Are ACE Inhibitors Interchangeable?

SEPTEMBER 19, 2016
Angiotensin-converting enzyme inhibitors (ACEIs) are widely used in clinical practice, from hypertension, to chronic kidney disease, to heart failure (HF). Currently, 10 ACEIs are approved in the United States, but a lack of evidence on the best choice may leave prescribers scratching their heads. 
Cost and experience with a particular ACEI may form the basis of selection, but this situation raises the question: are all drugs in the class clinically interchangeable? That is, are they equally effective?

The Evidence
One 2009 meta-analysis included 30 studies that measured at least one outcome (myocardial infarction [MI], stroke, cardiovascular [CV] events, mortality due to CV events, and all-cause mortality) and had a duration of at least 6 months. Primary outcomes were significantly reduced in trials with composite endpoints. A total of 18 trials examined fatal and/or non-fatal MI, with ACEIs significantly reducing these events. 
As a class, ACEI reduced the rate of stroke. However, a theme emerged showing trials involving perindopril seemed to drive the magnitude of ACEI benefit. For example, all-cause mortality was significantly reduced in 6 trials using perindopril, but the effect was less pronounced in trials using a different ACEI. Similarly, excluding perindopril from ACEI trials assessing stroke reduction resulted in a nonsignificant reduction in stroke rates.1

These results are by no means definitive, and caution should be used when interpreting them. Varying doses of ACEIs were used, and the meta-analysis didn’t account for other cardiovascular medications being used concomitantly. In addition, the studies included didn’t have a standardized primary outcome and, perhaps of most significance, had varying baseline demographics.1 
To illustrate the impact of baseline characteristics on study results, consider the HOPE and PEACE trials. The HOPE trial, which showed that ramipril prevented adverse cardiac events in patients with normal ejection fractions (EF), stood in contrast to the PEACE trial, where the use of trandolapril showed no benefit. The differences in baseline characteristics, where PEACE had more patients optimally treated with statins and aspirin than HOPE, is commonly cited as the reason for the difference in outcomes.

The aforementioned meta-analysis didn’t investigate the use of ACEIs in HF;1 this class is recommended to reduce mortality in patients with HF with reduced EF, but no guidance is given on which ACEIs are most effective.
Another 2016 meta-analysis included 29 trials involving patients who were predominately male and of varying ages. The sample size varied from 16 to 287, and follow-up ranged from 8 days to 12 months. Studies that included 5 ACEIs (captopril, enalapril, lisinopril, ramipril, and trandolapril) were used in the analysis.2

The results showed all-cause mortality was higher in patients taking lisinopril than placebo, while no differences were seen among captopril, enalapril, and ramipril. No differences were found among captopril, enalapril, and lisinopril when assessing their impact on stroke volume or EF.2
Secondary outcomes, including blood pressure (BP), cough, deterioration of renal function, and gastrointestinal (GI) discomfort, were also evaluated. Enalapril significantly reduced BP compared with placebo, but both enalapril and captopril were associated with a higher incidence of cough compared with placebo. Captopril was associated with a lower incidence of renal impairment than enalapril, and no differences were seen among the drugs included (captopril, enalapril, and lisinopril) when assessing GI discomfort.2
The authors concluded that enalapril was the most effective ACEI when taking increased EF, stroke volume, and BP into account, and lisinopril was deemed the poorest choice due to an increase in all-cause mortality and limited effects on BP.2

This meta-analysis has several limitations, including small sample size, short duration of follow-up, and limited studies, with only 1 trial including ramipril. Hospitalization and cardiac death, commonly used endpoints in assessing HF therapy, weren’t included. The results aren’t conclusive, and further studies and analyses must be performed.

Bottom Line
Insufficient evidence is available to definitively say one ACEI is superior to another and should be used preferentially, even with new meta-analyses emerging. The assumption that all drugs in one class are interchangeable is difficult to refute or support, but the lack of evidence on both sides shouldn’t form the basis for drug selection. 
Me-too drugs that have shown to be beneficial in large, randomized, controlled trials should be used over drugs that haven’t. Substituting an unproven drug for an evidence-based therapy may lead to increased adverse effects and decreased benefit.3
1. Snyman JR, Wessels F. Perindopril: do randomised, controlled trials support an ACE inhibitor class effect? A meta-analysis of clinical trials. Cardiovasc J Afr 2009;20(2):127-134.
2. Sun W, et al. Comparison of the efficacy and safety of different ACE inhibitors in patients with chronic heart failure. Medicine (Baltimore) 2016;95(6).
3. Furberg CD, Pitt B. Are all angiotensin-converting enzyme inhibitors interchangeable? J Am Coll Cardiol 2001;37(5):1456-1460.

Thomas Szymanski, PharmD
Thomas Szymanski, PharmD
Thomas Szymanski is PGY1 resident at Memorial Hermann-Texas Medical Center in Houston, TX. He earned his PharmD and a BA in French from the University of Rhode Island. His professional interests include cardiology and critical care. Thomas is an active member of ASHP and ACCP and has served on various national committees and advisory groups.
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