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Labetolol vs. Other Beta-blockers Replacement/Addition to the List Peer Feedback: "Most common used beta blockers are Acebotolol, Atenolol, Metoprolol, Carvedilol and Sotolol” “(Metaprolol is a) Very commonly used beta blocker" Comment: "Labetalol - also should be reassessed - replaced by alterantive beta-blocker" Literature Review Question: What is the most effacious and safe beta blocker? Literature Search: eCPS – Hypertension, Heart Failure PubMed - beta blockers AND (acebutolol OR atenolol OR metoprolol OR carvedilol OR sotalol OR labetolol) AND comparison AND efficacy; “pregnancy AND beta blockers AND (labetalol OR labetolol) AND safety” Large scale comparison of bisoprolol, metoprolol, carvedilol and nebivolol (2014) 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. 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. Wikstrand, John, et al. "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." Journal of internal medicine 275.2 (2014): 134-143. Benefits of β blockers (2013) Retrospective analyses have compared different β blockers and their effect on clinical endpoints in chronic heart failure, and no superiority was found for one individual class over another in reducing mortality or readmissions.40 41 When the surrogate endpoint of improvement in ejection fraction has been investigated, superiority of any one class of β blockers could not be definitely established.42 With this robust evidence in favor of β blockers in chronic heart failure, we decided to assess the efficacy of one β blocker over another by comparing them using a Bayesian network meta-analysis, in view of paucity of head to head trial data, except for the COMET study.10 Also, to our knowledge, the question of tolerability and premature discontinuation of β blockers in chronic heart failure has not been investigated, except in isolated trials,so we decided to pool the data from different trials to assess the important question of tolerability and the discontinuation rates of different β blockers in heart failure with reduced ejection fraction.43 Our analysis reassuringly shows that overall, the tolerability, as indicated by discontinuation rates in different randomized trials, of β blockers as a class of drugs is generally good and comparable to a range of pharmacologically active and inactive comparators. Our analysis shows that among the different β blockers in current use, bisoprolol, carvedilol, and metoprolol all had significant mortality benefit compared with placebo/standard heart failure treatment. However, our data additionally indicate that carvedilol was not only superior to placebo/standard heart failure treatment for all-cause mortality but also had the lowest cardiac mortality numerically among all β blockers tested, although this was not statistically significant, indicating a benefit for its use in patients with cardiovascular comorbidities as an empiric initial treatment of choice. This finding was congruent in our analysis with the results and subgroup analyses from COMET,10 44 possibly as a result of a beneficial effect of carvedilol on endothelial function, its stimulatory effects on β arresting signaling, and its anti-oxidant properties.45-47 Carvedilol has also been found to be superior to metoprolol in maintaining a favorable glycemic profile in patients with diabetes, improved insulin sensitivity, and decreased progression to microalbuminuria, all of which have been shown to have cardio protective effects.48 Considering the lack of differences in improvement of mortality with use of individual β blockers in chronic heart failure, as shown in our data, we consider it pragmatic to infer that, although the data may be limited, we have three agents (bisoprolol, sustained release metoprolol succinate, and carvedilol) that have been tested more extensively and have been shown to be superior to placebo in our analysis (95% credible interval did not include 1) Chatterjee, Saurav, et al. "Benefits of β blockers in patients with heart failure and reduced ejection fraction: network metaanalysis." BMJ 346 (2013): f55. Cochrane Review (2012) Though beta-blockers are a heterogeneous group of pharmacological agents, differing in betaadrenergic receptor selectivity, intrinsic sympathomimetic activity, and vasodilatory capabilities (Pedersen 2007; Kamp 2010; Polónia 2010), we found no outcome trials with head-to-head comparisons between beta-blockers for the treatment of hypertension. Of the 40,245 participants using beta-blockers in this review, atenolol was used by 30,150 participants (75%). Due to the paucity of data using beta-blockers other than atenolol, it is not possible to say whether the (lack of) effectiveness and (in)tolerability of beta-blockers seen in this review is a property of atenolol or is a class effect of beta-blockers across the board. From this review we cannot support the claim by Lindhom and