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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.
Size Matters ... Sometimes
Meta-analysis (META) is intended to provide greater strength of evidence by combining like populations of similar clinical trials in similar circumstances. The operative word here, of course, is "similar." Unfortunately, no two populations or sets of circumstances are identical, resulting in conclusions being drawn from large data sets which may not be reliable. Indeed, there are numerous examples of META based on huge population size that were ultimately disproven on the basis of a single large randomized controlled trial.
The reader would likely assume that when reviewing literature in reputable journals, reporting of the evidence would be accurate. According to Gotzsche, et al, readers should "approach such meta-analyses with caution."
Because not all trials use the same scale for measuring outcomes, standardized mean difference (SMD) is a tool utilized to make outcomes measured by a variety of metrics fit the same, uniform, comparative scale. Simple in theory and application, Gotzsche evaluated META to see whether SMD had been accurately applied.
When "rechecking" the analyses, the authors could not replicate results in 37% of meta-analyses they examined. Of 10 meta-analyses employing SMD, 70% were erroneous. The degrees of error in some meta-analyses were sufficient to reverse the conclusions of the investigation.
The authors call for greater vigilance by readers and reviewers in reference to meta-analyses that utilize SMD methodology.
Gotzsche PC, et al. JAMA. 2007;298(4):430
PAD and Antithrombotic Therapy: Sometimes Less is More
It is increasingly recognized that vasculopathy is usually not compartmentalized. Persons with CAD are at greater risk of stroke; those with peripheral arterial disease (PAD) are at increased risk of stroke and MI, and so on.
Aspirin reduces risk of CVD endpoints in persons with PAD, and at least one trial (CAPRIE) has shown that clopidogrel is modestly more effective than aspirin (absolute risk reduction 0.5%) in this regard. Recent years have seen trials in atrial fibrillation, post-stroke, stable coronary disease, and other mixed populations to determine whether combination therapies (eg, aspirin plus clopidogrel, warfarin plus antiplatelet) might be more beneficial than monotherapy. With the exception of acute coronary syndromes, combination therapies have generally been no more effective than monotherapy (for secondary prevention of stroke, the combination proprietary product aspirin-extended release dipyridamole is an exception to this rule).
The Warfarin Antiplatelet Vascular Evaluation Trial Investigators studied PAD patients (n=2161) randomly assigned to either antiplatelet therapy alone (ASA, clopidogrel, or ticlopidine) vs an antiplatelet agent plus warfarin, targeted to an INR of 2-3, for a mean of 35 months. The two coprimary outcomes were MI, stroke, or CV death (composite) and MI, stroke, CV death, or need for surgical vascular intervention (composite).
Combination therapy did NOT show any statistically significant reduction in either coprimary endpoint. Additionally, however, combination therapy was associated with a three-fold greater incidence of life-threatening bleeding (4% vs 1.2%).
The Warfarin Antiplatelet Vascular Evaluation Trial Investigators. N Engl J Med. 2007;357:217-227.
Osteoporosis in Men: Cost-effectiveness Issues
Many clinicians probably immediately think "woman" when they hear the word "osteoporosis," despite the fact that 1/3 of all hip fractures happen in men. Similarly, literature to support the use of interventions to prevent osteoporotic fracture in men has lagged behind the data set in women. The current report by Schousboe, et al, will help add gender balance to the knowledge base.
Unfortunately, there has been only one prior cost-effectiveness modeling study of osteoporosis (OSPS) in men, and this study did not include the cost of bone densitometry (DEXA) in their model. The current study assumed that once OSPS was detected, bisphosphonate therapy would be initiated at an average cost of $1000 per year. DEXA cost was set at $82 (current Medicare reimbursement rate). The currently accepted threshold for an intervention to be considered cost effective is that it cost less than $50,000 per Quality Adjusted Life-Year.
For men at highest risk (those with a previous fracture), DEXA and bisphosphonate therapy was cost effective. In men older than 80 years, even amongst those without a fracture history, DEXA and bisphosphonate was also cost effective. In men between the ages of 70-80 years, unless the cost of bisphosphonate therapy could be reduced by half, intervention was NOT cost effective (cost would be approximately $100,000/QALY, or double the acceptable level of cost-effectiveness.
Schousboe JT, et al. JAMA. 2007;298(6):629-637.