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The New England Journal of Medicine Apr 2024Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an era before modern biomarker-based diagnosis of myocardial infarction and treatment with percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin-angiotensin-aldosterone system antagonists.
METHODS
In a parallel-group, open-label trial performed at 45 centers in Sweden, Estonia, and New Zealand, we randomly assigned patients with an acute myocardial infarction who had undergone coronary angiography and had a left ventricular ejection fraction of at least 50% to receive either long-term treatment with a beta-blocker (metoprolol or bisoprolol) or no beta-blocker treatment. The primary end point was a composite of death from any cause or new myocardial infarction.
RESULTS
From September 2017 through May 2023, a total of 5020 patients were enrolled (95.4% of whom were from Sweden). The median follow-up was 3.5 years (interquartile range, 2.2 to 4.7). A primary end-point event occurred in 199 of 2508 patients (7.9%) in the beta-blocker group and in 208 of 2512 patients (8.3%) in the no-beta-blocker group (hazard ratio, 0.96; 95% confidence interval, 0.79 to 1.16; P = 0.64). Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points (death from any cause, 3.9% in the beta-blocker group and 4.1% in the no-beta-blocker group; death from cardiovascular causes, 1.5% and 1.3%, respectively; myocardial infarction, 4.5% and 4.7%; hospitalization for atrial fibrillation, 1.1% and 1.4%; and hospitalization for heart failure, 0.8% and 0.9%). With regard to safety end points, hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker occurred in 3.4% of the patients in the beta-blocker group and in 3.2% of those in the no-beta-blocker group; hospitalization for asthma or chronic obstructive pulmonary disease in 0.6% and 0.6%, respectively; and hospitalization for stroke in 1.4% and 1.8%.
CONCLUSIONS
Among patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (≥50%), long-term beta-blocker treatment did not lead to a lower risk of the composite primary end point of death from any cause or new myocardial infarction than no beta-blocker use. (Funded by the Swedish Research Council and others; REDUCE-AMI ClinicalTrials.gov number, NCT03278509.).
Topics: Humans; Adrenergic beta-Antagonists; Bisoprolol; Heart Failure; Myocardial Infarction; Stroke Volume; Treatment Outcome; Ventricular Function, Left; Metoprolol; Secondary Prevention
PubMed: 38587241
DOI: 10.1056/NEJMoa2401479 -
The New England Journal of Medicine Dec 2019Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.
METHODS
In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.
RESULTS
A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.
CONCLUSIONS
Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Aged, 80 and over; Disease Progression; Female; Forced Expiratory Volume; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Metoprolol; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Treatment Failure
PubMed: 31633896
DOI: 10.1056/NEJMoa1908142 -
JAMA May 2024Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly... (Comparative Study)
Comparative Study
IMPORTANCE
Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation.
OBJECTIVE
To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024.
EXPOSURES
Diltiazem and metoprolol.
MAIN OUTCOMES AND MEASURES
The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting.
RESULTS
The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26).
CONCLUSIONS AND RELEVANCE
In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Atrial Fibrillation; Diltiazem; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Hemorrhage; Hospitalization; Medicare; Metoprolol; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; United States
PubMed: 38619832
DOI: 10.1001/jama.2024.3867 -
Clinical Pharmacokinetics Aug 2022Metoprolol is recommended for therapeutic use in multiple cardiovascular conditions, thyroid crisis, and circumscribed choroidal hemangioma. A detailed systematic review...
BACKGROUND
Metoprolol is recommended for therapeutic use in multiple cardiovascular conditions, thyroid crisis, and circumscribed choroidal hemangioma. A detailed systematic review on the metoprolol literature would be beneficial to assess all pharmacokinetic parameters in humans and their respective effects on patients with hepatic, renal, and cardiovascular diseases. This review combines all the pharmacokinetic data on metoprolol from various accessible studies, which may assist in clinical decision making.
METHODOLOGY
The Google Scholar and PubMed databases were searched to screen articles associated with the clinical pharmacokinetics of metoprolol. The comprehensive literature search retrieved 41 articles including data on plasma concentration-time profiles after intravenous and oral (immediate-release, controlled-release, slow-release, or extended-release) routes of administration, and at least one pharmacokinetic parameter was reported in all studies included.
