT Cooperative Research Group. INTERnational study of SALT and blood pressure.Stamler J, Elliott P, Kesteloot H, Nichols R, Claeys G, Dyer AR, Stamler R.Circulation.1996 Oct 1 ;94(7):1629-34.PMID : 8840854 Copy PMIDFree ArticleSimilar articles. 8840854

Intersalt revisited : further analyses of 24 hour sodium excretion and blood pressure within and across populations.
Intersalt Cooperative Research Group.
Elliott P, Stamler J, Nichols R, Dyer AR, Stamler R, Kesteloot H, Marmot M. BMJ.1996 May 18 ;312(7041):1249-53.Erratum in : BMJ 1997 Aug 23 ;315(7106):458. 8634612

Estimating 24-hour urinary sodium excretion from casual urinary sodium concentrations in Western populations : the INTERSALT study.
Brown IJ, Dyer AR, Chan Q, Cogswell ME, Ueshima H, Stamler J, Elliott P ; INTERSALT Co-Operative Research Group.
Am J Epidemiol. 2013 Jun 1 ; 177(11):1180-92. 23673246

INVEST

INVEST? : International Verapamil SR/Trandolapril study.

L’essai thérapeutique INVEST a inclus 22 576 patients hypertendus coronariens de plus de 50 ans, recevant soit une stratégie basée sur un BCC? non dihydropyridine le vérapamil à une stratégie basée sur un bêta-bloqueur l’aténolol. Des combinaisons thérapeutiques étaient possibles et les patients pouvaient recevoir un IEC? (trandolapril) et un diurétique thiazidique.
Sur un critère d’évaluation associant les décès cardiovasculaires, un infarctus du myocarde ou un AVC? non fatal, il n’y a pas eu de différence significative entre les deux groupes. Cette étude permet de valider l’utilisation d’une stratégie incluant un BCC non dihydropyridine, à la place d’un bêta-bloqueur.
L’étude INVEST « diabète » récemment publiée confirme le bénéfice dans la population diabétique (6 400 patients), mais une courbe en J est observée pour la PAS? et la PAD? sous traitement pour un niveau de PA? < à 110/70 mmHg.

Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR?, Bakris GL, Cohen JD, Parmley WW ; INVEST Investigators. A calcium antagonist vs? a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST) : a randomized controlled trial. JAMA. 2003 Dec 3 ;290(21):2805-16. pdf

Bakris GL, Gaxiola E, Messerli FH, Mancia G, Erdine S, Cooper-DeHoff R, Pepine CJ ; INVEST Investigators. Clinical outcomes in the diabetes cohort of the INternational VErapamil SR-Trandolapril study. Hypertension. 2004 Nov ;44(5):637-42. pdf15381674

IRMA2

IRMA 2? : Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria

Cette étude a inclus 590 patients traités par irbesartan 150 à 300 mg par jour comparé au placebo suivi 2 ans. Le critère principal était le délai d’apparition d’une microalbuminurie > à 200 µg/mn ou un taux initial x 130 %. 5,2 % des patients sous 300 mg et 9.7 % sous 150 mg et 14.9 % sous placebo atteignaient le critère principal. Ce bénéfice était particulièrement significatif pour la posologie de 300 mg d’irbesartan et l’effet apparaît indépendant de la diminution de la pression artérielle.

Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P ; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 ;345:870-8. pdf11565519

JUPITER

JUPITER? : Justification for the Use of Statins in Primary Prevention : An Intervention Trial Evaluating Rosuvastatin.

Abstract

BACKGROUND :
Statin therapy in women without cardiovascular disease (CVD) is controversial, given the insufficient evidence of benefit. We analyzed sex-specific outcomes in the Justification for the Use of Statins in Prevention : An Intervention Trial Evaluating Rosuvastatin (JUPITER?) and synthesized the results with prior trials.
METHODS AND RESULTS :
JUPITER? participants included 6801 women > or =60 years of age and 11 001 men > or =50 years of age with high-sensitivity C-reactive protein > or =2 mg/L and low-density lipoprotein cholesterol <130 mg/dL randomized to rosuvastatin versus placebo. Meta-analysis studies were randomized placebo-controlled statin trials with predominantly or exclusively primary prevention in women and sex-specific outcomes (20 147 women ; >276 CVD events ; mean age, 63 to 69 years). Absolute CVD rates (per 100 person-years) in JUPITER? women for rosuvastatin and placebo (0.57 and 1.04, respectively) were lower than for men (0.88 and 1.54, respectively), with similar relative risk reduction in women (hazard ratio, 0.54 ; 95% confidence interval, 0.37 to 0.80 ; P=0.002) and men (hazard ratio, 0.58 ; 95% confidence interval, 0.45 to 0.73 ; P<0.001).> 20176986

Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein : a secondary analysis from the JUPITER? (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial.J Am Coll Cardiol.2010 Mar 23 ;55(12):1266-73. 20206456

LEADER

BACKGROUND :
The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.

METHODS :
In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes.

RESULTS :
A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87 ; 95% confidence interval [CI], 0.78 to 0.97 ; P<0.001> 27295427

LIFE

LIFE? : Losartan Intervention For Endpoint Reduction in Hypertension.

L’étude LIFE a inclus 9 193 patients hypertendus de 55 ans à 80 ans, présentant une HVG? définie par des critères électrocardiographiques. Elle compare une stratégie basée sur un antagoniste de l’angio II, le losartan ± associé à un diurétique à une stratégie basée sur un bêta-bloqueur l’aténolol ± diurétique avec un suivi de 4,8 ans. La stratégie losartan-diurétique s’est révélée plus efficace que la stratégie bêta-bloqueur + diurétique sur un critère principal d’évaluation composite comprenant mortalité cardiovasculaire, AVC? et infarctus du myocarde avec une RRR? de 13 %. La différence de bénéfice est surtout le fait de la RRR d’AVC de - 25 %, critère secondaire d’évaluation. Ce bénéfice est obtenu avec une diminution de pression artérielle comparable dans les deux groupes.

Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H ; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE) : a randomised trial against atenolol. Lancet. 2002 ;359(9311):995-1003. 11937178

Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S ; LIFE Study Group .Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE) : a randomised trial against atenolol. Lancet. 2002 ;359(9311):1004-10. 11937179

MAPEC

Chronobiol Int. 2010 ;27(8):1629-51
Influence of circadian time of hypertension treatment on cardiovascular risk : results of the MAPEC? study.
Hermida RC1, Ayala DE, Mojón A, Fernández JR.

Abstract

Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP)-lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively.
The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with 1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6±13.6 (mean±SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or 1 of them at bedtime.

At baseline, BP was measured at 20-min intervals from 07:00 to 23:00h and at 30-min intervals at night for 48h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62% ; p<.001), and higher prevalence of controlled ambulatory BP (62% versus 53% ; p<.001). After a median follow-up of 5.6 yrs, subjects ingesting 1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29-0.51] ; number of events 187 versus 68 ; p<.001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19-0.55] ; number of events : 55 versus 18 ; p<.001).

The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with 1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality.

pdf20854139

MDRD

MDRD? : Modification of Diet in Renal Disease.

BACKGROUND :
Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases.
METHODS :
In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with glomerular filtration rates of 13 to 24 ml per minute per 1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). An 18-to-45-month follow-up was planned, with monthly evaluations of the patients.
RESULTS :
The mean follow-up was 2.2 years. In study 1, the projected mean decline in the glomerular filtration rate at three years did not differ significantly between the diet groups or between the blood-pressure groups. As compared with the usual-protein group and the usual-blood-pressure group, the low-protein group and the low-blood-pressure group had a more rapid decline in the glomerular filtration rate during the first four months after randomization and a slower decline thereafter. In study 2, the very-low-protein group had a marginally slower decline in the glomerular filtration rate than did the low-protein group (P = 0.07). There was no delay in the time to the occurrence of end-stage renal disease or death. In both studies, patients in the low-blood-pressure group who had more pronounced proteinuria at base line had a significantly slower rate of decline in the glomerular filtration rate.
CONCLUSIONS :
Among patients with moderate renal insufficiency, the slower decline in renal function that started four months after the introduction of a low-protein diet suggests a small benefit of this dietary intervention. Among patients with more severe renal insufficiency, a very-low-protein diet, as compared with a low-protein diet, did not significantly slow the progression of renal disease.

Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994 ;330:877-84. pdf

OBJECTIVE :
To examine the relations among proteinuria, prescribed and achieved blood pressure, and decline in glomerular filtration rate in the Modification of Diet in Renal Disease Study.

DESIGN :
2 randomized trials in patients with chronic renal diseases of diverse cause.

SETTING :
15 outpatient nephrology practices at university hospitals.

PATIENTS :
840 patients, of whom 585 were in study A (glomerular filtration rate, 25 to 55 mliters/min.1.73 m2) and 255 were in study B (glomerular filtration rate, 13 to 24 mliters/min.1.73 m2). Diabetic patients who required insulin were excluded.

INTERVENTIONS :
Patients were randomly assigned to a usual blood pressure goal (target mean arterial pressure, < or = 107 mm Hg for patients < or = 60 years of age and < or = 113 mm Hg for patients > or = 61 years of age) or a low blood pressure goal (target mean arterial pressure, < or = 92 mm Hg for patients < or = 60 years of age and < or = 98 mm Hg for patients > or = 61 years of age).
MAIN OUTCOME MEASURES :
Rate of decline in glomerular filtration rate and change in proteinuria during follow-up.

RESULTS :
The low blood pressure goal had a greater beneficial effect in persons with higher baseline proteinuria in both study A (P = 0.02) and study B (P = 0.01). Glomerular filtration rate declined faster in patients with higher achieved blood pressure during follow-up in both study A (r = -0.20 ; P < 0.001) and study B (r = -0.34 ; P < 0.001), and these correlations were stronger in persons with higher baseline proteinuria (P < 0.001 in study A ; P < 0.01 in study B). In study A, the association between decline in glomerular filtration rate and achieved follow-up blood pressure was nonlinear (P = 0.011) and was stronger at higher mean arterial pressure. In both studies, the low blood pressure goal significantly reduced proteinuria during the first 4 months after randomization. This, in turn, correlated with a slower subsequent decline in glomerular filtration rate.

CONCLUSIONS :
Our study supports the concept that proteinuria is an independent risk factor for the progression of renal disease. For patients with proteinuria of more than 1 g/d, we suggest a target blood pressure of less than 92 mm Hg (125/75 mm Hg). For patients with proteinuria of 0.25 to 1.0 g/d, a target mean arterial pressure of less than 98 mm Hg (about 130/80 mm Hg) may be advisable. The extent to which lowering blood pressure reduces proteinuria may be a measure of the effectiveness of this therapy in slowing the progression of renal disease.

Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995 ;123:754-62. 7574193

Effects of dietary protein restriction on the progression of moderate renal disease in the Modification of Diet in Renal Disease Study.J Am Soc Nephrol. 1996 Dec ;7(12):2616-26. Erratum in : J Am Soc Nephrol 1997 Mar ; 8(3):493. 8989740

Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study.Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE.
Am J Kidney Dis. 1996 May ; 27(5):652-63. 8629624

Short-term effects of protein intake, blood pressure, and antihypertensive therapy on glomerular filtration rate in the Modification of Diet in Renal Disease Study. J Am Soc Nephrol. 1996 Oct ;7(10):2097-109. 8915969

Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, Levey AS. The effect of a lower target blood pressure on the progression of kidney disease : long-term follow-up of the modification of diet in renal disease study. Ann Intern Med. 2005 Mar 1 ; 142(5):342-51. 15738453

The Modification of Diet in Renal Disease Study : design, methods, and results from the feasibility study. Am J Kidney Dis. 1992 Jul ;20(1):18-33. 1621675

Lazarus JM, Bourgoignie JJ, Buckalew VM, et al. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modification of Diet in Renal Disease Study Group. Hypertension.1997 Feb ;29(2):641-50. 9040451

Hebert LA, Kusek JW, Greene T, et al. Effects of blood pressure control on progressive renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group. Hypertension.1997 Sep ;30(3 Pt 1):428-35. 9314428

Buckalew VM Jr, Berg RL, Wang SR, Porush JG, Rauch S, Schulman G. Prevalence of hypertension in 1,795 subjects with chronic renal disease : the modification of diet in renal disease study baseline cohort. Modification of Diet in Renal Disease Study Group. Am J Kidney Dis.1996 Dec ;28(6):811-21. 8957032

MICROHOPE

MICROHOPE? : Microalbuminuria, Cardiovascular and Renal Outcomes in the Heart Outcomes Prevention Evaluation.

Cette étude a inclus 3 577 patients diabétiques normotendus ou hypertendus avec des antécédents d’IDM? ou de maladie artérielle symptomatique, recevant un IEC? (ramipril jusqu’à 10 mg/j) comparé au placebo. Un peu plus de la moitié des patients sont hypertendus. Le critère principal associe infarctus du myocarde, AVC? ou décès cardiovasculaire, et il est observé dans la population diabétique une RRR? de 25 % sous ramipril. La RRR de décès cardiovasculaire est de 37 %, la RRR d’AVC est de - 33 %, la RRR d’infarctus du myocarde de - 22 %

BACKGROUND :
Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes.

METHODS :
3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy.

FINDINGS :
The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) blood pressures, ramipril still lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004).

INTERPRETATION :
Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus : results of the HOPE? study and MICRO-HOPE substudy. Lancet. 2000 ;355:253-9. 10675071

MRC

MRC? : Medical Research Council Trial of Treatment of Mild Hypertension.

