How evidence-based are the recommendations in evidence-based guidelines?

Abstract

Background: Treatment recommendations for the same condition from different guideline bodies often disagree, even when the same randomized controlled trial (RCT) evidence is cited. Guideline appraisal tools focus on methodology and quality of reporting, but not on the nature of the supporting evidence. This study was done to evaluate the quality of the evidence (based on consideration of its internal validity, clinical relevance, and applicability) underlying therapy recommendations in evidence-based clinical practice guidelines.

Methods and findings: A cross-sectional analysis of cardiovascular risk management recommendations was performed for three different conditions (diabetes mellitus, dyslipidemia, and hypertension) from three pan-national guideline panels (from the United States, Canada, and Europe). Of the 338 treatment recommendations in these nine guidelines, 231 (68%) cited RCT evidence but only 105 (45%) of these RCT-based recommendations were based on high-quality evidence. RCT-based evidence was downgraded most often because of reservations about the applicability of the RCT to the populations specified in the guideline recommendation (64/126 cases, 51%) or because the RCT reported surrogate outcomes (59/126 cases, 47%).

Conclusions: The results of internally valid RCTs may not be applicable to the populations, interventions, or outcomes specified in a guideline recommendation and therefore should not always be assumed to provide high-quality evidence for therapy recommendations.

Figure 1. The Evidence-Grading Scheme Employed in this Study

Adapted from CHEP [9]. An “adequate” RCT is one with allocation concealment, blinded assessment of outcomes (if subjective), intention-to-treat analysis, adequate follow-up (i.e., at least 90%, or losses to follow-up are too few to materially affect the results), and sufficient sample size to detect a clinically important difference with power > 80% (1). Subgroup analysis was a priori, done within an adequate RCT, one of only a few tested, and there was sufficient sample size within the examined subgroup to detect a clinically important difference with power > 80% (2). A sytematic review (SR) with direct comparisons is one in which the comparison arms are derived from head-to-head comparisons within the same RCT (3). A systematic review with indirect comparisons is one in which the comparison arms are derived from different RCTs, then extrapolations are made across RCTs (4). Adequate power in a negative study implies that the 95% confidence interval excludes a clinically important difference (5). Effect estimates in each study included in the systematic review are qualitatively similar (i.e., in the same direction) (6). Clinically important outcomes are “hard” endpoints such as death, stroke, or myocardial infarction (7). End points have been consistently shown to be associated with the clinical end point in multiple studies (observational or RCT), and RCTs have consistently demonstrated that improvement in the surrogate translates into a consistent and predictable improvement in the clinical end point (8).

Figure 2. Summary of AGREE Domain Scores for Guidelines, Averaged over Each Condition

Figure 3. Percentage of Recommendations Citing RCTs That Were Based on High-Quality Evidence in Each Guideline

Legend and references: ADA, American Diabetes Association [11]; Canadian Lipids, the Canadian Working Group on Hypercholesterolemia and Other Dyslipidemias [13]; CDA, Canadian Diabetes Association [10]; CHEP, the Canadian Hypertension Education Program [16,17]; ESH/ISH, European Society of Hypertension/International Society of Hypertension [19]; JNC 7, Joint National Committee seventh report [18]; NCEP III, Third Report of the National Cholesterol Education Program [14].