- Email: [email protected]
Effect of Zofenopril and Ramipril on Cardiovascular Mortality in Patients With Chronic Heart Failure
Effect of Zofenopril and Ramipril on Cardiovascular Mortality in Patients With Chronic Heart Failure Claudio Borghi, MD*, Eugenio Roberto Cosentino, MD, Elisa Rebecca Rinaldi, MD, and Arrigo Francesco G. Cicero, MD, PhD A head-to-head evaluation of the effect of ramipril and zofenopril on the cardiovascular mortality rate of patients with chronic heart failure (HF) in the setting of clinical practice is not yet available. We prospectively enrolled 224 patients with all-cause HF, who were untreated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. These patients were then assigned to zofenopril 15 to 30 mg/day or ramipril 5 to 10 mg/day on the basis of a prospective, randomized, open, blinded, end point trial. The primary outcome of the trial was patient survival during the follow-up period. The groups were similar in a large number of clinical parameters. The mean follow-up of this cohort was 6.1 – 1.2 years. Overall, during the follow-up period, we observed 45 deaths in the zofenopril-treated group and 48 in the ramipril-treated group (p [ 0.251). Zofenopril and ramipril appears to be equivalent regarding the effects on cardiovascular mortality in the entire sample. Zofenopril was a significant predictor of better survival in patients who were the median age or older (odds ratio 0.56, 95% confidence interval 0.35 to 0.91), in men (odds ratio 0.57, 95% confidence interval 0.30 to 0.98), and in patients with a lower ejection fraction (odds ratio 0.52, 95% confidence interval 0.26 to 0.97). In conclusion, in the clinical practice setting, ramipril and zofenopril seem to have similar effects on cardiovascular mortality. However zofenopril might be more efficacious in elderly patients, male patients, and patients with a lower ejection fraction. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:90e93) Angiotensin-converting enzyme (ACE) inhibitors have not been uniformly studied in patients with heart failure (HF) and left ventricular dysfunction. No large clinical trials have compared the efficacy of 1 ACE inhibitor with another to determine which best improves patient survival. Once the early ACE inhibitors were shown to be beneficial, the later studies mainly compared them with other vasodilators. However, because the patents for ACE inhibitors have ended, the incentives for funding head-to-head trials of ACE inhibitors never materialized. Instead, manufacturers have chosen to increase their market share by considering previously unstudied indications or focusing on advertising rather than comparative studies.1 However, pharmacoepidemiologic data sampled in the setting of clinical practice have recently raised, once again, the doubt that not all ACE inhibitors have the same effect on HF prognosis, with ramipril associated with better outcomes than other, different, molecules, in particular, enalapril and captopril (but not zofenopril, which was not compared in that analysis).2 Thus, a head-to-head comparison of the efficacy data derived from
Heart Failure Outpatient Service, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy. Manuscript received January 22, 2013; revised manuscript received and accepted February 19, 2013. This study was performed with institutional support from the University of Bologna (Oriented Fundamental Research -RFO- ex-60%) (Bologna, Italy). See page 93 for disclosure information. *Corresponding author: Tel: þ39 051 636 2848; fax: þ39 051 391 320. E-mail address: [email protected] (C. Borghi). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.02.058