Abstract
The main aim of the trial was to determine whether drug treatment of mild hypertension (phase V diastolic pressure 90-109 mm Hg) reduced the rates of stroke, of death due to hypertension, and of coronary events in men and women aged 35-64 years. Subsidiary aims were : to compare the course of blood pressure in two groups, one taking bendrofluazide and one taking propranolol, and to compare the incidence? of suspected adverse reactions to these two drugs. The study was single blind and based almost entirely in general practices ; 17 354 patients were recruited, and 85 572 patient years of observation have accrued. Patients were randomly allocated at entry to take bendrofluazide or propranolol or placebo tablets. The primary results were as follows. The stroke rate was reduced on active treatment : 60 strokes occurred in the treated group and 109 in the placebo group, giving rates of 1.4 and 2.6 per 1000 patient years of observation respectively (p less than 0.01 on sequential analysis). Treatment made no difference, however, to the overall rates of coronary events : 222 events occurred on active treatment and 234 in the placebo group (5.2 and 5.5 per 1000 patient years respectively). The incidence of all cardiovascular events was reduced on active treatment : 286 events occurred in the treated group and 352 in the placebo group, giving rates of 6.7 and 8.2 per 1000 patient years respectively (p less than 0.05 on sequential analysis). For mortality from all causes treatment made no difference to the rates. There were 248 deaths in the treated group and 253 in the placebo group (rates 5.8 and 5.9 per 1000 patient years respectively). Several post hoc analyses of subgroup results were also performed but they require very cautious interpretation. The all cause mortality was reduced in men on active treatment (157 deaths versus 181 in the placebo group ; 7.1 and 8.2 per 1000 patient years respectively) but increased in women on active treatment (91 deaths versus 72 ; 4.4 and 3.5 per 1000 patient years respectively). The difference between the sexes in their response to treatment was significant (p = 0.05). Comparison of the two active drugs showed that the reduction in stroke rate on bendrofluazide was greater than that on propranolol (p = 0.002). The stroke rate was reduced in both smokers and non-smokers taking bendrofluazide but only in non-smokers taking propranolol. This difference between the responses to the two drugs was significant (p = 0.03).(ABSTRACT TRUNCATED AT 400 WORDS)

MRC trial of treatment of mild hypertension : principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed). 1985 Jul 13 ;291(6488):97-104. 2861880

MRC elderly

MRC? elderly : Medical Research Council Trial of Treatment of Hypertension in Older Adults.

OBJECTIVE :
To establish whether treatment with diuretic or beta blocker in hypertensive older adults reduces risk of stroke, coronary heart disease, and death.
DESIGN :
Randomised, placebo controlled, single blind trial.
SETTING :
226 general practices in the MRC general practice research framework.
SUBJECTS :
4396 patients aged 65-74 randomised to receive diuretic, beta blocker, or placebo. Patients had mean systolic pressures of 160-209 mm Hg and mean diastolic pressures less than 115 mm Hg during an eight week run in and were not taking antihypertensive treatment.
INTERVENTION :
Patients were randomised to atenolol 50 mg daily ; hydrochlorothiazide 25 mg or 50 mg plus amiloride 2.5 mg or 5 mg daily ; or placebo. The regimens were adjusted to achieve specified target pressures. Mean follow up was 5.8 years.
MAIN OUTCOME MEASURES :
Strokes, coronary events, and deaths from all causes.
RESULTS :
Both treatments reduced blood pressure below the level in the placebo group. Compared with the placebo group, actively treated subjects (diuretic and beta blocker groups combined) had a 25% (95% confidence interval 3% to 42%) reduction in stroke (p = 0.04), 19% (-2% to 36%) reduction in coronary events (p = 0.08), and 17% (2% to 29%) reduction in all cardiovascular events (p = 0.03). After adjusting for baseline characteristics the diuretic group had significantly reduced risks of stroke (31% (3% to 51%) p = 0.04), coronary events (44% (21% to 60%), p = 0.0009), and all cardiovascular events (35% (17% to 49%), p = 0.0005) compared with the placebo group. The beta blocker group showed no significant reductions in these end points. The reduction in strokes was mainly in non-smokers taking the diuretic.
CONCLUSION :
Hydrochlorothiazide and amiloride reduce the risk of stroke, coronary events, and all cardiovascular events in older hypertensive adults.

Medical Research Council trial of treatment of hypertension in older adults : principal results. MRC Working Party.
BMJ. 1992 Feb 15 ;304(6824):405-12. 1445513

NORDIL

NORDIL? : Nordic Diltiazem (NORDIL) study

10 881 patients hypertendus sont randomisés pour recevoir du diltiazem ou un diurétique thiazidique ou un bêtabloqueur ou les deux. Aucune différence significative n’a été retrouvée entre les deux groupes sur le critère primaire d’évaluation, mais il a été noté une moindre incidence? d’AVC? dans le groupe diltiazem avec un RR? de 0.8 bien que le niveau de la PAS? soit plus élevé à la fin de l’étude dans le groupe diltiazem que dans le groupe bêta-bloqueur + diurétique (152,2 vs? 149,1 mmHg)

Lancet 2000 ; 356 : 359-65 10972367

ONTARGET

ONTARGET? : Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial.

CONTEXTE :
Chez les patients qui ont une maladie vasculaire ou de diabète à haut risque? sans insuffisance cardiaque, l’angiotensine enzyme de conversion (IEC?) de réduire la mortalité et la morbidité d’origine cardiovasculaire, mais le rôle des sartans (ARA) chez ces patients est inconnue. Nous avons comparé l’inhibiteur de l’ECA ramipril, le telmisartan ARB, et la combinaison des deux médicaments chez les patients atteints de maladies vasculaires ou diabète à haut risque.

MÉTHODES :
Après une semaine à 3, en simple aveugle période de rodage, les patients ont subi la randomisation en double aveugle, avec 8576 pour recevoir 10 mg de ramipril par jour, 8542 pour recevoir 80 mg de telmisartan par jour, et 8502 attribuées à recevoir à la fois médicaments (traitement combiné). Le critère principal composite était décès d’origine cardiovasculaire, infarctus du myocarde, accident vasculaire cérébral ou hospitalisation pour insuffisance cardiaque.

Résultats :
La pression artérielle moyenne a été inférieure à la fois dans le groupe telmisartan (0.9/0.6 mm Hg une réduction plus importante) et le groupe de thérapie combinée (2.4/1.4 mm Hg une réduction plus importante) que dans le groupe ramipril. Après une période médiane de suivi de 56 mois, le résultat principal a eu lieu en 1412 patients dans le groupe ramipril (16,5%), par rapport à 1423 patients dans le groupe recevant le telmisartan (16,7%, risque relatif : 1,01 ; intervalle de confiance 95% [ IC], 0,94 à 1,09). En comparaison avec le groupe ramipril, le groupe telmisartan présentaient des taux de toux (1,1% vs? 4,2%, P <0,001) et d’oedème angioneurotique (0,1% vs 0,3%, P = 0,01) et un taux plus élevé de symptômes d’hypotension (2,6 % vs 1,7%, <0,001 P), le taux de syncope était la même dans les deux groupes (0,2%). Dans le groupe de thérapie combinée, le résultat principal a été observé en 1386 patients (16,3%, risque relatif, 0,99, IC 95%, 0,92 à 1,07) ; par comparaison avec le groupe ramipril, il y avait un risque accru de symptômes d’hypotension (4,8% vs 1,7%, P <0,001), syncope (0,3% vs 0,2%, P = 0,03) et une dysfonction rénale (13,5% vs 10,2%, P <0,001).

CONCLUSIONS :
Le telmisartan est équivalent au ramipril chez des patients atteints de maladies vasculaires ou diabète à haut risque et a été associée à une moindre œdème de Quincke. La combinaison des deux médicaments a été associée à plusieurs effets indésirables sans une augmentation des prestations.

N Engl J Med. 2008 ;358:1547-59. 18378520

PAMELA

Pressioni Arteriose Monitorate E Loro Associazioni.

BACKGROUND :
Previous studies have shown that in the treated fraction of the hypertensive population, blood pressure (BP) control is less common for systolic BP (SBP) than for diastolic BP (DBP) as measured in the physician’s office. Whether this phenomenon is artifactually attributable to a temporary increase in BP owing to a "white-coat" effect or represents a true rarity of SBP control in daily life is unknown.

METHODS :
Data were obtained from the PAMELA? (Pressioni Arteriose Monitorate E Loro Associazioni) study population, which involved individuals ranging in age from 25 to 74 years who were representative of the residents of Monza (a city near Milan, Italy) and who were stratified according to sex. Office (an average of 3 sphygmomanometric measurements), home (an average of morning and evening self-measurements using a semiautomatic device), and 24-hour ambulatory (average of measurements performed every 20 minutes during the day and at night) BP values were obtained in all study subjects. In the treated hypertensive patients, BP was regarded as controlled if office values were less than 140 (SBP) or 90 (DBP) mm Hg. Home and 24-hour average SBP and DBP were regarded as controlled if the values were lower than 132/83 and 125/79 mm Hg, respectively.

RESULTS :
In the study participants (n = 2051), the number of patients with hypertension who were receiving antihypertensive treatment was 398, or approximately 42% of all individuals with hypertension. In-office SBP control by treatment was less frequent than DBP control (29.9% vs? 41.5%, P<.05). This was also the case when home and 24-hour SBP and DBP control was considered (38.3% vs 54.6% and 50.8 vs 64.9%, respectively, P<.05 for both).

CONCLUSIONS :
In the PAMELA? population, SBP control by treatment was much less frequent than DBP control by treatment. This was the case not only for office BP values but also for home and 24-hour BP values, demonstrating that inadequate SBP control is not limited to artificial BP-measuring methods but occurs in daily life.

Mancia G, Bombelli M, Lanzarotti A, Grassi G, Cesana G, Zanchetti A, Sega R. Systolic vs? diastolic blood pressure control in the hypertensive patients of the PAMELA? population. Pressioni Arteriose Monitorate E Loro Associazioni.
Arch Intern Med. 2002 Mar 11 ;162(5):582-6. 11871927

Abstract
In hypertensive patients, 24-hour blood pressure (BP) variability (V) shows a positive relationship with organ damage, organ damage progression, and cardiovascular morbidity. The clinical relevance of BPV in the population has never been investigated. In a sample of 3200 individuals, randomly selected from the general population of Monza (Milan, Italy), we evaluated BP by an automatic oscillometric device every 20 minutes for 24 hours and left ventricular mass index (LVMI) by echocardiography. In each subject, individual systolic and diastolic BP readings were averaged to obtain a 24-hour mean. Systolic BPV was obtained by calculating (1) the standard deviation of the 24-hour mean, which was taken as the overall BPV, (2) the cyclic components (Fourier spectral analysis) that in the population as a whole explained >95% of the overall BPV, and (3) the fraction of the overall BPV that in each subject was not accounted for by the 2 cyclic components, termed individual residual BPV. A similar procedure was used for diastolic BP and heart rate. Participation rate was 64.1%. Patients receiving antihypertensive therapy (n=403) were excluded from the analysis, which was therefore limited to 1648 participants. In the population as a whole, LVMI significantly related to 24-hour systolic and diastolic BP mean (beta=0.40 and beta=0.37, respectively, P<0.001> 11882636

BACKGROUND :
Studies in hypertensive patients suggest that ambulatory blood pressure (BP) is prognostically superior to office BP. Much less information is available in the general population, however. Obtaining this information was the purpose of the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA?) study.

METHODS AND RESULTS :
Office, home, and 24-hour ambulatory BP values were obtained in 2051 subjects between 25 and 74 years of age who were representative of the general population of Monza (Milan, Italy). Subjects were followed up for an average of 131 months, during which time cardiovascular and noncardiovascular fatal events were recorded (n=186). Office, home, and ambulatory BP values showed a significant exponential direct relationship with risk of cardiovascular or all-cause death. The goodness of fit of the relationship was greater for systolic than for diastolic BP and for night than for day BP, but its overall value was not better for home or ambulatory than for office BP. The slope of the relationship, however, was progressively greater from office to home and ambulatory BP. Home and night BP modestly improved the goodness of fit of the risk model when added to office BP.

CONCLUSIONS :
In the PAMELA? population, risk of death increased more with a given increase in home or ambulatory than in office BP. The overall ability to predict death, however, was not greater for home and ambulatory than for office BP, although it was somewhat increased by the combination of office and outside-of-office values. Systolic BP was almost invariably superior to diastolic BP, and night BP was superior to day BP.

Sega R, Facchetti R, Bombelli M, Cesana G, Corrao G, Grassi G, Mancia G. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population : follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA?) study. Circulation. 2005 ;111:1777-83. 15809377

PATHWAY-2

Williams B, MacDonald TM, Morant S, et al.
Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2?), a randomised, double-blind, crossover trial. Lancet 2015 ;386:2059

Abs
Background : Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure.

Methods : In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18-79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or >135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK.
Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25-50 mg), bisoprolol (5-10 mg), doxazosin modified release (4-8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle.
The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat.

Findings : Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned.
After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo ; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (-8.70 mm Hg [95% CI -9.72 to -7.69] ; p<0.0001),> 26414968

PATHWAY-3

Williams B, MacDonald TM, Morant SV, et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride : the PATHWAY-2? mechanisms substudies. Lancet Diabetes Endocrinol 2018 ;6:4464

Abstract
Background : In the PATHWAY-2? study of resistant hypertension, spironolactone reduced blood pressure substantially more than conventional antihypertensive drugs. We did three substudies to assess the mechanisms underlying this superiority and the pathogenesis of resistant hypertension.

