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.
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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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