prospective, randomized, open, blinded, end point (PROBE) trials could be useful and interesting. Our aim was to evaluate the effect of ramipril and zofenopril on the cardiovascular mortality rate of patients with chronic HF in the clinical practice setting. Methods For the present study, we prospectively enrolled 224 white patients seen for the first time in the HF ambulatory service of the internal medicine, aging, and kidney disease department of the University of Bologna from January 2000 to December 2005. The eligibility criteria were as follows: age 40 to 90 years, a first diagnosis of all-cause HF (New York Heart Association functional classes I to III), not yet treated with ACE inhibitors or angiotensin receptor blockers, and receiving stabilized treatment with other drugs for 6 months. The key exclusion criteria were New York Heart Association class IV HF, a serum potassium level >5.0 mmol/L, an estimated glomerular filtration rate of <30 ml/min/1.73 m2 body surface area, and any other clinically significant co-existing known condition that could limit the adherence of the patient to the protocol or limit the patient’s survival because of reasons unrelated to HF. The main characteristics of the studied patients are listed in Tables 1 and 2. The trial was performed on the basis of a PROBE trial. The treatment with zofenopril 15 to 30 mg/day or ramipril 5 to 10 mg/day was then assigned according to clinical judgment. Among the advantages of the PROBE design are the lower cost and greater similarity to standard clinical practice, which should make the results more easily www.ajconline.org
Heart Failure/Zofenopril, Ramipril, and Heart Failure Mortality
91
Table 1 Main baseline characteristics of studied patients (n ¼ 224) Characteristic
Zofenopril (n ¼ 102)
Ramipril (n ¼ 73)
Age (yrs) Gender Men Women Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial pressure (mm Hg) Pulse pressure (mm Hg) Heart rate (beats/min) Brain natriuretic peptide (pg/ml) Smoker Hypertension Coronary artery disease Arrhythmias Mitral valve disease Aortic valve disease Mitral-aortic valve disease Diabetes mellitus Hypercholesterolemia† Mixed dyslipidemiaz Chronic renal failure NYHA functional class I II III Ejection fraction (%)
73.9 9.1
73.6 10.3
65 (64%) 37 (36%) 123.1 12.4 79.9 9.3 95.4 10.4 43.1 8.9 63.3 10.1 293.5 311.2 24 (28%) 82 (81%) 67 (67%) 40 (40%) 55 (54%) 22 (22%) 14 (14%) 27 (26%) 41 (41%) 27 (27%) 9 (9%)
55 (60%) 36 (40%) 120.5 13.5 80.3 8.7 94.8 9.9 39.9 9.3 59.4 11.7 284.7 281.6 8 (13%)* 83 (91%) 55 (60%) 30 (33%) 53 (58%) 22 (24%) 8 (9%) 33 (33%) 41 (45%) 33 (38%) 11 (12%)
22 (22%) 57 (56%) 23 (22%) 51.9 13.9
28 (31%) 41 (45%) 22 (24%) 54.4 13.5
Figure 1. Cumulative survival in the overall group stratified by ACE inhibitor (ACE-Is) treatment.
* p <0.05. † Low-density lipoprotein cholesterol >130 mg/dl. z Low-density lipoprotein cholesterol >130 mg/dl and triglycerides >150 mg/dl.
Table 2 Therapy other than angiotensin-converting enzyme (ACE) inhibitors received by studied patients Zofenopril (n) Calcium antagonists b Blockers Diuretics Antialdosterone medication Digitalis Nitroderivatives Antiaggregatory drugs Oral anticoagulants
23 45 74 19 27 49 94 28
(22%) (44%) (72%) (19%) (26%) (48%) (94%) (27%)
Ramipril (n) 18 49 59 15 16 35 75 17
(20%) (54%) (65%) (16%) (18%) (38%) (82%) (19%)*
* p <0.05.
applicable to routine medical care. Because the end points were evaluated by a blinded end point committee, no difference should be present between the 2 types of trials in this regard.3 The primary outcome of the present trial was patient survival during the follow-up period. The local ethical board approved the trial, which was performed in accordance with the rules suggested by the Declaration of Helsinki, and all patients provided written informed consent. The comparability of the baseline characteristics between the 2 study groups was assessed using a 2-sample t test for continuous variables or Fisher’s exact
Figure 2. Cardiovascular mortality stratified by ACE inhibitor use (ACE-Is) in patients aged (A) <76 years and (B) >76 years (median age of enrolled patients).
test for categorical variables. Analysis of the adjudicated outcome was conducted on the data from all patients who had undergone randomization, according to the intentionto-treat principle, using the Kaplan-Meier estimates and Cox proportional hazards models. The hazard ratios, 95%
92
The American Journal of Cardiology (www.ajconline.org)
Figure 3. Cardiovascular mortality stratified by ACE inhibitor use (ACE-Is) in (A) men and (B) women.