Methods : PATHWAY-2? was a randomised, double-blind crossover trial done at 14 UK primary and secondary care sites in 314 patients with resistant hypertension. Patients were given 12 weeks of once daily treatment with each of placebo, spironolactone 25-50 mg, bisoprolol 5-10 mg, and doxazosin 4-8 mg and the change in home systolic blood pressure was assessed as the primary outcome. In our three substudies, we assessed plasma aldosterone, renin, and aldosterone-to-renin ratio (ARR) as predictors of home systolic blood pressure, and estimated prevalence of primary aldosteronism (substudy 1) ; assessed the effects of each drug in terms of thoracic fluid index, cardiac index, stroke index, and systemic vascular resistance at seven sites with haemodynamic monitoring facilities (substudy 2) ; and assessed the effect of amiloride 10-20 mg once daily on clinic systolic blood pressure during an optional 6-12 week open-label runout phase (substudy 3). The PATHWAY-2? trial is registered with EudraCT, number 2008-007149-30, and ClinicalTrials.gov, number NCT02369081.

Findings : Of the 314 patients in PATHWAY-2?, 269 participated in one or more of the three substudies : 126 in substudy 1, 226 in substudy 2, and 146 in substudy 3. Home systolic blood pressure reduction by spironolactone was predicted by ARR (r2=0·13, p<0·0001) and plasma renin (r2=0·11, p=0·00024). 42 patients had low renin concentrations (predefined as the lowest tertile of plasma renin), of which 31 had a plasma aldosterone concentration greater than the mean value for all 126 patients (250 pmol/L). Thus, 31 (25% [95% CI 17-33]) of 126 patients were deemed to have inappropriately high aldosterone concentrations. Thoracic fluid content was reduced by 6·8% from baseline (95% CI 4·0 to 8·8 ; p<0·0001) with spironolactone, but not other treatments. Amiloride (10 mg once daily) reduced clinic systolic blood pressure by 20·4 mm Hg (95% CI 18·3-22·5), compared with a reduction of 18·3 mm Hg (16·2-20·5) with spironolactone (25 mg once daily). No serious adverse events were recorded, and adverse symptoms were not systematically recorded after the end of the double-blind treatment. Mean plasma potassium concentrations increased from 4·02 mmol/L (95% CI 3·95-4·08) on placebo to 4·50 (4·44-4·57) on amiloride (p<0·0001).

Interpretation : Our results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension.

pdf29655877

PEACE

Prevention of Events with Angiotensin Converting Enzyme Inhibition.

L’étude PEACE? au design proche de celui de l’étude EUROPA? a inclus 8290 patients coronariens stables recevant un IEC? (trandolapril 4 mg/j) comparé à un placebo avec un suivi de 4.8 ans. Aucune différence n’a été observée sur le critère primaire d’évaluation. Le résultat négatif de cet essai, à la différence d’EUROPA, suggère que le bénéfice apporté par l’adjonction d’un IEC peut être limité chez les patients à risque? de décès cardiovasculaire moindre dont le traitement a été optimisé par une plus grande fréquence de la revascularisation et un recours plus large à l’utilisation des statines.

Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL ; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004 ;351(20):2058-68 15531767

BACKGROUND :
Angiotensin-converting-enzyme (ACE) inhibitors are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure. ACE inhibitors have also been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure.

METHODS :
In the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial, we tested the hypothesis that patients with stable coronary artery disease and normal or slightly reduced left ventricular function derive therapeutic benefit from the addition of ACE inhibitors to modern conventional therapy. The trial was a double-blind, placebo-controlled study in which 8290 patients were randomly assigned to receive either trandolapril at a target dose of 4 mg per day (4158 patients) or matching placebo (4132 patients).

RESULTS :
The mean (+/-SD) age of the patients was 64+/-8 years, the mean blood pressure 133+/-17/78+/-10 mm Hg, and the mean left ventricular ejection fraction 58+/-9 percent. The patients received intensive treatment, with 72 percent having previously undergone coronary revascularization and 70 percent receiving lipid-lowering drugs. The incidence? of the primary end point—death from cardiovascular causes, myocardial infarction, or coronary revascularization—was 21.9 percent in the trandolapril group, as compared with 22.5 percent in the placebo group (hazard ratio in the trandolapril group, 0.96 ; 95 percent confidence interval, 0.88 to 1.06 ; P=0.43) over a median follow-up period of 4.8 years.

CONCLUSIONS :
In patients with stable coronary heart disease and preserved left ventricular function who are receiving "current standard" therapy and in whom the rate of cardiovascular events is lower than in previous trials of ACE inhibitors in patients with vascular disease, there is no evidence that the addition of an ACE inhibitor provides further benefit in terms of death from cardiovascular causes, myocardial infarction, or coronary revascularization.

Solomon SD, Rice MM, A Jablonski K, Jose P, Domanski M, Sabatine M, Gersh BJ, Rouleau J, Pfeffer MA, Braunwald E ; Prevention of Events with ACE inhibition (PEACE) Investigators. Renal function and effectiveness of angiotensin-converting enzyme inhibitor therapy in patients with chronic stable coronary disease in the Prevention of Events with ACE inhibition (PEACE) trial. Circulation. 2006 ;114(1):26-31 16801465

BACKGROUND :
Patients with reduced renal function are at increased risk for adverse cardiovascular outcomes. In the post-myocardial infarction setting, angiotensin-converting enzyme (ACE) inhibitors have been shown to be as effective in patients with impaired renal function as in those with preserved renal function.

METHODS AND RESULTS :
We assessed the relation between renal function and outcomes, the influence of ACE inhibition on this relation, and whether renal function modifies the effectiveness of ACE inhibition in patients with stable coronary artery disease and preserved systolic function enrolled in the Prevention of Events with ACE inhibition trial (PEACE). Patients (n=8290) were randomly assigned to receive trandolapril (target, 4 mg/d) or placebo. Clinical creatinine measures were available for 8280 patients before randomization. The estimated glomerular filtration rate (eGFR) was calculated with the 4-point Modification of Diet in Renal Disease equation. Renal function was related to outcomes, and the influence of ACE-inhibitor therapy was assessed with formal interaction modeling. The mean eGFR in PEACE was 77.6+/-19.4, and 1355 (16.3%) patients had reduced renal function (eGFR <60 mg.mL(-1).1.73 m(-2)). We observed a significant interaction between eGFR and treatment group with respect to cardiovascular and all-cause mortality (P=0.02). Trandolapril was associated with a reduction in total mortality in patients with reduced renal function (adjusted HR?, 0.73 ; 95% CI, 0.54 to 1.00) but not in patients with preserved renal function (adjusted HR, 0.94 ; 95% CI, 0.78 to 1.13).

CONCLUSIONS :
Although trandolapril did not improve survival in the overall PEACE cohort, in which mean eGFR was relatively high, trandolapril reduced mortality in patients with reduced eGFR. These data suggest that reduced renal function may define a subset of patients most likely to benefit from ACE-inhibitor therapy for cardiovascular protection.

PHARAO

PHARAO? : Prevention of Hypertension with the Angiotensin-converting enzyme inhibitor Ramipril in Patients with High-Normal Blood Pressure.

Lüders S, Schrader J, Berger J, Unger T, Zidek W, Böhm M, Middeke M, Motz W, Lübcke C, Gansz A, Brokamp L, Schmieder RE, Trenkwalder P, Haller H, Dominiak P ; PHARAO Study Group. The PHARAO study : prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure : a prospective, randomized, controlled prevention trial of the German Hypertension League. J Hypertens. 2008 ;26:1487-96. 18551027

Abstract
BACKGROUND :
The prevention of hypertension with the angiotensin-converting enzyme inhibitor ramipril in patients with high-normal blood pressure study addresses the issue of whether progression to manifest hypertension in patients with high-normal blood pressure can be prevented with treatment.

METHODS :
A total of 1008 participants with high-normal office blood pressure were randomized to ramipril treatment group (n = 505) and a control group (n = 503). The patients were followed up for 3 years. Primary endpoint was to prevent or delay the progression to manifest hypertension. Secondary endpoints were reduction in the incidence? of cerebrovascular and cardiovascular events, as well as the development of hypertension as defined by ambulatory blood pressure monitoring.

FINDINGS :
One hundred and fifty-five patients (30.7%) in the ramipril group, and 216 (42.9%) in the control group reached the primary endpoint (relative risk reduction 34.4%, P = 0.0001). Ramipril also proved to be more effective in reducing the incidence of manifest office hypertension in patients with baseline ambulatory blood pressure monitoring high-normal blood pressure. The incidence of cerebrovascular and cardiovascular events showed no statistically significant differences between the two groups. Cough was more frequent in the ramipril group (4.8 vs.? 0.4%).

INTERPRETATION :
There is now good clinical evidence that patients with high-normal blood pressure (prehypertension) are more likely to progress to manifest hypertension than patients with optimal or normal blood pressure. Additional ambulatory blood pressure monitoring seems to be essential to achieve correct diagnosis. Treatment of patients with high-normal office blood pressure with the angiotensin-converting enzyme inhibitor was well tolerated, and significantly reduced the risk of progression to manifest hypertension.

PREVEND

PREVEND? : Prevention of Renal and Vascular End Stage Disease.

Brouwers FP, Asselbergs FW, Hillege HL, de Boer RA?, Gansevoort RT, van Veldhuisen DJ, van Gilst WH. Long-term effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria:Ten years of follow-up of Prevention of Renal and Vascular End-stage Disease Intervention Trial (PREVEND IT). Am Heart J. 2011 Jun ;161(6):1171-8. 21641365

BACKGROUND :
The PREVEND IT investigated whether treatment targeted at lowering urinary albumin excretion (UAE?) would reduce adverse cardiovascular events. We obtained extended follow-up data to approximately 10 years to investigate the long-term effects of fosinopril 20 mg and pravastatin 40 mg on cardiovascular outcomes in subjects with UAE >15 mg per 24 hours.

METHODS :
The original PREVEND IT consisted of 864 participants and 839 survivors after 4 years. For every survivor, the primary end point determined by the combined incidence? of cardiovascular mortality and hospitalization for cardiovascular morbidity was registered in several national databases and electronic hospital systems.

RESULTS :
Mean total follow-up of the extended PREVEND IT was 9.5 years (range 9.4-10.7 years). Four years of treatment with fosinopril was not associated with a reduction in the primary end point compared with placebo (hazard ratio 0.87, 95% CI 0.61-1.24 [P = .42]) during long-term follow-up. After 9.5 years, subjects with a baseline UAE in the upper quintile (>50 mg/24 hours) had a total event rate of 29.5% and were at a higher risk for developing cardiovascular disease compared with less UAE (hazard ratio 2.03, 95% CI 1.38-2.97 [P ? .01]). In addition, 4 years of fosinopril treatment resulted in a risk reduction of 45% (95% CI 6%-75% [P = .04]) in this group compared with placebo. Subjects originally assigned to pravastatin had no overall risk reduction in the primary end point (P = .99).

CONCLUSIONS :
Elevated UAE is associated with increased cardiovascular mortality and morbidity after 9.5 years of follow-up, with a doubling of the risk if the UAE is >50 mg per 24 hours. In this group, the benefits of 4-year treatment with fosinopril were sustained during posttrial follow-up for cardiovascular mortality and morbidity. We propose that UAE be used to estimate risk in the general population and that large clinical trials be designed to confirm the hypothesis that angiotensin-converting enzyme-inhibitor treatment may be beneficial in patients with mildly elevated UAE despite the absence of other comorbidities.

PREVENT

PREVENT? : Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial.

Abstract

BACKGROUND :
The results of angiographic studies have suggested that calcium channel-blocking agents may prevent new coronary lesion formation, the progression of minimal lesions, or both.

METHODS AND RESULTS :
The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) was a multicenter, randomized, placebo-controlled, double-masked clinical trial designed to test whether amlodipine would slow the progression of early coronary atherosclerosis in 825 patients with angiographically documented coronary artery disease. The primary outcome was the average 36-month angiographic change in mean minimal diameters of segments with a baseline diameter stenosis of 30%. A secondary hypothesis was whether amlodipine would reduce the rate of atherosclerosis in the carotid arteries as assessed with B-mode ultrasonography, which measured intimal-medial thicknesses (IMT). The rates of clinical events were also monitored. The placebo and amlodipine groups had nearly identical average 36-month reductions in the minimal diameter : 0.084 versus 0.095 mm, respectively (P :=0.38). In contrast, amlodipine had a significant effect in slowing the 36-month progression of carotid artery atherosclerosis : the placebo group experienced a 0.033-mm increase in IMT, whereas there was a 0. 0126-mm decrease in the amlodipine group (P :=0.007). There was no treatment difference in the rates of all-cause mortality or major cardiovascular events, although amlodipine use was associated with fewer cases of unstable angina and coronary revascularization.

CONCLUSIONS :
Amlodipine has no demonstrable effect on angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but is associated with fewer hospitalizations for unstable angina and revascularization.

Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, Riley W. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation. 2000 ;102(13):1503-10. 11004140

PROFESS

PROFESS? : Prevention Regimen for Effectively Avoiding Second Strokes.

Abstract

BACKGROUND :
The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

METHODS :
Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP?) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NCT00153062.

FINDINGS :
20,332 patients (mean age 66 years) were randomised and followed-up for a median of 2.4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel ; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0.38), or with telmisartan versus placebo (p=0.61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups.

INTERPRETATION :
Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.

Références :

Diener HC, Sacco RL, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlöf B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, VanderMaelen C, Voigt T, Weber M, Yoon BW ; Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group. Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial : a double-blind, active and placebo-controlled study. Lancet Neurol. 2008 ;7:875-84. pdf

Stroke. 2012 ;43(9):2336-42 22738922

PROGRESS

PROGRESS? : Perindopril Protection against Recurrent Stroke Study.

PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001 Sep 29 ;358(9287):1033-41.
11589932

L’étude PROGRESS inclut 6 105 patients normotendus ou hypertendus ayant un antécédent d’AVC? ou d’AIT? au cours des 5 dernières années. Les patients ont reçu un IEC?, le périndopril, secondairement associé à un diurétique thiazidique-like, l’indapamide, introduit de façon pragmatique en fonction du niveau tensionnel comparé à placebo. Le critère principal était la récurrence d’AVC et l’étude montre qu’une réduction du risque? d’AVC de - 28 % dans le groupe périndopril ± indapamide. Le bénéfice est à porter au crédit de la combinaison avec une RRR? à 0.57 alors qu’il est de 0,95 en monothérapie par IEC. Une différence de pression artérielle est observée entre les deux groupes de patients -9 mmHg PAS?/-4 mmHg PAD?.

