Recombinant factor VIIa: Hype or hope? Jed Gorlin MD, MBA

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1 Recombinant factor VIIa: Hype or hope? Jed Gorlin MD, MBA

2 Goals of presentation Challenge current use of rviia using data Review how rviia works Approved indications Review results of randomized trials for unapproved indications Review thrombotic risks

3 Assumptions we can agree upon The transfusion service exists to support patients and those taking care of patients We all want what is best for patient outcome Bleeding into a small confined space is bad rviia does (somewhat) slow bleeding The reason we need controlled trials is none of us wants to learn at the expense of our mistakes on patients (to paraphase Atul Gewande- The Bell Curve)

4 Casting the gauntlet Use of VIIa follows a predictable pattern Initial sporadic use followed by overenthusiastic recommendations following anecdotal successes. Complications bring caution and controlled trials delineate true proven indications Use by the US military in Mideast has dramatically declined Note, there are NO (few) randomized prospective rviia trials supporting better patient outcome following use in either trauma or neurosurgery!

5 Recombinant VIIa Only licensed indication is treating bleeding in patients with hemophilia (VIII, IX) and inhibitors (antibodies) or patients missing factor VII. All other uses are off label There are many prospective clinical trials of use of factor VIIa in various settings. most show NO benefit to VIIa The phase II (Mayer-NEJM) study suggesting benefit to early use in hemorrhagic stroke was followed by a larger phase III study failing to show outcome benefit!

6 Cochrane Review: Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia Selection criteria: META-ANALYSIS of Randomised controlled trials (RCTs) comparing rfviia with placebo, or various doses Outcomes were mortality, blood loss or control of bleeding, red cell transfusion, number of patients transfused and thromboembolic adverse events. Results: Twenty-five RCTs were included: 24 were placebo-controlled double-blind RCTs and one compared different doses of rfviia. Fourteen trials involving 1137 participants examined the prophylactic use of rfviia; 713 received rfviia. There was no evidence of mortality benefit (RR 1.06; 95% CI 0.50 to 2.24). There was decreased blood loss and decreased red cell transfusion requirements with rfviia treatment; however these values were likely overestimated due to the inability to incorporate data from trials showing no difference of rfviia treatment compared to placebo. There was a trend in favour of rfviia in the number of participants transfused (RR 0.91). But there was a trend against rfviia with respect to thromboembolic adverse events (RR 1.32). Less blood loss, more pathologic clotting, no difference in mortality outcome!

7 Cochrane review cont. Eleven trials involving 2366 participants examined the therapeutic use of rfviia; 1507 received rfviia. There were no outcomes where any observed advantage, or disadvantage, of rfviia over placebo could not have been observed by chance alone. There was a trend in favour of rfviia for reducing mortality (RR 0.89). However, there was a trend against rfviia for increased thromboembolic adverse events (RR 1.21). Authors' conclusions The effectiveness of rfviia as a more general haemostatic drug, either prophylactically or therapeutically, remains unproven. The use of rfviia outside its current licensed indications should be restricted to clinical trials Citation: Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database of Systematic Reviews 2007, Issue 2.

8 Hemostasis Subendothelial matrix Endothelial cell Nitric oxide

9 Coagulation Pathways Contact XIIa XI XIa HKa Intrinsic Pathway IX IXa TF Pathway TF-VII VIIa PL VIIIa PL Protein C, Protein S, Antithrombin III (Tenase ) Tissue Factor + VII Xa Va (Prothrombinase) Extrinsic Pathway X Fibrinogen Common Pathway Prothrombin PL Thrombin Fibrin (weak) XIII XIIIa Fibrin (strong)

10 Recombinant VIIa dosing Varies from ug/kg Very short ½ life. Needs to be repeated q 2 hours if bleeding persists Vial sizes available in 1, 2, 5 mg Cost is about $1.20/ug, = $1.2, 2.4, 6 K! Economic issues The idea that rviia use spares other precious blood products is not supported by economics RBC ~$200, Platelet dose ~$500, FFP ~$50 Therefore 5mg dose 15 RBC, 10 FFP, 5 aph platelets

