Metoprolol reverses left ventricular remodeling in patients with asymptomatic systolic dysfunction: the REversal of VEntricular Remodeling with Toprol-XL (REVERT) trial.

BACKGROUND: There are no randomized, controlled trial data to support the benefit of beta-blockers in patients with asymptomatic left ventricular systolic dysfunction. We investigated whether beta-blocker therapy ameliorates left ventricular remodeling in asymptomatic patients with left ventricular systolic dysfunction. METHOD AND RESULTS: Patients with left ventricular ejection fraction <40%, mild left ventricular dilation, and no symptoms of heart failure (New York Heart Association class I) were randomly assigned to receive extended-release metoprolol succinate (Toprol-XL, AstraZeneca) 200 mg or 50 mg or placebo for 12 months. Echocardiographic assessments of left ventricular end-systolic volume, end-diastolic volume, mass, and ejection fraction were performed at baseline and at 6 and 12 months. The 149 patients randomized to the 3 treatment groups (200 mg, n=48; 50 mg, n=48; and placebo, n=53) were similar with regard to all baseline characteristics including age (mean, 66 years), gender (74% male), plasma brain natriuretic peptide (79 pg/mL), left ventricular end-diastolic volume index (110 mL/m2), and left ventricular ejection fraction (27%). At 12 months in the 200-mg group, there was a 14+/-3 mL/m2 decrease (least square mean+/-SE) in end-systolic volume index and a 6+/-1% increase in left ventricular ejection fraction (P<0.05 versus baseline and placebo for both). The decrease in end-diastolic volume index (14+/-3) was different from that seen at baseline (P<0.05) but not with placebo. In the 50-mg group, end-systolic and end-diastolic volume indexes decreased relative to baseline but were not different from what was seen with placebo, whereas ejection fraction increased by 4+/-1% (P<0.05 versus baseline and placebo). CONCLUSION: Beta-blocker therapy can ameliorate left ventricular remodeling in asymptomatic patients with left ventricular systolic dysfunction.

Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience.

OBJECTIVE: To evaluate the efficacy, tolerability, and blood pressure (BP) lowering effect of extended release metoprolol succinate (ER metoprolol) in children 6 to 16 years of age with established hypertension. STUDY DESIGN: Patients were randomized to one of four treatment arms: placebo or ER metoprolol (0.2 mg/kg, 1.0 mg/kg, or 2.0 mg/kg). Data were analyzed on 140 intent-to-treat patients. RESULTS: Mean age (+/-SD) was 12.5 +/- 2.8 years and mean baseline BP was 132/78 +/- 9/9 mmHg. Following 4 weeks of treatment, mean changes in sitting BP were: placebo = -1.9/-2.1 mmHg; ER metoprolol 0.2 mg/kg = -5.2/-3.1 mmHg; 1.0 mg/kg = -7.7/-4.9 mmHg; 2.0 mg/kg = -6.3/-7.5 mmHg. Compared with placebo, ER metoprolol significantly reduced systolic blood pressure (SBP) at the 1.0 and 2.0 mg/kg dose (P = .027 and P = .049, respectively), reduced diastolic blood pressure (DBP) at the 2.0 mg/kg dose (P = .017), and showed a statistically significant dose response relationship for the placebo-corrected change in DBP from baseline. There were no serious adverse events or adverse events requiring study drug discontinuation among patients receiving active therapy. CONCLUSION: These data indicate that ER metoprolol is an effective and well-tolerated treatment for hypertension in children.

Efficacy, safety and tolerability of metoprolol CR/XL in patients with diabetes and chronic heart failure: experiences from MERIT-HF.