BACKGROUND :
Blood pressure is a determinant of the risk of stroke among both hypertensive and non-hypertensive individuals with cerebrovascular disease. However, there is uncertainty about the efficacy and safety of blood-pressure-lowering treatments for many such patients. The perindopril protection against recurrent stroke study (PROGRESS) was designed to determine the effects of a blood-pressure-lowering regimen in hypertensive and non-hypertensive patients with a history of stroke or transient ischaemic attack.

METHODS :
6105 individuals from 172 centres in Asia, Australasia, and Europe were randomly assigned active treatment (n=3051) or placebo (n=3054). Active treatment comprised a flexible regimen based on the angiotensin- converting-enzyme inhibitor perindopril (4 mg daily), with the addition of the diuretic indapamide at the discretion of treating physicians. The primary outcome was total stroke (fatal or non-fatal). Analysis was by intention to treat.

FINDINGS :
Over 4 years of follow up, active treatment reduced blood pressure by 9/4 mm Hg. 307 (10%) individuals assigned active treatment suffered a stroke, compared with 420 (14%) assigned placebo (relative risk reduction 28% [95% CI 17-38], p<0.0001). Active treatment also reduced the risk of total major vascular events (26% [16-34]). There were similar reductions in the risk of stroke in hypertensive and non-hypertensive subgroups (all p<0.01). Combination therapy with perindopril plus indapamide reduced blood pressure by 12/5 mm Hg and stroke risk by 43% (30-54). Single-drug therapy reduced blood pressure by 5/3 mm Hg and produced no discernable reduction in the risk of stroke.

INTERPRETATION :
This blood-pressure-lowering regimen reduced the risk of stroke among both hypertensive and non-hypertensive individuals with a history of stroke or transient ischaemic attack. Combination therapy with perindopril and indapamide produced larger blood pressure reductions and larger risk reductions than did single drug therapy with perindopril alone. Treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischaemic attack, irrespective of their blood pressure.

PURE

PURE? study

Abstract

BACKGROUND :
Higher levels of sodium intake are reported to be associated with higher blood pressure. Whether this relationship varies according to levels of sodium or potassium intake and in different populations is unknown.

METHODS :
We studied 102,216 adults from 18 countries. Estimates of 24-hour sodium and potassium excretion were made from a single fasting morning urine specimen and were used as surrogates for intake. We assessed the relationship between electrolyte excretion and blood pressure, as measured with an automated device.

RESULTS :
Regression analyses showed increments of 2.11 mm Hg in systolic blood pressure and 0.78 mm Hg in diastolic blood pressure for each 1-g increment in estimated sodium excretion. The slope of this association was steeper with higher sodium intake (an increment of 2.58 mm Hg in systolic blood pressure per gram for sodium excretion >5 g per day, 1.74 mm Hg per gram for 3 to 5 g per day, and 0.74 mm Hg per gram for <3 g per day ; P<0.001> 55 years of age, 2.43 mm Hg per gram at 45 to 55 years of age, and 1.96 mm Hg per gram at <45 years of age ; P<0.001> 25119606

Urinary sodium and potassium excretion, mortality, and cardiovascular events.
N Engl J Med. 2014 Aug 14 ;371(7):612-2. doi : 1.1056/NEJMoa131188.
Reference : O’Donnell M, Mente A, Rangarajan S, McQueen MJ, Wang X, Liu L, Yan H, Lee SF, Mony P, Devanath A, Rosengren A, Lopez-Jaramillo P, Diaz R, Avezum A, Lanas F, Yusoff K, Iqbal R, Ilow R, Mohammadifard N, Gulec S, Yusufali AH, Kruger L, Yusuf R, Chifamba J, Kabali C, Dagenais G, Lear SA, Teo K, Yusuf S ; PURE? Investigators. Urinary sodium and potassium excretion, mortality, and cardiovascular events.N Engl J Med.2014 Aug 14 ;371(7):612-23. doi : 10.1056/NEJMoa1311889.. 25119607

Sodium and cardiovascular disease.
N Engl J Med. 2014 Nov 27 ;371(22):2137-. doi : 1.1056/NEJMc141211.
Reference : O’Donnell M, Mente A, Yusuf S. Sodium and cardiovascular disease.N Engl J Med.2014 Nov 27 ;371(22):2137-8. doi : 10.1056/NEJMc1412113.. 25427117

Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension : a pooled analysis of data from four studies.
Lancet. 2016 Jul 30 ;388(10043):465-7. doi : 1.1016/S0140-6736(16)30467-. Epub 2016 May 2.
Reference : Mente A1, O’Donnell M2, Rangarajan S3, Dagenais G4, Lear S5, McQueen M6, Diaz R7, Avezum A8, Lopez-Jaramillo P9, Lanas F10, Li W11, Lu Y12, Yi S12, Rensheng L13, Iqbal R14, Mony P15, Yusuf R16, Yusoff K17, Szuba A18, Oguz A19, Rosengren A20, Bahonar A21, Yusufali A22, Schutte AE23, Chifamba J24, Mann JF25, Anand SS26, Teo K3, Yusuf S26 ; PURE?, EPIDREAM and ONTARGET?/TRANSCEND? Investigators. Associations of urinary sodium excretion with cardiovascular events in individuals with and without hypertension : a pooled analysis of data from four studies.Lancet.2016 Jul 30 ;388(10043):465-75. doi : 10.1016/S0140-6736(16)30467-6. 27216139

REIN

REIN? : Ramipril Efficacy in Nephropathy.

The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997 Jun 28 ;349(9069):1857-63. 9217756

Ramipril Efficacy in Nephropathy. Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril : REIN follow-up trial. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Lancet.1998 Oct 17 ;352(9136):1252-6. 9788454

Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2) : multicentre, randomised controlled trial.
Ruggenenti P, Perna A, Loriga G, Ganeva M, Ene-Iordache B, Turturro M, Lesti M, Perticucci E, Chakarski IN, Leonardis D, Garini G, Sessa A, Basile C, Alpa M, Scanziani R, Sorba G, Zoccali C, Remuzzi G ; REIN-2 Study Group. Lancet. 2005 ; 365(9463):939-46. 15766995

Ruggenenti P, Perna A, Remuzzi G ; GISEN Group Investigators. Retarding progression of chronic renal disease : the neglected issue of residual proteinuria. Kidney Int. 2003 Jun ; 63(6):2254-61. 12753315

Ruggenenti P, Perna A, Remuzzi G ; Gruppo Italiano di Studi Epidemiologici in Nefrologia. ACE inhibitors to prevent end-stage renal disease : when to start and why possibly never to stop : a post hoc analysis of the REIN trial results. Ramipril Efficacy in Nephropathy. J Am Soc Nephrol.2001 Dec ;12(12):2832-7. 11729254

Ruggenenti P, Perna A, Gherardi G, Benini R, Remuzzi G. Chronic proteinuric nephropathies : outcomes and response to treatment in a prospective cohort of 352 patients with different patterns of renal injury. Am J Kidney Dis. 2000 Jun ; 35(6):1155-65. 10845831

Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G.Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999 ; 354(9176):359-64. 10437863

Ruggenenti P, Perna A, Gherardi G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotective properties of ACE-inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999 ; 354(9176):359-64. 10437863

Ruggenenti P, Perna A, Mosconi L, Pisoni R, Remuzzi G. "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN). Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. Kidney Int.1998 May ;53(5):1209-16. 9573535

RENAAL

RENAAL? : Reduction of Endpoints in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan.

Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S ; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 ;345(12):861-9. 11565518

Cette étude a inclus 1513 patients. Elle compare un ARA2? (losartan) à un placebo. Le critère principal est l’incidence? du critère combiné primaire (identique à celui de l’étude IDNT?). La réduction est de -16 % pour le critère principal combiné et de -28 % pour la survenue d’IRT dans le groupe losartan comparé au placebo. L’étude démontre l’effet néphroprotecteur du losartan chez le diabétique de type 2 avec néphropathie

van der Sande NG, Dorresteijn JA, Visseren FL, Dwyer JP, Blankestijn PJ, van der Graaf Y, Heerspink HL. Individualized prediction of the effect of angiotensin receptor inhibition on renal and cardiovascular outcomes in patients with diabetic nephropathy. Diabetes Obes Metab. 2016 Jun 23. 27337598

Felix Kröpelin T, de Zeeuw D, Holtkamp FA, Packham DK, L Heerspink HJ. Individual long-term albuminuria exposure during angiotensin receptor blocker therapy is the optimal predictor for renal outcome. Nephrol Dial Transplant. 2016 Jan 19. pii : gfv429. 26790449

Vart P, Scheven L, Lambers Heerspink HJ, de Jong PE, de Zeeuw D, Gansevoort RT ; PREVEND? Study Group and the RENAAL Investigators. Urine Albumin-Creatinine Ratio Versus Albumin Excretion for Albuminuria Staging : A Prospective Longitudinal Cohort Study. Am J Kidney Dis. 2016 Jan ; 67(1):70-8. 26188433

Schievink B, de Zeeuw D, Parving HH, Rossing P, Lambers Heerspink HJ. The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers. Br J Clin Pharmacol. 2015 Oct ; 80(4):678-86. 25872610

Schutte E, Lambers Heerspink HJ, Lutgers HL, Bakker SJ, Vart P, Wolffenbuttel BH, Umanath K, Lewis JB, de Zeeuw D, Gansevoort RT. Serum Bicarbonate and Kidney Disease Progression and Cardiovascular Outcome in Patients With Diabetic Nephropathy : A Post Hoc Analysis of the RENAAL (Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan) Study and IDNT (Irbesartan Diabetic Nephropathy Trial). Am J Kidney Dis. 2015 Sep ; 66(3):450-8. 25987260

McMullan CJ, Lambers Heerspink HJ, Parving HH, Dwyer JP, Forman JP, de Zeeuw D. Visit-to-visit variability in blood pressure and kidney and cardiovascular outcomes in patients with type 2 diabetes and nephropathy : a post hoc analysis from the RENAAL study and the Irbesartan Diabetic Nephropathy Trial. Am J Kidney Dis. 2014 Nov ; 64(5):714-22. 25064674

Lambers Heerspink HJ, Weldegiorgis M, Inker LA, Gansevoort R, Parving HH, Dwyer JP, Mondal H, Coresh J, Greene T, Levey AS, de Zeeuw D. Estimated GFR decline as a surrogate end point for kidney failure : a post hoc analysis from the Reduction of End Points in Non-Insulin-Dependent Diabetes With the Angiotensin II Antagonist Losartan (RENAAL) study and Irbesartan Diabetic Nephropathy Trial (IDNT). Am J Kidney Dis. 2014 Feb ; 63(2):244-50. 24210590

Smink PA?, Miao Y, Eijkemans MJ, Bakker SJ, Raz I, Parving HH, Hoekman J, Grobbee DE, de Zeeuw D, Lambers Heerspink HJ. The importance of short-term off-target effects in estimating the long-term renal and cardiovascular protection of angiotensin receptor blockers. Clin Pharmacol Ther. 2014 Feb ; 95(2):208-15. 24067744

Lambers Heerspink HJ, Holtkamp FA, Parving HH, Navis GJ, Lewis JB, Ritz E, de Graeff PA, de Zeeuw D. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int. 2012 Aug ; 82(3):330-7. /22437412

Packham DK, Alves TP, Dwyer JP, Atkins R, de Zeeuw D, Cooper M, Shahinfar S, Lewis JB, Lambers Heerspink HJ. Relative incidence of ESRD versus cardiovascular mortality in proteinuric type 2 diabetes and nephropathy : results from the DIAMETRIC (Diabetes Mellitus Treatment for Renal Insufficiency Consortium) database. Am J Kidney Dis. 2012 Jan ; 59(1):75-83. 22051245

Holtkamp FA, de Zeeuw D, de Graeff PA, Laverman GD, Berl T, Remuzzi G, Packham D, Lewis JB, Parving HH, Lambers Heerspink HJ. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy : a post hoc analysis of the combined RENAAL and IDNT trials. Eur Heart J. 2011 Jun ; 32(12):1493-9. 21421598

Eijkelkamp WB, Zhang Z, Remuzzi G, Parving HH, Cooper ME, Keane WF, Shahinfar S, Gleim GW, Weir MR, Brenner BM, de Zeeuw D. Albuminuria is a target for renoprotective therapy independent from blood pressure in patients with type 2 diabetic nephropathy : post hoc analysis from the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial. J Am Soc Nephrol. 2007 May ; 18(5):1540-6. 17409317

Keane WF, Zhang Z, Lyle PA, Cooper ME, de Zeeuw D, Grunfeld JP, Lash JP, McGill JB, Mitch WE, Remuzzi G, Shahinfar S, Snapinn SM, Toto R, Brenner BM ; RENAAL Study Investigators. Risk scores for predicting outcomes in patients with type 2 diabetes and nephropathy : the RENAAL study. Clin J Am Soc Nephrol. 2006 Jul ; 1(4):761-7. 17699284

Zhang Z, Shahinfar S, Keane WF, Ramjit D, Dickson TZ?, Gleim GW, Mogensen CE, de Zeeuw D, Brenner BM, Snapinn SM. Importance of baseline distribution of proteinuria in renal outcomes trials : lessons from the reduction of endpoints in NIDDM with the angiotensin II antagonist losartan (RENAAL) study. J Am Soc Nephrol. 2005 Jun ; 16(6):1775-80. 15872078

de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation. 2004 Aug 24 ; 110(8):921-7. 15302780