confidence intervals, and p values were calculated using models adjusted for the following prespecified baseline prognostic factors: age, gender, body mass index, estimated glomerular filtration rate, ejection fraction, heart rate, systolic blood pressure, diastolic blood pressure, a history of hypertension, previous myocardial infarction, and atrial fibrillation. Sensitivity analyses were also performed using unadjusted Cox models. The consistency of the treatment effect was assessed among 5 prespecified subgroups. The effect in each subgroup was analyzed using a Cox proportional hazards model, without adjustment for covariates. The treatment by subgroup interaction was evaluated using a Cox proportional hazards model with terms for treatment, subgroup, and their interaction.
Results Among the enrolled patients, those with continuous treatment included 102 subjects treated with zofenopril (64.7% men) and 73 treated with ramipril (60.4% men), followed up every 4 months until withdrawal or the end of the study. Of the 102 patients, 7 in the zofenopril group and 9 in the ramipril group interrupted treatment because of cough, and 7 in the zofenopril group and 6 in the ramipril group were lost to follow-up. One patient in each group died from noncardiac causes and was excluded from the analysis. No severe adverse drug event was registered during the
Figure 4. Cardiovascular mortality stratified by ACE inhibitor use (ACE-Is) in patients with ejection fraction (A) <54% and (B) >54% (median ejection fraction of enrolled patients).
observation. The mean follow-up of this cohort was 6.1 1.2 years. The groups were similar in gender distribution, diseases, and HF class at the baseline. Only smokers were significantly more represented in the zofenopril group than in the ramipril group (Table 1). The groups were also mostly similar in the receipt of co-therapy (Table 2), other than that antiplatelet drugs were used significantly more often in the zofenopril group than in the ramipril group. Overall, during follow-up, we observed 45 deaths in the zofenopril group and 48 in the ramipril group (p ¼ 0.251). In the Cox regression model, ACE inhibitor use was not a significant predictor of events (Figure 1); thus, zofenopril and ramipril appeared to be equivalent regarding the effect on cardiovascular mortality for the whole sample. The only significant predictors of mortality among the considered variables were age (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.03 to 1.13), female gender (OR 0.58, 95% CI 0.31 to 0.99), and ejection fraction (OR 1.04, 95% CI 1.01 to 1.07). Considering the median age of 76 years as a cutoff point, the treatment with zofenopril was a significant predictor of better survival in patients aged 76 years (OR 0.56, 95% CI 0.35 to 0.91), but not in the younger patients (OR 1.38, 95% CI 0.34 to 5.61; Figure 2). Repeating the analysis by gender (Figure 3), the treatment with zofenopril was a significant predictor of better survival for men (OR 0.57, 95% CI 0.30 to 0.98) but not women (OR 0.66, 95% CI 0.30 to 1.46).
