By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is a consultant for GlaxoSmithKline and is on the speaker's bureau of GlaxoSmithKline, 3M, Wyeth-Ayerst, Pfizer, Novartis, Bristol-Myers Squibb, AstraZeneca, Jones Pharma, and Boehringer Ingelheim.
Does Published Evidence Reflect the Whole Story?
Currently, when industry applies to the FDA for new drug licensing, they must register all trials performed, whether published or not. The evidence base readily available to clinicians often does not contain all of these trials; hence concern has been raised that non-published trials might have outcomes less favorable to sponsor interests, thereby providing a more rosy portrait of efficacy in the published literature than in the total evidence base.
Turner et al chose to consider clinical trials of FDA-approved antidepressants. They examined 74 studies that had been registered with the FDA. Among these clinical trials, half were positive, and all but 1 of these was published. Of the remaining 37 negative trials (negative or of questionable results as assessed by FDA reviewers), 22 were not published. Some of the negative trials (n = 11) that were published portrayed outcomes in an overly optimistic light according to the assessment of the authors.
"Publication bias" is the term used to account for the variability in likelihood that a study will achieve published status due to some particular characteristic, rather than on the merits of its scientific integrity alone. Trials with a positive outcome (Drug A is better than Drug B for Disease X) are more likely to be published than negative trials (Drug A failed to improve the outcome of disease X); a failed trial (Drug A did not achieve its primary endpoint, but secondary endpoints are favorably hypothesis-generating) has historically fared similarly.
The authors suggest the efficacy of antidepressants as demonstrated in published clinical trials is more robust than would be concluded on the basis of the entirety of clinical trial experience.
Turner EH, et al. N Engl J Med. 2008;358:252-260.
Vitamin E levels and Physical Decline with Aging
Most of us anticipate that our older years will be associated with a decline in physical function. The graying of America is associated with a decline to the level of disability for some, which reduces quality of life and taxes the health care system. The SPPB (Short Physical Performance Battery) is a tool that quantifies the progression of functional decline.
Using a suburban population of seniors (>age 65) from Florence, Italy, investigators followed 698 subjects for 3 years. In addition to monitoring with the SPPB, the micronutrients vitamin B6, vitamin B12, vitamin D, vitamin E, and folate were measured.
After adjustment for confounders, multivariate analysis found a significant relationship between lower vitamin E levels and physical decline, but none of the other micronutrients demonstrated a meaningful relationship after multivariate analysis.
Based upon this data, the authors conclude that a relationship between lower vitamin E levels and physical decline has been demonstrated. Whether the relationship between vitamin E and physical function is causally related is not established by this longitudinal observational trial. Even if vitamin E is someday determined to affect physical decline, the clinical trials to date have been discouraging about other cardiovascular outcomes in persons supplemented with vitamin E.
Bartali B, et al. JAMA. 2008;299(3):308-315.
Effort, Efficacy, and Effectiveness
The vicissitudes of enabling lifestyle changes to effect reductions in blood pressure are sufficiently well accepted that clinicians may be tempted to sidestep this phase of management in preference for the more routinely effective pharmacotherapies. Recall that the distinction between "efficacy" and "effectiveness," in evidence-based-medicine parlance, is that the former refers to outcomes seen in a controlled clinical trial, and the latter to outcomes seen/anticipated in the hands of the typical community clinician. Even though the efficacy of lifestyle interventions is well established, clinicians may wonder whether it is worth the effort to try and achieve the effectiveness that might be attained in the typical practice setting.
The Behavior Risk Factor Surveillance System, administered under the auspices of the CDC, has indicated that 90% of hypertensive adults reported receiving advice about lifestyle modification for blood pressure control (n = >27,000).
When comparing those who did vs those who did not recall receiving clinician advice about behavior modification, those who recalled advice from their clinician were over 1.6 times more likely to have modified their behavior. In other words, our efforts do impact effectiveness.
Viera AJ, et al. J Clin Hypertens. 2008;10;105-111.