Angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers in the treatment of hypertension: Adding more fuel for the fire?

‘In seeking absolute truth we aim at the unattainable, and must be content with broken portions’ (Sir William Osler; 1849–1919) The renin–angiotensin axis plays a determinant role in the pathophysiology of several cardiovascular diseases, including in hypertension. Its inhibition – by angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs) or renin inhibitors – has been undoubtedly one of the greatest advances in cardiovascular medicine. Nevertheless, the discussion on which of these therapies should be preferred in arterial hypertension is much more controversial. Unfortunately, this discussion has been too often based on faith, dogmas and beliefs, and not always on scientific evidence. It is also a story of scientific doubts and article retractions due to studies’ misconduct.4 Therefore, over the years, this controversy has served to confuse rather than to clarify the topic. The history of cardiovascular medicine has taught us, several times, the importance of looking beyond the effects on surrogate endpoints.5 For example, in the field of hypertension, previous studies have shown that the reduction in brachial blood pressure does not necessarily translate into a proportional reduction in cardiovascular events.6 We have come to an era when, beyond blood pressure reduction, it is important to demonstrate a significant reduction in major cardiovascular outcomes and mortality. In this issue, Salvador et al.7 report the results of a new meta-analysis evaluating the effects of ACEis and ARBs on cardiovascular outcomes, in comparison with a control. In brief, they show that both classes of drugs have similar benefits on the reduction of acute myocardial infarction, stroke and heart failure hospitalization, but only ACEis significantly reduced cardiovascular death and total mortality. Does this data add more fuel to the fire, or are these results consistent with currently available evidence? Meta-analyses are usually considered to provide the best level of scientific evidence. Nevertheless, it is also true that meta-analysis results should be interpreted with care because they can be highly influenced by the methodology used. In general, this was a rigorously conducted meta-analysis that included 17 clinical trials of hypertension, with more than 70,000 individuals. However, the authors observed that the included trials had a wide variation in population samples, definition of hypertension, doses of the drugs, time of follow-up and baseline anti-hypertensive therapy. In spite of these limitations, the benefits of ACEis on cardiovascular events and mortality were robust, with low heterogeneity in the meta-analysis results. It must be emphasized that this meta-analysis is not a head-to-head comparison between these two classes. More importantly, the different clinical trials used different comparator drug regimens in the control group, which can potentially influence the final results. Furthermore, because most of the ACEi studies were conducted in the beginning of the century, whereas studies testing the effects of ARBs were done more recently, this can introduce another bias because cardiovascular background therapies can vary over time. Finally, this meta-analysis used data obtained at the global trial level, rather than individual patient information. Independently of these inherent limitations, these results were consistent with several previous meta-analyses that also demonstrated an added cardiovascular protection with ACEis.8–10 This has been also demonstrated in other analyses of patients with heart failure or coronary artery disease populations (with or without hypertension). Unfortunately, there are only two head-to-head clinical trials directly comparing these two classes of drugs. The ONTARGET trial11 (telmisartan versus ramipril) included high risk hypertensive patients and did not show significant differences in the primary cardiovascular endpoint. There was a trend for better stroke prevention with telmisartan, and better prevention of coronary artery disease with ramipril. The DETAIL12 was a small trial comparing the renoprotective effect of telmisartan versus enalapril in patients with diabetic nephropathy and did not find significant differences between the two. Both trials were underpowered to detect small reductions in cardiovascular or total mortality between the two classes. What can explain an added value of ACEis versus ARBs? Although both classes inhibit the renin–angiotensin system, they exert this effect by different mechanisms of action. The added cardiovascular protection of ACEis is usually attributed to the simultaneous inhibition of bradykinin degradation, a molecule that has several benefits in the cardiovascular system, including nitric oxide and prostaglandins release, endothelial function improvement and vasodilation.13 Those that prefer ARBs argue that the selective blockage of the AT1 receptor can offer a more complete inhibition of the renin–angiotensin system (less ‘escape phenomenon’) and better tolerability (cough). In summary, as doctors and scientists, we always pursue an ‘absolute truth’ and ability to give definite answers. However, as stated by Sir William Osler, absolute truths are ‘unattainable’ in Medicine. Regarding this unresolved question, we will never have a clinical trial with sufficient statistical power to detect a small difference in cardiovascular events between ACEis and ARBs. Until then, we ‘must be content with broken portions’ of evidence, with all their inherent limitations. The results of this meta-analysis provide another valuable broken portion in search of this truth. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.