Heart Failure/Zofenopril, Ramipril, and Heart Failure Mortality
Considering the median ejection fraction of 54% as a cutoff point, the treatment with zofenopril was a significant predictor of better survival in patients with a lower ejection fraction (OR 0.52, 95% CI 0.26 to 0.97) but not in patients with a preserved ejection fraction (OR 0.80, 95% CI 0.43 to 1.49; Figure 4). Discussion We prospectively evaluated the effect of zofenopril on the cardiovascular mortality of patients affected by HF compared with a well-known efficacious comparator, ramipril.4 Overall, we did not find a significant difference in cardiovascular mortality trends among the ramipril and zofenopril groups, leading us suppose an equivalence of the 2 drugs. The subgroup analysis, however, showed that zofenopril, compared with ramipril, was associated with a relative risk of cardiovascular mortality of 44% in elderly patients, 43% in men and 48% in patients with a low ejection fraction. These subcategories of patients were those, a priori, with a greater probability of readmittance to the hospital because of HF,5 and those with greater costs for their management.6,7 These data are partially in agreement with those from the recently published Survival of Myocardial Infarction LongTerm Evaluatione4 (SMILE-4), in which 771 patients with clinical signs of HF or a left ventricular ejection <45% after acute myocardial infarction were randomized to treatment with zofenopril 60 mg/day or ramipril 10 mg/day for 1 year. In that study, the primary outcome (cardiovascular death or hospitalization) was significantly reduced by zofenopril (n ¼ 365) compared with ramipril (n ¼ 351; OR 0.70, 95% CI 0.51 to 0.96; p ¼ 0.028).8 In the present study, we also observed a difference in mortality in older subjects, who were probably at higher risk and because of the longer follow-up duration. The main limitation of our study was that was not a double-blind randomized clinical trial. Instead, we used a PROBE design, which does not have not the same scientific strength. However, as stated, the PROBE design is reliable for clinical practice,3 because the obtained results are more directly applicable to unselected patients. Also, the number of enrolled subjects was relatively small; however, the patient numbers also reflect the prevalence of these types of patients in the setting of clinical practice in our HF ambulatory service. The small patient sample influenced
93
the reliability of the subsample analyses, which, however, did result in some speculations. Moreover, we only considered cardiovascular mortality and hospital admission as outcome variables. This was done because our HF ambulatory service systematically visits the patients each 4 months (more often if needed) for drug efficacy and tolerability monitoring, and this has been associated with a very low rate of rehospitalization. Another limitation was the relatively low number of factors by which we adjusted the model, because we only considered the more relevant factors, and many others could have been evaluated, such as serum electrolytes. However, the present study was also the first to directly compare the effects of zofenopril and ramipril on cardiovascular mortality in patients with HF from different causes in the clinical practice setting, including a large number of elderly patients. Disclosures The authors have no conflicts of interest to disclose. 1. Hernandez AF, Harrington RA. Comparative effectiveness of angiotensin-converting-enzyme inhibitors: is an ACE always an ace? Can Med Assoc J 2008;178:1316e1319. 2. Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H, Tu JV. Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure. Can Med Assoc J 2008;178:1303e1311. 3. Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded end-point (PROBE) study: a novel design for intervention trials. Blood Pressure 1992;1:113e119. 4. Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, Yusuf S; HOPE/ HOPE-TOO Study Investigators. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension. Circulation 2005;112:1339e1346. 5. Coffey RM, Misra A, Barrett M, Andrews RM, Mutter R, Moy E. Congestive heart failure: who is likely to be readmitted? Med Care Res Rev 2012;69:602e616. 6. Norton C, Georgiopoulou VV, Kalogeropoulos AP, Butler J. Epidemiology and cost of advanced heart failure. Prog Cardiovasc Dis 2011;54: 78e85. 7. Greiner MA, Hammill BG, Fonarow GC, Whellan DJ, Eapen ZJ, Hernandez AF, Curtis LH. Predicting costs among Medicare beneficiaries with heart failure. Am J Cardiol 2012;109:705e711. 8. Borghi C, Ambrosioni E, Novo S, Vinereanu D, Ambrosio G; SMILE-4 Working Party. 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). Clin Cardiol 2012;35:416e423.
