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23 juin 2016

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.

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.
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.
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 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient-years ; hazard ratio 1.04, 95% CI 0.94-1.15, p=0.49).
The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekman S, Hansson L, Hua T, Laragh JH, McInnes GT, Mitchell L, Plat F, Schork MA, Smith B, Zanchetti A. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004 ;363:2049-51 15207957

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

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


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