Angiotensin-converting enzyme inhibitors show an edge over angiotensin II receptor blockers in cardiovascular outcomes

This editorial refers to ‘Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular and non-cardiovascular outcomes in patients at high/very-high cardiovascular risk without heart failure: a systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials’, by S. Masi et al., https://doi.org/10.1093/ehjopen/oeag119

Certainly angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are major inhibitors of the renin–angiotensin–aldosterone system (RAAS) and are mainstays in the primary and secondary prevention of cardiovascular diseases (CVDs), as well as cerebrovascular and chronic kidney diseases. In the area of CVDs, these agents are major players in the treatment of hypertension (HTN), heart failure (HF), and coronary heart disease (CHD), as well as secondary prevention of stroke. Many clinicians, with some support from guidelines, list ACEIs and ARBs in the same class,^1,2 although there are some major differences between them. For the most part, ARBs in recent times have been preferred, as they are perceived as better tolerated. Some experts in the fields of HTN and CVD have questioned prescribing ACEIs,³ based on published meta-analyses of head-to-head ACEI vs. ARB trials that showed no differences in major cardiovascular outcomes—despite a generally greater effect for ACEIs (regardless of when the study was conducted)—and noting that 98% of deaths in the meta-analysis came from a single trial.⁴ On the other hand, no ARB trials have demonstrated reductions in mortality and, in fact, the ARB—olmesartan increased mortality compared with placebo in type 2 diabetes patients.⁵ Also, in a HTN meta-analysis that included 150 000 patients by van Vark et al., ACEIs significantly reduced all-cause mortality by 10%, whereas ARBs did not (hazard ratio 0.99, 95% confidence interval: 0.94–1.04, P = 0.683).⁶ In our meta-analysis of the anti-inflammatory effects of ACEIs and ARBs, ACEIs significantly reduced levels of C-reactive protein, interleukin (IL)-6, and tumour necrosis factor-α, whereas ARBs were associated only with reductions in IL-6.⁷ Since inflammation plays a central role in the pathogenesis of atherosclerosis and of CHD, atherosclerotic cardiovascular disease, and cerebrovascular events, the more pronounced anti-inflammatory effects of ACEIs may help explain their potentially greater impact on major CVD outcomes.^7,8 Moreover, ACEIs differ mechanistically from ARBs by inhibiting the degradation of bradykinin, thereby increasing nitric oxide (NO) and prostacyclin bioavailability, improving endothelial function, and exerting anti-inflammatory and anti-atherosclerotic effects beyond blood pressure (BP) reduction alone.⁶

In this issue of European Heart Journal Open, Masi et al.⁹ performed a major parallel meta-analysis of randomized controlled trials (RCTs) comparing ACEIs or ARBs vs. placebo, and they only included RCTs that reported all-cause mortality with a prespecified duration of over 1 year, and over 100 patients in each arm and 1000 patient years of follow-up with the outcomes of interest at least occurring in over 10 participants in each arm. Importantly, HF trials were excluded. A total of 17 trials (9 trials of ACEIs and 8 of ARBs with a total of nearly 88 000 patients) was included. Compared with placebo, ACEIs reduced the rate of CVD mortality, all-cause mortality, and myocardial infarction (MI) by 12%, 8%, and 17% respectively and all statistically significant, whereas ARBs did not. On the other hand, the rates of HF, stroke, and major CVD events were significantly reduced by both classes. Importantly, compared with ARBs, ACEIs significantly reduced the rate of CVD mortality (P = 0.03). Notably, event rates in the placebo groups were comparable between the ACEI and ARB trial programmes, strengthening the validity of the indirect comparison and reducing concerns that differences were driven by underlying baseline risk (Figure 1).

Figure 1.

Summary of the main results of a meta-analysis on the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on cardiovascular and non-cardiovascular outcomes in patients at high or very-high cardiovascular risk without heart failure.

Many clinicians worldwide preferentially prescribe ARBs over ACEIs, largely because of the perception that all RAAS inhibitors confer similar CVD benefits and that ARBs are better tolerated, particularly with respect to cough and, potentially, angioedema. However, the comprehensive analysis by Masi et al.⁹ challenges this assumption, demonstrating that ACEIs, compared with placebo, significantly reduced CVD mortality, all-cause mortality, and MI, whereas comparable benefits were not observed with ARBs. These findings suggest that ACEIs and ARBs in patients without left ventricular impairment may not be interchangeable with respect to CVD outcomes and support consideration of ACEIs as the preferred RAAS inhibitor when tolerated. In fact, ACEIs compared with ARBs significantly reduced CVD mortality with borderline statistical significance for better reduction in all-cause mortality. Although both ACEIs and ARBs reduced HF and stroke, only the ACEIs reduced mortality in a broad range of patients with multiple co-morbidities, whereas ARBs did not have these effects. It is also very important to recognize that the lack of mortality reduction with the ARBs occurred despite starting with higher BP levels and having greater BP reductions than did the ACEIs. Importantly, this was not just a HTN study, as HTN was not even an entry criterion but rather based on follow-up of > than 1 year and a prespecified number of CVD events to define high/very high risk in each of the arms of the trials. Additionally, the methodology of Masi et al.⁹ was particularly robust and included a ‘leave one trial out’ analysis to make sure that one trial did not drive the final results.

Despite this body of evidence favouring ACEIs, real-world prescribing patterns have continued to drift towards ARBs over recent decades, driven by tolerability concerns and guidelines that have largely treated the two classes as interchangeable. As of 2019, ARBs accounted for 17% of antihypertensives dispensed in the United States, with their use as initial agents in the treatment of incident HTN increasing significantly over the last decade.¹⁰ This shift has occurred despite the absence of any ARB trial demonstrating mortality benefit. Notably, real-world comparative studies have concluded that ARBs demonstrate no statistically significant difference in effectiveness compared with ACEIs at the class level,¹¹ yet they carry a significantly better safety profile, a finding that has led some to recommend preferentially starting ARBs rather than ACEIs when initiating HTN treatment. While tolerability is a legitimate clinical consideration, it should not override a mortality signal of the magnitude observed with ACEIs, particularly given that ACEI-induced cough is manageable in the majority of patients and that angioedema, though serious, remains uncommon.

In conclusion, these intriguing results from the large meta-analysis by Masi et al.⁹ contribute significantly to the ongoing, long-standing debate about drug choice for selected patient groups and to HTN therapy personalization. They also suggest that, despite potentially greater adverse effects, the overall clinical benefits of ACEIs on major CVD outcomes—including CVD and all-cause mortality—may outweigh those of ARBs, implying that high-risk patients (e.g. for CHD/MI and CVD or all-cause mortality) might benefit more from initial treatment with ACEIs, with ARBs reserved for those who cannot tolerate ACEIs. Although further RCTs would be ideal, these are not likely coming with older drugs such as ACEIs and ARBs, which have been off-patent for years. Finally, one could question whether these results should impact the guidelines and clinical practice? While guideline updates are usually driven by large, high-quality RCTs rather than by meta-analyses, the present evidence may remain our most robust resource for some time. It may therefore be worth considering preferentially recommending ACEIs over ARBs in most high-risk patients for both primary and secondary CVD prevention, except in HF, where the two drug classes appear comparable.

Author contributions

Carl J. Lavie (Supervision, Writing—original draft [lead], Writing—review & editing [supporting]) and Maciej Banach (Writing—original draft [supporting], Writing—review & editing [lead]).