11 In Summary: Off-Label use of r7a UGI bleed cirrhosis UGI bleed cirrhosis (childs C & D) Multicenter n = 242 No benefit RBC use or survival Multicenter n= 256 No benefit Trauma (blunt) Multicenter n = 142 No benefit RBC use; survival Trauma (penetrating) Multicenter n = 130 No benefit RBC use; survival Trauma (USA) Trauma (Global) Multicenter n=1502 planned Multicenter n= 576 planned Company closed for futility Company closed for futility

12 Off-label use of r7a (continued) CNS bleed # 1 Multicenter n = 399 No benefit on survival;? Outcome benefit. Toxicity at doses that reduced hematoma growth CNS bleed # 2 Multicenter n= 841 No benefit on survival; reduced hematoma growth Cardiac surgery Multicenter n = 172 Closed by company; SAE s Partial hepatectomy Significant increased toxicity Multicenter n = 200 No benefit on blood loss or RBC use. Liver txplant #1 Multicenter n = 82 No benefit on blood loss or RBC use. Liver txplant #2 Multicenter n = 179 No benefit on blood loss or RBC use. Major pelvic Single center n = 48 No benefit on blood loss. Prostate Single center n = 36 Benefit~1-2 units RBCs

13 Retrospective cardiac surgery Use of rviia for critical bleeding in cardiac surgery: dose variation and patient outcomes C. Willis et al. Vox Sang 98:531 Retrospective data base review of 804 cardiac surgery patients who received rviia off protocol. Univariate analysis <40ug/kg vs , 61-80, & >100ug/kg No benefit to doses higher than 40ug/kg in any outcome measure or rates of thrombosis

14 Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage BACKGROUND: This phase 3 trial was intended to confirm a previous study in which (rfviia) reduced growth of the hematoma and improved survival and functional outcomes. METHODS: n=841 [placebo (268), 20 g/kg (276), or 80 g/kg (297) within 4 h after onset of stroke. Primary end point: poor outcome, defined as severe disability or death 90 days after the stroke. RESULTS: Treatment with 80 g/kg resulted in a significant reduction in growth in volume of the hemorrhage. The mean increase at 24 hours was 26% placebo, 18% 20 g/kg (P=0.09) and 11% in the group receiving 80 g (P<0.001). The growth in volume was reduced by 2.6 ml (95% confidence interval [CI], -0.3 to 5.5; P=0.08) in the group receiving 20 g/kg and by 3.8 ml (95% CI, 0.9 to 6.7; P=0.009) in the group receiving 80 g, as compared with the placebo group. Despite this reduction in bleeding, there was no significant difference among the three groups in the proportion of patients with poor clinical outcome (24% in the placebo group, 26% in the group receiving 20 g/kg, and 29% in the group receiving 80 g). The overall frequency of thromboembolic serious adverse events was similar in the three groups; however, arterial events were more frequent in the group receiving 80 g of rfviia than in the placebo group (9% vs. 4%, P=0.04). CONCLUSIONS: rfviia reduced growth of the hematoma but did not improve survival or functional outcome after intracerebral hemorrhage. Mayer SA, Brun NC, Begtrup K, NEJM (2008) 358:2127

15 Intracerbral hemorrhage- Rx rviia quality of life scales Randomized prospective Washington University St. Louis (n=399) Arms = placebo, 40,80,160 g/kg rviia Only mobility rating better for rviia Rx patients, but some subjective (patient scored) significant differences Diringer, MN in Cerbrovasc Dis (2007) 24:219