RESULTS
Out of 41 retrieved articles, six were after intravenous and 12 were after oral administration in healthy individuals. The oral studies depict a dose-dependent increase in maximum plasma concentration (C), time to reach maximum plasma concentration (T), and area under the concentration-time curve (AUC). Two studies were conducted in R- and S-enantiomers, in which one study reported the gender differences, depicting greater C and AUC among women, whereas in another study S-metoprolol was found to have higher values of C, T, and AUC in comparison with R-metoprolol. Results in different diseases depicted that after IV administration of 20 mg, patients with renal impairment showed an increase in clearance (CL) (60 L/h vs 48 L/h) compared with healthy subjects, whereas a decrease in CL (36.6 ± 7.8 L/h vs 48 ± 6.6 L/h) was seen in patients with hepatic cirrhosis at a similar dose. In comparison with a single oral dose following administration of 15 mg IV in three divided doses, patients having an acute myocardial infarction (AMI) showed an increase in C (823 nmol/L vs 248 nmol/L) at a steady state. Twenty different studies have reported significant changes in CL, C and AUC of metoprolol when it is co-administered with other drugs. One study has reported a drug-food interaction for metoprolol but no significant changes were seen in the C and AUC.
CONCLUSION
This review summarizes all the pharmacokinetic parameters of metoprolol after pooling up-to-date data from all the studies available. The summarized pharmacokinetic data presented in this review can assist in developing and evaluating pharmacokinetic models of metoprolol. Moreover, this data can provide practitioners with an insight into dosage adjustments among the diseased populations and can assist in preventing potential adverse drug reactions. This review can also help avoid side effects and drug-drug interactions.
Topics: Administration, Oral; Area Under Curve; Female; Food-Drug Interactions; Humans; Liver; Metoprolol
PubMed: 35764772
DOI: 10.1007/s40262-022-01145-y -
The American Journal of Emergency... Jan 2022Intravenous diltiazem and metoprolol are both commonly used to treat atrial fibrillation (AF) with rapid ventricular rate (RVR) in the emergency department (ED), but the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intravenous diltiazem and metoprolol are both commonly used to treat atrial fibrillation (AF) with rapid ventricular rate (RVR) in the emergency department (ED), but the advantages and disadvantages of these drugs cannot be verified. This meta-analysis aimed to assess the efficacy and safety of intravenous diltiazem versus metoprolol for AF with RVR.
METHOD
We systematically searched PubMed, Web of Science, Embase, Cochrane library, the China National Knowledge Infrastructure (CNKI), Wanfang, China Biology Medicine disc (CBM) and the WeiPu (VIP). Meta-analysis was performed using weighted mean difference (WMD), relative risk (RR) and 95% confidence interval (CI). Statistical analysis was performed using Review Manager 5.4.1.
RESULTS
Seventeen studies involving 1214 patients in nine randomized controlled trials (RCTs) and eight cohort studies were included in meta-analysis, including 643 patients in the intravenous diltiazem group and 571 patients group in the intravenous metoprolol. The results of the meta-analysis showed that compared with intravenous metoprolol, intravenous diltiazem was found higher efficacy (RR =1.11; 95% CI = 1.06 to 1.16, p < 0.00001), shorter average onset time (RR = -1.13; 95% CI = -1.97 to -0.28, p = 0.009), lower ventricular rate (RR = -9.48; 95% CI = -12.13 to -6.82, p<0.00001), less impact on systolic blood pressure (WMD = 3.76; 95% CI: 0.20 to 7.33, P = 0.04), and no significant difference in adverse events (RR = 0.80, 95% CI = 0.55 to 1.14, P = 0.22) and diastolic blood pressure (WMD = -1.20; 95% CI: -3.43 to 1.04, P = 0.29) was found between intravenous diltiazem and metoprolol.
CONCLUSION
Intravenous diltiazem has higher efficacy, shorter average onset time, lower ventricular rate, less impact on blood pressure, and with no increase in adverse events compared to intravenous metoprolol.