Bakris GL, Weir MR, Shanifar S, Zhang Z, Douglas J, van Dijk DJ, Brenner BM ; RENAAL Study Group. Effects of blood pressure level on progression of diabetic nephropathy : results from the RENAAL study. Arch Intern Med. 2003 Jul 14 ; 163(13):1555-65. 12860578

Thomas MC, Cooper ME, Shahinfar S, Brenner BM. Dialysis delayed is death prevented : a clinical perspective on the RENAAL study. Kidney Int. 2003 Apr ; 63(4):1577-9. 12631376

Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, Ribeiro AB, Shahinfar S, Simpson RL, Snapinn SM, Toto R ; RENAAL Study Investigators. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy : the RENAAL study. Kidney Int. 2003 Apr ; 63(4):1499-507. 12631367

Brenner BM, Cooper ME, de Zeeuw D, Grunfeld JP, Keane WF, Kurokawa K, McGill JB, Mitch WE, Parving HH, Remuzzi G, Ribeiro AB, Schluchter MD, Snavely D, Zhang Z, Simpson R, Ramjit D, Shahinfar S ; RENAAL Study Investigators. The losartan renal protection study—rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan). J Renin Angiotensin Aldosterone Syst. 2000 Dec ; 1(4):328-35. 11967819

ROADMAP

ROADMAP? : Randomized Olmesartan and Diabetes Microalbuminuria Prevention

N Engl J Med. 2011 ;364(10):907-17 21388309

Abstract
BACKGROUND :
Microalbuminuria is an early predictor of diabetic nephropathy and premature cardiovascular disease. We investigated whether treatment with an angiotensin-receptor blocker (ARB) would delay or prevent the occurrence of microalbuminuria in patients with type 2 diabetes and normoalbuminuria.
METHODS :
In a randomized, double-blind, multicenter, controlled trial, we assigned 4447 patients with type 2 diabetes to receive olmesartan (at a dose of 40 mg once daily) or placebo for a median of 3.2 years. Additional antihypertensive drugs (except angiotensin-converting-enzyme inhibitors or ARBs) were used as needed to lower blood pressure to less than 130/80 mm Hg. The primary outcome was the time to the first onset of microalbuminuria. The times to the onset of renal and cardiovascular events were analyzed as secondary end points.
RESULTS :
The target blood pressure (<130/80 mm Hg) was achieved in nearly 80% of the patients taking olmesartan and 71% taking placebo ; blood pressure measured in the clinic was lower by 3.1/1.9 mm Hg in the olmesartan group than in the placebo group. Microalbuminuria developed in 8.2% of the patients in the olmesartan group (178 of 2160 patients who could be evaluated) and 9.8% in the placebo group (210 of 2139) ; the time to the onset of microalbuminuria was increased by 23% with olmesartan (hazard ratio for onset of microalbuminuria, 0.77 ; 95% confidence interval, 0.63 to 0.94 ; P=0.01). The serum creatinine level doubled in 1% of the patients in each group. Slightly fewer patients in the olmesartan group than in the placebo group had nonfatal cardiovascular events—81 of 2232 patients (3.6%) as compared with 91 of 2215 patients (4.1%) (P=0.37)—but a greater number had fatal cardiovascular events—15 patients (0.7%) as compared with 3 patients (0.1%) (P=0.01), a difference that was attributable in part to a higher rate of death from cardiovascular causes in the olmesartan group than in the placebo group among patients with preexisting coronary heart disease (11 of 564 patients [2.0%] vs.? 1 of 540 [0.2%], P=0.02).
CONCLUSIONS :
Olmesartan was associated with a delayed onset of microalbuminuria, even though blood-pressure control in both groups was excellent according to current standards. The higher rate of fatal cardiovascular events with olmesartan among patients with preexisting coronary heart disease is of concern. (Funded by Daiichi Sankyo ; ClinicalTrials.gov number, NCT00185159.).

SCOPE

SCOPE? : Study on Congnition and Prognosis in the Elderly.

Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A ; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE) : principal results of a randomized double-blind intervention trial. J Hypertens. 2003 ;21:875-86. 12714861

Cette étude a inclus 4 964 patients âgés de 70 à 89 ans qui recevaient soit un ARA2? (candésartan) soit un placebo. Un autre traitement antihypertenseur pouvait être introduit et particulièrement le groupe placebo pouvait recevoir un diurétique thiazidique. Sur un critère principal d’évaluation reposant sur un événement cardiovasculaire majeur, un infarctus du myocarde ou un AVC? non fatal, il n’a pas été observé de différence significative entre les deux stratégies. Cependant au regard des critères secondaires, l’incidence? des AVC non fatals est moindre dans le groupe candésartan avec une RRR? de - 27,8 %.

BACKGROUND :
The prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago, but are less clear in those with mildly to moderately elevated blood pressure.

OBJECTIVE :
To assess whether candesartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events, cognitive decline and dementia.

DESIGN :
Prospective, double-blind, randomized, parallel-group study conducted in 1997-2002.

SETTING AND PARTICIPANTS :
The study was of 4964 patients aged 70-89 years, with systolic blood pressure 160-179 mmHg, and/or diastolic blood pressure 90-99 mmHg, and a Mini Mental State Examination (MMSE) test score >or= 24. A total of 527 centres in 15 countries participated in the study.

INTERVENTION :
Patients were assigned randomly to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive therapy added as needed. As a consequence, active antihypertensive therapy was extensively used in the control group (84% of patients). Mean follow-up was 3.7 years.

MAIN OUTCOME MEASURES :
The primary outcome measure was major cardiovascular events, a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction. Secondary outcome measures included cardiovascular death, non-fatal and fatal stroke and myocardial infarction, cognitive function measured by the MMSE and dementia.

RESULTS :
Blood pressure fell by 21.7/10.8 mmHg in the candesartan group and by 18.5/9.2 mmHg in the control group. A first major cardiovascular event occurred in 242 candesartan patients and in 268 control patients ; risk reduction with candesartan was 10.9% [95% confidence interval (CI), -6.0 to 25.1, P = 0.19]. Candesartan-based treatment reduced non-fatal stroke by 27.8% (95% CI, 1.3 to 47.2, P = 0.04), and all stroke by 23.6% (95% CI, -0.7 to 42.1, P = 0.056). There were no significant differences in myocardial infarction and cardiovascular mortality. Mean MMSE score fell from 28.5 to 28.0 in the candesartan group and from 28.5 to 27.9 in the control group (P = 0.20). The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups.

CONCLUSIONS :
In elderly hypertensive patients, a slightly more effective blood pressure reduction during candesartan-based therapy, compared with control therapy, was associated with a modest, statistically non-significant, reduction in major cardiovascular events and with a marked reduction in non-fatal stroke. Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions. Both treatment regimens were generally well tolerated.

Papademetriou V, Farsang C, Elmfeldt D, Hofman A, Lithell H, Olofsson B, Skoog I, Trenkwalder P, Zanchetti A ; Study on Cognition and Prognosis in the Elderly study group. Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension : the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol. 2004 Sep 15 ;44(6):1175-80. 15364316

OBJECTIVES :
The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker (ARB) candesartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension (ISH?).

BACKGROUND :
Isolated systolic hypertension is the predominant form of hypertension in the elderly, and stroke is the most common cardiovascular (CV) complication.

METHODS :
In the Study on Cognition and Prognosis in the Elderly (SCOPE), 4,964 patients age 70 to 89 years were randomly assigned to double-blind candesartan or placebo with open-label antihypertensive therapy (mostly thiazide diuretics) added as needed to control blood pressure. Of the 4,964 patients, 1,518 had ISH (systolic blood pressure >160 mm Hg and diastolic blood pressure <90 mm Hg). The present study is a predefined subgroup analysis of outcome results in the ISH patients.

RESULTS :
Of the ISH patients, 754 were randomized to the candesartan group and 764 to the control group. Over the study period, blood pressure was reduced by 22/6 mm Hg in the candesartan group and by 20/5 mm Hg in the control group (difference between treatments 2/1 mm Hg ; p = 0.101 and 0.064). A total of 20 fatal/non-fatal strokes occurred in the candesartan group (7.2/1,000 patient-years) and 35 in the control group (12.5/1,000 patient-years) ; relative risk (RR?) was 0.58 (95% confidence interval 0.33 to 1.00), that is, a RR reduction of 42% (p = 0.050 unadjusted, p = 0.049 adjusted for baseline risk). There were no marked or statistically significant differences between the treatment groups in other CV end points or all-cause mortality.

CONCLUSIONS :
In elderly patients with ISH, antihypertensive treatment based on the ARB candesartan resulted in a significant 42% RR reduction in stroke in comparison with other antihypertensive treatment, despite little difference in blood pressure reduction.

SCORE

SCORE? : Systematic Coronary Risk Evaluation.

Systematic COronary Risk Evaluation : High & Low cardiovascular Risk Charts based on gender, age, total cholesterol, systolic blood pressure and smoking status, with relative risk chart, qualifiers and instructions

SHEP

SHEP? : Systolic Hypertension in the Elderly Program.

JAMA. 1991 ;265:3255-64. 2046107

DESIGN :
Multicenter, randomized, double-blind, placebo-controlled.
SETTING :
Community-based ambulatory population in tertiary care centers.
PARTICIPANTS :
4736 persons (1.06%) from 447,921 screenees aged 60 years and above were randomized (2365 to active treatment, 2371 to placebo). Systolic blood pressure ranged from 160 to 219 mm Hg and diastolic blood pressure was less than 90 mm Hg. Of the participants, 3161 were not receiving antihypertensive medication at initial contact, and 1575 were. The average systolic blood pressure was 170 mm Hg ; average diastolic blood pressure, 77 mm Hg. The mean age was 72 years, 57% were women, and 14% were black.
INTERVENTIONS :
— Participants were stratified by clinical center and by antihypertensive medication status at initial contact. For step 1 of the trial, dose 1 was chlorthalidone, 12.5 mg/d, or matching placebo ; dose 2 was 25 mg/d. For step 2, dose 1 was atenolol, 25 mg/d, or matching placebo ; dose 2 was 50 mg/d.
MAIN OUTCOME MEASURES :
Primary. Nonfatal and fatal (total) stroke. Secondary. Cardiovascular and coronary morbidity and mortality, all-cause mortality, and quality of life measures.
RESULTS :
Average follow-up was 4.5 years. The 5-year average systolic blood pressure was 155 mm Hg for the placebo group and 143 mm Hg for the active treatment group, and the 5-year average diastolic blood pressure was 72 and 68 mm Hg, respectively. The 5-year incidence? of total stroke was 5.2 per 100 participants for active treatment and 8.2 per 100 for placebo. The relative risk by proportional hazards regression analysis was 0.64 (P = .0003). For the secondary end point of clinical nonfatal myocardial infarction plus coronary death, the relative risk was 0.73. Major cardiovascular events were reduced (relative risk, 0.68). For deaths from all causes, the relative risk was 0.87.
CONCLUSION :
In persons aged 60 years and over with isolated systolic hypertension, antihypertensive stepped-care drug treatment with low-dose chlorthalidone as step 1 medication reduced the incidence of total stroke by 36%, with 5-year absolute benefit of 30 events per 1000 participants. Major cardiovascular events were reduced, with 5-year absolute benefit of 55 events per 1000.

SPRINT

SPRINT? : A Randomized Trial of Intensive versus Standard Blood-Pressure Control

SPRINT? Research Group, Wright JT Jr, Williamson JD, Whelton PK, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26 ;373(22):2103-16. 26551272

Abstract
BACKGROUND :
The most appropriate targets for systolic blood pressure to reduce cardiovascular morbidity and mortality among persons without diabetes remain uncertain.

METHODS :
We randomly assigned 9361 persons with a systolic blood pressure of 130 mm Hg or higher and an increased cardiovascular risk, but without diabetes, to a systolic blood-pressure target of less than 120 mm Hg (intensive treatment) or a target of less than 140 mm Hg (standard treatment). The primary composite outcome was myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes.

RESULTS :
At 1 year, the mean systolic blood pressure was 121.4 mm Hg in the intensive-treatment group and 136.2 mm Hg in the standard-treatment group. The intervention was stopped early after a median follow-up of 3.26 years owing to a significantly lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (1.65% per year vs.? 2.19% per year ; hazard ratio with intensive treatment, 0.75 ; 95% confidence interval [CI], 0.64 to 0.89 ; P<0.001).> 27195814

Ambrosius WT, Sink KM, Foy CG, et al. ; SPRINT? Study Research Group. The design and rationale of a multicenter clinical trial comparing two strategies for control of systolic blood pressure : the Systolic Blood Pressure Intervention Trial (SPRINT?). Clin Trials. 2014 Oct ; 11(5):532-46. 24902920

Chang TI, Evans G, Cheung AK, et al. ; SPRINT? Study Research Group. Patterns and Correlates of Baseline Thiazide-Type Diuretic Prescription in the Systolic Blood Pressure Intervention Trial. Hypertension. 2016 Mar ; 67(3):550-5. 26865200

STENO 2

STENO 2? : Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

Cette étude avait pour objectif d’évaluer une intervention multifactorielle intensive comparée à une prise en charge conventionnelle des hypertendus diabétiques de type 2 microalbuminuriques. Sur un objectif principal combiné associant : décès cardiovasculaire, infarctus du myocarde non fatal, revascularisation coronaire, AVC? non fatal, chirurgie d’artériopathie périphérique, la RRR? observé est de - 20 %. La prise en charge intensive permet d’éviter 1 événement cardiovasculaire pour 5 malades traités pendant 7.8 ans

Références :

Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003 ;348(5):383-93. 12556541

Extension à 10 ans
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008 ;358(6):580-91. 18256393

Gaede P, Pedersen O. Intensive integrated therapy of type 2 diabetes : implications for long-term prognosis. Diabetes. 2004 Dec ; 53 Suppl 3:S39-47. 15561920

Gaede P, Tarnow L, Vedel P, Parving HH, Pedersen O. Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria. Nephrol Dial Transplant. 2004 Nov ;19(11):2784-8 15328385

Gaede P, Vedel P, Parving HH, Pedersen O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria : the Steno type 2 randomised study. Lancet. 1999 ;353(9153):617-22 10030326

STOP

STOP? / STOP2 : Swedish Trial in Old Patients with Hypertension.

