Donal McMahon

Systematic Review: Benefits and Harms of In-Hospital Use of Recombinant Factor VIIa for Off-Label Indications

BACKGROUND Recombinant factor VIIa (rFVIIa), a hemostatic agent approved for hemophilia, is increasingly used for off-label indications. PURPOSE To evaluate the benefits and harms of rFVIIa use for 5 off-label, in-hospital indications: intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy. DATA SOURCES Ten databases (including PubMed, EMBASE, and the Cochrane Library) queried from inception through December 2010. Articles published in English were analyzed. STUDY SELECTION Two reviewers independently screened titles and abstracts to identify clinical use of rFVIIa for the selected indications and identified all randomized, controlled trials (RCTs) and observational studies for full-text review. DATA EXTRACTION Two reviewers independently assessed study characteristics and rated study quality and indication-wide strength of evidence. DATA SYNTHESIS 16 RCTs, 26 comparative observational studies, and 22 noncomparative observational studies met inclusion criteria. Identified comparators were limited to placebo (RCTs) or usual care (observational studies). For intracranial hemorrhage, mortality was not improved with rFVIIa use across a range of doses. Arterial thromboembolism was increased with medium-dose rFVIIa use (risk difference [RD], 0.03 [95% CI, 0.01 to 0.06]) and high-dose rFVIIa use (RD, 0.06 [CI, 0.01 to 0.11]). For adult cardiac surgery, there was no mortality difference, but there was an increased risk for thromboembolism (RD, 0.05 [CI, 0.01 to 0.10]) with rFVIIa. For body trauma, there were no differences in mortality or thromboembolism, but there was a reduced risk for the acute respiratory distress syndrome (RD, -0.05 [CI, -0.02 to -0.08]). Mortality was higher in observational studies than in RCTs. LIMITATIONS The amount and strength of evidence were low for most outcomes and indications. Publication bias could not be excluded. CONCLUSION Limited available evidence for 5 off-label indications suggests no mortality reduction with rFVIIa use. For some indications, it increases thromboembolism.

Lack of Significant Interactions Between Clopidogrel and Proton Pump Inhibitor Therapy: Meta-Analysis of Existing Literature

BackgroundPublished data regarding the effect of concomitant clopidogrel and proton pump inhibitor (PPI) therapy on cardiovascular outcomes have been conflicting.AimTo perform an updated meta-analysis in order to determine changes in risk differences (RD) between primary and secondary outcome analyses.MethodsPrimary analysis was based on definite vascular outcomes, including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events, which included re-hospitalization for cardiac symptoms or revascularization procedures. RD were combined using a random-effects model.ResultsWe reviewed 1,204 publications of which 26 studies (16 published articles, 10 abstracts) met inclusion criteria. The meta-analysis of outcomes from the two randomized controlled trials did not show an increased risk (RD 0.0, 95% CI −0.01, 0.01) for adverse outcomes. The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01–0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03–0.06).ConclusionsIn patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders.

W1108 Meta-Analysis of Interaction Between Clopidogrel and Proton Pump Inhibitor Therapy

Background: Clopidogrel is a prodrug requiring a cytochrome (CYP)2C19-dependent conversion to become active. Usage of proton pump inhibitors (PPIs) might attenuate clopidogrels platelet inhibitory effect. Methods: We performed a meta-analysis of studies in Pubmed, Ovid, ISI Science, and Embase. Primary analysis was based on definite outcomes including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events which included re-hospitalization for cardiac symptoms or revascularization procedures. Odds ratios were obtained for studies with definite and probable endpoints and were combined using a random-effects model. Risk difference (RD) was defined as the difference in disease/event rate between the control and treatment. Results: We reviewed 898 publications and found 8 relevant studies: 2 were excluded due to data quality and 1 was excluded because controls used PPIs. 5 studies were analyzed, including 2 published articles and 3 abstracts. 2 meta-analysis were conducted: the first considered only the published articles and the second considered all 5 studies. (Figure) Usage of clopidogrel + PPI was associated with a small non-significant increase in definite events (Risk Difference (RD) 0.0083, 95% CI -0.00022 to 1.2). When probable events were included, the risk difference was significant (RD 0.066, 95% CI 0.055 to 0.077). There was evidence of heterogeneity (p=0.028) between studies. Conclusions: This metaanalysis does not support an adverse relationship between clopidogrel and PPIs when the primary focus was death or definite cardiovascular events.