Franz H. Messerli, MD; Chirag Bavishi, MD, MPH; Sripal Bangalore, MD, MHA
Abstract and Introduction
Introduction
The human understanding when it has once adopted an opinion (either as being the received opinion or as being agreeable to itself) draws all things else to support and agree with it.
—Sir Francis Bacon, 1620
Prospective randomized controlled trials remain the gold standard in medicine because, when well performed, they provide us with knowledge untainted by bias. However, their outcome can be unpredictable. The VALUE trial (Valsartan Antihypertensive Long-Term Use Evaluation) comprising 15 245 patients unexpectedly fell short, documenting that the incidence of myocardial infarction (MI) was 19% more common in the valsartan arm than in the amlodipine arm. This happened at a time when, on the basis of the results of the HOPE trial (Heart Outcomes Prevention Evaluation), the cardioprotective benefit of angiotensin-converting enzyme (ACE) inhibitors was firmly established in the minds of clinicians. The failure of valsartan in reducing MIs compared with amlodipine in VALUE was blamed on the angiotensin receptor blockers (ARBs) as a class and led to the concept of an MI paradox associated with ARBs—despite lowering blood pressure, these drugs did not reduce or perhaps even increased the risk of MI.
Efficacy
Unlike with ACE inhibitors, solid data on ARBs in 2004 were few and far between. However, subsequent randomized trials cast doubt on this MI paradox of the ARB class. In a comprehensive meta-analysis with 106 randomized trials that enrolled 254 301 patients,] we concluded that evidence from placebo-controlled, active-controlled, and head-to-head randomized trials suggested that ARBs are as efficacious and safe as ACE inhibitors but have fewer adverse effects and a lower risk of angioedema.
The recent comprehensive data set from Chen et al corroborates and extends these findings. Across 8 databases, the authors identified 229 7881 patients initiating treatment with ACE inhibitors and 673 938 patients with ARBs. They documented no significant differences in the primary outcomes of acute MI (hazard ratio, 1.11 for ACE versus ARB [95% CI, 0.95–1.32]). Likewise, the hazard ratios for heart failure, stroke, or composite cardiovascular events were not different between the 2 drug classes. Chen et al] concluded, “ARBs do not differ statistically significantly in effectiveness at the class level compared with ACE inhibitors as first-line treatment for hypertension but present a better safety profile.” It is not surprising that the effect estimates in the 2 large independent studies are strikingly similar (Figure). Simply put, ARBs reduce cardiovascular events, including the risk of MI, as effectively as, but do so more safely than, ACE inhibitors.
Compared with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers showed similar efficacy in terms of CV mortality, MI, stroke, and ESKD. CV indicates cardiovascular; ESKD, end-stage kidney disease; and MI, myocardial infarction. Data from Bangalore et al1 and Chen et al.2
It is conceivable that the so-called MI paradox was based on indirect comparisons only and merely reflected the so-called generation gap between the 2 sets of studies. Because ACE inhibitor trials were run about a decade earlier, concomitant statin therapy was decidedly less common and patients in the placebo arm were at a substantially higher risk than in the later ARB trials. Eight head-to-head trials randomly assigned 22 542 patients who were followed for a mean of 3.4 years. ARBs had a similar risk for all outcomes, including all-cause mortality, cardiovascular death, and MI, except for drug withdrawal attributable to adverse effects, in which case, ARBs were associated with a 28% lower risk.
Safety
The authors also studied 51 secondary and safety outcomes including angioedema, cough, syncope, and electrolyte abnormalities. Patients on ACE inhibitors had significantly higher risks of angioedema, cough, pancreatitis, and gastrointestinal bleeding than patients on ARBs. Angioedema associated with ACE inhibitors was >3 times as common (hazard ratio, 3.31 [95% CI, 2.55–4.51]; P<0.01) as with ARBs, although the absolute risk is low. In a meta-analysis of 74 857 patients on ACE inhibitors, 394 developed angioedema during a mean duration of 129 weeks with a weighted incidence of 0.30% (95% CI, 0.28–0.32). It is particularly prevalent among patients of African American origin and occasionally can be fatal. Although deaths are rare, millions of patients worldwide continue to be exposed to ACE inhibitors, which might account for numerous fatalities every year.[4 Potentially fatal adverse effects notwithstanding, ACE inhibitors continue to be far more commonly prescribed in the treatment of hypertension than ARBs, with lisinopril still being the most used antihypertensive drug worldwide.
A dry cough remains a nuisance adverse event with ACE inhibitors. It is more common in women than men and particularly prevalent in Chinese patients.[5 Severe nonproductive ACE inhibitor cough may give rise to stress incontinence in postmenopausal women.
Heart Failure
With ACE inhibitors, the incidence of both cough and angioedema was found to be higher in systolic heart failure trials compared with hypertension or coronary artery disease trials. However, in patients with systolic heart failure, cough can be multifactorial (pulmonary edema or heart failure exacerbation). There also is a higher threshold to withdraw ACE inhibitors given their well-documented morbidity and mortality benefits in this patient subset. Hence, in the setting of systolic heart failure, the risk: benefit ratio of ACE inhibitor use is different from that of hypertension.
Guidelines
The most recent hypertension guidelines recognize that the efficacy of ACE inhibitors and ARBs is comparable, but adverse events are not. We are baffled that the difference in safety is not deemed important enough to give ARBs a preferred status. However, safety has become of paramount importance in view of the ever-increasing number of patients requiring therapy.
Clinical use
The reason that many continue prescribing ACE inhibitors in hypertension may well be that, years ago, our attending taught us that this drug class exerted unique cardioprotective properties. There is no question that this drug class has been shown to have more cardiovascular benefit than harm in placebo-controlled trials.
However, today’s attending will teach us that efficacy and outcomes are similar for ACE inhibitors and ARBs, but adverse events are not. For practicing clinicians, this means that there is no longer any good reason to subject patients to the adverse effects of ACE inhibitors. ACE inhibitors may rapidly become a drug class of historical interest only.
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