Key points are not available for this paper at this time.
The recent publication of the Heart failure Endpoint evaluation of Angiotensin II Antagonists Losartan trial (HEAAL) brings to end an era of randomized controlled trials conducted to evaluate the place of angiotensin receptor blockers (ARBs) in the treatment of patients with heart failure. Seven such trials were published in the last decade, with studies using losartan beginning and ending the story of ARBs in heart failure (Table 1).1–7 With the benefit of hindsight, what can we learn from these trials? The ARB trials were innovative in many ways. The use of disease-specific composite mortality–morbidity endpoints instead of all-cause mortality was largely pioneered in these trials.2–7 Similarly, in order to achieve sufficient power in an affordable sample size, the investigators recognized the need to augment risk by enriching certain characteristics of randomized patients (e.g. prior hospital admission for heart failure or a cardiovascular reason).4 The first large-scale attempts to improve outcomes in patients with symptomatic heart failure, but a preserved ejection fraction were also conducted with ARBs.5,6 The ARB trials were also the first to deal with the issue of comparing and combining two drugs acting through the same pathophysiological pathway.2,4 Comparison of an ARB with an ACE-inhibitor raised questions about ethics, statistics, and dosing. Was it ethical to withhold a treatment proven to reduce mortality (i.e. an ACE-inhibitor) in order to test a new treatment? The surprising and, as it turned out misleading, results of the first Evaluation of Losartan In The Elderly (ELITE) study made this question easier to answer than it might have been.8 ELITE-2 was the first ‘comparative effectiveness’ trial in heart failure and ground-breaking in the sense that a new treatment was being considered as an alternative as opposed to an ‘add-on’ therapy, which had been the norm to that point.1 Although the second ELITE trial was designed to test for superiority of losartan over captopril, when it completed (and failed to show superiority) it raised for the first time in trials in heart failure the complex statistical question of non-inferiority.9 Most of all perhaps, ELITE-2 (and a related neutral trial in myocardial infarction10) along with subsequent successful trials in diabetic nephropathy11 and hypertension,12 raised the question of dose of ARB and the suggestion that 50 mg losartan once daily was suboptimal (and not as effective as captopril 50 mg thrice daily). Indeed in an imputed placebo analysis, losartan 50 mg daily could not be shown to be superior to placebo.9 Hence the brave decision to conduct HEAAL and the clear demonstration that a bigger dose of losartan was better (Table 1).7 In this respect, the findings of HEAAL mirror those of the Assessment of Treatment with Lisinopril and Survival trial (ATLAS).13 Post hoc examination of the same composite outcome used as the primary endpoint in HEAAL (all-cause mortality or hospitalization for heart failure) in ATLAS showed that higher-dose lisinopril (32.5–35 mg daily) was more effective than lower-dose lisinopril (2.5–5.0 mg daily): hazard ratio 0.85 (95% CI 0.78–0.93), P < 0.001.13 This is an important lesson for clinical practice as well as treatment dosing in future trials. Although innovative in so many ways, unfortunately the ELITE trials did not advance clinical practice. Physicians were left uncertain as to the value of ARBs in heart failure. A year later, however, the Valsartan Heart Failure trial (Val-HeFT) reported.2 Val-HeFT was quite different in design than ELITE-2, testing the strategy of adding an ARB to conventional therapy, including an ACE-inhibitor. The premise behind this strategy was that angiotensin II could be generated through non-ACE enzymatic pathways (e.g. chymase) and that to fully block the renin–angiotensin system (while maintaining the putative benefits of inhibiting bradykinin breakdown) both an ACE-inhibitor and ARB were needed. Notably, in Val-HeFT, ACE-inhibitor treatment was not required and investigators were free to use any ACE-inhibitor and whatever dose they considered appropriate. So used, valsartan did not reduce mortality but did reduce the co-primary composite mortality–morbidity outcome (Table 1). Subsequently, the interpretation of results of Val-HeFT became mired in controversies related, essentially, to subgroup analyses. Initially, there was concern about a negative interaction between ARBs and beta-blockers (whereby risk was increased when an ARB was given to patients taking a beta-blocker), although this was dispelled by later ARB trials.3,4,7 A second analysis suggested that most if not all of the benefit of valsartan was confined to the minority of patients not taking an ACE-inhibitor at study entry.14 The publication of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) trials clarified some of these issues.3–5 The CHARM-Alternative study compared candesartan to placebo in patients intolerant of an ACE-inhibitor, showing a reduction in the risk of the primary composite outcome of cardiovascular mortality or heart failure hospitalization with active therapy (Table 1).3 In CHARM-Added the effect of candesartan was compared with placebo with both drugs added to conventional therapy, including, in all patients, an ACE-inhibitor.4 Treatment with candesartan resulted in a reduction in the primary endpoint (Table 1) and in the all-cause mortality or hospitalization for heart failure composite used in HEAAL (and reported above for ATLAS): hazard ratio 0.87 (95% CI 0.78–0.98), P = 0.021. Understandably, regulatory review of both Val-HeFT and CHARM-Added focused on background dose of ACE-inhibitor. Inevitably, the question of whether the benefit of an ARB would still have been apparent if added to a ‘full-dose’ of an ACE-inhibitor was asked (and even what a ‘full dose’ of ACE-inhibitor is).15 This question reflected the new scientific and regulatory challenge of how to evaluate the addition of two drugs acting on the same pathway in heart failure (although the same issue had been faced elsewhere, e.g. in relation to the use of dual anti-platelet therapy). The United States Food and Drug Administration requested an analysis of the effect of candesartan in CHARM-Added according to background dose of ACE-inhibitor which showed that the benefit of candesartan was similar in patients taking and not taking an ‘evidenced-based’ dose of ACE-inhibitor.15 On reflection, however, a better design for such studies is to test the new therapy on top of a proven dose of a proven gold standard therapy. Subsequent trials in patients with ARBs in acute myocardial infarction (VALIANT)16 and in those with chronic atherosclerotic disease, diabetes, and other risk factors (ONTARGET)17 used such a design. Indeed, the lack of benefit of adding an ARB to a proven dose of a proven ACE-inhibitor in these latter two trials has, for some, cast doubt upon the results of CHARM-Added and Val-HeFT. However, we believe that it is also plausible that patients with heart failure represent a distinct population in which renin–angiotensin system activation is more marked and non-ACE angiotensin II generating pathways more activated. In support of this is the additional observation that, when added to full dose enalapril in the RESOLVD pilot study,18 candesartan improved ejection fraction and reduced neurohumoral activity, two surrogates closely related to clinical outcomes in heart failure. A final observation from the ARB low ejection fraction heart failure trials, unrelated to randomized therapy, is that event rates in such studies have declined steeply over the decade in question, possibly related to improved background therapy, particularly with beta-blockers (Table Table 2). In addition (and assuming a similar adjudication process), the proportion of deaths that are cardiovascular seems to have declined (about 80–70%). This observation is consistent with recent findings in other cardiovascular studies where most patients receive a cocktail of effective background therapies (e.g. the Treatment to New Targets trial where there were more non-coronary than coronary deaths19) and emphasises the importance of using disease-specific endpoints.20 Of course, the other unique aspect of the ARB heart failure trials was the inclusion of patients with heart failure with preserved ejection fraction (HF-PEF). Although there was a strong trend to a reduction in the primary outcome in CHARM-Preserved, there was no effect whatsoever of ARB treatment in I-Preserve.6 Whether this ‘difference’, if real, reflects the drug (or dose of drug) used, patients enrolled or endpoint is uncertain. CHARM-Preserved5 did, however include patients with ejection fractions in the range 40–50% who could be considered as having mild systolic dysfunction and post hoc analysis suggests that it was in these patients that the apparent benefit of candesartan was found. Both trials, however, emphasised the difficulty in recruiting and retaining such patients and how mortality (more non-cardiovascular death) and morbidity (lower rates of heart failure hospitalization) differ from patients with low ejection fraction heart failure.21 In summary, the ARB heart failure trials informed both clinical practice and clinical trial design and conduct. They showed that, used in the right dose, ARBs are an effective alternative to ACE-inhibitors in patients with an intolerable cough (but cause as much hyperkalaemia and renal dysfunction as ACE-inhibitors). Losartan is not one of the ARB recommended for patients with heart failure in the current European Society of Cardiology (ESC) guidelines, although these pre-dated the results of HEAAL and are due to be updated this year (2010).22 Certainly, it is clear from HEAAL that should losartan be used to treat a patient with heart failure the target dose should be 150 mg (and it was notable that this dose caused very little additional serious hyperkalaemia, renal dysfunction, or hypotension compared with a dose of 50 mg daily).7 Two of the ARB trials also showed benefit from adding an ARB in patients remaining symptomatic despite an ACE-inhibitor and this therapeutic approach is recommended in the current ESC and other international guidelines.22 Finally, the lessons learnt from the ARB trials have helped (and will help) the design of future trials, particularly those using other renin–angiotensin aldosterone system blockers (such as aliskiren23) and those conducted in HF-PEF (e.g. TOPCAT) (http://clinicaltrials.gov/ct2/show/NCT00094302). Conflict of interest: Both authors or their institutions have received research support, consulting and/or lecture fees from the manufacturers of a number of different renin–angiotensin–aldosterone system blockers (and other cardiovascular drugs).
McMurray et al. (Mon,) studied this question.