Controlled Release/extended Release Research Articles

Current guidelines for β-adrenoblockers use in cardiovascular diseases: focus on metoprolol succinate CR/XL: A review

The objective of this review was to systematize current data on the -adrenoblockers (-ABs) used in the treatment of cardiovascular diseases and to analyze the results of studies performed with a focus on metoprolol succinate controlled release/extended release (CR/XL) formulation. The article addresses issues related to pharmacological features of metoprolol succinate CR/XL, the use of -AB in arterial hypertension, coronary heart disease, chronic heart failure, and cardiac arrhythmias based on international and Russian clinical guidelines. Results of randomized clinical trials evaluating the efficacy of metoprolol succinate CR/XL are presented. In preparing the literature review, a review of publications over the past 34 years in the MEDLINE/PubMed, Scopus, Cochrane Library, eLIBRARY, and Google Scholar databases was performed. The presented data indicate the need for more extensive use of -ABs, including metoprolol succinate CR/XL, in clinical practice.

Comparison of Real-world Outcomes Between Patients Treated with Tapentadol ER or Oxycodone CR.

Background: The objective of this study was to compare health care utilization and costs between matched cohorts of chronic pain patients treated with the opioids tapentadol extended release (ER) or oxycodone controlled release (CR). Methods: This retrospective study used claims data from the Optum Research Database. Commercial and Medicare Advantage adult patients with ≥1 prescription fill for oxycodone CR or tapentadol ER between September 1, 2011 and September 30, 2012 were eligible. The date of the first observed oxycodone CR or tapentadol ER claim was the index date. Patients had continuous health plan enrollment for 6 months before and after the index date, ≥ 90 days supply of opioid therapy, and no index drug claims in the preindex period. Patients were propensity score matched in a 1:2 ratio (tapentadol ER : oxycodone CR). Results: The attributes of the matched cohorts (1,120 tapentadol ER and 2,240 oxycodone CR patients) appeared similar. In the 6 month post-index period, lower proportions of the tapentadol ER cohort than the oxycodone CR cohort had ≥1 inpatient stay (14.6% versus 20.5%; p<0.001) and ≥1 emergency department visit (33.4% versus 37.5%; p=0.021). The tapentadol ER compared with the oxycodone CR cohort had higher mean pharmacy costs ($4,263 versus $3,694; p <0.001), lower mean inpatient costs ($3,625 versus $6,309; p<0.001), and lower mean total healthcare costs ($16,510 versus $19,330; p=0.004). Conclusions: During follow-up, total mean healthcare costs were lower among tapentadol ER patients than oxycodone CR patients, and tapentadol ER patients were less likely to have an inpatient admission or emergency department visit.

The large‐scale placebo‐controlled beta‐blocker studies in systolic heart failure revisited: results from CIBIS‐II, COPERNICUS and SENIORS‐SHF compared with stratified subsets from MERIT‐HF

The four pivotal beta-blocker trials in heart failure (HF) had different inclusion criteria, making comparison difficult without patient stratifying. The aim of this study was to compare, in similar patients, the effects of bisoprolol, metoprolol controlled release/extended release (CR/XL), carvedilol and nebivolol on (i) total mortality, (ii) all-cause mortality or hospitalization due to cardiovascular causes (time to first event), (iii) all-cause mortality or hospitalization because of HF and (iv) tolerability, defined as discontinuation of randomized treatment. We compared stratified (s ) subsets in MERIT-HF with patients in CIBIS-II [New York Heart Association (NYHA) class III/IV and ejection fraction (EF) ≤ 35%] and COPERNICUS (NYHA III/IV and EF <25%) and in patients with systolic HF in SENIORS-SHF (age ≥ 70 years and EF ≤ 35%). The annual mortality rates in the placebo and beta-blocker arms were: (i) CIBIS-II (n = 2647), 13.2% vs. 8.8% (relative risk reduction 34%, 95% CI: 19-46, P < 0.0001) and MERIT-HFs (n = 2002), 14.8% vs. 8.6% (relative risk reduction 42%, 95% CI: 24-56, P < 0.0001); (ii) COPERNICUS (n = 2289), 19.7% vs. 12.8% (relative risk reduction 35%, 95% CI: 19-48, P = 0.0014) and MERIT-HFs (n = 795), 19.1% vs. 11.7% (relative risk reduction 39%; 95% CI: 11-58, P = 0.0086); (iii) SENIORS-SHF (n = 1359), 11.3% vs. 9.7% (relative risk reduction 16%, NS) and MERIT-HFs (n = 985), 14.8% vs. 10.1% (relative risk reduction 32%, 95% CI: 2-53, P = 0.038). The effects on the other outcomes assessed were similar. Analyses indicated fewer discontinuations from randomized treatment on beta-blockers compared with placebo in COPERNICUS and the MERIT-HFs subsets. The efficacy and tolerability of bisoprolol, carvedilol and metoprolol CR/XL are similar in patients with systolic HF, irrespective of NYHA class or ejection fraction. Nebivolol is less effective and not better tolerated.

