The Food and Drug Administration considers a side effect serious if it is life-threatening, requires a hospital stay, or causes permanent damage or disability.1 The agency requires medication guides be issued when, in their view, serious side effects could occur while taking a medication. There are no medication guides issued for beta blockers.2 However, serious side effects can occur.
Manufacturers of beta blockers warn that continued depression of myocardial contractility with beta blockers can worsen or lead to cardiac failure.3-5 They also caution that beta blockers may worsen severe anaphylactic allergic reactions and reduce the effectiveness of epinephrine used to treat them.3-11
Serious Side Effects of Different Beta Blockers
A 2017 Cochrane Review meta-analysis of beta blockers analyzed 13 randomized-controlled trials with 40,245 hypertensive patients.14 Three-quarters of the studies used atenolol, and no studies on vasodilating beta blockers were included in this analysis. Participants taking beta-blockers were more likely to discontinue treatment due to adverse events than participants taking renin-angiotensin system inhibitors (risk ratio [RR] 1.41, 95% confidence interval [CI] [1.29 – 1.54]), but the difference of withdrawal rates were not significant when compared with placebo, diuretics, or calcium channel blockers. The certainty of the author’s conclusions, however, was moderate to low because of the heterogeneity of the studies involved. The study did not specify incidences of serious side effects.
Atenolol. Manufacturers of atenolol report the potentially serious adverse effects bradycardia, dyspnea, and wheezing in more than 1% of the studied hypertensive patients, regardless of causality.3,15 A randomized, double-blind study of 1,292 hypertensive men (mean age 59 ± 10 years; 48% black) compared six antihypertensive drugs and placebo for efficacy and tolerability.16 It found that the withdrawal rate due to subjective side effects for patients on atenolol (5%) was less than those of patients on captopril (7%) or placebo (6%). No side effects occurred more frequently in patients taking atenolol than placebo.
Carvedilol. Many trials studying the safety of carvedilol report that serious adverse reactions occur less often in participants on carvedilol than in those on placebo.17-22 A double-blind, placebo-controlled trial studied the efficacy of carvedilol extended-release capsules on 320 patients with either essential hypertension, history of hypertension, or uncontrolled hypertension despite antihypertensive treatment.21 There were no differences found between the placebo and the carvedilol group in adverse events that resulted in discontinuation of treatment. There were two separate incidences of serious adverse events (pneumonia and myocardial infarction [MI]), neither of which were caused by the therapy.
Studies on patients with heart failure also report similar findings.18-20 The US Carvedilol Heart Failure Study Group conducted a double-blinded, stratified study on 1094 patients with mild, moderate, or severe chronic heart failure with left ventricular ejection fraction (LVEF) ≤35%.18 The carvedilol group (n=696), compared to the placebo group (n=398), had a reduced risk of hospitalization for cardiovascular causes (14.1% vs. 19.6%) by 27% (95% CI [2 – 45], p=0.036) and a reduced combined risk of hospitalization for cardiovascular causes or death (15.8% vs. 24.6%) by 38% (95% CI [18 – 53], p<0.001). In another double-blind, placebo-controlled trial of 2,289 patients with severe heart failure and LVEF <25%, 1,133 patients were randomized to the placebo group and 1,156 to the carvedilol group.20 Serious adverse events were experienced less in patients randomized to the carvedilol group (39.0%) than those randomized to the placebo group (45.5%) (p=0.002). Many serious adverse events were reported significantly less often in patients on carvedilol than in patients on placebo, including heart failure (16.6% in the carvedilol group vs. 24.1% p<0.0001), sudden death (3.9% vs. 6.1%, p=0.016), MI/unstable angina (3.0% vs. 4.4%, p=0.080), and many others.
Metoprolol. Manufacturers of metoprolol report the potentially serious adverse effects shortness of breath, wheezing, bradycardia, palpitations, and congestive heart failure in more than 1% of the studied hypertensive patients, regardless of causality.5,11 Efficacy and tolerability of metoprolol as a monotherapy or a combined therapy with hydrochlorothiazide (HCTZ) were studied in 21,692 older hypertensive patients.23 Adverse effects were reported in 4.5% of the total study population, including fatigue (0.8%), dizziness (0.8%), weakness (0.4%), and nausea (0.4%), none of which were serious. Among those who did not complete the study, 3.1% of patients withdrew from the study due to adverse experiences. The study did not report any further analysis on the occurrence of side effects, but the participating physicians noted excellent or good tolerability for 93.5% of the patients.