16 Recombinant factor VIIA in traumatic intracerebral hemorrhage: results of a doseescalation clinical trial OBJECTIVE: This prospective, randomized, placebo-controlled, dose-escalation study evaluated the safety and preliminary effectiveness of rfviia to limit tich progression. METHODS: Patients were enrolled if they had tich lesions of at least 2 ml on a baseline CT scan obtained within 6 h of injury. rfviia or placebo was administered within 2.5 hours of the baseline computed tomographic scan but no later than 7 hours after injury. CT scans were repeated at 24 and 72 hours. Five escalating dose tiers were evaluated (40, 80, 120, 160, and 200 g/kg rfviia). RESULTS: No significant differences were detected in mortality rate or number and type of adverse events among treatment groups. Asymptomatic deep vein thrombosis, detected on routinely performed ultrasound at Day 3, was observed more frequently in the combined rfviia treatment group (placebo, 3%; rfviia, 8%; not significant). A nonsignificant trend for rfviia dose-response to limit tich volume increase was observed (placebo, 21.0 ml; rfviia, 10.1 ml). CONCLUSION: There appeared to be less hematoma progression in rfviia-treated patients ( g/kg) compared with that seen in placebo treated patients. The potential significance of this biological effect on clinical outcomes and the significance of the somewhat higher incidence of ultrasound-detected deep vein thromboses in the rfviia-treated group need to be examined in a larger prospective randomized clinical trial. Narayan RK, Maas AI, Marshall LF Neurosurgery (2008) 62:776

17 Dickneite G. Thrombosis Res 2006; Jul 12: Epub ahead of print Prothrombin complex concentrate vs rviia reversal of coumarin anticoagulation Saline rviia PCC

18 rviia reverses INR, not bleeding! Dickneite G. Thrombosis Res 2006

19 Human punch biopsy model: VIIa Blood Apr 12. [Epub ahead of print] Exploratory study on the reversal of warfarin with rfviia in healthy subjects. Skolnick BE, et alnovo Nordisk Inc., Princeton, NJ, United States; Abstract Randomized, placebo-controlled, double-blinded, dose-escalation, punch-biopsy-induced bleeding model in healthy subjects. However, bleeding post-rfviia treatment was not significantly different from placebo (Experiment 2, 114 subjects). Mean aptt, PT and INR were reduced from warfarin-elevated levels. Recombinant FVIIa (80mcg/kg) significantly reversed warfarin effects on all thromboelastography parameters, compared to placebo (p<0.05). In this exploratory trial, the reversal of warfarin effects was observed in the thromboelastography, thrombin generation and clotting assays. However, this reversal did not translate to improvements in the bleeding model parameters evaluated by the punch-biopsy model.

20 ASH education 2008: Coumadin reversal using VIIa Based on this review, we conclude that rviia appears to rapidly correct the INR; however, its clinical impact on bleeding in patients taking warfarin remains unclear. This conclusion is based on the observation that currently available evidence consists mainly of small (1 16 patients), non-randomized, retrospective, case series and case reports without adequate controls. Furthermore, the majority of the studies include the use of standard modalities (FFP and vitamin K), which will also impact bleeding. We thus recommend against routine use of rfviia in acute warfarin reversal (Grade 2C).

21 Risks of VIIa Pathologic thromboses 431 adverse event reports submitted to FDA, 168 described 185 thromboembolic events-151 were off label use CVA 34, MI 34, PE 32, other arterial thrombi 26, venous 42 36/50 reported fatalities attributed to thromboses Most events within hours of administration- Inadequate correction of other factors It will shorten the PT/INR- but this does not mean bleeding is controlled Weakness of study: Only bad stuff reported to FDA O Connell JAMA (2006) 295:293 Thromboembolic adverse events after use of rviia

22 Risks of VIIa- controlled study Thrombotic events with rviia in FAST trial N =841 patients enrolled 178 arterial, 47 venous thromboembolic events Art: 49 (27% P), 47 (26% 20 g), 82 (46%, 80 g) p = 0.04 Myocardial events: 17 placebo (6.3%), 57 rviia (9.9%) p = 0.09 Conc: higher doses of VIIa in high risk population are associated with a small increased thrombotic risk Diringer, MN et al. Stroke (2010) 41:48