The Arg389Gly β1-adrenoceptor gene polymorphism influences the acute effects of β-adrenoceptor blockade on contractility in the human heart

The β(1)-adrenoceptor (β(1)AR) mediates cardiostimulatory effects of catecholamines in the heart. The Arg389Gly polymorphism of the β(1)AR gene has recently been shown to determine the responsiveness to catecholamines in vitro, and we previously reported that dobutamine induced an augmented contractile response in humans homozygous for the Arg389 allele. The aim of the present study was to evaluate whether the Arg389Gly β(1)AR gene polymorphism influences the responsiveness to β-blocker treatment on cardiac contractility. We investigated 30 healthy male volunteers who were genotyped for the Arg389Gly polymorphism and subjected to modified dobutamine stress-echocardiography (DSE) with and without pretreatment with metoprolol controlled release/extended release (CR/XL). Fractional shortening (FS) as a parameter for left-ventricular contractility and heart rate were measured. To control for pre- and afterload effects, rate corrected velocity of circumferential fiber shortening (Vcfc) was calculated. Homozygous Arg389 carriers had a significantly higher increase in contractility upon dobutamine stimulation than individuals carrying the Gly389 allele. Pretreatment with metoprolol CR/XL prior to DSE blunted the dobutamine-induced increase of FS and Vcfc in homozygous Arg389 carriers to the level of subjects carrying the Gly389 allele. In the latter group, metoprolol had a modest effect on the dobutamine-induced increase in FS at low concentrations of dobutamine, and no significant effect at peak stress (40μg/kg/min of dobutamine). The responsiveness to β-blockers with respect to cardiac contractility is determined by the Arg389Gly β(1)AR gene polymorphism. These findings offer a molecular explanation for interindividual differences in the responsiveness to β-blocker treatment in humans.

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

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 β-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.

What resting heart rate should one aim for when treating patients with heart failure with a beta-blocker?: Experiences from the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF)

The goal of this study was to explore the question: what resting heart rate (HR) should one aim for when treating patients with heart failure with a beta-blocker?The interaction of pretreatment and achieved resting HR with the risk-reducing effect of beta-blocker treatment needs further evaluation.Cardiovascular risk and risk reduction were analyzed in five subgroups defined by quintiles (Q) of pretreatment resting HR in the Metoprolol Controlled Release/Extended Release Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF).Mean baseline HR in the 5 Qs were 71, 76, 81, 87, and 98 beats/min; achieved HR 63, 66, 68, 72, and 75 beats/min; and net change -8, -10, -11, -13, and -14 beats/min, respectively. Baseline HR was related to a number of baseline characteristics. Cardiovascular risk was no different in Q1 to Q4 (placebo groups) but increased in Q5 (HR above 90 beats/min). No relationship was observed between the risk-reducing effect of metoprolol controlled release/extended release (CR/XL) and baseline HR in the five Qs of baseline HR, or achieved HR, or change in HR during follow-up, respectively.Metoprolol CR/XL significantly reduced mortality and hospitalizations independent of resting baseline HR, achieved HR, and change in HR. Achieved HR and change in HR during follow-up were closely related to baseline HR; therefore, it was not possible to answer the question posed. Instead, one has to apply a very simple rule: aim for the target beta-blocker dose used in clinical trials, and strive for the highest tolerated dose in all patients with heart failure, regardless of baseline and achieved HR.

