Physicians' Academy for Cardiovascular Education

An end to the common dilemma to treat with ACE inhibitors or ARBs to lower CV risk?

Literature - Bangalore S et al., Mayo Clin Proc. 2016

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers in Patients Without Heart Failure? Insights From 254,301 Patients From Randomized Trials

Bangalore S, Fakheri R, Toklu B, et al
Mayo Clin Proc. 2016;91(1):51-60


Patients with cardiovascular disease (CVD) or individuals with CV risk factors are often treated with angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs). The efficacy outcomes of head-to-head randomised trials of ACEis vs ARBs were equivalent between the two drug classes [1]. While randomised trials of ACEis showed a mortality benefit compared with placebo, this was not the case with ARBs [2-5]. These findings were consequently endorsed by guideline committees [6,7]. However, ACEis trials were conducted a decade earlier, and the risk profile of the placebo groups for comparison in the two sets of trials were different [8].
The objective of the present study was to assess the effectiveness of ACEis compared to ARBs in patients without heart failure.
A meta-analysis was performed on randomised trials conducted from January 1, 1980, through April 13, 2015. The meta-analysis included 106 trials that enrolled 254,301 patients followed for a mean of 3.2±1.7 years and a total of 805,076 patient-years of follow-up. Out of 106 trials
  • 58 included 126,025 patients randomised to an ACEi vs. placebo or active control
  • 42 included 105,734 patients randomised to an ARB vs. placebo or active control
  • 8 included 22,542 patients randomised to an ACEi vs. an ARB.

Main results

ACEis/ARBs vs Placebo

• Compared with placebo, ACEis but not ARBs reduced the outcomes of
  • all-cause mortality (ACEis vs placebo: relative risk [RR]: 0.89, 95%CI: 0.80-1.00; ARBs vs placebo: RR: 1.01, 95%CI: 0.96-1.06; Pinteraction=0.04)
  • CV death (RR: 0.83, 95%CI: 0.70-0.99 and RR: 1.02, 95%CI: 0.92-1.14; Pinteraction=0.05)
  • MI (RR: 0.83; 95%CI: 0.78-0.90 and RR: 0.93; 95%CI: 0.85-1.03; Pinteraction=0.06).
• An increase in drug withdrawal due to adverse effects was observed with ACEis (RR: 1.24; 95%CI: 1.19-1.29).
• The meta-regression analysis showed that the difference between ACEis and ARBs compared with placebo for the outcomes of all-cause mortality (P=0.001), CV death (P<0.001), and MI (P=0.02), could be attributed to a higher placebo event rate in the ACEis trials (most conducted a decade earlier)
• Sensitivity analyses restricted to trials published after 2000 showed similar outcomes with ACEis vs placebo and ARBs vs placebo (Pinteraction>0.05).

ACEis/ARBs vs Active Controls

• Compared with active controls, ACEis reduced the risk of
  • MI (RR: 0.88, 95%CI: 0.80-0.96)
  • new-onset diabetes (RR: 0.78, 95%CI: 0.72-0.84)
  • doubling of serum creatinine (RR: 0.56, 95%CI: 0.36-0.89)
• Compared with active controls, ARBs reduced the risk of
  • heart failure (RR: 0.84, 95%CI: 0.76-0.93)
  • new-onset diabetes (RR: 0.78, 95%CI: 0.72-0.85)
  • ESRD (RR: 0.74, 95%CI: 0.59-0.93)
  • doubling of serum creatinine (RR: 0.62, 95%CI: 0.49-0.78)
  • drug withdrawal due to adverse effects (RR: 0.82, 95%CI: 0.76-0.88)
• The test for interaction was significant for the outcomes of
  • MI (Pinteraction=0.01) (benefit of ACEis vs controls but not of ARBs vs controls)
  • stroke (Pinteraction=0.04) (increased risk with ACEis vs controls but not with ARBs vs controls)
  • drug withdrawal due to adverse effects (Pinteraction=0.01) (decreased risk with ARBs vs controls but not with ACEis vs controls).

ARBs vs ACEis

Head-to-head comparison trials of ARBs vs ACEis exhibited no difference in outcomes except for a lower risk of drug withdrawal due to adverse effects with ARBs (RR: 0.72, 95%CI: 0.65-0.81).


A meta-analysis of 106 trials using data from more than 800,000 patient-years of follow up shows that in patients without heart failure, ARBs are as efficacious and safe as ACEis, with the added advantage of better tolerability.
According to a sensitivity analysis restricted to trials after 2000, the lack of benefit of ARBs vs placebo compared with ACEis vs placebo for the outcomes of all-cause mortality, CV death and MI could be attributed to a higher event rate in the placebo arms in the ARB trials. 
Find this article online at Mayo Clinic Proceedings


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