Reversing novel anticoagulants to divert catastrophe SEAN P. WILSON, MD DEPARTMENT OF EMERGENCY MEDICINE HENRY FORD HOSPITAL, DETROIT, MI

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1 Reversing novel anticoagulants to divert catastrophe SEAN P. WILSON, MD DEPARTMENT OF EMERGENCY MEDICINE HENRY FORD HOSPITAL, DETROIT, MI

2 Novel anticoagulants? Dabigatran (Pradaxa) Stroke and systemic embolism prevention in non-valvular atrial fibrillation Acute treatment and reduction in risk of recurrence of DVT and PE Rivaroxaban (Xarelto) Stoke and systemic embolism prevention in non-valvular atrial fibrillation Prophylaxis of DVT and PE in patients undergoing: hip replacement surgery or knee replacement surgery Acute treatment and reduction in risk of recurrence of DVT and PE Apixaban (Eliquis) Stoke and systemic embolism prevention in non-valvular atrial fibrillation Acute treatment and reduction in risk of recurrence of DVT and PE

3 A-fib? Not warfarin? NEJM 09/2009: Dabigatran vs. Warfarin in patients with A-Fib (RE-LY) Randomized, non-inferiority trial; 18,113 pts; 2 year follow-up Dabigatran vs. Warfarin Stroke or systemic embolism: 1.11% vs. 1.69% per year (p<0.001) Major bleeding: 3.11% vs. 3.36% pear year (p=0.31) Hemorrhagic stroke: 0.10% vs. 0.38% per year (p<0.001) All cause mortality: 3.64% vs. 4.13% per year (p=0.051)

4 Bad press was RE-LY study flawed? NEJM 04/2013: Dabigatran and postmarket reports of bleeding Review of insurance-claim and administrative data from the FDA Mini- Sentinal database from Oct 2010 through Dec 2011 Have a-fib? Dabigatran vs. Warfarin GI Hemorrhage 16 (n=10,599) vs. 160 (n=43,541) Intracranial Hemorrhage 8 (n=10,578) vs. 109 (n=43,594) Significantly limited, but supports RE-LY findings NEJM 09/2014: Data internally reviewed by Boehringer Ingelheim and correspondence published with minimal change

5 DVT: hold the warfarin too? NEJM 10/2009: Dabigatran in acute DVT (RE-COVER) Double-blinded, randomized non-inferiority trial; 2564 patients, 6 month follow-up Dabigatran vs. Warfarin Recurrent DVT of death due to DVT: 2.4% vs. 2.1% Major bleeding: 1.6% vs. 1.9% Non-major bleeding: 5.6% vs. 8.8% (p=0.002) NEJM 02/2013: Dabigatran in recurrent DVT (RE-MEDY) Double-blinded, randomized non-inferiority trial; 2866 patients, 3-36 month follow-up Prior >3 month treatment w/ any warfarin or study anticoagulant Dabigatran vs. Warfarin Recurrent DVT or death due to DVT: 1.8% vs. 1.3% (p=0.01) Major bleeding: 0.09% vs. 1.8% (p=0.06) Any bleeding event 19.4% vs. 26.2% (p<0.001)

6 What about Rivaroxaban? NEJM 09/2011: Rivaroxaban in non-valvular a-fib (ROCKET) Double-blinded, randomized non-inferiority trial; 14,264 patients; variable follow-up Rivaroxaban vs. Wafarin Stroke or systemic embolism: 1.7% vs. 2.2% per year (p<0.001) Major bleeding: 3.6% vs. 3.4% per year (p=0.58) Hemorrhagic stroke 0.5% vs. 0.7% per year (p=0.02) NEJM 12/2010: Rivaroxaban for acute DVT (EINSTEIN) Double-blinded, randomized non-inferiority trial; 3449 patients; 3,6,12 month follow-up Rivaroxaban vs. Warfarin Recurrent VTE or death due to VTE: 2.1% vs. 3.0% (p<0.001) Major bleeding: 0.8% vs. 1.2% (p=0.21) NEJM 04/2012: Rivaroxaban for acute PE (EINSTEIN-PE) Double-blinded, randomized non-inferiority trial; 4832 patients; 3,6,12 month follow-up Rivaroxaban vs. Warfarin Recurrent VTE or death due to PE: 2.1% vs. 1.8% (p=0.003) Major bleeding: 1.1% vs. 2.2% (p=0.003)

7 What about Apixaban? NEJM 09/2011: Apixaban in non-valvular a-fib (ARISTOTLE) Double-blinded, randomized non-inferiority trial; 18,201 patients; 1.8 year follow-up Apixaban vs. Wafarin Stroke or systemic embolism: 1.27% vs. 1.60% per year (p<0.001) Major bleeding: 2.13% vs. 3.09% per year (p<0.001) Hemorrhagic stroke 0.24% vs. 0.47% per year (p<0.001) Mortality from any cause: 3.52% vs. 3.94% (p=0.047) NEJM 08/2013: Apixiban for acute DVT (AMPLIFY) Double-blinded, randomized non-inferiority trial; 5395 patients, 6 month follow-up Apixiban vs. Warfarin Recurrent VTE or death due to VTE: 2.3% vs. 2.7% (p<0.001) Major bleeding: 0.6% vs. 1.8% (p<0.001)