Consistency of the beneficial effect of metoprolol succinate extended release across a wide range dose of angiotensin-converting enzyme inhibitors and digitalis

Background The effects of β-blockade with different extent of angiotensin-converting enzyme inhibitors (ACEI) and digitalization are unknown. To assess the effect of metoprolol succinate controlled release/extended release (CR/XL) combined with high versus low doses of ACEI and digitalis, we analyzed data from The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) in which patients with heart failure and left ventricular ejection fraction ≤40% were randomized to metoprolol CR/XL versus placebo. Methods and results Outcome was analyzed separately for those on a low dose (≤median) of the ACEI or digitalis versus high dose (>median). The mean dose of ACEI in the high-dose group (n = 1457) was 3 times higher than that in the low-dose group (n = 2094). Mortality was reduced to a similar extent in the high- and low-dose ACEI subgroups (RR = .69 versus .64, respectively). Corresponding figures for combined mortality/all hospitalization and for mortality/hospitalization for heart failure were .85 versus .83, and .70 versus .68, respectively. Likewise, reduction in total mortality with metoprolol CR/XL was similar in patients receiving no digitalis (n = 1447; RR = .56), low dose (n = 1122; RR = .71), or high dose (n = 1421; RR = .71). Conclusion This analysis of MERIT-HF demonstrates consistent and similar improvement in outcome of patients receiving metoprolol CR/XL when combined with either a high or low dose of an ACEI or digitalis, or no digitalis at all. Thus regardless of ACEI and digitalis dose and whether patients are treated with digitalis or not, it is very important to add a β-blocker to the existing heart failure therapy. β-blockers should not be withheld until target doses of ACEI have been achieved.

Establishing the dosage equivalency of oxymorphone extended release and oxycodone controlled release in patients with cancer pain: a randomized controlled study

SUMMARYObjective: To compare the analgesic efficacy and safety of oxymorphone extended release (ER) and oxycodone controlled release (CR) in patients with moderate to severe cancer pain.Research design and methods: This randomized, multicenter, double-blind, 2-period crossover study included adult outpatients (≥ 18 years of age) with moderate or severe cancer pain who were first titrated for 3–10 days with open-label oxymorphone or oxycodone to achieve a stable dose that provided adequate analgesia with tolerable adverse events and no requirement for more than 2 doses of rescue medication per day. The subsequent double-blind treatment phase was a 7- to 10-day period of oxycodone CR or oxymorphone ER treatment followed by crossing over to the alternate medication for another 7–10 days. During the treatment phase, up to 2 doses per day of morphine sulfate 15-mg tablets were allowed as rescue.Main outcomes and measures: Assessments included the Brief Pain Inventory, global evaluations, Karnofsky performance status, and clinical laboratory evaluations (serum chemistry profile, complete blood count, urinalysis). Efficacy variables were analyzed using a mixed-effects model with treatment, sequence, and period as fixed effects and subject as a random effect.Results: Forty-seven patients entered the titration/stabilization phase, 44 received at least 1 dose of study drug, 42 completed the first double-blind phase, and 40 completed the second double-blind phase. Mean pain intensity scores and other efficacy parameters were comparable for the 2 groups. The mean daily dosage of oxycodone CR (91.9 mg) was twice that of oxymorphone ER (45.9 mg), an equianalgesic dose ratio of 2:1. Rescue medication use was low in both groups (approximately 1 tablet of morphine sulfate 15 mg/day). No significant differences in opioid adverse events were observed between the groups.Conclusions: Adult patients with cancer who were taking oxycodone CR were readily converted to oxymorphone ER and required half the milligram dose to stabilize their pain. Within 72 h, most patients achieved a stable dose that provided adequate relief with similar opioid adverse events.

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

Background The benefit of β-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 β-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) ≤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, β-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.

How should subgroup analyses affect clinical practice? Insights from the Metoprolol Succinate Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure (MERIT-HF).