colleagues that cardioselective beta-blockers may be inferior to nonselective ones in the treatment of hypertension (Carlberg 2004). A limitation of both previous reviews and ours is the absence of trials assessing the effects of the new vasodilating beta-blockers (e.g. carvedilol, bucindolol, and nebivolol) on mortality and hard cardiovascular outcomes. Possible mechanisms to explain the poor ability of beta-blockers to reduce stroke include a propensity to cause diabetes (Opie 2004), a failure to decrease central aortic pressure as much as brachial pressure (Williams 2006; Polónia 2010), and others. Diabetes likely requires years to develop cardiovascular complications (Verdecchia 2004), so we favour the mechanism involving lesser reduction of central aortic pressure by beta-blockers. Vasodilating beta-blockers (Broeders 2000;Kalinowski 2003) have been shown to reduce central pressures better than conventional beta-blockers (Kamp 2010; Polónia 2010); most probably because vasodilatation favourably alters the pattern of the pressure wave reflecting back from the periphery, thereby lowering the central pressure. Nonetheless, carvedilol and nebivolol also cause bradycardia, which is thought to be the principal mechanism whereby atenolol ± thiazide may be less able to lower the central pressure than amlodipine ± perindopril (Williams 2006). At any rate, high-quality outcome studies are required to show that hard cardiovascular endpoints such as stroke and coronary heart disease are significantly reduced by beta-blockers not studied in this review. Wiysonge, Charles Shey, et al. "Beta-blockers for hypertension." Cochrane Database Syst Rev 11 (2012). Hypertension in Pregnancy (2012) Methyldopa (FDA pregnancy category B) is the preferred first-line agent to lower maternal blood pressures in chronic or gestational hypertension.153,155,156 Labetalol (FDA pregnancy category C) is considered an equally appropriate firstline agent and may be better tolerated than methyldopa by the mother.153,155,156,158 Six head-to-head studies159-164 compare labetalol and methyldopa and in all but one,164 maternal tolerance was reported with either agent. In this study, women with pregnancy-induced hypertension reported less drowsiness, headache, and hypotension with labetalol compared to methyldopa.164 The small study populations and the trial designs limit the ability to draw firm conclusions from this data. The adverse effect profile in general is more favorable for labetalol compared to methyldopa. The most commonly expected adverse effects associated with labetalol include hypotension, dizziness, and fatigue, while those most commonly expected with methyldopa include peripheral edema, depression, anxiety, drowsiness, headache, and dry mouth. The preferred first-line agent for management of acute, severely elevated blood pressure during pregnancy is hydralazine, an FDA pregnancy category C drug154-156 (Table 5). Labetalol is an equally appropriate first-line treatment option whose use is growing with its evolving safety profile Bulloch, Marilyn N., and Dana G. Carroll. "When One Drug Affects 2 Patients A Review of Medication for the Management of Nonlabor-Related Pain, Sedation, Infection, and Hypertension in the Hospitalized Pregnant Patient." Journal of pharmacy practice 25.3 (2012): 352-367. eCPS (2015) Class Beta1-adrenergic Antagonists, β1selective with ISA Beta1-adrenergic Antagonists, β1selective Drug acebutolol Sectral, generics atenolol Tenormin, generics Dose Adverse Effects Drug Interactions Commentsd Initial: 100 mg/day Usual: 400 mg/day Maximum: 800 mg/day Once daily or divided BID po Fatigue, bradycardia, decreased exercise capacity, headache, impotence, vivid dreams. Less common: hyperglycemia, depression, heart failure, heart block. Bradycardia with digoxin or nondihydropyridine CCBs. Cardiodepressant effects with nondihydropyridine CCBs and amiodarone. Agents with ISA have less effect on resting heart rate than those without ISA. Initial: 25 mg/day Usual: 50 mg/day Maximum:100 mg/day Fatigue, bradycardia, decreased exercise capacity, headache, impotence, vivid dreams. Less common: hyperglycemia, depression, heart failure, heart block. Once daily or divided BID po Beta1-adrenergic Antagonists carvedilol generics Initial: 3.125 mg BID po Fewer noncardiac effects due to cardioselectivity. Fewer noncardiac effects due to cardioselectivity. Orthostatic hypotension, worsening HF/fluid retention, bronchospasm (less with beta1Target: 25 mg BID selective), dyspnea, bradycardia, malaise, fatigue, asthenia, erectile dysfunction, may mask hypoglycemia. More likely to cause orthostatic Bradycardia with digoxin or nondihydropyridine CCBs. Cardiodepressant effects with nondihydropyridine CCBs and amiodarone. Digoxin, amiodarone, diltiazem, verapamil: increased bradycardia. Nondihydropyridine calcium channel blockers: additive cardiodepressant effect. Costa $ $ Nonselective beta-blocker