Heart Failure Outpatient Service, Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy. Manuscript received January 22, 2013; revised manuscript received and accepted February 19, 2013. This study was performed with institutional support from the University of Bologna (Oriented Fundamental Research -RFO- ex-60%) (Bologna, Italy). See page 93 for disclosure information. *Corresponding author: Tel: þ39 051 636 2848; fax: þ39 051 391 320. E-mail address: [email protected] (C. Borghi). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.02.058
prospective, randomized, open, blinded, end point (PROBE) trials could be useful and interesting. Our aim was to evaluate the effect of ramipril and zofenopril on the cardiovascular mortality rate of patients with chronic HF in the clinical practice setting. Methods For the present study, we prospectively enrolled 224 white patients seen for the first time in the HF ambulatory service of the internal medicine, aging, and kidney disease department of the University of Bologna from January 2000 to December 2005. The eligibility criteria were as follows: age 40 to 90 years, a first diagnosis of all-cause HF (New York Heart Association functional classes I to III), not yet treated with ACE inhibitors or angiotensin receptor blockers, and receiving stabilized treatment with other drugs for 6 months. The key exclusion criteria were New York Heart Association class IV HF, a serum potassium level >5.0 mmol/L, an estimated glomerular filtration rate of <30 ml/min/1.73 m2 body surface area, and any other clinically significant co-existing known condition that could limit the adherence of the patient to the protocol or limit the patient’s survival because of reasons unrelated to HF. The main characteristics of the studied patients are listed in Tables 1 and 2. The trial was performed on the basis of a PROBE trial. The treatment with zofenopril 15 to 30 mg/day or ramipril 5 to 10 mg/day was then assigned according to clinical judgment. Among the advantages of the PROBE design are the lower cost and greater similarity to standard clinical practice, which should make the results more easily www.ajconline.org
Heart Failure/Zofenopril, Ramipril, and Heart Failure Mortality
91
Table 1 Main baseline characteristics of studied patients (n ¼ 224) Characteristic
Zofenopril (n ¼ 102)
Ramipril (n ¼ 73)
Age (yrs) Gender Men Women Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mean arterial pressure (mm Hg) Pulse pressure (mm Hg) Heart rate (beats/min) Brain natriuretic peptide (pg/ml) Smoker Hypertension Coronary artery disease Arrhythmias Mitral valve disease Aortic valve disease Mitral-aortic valve disease Diabetes mellitus Hypercholesterolemia† Mixed dyslipidemiaz Chronic renal failure NYHA functional class I II III Ejection fraction (%)
73.9 9.1
73.6 10.3
65 (64%) 37 (36%) 123.1 12.4 79.9 9.3 95.4 10.4 43.1 8.9 63.3 10.1 293.5 311.2 24 (28%) 82 (81%) 67 (67%) 40 (40%) 55 (54%) 22 (22%) 14 (14%) 27 (26%) 41 (41%) 27 (27%) 9 (9%)
55 (60%) 36 (40%) 120.5 13.5 80.3 8.7 94.8 9.9 39.9 9.3 59.4 11.7 284.7 281.6 8 (13%)* 83 (91%) 55 (60%) 30 (33%) 53 (58%) 22 (24%) 8 (9%) 33 (33%) 41 (45%) 33 (38%) 11 (12%)
22 (22%) 57 (56%) 23 (22%) 51.9 13.9
28 (31%) 41 (45%) 22 (24%) 54.4 13.5
Figure 1. Cumulative survival in the overall group stratified by ACE inhibitor (ACE-Is) treatment.
* p <0.05. † Low-density lipoprotein cholesterol >130 mg/dl. z Low-density lipoprotein cholesterol >130 mg/dl and triglycerides >150 mg/dl.
Table 2 Therapy other than angiotensin-converting enzyme (ACE) inhibitors received by studied patients Zofenopril (n) Calcium antagonists b Blockers Diuretics Antialdosterone medication Digitalis Nitroderivatives Antiaggregatory drugs Oral anticoagulants
23 45 74 19 27 49 94 28
(22%) (44%) (72%) (19%) (26%) (48%) (94%) (27%)
Ramipril (n) 18 49 59 15 16 35 75 17
(20%) (54%) (65%) (16%) (18%) (38%) (82%) (19%)*
* p <0.05.
applicable to routine medical care. Because the end points were evaluated by a blinded end point committee, no difference should be present between the 2 types of trials in this regard.3 The primary outcome of the present trial was patient survival during the follow-up period. The local ethical board approved the trial, which was performed in accordance with the rules suggested by the Declaration of Helsinki, and all patients provided written informed consent. The comparability of the baseline characteristics between the 2 study groups was assessed using a 2-sample t test for continuous variables or Fisher’s exact
Figure 2. Cardiovascular mortality stratified by ACE inhibitor use (ACE-Is) in patients aged (A) <76 years and (B) >76 years (median age of enrolled patients).