The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF), the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), and the Carvedilol Prospective Randomized Cumulative Survival Study (COPERNICUS) have all demonstrated highly significant positive effects on total mortality as well as total mortality plus all-cause hospitalization in patients with heart failure. While none of these trials are large enough to provide definitive results in any particular subgroup, it is of interest for physicians to examine the consistency of results as regards efficacy and safety for various subgroups or risk groups. To summarize results from both predefined as well as post-hoc subgroup analyses performed in the MERIT-HF trial, and to provide guidance as to whether any subgroup is at increased risk, despite an overall strongly positive effect, and to discuss the difficulties and limitations in conducting such subgroup analyses. For some subgroups we performed metaanalyses with data from the CIBIS II and COPERNICUS trials in order to obtain more robust data on mortality in subgroups with a small number of deaths (e.g. for women). MERIT-HF was run in 14 countries, and randomized a total of 3,991 patients with symptomatic systolic heart failure (NYHA class II to IV with ejection fraction < or =0.40). Treatment was initiated with a very low dose with careful titration to a maximum target dose of 200 mg metoprolol succinate controlled release/extended release (CR/XL), or highest tolerated dose. Total mortality (first primary endpoint), total mortality plus all-cause hospitalization (second primary endpoint), and total mortality plus hospitalization for heart failure (first secondary endpoint) analyzed on a time to first event basis. Overall, MERIT-HF demonstrated a 34% reduction in total mortality ( p = 0.00009 nominal) and a 19% reduction for mortality plus all-cause hospitalization ( p = 0.00012). The first secondary endpoint of mortality plus hospitalization for heart failure was reduced by 31% ( p = 0.0000008). The results were remarkably consistent for both primary outcomes and the first secondary outcome across all predefined subgroups as well as nearly all post-hoc subgroups. Metoprolol CR/XL has been very well tolerated, overall as well as in all subgroups analyzed. Overall 87% of the patients reached a dose of 100 mg or more of metoprolol CR/XL once daily, and 64% reached the target dose of 200 mg once daily. Our results show that when carefully titrated, metoprolol CR/XL can safely be instituted for the overwhelming majority of outpatients with clinically stable systolic heart failure, with minimal side effects or deterioration. The time has come to overcome the barriers that physicians perceive to beta-blocker treatment, and to provide it to the large number of patients with heart failure in need of this therapy, including also high risk patients like elderly patients, patients with severe heart failure, and patients with diabetes. Because of the increased risk, these are the patients in whom treatment will have the greatest impact as shown by number of lives saved and number of hospitalizations avoided. The target dose should be strived for in all patients who tolerate this dose. We should expect some variation of the treatment effect around the overall estimate as we examine a large number of subgroups due to small sample size in subgroups and due to chance. However, we believe that the best estimate of treatment effect for any particular subgroup should be the overall effect observed in the trial.

Antiatherosclerotic effects of β-blockers

Accumulating data from studies in animals and humans indicate that β-blockade has antiatherosclerotic effects. To date, 2 long-term ultrasound studies provide the strongest evidence. The Beta-Blocker Cholesterol-Lowering Asymptomatic Plaque Study (BCAPS) trial reported favorable effects with β-blockade on early stages of atherosclerosis in patients with carotid plaque but no symptoms of carotid artery disease. Compared with placebo, metoprolol controlled release/extended release (CR/XL) 25 mg once daily significantly reduced plaque thickness after 18 months of treatment (net difference −0.058 mm/year; p <0.001) and at 3 years’ follow-up (net difference −0.023 mm/year; p = 0.018). The Effects of Long-Term Treatment of Metoprolol CR/XL on Surrogate Variables for Atherosclerotic Disease (ELVA) trial demonstrated that β-blockers and statins affect different mechanisms in the atherosclerotic process and have additive beneficial effects. Patients with hypercholesterolemia were randomized to metoprolol CR/XL 100 mg once daily or placebo once daily and concomitant statin therapy. The metoprolol CR/XL group had a significantly lower rate of progression of the composite carotid bulb intima-media thickness (IMT) plus common carotid IMT than the placebo group, both at 1 year (−0.08 vs −0.01 mm; p = 0.004) and after 3 years’ follow-up (−0.06 vs +0.03 mm; p = 0.011). Several factors may contribute to the mechanism of benefit in these trials, including reduced sympathetic activity, improved hemodynamic parameters, and direct effects on the vascular endothelium.

Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and history of hypertension

Background: We describe the effect of controlled-release/extended-release (CR/XL) metoprolol succinate once daily on mortality and hospitalizations among patients with a history of hypertension complicated by chronic systolic heart failure. Methods and Results: We enrolled 3,991 patients with chronic heart failure of New York Heart Association functional class II–IV with an ejection fraction of ≤0.40, stabilized with optimum standard therapy, in a double-blind randomized placebo-controlled study. A total of 1,747 patients (44%) had a history of hypertension; 871 were randomized to receive metoprolol CR/XL and 876 to receive placebo. Treatment with metoprolol CR/XL compared with placebo resulted in a significant reduction in total mortality (relative risk [RR], 0.61; 95% confidence interval [CI], 0.44–0.84; P =.0022), mainly because of reductions in sudden death (RR, 0.51; 95% CI, 0.33–0.79; P =.0022) and mortality from worsening heart failure (RR, 0.49; 95% CI, 0.25–0.99; P =.042). Total number of hospitalizations for worsening heart failure was reduced by 30% in the metoprolol CR/XL group compared with placebo (P =.015). Metoprolol CR/XL was well tolerated: 12% fewer patients withdrew from study medication (all-cause) compared with placebo (P =.048). Conclusions: A subgroup analysis of MERIT-HF shows that patients with heart failure and a history of hypertension received a similar benefit from metoprolol CR/XL treatment as all patients included in the total study.

Metoprolol controlled release/extended release in patients with severe heart failure: Analysis of the experience in the MERIT-HF study

OBJECTIVESThis study analyzed the effect of the beta1-selective beta-blocker metoprolol succinate controlled release/extended release (CR/XL) once daily on mortality, hospitalizations and tolerability in patients with severe heart failure.BACKGROUNDThere continues to be resistance to the incorporation of beta-blockers into clinical care, largely due to concerns about their benefit in patients with more severe heart failure.METHODSA subgroup of patients from Metoprolol CR/XL Randomized Intervention Trial in chronic Heart Failure (MERIT-HF) in New York Heart Association (NYHA) functional class III/IV with left ventricular ejection fraction <0.25 were identified (n = 795). The analysis was by intention-to-treat.RESULTSThe mean ejection fraction at baseline was 0.19, and the yearly placebo mortality during follow-up was 19.1%. Treatment with metoprolol CR/XL compared to placebo resulted in significant reductions in all predefined mortality end points including: total mortality, 45 versus 72 deaths (risk reduction 39%; 95% confidence interval 11% to 58%; p = 0.0086); sudden death, 22 vs. 39 deaths (45% [7% to 67%]; p = 0.024); and death due to worsening heart failure, 13 vs. 28 deaths (55% [13% to 77%]; p = 0.015). Metoprolol CR/XL also reduced the number of hospitalizations for worsening heart failure by 45% compared with placebo (p < 0.0001). The NYHA functional class improved in the metoprolol CR/XL group compared with placebo (p = 0.0031). Metoprolol CR/XL was well tolerated, with 31% fewer patients withdrawn from study medicine (all causes) compared with placebo (p = 0.027).CONCLUSIONSThis subgroup analysis of the MERIT-HF study shows that patients with severe heart failure receive a similar mortality benefit and a similar reduction in hospitalizations for worsening heart failure with metoprolol CR/XL treatment as those patients included in the total study.

Metoprolol: a review of its use in chronic heart failure.