Lancet. 1991 ;338(8778):1281-5. 1682683

Hansson L, Lindholm LH, Ekbom T, Dahlöf B, Lanke J, Scherstén B, Wester PO, Hedner T, de Faire U. Randomised trial of old and new antihypertensive drugs in elderly patients : cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999 ;354:1751-6. 10577635

Cette étude a été réalisée selon un design PROBE? et 6 614 patients ont été inclus de 70 à 84 ans. Il compare les « nouveaux antihypertenseurs » à savoir les IEC? et les BCC? à un traitement bêtabloquant-diurétique. En référence à un critère principal d’évaluation composite (AVC? + infarctus du myocarde + événements cardiovasculaires fatals) aucune différence d’événement n’est observée entre les 2 stratégies conventionnelle bêtabloquant-diurétique ou « nouvelle » par IEC ou BCC. Parmi les critères secondaires d’évaluation aucune différence n’est observée dans la survenue d’AVC, mais il existe une incidence? moindre d’infarctus du myocarde d’issue fatale et non fatale dans le groupe IEC comparée à celui recevant un BCC.

BACKGROUND :
The efficacy of new antihypertensive drugs has been questioned. We compared the effects of conventional and newer antihypertensive drugs on cardiovascular mortality and morbidity in elderly patients.

METHODS :
We did a prospective, randomised trial in 6614 patients aged 70-84 years with hypertension (blood pressure > or = 180 mm Hg systolic, > or = 105 mm Hg diastolic, or both). Patients were randomly assigned conventional antihypertensive drugs (atenolol 50 mg, metoprolol 100 mg, pindolol 5 mg, or hydrochlorothiazide 25 mg plus amiloride 2.5 mg daily) or newer drugs (enalapril 10 mg or lisinopril 10 mg, or felodipine 2.5 mg or isradipine 2-5 mg daily). We assessed fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease. Analysis was by intention to treat.

FINDINGS :
Blood pressure was decreased similarly in all treatment groups. The primary combined endpoint of fatal stroke, fatal myocardial infarction, and other fatal cardiovascular disease occurred in 221 of 2213 patients in the conventional drugs group (19.8 events per 1000 patient-years) and in 438 of 4401 in the newer drugs group (19.8 per 1000 ; relative risk 0.99 [95% CI 0.84-1.16], p=0.89). The combined endpoint of fatal and non-fatal stroke, fatal and non-fatal myocardial infarction, and other cardiovascular mortality occurred in 460 patients taking conventional drugs and in 887 taking newer drugs (0.96 [0.86-1.08], p=0.49).

INTERPRETATION :
Old and new antihypertensive drugs were similar in prevention of cardiovascular mortality or major events. Decrease in blood pressure was of major importance for the prevention of cardiovascular events.

Syst-China

Syst-China? : Systolic Hypertension in China.

Abstract

BACKGROUND :
In 1988, the Systolic Hypertension in China (Syst-China) Collaborative Group initiated the placebo-controlled Syst-China trial to investigate whether antihypertensive drug treatment could reduce the incidence? of fatal and nonfatal stroke in older Chinese patients with isolated systolic hypertension.

OBJECTIVES :
To explore (1) whether the benefits of active treatment were evenly distributed across 4 strata, prospectively defined according to sex and previous cardiovascular complications, and (2) whether the morbidity and mortality results were influenced by age, level of systolic or diastolic blood pressure (BP), smoking or drinking habits, or diabetes mellitus at enrollment.

METHODS :
Eligible patients had to be 60 years or older with a sitting systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg. After stratification for center, sex, and previous cardiovascular complications, 1253 patients were assigned to active treatment starting with nitrendipine (10-40 mg/d), with the possible addition of captopril (12.5-50.0 mg/d), and/or hydrochlorothiazide (12.5-50 mg/d). In the 1141 control patients, matching placebos were used similarly.

RESULTS :
Male sex, previous cardiovascular complications, older age, higher systolic BP or lower diastolic BP, living in northern China, smoking, and diabetes mellitus significantly and independently increased the risk of 1 or more of the following end points : total or cardiovascular mortality, all fatal and nonfatal cardiovascular end points, all strokes, and all cardiac end points. In the placebo-control group diabetes raised the risk of all end points 2- to 3-fold (P< or =.05). However, active treatment reduced the excess risk associated with diabetes to a nonsignificant level (P values ranging from .12-.86) except for cardiovascular mortality (P = .04). Cox regression with adjustments applied for significant covariates suggested that active treatment may reduce total mortality more (P = .06) in women and stroke more (P = .07) in men and that it may provide better protection against cardiac end points in nonsmokers than smokers (P = .04). Otherwise, the benefits of active treatment were equally manifest, regardless of the enrollment characteristics of the patients, and regardless of whether active treatment consisted of only nitrendipine or of nitrendipine associated with other active drugs.

CONCLUSIONS :
In elderly Chinese patients with isolated systolic hypertension, stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improved prognosis. The benefit was particularly evident in diabetic patients ; for cardiac end points it tended to be larger in nonsmokers. Otherwise, the benefit of active treatment was not significantly influenced by the characteristics of the patients at enrollment in the trial.

Référence :

Wang JG, Staessen JA, Gong L, Liu L. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative Group. Arch Intern Med. 2000 ;160:211-20. 10647760

Syst-Eur

Syst-Eur? : Systolic Hypertension in Europe.

Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur?) Trial Investigators. Lancet. 1997 ;350(9080):757-64. 9297994

BACKGROUND :
Isolated systolic hypertension occurs in about 15% of people aged 60 years or older. In 1989, the European Working Party on High Blood Pressure in the Elderly investigated whether active treatment could reduce cardiovascular complications of isolated systolic hypertension. Fatal and non-fatal stroke combined was the primary endpoint.

METHODS :
All patients (> 60 years) were initially started on masked placebo. At three run-in visits 1 month apart, their average sitting systolic blood pressure was 160-219 mm Hg with a diastolic blood pressure lower than 95 mm Hg. After stratification for centre, sex, and previous cardiovascular complications, 4695 patients were randomly assigned to nitrendipine 10-40 mg daily, with the possible addition of enalapril 5-20 mg daily and hydrochlorothiazide 12.5-25.0 mg daily, or matching placebos. Patients withdrawing from double-blind treatment were still followed up. We compared occurrence of major endpoints by intention to treat.

FINDINGS :
At a median of 2 years’ follow-up, sitting systolic and diastolic blood pressures had fallen by 13 mm Hg and 2 mm Hg in the placebo group (n = 2297) and by 23 mm Hg and 7 mm Hg in the active treatment group (n = 2398). The between-group differences were systolic 10.1 mm Hg (95% CI 8.8-11.4) and diastolic, 4.5 mm Hg (3.9-5.1). Active treatment reduced the total rate of stroke from 13.7 to 7.9 endpoints per 1000 patient-years (42% reduction ; p = 0.003). Non-fatal stroke decreased by 44% (p = 0.007). In the active treatment group, all fatal and non-fatal cardiac endpoints, including sudden death, declined by 26% (p = 0.03). Non-fatal cardiac endpoints decreased by 33% (p = 0.03) and all fatal and non-fatal cardiovascular endpoints by 31% (p < 0.001). Cardiovascular mortality was slightly lower on active treatment (-27%, p = 0.07), but all-cause mortality was not influenced (-14% ; p = 0.22).

INTERPRETATION :
Among elderly patients with isolated systolic hypertension, antihypertensive drug treatment starting with nitrendipine reduces the rate of cardiovascular complications. Treatment of 1000 patients for 5 years with this type of regimen may prevent 29 strokes or 53 major cardiovascular endpoints.

Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur?) trial. Lancet. 1998 ;352:1347-51. 9802273

BACKGROUND :
Systolic hypertension increases the risk of dementia in elderly people. The vascular dementia project, set up in the framework of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur?) trial, investigated whether antihypertensive drug treatment could reduce the incidence? of dementia.

METHODS :
Eligible patients had no dementia, were at least 60 years old, and had a blood pressure when seated of 160-219 mm Hg systolic and below 95 mm Hg diastolic. Active treatment consisted of nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both drugs, titrated or combined to reduce the systolic blood pressure by at least 20 mm Hg to reach a value below 150 mm Hg. Cognitive function was assessed by the mini mental state examination (MMSE). If the MMSE score was 23 or less, diagnostic tests for dementia were done (DSM-III-R criteria). The cause of dementia was established by the modified ischaemic score with brain imaging or the Hachinski score.

FINDINGS :
Median follow-up by intention to treat was 2.0 years. Compared with placebo (n=1180), active treatment (n=1238) reduced the incidence of dementia by 50% from 7.7 to 3.8 cases per 1000 patient-years (21 vs? 11 patients, p=0.05). The median MMSE score at randomisation was 29 in both treatment groups. At the last available assessment, systolic and diastolic blood pressure were, respectively, 8.3 mm Hg and 3.8 mm Hg lower (p<0.001)> 12374512

BACKGROUND :
After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur?) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation.

OBJECTIVE :
To refine the estimates of the long-term effects of antihypertensive therapy on the incidence? of dementia.

METHODS :
Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs.

RESULTS :
Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg ; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs? 21 cases, P<.001). After adjustment for sex, age, education, and entry blood pressure, the relative hazard rate associated with the use of nitrendipine was 0.38 (95% confidence interval, 0.23-0.64 ; P<.001). Treatment of 1000 patients for 5 years can prevent 20 cases of dementia (95% confidence interval, 7-33).

CONCLUSION :
The extended follow-up of Syst-Eur? patients reinforces the evidence that blood pressure-lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

De Leeuw PW, Thijs L, Birkenhäger WH, Voyaki SM, Efstratopoulos AD, Fagard RH, Leonetti G, Nachev C, Petrie JC, Rodicio JL, Rosenfeld JJ, Sarti C, Staessen JA ; Systolic Hypertension in Europe (Syst-Eur?) Trial Investigators. Prognostic significance of renal function in elderly patients with isolated systolic hypertension : results from the Syst-Eur? trial. J Am Soc Nephrol. 2002 ;13:2213-22. 12191965

Abstract
Several reports suggest that markers of renal function such as serum creatinine, serum uric acid, and urinary excretion of protein may be related to cardiovascular complications and mortality. This study analyzed the data from the Syst-Eur? trial, which was a randomized, placebo-controlled, double-blind intervention trial in elderly patients with isolated systolic hypertension. The purpose was to evaluate whether serum levels of creatinine and uric acid and urinary protein excretion at entry are related to subsequent morbidity and mortality. Incidence? rates of total mortality, cardiovascular mortality, stroke (fatal as well as nonfatal), coronary events, and all cardiovascular endpoints were calculated for each quintile of serum creatinine or serum uric acid or for each category of protein excretion (none, trace, and overt). Crude and adjusted relative hazard rates were also determined for each 20 micro M increase in serum creatinine, each 50 micro M increase in serum uric acid, and for each protein excretion category. Even when adjusted for age, gender, and various other covariates, serum creatinine was significantly associated with a worse prognosis. There was an U-shaped relationship between serum uric acid and total mortality, but otherwise no obvious relationships were detected between serum uric acid levels and complications when appropriate adjustments were made for confounding variables. Proteinuria at entry was a significant predictor of total mortality and all cardiovascular endpoints. It is concluded that higher levels of serum creatinine and trace or overt proteinuria are associated with an increased number of cardiovascular events and with a higher mortality in patients with isolated systolic hypertension.

TNT

TNT? : Treating to New Targets.

Abstract

BACKGROUND :
Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD).

METHODS :
A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke.