test for categorical variables. Analysis of the adjudicated outcome was conducted on the data from all patients who had undergone randomization, according to the intentionto-treat principle, using the Kaplan-Meier estimates and Cox proportional hazards models. The hazard ratios, 95%
92
The American Journal of Cardiology (www.ajconline.org)
Figure 3. Cardiovascular mortality stratified by ACE inhibitor use (ACE-Is) in (A) men and (B) women.
confidence intervals, and p values were calculated using models adjusted for the following prespecified baseline prognostic factors: age, gender, body mass index, estimated glomerular filtration rate, ejection fraction, heart rate, systolic blood pressure, diastolic blood pressure, a history of hypertension, previous myocardial infarction, and atrial fibrillation. Sensitivity analyses were also performed using unadjusted Cox models. The consistency of the treatment effect was assessed among 5 prespecified subgroups. The effect in each subgroup was analyzed using a Cox proportional hazards model, without adjustment for covariates. The treatment by subgroup interaction was evaluated using a Cox proportional hazards model with terms for treatment, subgroup, and their interaction.
Results Among the enrolled patients, those with continuous treatment included 102 subjects treated with zofenopril (64.7% men) and 73 treated with ramipril (60.4% men), followed up every 4 months until withdrawal or the end of the study. Of the 102 patients, 7 in the zofenopril group and 9 in the ramipril group interrupted treatment because of cough, and 7 in the zofenopril group and 6 in the ramipril group were lost to follow-up. One patient in each group died from noncardiac causes and was excluded from the analysis. No severe adverse drug event was registered during the
Figure 4. Cardiovascular mortality stratified by ACE inhibitor use (ACE-Is) in patients with ejection fraction (A) <54% and (B) >54% (median ejection fraction of enrolled patients).
observation. The mean follow-up of this cohort was 6.1 1.2 years. The groups were similar in gender distribution, diseases, and HF class at the baseline. Only smokers were significantly more represented in the zofenopril group than in the ramipril group (Table 1). The groups were also mostly similar in the receipt of co-therapy (Table 2), other than that antiplatelet drugs were used significantly more often in the zofenopril group than in the ramipril group. Overall, during follow-up, we observed 45 deaths in the zofenopril group and 48 in the ramipril group (p ¼ 0.251). In the Cox regression model, ACE inhibitor use was not a significant predictor of events (Figure 1); thus, zofenopril and ramipril appeared to be equivalent regarding the effect on cardiovascular mortality for the whole sample. The only significant predictors of mortality among the considered variables were age (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.03 to 1.13), female gender (OR 0.58, 95% CI 0.31 to 0.99), and ejection fraction (OR 1.04, 95% CI 1.01 to 1.07). Considering the median age of 76 years as a cutoff point, the treatment with zofenopril was a significant predictor of better survival in patients aged 76 years (OR 0.56, 95% CI 0.35 to 0.91), but not in the younger patients (OR 1.38, 95% CI 0.34 to 5.61; Figure 2). Repeating the analysis by gender (Figure 3), the treatment with zofenopril was a significant predictor of better survival for men (OR 0.57, 95% CI 0.30 to 0.98) but not women (OR 0.66, 95% CI 0.30 to 1.46).