Metoprolol, a relatively selective beta1-blocker, is devoid of intrinsic sympathomimetic activity and possesses weak membrane stabilising activity. The drug has an established role in the management of essential hypertension and angina pectoris, and more recently, in patients with chronic heart failure. The effects of metoprolol controlled-release/extended-release (CR/XL) in patients with stable, predominantly mild to moderate (NYHA functional class II to III) chronic heart failure have been evaluated in the large Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) trial and the much smaller Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Treatment with metoprolol CR/XL was initiated at a low dosage of 12.5 to 25 mg once daily and gradually increased at 2-weekly intervals until the target dosage (200 mg once daily) or maximal tolerated dosage had been attained in patients receiving standard therapy for heart failure. At 12 months, metoprolol CR/XL was associated with a 34% reduction in relative risk of all-cause mortality in patients with chronic heart failure due to ischaemic or dilated cardiomyopathy in the MERIT-HF trial. The incidence of sudden death and death due to progressive heart failure were both significantly decreased with metoprolol CR/XL. Similarly, a trend towards decreased mortality in the metoprolol CR/XL group compared with placebo was observed in the RESOLVD trial. Data from small numbers of patients with severe (NYHA functional class IV) heart failure indicate that metoprolol CR/XL is effective in this subset of patients. However, no firm conclusions can yet be drawn. Improvement from baseline values in NYHA functional class, exercise capacity and some measures of quality of life with metoprolol CR/XL or immediate-release metoprolol were significantly greater than those with placebo. The drug is well tolerated when treatment is initiated in low dosages and gradually increased at intervals of 1 to 2 weeks. Metoprolol CR/XL effectively decreases mortality and improves clinical status in patients with stable mild to moderate (NYHA functional class II or III) chronic heart failure due to left ventricular systolic dysfunction, and the drug is effective in patients with ischaemic or dilated cardiomyopathy. Although limited data indicate that metoprolol CR/XL is effective in patients with severe (NYHA functional class IV) chronic heart failure, more data are needed to confirm these findings. Treatment with metoprolol CR/XL significantly reduced the incidence of sudden death and death due to progressive heart failure.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in-Congestive Heart Failure (MERIT-HF)

Metoprolol can improve haemodynamics in chronic heart failure, but survival benefit has not been proven. We investigated whether metoprolol controlled release/extended release (CR/XL) once daily, in addition to standard therapy, would lower mortality in patients with decreased ejection fraction and symptoms of heart failure. We enrolled 3991 patients with chronic heart failure in New York Heart Association (NYHA) functional class II-IV and with ejection fraction of 0.40 or less, stabilised with optimum standard therapy, in a double-blind randomised controlled study. Randomisation was preceded by a 2-week single-blind placebo run-in period. 1990 patients were randomly assigned metoprolol CR/XL 12.5 mg (NYHA III-IV) or 25.0 mg once daily (NYHA II) and 2001 were assigned placebo. The target dose was 200 mg once daily and doses were up-titrated over 8 weeks. Our primary endpoint was all-cause mortality, analysed by intention to treat. The study was stopped early on the recommendation of the independent safety committee. Mean follow-up time was 1 year. All-cause mortality was lower in the metoprolol CR/XL group than in the placebo group (145 [7.2%, per patient-year of follow-up]) vs 217 deaths [11.0%], relative risk 0.66 [95% CI 0.53-0.81]; p=0.00009 or adjusted for interim analyses p=0.0062). There were fewer sudden deaths in the metoprolol CR/XL group than in the placebo group (79 vs 132, 0.59 [0.45-0.78]; p=0.0002) and deaths from worsening heart failure (30 vs 58, 0.51 [0.33-0.79]; p=0.0023). Metoprolol CR/XL once daily in addition to optimum standard therapy improved survival. The drug was well tolerated.

Rationale, Design, and Organization of the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF)

Metoprolol is a cardioselective β blocker that has been shown to improve left ventricular function and symptoms of congestive heart failure (CHF) and also to decrease the number of hospitalizations due to CHF. However, the effects of metoprolol on mortality in patients with CHF have yet to be determined. Accordingly, the Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF) has been designed to investigate the effect of once-daily dosing of metoprolol succinate controlled release/extended release (CR/XL) when added to standard therapy in patients with CHF. A total of 3,200 patients will be recruited for this international, double-blind, randomized, placebo-controlled survival study. The 2 primary objectives of MERIT-HF are to determine the effect of metoprolol CR/XL on (1) total mortality and (2) the combined endpoint of all-cause mortality and all-cause hospitalizations (time to first event). Eligible patients are 40–80 years old, with a reduced left ventricular ejection fraction (≤0.40) and symptoms of CHF (New York Heart Association functional classes II–IV). After a 2-week placebo run-in period, an optimal allocation procedure will be used to randomize patients in a 1:1 ratio to metoprolol CR/XL or matching placebo. After an initial titration phase starting with 12.5 mg or 25 mg once daily (depending on functional class), the target dose will be 200 mg in all patients who tolerate this dose. The mean follow-up is estimated to be 2.4 years. The study data will be analyzed on an intention-to-treat basis. An Independent Safety Committee will monitor the safety aspects of the trial, and an Independent Endpoint Committee will classify all endpoints.