Comparison between zofenopril and ramipril in combination with acetylsalicylic acid in patients with left ventricular systolic dysfunction after acute myocardial infarction: results of a randomized, double-blind, parallel-group, multicenter, European study (SMILE-4).
BACKGROUND
Angiotensin-converting enzyme inhibitors (ACEIs) are largely employed for treating patients with left ventricular dysfunction (LVD), but their efficacy may be negatively affected by concomitant administration of acetylsalicylic acid (ASA), with some difference among the different compounds.


OBJECTIVE
The interaction between ASA and the two ACEIs zofenopril and ramipril may result in a different impact on survival of cardiac patients, due to differences in the pharmacological properties of the two ACEIs.


METHODS
This phase IIIb, randomized, double-blind, parallel-group, multicenter, European study compared the safety and efficacy of zofenopril (60 mg/day) and ramipril (10 mg/day) plus ASA (100 mg/day), in 771 patients with LVD (clinical signs of heart failure or a left ventricular ejection fraction <45%) following acute myocardial infarction (AMI). The primary study end point was 1-year combined occurrence of death or hospitalization for cardiovascular causes.


RESULTS
In the intention-to-treat population, the primary outcome was significantly reduced by zofenopril (n = 365) vs ramipril (n = 351) (odds ratio [OR]: 0.70, and 95% confidence interval [CI]: 0.51-0.96; P = 0.028) as a result of a decrease in cardiovascular hospitalization (OR: 0.64,95% CI: 0.46-0.88; P = 0.006). Mortality rate was not significantly different between the 2 treatments (OR: 1.51, 95% CI: 0.70-3.27; P = 0.293). Blood pressure values did not significantly change during the 1-year follow-up. N-terminal pro-brain natriuretic peptide levels were progressively reduced during the study, with no statistically significant between-treatment differences. Proportion of patients with deterioration of renal function during the study was similar between the 2 groups. Drug safety profile was comparable between treatments.


CONCLUSIONS
In patients with LVD following AMI, the efficacy of zofenopril associated with ASA was superior to that of ramipril plus ASA, indicating some important clinical implications for the future use of ACEIs in patients with LVD or overt heart failure.
Unit of Internal Medicine, Policlinico S. Orsola, University of Bologna, Italy. claudio.borghi@unibo.it
Claudio
C
Borghi
Ettore
E
Ambrosioni
Salvatore
S
Novo
Dragos
D
Vinereanu
Giuseppe
G
Ambrosio
D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D001241:Aspirin / Q000009:adverse effects / Q000627:therapeutic use*; D002216:Captopril / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016009:Chi-Square Distribution; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006760:Hospitalization; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications* / Q000401:mortality; D016017:Odds Ratio; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D017257:Ramipril / Q000009:adverse effects / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects*; D013997:Time Factors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D010975:Platelet Aggregation Inhibitors; C044958:zofenopril; D002216:Captopril; D017257:Ramipril; D001241:Aspirin