Background Recombinant Factor VIIa (rFVIIa), a hemostatic agent approved for hemophilia, is increasingly used for off-label indications. Purpose To evaluate benefits and harms of rFVIIa use for five off-label, in-hospital indications: intracranial hemorrhage, cardiac surgery, trauma, liver transplantation, and prostatectomy. Data Sources Ten databases (including PubMed, EMBASE, and Cochrane Library) queried from the advent of each through December 2010. English language articles 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 Inclusion criteria were met by 17 RCTs, 33 comparative observational studies, and 23 non-comparative observational studies. Identified comparators were limited to placebo (RCTs) or usual care (observational studies). For intracerebral hemorrhage, mortality was not improved with FVIIa use across a range of rFVIIa doses. Arterial thromboembolism was increased with rFVIIa for medium-dose (risk difference 0.03 [0.01, 0.06]) and high-dose use (0.06 [0.01, 0.11]). For adult cardiac surgery, there was no mortality difference, but an increased risk of thromboembolism (0.05 [0.01, 0.10]) with rFVIIa. For body trauma, there were no differences in mortality or thromboembolism, but a reduced risk of acute respiratory distress syndrome (−0.05 [−0.02, −0.08]). Mortality and thromboembolism were consistently higher in observational studies compared to RCTs. Limitations The amount and strength of evidence was low for the majority of outcomes and indications. Publication bias could not be excluded. Conclusion Limited available evidence for five off-label indications indicates no mortality reduction with rFVIIa use. For some indications, rFVIIa increases thromboembolism. Primary Funding Source Agency for Healthcare Research and Quality

BackgroundSleep disordered breathing (SDB) such as sleep apnea is associated with cardiovascular disease in the general population. However, little is known about the cardiovascular risks of SDB in patients with end-stage renal disease (ESRD).MethodsWe identified Medicare fee-for-service beneficiaries aged ≥67 years initiating dialysis between 2004 and 2009. Outcomes of interest included all-cause mortality, incident myocardial infarction, ischemic stroke, and atrial fibrillation. We compared patients with and without diagnosed SDB using Cox proportional hazards regression.ResultsBetween 2004 and 2009, 184,217 older patients developed ESRD, of whom 15,121 (8.2 %) were previously diagnosed with SDB. Patients diagnosed with SDB were younger, more likely to be male and Caucasian, less Medicaid eligible, had more non-Nephrology clinic visits, higher body mass index, and more comorbidity. In analyses adjusting for demographics and BMI, diagnosed SDB was associated with higher risk of death and atrial fibrillation, but not associated with myocardial infarction or ischemic stroke risk. After further adjustment for all baseline characteristics, diagnosed SDB was associated with slightly lower risks of death (hazard ratio [HR]: 0.93, 95 % confidence interval [CI]: 0.91–0.96), myocardial infarction (HR: 0.92, CI: 0.87–0.98), and ischemic stroke (HR: 0.90, 95 % CI: 0.82–0.98), and not associated with atrial fibrillation (HR: 1.02, CI: 0.98–1.07).ConclusionsIn older patients initiating dialysis in the U.S., diagnosed SDB was weakly associated with lower risks of death and important cardiovascular outcomes, thus adding to the list of established risk factors that are paradoxically associated with cardiovascular outcomes in the ESRD population.

No abstract

1403 Poster Board I-425 Background: Recombinant factor VIIa (rFVIIa) is a potent hemostatic agent licensed for treatment of bleeding in hemophiliac patients with inhibitors but has been increasingly used off-label to treat or prevent bleeding, despite sparse data to support its efficacy and a possible increase in thromboembolic events. While randomized controlled trials (RCTs) provide the best evidence regarding efficacy, they may not identify rare but important adverse events. Observational studies may capture the rate of such events in clinical practice more accurately. Objectives: To compare rates of thromboembolic events associated with off-label use of rFVIIa in RCTs and observational studies. Methods: Studies of off-label application of rFVIIa were identified by review of 10 literature and clinical trial databases through February, 2009. The off-label indications examined were trauma, non-traumatic intracranial hemorrhage (ICH), and adult cardiac surgery. When an appropriate number and quality of studies were available, data from RCTs and higher quality comparative observational studies were combined via meta-analysis using the arc sine statistical method, a method that characterizes uncommon events more accurately than more conventional methods. To describe the absolute rate of thromboembolism for patients treated with rFVIIa in RCTs versus observational studies, we analyzed data from the interventional arms of RCTs and comparative observational studies, as well as data from non-comparative observational studies with 15 or more patients. Results: Included Studies Our search identified 4 RCTs and 4 observational studies of rFVIIa use in ICH. Two RCTs and 5 observational studies were identified for trauma. For cardiac surgery, 2 RCTs, 2 higher quality comparative observational studies (included in the meta-analysis), and 8 additional observational studies were identified. Meta-analyses The meta-analysis of the RCTs investigating use of rFVIIa in ICH showed a trend toward increased thromboembolic risk with rFVIIa (arcsine summary effect size 0.100, 95% CI -0.072-0.272). For trauma, the two RCTs did not provide sufficient data to perform meta-analysis. Individually, they did not demonstrate significantly different incidences of thromboembolic events with rFVIIa compared to placebo but may have been underpowered to detect such differences. For cardiac surgery, the meta-analysis of the 4 studies showed a significant increase in thromboembolic events in the rFVIIa group (arcsine summary effect 0.14; 95% CI 0.038- 0.242). Absolute rates of thromboembolic events in RCTs versus observational studies In ICH, thromboembolic event rates in the treatment arms of the RCTs ranged from 0.07-0.11, while those in the observational studies ranged from 0-0.20. In trauma, thromboembolic event rates in the RCT treatment arms ranged from 0.03-0.06, whereas those in the observational studies ranged from 0.02-0.11. In cardiac surgery, thromboembolic event rates in the RCTs ranged from 0.07-0.22 compared to a range of 0-0.25 in the observational studies. For all three indications, Figure 1 shows that the weighted mean thromboembolic event rates associated with rFVIIa use are higher in the observational studies than in the RCTs. Patients in the observational studies tended to be older and have a worse prognosis than those enrolled in the RCTs. Conclusions: We identified a trend toward significantly higher rates of thromboembolic adverse events with off-label use of rFVIIa compared to placebo in our meta-analyses of ICH and cardiac surgery, but no similar pattern in trauma trials. For each of these indications, we identified a higher rate of thromboembolic adverse events associated with the use of rFVIIa in observational trials compared to RCTs. This finding suggests that patients receiving off-label rFVIIa for these off-label indications in real-world practice may be at higher risk of thromboembolic events than patients enrolled in clinical trials and may caution against widespread use, especially in the absence of convincing data on efficacy. Disclosures: Off Label Use: This study examines the off-label use of rFVIIa in randomized controlled trials and observational studies of intracranial hemorrhage, trauma, and cardiac surgery.