Topics: Administration, Intravenous; Atrial Fibrillation; Blood Pressure; Diltiazem; Heart Rate; Humans; Metoprolol; Randomized Controlled Trials as Topic
PubMed: 34781150
DOI: 10.1016/j.ajem.2021.08.082 -
Journal of the American College of... Dec 2021The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and observational cohort studies.
OBJECTIVES
This study aimed to investigate the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in patients with obstructive HCM.
METHODS
This double-blind, placebo-controlled, randomized crossover trial enrolled 29 patients with obstructive HCM and New York Heart Association (NYHA) functional class II or higher symptoms from May 2018 to September 2020. Patients received metoprolol or placebo for 2 consecutive 2-week periods in random order. The effect parameters were LVOT gradients, NYHA functional class, Canadian Cardiovascular Society (CCS) angina class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and cardiopulmonary exercise testing.
RESULTS
Compared with placebo, the LVOT gradient during metoprolol was lower at rest (25 mm Hg [interquartile range (IQR): 15-58 mm Hg] vs 72 mm Hg [IQR: 28-87 mm Hg]; P = 0.007), at peak exercise (28 mm Hg [IQR: 18-40 mm Hg] vs 62 mm Hg [IQR: 31-113 mm Hg]; P < 0.001), and postexercise (45 mm Hg [IQR: 24-100 mm Hg] vs 115 mm Hg [IQR: 55-171 mm Hg]; P < 0.0001). During metoprolol treatment, 14% of patients were in NYHA functional class III or higher compared with 38% of patients receiving placebo (P < 0.01). Similarly, no patients were in CCS class III or higher during metoprolol treatment compared with 10% during placebo treatment (P < 0.01). These findings were confirmed by higher KCCQ-OSS during metoprolol treatment (76.2 ± 16.2 vs 73.8 ± 19.5; P = 0.039). Measures of exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide did not differ between the study arms.
CONCLUSIONS
Compared with placebo, metoprolol reduced LVOT obstruction at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. (The Effect of Metoprolol in Patients with Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Cardiomyopathy, Hypertrophic; Cross-Over Studies; Double-Blind Method; Exercise Tolerance; Female; Humans; Male; Metoprolol; Middle Aged; Ventricular Outflow Obstruction
PubMed: 34915981
DOI: 10.1016/j.jacc.2021.07.065 -
The Journal of Experimental Medicine Nov 2023Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release...
Chimeric antigen receptor (CAR) T therapies have achieved remarkable success for treating hematologic malignancies, yet are often accompanied by severe cytokine release syndrome (CRS). Here, an accidental clinical observation raised the possibility that metoprolol, an FDA-approved β1 adrenergic receptor blocker widely used for cardiovascular conditions, may alleviate CAR T-induced CRS. Metoprolol effectively blocked IL-6 production in human monocytes through unexpected mechanisms of action of targeting IL-6 protein translation but not IL6 mRNA expression. Mechanistically, metoprolol diminished IL-6 protein synthesis via attenuating eEF2K-eEF2 axis-regulated translation elongation. Furthermore, an investigator-initiated phase I/II clinical trial demonstrated a favorable safety profile of metoprolol in CRS management and showed that metoprolol significantly alleviated CAR T-induced CRS without compromising CAR T efficacy. These results repurposed metoprolol, a WHO essential drug, as a potential therapeutic for CRS and implicated IL-6 translation as a mechanistic target of metoprolol, opening venues for protein translation-oriented drug developments for human inflammatory diseases.
Topics: Humans; Receptors, Chimeric Antigen; Interleukin-6; Cytokine Release Syndrome; Cytokines; Metoprolol; Immunotherapy, Adoptive
PubMed: 37584653
DOI: 10.1084/jem.20230577 -
The Journal of Emergency Medicine Aug 2015Diltiazem (calcium channel blocker) and metoprolol (beta-blocker) are both commonly used to treat atrial fibrillation/flutter (AFF) in the emergency department (ED).... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Diltiazem (calcium channel blocker) and metoprolol (beta-blocker) are both commonly used to treat atrial fibrillation/flutter (AFF) in the emergency department (ED). However, there is considerable regional variability in emergency physician practice patterns and debate among physicians as to which agent is more effective. To date, only one small prospective, randomized trial has compared the effectiveness of diltiazem and metoprolol for rate control of AFF in the ED and concluded no difference in effectiveness between the two agents.
