Results of the SMILE-2 Study
Results of the SMILE-2 Study
Background: Angiotensin-converting enzyme (ACE) inhibitors have been reported to be effective in placebo-controlled trials in various subsets of patients with acute myocardial infarction (MI). However, no direct comparisons have been performed between different ACE inhibitors in the same patient population.
Methods: This phase III, double-blind, parallel-group, multicenter study compared the safety and efficacy of zofenopril and lisinopril in 1024 thrombolyzed patients with acute MI. Patients, aged 18 to 75 years, were randomized to receive oral zofenopril (30-60 mg/day) or lisinopril (5-10 mg/day), starting within 12 hours of completion of thrombolytic therapy and continuing for 42 days. The primary study end point was the incidence of severe hypotension (systolic blood pressure <90 mm Hg), either cumulative or drug-related. Secondary end points included additional safety and efficacy parameters.
Results: The overall incidence of severe hypotension was slightly 5more reduced with zofenopril (10.9%) than with lisinopril (11.7%, P = .38). The incidence of drug-related severe hypotension was slightly but significantly lower with zofenopril than with lisinopril (6.7 vs 9.8%, 2-tailed P = .048). The 6-week mortality rate was 3.2% in the zofenopril group and 4.0% in the lisinopril group (P = .38), and no significant differences were observed in the incidence of major cardiovascular complications or any safety variables between the 2 ACE inhibitors.
Conclusions: The SMILE-2 study demonstrates that both zofenopril and lisinopril are safe and associated with a rather low rate of severe hypotension when given in accordance with a dose-titrated scheme to thrombolyzed patients with acute MI. These findings could have a positive clinical impact and increase the proportion of patients with acute MI who can be safely treated with ACE inhibitors.
Angiotensin-converting enzyme (ACE) inhibitors are well-established agents for the treatment of hypertension and congestive heart failure. In recent years, the use of ACE inhibitors has been extended to patients with acute myocardial infarction (MI), and the results of the Heart Outcome Prevention Evaluation (HOPE) study have demonstrated the therapeutic role of ACE inhibition in the large population of patients at risk of cardiovascular events.
The clinical evaluation of ACE inhibitors in acute MI has involved thousands of patients enrolled into several placebo-controlled trials involving a wide range of patients -- from those with asymptomatic LV dysfunction to patients with acute MI complicated by overt congestive heart failure (CHF). The beneficial role of ACE inhibitors has been confirmed in nonselected populations of patients with MI as well as in selected high-risk patients with anterior MI not undergoing thrombolysis. Finally, the use of ACE inhibitors has resulted in a sizeable benefit in patients treated early after the onset of symptoms or in those where drug administration has been delayed for days or weeks after the acute event. Despite this large amount of evidences, no studies have been carried out so far to directly compare ACE inhibitors with different pharmacologic profiles in patients with MI. Zofenopril calcium, a prodrug of the active metabolite zofenoprilat, is a typical ACE inhibitor producing a longer lasting inhibition of tissue and cardiac ACE activity than captopril. The clinical efficacy of zofenopril has been evaluated in the treatment of arterial hypertension and acute MI. In the SMILE (Survival of Myocardial Infarction Long-term Evaluation) study, zofenopril reduced the 6-week mortality and the risk of progression to severe CHF when started within 24 hours of symptom onset in patients with acute anterior MI. In addition, the SMILE data provided clear-cut evidence of a satisfactory safety profile of zofenopril in patients with MI where the drug was well tolerated, with a rate of treatment discontinuation due to severe symptomatic hypotension comparable to that observed in patients treated with placebo. Conversely, a similar favorable safety profile has not been described in patients with acute MI treated with different ACE inhibitors (enalapril, lisinopril), suggesting that some drug-specific features of ACE inhibitors can reduce the risk of adverse events and improve individual tolerability and compliance to treatment.
The objective of this study was to investigate the safety and tolerability of early administration of the ACE inhibitors zofenopril and lisinopril in patients with acute MI treated with intravenous thrombolysis.