8 More safety information JAMA 09/2014: Clinical and safety outcomes with treatment of VTE Meta-analysis of 45 trials, 14,989 patients Adverse bleeding compared with Warfarin Rivaroxaban HR 0.55; 95% CI, Apixaban HR 0.31; 95% CI, Major bleeding compared with Warfarin over 3 months Rivaroxaban 0.49% (95% CI, 0.29%-0.85%) Apixaban 0.28% (95% CI, 0.14%-0.50%) Warfarin 0.89% (95% CI, %)

9 More bad press? Boehringer Ingelheim settled $650 million in May 2014 for cases associated with adverse bleeding

10 Pharmacokinetics Anticoagulant Dabigatran Rivaroxaban Apixaban Mechanism of Action Direct inhibition of thrombin Direct inhibition of factor Xa Direct inhibition of factor Xa Time to peak concentration (h) Half-life (h) 1-3 Adults, single dose 7-9 Adults, multiple doses Adults, single dose 7-17 Elderly, single dose Adults, multiple doses Renal excretion (%) 80-85% 66% 1-3 Adults, single dose %

11 Obligatory coagulation cascade

12 Monitoring Novel Anticoagulant Prothrombin time (PT) International normalized ratio (INR) Activated partial thromboplastin time (aptt) Thrombin time (TT) Dabigatran Increased or normal No change Increased or normal Increased Rivaroxaban Increased or normal No change Increased or normal No change Apixaban Increased or normal No change Increased or normal No change

13 Procoagulant Agents Agent Coagulation Factors Misc. Details Fresh Frozen Plasma (FFP) II, V, VII, IX, X, XI Frozen, requiring thaw ABO Crossmatch Larger volume, 1U = ml Cryoprecipitate Prothrombin Complex Concentrate (PCC) Fibrinogen, VIII, XIII and von Willebrand factor PCC-3: II, IX, X PCC-4: II, VII, IX, X (Kcentra) apcc, II, avii, IX, X (FIEBA) Frozen, requiring thaw Can produce thrombotic complications (DVT, PE, MI, DIC) Recombinant activated factor VII (rfviia) US Versions of PCC-4 include some protein C & S VII

14 Evidence to support PCC Circulation 09/2011: Reversal of Rivaroxaban and Dabigatran by 4-PCC Randomized, placebo-controlled, crossover study in 12 healthy subjects Rivaroxaban PT after Rivaroxaban, 12.3 vs seconds (p<0.001) PT after 4-PCC, 15.8 vs seconds (p<0.001) PT after normal saline, 15.8 vs seconds (p=.4) Also reversal of ETP Dabigatran aptt after Dabigatran, 33.6 vs (p<0.001) aptt after 4-PCC, 59.4 vs (p=0.21) aptt after saline, 59.4 vs (p=0.64) Also no reversal of ETP lag time, TT, ECT

15 Evidence to support PCC Thrombosis and Haemostasis 01/2012: Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban Randomized, ex vivo, crossover study in 10 healthy subjects Evaluated, in vitro, use of 4-PCC, a-4pcc and rviia on ETP, LT, TTP Dabigatran aptt prolonged by 1.47x (p<0.001) 4-PCC and a-4pcc had a dose-dependent reversal, while rviia was inert Rivaroxaban PT prolonged by 1.37x (p<0.001) 4-PCC and a-4pcc had a dose-dependent reversal, while rviia was inert

16 Coagulation cascade again

17 Cost of apcc FIEBA (and Kcentra) have average wholesale price of $2.17/U FIEBA dosing is recommended at 25 U/kg 70 kg person requires 1,750 $3, kg person requires 2,500 $5,425

18 Thrombotic complications DVT PE DIC MI All have been reported at different rates Range between 1/20,000 to 1/400,000.

19 Case Reports 69 y/o male on dabigatran w/ non-traumatic subdural and elevated PTT, reversed with FIEBA and discharged in good condition. 86 y/o male on rivaroxaban w/ iliac artery aneurysm and extensive retroperitoneal hemorrhage and elevated PT, reversed with FIEBA and discharged in good condition (on rivaroxaban). 85 y/o female on dabigatran w/ GCS 9 and extensive hemorrhagic stroke, had mental status improvement after FIEBA. Ultimately suffered a ischemic stroke 6 days after discharge, transitioned to hospice and died on day y/o male on dabigatran in septic shock & renal failure 2/2 to cholecystitis w/ uncomplicated biliary drain placement after FIEBA. 67 y/o male on dabigatran w/ myocardial perforation 2/2 to invasive cardiac procedure 3L tamponade, only stopped after FIEBA administered.