BACKGROUND: The objective of the current study was to examine the efficacy and tolerability of the beta-blocker metoprolol succinate controlled release/extended release (CR/XL) in patients with diabetes in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF). METHODS: The Cox proportional hazards model was used to calculate hazard ratios (HR) for convenience expressed as relative risks (risk reduction = 1-HR), and 95% confidence intervals (CI). RESULTS: The risk of hospitalization for heart failure was 76% higher in diabetics compared to non-diabetics (95% CI 38% to 123%). Metoprolol CR/XL was well tolerated and reduced the risk of hospitalization for heart failure by 37% in the diabetic group (95% CI 53% to 15%), and by 35% in the non-diabetic group (95% CI 48% to 19%). Pooling of mortality data from the Cardiac Insufficiency Bisoprolol Study II (CIBIS II), MERIT-HF, and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) showed similar survival benefits in patients with diabetes (25%; 95% CI 40% to 4%) and without diabetes (36%; 95% CI 44% to 27%); test of diabetes by treatment interaction was non-significant. Adverse events were reported more often on placebo than on metoprolol CR/XL. CONCLUSIONS: Patients with heart failure and diabetes have a much higher risk of hospitalization than patients without diabetes. Regardless of diabetic status, a highly significant reduction in hospitalizations for heart failure was observed with metoprolol CR/XL therapy, which was very well tolerated also by patients with diabetes. Furthermore, the pooled data showed a statistically significant survival benefit in patients with diabetes.

Metoprolol CR/XL in postmyocardial infarction patients with chronic heart failure: experiences from MERIT-HF.

BACKGROUND: The benefit of beta-blockers post-myocardial infarction (MI) was established in the late 1970s. Major advances in the treatment of MI have since occurred. However, patients with chronic heart failure (CHF) were excluded from those trials. The purpose of this study was to assess the effect of beta-blockers in post-MI patients with CHF receiving contemporary management. METHODS: This was a prespecified subgroup analysis of a double-blind, randomized trial: the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). Patients with CHF in New York Heart Association class II to IV with an ejection fraction (EF) < or =0.40 and a history of being hospitalized for an acute MI (n = 1926) were randomized to metoprolol succinate controlled release/extended release (CR/XL) versus placebo. Mean EF was 0.28, and the mean follow-up was 1 year. RESULTS: Metoprolol CR/XL reduced total mortality by 40% (95% CI 0.20-0.55, P =.0004), and sudden death by 50% (95% CI 0.26-0.66, P =.0004). The combined end point of all-cause mortality/hospitalization for worsening CHF was reduced by 31% (95% CI 0.16-0.44, P <.0001), and cardiac death/nonfatal acute MI by 45% (95% CI 0.26-0.58, P <.0001). A post-hoc analysis showed that the outcome in patients with earlier revascularization (44%) and outcome in those with more severe CHF (20%) was similar to the entire post-MI population. CONCLUSIONS: In post-MI patients with symptomatic CHF, beta-blockade continues to exert a profound reduction in mortality and morbidity in the presence of contemporary management that includes early and late revascularization, angiotensin-converting enzyme inhibitors, aspirin, and statins.

Clinical trial of extended-release felodipine in pediatric essential hypertension.

Essential hypertension in pediatric patients may require pharmacological treatment. There is a need for efficacious, safe, and well-tolerated antihypertensive agents with a once-a-day dosing regimen in children and adolescents. The aim of the trial was to evaluate the dose-response and tolerability of the dihydropyridine calcium channel blocker, felodipine extended-release tablets (felodipine ER), given once daily to pediatric patients with essential hypertension. A randomized double-blind, parallel-group, multi-center clinical study comparing felodipine ER (2.5, 5, or 10 mg once daily) and placebo was performed on pediatric patients with a baseline systolic (SBP) or diastolic blood pressure (DBP) above the 95th percentile for age, sex, and height. Of 133 randomized patients, 128 (96.2%) completed the 3 weeks of double-blind treatment. The study population included 50% children 6-12 years of age or Tanner stage

Pharmacokinetic considerations of formulation: extended-release metoprolol succinate in the treatment of heart failure.

Extended-release (ER) metoprolol succinate is a controlled-release formulation designed to deliver metoprolol succinate at a near constant rate for approximately 20 h, independent of food intake and gastrointestinal pH. Once-daily dosing of ER metoprolol succinate 12.5-200 mg produces even plasma concentrations over a 24-h period, without the marked peaks and troughs characteristically observed with the immediate-release (IR) formulation. This leads to consistent beta1-blockade over 24 h, while maintaining cardioselectivity at doses up to 200 mg daily. Pharmacokinetic studies have also been performed in heart failure patients and have demonstrated that ER metoprolol succinate is associated with a more pronounced and even beta1-blockade over a 24-h period than the IR formulation. The efficacy and good tolerability of ER metoprolol succinate in heart failure patients has now been demonstrated in a large-scale clinical trial.