with alphablocking activity. Has some vasodilating Class Drug Beta1-adrenergic Antagonists with alpha1-blocking activity Dose labetalol Trandate, generics Adverse Effects Initial: 50 mg BID po Usual: 200 mg BID po Maximum: 1200 mg/day Drug Interactions Class III Antiarrhythmics metoprolol, Lopresor, generics sotalol CYP2D6 inhibitors. Fatigue, bradycardia, decreased exercise capacity, headache, impotence, vivid dreams. Less common: hyperglycemia, depression, heart failure, heart block. Bradycardia with digoxin or nondihydropyridine CCBs. Cardiodepressant effects with nondihydropyridine CCBs and amiodarone. $$ Bradycardia with digoxin or nondihydropyridine CCBs. Cardiodepressant effects with nondihydropyridine CCBs and amiodarone. $ Initial: 50 mg/day Usual: 100–200 mg/day Maximum: 400 mg/day Give regular formulations BID po; SR formulations once daily po Fatigue, bradycardia, decreased exercise capacity, headache, impotence, vivid dreams. Less common: hyperglycemia, depression, heart failure, heart block. Usual: Digoxin, verapamil, other betablockers may cause AV block, bradycardia. 160–480 mg/day po generics Elderly: Reduce initial dose to 40 mg Q12H po a. Costa hypotension than bisoprolol. Edema, dizziness and nasal congestion and postural hypotension due to alpha1antagonism. Beta1-adrenergic Antagonists, β1selective Commentsd effects. Fewer noncardiac effects due to cardioselectivity. CYP2D6 inhibitors increase levels of metoprolol. With digoxin, Ca++ channel blockers, amiodarone, reduce dose 25–50%. Torsades de pointes, especially at higher doses or with renal dysfunction. Fatigue, bradycardia, AV block, decreased exercise capacity, headache, erectile dysfunction, vivid dreams. Less common: hyperglycemia, depression, heart failure. May be $ especially effective in exerciserelated arrhythmias. Likely more effective than other drugs in suppressing inducibility of VT. Contraindicated in asthma. Cost of 30-day supply of usual dose of drug; includes drug cost only. b. The Canadian Hypertension Education Program recommends initiating therapy with a combination of two first-line agents if a patient's SBP is ≥20 or DBP is ≥10 mm Hg above the recommended target. c. It is generally recommended that the dose of each component is titrated before starting a combination product.z d. Beta-blockers should not be used as initial therapy in patients aged >60 y unless specifically indicated. Avoid in patients with asthma.29 Avoid abrupt withdrawal (may precipitate rebound hypertension and ischemia). Taper the dose before discontinuation. Avoid in patients with severe PAD. Contraindicated in patients with 2ndor 3rd degree heart block in the absence of a pacemaker. Legend: $ <$20 $-$$ <$20–40 $$ $20–40 $$$ $40–60 $$$$ $60–80 Cardiovascular Disorders: Hypertension; Norm R.C. Campbell, MD, FRCPC, Paul Gibson, MD, FRCPC and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of revision: March 2015 Table 1 : Beta-adrenergic Blocking Agents - Health Canada-approved Indications Beta-adrenergic Blocking Agent HTN, Mild to Moderate HTN Crisis, Emergency Treatment HF Angina Pectoris Acute MI Post-MI Perioperative HTN Supraventricular Arrhythmias Ventricular Arrhythmias Migraine Prophylaxis Hypertrophic Subaortic Stenosis Pheochromocytoma Acebutolol Yes — — Yes — — — — — — — — Atenolol Yes — — Yes — — — — — — — — Bisoprolol Yes — — — — — — — — — — — Carvedilol — — Yes — — — — — — — — — Esmolol — — — — — — Yes Yes — — — — Yes (oral) Yes (iv) — — — — — — — — — — Metoprolol Yes — — Yes Yes (iv) Yes (oral) — — — — — — Nadolol Yes — — Yes — — — — — — — — Nebivolol Yes — — — — — — — — — — — Pindolol Yes — — Yes — — — — — — — — Propranolol Yes — — Yes — Yes (oral) — Yes Yes Yes Yes Yes Sotalol — — — — — — — — Yes — — — Timolol Yes — — Yes — Yes — — — Yes — — Labetalol Medication Uses Contraindications (CI), drug interactions (DI) or cautions labetalol hypertension, ischemic heart disease CI: asthma, bradycardia, AV block, 2nd/3rd deg block or PR>0.24sec, hepatic dysfunction, uncompensated HF severe peripheral arterial disease DI: amiodarone, CCB (decrease HR), cimetidine(increases effect), digoxin(decreases HR), NSAIDs (increase BP and decrease renal function) and phenobarbital (decreases efficacy) bisoprolol hypertension , heart failure (HF) CI: COPD, asthma, bradycardia, AV block, 2nd/3rd deg block or PR>0.24sec, renal and hepatic dysfunction, uncompensated HF, peripheral arterial disease, pheochromocytoma DI: amiodarone, calcium channel blockers (CCB), cimetidine (increases effect), digoxin (decreases HR), NSAIDs (increase BP and decrease renal function), phenobarbital (decrease efficacy) Adverse Effects (common and severe) hypotension, bronchospasm, dizziness, lightheadedness, fatigue, nausea, impotence hypotension, bronchospasm, dizziness, lightheadedness, fatigue, nausea, impotence Initial dose; typical dose Monitoring 100mg; 100600mg one time a day BP 5mg; 5-20mg one time a day BP