Prepared for Agency for Healthcare Research and Quality AHRQ wwwahrqgov Introduction to recombinant activated factor VII rFVIIa Process for developing the comparative effectiveness review CER ID: 1035943
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1. Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Uses vs. Usual Care in the Hospital SettingPrepared for:Agency for Healthcare Research and Quality (AHRQ)www.ahrq.gov
2. Introduction to recombinant activated factor VII (rFVIIa)Process for developing the comparative effectiveness review (CER)Results on rFVIIa off-label use in the hospitalResults of rFVIIa comparative effectivenessGaps in knowledgeOutline of StudyYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
3. Approved by the FDA for use in patients with hemophilia A or B with inhibitors, acquired hemophilia, and congenital factor VII deficiency. Increasingly used off-label beyond hemophilia-related indications to prevent excessive bleeding for a range of surgical and medical conditions.In the past decade, off-label use of rFVIIa in the hospital has significantly increased. The three most common uses are for spontaneous intracranial hemorrhage, bleeding secondary to trauma, and adult cardiac surgery.Introduction to Recombinant Activated Factor VII (rFVIIa)Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
4. The Coagulation Cascade: rFVIIa Mechanism of ActionTF = tissue factor
5. Since 1999, the FDA has approved four separate applications that have gradually expanded the scope of rFVIIa use in hemophilia:Hemophilia A or B with inhibitors for bleeding episodes (March 25, 1999)Bleeding and surgery in congenital factor VII deficiency (July 11, 2005)Surgery and invasive procedures in hemophilia A or B with inhibitors (August 12, 2005)Bleeding and surgery in acquired hemophilia (October 13, 2006)FDA–Approved Indications for rFVIIaYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
6. Chronic prophylactic use in hemophilia A and BEpisodic use for:Other isolated, congenital, or acquired clotting factor defects Disease states where impaired coagulation is but one manifestationAnticoagulant therapy-associated bleeding problems Consumptive coagulopathy from substantial blood lossProphylactic use for anticipated blood lossTraumatic, surgical, or spontaneous bleeding in noncoagulopathic patientsOff-Label Uses of rFVIIaYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
7. The publicly nominated topic was reviewed and selected based on need, importance, and feasibility. Experts and stakeholders guided the development of the clinical questions that were made available for public comment.A specialized Technical Expert Panel assisted the research process and development of the draft report. The CER Development Process (1)Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
8. Methods for literature review, data collection, and meta-analysis followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews.The draft CER was subject to public comment and peer review.The complete final report is available online.The CER Development Process (2)Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
9. Framework for Analyzing Outcomes for Off-Label rFVIIa Use in the Hospital SettingProphylactic Useof rFVIIa (repeat dosing possible)Treatment Useof rFVIIa (repeat dosing possible)End-Stage Useof rFVIIa (repeat dosing possible)Overall Use of rFVIIaICH and TraumaCardiac, Liver, and Prostate SurgeryClinical Situationwith BleedingPotentialMajor BleedingNo Bleeding orMinor BleedingDeteriorationImprovement
10. Overview of rFVIIa real-world use and description of comparative studiesThe benefits and harms of rFVIIa for:Spontaneous intracranial hemorrhageBleeding from body traumaBleeding from brain traumaAdult cardiac surgeryPediatric cardiac surgeryLiver transplantationProstatectomyClinical Questions Addressed by the Comparative Effectiveness ReviewYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
11. Direct outcomes:Clinical endpoints: death, functional status, ARDSAdverse effects: thromboembolism (PE, DVT, MI, stroke)Indirect outcomes:Health care process/resource use: transfusion requirements, length of ICU/hospital stay, operating room timeIntermediate/surrogate: hematoma expansion, blood loss/chest tube output, surgical re-exploration, coagulation testsOutcomes of Interest for Off-Label rFVIIa Usein the Hospital SettingYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
12. Risk of biasConsistencyDirectnessPrecisionFour Domains Used To AssessRelevant StudiesYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