RESULTS :
The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence? of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001).> 15755765

Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes : the Treating to New Targets (TNT?) study. Diabetes Care. 2006 Jun ; 29(6):1220-6. 16731999

Deedwania P, Barter P, Carmena R, Fruchart JC, Grundy SM, Haffner S, Kastelein JJ, LaRosa JC, Schachner H, Shepherd J, Waters DD ; Treating to New Targets Investigators. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome : analysis of the Treating to New Targets study. Lancet. 2006 Sep 9 ; 368(9539):919-28. 16962881

Waters DD, LaRosa JC, Barter P, Fruchart JC, Gotto AM Jr, Carter R, Breazna A, Kastelein JJ, Grundy SM. Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT? (treating to new targets) study. J Am Coll Cardiol. 2006 Nov 7 ; 48(9):1793-9. 17084252

Kostis JB, Breazna A, Deedwania PC, LaRosa JC ; Treating to New Targets Steering Committee and Investigators. The benefits of intensive lipid lowering in patients with stable coronary heart disease with normal or high systolic blood pressure : an analysis of the Treating to New Targets (TNT?) study. J Clin Hypertens (Greenwich). 2008 May ; 10(5):367-76. 18453796

Bangalore S, Messerli FH, Wun CC, Zuckerman AL, DeMicco D, Kostis JB, LaRosa JC ; Treating to New Targets Steering Committee and Investigators. J-curve revisited : An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT?) Trial. Eur Heart J. 2010 Dec ; 31(23):2897-908. 20846991

Frey P, Waters DD, DeMicco DA?, Breazna A, Samuels L, Pipe A, Wun CC, Benowitz NL. Impact of smoking on cardiovascular events in patients with coronary disease receiving contemporary medical therapy (from the Treating to New Targets [TNT?] and the Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL] trials). Am J Cardiol. 2011 Jan 15 ; 107(2):145-50. 21129718

Mora S, Wenger NK, Demicco DA?, Breazna A, Boekholdt SM, Arsenault BJ, Deedwania P, Kastelein JJ, Waters DD. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy : the Treating to New Targets (TNT?) study. Circulation. 2012 Apr 24 ; 125(16):1979-87. 22461416

Waters DD, Ho JE, Boekholdt SM, DeMicco DA?, Kastelein JJ, Messig M, Breazna A, Pedersen TR. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy : effect of baseline risk factors for diabetes. J Am Coll Cardiol. 2013 Jan 15 ; 61(2):148-52. 23219296

Relation of improvement in estimated glomerular filtration rate with atorvastatin to reductions in hospitalizations for heart failure (from the Treating to New Targets [TNT?] study).
Ho JE, Waters DD, Kean A, Wilson DJ, Demicco DA?, Breazna A, Wun CC, Deedwania PC, Khush KK ; TNT? Investigators.
Am J Cardiol. 2012 Jun 15 ; 109(12):1761-6. 22459310

Dorresteijn JA, Boekholdt SM, van der Graaf Y, Kastelein JJ, LaRosa JC, Pedersen TR, DeMicco DA?, Ridker PM, Cook NR, Visseren FL. High-dose statin therapy in patients with stable coronary artery disease : treating the right patients based on individualized prediction of treatment effect. Circulation. 2013 Jun 25 ; 127(25):2485-93. 23674398

Arsenault BJ, Boekholdt SM, Mora S, DeMicco DA, Bao W, Tardif JC, Amarenco P, Pedersen T, Barter P, Waters DD. Impact of high-dose atorvastatin therapy and clinical risk factors on incident aortic valve stenosis in patients with cardiovascular disease (from TNT?, IDEAL, and SPARCL). Am J Cardiol. 2014 Apr 15 ; 113(8):1378-82. 24582532

Bangalore S, Breazna A, DeMicco DA?, Wun CC, Messerli FH ; TNT? Steering Committee and Investigators. Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes : insights from the TNT? trial. J Am Coll Cardiol. 2015 Apr 21 ; 65(15):1539-48. 25881936

Deedwania PC, Shepherd J, Breazna A, DeMicco DA? ; Treating to New Targets (TNT?) Steering Committee Investigators. Effect of high-dose atorvastatin on the cardiovascular risk associated with individual components of metabolic syndrome : a subanalysis of the Treating to New Targets (TNT?) study. Diabetes Obes Metab. 2016 Jan ; 18(1):56-63. 26434404

Shepherd J, Breazna A, Deedwania PC, LaRosa JC, Wenger NK, Messig M, Wilson DJ ; Treating to New Targets Steering Committee and Investigators. Relation Between Change in Renal Function and Cardiovascular Outcomes in Atorvastatin-Treated Patients (from the Treating to New Targets [TNT?] Study). Am J Cardiol. 2016 Apr 15 ; 117(8):1199-205. 26940556

Deedwania PC, Pedersen TR, DeMicco DA?, Breazna A, Betteridge DJ, Hitman GA, Durrington P, Neil A ; TNT?, CARDS and IDEAL Steering Committees and Investigators. Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes. Int J Cardiol. 2016 Jul 30 ; 222:548-556. 27513651

TRANSCEND

TRANSCEND? : Telmisartan Randomized Assessment Study inACE-I Intolerant Subjects withCardiovascular Disease.

Abstract

BACKGROUND :
Angiotensin-converting enzyme (ACE) inhibitors reduce major cardiovascular events, but are not tolerated by about 20% of patients. We therefore assessed whether the angiotensin-receptor blocker telmisartan would be effective in patients intolerant to ACE inhibitors with cardiovascular disease or diabetes with end-organ damage.

METHODS :
After a 3-week run-in period, 5926 patients, many of whom were receiving concomitant proven therapies, were randomised to receive telmisartan 80 mg/day (n=2954) or placebo (n=2972) by use of a central automated randomisation system. Randomisation was stratified by hospital. The primary outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00153101.

FINDINGS :
The median duration of follow-up was 56 (IQR 51-64) months. All randomised patients were included in the efficacy analyses. Mean blood pressure was lower in the telmisartan group than in the placebo group throughout the study (weighted mean difference between groups 4.0/2.2 [SD 19.6/12.0] mm Hg). 465 (15.7%) patients experienced the primary outcome in the telmisartan group compared with 504 (17.0%) in the placebo group (hazard ratio 0.92, 95% CI 0.81-1.05, p=0.216). One of the secondary outcomes-a composite of cardiovascular death, myocardial infarction, or stroke-occurred in 384 (13.0%) patients on telmisartan compared with 440 (14.8%) on placebo (0.87, 0.76-1.00, p=0.048 unadjusted ; p=0.068 after adjustment for multiplicity of comparisons and overlap with primary outcome). 894 (30.3%) patients receiving telmisartan were hospitalised for a cardiovascular reason, compared with 980 (33.0%) on placebo (relative risk 0.92, 95% CI 0.85-0.99 ; p=0.025). Fewer patients permanently discontinued study medication in the telmisartan group than in the placebo group (639 [21.6%] vs? 705 [23.8%] ; p=0.055) ; the most common reason for permanent discontinuation was hypotensive symptoms (29 [0.98%] in the telmisartan group vs 16 [0.54%] in the placebo group).

INTERPRETATION :
Telmisartan was well tolerated in patients unable to tolerate ACE inhibitors. Although the drug had no significant effect on the primary outcome of this study, which included hospitalisations for heart failure, it modestly reduced the risk of the composite outcome of cardiovascular death, myocardial infarction, or stroke.

Références

Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors : a randomised controlled trial. Lancet. 2008 Sep 27 ; 372(9644):1174-83. pdf

Bloch MJ, Basile JN. In angiotensin-converting enzyme inhibitor-intolerant individuals, the angiotensin receptor blocker telmisartan does not reduce the incidence? of major cardiovascular events in high-risk patients : lessons learned from the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects Wtih Cardiovascular Disease (TRANSCEND).
J Clin Hypertens (Greenwich). 2008 ;10:876-80 19128279

Teo K, Yusuf S, Sleight P, Anderson C, Mookadam F, Ramos B, Hilbrich L, Pogue J, Schumacher H ; ONTARGET?/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients : the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004 Jul ; 148(1):52-61. 15215792

Cowan BR, Young AA?, Anderson C, Doughty RN, Krittayaphong R, Lonn E, Marwick TH, Reid CM, Sanderson JE, Schmieder RE, Teo K, Wadham AK, Worthley SG, Yu CM, Yusuf S, Jennings GL. The cardiac MRI substudy to ongoing telmisartan alone and in combination with ramipril global endpoint trial/telmisartan randomized assessment study in ACE-intolerant subjects with cardiovascular disease : analysis protocol and baseline characteristics. Clin Res Cardiol. 2009 Jul ; 98(7):421-33. 19347385

Mann JF, Schmieder RE, Dyal L, McQueen MJ, Schumacher H, Pogue J, Wang X, Probstfield JL, Avezum A, Cardona-Munoz E, Dagenais GR, Diaz R, Fodor G, Maillon JM, Rydén L, Yu CM, Teo KK, Yusuf S ; TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) Investigators. Effect of telmisartan on renal outcomes : a randomized trial. Ann Intern Med. 2009 Jul 7 ; 151(1):1-10, W1-2. 19451556

Verdecchia P, Sleight P, Mancia G, Fagard R, Trimarco B, Schmieder RE, Kim JH, Jennings G, Jansky P, Chen JH, Liu L, Gao P, Probstfield J, Teo K, Yusuf S ; ONTARGET/TRANSCEND Investigators. Effects of telmisartan, ramipril, and their combination on left ventricular hypertrophy in individuals at high vascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial and the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease. Circulation. 2009 Oct 6 ; 120(14):1380-9. 19770395

Böhm M, Baumhäkel M, Teo K, Sleight P, Probstfield J, Gao P, Mann JF, Diaz R, Dagenais GR, Jennings GL, Liu L, Jansky P, Yusuf S ; ONTARGET/TRANSCEND Erectile Dysfunction Substudy Investigators. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both : The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation. 2010 Mar 30 ; 121(12):1439-46. 20231536

Anderson C, Teo K, Gao P, Arima H, Dans A, Unger T, Commerford P, Dyal L, Schumacher H, Pogue J, Paolasso E, Holwerda N, Chazova I, Binbrek A, Young J, Yusuf S ; ONTARGET and TRANSCEND Investigators. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease : analysis of data from the ONTARGET and TRANSCEND studies. Lancet Neurol. 2011 Jan ; 10(1):43-53. 20980201

Estimated glomerular filtration rate and albuminuria as predictors of outcomes in patients with high cardiovascular risk : a cohort study.
Clase CM, Gao P, Tobe SW, McQueen MJ, Grosshennig A, Teo KK, Yusuf S, Mann JF ; ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized Assessment Study in Angiotensin-Converting-Enzyme-Inhibitor Intolerant Subjects with Cardiovascular Disease). Ann Intern Med. 2011 Mar 1 ; 154(5):310-8. 21357908

Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk : results from the ONTARGET and TRANSCEND studies.
Tobe SW, Clase CM, Gao P, McQueen M, Grosshennig A, Wang X, Teo KK, Yusuf S, Mann JF ; ONTARGET and TRANSCEND Investigators. Circulation. 2011 Mar 15 ; 123(10):1098-107. 21357827

Verdecchia P, Dagenais G, Healey J, Gao P, Dans AL, Chazova I, Binbrek AS, Iacobellis G, Ferreira R, Holwerda N, Karatzas N, Keltai M, Mancia G, Sleight P, Teo K, Yusuf S ; Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint TrialTelmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease Investigators. Blood pressure and other determinants of new-onset atrial fibrillation in patients at high cardiovascular risk in the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease studies. J Hypertens. 2012 May ; 30(5):1004-14. 22495138

Kappert K, Böhm M, Schmieder R, Schumacher H, Teo K, Yusuf S, Sleight P, Unger T ; ONTARGET/TRANSCEND Investigators. Impact of sex on cardiovascular outcome in patients at high cardiovascular risk : analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET). Circulation. 2012 Aug 21 ; 126(8):934-41. 22829023

Cukierman-Yaffe T, Anderson C, Teo K, Gao P, Gerstein HC, Yusuf S ; ONTARGET/TRANSCEND Investigators. Dysglycemia and Cognitive Dysfunction and Ill Health in People With High CV Risk : Results From the ONTARGET/TRANSCEND Studies. J Clin Endocrinol Metab. 2015 Jul ; 100(7):2682-9. 26020764

TROPHY

TROPHY? : Trial of Preventing Hypertension.

Julius S, Nesbitt SD, Egan BM, Weber MA, Michelson EL, Kaciroti N, Black HR?, Grimm RH Jr, Messerli FH, Oparil S, Schork MA ; Trial of Preventing Hypertension (TROPHY) Study Investigators. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006 ;354:1685-97 16537662

Abstract
BACKGROUND :
Prehypertension is considered a precursor of stage 1 hypertension and a predictor of excessive cardiovascular risk. We investigated whether pharmacologic treatment of prehypertension prevents or postpones stage 1 hypertension.

METHODS :
Participants with repeated measurements of systolic pressure of 130 to 139 mm Hg and diastolic pressure of 89 mm Hg or lower, or systolic pressure of 139 mm Hg or lower and diastolic pressure of 85 to 89 mm Hg, were randomly assigned to receive two years of candesartan (Atacand, AstraZeneca) or placebo, followed by two years of placebo for all. When a participant reached the study end point of stage 1 hypertension, treatment with antihypertensive agents was initiated. Both the candesartan group and the placebo group were instructed to make changes in lifestyle to reduce blood pressure throughout the trial.

RESULTS :
A total of 409 participants were randomly assigned to candesartan, and 400 to placebo. Data on 772 participants (391 in the candesartan group and 381 in the placebo group ; mean age, 48.5 years ; 59.6 percent men) were available for analysis. During the first two years, hypertension developed in 154 participants in the placebo group and 53 of those in the candesartan group (relative risk reduction, 66.3 percent ; P<0.001). After four years, hypertension had developed in 240 participants in the placebo group and 208 of those in the candesartan group (relative risk reduction, 15.6 percent ; P<0.007). Serious adverse events occurred in 3.5 percent of the participants assigned to candesartan and 5.9 percent of those receiving placebo.

CONCLUSIONS :
Over a period of four years, stage 1 hypertension developed in nearly two thirds of patients with untreated prehypertension (the placebo group). Treatment of prehypertension with candesartan appeared to be well tolerated and reduced the risk of incident hypertension during the study period. Thus, treatment of prehypertension appears to be feasible. (ClinicalTrials.gov number, NCT00227318.).

UKPDS

UKPDS? : United Kingdom Prospective Diabetes Study.

UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes : UKPDS? 38. BMJ. 1998 ;317:703-13. 9732337

OBJECTIVE :
To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes.

DESIGN :
Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg.

SETTING :
20 hospital based clinics in England, Scotland, and Northern Ireland.

SUBJECTS :
1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg) ; 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years.

MAIN OUTCOME MEASURES :
Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography.

RESULTS :
Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001).> 9732338

OBJECTIVE :
To determine whether tight control of blood pressure with either a beta blocker or an angiotensin converting enzyme inhibitor has a specific advantage or disadvantage in preventing the macrovascular and microvascular complications of type 2 diabetes.

DESIGN :
Randomised controlled trial comparing an angiotensin converting enzyme inhibitor (captopril) with a beta blocker (atenolol) in patients with type 2 diabetes aiming at a blood pressure of <150/<85 mm Hg.

SETTING :
20 hospital based clinics in England, Scotland, and Northern Ireland.

