Drug Class Review

on Beta Adrenergic Blockers

Final Report

May 2005

The purpose of this report is to make available information regarding the comparative effectiveness and safety profiles of different drugs within

pharmaceutical classes. Reports are not usage guidelines, nor should they be read as an endorsement of, or recommendation for, any particular drug, use or

approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports.

Mark Helfand, MD, MPH Kim Peterson, MS Oregon Evidence-based Practice Center Oregon Health & Science University Mark Helfand, MD, MPH, Director Copyright 2005 by Oregon Health & Science University Portland, Oregon 97201. All rights reserved.

TABLE OF CONTENTS Introduction........................................................................................................................4

Scope and Key Questions ........................................................................................6 Methods...............................................................................................................................7

Study Selection ........................................................................................................7 Data Abstraction ......................................................................................................8 Quality Assessment..................................................................................................9 Data Synthesis..........................................................................................................9

Results .................................................................................................................................9 Key Question 1. For adult patients with various indications, do beta blockers differ in efficacy?..........................................................................9

1a. Hypertension .........................................................................................9 1b. Angina..................................................................................................12 1c. Coronary Artery Bypass Grafting ........................................................14 1d. Recent Myocardial Infarction ..............................................................14 1e. Heart Failure.........................................................................................19 1f. Atrial arrhythmias.................................................................................29 1g. Migraine Headache ..............................................................................30 1h. Bleeding esophageal varices ................................................................33

Key Question 2. For adult patients with various indications, do beta blockers differ in adverse effects?....................................................35 Key Question 3. Are there subgroups for which one beta blocker is more

effective or associated with fewer adverse events? ......................................38 Summary...........................................................................................................................39 References .........................................................................................................................44 In-text Tables Table 1. Beta blockers included in the review.........................................................4

Table 2. Approved indications.................................................................................5 Table 3. Included outcome measures.......................................................................8 Table 4. Quality of Life outcomes in HTH trials of hypertensives .......................11 Table 5. Results of head to head trials in patients with angina..............................13 Table 6. Comparison of outcomes of mortality-reducing beta blockers

in patients following myocardial infarction...............................................15 Table 7. Summary of results from placebo-controlled trials of beta blocker

therapy following myocardial infarction ...................................................18 Table 8. Main findings in placebo-controlled trials of patients with

mild-moderate heart failure........................................................................20 Table 9. Comparison of major beta blocker trials in heart failure .........................21 Table 10. Patient characteristics and annualized mortality rates adjusted for

active drug run-in periods in trials of beta blockers for heart failure ........24 Table 11. Outcomes in placebo controlled trials of beta blockers for

heart failure ..............................................................................................26 Table 12. Outcomes in head-to-head trials of migraine patients ...........................31 Table 13. Variceal rebleeding rates .......................................................................34 Table 14. Death due to variceal rebleeding ...........................................................35 Table 15. All cause mortality in patients with bleeding esophageal varices .........35

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Beta Adrenergic Blockers Page 2 of 414

Table 16. Results of Shekelle (2003) meta-analysis by gender, race and diabetics .....................................................................................................38

Table 17. Strength of the evidence ........................................................................39 Table 18. Summary of comparative efficacy.........................................................42

Evidence Tables Evidence Table 1. Randomized controlled trials for hypertension........................54 Evidence Table 1a. Quality assessment of randomized controlled trials

for hypertension .........................................................................................78 Evidence Table 2. Randomized controlled trials for angina..................................87 Evidence Table 2a. Quality assessments of randomized controlled trials

for angina ................................................................................................103 Evidence Table 3. Randomized controlled trials for coronary artery

bypass graft ..............................................................................................109 Evidence Table 3a. Quality assessments of randomized controlled trials

for coronary artery bypass graft ...............................................................112 Evidence Table 4. Randomized controlled trials for post myocardial

infarction ..................................................................................................115 Evidence Table 4a. Quality assessments of randomized controlled trials

for post myocardial infarction..................................................................160 Evidence Table 5. Placebo controlled trials for heart failure..............................172 Evidence Table 5a. Quality assessments of placebo controlled trials for

heart failure ..............................................................................................236 Evidence Table 5b. Head to head trials for heart failure .....................................260 Evidence Table 5c. Quality assessments of head to head trials for heart failure.269 Evidence Table 6. Outcomes of head to head trials for heart failure...................281 Evidence Table 7. Randomized controlled trials for arrhythmia.........................283 Evidence Table 7a. Quality assessments of randomized controlled trials

for arrhythmia ..........................................................................................292 Evidence Table 8. Placebo controlled trials for migraine....................................296 Evidence Table 8a. Quality assessments of placebo controlled trials

for migraine..............................................................................................353 Evidence Table 9. Randomized controlled trials for bleeding esophageal

varices ......................................................................................................365 Evidence Table 9a. Quality assessments of randomized controlled trials

for bleeding esophageal varices ...............................................................383 Evidence Table 10. Adverse events in head to head trials for hypertension .......389

Evidence Table 11. Safety of all head to head trials of beta blockers .................391 Figures

Figure 1. Total mortality in patients following MI .............................................393 Figure 2. Effect of beta blockers on all cause mortality in patients with

mild-moderate heart failure in placebo controlled trials..........................394 Appendices

Appendix A. Search strategy ..............................................................................395 Appendix B. Quality assessment methods for drug class reviews......................398 Appendix C. List of included studies..................................................................402

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INTRODUCTION Beta blockers inhibit the chronotropic, inotropic and vasoconstrictor responses to the catecholamines, epinephrine and norepinephrine. Most beta blockers have half-lives of over six hours (Table 1). The shortest acting are pindolol (3-4 hours) and propranolol (3-5 hours). Most beta blockers are metab