Effects of PG-116800, a Matrix Metalloproteinase Inhibitor, to Prevent Left Ventricular Remodeling After Acute Myocardial Infarction - PREMIER

Description:

The goal of the trial was to evaluate treatment with a matrix metalloproteinase (MMP) inhibitor, PG-116800, compared with placebo, among patients with ST elevation myocardial infarction (MI) and signs of heart failure.

Study Design

Study Design:

Patients Enrolled: 253
Mean Follow Up: Six months
Mean Patient Age: Mean age 60 years
Female: 30

Patient Populations:

Age 18-80 years; first ST-segment elevation MI; cardiac troponin or creatine kinase-MB ≥3 times upper limit of normal; and echocardiogram with an ejection fraction of 15-40% within 48 hours of MI

Exclusions:

Previous chronic heart failure or abnormal LV ejection fraction; severe renal, hepatic, or hematological disease; presence of any co-morbid condition likely to cause death by 90 days; or current administration of intravenous inotropes or intra-aortic balloon pump

Primary Endpoints:

LVEDVI change at 90 days

Secondary Endpoints:

LVEDVI change at 30 days; LV end-systolic volume, LV ejection fraction, and LV sphericity changes; and clinical events

Drug/Procedures Used:

Patients were randomized within 48 hours of MI to the MMP inhibitor PG-116800 (200 mg twice daily for 90 days; n = 125) or placebo (n = 128). Patients were enrolled in North America and Poland. Patients underwent echocardiography at baseline and 90-day follow-up.

Principal Findings:

The majority of patients were enrolled in Poland (n = 173), with 45 patients in Canada and 35 patients in the United States. Randomized treatment was complete through 90 days in 79% of patients in the PG-116800 group and 84% of patients in the placebo group. Discontinuation due to adverse event occurred in 6% of the PG-116800 group and 9% of the placebo group.

An evaluable echocardiogram at baseline and 90 days was available in 80% of patients. Baseline characteristics were well-balanced by treatment group, with 80% of patients having an anterior MI and 90% treated with primary percutaneous coronary intervention (PCI).

The change in left ventricular end-diastolic volume index (LVEDVI) did not differ by treatment group (5.1 ml/m2 for PG-116800 vs. 5.5 ml/m2 for placebo, p = 0.42). There was also no difference in change in LVEDV (8.43 ml vs. 10.35 ml, p = 0.31), LV end-systolic volume (0.58 ml vs. 2.23 ml, p = 0.30), LV ejection fraction (4.85% vs. 4.25%, p = 0.32), or sphericity index (0.01 each, p = 0.44).

In addition, there was no difference in clinical events at 90 days, including death (3% vs. 1%, p = 0.21), severe heart failure (10% vs. 9%, p = 0.84), reinfarction (4% vs. 3%, p = 0.50), or recurrent ischemia (1% each, p = 1.0). The frequency of serious adverse events was similar in both groups.

Interpretation:

Among patients with ST elevation MI and signs of heart failure, treatment with the MMP inhibitor PG-116800 was not associated with an improvement in LVEDVI at 90 days or other measures of LV remodeling compared with placebo.

MMPs play a direct role in the remodeling process following ST elevation MI. In animal models, inhibition of MMP slows progression of LV remodeling. Despite these effects, the MMP inhibitor used in the present study did not show an effect on LV remodeling. The present inhibitor was designed to have high affinity for MMP 13 and low affinity for MMP 1 and 7. It is possible that targeting of other MMPs may have different therapeutic effects, or that timing of the therapy may be more beneficial earlier post-MI.

References:

Hudson MP, Armstrong PW, Ruzyllo W, et al. Effects of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricular remodeling after myocardial infarction: results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) trial. J Am Coll Cardiol 2006;48:15–20.

Presented by Dr. W. Douglas Weaver at the March 2005 ACC Annual Scientific Session, Orlando, FL.

Clinical Topics: Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Acute Heart Failure, Interventions and Imaging, Echocardiography/Ultrasound

Keywords: Myocardial Infarction, Follow-Up Studies, Creatine Kinase, Hydroxamic Acids, Heart Failure, Ventricular Remodeling, Stroke Volume, Matrix Metalloproteinase Inhibitors, Troponin, Echocardiography, Percutaneous Coronary Intervention


< Back to Listings