13. The strength of evidence was classified into four broad categories:Rating the Strength of Evidence From the CERHigh ●●●Further research is very unlikely to change the confidence in the estimate of effect.Moderate ●●○Further research may change the confidence in the estimate of effect and may change the estimate.Low ●○○Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.InsufficientEvidence either is unavailable or does not permit estimation of an effect.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
14. Overview of In-Hospital, Off-Label vs. On-Label rFVIIa Use From the Premier Database (2000-2008)In 2008, 97% of rFVIIa in-hospital use was off-label.The most common off-label uses from 2000–2008 were:Adult cardiac surgery (16.4%)Trauma to the body (excluding brain trauma) (15.9%)Spontaneous intracranial hemorrhage (10.5%)Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
15. 24 randomized controlled trials and 31 comparative observational studies on rFVIIa use across several clinical indications:Cardiac surgery (12 studies)Trauma (9 studies)Intracranial hemorrhage (8 studies)Liver transplantation (8 studies)Other liver disease (5 studies)Comparative Studies on Off-Label rFVIIa UseYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
16. Strength of evidence available from existing studies was compromised by:Small study sizeUse of indirect outcomesHeterogeneity in dosage/indicationApplicability diminished by mismatch between existing research and real-world patterns of indication and types of useCharacteristics of Comparative Studies on Off-Label rFVIIa UseYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
17. Mean Differences in Mortality and Thromboembolic Event Rates by Study and rFVIIa IndicationThe area of each circle approximates the total sample size of each respective study; shaded circles represent studies on treatment use of rFVIIa and clear circles represent studies on prophylactic use of rFVIIa.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
18. Evidence for rFVIIa Use for Spontaneous Intracranial Hemorrhage vs. Usual Care
19. No effect of rFVIIa on mortality or rate of poor functional status. ●●○Increased rate of arterial thromboembolic events for medium- (41–119 μg/kg) and high-dose (≥120 μg/kg) groups. ●●○Associated with a decrease in the percent hematoma expansion. ●●○Evidence suggests that neither benefits nor harms exceed each other for rFVIIa use in spontaneous intracranial hemorrhage.Overview of Comparative Effectiveness of rFVIIa for Spontaneous Intracranial HemorrhageYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
20. Relative Hematoma Expansion Is Reduced After rFVIIa Use in Spontaneous Intracranial HemorrhageDose of rFVIIa for SpontaneousIntracranial HemorrhageRelative change in hematoma volumeStandardized mean difference(95% CI)Low (≤40 mg/kg)-0.157 (-0.302 to -0.012)Medium (41-119 mg/kg)-0.293 (-0.439 to -0.1)High (≥120 mg/kg) -0.304 (-0.549 to -0.06)Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
21. Increased Risk of Arterial Thromboembolic Events With rFVIIa for Spontaneous Intracranial Hemorrhage vs. Usual CareDose of rFVIIa for Spontaneous Intracranial HemorrhageTE Events/Total Patients (%)rFVIIa Usual CareRisk Difference Summary Effect Size (95% CI)Estimated Effect on TE Events (Strength of Evidence)Low (≤40 mg/kg)24/415(5.8)13/378(3.4)0.025(-0.004 to 0.053)No effect* (●●○)Medium (41-119 mg/kg)29/399(7.3)13/378(3.4)0.035(0.008 to 0.062)Increase withrFVIIa (●●○)High (≥120 mg/kg)8/115(7.0)0/107(0)0.063(0.011 to 0.114)Increase withrFVIIa (●●○)*While this effect was not significantly different from zero, there may have been insufficient statistical power to detect a difference.CI = confidence interval; TE = thromboembolic.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
22. Evidence of rFVIIa Use for Bleeding Secondary to Body Trauma vs. Usual Care
23. Overview of rFVIIa Use in BleedingSecondary to Body TraumaOutcome of InterestNumber of Studies(RCT/COS)Number of SubjectsrFVIIa Usual CareEstimatedEffect of rFVIIaOverall Strength of EvidenceMortality(30 days)2139138No effect●○○3128279Weakly favors rFVIIaThromboembolic events5301469No effect●○○Units of RBCs transfused2139138Favors rFVIIa●○○14975Favors usual careARDS3188213Weakly favors rFVIIa●○○RCT = randomized controlled trials; COS = comparative observational studies; ARDS = acute respiratory distress syndrome; RBCs = red blood cells.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
24. Evidence of rFVIIa Use forBleeding Secondary to Brain Traumavs. Usual Care
25. Overview of rFVIIa for BleedingSecondary to Brain TraumaOutcome of InterestNumber of StudiesNumber of SubjectsEstimatedEffect of rFVIIaOverall Strength of EvidencerFVIIaUsual CareMortality(15 days)27953No effect●○○Thromboembolic events (72 hours)27953No effect●○○Glasgow Coma Scale (15 days)27953No effect●○○Hematoma volume change16136No effect●○○Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
