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Pravastatin or atorvastatin evaluation and infection therapy - PROVE IT-TIMI 22 (Gatifloxacin) Trial
Description:
The goal of the trial was to evaluate the use of the antibiotic gatifloxacin compared with placebo for secondary prevention of coronary events in patients with recent acute coronary syndrome (ACS).
Hypothesis:
Treatment with the antibiotic gatifloxacin compared with placebo will be associated with a lower rate of the composite endpoint of all-cause mortality, myocardial infarction (MI), documented unstable angina requiring rehospitalization, revascularization, and stroke in patients hospitalized for an ACS.
Study Design
Study Design:
Patients Enrolled: 4,162
Mean Follow Up: Mean two years
Mean Patient Age: Mean age 58 years
Female: 22
Patient Populations:
Age ≥18 years; hospitalized for an ACS (ST elevation MI, non-ST elevation MI, or high-risk unstable angina) in the prior 10 days; stable condition at the time of enrollment; total cholesterol ≤240 mg/dl if not on lipid-lowering therapy or ≤200 mg/dl if on lipid-lowering therapy; and low-density lipoprotein 200-240
Exclusions:
Coexisting condition that shortened expected survival to <2 years, use of any statin at a dose of 80 mg/day at time of index event, need for antiarrhythmic medication, CABG for treatment of ACS, liver disease or unexplained creatine kinase elevations, and prolonged QT intervals
Primary Endpoints:
Composite of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed at least 30 days after randomization), and stroke during follow-up
Secondary Endpoints:
Death from coronary heart disease, nonfatal MI, or revascularization (if performed at least 30 days after randomization), death from coronary heart disease or nonfatal MI, and the individual components of the primary endpoint
Drug/Procedures Used:
Patients were randomized in a double-blind, 2 x 2 factorial, parallel-group design to either standard lipid lowering with pravastatin (40 mg/day; n=2,063) or aggressive lipid lowering using atorvastatin (80 mg/day; n=2,099). Patients were then randomized to either the antibiotic gatifloxacin (n=2,076) or placebo (n=2,086). Gatifloxacin therapy (400 mg/day) was started 15 days and continued for two years, with patients taking a 10-day cycle each month followed by 20 days with no study medication. Patients were followed for a minimum of 18 months, with a mean duration of 24 months.
Concomitant Medications:
Standard medical and interventional treatment for ACSs, including aspirin (75-325 mg/day) and clopidogrel or warfarin. Treatment with a nonstudy lipid-lowering medication was not allowed.
Principal Findings:
Patients received optimal medical therapy, with 93% receiving aspirin, 85% receiving beta-blockers, and 69% receiving ACE inhibitor therapy. Percutaneous coronary intervention (PCI) for the index event was performed in 69% of patients. Mean duration of treatment was 1.6 years in the gatifloxacin group and 1.7 years in the placebo group.
There was no difference in the primary composite endpoint of death, MI, stroke, revascularization, or unstable angina requiring hospitalization (23.7% in the gatifloxacin group vs. 25.1% in the placebo group, hazard ratio [HR] 0.95, p=0.41). There was also no difference in the composite of death or MI (8.9% vs. 9.3%, HR 0.93, p=0.76) or either endpoint individually (death 3.1% vs. 2.4%, p=NS; MI 6.6% vs. 7.4%, p=NS). C-reactive protein was similar between treatment groups at both four months (1.7 mg/dl each, p=NS) and at the end of the study (1.8 mg/dl each, p=NS).
Among the adverse events, diarrhea was more common in the gatifloxacin group (8.1% vs. 6.1%, p=0.01) and new diabetes trended higher (4.6% vs. 3.4%, p=0.08). Upper respirator infections were lower in the gatifloxacin group (10.9% vs. 14.8%, p<0.001), indicating the drug was active against pathogens.
Interpretation:
Among patients with recent ACS, a secondary prevention strategy of treatment with the antibiotic gatifloxacin was not associated with a reduction in the primary composite endpoint of cardiac events compared with placebo.
Previous studies have found C pneumoniae in approximately 50% of plaque lesions, suggesting the presence of C pneumoniae may increase the risk for MI and vascular disease. The findings of a lack of benefit with antibiotic therapy in the present trial are similar to the findings seen in the WIZARD and ACES trial. Unlike patients in the present trial who were enrolled within 10 days of an ACS, patients in the WIZARD trial had stable coronary artery disease (>6 weeks post-MI) and known C pneumoniae exposure. Several subgroups in WIZARD showed a benefit with antibiotic therapy, including diabetics and smokers. However, there were no subgroups identified in PROVE IT-TIMI 22 that showed a reduction in cardiac events.
Given the consistent lack of benefit with use of antibiotics for widespread secondary prevention in ACS, therapy will likely continue to be directed toward other methods of prevention including high-dose statins and ACE inhibitors.
References:
Cannon CP, et al. Antibiotic Treatment of Chlamydia pneumoniae after Acute Coronary Syndrome. N Engl J Med 2005;352:1646-54.
Cannon CP. PROVE IT-TIMI 22: Pravastatin or atorvastatin evaluation and infection therapy
(Gatifloxacin trial). Paper presented at the European Society of Cardiology Congress 2004, 29 August-1 September, Munich, Germany.
Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Acute Coronary Syndrome, Diarrhea, Heptanoic Acids, Fluoroquinolones, Percutaneous Coronary Intervention, Lipoproteins, LDL, Pyrroles, Cholesterol, C-Reactive Protein, Secondary Prevention, Pravastatin, Diabetes Mellitus
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