Heart Failure/Zofenopril, Ramipril, and Heart Failure Mortality
Considering the median ejection fraction of 54% as a cutoff point, the treatment with zofenopril was a significant predictor of better survival in patients with a lower ejection fraction (OR 0.52, 95% CI 0.26 to 0.97) but not in patients with a preserved ejection fraction (OR 0.80, 95% CI 0.43 to 1.49; Figure 4). Discussion We prospectively evaluated the effect of zofenopril on the cardiovascular mortality of patients affected by HF compared with a well-known efficacious comparator, ramipril.4 Overall, we did not find a significant difference in cardiovascular mortality trends among the ramipril and zofenopril groups, leading us suppose an equivalence of the 2 drugs. The subgroup analysis, however, showed that zofenopril, compared with ramipril, was associated with a relative risk of cardiovascular mortality of 44% in elderly patients, 43% in men and 48% in patients with a low ejection fraction. These subcategories of patients were those, a priori, with a greater probability of readmittance to the hospital because of HF,5 and those with greater costs for their management.6,7 These data are partially in agreement with those from the recently published Survival of Myocardial Infarction LongTerm Evaluatione4 (SMILE-4), in which 771 patients with clinical signs of HF or a left ventricular ejection <45% after acute myocardial infarction were randomized to treatment with zofenopril 60 mg/day or ramipril 10 mg/day for 1 year. In that study, the primary outcome (cardiovascular death or hospitalization) was significantly reduced by zofenopril (n ¼ 365) compared with ramipril (n ¼ 351; OR 0.70, 95% CI 0.51 to 0.96; p ¼ 0.028).8 In the present study, we also observed a difference in mortality in older subjects, who were probably at higher risk and because of the longer follow-up duration. The main limitation of our study was that was not a double-blind randomized clinical trial. Instead, we used a PROBE design, which does not have not the same scientific strength. However, as stated, the PROBE design is reliable for clinical practice,3 because the obtained results are more directly applicable to unselected patients. Also, the number of enrolled subjects was relatively small; however, the patient numbers also reflect the prevalence of these types of patients in the setting of clinical practice in our HF ambulatory service. The small patient sample influenced
93
the reliability of the subsample analyses, which, however, did result in some speculations. Moreover, we only considered cardiovascular mortality and hospital admission as outcome variables. This was done because our HF ambulatory service systematically visits the patients each 4 months (more often if needed) for drug efficacy and tolerability monitoring, and this has been associated with a very low rate of rehospitalization. Another limitation was the relatively low number of factors by which we adjusted the model, because we only considered the more relevant factors, and many others could have been evaluated, such as serum electrolytes. However, the present study was also the first to directly compare the effects of zofenopril and ramipril on cardiovascular mortality in patients with HF from different causes in the clinical practice setting, including a large number of elderly patients. Disclosures The authors have no conflicts of interest to disclose. 1. Hernandez AF, Harrington RA. Comparative effectiveness of angiotensin-converting-enzyme inhibitors: is an ACE always an ace? Can Med Assoc J 2008;178:1316e1319. 2. Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H, Tu JV. Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure. Can Med Assoc J 2008;178:1303e1311. 3. Hansson L, Hedner T, Dahlöf B. Prospective randomized open blinded end-point (PROBE) study: a novel design for intervention trials. Blood Pressure 1992;1:113e119. 4. Bosch J, Lonn E, Pogue J, Arnold JM, Dagenais GR, Yusuf S; HOPE/ HOPE-TOO Study Investigators. Long-term effects of ramipril on cardiovascular events and on diabetes: results of the HOPE study extension. Circulation 2005;112:1339e1346. 5. Coffey RM, Misra A, Barrett M, Andrews RM, Mutter R, Moy E. Congestive heart failure: who is likely to be readmitted? Med Care Res Rev 2012;69:602e616. 6. Norton C, Georgiopoulou VV, Kalogeropoulos AP, Butler J. Epidemiology and cost of advanced heart failure. Prog Cardiovasc Dis 2011;54: 78e85. 7. Greiner MA, Hammill BG, Fonarow GC, Whellan DJ, Eapen ZJ, Hernandez AF, Curtis LH. Predicting costs among Medicare beneficiaries with heart failure. Am J Cardiol 2012;109:705e711. 8. Borghi C, Ambrosioni E, Novo S, Vinereanu D, Ambrosio G; SMILE-4 Working Party. 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). Clin Cardiol 2012;35:416e423.