OBJECTIVE
Our aim was to compare the effectiveness of diltiazem with metoprolol for rate control of AFF in the ED.
METHODS
A convenience sample of adult patients presenting with rapid atrial fibrillation or flutter was randomly assigned to receive either diltiazem or metoprolol. The study team monitored each subject's systolic and diastolic blood pressures and heart rates for 30 min.
RESULTS
In the first 5 min, 50.0% of the diltiazem group and 10.7% of the metoprolol group reached the target heart rate (HR) of <100 beats per minute (bpm) (p < 0.005). By 30 min, 95.8% of the diltiazem group and 46.4% of the metoprolol group reached the target HR < 100 bpm (p < 0.0001). Mean decrease in HR for the diltiazem group was more rapid and substantial than that of the metoprolol group. From a safety perspective, there was no difference between the groups with respect to hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (HR < 60 bpm).
CONCLUSIONS
Diltiazem was more effective in achieving rate control in ED patients with AFF and did so with no increased incidence of adverse effects.
Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Blood Pressure; Diltiazem; Double-Blind Method; Emergency Service, Hospital; Female; Heart Rate; Humans; Male; Metoprolol; Prospective Studies; Sampling Studies; Tachycardia, Ventricular
PubMed: 25913166
DOI: 10.1016/j.jemermed.2015.01.014 -
Academic Emergency Medicine : Official... Feb 2023The objective was to evaluate the comparative effectiveness and safety of pharmacological and nonpharmacological management options for atrial fibrillation/atrial... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The objective was to evaluate the comparative effectiveness and safety of pharmacological and nonpharmacological management options for atrial fibrillation/atrial flutter with rapid ventricular response (AFRVR) in patients with acute decompensated heart failure (ADHF) in the acute care setting.
METHODS
This study was a systematic review of observational studies or randomized clinical trials (RCT) of adult patients with AFRVR and concomitant ADHF in the emergency department (ED), intensive care unit, or step-down unit. The primary effectiveness outcome was successful rate or rhythm control. Safety outcomes were adverse events, such as symptomatic hypotension and venous thromboembolism.
RESULTS
A total of 6577 unique articles were identified. Five studies met inclusion criteria: one RCT in the inpatient setting and four retrospective studies, two in the ED and the other three in the inpatient setting. In the RCT of diltiazem versus placebo, 22 patients (100%) in the treatment group had a therapeutic response compared to 0/15 (0%) in the placebo group, with no significant safety differences between the two groups. For three of the observational studies, data were limited. One observation study showed no difference between metoprolol and diltiazem for successful rate control, but worsening heart failure symptoms occurred more frequently in those receiving diltiazem compared to metoprolol (19 patients [33%] vs. 10 patients [15%], p = 0.019). A single study included electrical cardioversion (one patient exposed with failure to convert to sinus rhythm) as nonpharmacological management. The overall risk of bias for included studies ranged from serious to critical. Missing data and heterogeneity of definitions for effectiveness and safety outcomes precluded the combination of results for quantitative meta-analysis.
CONCLUSIONS
High-level evidence to inform clinical decision making regarding effective and safe management of AFRVR in patients with ADHF in the acute care setting is lacking.
Topics: Adult; Humans; Atrial Fibrillation; Atrial Flutter; Diltiazem; Metoprolol; Anti-Arrhythmia Agents; Heart Failure; Randomized Controlled Trials as Topic; Observational Studies as Topic
PubMed: 36326565
DOI: 10.1111/acem.14618 -
Journal of Critical Care Jun 2018
Topics: Amiodarone; Arrhythmias, Cardiac; Humans; Metoprolol; Propafenone; Shock, Septic
PubMed: 29397254
DOI: 10.1016/j.jcrc.2018.01.024