Sverre E Kjeldsen
MD PhD FAHA
Department of Cardiology
The VALUE (Valsartan Antihypertensive Long-term Use Evaluation) trial randomised 15,313 hypertensive patients with high cardiovascular risk into a double-blind comparison of treatments based on the angiotensin receptor blocker (ARB) valsartan and on the calcium antagonist amlodipine. Inclusion ended in December 1999, study closeout lasted from September to December 2003, the database was locked by the end of March 2004 and the data were released in June 2004.(1)
A total of 15,245 randomised patients were included in the analysis, and 68 patients in nine centres were excluded because of deficiencies in clinical practice. Only 90 patients (0.6%) were lost to follow-up. The mean duration of exposure to study medication was 3.6 years in both treatment groups. The median daily doses were 151.7mg of valsartan and 8.5mg of amlodipine. As indicated in the 30-month analysis, the majority of patients in both groups were on combination treatment by the end of the trial. Fewer patients remained on monotherapy during the course of the study in the valsartan-based group (27.0%) than in the amlodipine group (35.3%).
Blood-pressure control rates in the VALUE trial were among the highest reported for an outcome trial: 56% of patients in the valsartan group and 62% of patients in the amlodipine group reached target blood pressure levels of below 140/90mmHg. However, although 92% of patients were treated for hypertension at baseline, only 22% had their blood pressure controlled at that time.
The effects of the amlodipine-based regimen in the VALUE trial were more pronounced than those of the valsartan- based regimen, particularly during the adjustment period (ie, the first six months). Differences in systolic/diastolic blood pressure were 4.0/2.1mmHg after one month, and were reduced to 1.5/1.3mmHg after one year (p<0.001 between groups). Despite this, there was no difference in the primary outcome of composite cardiac endpoints between the valsartan and the amlodipine groups.
The primary endpoint occurred in 10.6% of patients in the valsartan arm and in 10.4% of patients in the amlodipine arm (hazard ratio 1.04; 95% CI 0.94–1.15; p=0.49). Rates of all-cause death were not different between the groups (hazard ratio 1.04; 95% CI 0.94–1.14; p=0.45). Of the secondary endpoints, fatal and nonfatal myocardial infarction occurred in more patients on valsartan-based therapy (hazard ratio 1.19; 1.02–1.38; p=0.02), although it should be noted that this was due to lower rates of nonfatal events with amlodipine (hazard ratio 1.22; 95% CI 1.04–1.44; p=0.02) and that the rate of fatal events was not different between the treatment groups (hazard ratio 1.04; 95% CI 0.74–1.47; p=0.81). There were trends towards fewer heart-failure hospitalisations in the valsartan group (hazard ratio 0.89; 95% CI 0.77–1.03; p=0.12) and more strokes (hazard ratio 1.15; 95% CI 0.98–1.35; p=0.08). Notably, new-onset diabetes developed in 690 patients on valsartan- and in 845 patients on amlodipine-based regimens (odds ratio 0.77; 95% CI 0.69–0.86; p<0.0001). This is the first demonstration of the benefits of an ARB in the prevention of diabetes compared with a metabolically neutral antihypertensive agent.
Tolerability was good in both groups. The most common adverse event, oedema (including peripheral oedema), was twice as frequent in amlodipine-treated patients. Hypokalaemia was more frequent in the amlodipine group. Although of low frequency, dizziness, headache and diarrhoea were more frequently reported in patients on valsartan-based regimens. Discontinuation rates from adverse events were significantly lower with valsartan-based treatment (13.4%, versus 14.5% with amlodipine; p=0.045). It should be noted that the rates of adverse events were somewhat higher than those previously reported for these drugs, almost certainly reflecting the influence of the agents added to the primary treatments.
The aim of the VALUE trial was to achieve control of blood pressure by six months. Thus, it was important to assess whether reaching this goal affected outcomes in each of the drug groups. Within each treatment group, hazard ratios for subsequent clinical events in patients with systolic blood pressure <140mmHg at six months were compared with those found in patients whose systolic blood pressure was not controlled.
Control of blood pressure was a powerful determinant for the primary and secondary endpoints (except myocardial infarction), as well as for all-cause death. The differences between the two groups were so minor that the data could be pooled to show the overall role of blood-pressure control in optimising outcomes. These findings provide evidence to validate the target recommendations (140/90mmHg) in European and US hypertension guidelines for this high-risk population.
The early blood pressure differences observed between treatment groups in the VALUE trial made the overall results difficult to interpret. In an attempt to test the hypothesis in a controlled population, the technique of serial median matching was applied to the dataset at six months.(2) Although this is a post-hoc analysis, this method should be considered in plans for new studies, and perhaps even tested in previously reported studies with substantial blood pressure inequalities. The method selected the most median patient (based on systolic blood pressure) within the valsartan group and paired this patient with an individual from the amlodipine group matched for systolic blood pressure (within 2mmHg), age, sex and the presence or absence of previous coronary disease, stroke and diabetes.
The process was repeated until all eligible patients were included. In this way, 5,006 comprehensively matched valsartan/amlodipine cohort pairs (a total of 10,012 patients) were created, with a mean systolic blood pressure of 139.9mmHg in each drug group. The analysis of this patient population, in which patients at the high and low extremes of achieved blood pressure were excluded, showed a nonsignificant trend in favour of valsartan for the combined cardiac endpoint. The rates of fatal and nonfatal myocardial infarction, stroke and mortality were close to identical in both treatment groups. However, admission to hospital for heart failure was significantly (p=0.040) lower with valsartan.
The results of the VALUE trial emphasise the fact that, in hypertensive patients at high risk of cardiac events, achieving blood pressure targets is a highly important determinant of outcomes. Most of these patients should be on combination therapies. If blood pressure is controlled, the VALUE trial indicates that valsartan-based therapy is associated with a reduced risk for hospitalisations due to heart failure, and is otherwise closely similar to amlodipine for other cardiovascular endpoints. Furthermore, regardless of blood pressure, valsartan-based treatment is associated with a significantly reduced number of cases of new-onset diabetes. These data were obtained with a valsartan dose range of 80–160mg, which is less than the 160–320mg currently recommended in the USA.
- Julius S, Kjeldsen SE, Weber MA, Brunner HR, Ekmann S, Hansson L, et al. 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.
- Weber MA, Julius S, Kjeldsen SE, Brunner HR, Ekmann S, Hansson L, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004;363:2047-9.