A large randomized, placebo-controlled trial of metoprolol on 45,852 patients with acute MI found that among survivors, patients on metoprolol experienced vascular adverse events (mainly sinus arrest or bradycardia, atrial arrhythmia, bundle branch block, or atrial-ventricular junctional escape) more often (0.5%) than patients on placebo (0.3%) (1.94 odds ratio [OR], 95% CI [1.44 – 2.61], p<0.0001) and respiratory adverse events (mainly asthma or bronchospasm) more often (0.2% vs. 0.0%, OR 3.46, 95% CI [2.07 – 5.80], p<0.0001).24
Nebivolol. Manufacturers of nebivolol report findings on adverse effects studied in three 12-week, placebo-controlled trials with the 1,597 hypertensive patients on 5 mg, 10 mg, and 20 – 40 mg of nebivolol.4 Bradycardia, chest pain, and dyspnea were reported in more than 1% of patients, regardless of causality. In a randomized, placebo-controlled trial of nebivolol on 2,016 hypertensive patients, more patients receiving the nebivolol treatment (1.2%) reported serious adverse events than did the patients receiving the placebo (0.5%).25 Most serious adverse events were due to cardiac disorders such as acute MI, unstable angina, congestive heart failure, and coronary artery disease and occurred in 0.06% with nebivolol and 0% with placebo. A study of 913 hypertensive patients found no significant difference between the nebivolol (46.1%) and the placebo (40.7%) group in the incidence of adverse events (p=0.273).26 However, they observed serious adverse events in the nebivolol group (n=11) more often than in the placebo group (n=1).26 Only two of the 11 serious adverse events were considered possibly drug-related – abnormal ECG waves that resolved spontaneously, without discontinuation of treatment.
References
- U.S. Department of Health and Human Services. What is a Serious Adverse Event? U.S. Food & Drug Administration. https://www.fda.gov/default.htm. Accessed September 6, 2018.
- Food and Drug Administration. Medication Guides. https://www.fda.gov/Drugs/DrugSafety/ucm085729.htm. Accessed Nov 16, 2018. .
- Tenormin [package insert]. Conovanas, PR: AstraZeneca Pharmaceuticals LP; 2011.
- Bystolic [package insert]. St. Louis, MO: Forest Pharmaceuticals; 2011.
- Lopressor [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2008.
- Auro-Carvedilol [package insert]. Ontario, CA: Aurobindo Pharma Inc.; 2013.
- Coreg [package insert]. Ciales, PR: GK Pharmaceuticals Contract Manufacturing Operations; 2008.
- Coreg CR [package insert]. Ciales, PR: GK Pharmaceuticals Contract Manufacturing Operations; 2008.
- APO-Carvedilol [package insert]. Toronto, Canada: Apotex Pharmaceutical Holdings Inc.; 2015.
- Trandate [package insert]. Oakville, ON: Prometheus Laboratories Inc.; 2010.
- Metoprolol succinate extended-release tablets [package insert]. Sodertalje, Sweden: AstraZeneca AB; 2006.
- Koro CE, Sowell MD, Stender M. An assessment of the association between carvedilol exposure and severe hypersensitivity reactions, angioedema, and anaphylactic reactions: a retrospective nested case-control analysis. Clin Ther. 2012;34(4):870-877.
- Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: Recommendations for patient information. Int J Cardiol. 2013;168(4):3572-3579.
- Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. The Cochrane Database of Systematic Reviews. 2017(1).
- Tenormin Injection [package insert]. Conovanas, PR: AstraZeneca Pharmaceuticals LP; 2016.
- Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med. 1993;328(13):914-921.
- Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996;94(11):2793-2799.
- Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334(21):1349-1355. 1996.
- Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344(22):1651-1658.
- Packer M. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194-2199.
- Weber MA, Bakris GL, Tarka EA, Iyengar M, Fleck R, Sica DA. Efficacy of a once-daily formulation of carvedilol for the treatment of hypertension. J Clin Hypertens. 2006;8(12):840-849.
- Weber K, Bohmeke T, van der Does R, Taylor SH. Comparison of the hemodynamic effects of metoprolol and carvedilol in hypertensive patients. Cardiovasc Drugs Ther. 1996;10(2):113-117.
- LaPalio L, Schork A, Glasser S, Tifft C. Safety and efficacy of metoprolol in the treatment of hypertension in the elderly. J Am Geriatr Soc. 1992;40(4):354-358.
- Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366(9497):1622-1632.
- Weiss RJ, Saunders E, Greathouse M. Efficacy and tolerability of nebivolol in stage I-II hypertension: a pooled analysis of data from three randomized, placebo-controlled monotherapy trials. Clin Ther. 2011;33(9):1150-1161.
- Weiss RJ, Weber MA, Carr AA, Sullivan WA. A randomized, double-blind, placebo-controlled parallel-group study to assess the efficacy and safety of nebivolol, a novel beta-blocker, in patients with mild to moderate hypertension. J Clin Hypertens. 2007;9(9):667-676.
