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REversal of VEntricular Remodeling with Toprol-XL - REVERT
Description:
The goal of the trial was to evaluate treatment with one of two doses of extended-release metoprolol compared with placebo on left ventricular (LV) remodeling in asymptomatic patients with LV systolic dysfunction.
Study Design
Study Design:
Patients Enrolled: 149
Mean Follow Up: 12 months
Mean Patient Age: Mean age, 66 years
Female: 26
Patient Populations:
LVEF <40%; mild LV dilatation (LVEDVI >75 ml/m2) due to idiopathic, ischemic, or hypertensive cardiomyopathy; no symptoms of heart failure for at least 2 months; use of an ACE inhibitor or angiotensin-receptor blocker for at least 3 months; and no changes is cardiovascular medication dose in prior 3 months
Exclusions:
Indications for or contraindications to beta-blocker therapy; use of beta-blockers for >1 week in prior 6 months; myocardial infarction, unstable angina, coronary intervention, or hospitalization for cardiovascular causes in prior 6 months; heart rate <60 bpm; sitting blood pressure >140/90 mm Hg; heart block > first degree not treated with a permanent pacemaker; history of ventricular or atrial fibrillation; or serum creatinine >3 mg/dl
Primary Endpoints:
Change in LVESVI from baseline to 12 months
Secondary Endpoints:
Change from baseline in LVESVI at month 6 and changes from baseline in LVEDVI, LV mass index, and LVEF at months 6 and 12
Drug/Procedures Used:
Screening LV ejection fraction (LVEF) and LV end-diastolic volume index (LVEDVI) was assessed using an echocardiogram done within 14 days of randomization and read by the core laboratory. Once inclusion criteria were established, patients were randomized in a double-blind manner to metoprolol 200 mg (n = 48), metoprolol 50 mg (n = 48), or placebo (n = 53). Repeat echocardiography was done at 6 and 12 months. In a substudy of 82 patients, B-type natriuretic peptide (BNP) was measured at baseline, 6 months, and 12 months.
Principal Findings:
At study entry, all patients had New York Heart Association class I. Cause of heart failure was ischemic in 54% of patients, idiopathic in 29%, hypertension in 12%, and "other" in 5%. The large majority of patients were on an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (94%). In the subgroup of patients with BNP assessed, the mean level was 79 pg/ml.
Heart rate was reduced from baseline to 12 months by a mean of 3 bpm in the placebo group, 8 bpm in the low-dose group, and 12 bpm in the high-dose metoprolol group (p < 0.05 for each metoprolol group vs. placebo). There was no significant difference in change in blood pressure.
The primary endpoint of change in LV end-systolic volume index (LVESVI) at 12 months decreased by 3.7, 7.6, and 14.5 ml/m2, respectively (p = 0.34 for metoprolol 50 mg vs. placebo; p = 0.009 for metoprolol 200 mg vs. placebo). The reduction in LVEDVI was 5.4, 6.7, and 13.5 for placebo, metoprolol 50 mg, and metoprolol 200 mg, respectively (p = 0.77 for metoprolol 50 mg vs. placebo; p = 0.083 for metoprolol 200 mg vs. placebo). The increase in EF from baseline to 12 months was higher in the metoprolol groups than the placebo group (0%, 3.9%, and 6.2% for placebo, metoprolol 50 mg, and metoprolol 200 mg; p = 0.032 for metoprolol 50 mg vs. placebo; p < 0.001 for metoprolol 200 mg vs. placebo).
Interpretation:
Among asymptomatic patients with LV systolic dysfunction, treatment with higher doses of the extended-release beta-blocker metoprolol was associated with greater improvements in LVESV and EF at 12 months compared with placebo.
Earlier studies have shown that in patients with symptomatic heart failure, metoprolol can reverse cardiac remodeling; the present study extends these findings to patients with asymptomatic LV systolic dysfunction. Beta-blockers have also been shown to improve survival and decrease heart failure–related hospitalizations in symptomatic heart failure patients.
Whether those findings would also be evident in asymptomatic LV systolic dysfunction patients is unknown, as the present study was much too small to evaluate clinical outcomes (n = 149) and a larger trial would be needed. Current guideline recommendations for beta-blocker use in patients with chronic reduction in LVEF but without heart failure symptoms is based only on expert opinion; the present study provides randomized trial evidence, albeit with a surrogate endpoint, to support the recommendations.
References:
Colucci WS, Kolias TJ, Adams KF, et al. Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial. Circulation 2007;116:49-56.
Keywords: Ventricular Function, Left, Blood Pressure, Heart Rate, Expert Testimony, Biomarkers, Ventricular Remodeling, Heart Failure, Metoprolol, Hypertension, Natriuretic Peptide, Brain, Echocardiography
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