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Helfand M, Peterson K, Christensen V, et al. Drug Class Review: Beta Adrenergic Blockers: Final Report Update 4 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Jul.

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Drug Class Review: Beta Adrenergic Blockers: Final Report Update 4 [Internet].

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To identify relevant citations, we searched Ovid MEDLINE (1966 to January Week 4 2009), the Cochrane Database of Systematic Reviews (Second Quarter 2008), Database of Abstracts of Reviews of Effects (Third Quarter 2008) and the Cochrane Central Register of Controlled Trials (Third Quarter 2008), using terms for included drugs, indications, and study designs (see Appendix B for complete search strategies). In addition, pharmaceutical manufacturers were invited to submit dossiers, including citations, using a protocol issued by the Center for Evidence-based Policy (available at: All citations were imported into an electronic database (EndNote® X2).

Study Selection

One reviewer assessed all citations and selected full articles for inclusion, with consultation from a second reviewer where necessary. All disagreements were resolved by consensus.

We included English-language reports of studies of the patient populations and efficacy outcomes listed in Table 3. For studies of hypertension, we excluded studies in which blood pressure lowering was the only endpoint; most of these studies sought to identify equivalent doses of beta blockers rather than differences in clinical effectiveness. Instead, we sought evidence of long-term effects on mortality, cardiovascular events, and quality of life. We only included studies in stable angina patients with duration of 2 months or longer. We only included studies of long-term treatment in post-coronary artery bypass graft patients, excluding studies of the short-term use of beta blockers to suppress atrial arrhythmias. With regard to placebo-controlled trials of recent myocardial infarction or heart failure, we only included studies with sample sizes of 100 patients or more.

Table 3

Table 3

Included outcome measures

We included the following safety outcomes: overall adverse event incidence, withdrawals due to adverse events, and frequency of important adverse events associated with beta blockers including bradycardia, heart failure, and hypotension. In some studies, only “serious” or “clinically significant” adverse events are reported. Some studies do not define these terms, and in other studies, the definitions vary between studies.

To evaluate efficacy, we included randomized controlled trials and good-quality systematic reviews. To evaluate effectiveness and safety, we included trials as well as good observational studies.

Data Abstraction

From included trials we abstracted information about the study design; setting; population characteristics (including sex, age, race, and diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome.

Validity Assessment

We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix C. These criteria are based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (UK) criteria.1, 2 We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to followup; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others are only possibly valid. A poor-quality trial is not valid—the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failing to meet combinations of items of the quality assessment checklist. A particular randomized trial might receive 2 different ratings, one for effectiveness and another for adverse events.

Appendix C also shows the criteria we used to rate observational studies of adverse events. These criteria reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair quality if they met 3 to 5 criteria, and poor quality if they met 2 or fewer criteria.

Included systematic reviews were also rated for quality based on pre-defined criteria (see Appendix C); clear statement of the questions(s), inclusion criteria, adequacy of search strategy, validity assessment, and adequacy of detail provided for included studies; and appropriateness of the methods of synthesis. Again, these studies were categorized as good when all criteria were met.

The overall strength of evidence for a particular key question or outcome reflects the risk of bias of the study (based on quality and study design), consistency, directness, and precision of the set of studies relevant to the question. The overall strength of evidence was graded as good, fair, and poor.

Data Synthesis

We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated one beta blocker against another provided direct evidence of comparative effectiveness and adverse event rates. Where possible, these data are the primary focus. As such, direct comparisons were preferred over indirect comparisons. Similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes.

In theory, trials that compared beta blockers to other drug classes or placebos could also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily issues of heterogeneity between trial populations, interventions, and assessment of outcomes. Data from indirect comparisons were used to support direct comparisons, where they exist, and were also used as the primary comparison where no direct comparisons existed. Such indirect comparisons should be interpreted with caution.

Copyright © 2009, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK47177


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