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? One 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.
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. These results are by no means definitive, and caution should be used when interpreting them.
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.
Overall, patients receiving ramipril were younger and more likely to have NYHA functional Class I or II symptoms than those on enalapril and lisinopril. In patients using lisinopril, systolic blood pressure was significantly higher when compared with patients on enalapril or ramipril. Table 1 Baseline characteristics of chronic heart failure patients with respect to angiotensin-converting enzyme inhibitor treatment.
Dose equivalent represent percentage achieved of the individual drug with respect to the guideline recommended target dose. Baseline characteristics of chronic heart failure patients with respect to angiotensin-converting enzyme inhibitor treatment. During that time In univariable analysis of the overall cohort, patients prescribed enalapril and lisinopril both had higher mortality when compared with those prescribed ramipril HR 1.
Survival on enalapril was similar to that on lisinopril HR 1. Kaplan—Meier curves for year survival for hospital outpatients with chronic heart failure with reduced ejection fraction receiving enalapril, lisinopril, and ramipril, respectively. The matching procedures identified , , and pairs of patients with similar dose equivalents for each of the three comparisons enalapril vs. Detailed descriptions of the matched samples are shown in Tables 2—4.
Table 2 Baseline characteristics of matched chronic heart failure patients treated with enalapril or ramipril. Baseline characteristics of matched chronic heart failure patients treated with enalapril or ramipril.
Baseline characteristics of matched chronic heart failure patients treated with lisinopril or ramipril. Baseline characteristics of matched chronic heart failure patients treated with enalapril or lisinopril. Absolute standardized differences before A and after B propensity score matching comparing covariate values for hospital outpatients with chronic heart failure with reduced ejection fraction receiving enalapril vs.
Univariable Cox proportional hazard analyses did not find any significant association between the particular ACEIs prescribed and all-cause mortality in any of the matched samples enalapril vs.
Results were confirmed after adjusting for covariates in the matched samples HR 1. Kaplan—Meier curves for year survival regarding all-cause mortality in the propensity and dose-equivalent matched cohort for hospital outpatients with chronic heart failure with reduced ejection fraction receiving enalapril or ramipril.
Kaplan—Meier curves for year survival regarding all-cause mortality in the propensity and dose-equivalent matched cohort for hospital outpatients with chronic heart failure with reduced ejection fraction receiving lisinopril or ramipril.
Kaplan—Meier curves for year survival regarding all-cause mortality in the propensity and dose-equivalent matched cohort for hospital outpatients with chronic heart failure with reduced ejection fraction receiving enalapril or lisinopril.
Similarly, we found no relationship between the type of ACEI and all-cause mortality in multivariable Cox regression analysis of the general sample including significant variables from univariable analyses HR 1.
Subgroup analyses confirmed that none of the ACEIs was superior to one of the others. The relevant plot is shown in Figure 7. Cox regression analyses for all-cause mortality regarding angiotensin-converting enzyme inhibitor use in the predefined subgroups for the propensity score-matched cohorts.
Asterisk in P for interaction refers to subgroups of each propensity-matched sample. The formal sensitivity analyses indicate only a small residual bias. This means that in order to attribute a possible survival benefit to an unobserved covariate rather than the receipt of e.
In this European multicentre cohort study of outpatients with stable HFrEF, we analysed the association of treatment with the three ACEIs enalapril, lisinopril, and ramipril and survival. Our main findings are that: patient characteristics differed significantly between treatment groups. Our study contrasts with other observational studies suggesting a different effectiveness of individual ACEIs in heart failure patients. An important limitation of both the Canadian and the American studies, however, is the lack of information on relevant patient characteristics such as LVEF, type of heart failure, and NYHA functional class.
The results may accordingly be susceptible to confounding by indication and severity of heart failure. Likewise, we found better survival in ramipril users in univariable analyses of the general sample.
Then again, another Canadian study of patients with newly diagnosed heart failure found no significant differences between enalapril, lisinopril, and ramipril in terms of heart failure effectiveness. Our study supports the results from the Danish study while paying particular attention on equivalent dosing of ACEIs.
The Assessment of Treatment with Lisinopril and Survival ATLAS trial reported significantly better outcomes in patients treated with high doses of lisinopril when compared with low-dose users. In addition, outcomes were verified in subgroups of patients according to heart rhythm and systolic blood pressure. As there are no other studies on the relative effectiveness of ACEIs providing subgroup analyses, our study expands the available evidence.
As with any non-randomized, observational design, the present study may be subject to unmeasured confounders. Sensitivity analyses cannot prove or rule out the presence of such an unmeasured confounder. However, our data result from comprehensive outpatient databases with continuous, prospective inclusion, and close surveillance.
The detailed characterization of patients allows consideration of various potential confounders through the use of comprehensive propensity score and multivariable Cox regression models. The large sample size and prospective inclusion of patients from three European countries are obvious strengths of the present study. The results are therefore likely to be generalizable to other HFrEF populations. We observed substantial differences in patient characteristics between countries, with the majority of patients being recruited in Norway.
However, as patient characteristics were used for propensity score calculation and matching, we expect that this should not have an impact on our results in the matched cohorts. We further cannot comment on the specific reasons for selection of a particular ACEI nor on medication adherence. As inclusion into the analyses of our study was performed after stabilization of both clinical status and medication in an ambulatory setting, however, this may reduce the necessity for further modulation of ACEI treatment.
From this observational study, we can infer that there is no association between the ACEI prescribed and mortality, but we cannot be sure that the lack of observed difference truly reflects similar benefit. Ideally, our results should be confirmed in a large-scale, randomized head-to-head comparison of ACEIs. Given the required sample size and associated costs, such a trial may never be done. In this European multicentre cohort study of patients with HFrEF, we found no difference in all-cause mortality for patients treated with enalapril, lisinopril, or ramipril.
The results were consistent in subgroups with respect to age, sex, NYHA functional class, LVEF, sinus rhythm, cause of heart failure, and blood pressure. Conflict of interest: J. Eur Heart J ; 37 : — J Am Coll Cardiol ; : e — Garg R , Yusuf S.
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