Background: Angiotensin-converting enzyme (ACE) inhibitors have been reported to be effective in placebo-controlled trials in various subsets of patients with acute myocardial infarction (MI). However, no direct comparisons have been performed between different ACE inhibitors in the same patient population.
Methods: This phase III, double-blind, parallel-group, multicenter study compared the safety and efficacy of zofenopril and lisinopril in 1024 thrombolyzed patients with acute MI. Patients, aged 18 to 75 years, were randomized to receive oral zofenopril (30-60 mg/day) or lisinopril (5-10 mg/day), starting within 12 hours of completion of thrombolytic therapy and continuing for 42 days. The primary study end point was the incidence of severe hypotension (systolic blood pressure <90 mm Hg), either cumulative or drug-related. Secondary end points included additional safety and efficacy parameters.
Results: The overall incidence of severe hypotension was slightly 5more reduced with zofenopril (10.9%) than with lisinopril (11.7%, P = .38). The incidence of drug-related severe hypotension was slightly but significantly lower with zofenopril than with lisinopril (6.7 vs 9.8%, 2-tailed P = .048). The 6-week mortality rate was 3.2% in the zofenopril group and 4.0% in the lisinopril group (P = .38), and no significant differences were observed in the incidence of major cardiovascular complications or any safety variables between the 2 ACE inhibitors.
Conclusions: The SMILE-2 study demonstrates that both zofenopril and lisinopril are safe and associated with a rather low rate of severe hypotension when given in accordance with a dose-titrated scheme to thrombolyzed patients with acute MI. These findings could have a positive clinical impact and increase the proportion of patients with acute MI who can be safely treated with ACE inhibitors.
Angiotensin-converting enzyme (ACE) inhibitors are well-established agents for the treatment of hypertension and congestive heart failure. In recent years, the use of ACE inhibitors has been extended to patients with acute myocardial infarction (MI), and the results of the Heart Outcome Prevention Evaluation (HOPE) study have demonstrated the therapeutic role of ACE inhibition in the large population of patients at risk of cardiovascular events.
The clinical evaluation of ACE inhibitors in acute MI has involved thousands of patients enrolled into several placebo-controlled trials involving a wide range of patients -- from those with asymptomatic LV dysfunction to patients with acute MI complicated by overt congestive heart failure (CHF). The beneficial role of ACE inhibitors has been confirmed in nonselected populations of patients with MI as well as in selected high-risk patients with anterior MI not undergoing thrombolysis. Finally, the use of ACE inhibitors has resulted in a sizeable benefit in patients treated early after the onset of symptoms or in those where drug administration has been delayed for days or weeks after the acute event. Despite this large amount of evidences, no studies have been carried out so far to directly compare ACE inhibitors with different pharmacologic profiles in patients with MI. Zofenopril calcium, a prodrug of the active metabolite zofenoprilat, is a typical ACE inhibitor producing a longer lasting inhibition of tissue and cardiac ACE activity than captopril. The clinical efficacy of zofenopril has been evaluated in the treatment of arterial hypertension and acute MI. In the SMILE (Survival of Myocardial Infarction Long-term Evaluation) study, zofenopril reduced the 6-week mortality and the risk of progression to severe CHF when started within 24 hours of symptom onset in patients with acute anterior MI. In addition, the SMILE data provided clear-cut evidence of a satisfactory safety profile of zofenopril in patients with MI where the drug was well tolerated, with a rate of treatment discontinuation due to severe symptomatic hypotension comparable to that observed in patients treated with placebo. Conversely, a similar favorable safety profile has not been described in patients with acute MI treated with different ACE inhibitors (enalapril, lisinopril), suggesting that some drug-specific features of ACE inhibitors can reduce the risk of adverse events and improve individual tolerability and compliance to treatment.
The objective of this study was to investigate the safety and tolerability of early administration of the ACE inhibitors zofenopril and lisinopril in patients with acute MI treated with intravenous thrombolysis.
