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.
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. 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). Thus, a head-to-head comparison of the efficacy data derived from 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 m 2 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 .
| Characteristic | Zofenopril (n = 102) | Ramipril (n = 73) |
|---|---|---|
| Age (yrs) | 73.9 ± 9.1 | 73.6 ± 10.3 |
| Gender | ||
| Men | 65 (64%) | 55 (60%) |
| Women | 37 (36%) | 36 (40%) |
| Systolic blood pressure (mm Hg) | 123.1 ± 12.4 | 120.5 ± 13.5 |
| Diastolic blood pressure (mm Hg) | 79.9 ± 9.3 | 80.3 ± 8.7 |
| Mean arterial pressure (mm Hg) | 95.4 ± 10.4 | 94.8 ± 9.9 |
| Pulse pressure (mm Hg) | 43.1 ± 8.9 | 39.9 ± 9.3 |
| Heart rate (beats/min) | 63.3 ± 10.1 | 59.4 ± 11.7 |
| Brain natriuretic peptide (pg/ml) | 293.5 ± 311.2 | 284.7 ± 281.6 |
| Smoker | 24 (28%) | 8 (13%) ∗ |
| Hypertension | 82 (81%) | 83 (91%) |
| Coronary artery disease | 67 (67%) | 55 (60%) |
| Arrhythmias | 40 (40%) | 30 (33%) |
| Mitral valve disease | 55 (54%) | 53 (58%) |
| Aortic valve disease | 22 (22%) | 22 (24%) |
| Mitral-aortic valve disease | 14 (14%) | 8 (9%) |
| Diabetes mellitus | 27 (26%) | 33 (33%) |
| Hypercholesterolemia † | 41 (41%) | 41 (45%) |
| Mixed dyslipidemia ‡ | 27 (27%) | 33 (38%) |
| Chronic renal failure | 9 (9%) | 11 (12%) |
| NYHA functional class | ||
| I | 22 (22%) | 28 (31%) |
| II | 57 (56%) | 41 (45%) |
| III | 23 (22%) | 22 (24%) |
| Ejection fraction (%) | 51.9 ± 13.9 | 54.4 ± 13.5 |
† Low-density lipoprotein cholesterol >130 mg/dl.
‡ Low-density lipoprotein cholesterol >130 mg/dl and triglycerides >150 mg/dl.
| Zofenopril (n) | Ramipril (n) | |
|---|---|---|
| Calcium antagonists | 23 (22%) | 18 (20%) |
| β Blockers | 45 (44%) | 49 (54%) |
| Diuretics | 74 (72%) | 59 (65%) |
| Antialdosterone medication | 19 (19%) | 15 (16%) |
| Digitalis | 27 (26%) | 16 (18%) |
| Nitroderivatives | 49 (48%) | 35 (38%) |
| Antiaggregatory drugs | 94 (94%) | 75 (82%) |
| Oral anticoagulants | 28 (27%) | 17 (19%) ∗ |
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 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. 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 test for categorical variables. Analysis of the adjudicated outcome was conducted on the data from all patients who had undergone randomization, according to the intention-to-treat principle, using the Kaplan-Meier estimates and Cox proportional hazards models. The hazard ratios, 95% 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.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
