Fosinopril in Acute Myocardial Infarction Study - FAMIS

Description:

The FAMIS trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial designed to assess the clinical and hemodynamic effects of the angiotensin-converting enzyme (ACE) inhibitor fosinopril in selected patients with anterior acute myocardial infarction (AMI) who received fibrinolytic therapy.

Hypothesis:

In patients with marginal left ventricular (LV) dysfunction after anterior AMI treated with fibrinolytic therapy, fosinopril would favorably influence long-term clinical outcomes and would delay progression of LV dilatation.

Study Design

Study Design:

Patients Screened: N/A
Patients Enrolled: 285
Mean Patient Age: 52-68
Female: 22%
Mean Ejection Fraction: At baseline: 51 ± 10 in the placebo group, and 49 ± 11 in the fosinopril group

Patient Populations:

Patients of either sex, aged 18 to 75 years, who presented to the intensive care unit within nine hours of onset of typical ischemic chest pain associated with ECG signs of definite anterior wall MI and were eligible for fibrinolytic therapy

Exclusions:

Killip class IV on admission, supine systolic blood pressure <100 mm Hg on admission, serum creatinine >2.1 mg/dl, previous history of CHF, coronary artery bypass graft within three months prior to study entry, current treatment with ACE inhibitors, contraindications to the use of ACE inhibitors, and inability or refusal to give informed consent

Primary Endpoints:

Efficacy and safety of fosinopril in preventing an increase in LV volumes (LV end-diastolic pressure, LV end-systolic pressure) in patients with anterior AMI

Secondary Endpoints:

Efficacy of fosinopril in reducing the long-term occurrence of death or moderate to severe CHF in patients with anterior AMI and in the subset of patients without acute CHF on initial presentation

Drug/Procedures Used:

Patients who presented with anterior AMI and were eligible for fibrinolytic therapy were randomized to receive one of the following: 1) placebo, or 2) fosinopril given as an initial dose of 5 mg, which was repeated after 24 hours and then progressively doubled to a final target dose of 20 mg once daily if systolic blood pressure was >100 mm Hg and if there were no signs or symptoms of hypotension. Patients were evaluated on admission to the cardiac care unit, on discharge (15 ± 3 days), and at the end of the active follow-up period (3 months ± 7 days). Patients underwent a 2-D echocardiographic evaluation at 24-48 hours after symptom onset and on discharge.

Upon completion of the three-month double-blinded period, the study medication was stopped and patients were maintained on their other therapy for an average of 24 ± 5 months. During that period, patients were followed up to assess the prevalence of major cardiovascular events (congestive heart failure [CHF] and death).

Concomitant Medications:

All patients received fibrinolytic therapy with intravenous rt-PA and usual therapy for AMI, including aspirin and beta-blockers. Analgesic agents, calcium channel blockers, inotropes, diuretics, and anticoagulants were given as indicated.

Principal Findings:

A total of 285 patients with anterior AMI were randomized; 143 allocated to placebo and 142 to fosinopril treatment. Complete follow-up was obtained in 285 and 277 patients after three months and two years, respectively. The mean LV end-diastolic and end-systolic volume indexes were within normal range at baseline and showed a slight increase during the three-month follow-up without any differences noted between patients treated with fosinopril or placebo (p=NS).

Ejection fraction at baseline and at three months was similar between the fosinopril and placebo groups (51 ± 10 vs. 49 ± 11 at baseline, 53 ± 12 vs. 52 ± 10 at three months, p=NS). However, in patients with reduced ejection fraction (<45%), treatment with fosinopril prevented the progressive LV dilatation noted in the placebo group (p<0.05).

During titration, the overall occurrence of hypotension was 17.4% in the placebo group versus 29.3% in the fosinopril group (p=0.04). However, persistent hypotension requiring specific treatment or withdrawal of the study medication occurred in the same proportion of patients in the placebo and fosinopril groups (9.8% vs. 9.7%, p=NS). The combined occurrence of death and moderate to severe CHF (New York Heart Association III to IV) after two-year follow-up was significantly reduced in the fosinopril group (17.5% vs. 26.8%, risk reduction 34.7%, p=0.04).

In patients without clinical signs of CHF on admission (Killip class II), the occurrence of CHF was reduced from 26.8% in the placebo group to 17.5% in the fosinopril group (risk reduction 34.1%, p=0.05). In these Killip class II patients, the combined occurrence of death and CHF was 47.8% in the placebo group and 33.9% in the fosinopril group (risk reduction 29.1%, p=0.04).

There were no statistically significant differences between the fosinopril and placebo groups in the incidence of skin rash (6.1% vs. 5.2%, p=NS), cough (0% vs. 2.2%, p=NS), as well as the occurrence of increasing serum creatinine (8.4% vs. 6%, p=NS) or serum potassium levels (4.6% vs. 3.7%, p=NS).

Interpretation:

Early short-term fosinopril treatment was associated with modest long-term benefit in patients with anterior AMI treated with fibrinolytic therapy, as indicated by an overall risk reduction of the combined occurrence of death and CHF. This short-term treatment was not associated with an improvement in ejection fraction or reduction in LV hypertrophy.

References:

Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E. Post acute myocardial infarction: the Fosinopril in Acute Myocardial Infarction Study (FAMIS). Am J Hypertens 1997;10:247S-254S.

Clinical Topics: Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: Hypertrophy, Left Ventricular, Thrombolytic Therapy, Fosinopril, Myocardial Infarction, Intensive Care Units, Follow-Up Studies, Risk Reduction Behavior, Reference Values, Hypotension, Dilatation, Electrocardiography, Creatinine, Potassium, Heart Failure, Cough, Exanthema, Echocardiography


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