26. Evidence of rFVIIa Use forAdult Cardiac Surgery vs. Usual Care
27. Overview of rFVIIa for Adult Cardiac Surgery: Clinical OutcomesOutcome of InterestNumber of StudiesNumber of SubjectsEstimatedEffect of rFVIIaOverall Strength of EvidencerFVIIaUsual careMortality(in-hospital)10455385No effect●○○Units of RBCs transfused4108108Weakly favors rFVIIa or no effect●○○ICU lengthof stay5147148Weak increase with rFVIIa or no effect●○○ICU = intensive care unit; RBCs = red blood cells. Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
28. Increased Risk of Thromboembolic Events With rFVIIa Use for Adult Cardiac SurgeryIn-Hospital, Off-Label Use of rFVIIaTE Events/Total Patients(%)rFVIIa Usual CareRisk Difference Summary Effect Size(95% CI)EstimatedEffect on TE EventsOverall Strength of EvidenceAdult cardiac surgery19/203(9.4)8/170(4.7)0.053(0.01 to 0.096)Increase withrFVIIa ●●○CI = confidence interval; TE = thromboembolic.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
29. Evidence of rFVIIa Use for Pediatric Cardiac Surgery, Liver Transplantation, and Prostatectomy vs. Usual Care
30. Overview of rFVIIa Use for Liver TransplantationOutcomesof InterestNumber of StudiesNumber of SubjectsEstimatedEffect of rFVIIaOverall Strength of EvidencerFVIIaUsual CareMortality(timeframe unclear)4201102No Effect●○○Thromboembolic events4201102No Effect●○○Units of RBCs transfusedin 24 hours4201102Weakly FavorsrFVIIa●○○Operating room time23036No Effect●○○ICU length of stay319590No Effect●○○ICU = intensive care unit; RBCs = red blood cells.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
31. Overview of rFVIIa Use forPediatric Cardiac SurgeryOutcomes of InterestNumber of StudiesNumber of SubjectsEstimatedMagnitudeof EffectEffect of rFVIIa DosageOverall Strength of Evidence GraderFVIIaUsual CareMortality14036No dataNo dataInsufficientThromboembolic events14036UnknownUnknownInsufficientUnits of whole blood/RBCs transfused14036Weakly favors rFVIIaUnknownInsufficientTime to chest closure14036Increase with rFVIIaUnknownInsufficientRBCs = red blood cells. Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
32. Overview of rFVIIa Use for ProstatectomyOutcome of InterestNumber of StudiesNumber of SubjectsrFVIIa Usual CareEstimatedEffect of rFVIIaOverallStrength of EvidenceMortality(10 day)12412UnknownInsufficientThromboembolic events12412UnknownInsufficientUnits of RBCstransfused12412Favors rFVIIaInsufficientOperating room time12412Favors rFVIIaInsufficientRBCs = red blood cells.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
33. Summary of Outcomes for Most Common Off-Label, In-Hospital Uses of rFVIIaIn-Hospital, Off-Label Uses for rFVIIaBenefitsStrengthofEvidenceHarmsStrengthofEvidenceSpontaneousintracranialhemorrhageNo effect on mortality or functional outcomes. Attenuation of hematoma expansion. ●●○●●○Increased risk for arterial thromboembolic events, particularly at doses >40 μg/kg of patient body weight. ●●○Adult cardiac surgeryNo significant effect on mortality, RBC transfusion rates, or ICU length of stay. ●○○Increased risk for thromboembolic eventswhen compared to usual care. ●●○Body traumaNo consistent effects on mortality.Possible reduction in acute respiratory distress syndrome. ●○○●○○No effect on thromboembolic events. ●○○Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.
34. Management of abdominal aortic aneurysm (with and without surgical intervention)Pediatric cardiac surgeryVascular surgeries (not related to abdominal aortic aneurysm)Surgical procedures beyond cardiac and vascular surgeryAdditional Off-Label Uses of rFVIIa Requiring Future Research: Surgery
35. Cancer-related conditionsGastrointestinal bleeding not related to liver diseaseHematopoietic stem cell transplantationLiver disease (other than transplantation)Neonatal conditions (beyond cardiac surgery)Obstetrical conditionsPrimary clotting disorders (other than hemophilia)Pulmonary conditions (e.g., pulmonary hemorrhage, pulmonary transplantation)Secondary clotting disorders (e.g., complications of warfarin anticoagulation)Additional Off-Label Uses of rFVIIa Requiring Future Research: Medical
36. For the uses examined, current evidence does not show that off-label use of rFVIIa reduces mortality or improves other direct outcomes. Thromboembolic events are increased by using rFVIIa to treat spontaneous intracranial hemorrhage and in adult cardiac surgery.Conclusions From Available EvidenceYank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.