Valuable lessons from VALUE

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial, which was started in 1997 by including the first patient by September 10 and closed-out by December 5, 2003, is one of the major outcome trials investigating angiotensin II type 1 receptor antagonism in hypertension [1–3]. The study compared treatment with valsartan with that of the calcium antagonist amlodipine, and the Executive Committee has now published the main outcome data from the 15313 randomized patients from 31 countries as well as their interpretations of the results [4, 5]. The main hypothesis in VALUE was that there would be a 12.5% incidence of cardiac morbidity and mortality in the amlodipine group and a 10.6% incidence in the valsartan group, i.e. a reduction by 15%, during the course of the follow-up of the hypertensive cohort with increased risks [4]. The study was event driven and the initial anticipation was that at least 1450 valid endpoints should occur in the cohort. At study closure, the primary composite cardiac mortality and morbidity endpoint had occurred in 1599 patients [4]. Secondary endpoints in VALUE were cardiac morbidity, cardiac mortality, total mortality, stroke morbidity or mortality, fatal and nonfatal myocardial infarction, fatal or worsening of heart failure, or new-onset diabetes mellitus [4]. The final results of VALUE showed that the primary composite cardiac outcome (RR 1.04; 95% CI 0.94–1.15, p = 0.49 valsartan vs amlodipine), did not differ between the treatment groups [4]. Thus, VALUE demonstrated no difference in its primary endpoint (i.e. time to first cardiac event), and was not able to demonstrate superiority of valsartan compared to amlodipine. As for pre-specified secondary outcomes, there were 19% more myocardial infarctions overall, more strokes in the valsartan group initially but not overall at study end [4] and a trend for less heart failure on valsartan. Interestingly, new-onset diabetes was reduced by 33% in the valsartan group [4]. What is clear from the published results of VALUE is that inferior blood pressure control was achieved in the valsartan group as compared with its comparator. This was achieved in spite of the ambition to reach below the 140/90 mmHg target by either valsartan (80–160 mg) or amlodipine (5 or 10 mg), which could be combined with HCTZ as well as other allowed drug combinations [1–4]. During the course of the trial, gradually larger proportions of the treated patient cohort achieved blood pressure targets, and after 30 months of treatment, 62% of all patients had reached the systolic target of 140 mmHg and 90% of patients had reached the diastolic target of below 90 mmHg [2, 3]. However, in the final analysis, it became clear that in patients randomized to starting treatment with amlodipine, there was a more rapid initial fall as well as more extensive reduction in systolic as well as diastolic blood pressures. Although this was not reflected in differences in the primary composite cardiac endpoint at study end, the discrepancy in blood pressure reduction between treatments was reflected in subcomponents of the primary endpoint, i.e. there were more myocardial infarctions overall. Furthermore, the blood pressure difference also influenced the most important of the secondary outcomes of the study in terms of more strokes initially but not overall at study end [4]. Despite lower blood pressures on amlodipine, valsartan prevented new-onset diabetes better and tended to prevent development of heart failure. So, what important messages can we extract from VALUE? Firstly, the trial failed to show its primary goal, i.e. a superiority of valsartan in lowering the composite cardiac endpoint in relation to its comparator amlodipine. On the contrary, the inferior initial blood pressure control by valsartan was reflected by more myocardial infarctions as well as strokes. From the results of the angiotensin II type 1 receptor cardiovascular outcome trials in hypertensives performed so far, we know from the LIFE study [6] that losartan lowers stroke morbidity and mortality compared with atenolol, and from the SCOPE trial that candesartan lowers the incidence of non-fatal strokes [7]. Certainly, so far, a mixed result for the group. As regards the calcium antagonist as comparator in VALUE, the amlodipine benefit on myocardial infarction was partially related to more effective lowering of blood pressure. It may also be speculated whether anti-ischaemic and antiangina properties may have played a role, particularly in light of no difference in fatal myocardial infarction. The trend in favour of valsartan over amlodipine regarding heart failure, and the benefit in preventing new-onset diabetes adds to previous data with inhibitors of RAS. What will be the immediate aftermath of VALUE? Certainly a discussion on which are optimal doses for valsartan in the treatment of hypertension, as well as a debate on whether or not there are true differences between the agents within the group of angiotensin II type 1 receptor blockers, or whether differences between agents in outcome trials so far merely reflect the design of the studies as well as the way they were in fact carried out.