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CLINICAL RESEARCH: CLINICAL TRIAL

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

Michael P. Hudson, MD, FACC^_*, Paul W. Armstrong, MD, FACC^,c, Witold Ruzyllo, MD^,d, Jose Brum, MD^,a, Lisa Cusmano, MS^,a, Piotr Krzeski, MD^,a, Robert Lyon, PhD^,a, Miguel Quinones, MD, FACC^||,d, Pierre Theroux, MD, FACC^¶,b,d, Diana Sydlowski, MS^_*, Henry E. Kim, MD, FACC^_*, Mario J. Garcia, MD, FACC^#, Wael A. Jaber, MD, FACC^# and W. Douglas Weaver, MD, FACC^_*,d,_*

^_* Henry Ford Heart and Vascular Institute, Detroit, Michigan
University of Alberta, Edmonton, Alberta, Canada
National Institute of Cardiology, Warsaw, Poland
Procter & Gamble Pharmaceuticals, Cincinnati, Ohio
^|| Montreal Heart Institute, Montreal, Quebec, Canada
^¶ Baylor College of Medicine, Houston, Texas
^# Cleveland Clinic Foundation, Cleveland, Ohio.

Manuscript received September 16, 2005; revised manuscript received January 6, 2006, accepted January 9, 2006.

^_* Reprint requests and correspondence: Dr. W. Douglas Weaver, Henry Ford Heart and Vascular Institute, Henry Ford Hospital (K-14), 2799 West Grand Boulevard, Detroit, Michigan 48202. (Email: wweaver1{at}hfhs.org).

Preliminary findings of this study were presented as Oral Abstract/Late Breaking Sessions of the 54th Annual Scientific Sessions of the American College of Cardiology, Orlando, Florida, March 7, 2005.

OBJECTIVES: We sought to determine whether matrix metalloproteinase (MMP) inhibitor, PG-116800, reduced left ventricular (LV) remodeling after myocardial infarction (MI).

BACKGROUND: PG-116800 is an oral MMP inhibitor with significant antiremodeling effects in animal models of MI and ischemic heart failure.

METHODS: 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.

RESULTS: 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/m² vs. 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).

CONCLUSIONS: Matrix metalloproteinase inhibition with PG-116800 failed to reduce LV remodeling or improve clinical outcomes after MI.

Abbreviations and Acronyms   ECM = extracellular matrix   LV = left ventricle/ventricular   LVEDVI = left ventricular end-diastolic volume index   MI = myocardial infarction   MMP = matrix metalloproteinase   PCI = percutaneous coronary intervention

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