20 Reversal Options Anticoagulant Charcoal (2h) Hemodialysis FFP Activated factor VIIa PCC Dabigatran Yes Yes No Unlikely Unclear, Possibly? Rivaroxaban Yes No No Unlikely Maybe, Possibly? Apixaban Yes No No Unlikely Maybe, Possibly?

21 Future studies Humanized monoclonal antibody against dabigatran Currently Phase III trial, May 2014 July 2017, goal 250 patients Recombinant, plasma-derived factor Xa antidotes Currently multiple phase II and III trials in process and development

22 Questions?

23 References Büller, Harry R., et al. "Oral rivaroxaban for the treatment of symptomatic pulmonary embolism." New England Journal of Medicine (2012): Agnelli, G., et al. "Oral rivaroxaban for symptomatic venous thromboembolism." N Engl J Med (2010): Agnelli, Giancarlo, et al. "Apixaban for extended treatment of venous thromboembolism." New England Journal of Medicine (2013): Agnelli, Giancarlo, et al. "Oral apixaban for the treatment of acute venous thromboembolism." New England Journal of Medicine (2013): Connolly, Stuart J., et al. "Dabigatran versus warfarin in patients with atrial fibrillation." New England Journal of Medicine (2009): Southworth, Mary Ross, Marsha E. Reichman, and Ellis F. Unger. "Dabigatran and postmarketing reports of bleeding." New England Journal of Medicine (2013): Schulman, Sam, et al. "Dabigatran versus warfarin in the treatment of acute venous thromboembolism." New England Journal of Medicine (2009): Schulman, Sam, et al. "Extended use of dabigatran, warfarin, or placebo in venous thromboembolism." New England Journal of Medicine (2013): Patel, Manesh R., et al. "Rivaroxaban versus warfarin in nonvalvular atrial fibrillation." New England Journal of Medicine (2011): Granger, Christopher B., et al. "Apixaban versus warfarin in patients with atrial fibrillation." New England Journal of Medicine (2011): Connolly, Stuart J., Lars Wallentin, and Salim Yusuf. "Additional Events in the RE-LY Trial." New England Journal of Medicine (2014). Cohen, Deborah. "Dabigatran: how the drug company withheld important analyses." BMJ 349 (2014): g4670. Alikhan, Raza, et al. "The acute management of haemorrhage, surgery and overdose in patients receiving dabigatran." Emergency Medicine Journal (2013): emermed Eerenberg, Elise S., et al. "Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects." Circulation (2011):

24 References Continued Miyares, Marta A., and Kyle Davis. "Newer oral anticoagulants: a review of laboratory monitoring options and reversal agents in the hemorrhagic patient." Am J Health Syst Pharm (2012): Faust, Andrew C., and Evan J. Peterson. "Management of Dabigatran-associated Intracerebral and Intraventricular Hemorrhage: A Case Report." The Journal of emergency medicine 46.4 (2014): Kiraly, Amy, et al. "Management of Hemorrhage Complicated by Novel Oral Anticoagulants in the Emergency Department: Case Report From the Northwestern Emergency Medicine Residency." American journal of therapeutics 20.3 (2013): Wong, Henna, and David Keeling. "Activated prothrombin complex concentrate for the prevention of dabigatran associated bleeding." British journal of haematology (2014). Castellucci, Lana A., et al. "Clinical and Safety Outcomes Associated With Treatment of Acute Venous Thromboembolism: A Systematic Review and Meta-analysis." JAMA (2014): Kreuziger, Lisa M. Baumann, Colleen T. Morton, and David J. Dries. "New anticoagulants: A concise review." Journal of Trauma and Acute Care Surgery 73.4 (2012): Kaatz, Scott, et al. "Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors." American journal of hematology 87.S1 (2012): S141-S145. Awad, Nadia I., and Craig Cocchio. "Activated Prothrombin Complex Concentrates for the Reversal of Anticoagulant-Associated Coagulopathy." Pharmacy and Therapeutics (2013): 696. Siegal, Deborah M., and Adam Cuker. "Reversal of novel oral anticoagulants in patients with major bleeding." Journal of thrombosis and thrombolysis 35.3 (2013): Babilonia, Katrina, and Toby Trujillo. "The role of prothrombin complex concentrates in reversal of target specific anticoagulants." Thrombosis journal 12.1 (2014): 8. Nitzki-George, Diane, Izabela Wozniak, and Joseph A. Caprini. "Current state of knowledge on oral anticoagulant reversal using procoagulant factors." Annals of Pharmacotherapy 47.6 (2013): Marlu, Raphael, et al. "Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban." Thromb Haemost (2012):