23 Futile uses of VIIa If ph is <7.0, VIIa does not function well Clark et al Vox Sanguinus (2004) 86: patients who received more than 10 units of red cells and also in 10 patient who got VIIa Overall mortality 24 h and 7 days Mortality in VIIa group 24h and Last ditch therapy, post arrest, or when coags were far from corrected all correlated with poor outcome

24 HCMC VIIa policy Developed by Drs. Robert Quickel and John Crosson Pathology consultation is required Attempt to measure and correct coagulopathy first Consider earlier therapy if closed space (CNS) bleeding where large volume of FFP etc. may not be tolerated

25 HCMC Beriplex trial HCMC is participating in a national trial of a European prothrombin complex concentrate (PCC = vitamin K dependent factors II, X, VII, IX) for emergent reversal of Coumadin Nonsurgical Surgical (but limited to relative small CNS bleed)

26 Donate to Memorial Blood Centers!

27 Extra slides if plasma Rx discussed

28 Transfusion Recipient Fatalities FDA Category FY03 FY04 FY05 FY06 FY07 FY08 TRALI HTR Non ABO Microbial HTR-ABO TACO

29 TRALI: Transfusion-related acute Lung Injury Acute onset of respiratory distress following within 6h of Tx. Multiple predisposing causes, but majority of cases associated with plasma containing anti-hla or neutrophil antibodies Most from multiparous (> 1 baby) female donors Implicated product usually FFP, platelets

30 AABB TRALI guidance Blood Centers must implement strategy to reduce TRALI 07-plasma 08- apheresis platelets Evidence based usage of blood components Improved adverse event reporting- AABB Biovigilance system Pilot ongoing in ~20 large hospital systems CDC/HHS collaboration

31 MBC-HCMC- Plasma usage reduction project HCMC RBC vs. FFP # Units RBC FFP Calendar Year Usage

32 Adult Plasma Guidelines Given to correct multiple deficiencies of plasma coagulation factors Inappropriate when PT or PTT < 1.5 X normal (When administered for lower values it rarely corrects to normal!) Diffuse microvascular bleeding in patient transfused > 1 blood volume (massive transfusion) (but check platelets first!) Therapeutic apheresis for TTP

33 FFP transfusions: volume Tx Transfusion (2006) 46:1921 Populationbased audit of fresh-frozen plasma transfusion practices Riikka Palo et al. Clearly, physicians order FFP in multiples of 2 instead of a more physiologic order of ml/kg!

34 TABLE 1. FFP and RBC use per 1000 population and FFP use per 100 RBC units Delivered units/1,000 population Country (year) FFP RBC Finland (2001) Finland (2002) Finland (2003) Finland (2004) Germany (2003) US (2001) Sweden (2003) Denmark (2003) Norway (2003) UK (2003) France (2003) Transfusion (2006) 46:1921 Populationbased audit of freshfrozen plasma transfusion practices Riikka Palo et al.

35 Coagulopathy: hypothermia & acidosis J Trauma (2009) 67:202-8 Hypothermia and acidosis inhibit coagulation by different mechanisms Hypothermia impairs initiation of clot forming Acidosis accelerates fibrinogen degradation, not immediately corrected by ph correction J Trauma (2008) 65:951 ph < 7.1, BE < -12.5, T< 34 o C all impair clotting

36 HCMC Massive Transfusion Policy Blood bank works with staff to monitor patients with large ongoing needs Obtain frequent labs (Hct/Hgb, plt, PT (INR), PTT, fibrinogen to guide Tx Don t wait for coagulopathy to develop After 4 u RBC are released in < 1h, staff ask about FFP As RBC transfused approaches 1 x blood volume platelets are often depleted before coag factors