SUBJECTS :
1148 hypertensive patients with type 2 diabetes (mean age 56 years, mean blood pressure 160/94 mm Hg). Of the 758 patients allocated to tight control of blood pressure, 400 were allocated to captopril and 358 to atenolol. 390 patients were allocated to less tight control of blood pressure.
MAIN OUTCOME MEASURES :
Predefined clinical end points, fatal and non-fatal, related to diabetes, death related to diabetes, and all cause mortality. Surrogate measures of microvascular and macrovascular disease included urinary albumin excretion and retinopathy assessed by retinal photography.

RESULTS :
Captopril and atenolol were equally effective in reducing blood pressure to a mean of 144/83 mm Hg and 143/81 mm Hg respectively, with a similar proportion of patients (27% and 31%) requiring three or more antihypertensive treatments. More patients in the captopril group than the atenolol group took the allocated treatment : at their last clinic visit, 78% of those allocated captopril and 65% of those allocated atenolol were taking the drug (P<0.0001).> =300 mg/l (5% and 9%). The proportion of patients with hypoglycaemic attacks was not different between groups, but mean weight gain in the atenolol group was greater (3.4 kg v 1.6 kg).

CONCLUSION :
Blood pressure lowering with captopril or atenolol was similarly effective in reducing the incidence? of diabetic complications. This study provided no evidence that either drug has any specific beneficial or deleterious effect, suggesting that blood pressure reduction in itself may be more important than the treatment used.

Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR?. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS? 36) : prospective observational study. BMJ. 2000 Aug 12 ;321(7258):412-9. 10938049

OBJECTIVE :
To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes.

DESIGN :
Prospective observational study. Setting : 23 hospital based clinics in England, Scotland, and Northern Ireland.
PARTICIPANTS :
4801 white, Asian Indian, and Afro-Caribbean UKPDS? patients, whether randomised or not to treatment, were included in analyses of incidence? ; of these, 3642 were included in analyses of relative risk.

OUTCOME MEASURES :
Primary predefined aggregate clinical outcomes : any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes : myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points : non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders.

RESULTS :
The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P<0.0001), 15% for deaths related to diabetes (12% to 18%, P<0.0001), 11% for myocardial infarction (7% to 14%, P<0.0001), and 13% for microvascular complications (10% to 16%, P<0.0001). No threshold of risk was observed for any end point.

CONCLUSIONS :
In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.

VA NEPHRON D

Veterans Affairs Nephropathy in Diabetes (VA NEPHRON?-D) study

Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA?, O’Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P ; VA NEPHRON?-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. Veterans Affairs Nephropathy in Diabetes
(VA NEPHRON?-D) study. N Engl J Med. 2013 ; 369(20):1892-903. 24206457

Abstract
BACKGROUND :
Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria ; however, its safety and effect on the progression of kidney disease are uncertain.

Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ? 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ? 60 ml per minute per 1.73 m(2) or a decline of ? 50% if the initial estimated GFR was <60> 26482258

VADT

VADT? : Veterans Affairs Diabetes Trial

Anderson RJ1, Bahn GD2, Emanuele NV3, Marks JB4, Duckworth WC5 ; VADT Study Group. Blood pressure and pulse pressure effects on renal outcomes in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care. 2014 Oct ;37(10):2782-8.
25048382

Abstract
OBJECTIVE :
Blood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR).

RESEARCH DESIGN AND METHODS :
The VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR?) were used to determine worsening of renal outcomes.

RESULTS :
Compared with SBP 105-129 mmHg, the risk of ACR worsening increased significantly for SBP 130-139 mmHg (HR 1.88 [95% CI 1.28-2.77] ; P = 0.001) and for SBP ?140 mmHg (2.51 [1.66-3.78] ; P < 0.0001). Compared with a PP range of 40-49 mmHg, PP <40 was associated with significantly lowered risk of worsening ACR (0.36 [0.15-0.87] ; P = 0.022) and PP ?60 with significantly increased risk (2.38 [1.58-3.59] ; P < 0.0001). Analyses of BP ranges associated with eGFR worsening showed significantly increased risk with rising baseline SBP and an interaction effect between SBP ?140 mmHg and on-study A1C. These patients were 15% more likely than those with SBP <140 mmHg to experience eGFR worsening (1.15 [1.00-1.32] ; P = 0.045) for each 1% (10.9 mmol/mol) A1C increase.

CONCLUSIONS :
SBP ?130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to <130 mmHg may lessen ACR worsening. The interaction between SBP ?140 mmHg and A1C suggests that the effect of glycemic control on reducing progression of renal disease may be greater in hypertensive patients.

TRIAL REGISTRATION :
ClinicalTrials.gov NCT00032487.

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD ; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8 ;360(2):129-39.

Hayward RA?, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV ; VADT Investigators. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 Jun 4 ;372(23):2197-206.

VALIANT

VALIANT? : Valsartan In Acute Myocardial Infarction Trial.

Anavekar NS1, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, White HD, Nordlander R, Maggioni A, Dickstein K, Zelenkofske S, Leimberger JD, Califf RM, Pfeffer MA. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004 Sep 23 ;351(13):1285-95. /15385655

Abstract
BACKGROUND :
The presence of coexisting conditions has a substantial effect on the outcome of acute myocardial infarction. Renal failure is associated with one of the highest risks, but the influence of milder degrees of renal impairment is less well defined.

METHODS :
As part of the Valsartan in Acute Myocardial Infarction Trial (VALIANT), we identified 14,527 patients with acute myocardial infarction complicated by clinical or radiologic signs of heart failure, left ventricular dysfunction, or both, and a documented serum creatinine measurement. Patients were randomly assigned to receive captopril, valsartan, or both. The glomerular filtration rate (GFR) was estimated by means of the four-component Modification of Diet in Renal Disease equation, and the patients were grouped according to their estimated GFR. We used a 70-candidate variable model to adjust and compare overall mortality and composite cardiovascular events among four GFR groups.

RESULTS :
The distribution of estimated GFR was wide and normally shaped, with a mean (+/-SD) value of 70+/-21 ml per minute per 1.73 m2 of body-surface area. The prevalence of coexisting risk factors, prior cardiovascular disease, and a Killip class of more than I was greatest among patients with a reduced estimated GFR (less than 45.0 ml per minute per 1.73 m2), and the use of aspirin, beta-blockers, statins, or coronary-revascularization procedures was lowest in this group. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, congestive heart failure, stroke, or resuscitation after cardiac arrest increased with declining estimated GFRs. Although the rate of renal events increased with declining estimated GFRs, the adverse outcomes were predominantly cardiovascular. Below 81.0 ml per minute per 1.73 m2, each reduction of the estimated GFR by 10 units was associated with a hazard ratio for death and nonfatal cardiovascular outcomes of 1.10 (95 percent confidence interval, 1.08 to 1.12), which was independent of the treatment assignment.

CONCLUSIONS :
Even mild renal disease, as assessed by the estimated GFR, should be considered a major risk factor for cardiovascular complications after a myocardial infarction.

Solomon SD1, Zelenkofske S, McMurray JJ, Finn PV, Velazquez E, Ertl G, Harsanyi A, Rouleau JL, Maggioni A, Kober L, White H, Van de Werf F, Pieper K, Califf RM, Pfeffer MA ; Valsartan in Acute Myocardial Infarction Trial (VALIANT) Investigators. Sudden death in patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. N Engl J Med. 2005 Jun 23 ;352(25):2581-8.

VALUE

VALUE? : Valsartan Antihypertensive Long-term Use Evaluation.

Julius S, Kjeldsen SE, Weber M, Brunner HR?, Ekman S, Hansson L, Hua T, Laragh J, McInnes GT, Mitchell L, Plat F, Schork A, Smith B, Zanchetti A ; VALUE? trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine : the VALUE? randomised trial. Lancet 2004 ;363 :2022-31 15207952

L’étude a inclus 15 245 patients hypertendus de plus de 50 ans à haut risque? cardiovasculaire. Ces patients ont reçu un traitement basé sur un ARA2? (valsartan) ± diurétique comparé à une stratégie basée sur un BCC? (amlodipine) ± diurétique thiazidique. Sur un critère principal composite associant morbidité et mortalité cardiovasculaire, il n’a pas été observé de différence entre les deux groupes. Cependant il existe une différence significative de PA? systolique et diastolique tout au long de l’essai. Cette différence de PA rend compte des résultats des critères secondaires d’évaluation à savoir RRR? d’infarctus du myocarde observée dans le groupe amlodipine de 19 % et une tendance à la RRR d’AVC? de 15 % sous amlodipine. Par contre il existait une moindre incidence? de diabète de novo dans le groupe valsartan, avec une RRR de 23 % (encadré 5). Cet essai a permis de valider l’association antihypertensive d’une DHP? et d’un diurétique.

Abstract
BACKGROUND :
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE?) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk.
METHODS :
15 ?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4.2 years.
FINDINGS :
Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month ; 1.5/1.3 mm Hg after 1 year ; p<0.001> 15207957

Abstract
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE?) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes ; the blood pressure response after just 1 month of treatment predicted events and survival.

Julius S, Weber MA, Kjeldsen SE, McInnes GT, Zanchetti A, Brunner HR?, Laragh J, Schork MA, Hua TA, Amerena J, Balazovjech I, Cassel G, Herczeg B, Koylan N, Magometschnigg D, Majahalme S, Martinez F, Oigman W, Seabra Gomes R, Zhu JR. The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE?) trial : outcomes in patients receiving monotherapy.Hypertension.2006 Sep ;48(3):385-91. 16864741

Abstract
In the main Valsartan Antihypertensive Long-Term Use Evaluation (VALUE?) report, we investigated outcomes in 15 245 high-risk hypertensive subjects treated with valsartan- or amlodipine-based regimens. In this report, we analyzed outcomes in 7080 patients (46.4%) who, at the end of the initial drug adjustment period (6 months), remained on monotherapy. Baseline characteristics were similar in the valsartan (N=3263) and amlodipine (N=3817) groups. Time on monotherapy was 3.2 years (78% of treatment exposure time). The average in-trial blood pressure was similar in both groups. Event rates in the monotherapy group were 16% to 39% lower than in the main VALUE? trial. In the first analysis, we censored patients when they discontinued monotherapy ("censored") ; in the second, we counted events regardless of subsequent therapy (intention-to-treat principle). We also assessed the impact of duration of monotherapy on outcomes. No difference was found in primary composite cardiac end points, strokes, myocardial infarctions, and all-cause deaths with both analyses. Heart failure in the valsartan group was lower both in the censored and intention-to-treat analyses (hazard ratios : 0.63, P=0.004 and 0.78, P=0.045, respectively). Longer duration of monotherapy amplified between-group differences in heart failure. New-onset diabetes was lower in the valsartan group with both analyses (odds ratios : 0.78, P=0.012 and 0.82, P=0.034). Thus, despite lower absolute event rates in monotherapy patients, the relative risks of heart failure and new-onset diabetes favored valsartan. Moreover, these findings support the feasibility of comparative prospective trials in lower-risk hypertensive patients.

Kjeldsen SE, Berge E, Bangalore S, Messerli FH, Mancia G, Holzhauer B, Hua TA, Zappe D, Zanchetti A, Weber MA, Julius S. No evidence for a J-shaped curve in treated hypertensive patients with increased cardiovascular risk : The VALUE? trial. Blood Press. 2016 ; 25(2):83-92. 26511535

Mehlum M, Liestøl K, Julius S, et al. VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY INCREASES RISK OF STROKE OR? CARDIAC EVENTS IN PATIENTS GIVEN VALSARTAN OR AMLODIPINE IN THE VALUE? TRIAL. J Hypertens.2015 Jun ;33 Suppl 1:e40. 26102813

Kjeldsen SE, McInnes GT, Mancia G, et al. Progressive effects of valsartan compared with amlodipine in prevention of diabetes according to categories of diabetogenic risk in hypertensive patients : the VALUE? trial. Blood Press. 2008 ; 17(3):170-7. 18608200

Schmieder RE, Kjeldsen SE, Julius S, McInnes GT, Zanchetti A, Hua TA ; VALUE? Trial Group. Reduced incidence? of new-onset atrial fibrillation with angiotensin II receptor blockade : the VALUE? trial. J Hypertens. 2008 Mar ; 26(3):403-11. 18300848

Pedersen OL, Mancia G, Pickering T, Høegholm A, Julius S, Kjeldsen SE, Nielsen ES, Refsgaard J, Weber M ; VALUE? trial group. Ambulatory blood pressure monitoring after 1 year on valsartan or amlodipine-based treatment : a VALUE? substudy. J Hypertens. 2007 Mar ; 25(3):707-12. 17278988

Staessen JA, Hansen TW, Birkenhäger WH. Added VALUE? of an ancillary study on ambulatory blood pressure monitoring. J Hypertens. 2007 Mar ; 25(3):513-5. 17278965

Kjeldsen SE, Julius S, Mancia G, McInnes GT, Hua T, Weber MA, Coca A, Ekman S, Girerd X, Jamerson K, Larochelle P, MacDonald TM, Schmieder RE, Schork MA, Stolt P, Viskoper R, Widimský J, Zanchetti A ; VALUE? Trial Investigators. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients : the VALUE? trial. J Hypertens. 2006 Jul ; 24(7):1405-12. 16794491

Kjeldsen SE, Julius S, Brunner H, Hansson L, Henis M, Ekman S, Laragh J, McInnes G, Smith B, Weber M, Zanchetti A. Characteristics of 15,314 hypertensive patients at high coronary risk. The VALUE? trial. The Valsartan Antihypertensive Long-term Use Evaluation. Blood Press.2001 ;10(2):83-91. 11467764

Mann J, Julius S. The Valsartan Antihypertensive Long-term Use Evaluation (VALUE?) trial of cardiovascular events in hypertension. Rationale and design. Blood Press.1998 May ;7(3):176-83. 9758088