Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction

• Published in: Journal of the American College of Cardiology 2006-07, Vol.48 (1), p.15-20
• Main Authors: Hudson, Michael P., Armstrong, Paul W., Ruzyllo, Witold, Brum, Jose, Cusmano, Lisa, Krzeski, Piotr, Lyon, Robert, Quinones, Miguel, Theroux, Pierre, Sydlowski, Diana, Kim, Henry E., Garcia, Mario J., Jaber, Wael A., Weaver, W. Douglas
• Format: Article
• Language: English
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2006.02.055

Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction: Results of the PREMIER (Prevention of the Myocardial Infarction Early Remodeling) Trial Michael P. Hudson, Paul W. Armstrong, Witold Ruzyllo, Jose Brum, Lisa Cusmano, MS, Piotr Krzeski, Robert Lyon, Miguel Quinones, Pierre Theroux, Diana Sydlowski, Henry E. Kim, Mario J. Garcia, Wael A. Jaber, W. Douglas Weaver In a multicenter clinical trial, 253 patients were randomized to oral selective matrix metalloproteinase inhibitor (PG-116800) versus placebo after ST-segment elevation myocardial infarction. At 90 days, there was no difference in left ventricular (LV) remodeling (ΔLV end diastolic volume index) between PG-116800 and placebo treatment groups (5.1 ± 1.45 ml/m2vs. 5.48 ± 1.41 ml/m2, p = 0.42). We sought to determine whether matrix metalloproteinase (MMP) inhibitor, PG-116800, reduced left ventricular (LV) remodeling after myocardial infarction (MI). PG-116800 is an oral MMP inhibitor with significant antiremodeling effects in animal models of MI and ischemic heart failure. In an international, randomized, double-blind, placebo-controlled study, 253 patients with first ST-segment elevation MI and ejection fraction between 15% and 40% were enrolled 48± 24 h after MI and treated with placebo or PG-116800 for 90 days. Major efficacy end points were changes in LV volumes as determined by serial echocardiography, and clinical and safety outcomes were also collected. In total, 203 patients (80%) completed 90 days of treatment and had evaluable baseline and 90-day echocardiograms. The proportion of patients with anterior MI (78% vs. 81%) and primary percutaneous coronary intervention (90% vs. 91%) along with baseline LV ejection fraction (35.5% vs. 36.8%) did not differ between PG-116800-treated and placebo-treated patients. There was no difference in the change in LV end-diastolic volume index from days 0 to 90 with PG-116800 versus placebo (5.09 ± 1.45 ml/m2vs. 5.48 ± 1.41 ml/m2, p = 0.42). Changes in LV diastolic volume, LV systolic volume, LV ejection fraction, sphericity index, plus rates of death or reinfarction were not significantly improved with PG-116800. PG-116800 was well tolerated; however, there was increased incidence of arthralgia and joint stiffness without significant increase in overall musculoskeletal adverse events (21% vs. 15%, p = 0.33). Matrix metalloproteinase inhibition with PG-116800 failed to reduce LV