Reversing novel

anticoagulants to

divert catastrophe SEAN P. WILSON, MD

DEPARTMENT OF EMERGENCY MEDICINE

HENRY FORD HOSPITAL, DETROIT, MI

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

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)

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

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)

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)

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)

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, 0.35-0.89

Apixaban HR 0.31; 95% CI, 0.15-0.62

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, 0.66-1.16%)

More bad press?

Boehringer Ingelheim settled $650 million in May 2014 for cases

associated with adverse bleeding…

Pharmacokinetics

Anticoagulant Mechanism of

Action

Time to peak

concentration

(h)

Half-life (h) Renal

excretion (%)

Dabigatran Direct inhibition

of thrombin

1-3 Adults, single dose 7-9

Adults, multiple doses 7-17

80-85%

Rivaroxaban Direct inhibition

of factor Xa

2-4 Adults, single dose 7-17

Elderly, single dose 12-13

Adults, multiple doses 12-13

66%

Apixaban Direct inhibition

of factor Xa

1-3 Adults, single dose 8-14 25%

Obligatory coagulation cascade

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

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 = 200-250ml

Cryoprecipitate Fibrinogen, VIII, XIII and von

Willebrand factor

Frozen, requiring thaw

Prothrombin Complex

Concentrate (PCC)

PCC-3: II, IX, X

PCC-4: II, VII, IX, X (Kcentra)

aPCC, II, aVII, IX, X (FIEBA)

US Versions of PCC-4 include

some protein C & S

Can produce thrombotic

complications (DVT, PE, MI, DIC)

Recombinant activated

factor VII (rFVIIa)

VII

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. 15.8 seconds (p<0.001)

PT after 4-PCC, 15.8 vs. 12.8 seconds (p<0.001)

PT after normal saline, 15.8 vs. 16.2 seconds (p=.4)

Also reversal of ETP

Dabigatran

aPTT after Dabigatran, 33.6 vs. 59.4 (p<0.001)

aPTT after 4-PCC, 59.4 vs. 70.3 (p=0.21)

aPTT after saline, 59.4 vs. 57.9 (p=0.64)

Also no reversal of ETP lag time, TT, ECT

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

Coagulation cascade again…

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 U @ $3,797

100 kg person requires 2,500 U @ $5,425

Thrombotic complications

DVT

PE

DIC

MI

All have been reported at different rates

Range between 1/20,000 to 1/400,000.

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 16.

80 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.

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?

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

Questions?

References Büller, Harry R., et al. "Oral rivaroxaban for the treatment of symptomatic pulmonary embolism." New England Journal of Medicine 366.14 (2012):

1287-97.

Agnelli, G., et al. "Oral rivaroxaban for symptomatic venous thromboembolism." N Engl J Med 363.26 (2010): 2499-510.

Agnelli, Giancarlo, et al. "Apixaban for extended treatment of venous thromboembolism." New England Journal of Medicine 368.8 (2013): 699-708.

Agnelli, Giancarlo, et al. "Oral apixaban for the treatment of acute venous thromboembolism." New England Journal of Medicine 369.9 (2013):

799-808.

Connolly, Stuart J., et al. "Dabigatran versus warfarin in patients with atrial fibrillation." New England Journal of Medicine 361.12 (2009): 1139-1151.

Southworth, Mary Ross, Marsha E. Reichman, and Ellis F. Unger. "Dabigatran and postmarketing reports of bleeding." New England Journal of

Medicine 368.14 (2013): 1272-1274.

Schulman, Sam, et al. "Dabigatran versus warfarin in the treatment of acute venous thromboembolism." New England Journal of Medicine 361.24

(2009): 2342-2352.

Schulman, Sam, et al. "Extended use of dabigatran, warfarin, or placebo in venous thromboembolism." New England Journal of Medicine 368.8

(2013): 709-718.

Patel, Manesh R., et al. "Rivaroxaban versus warfarin in nonvalvular atrial fibrillation." New England Journal of Medicine 365.10 (2011): 883-891.

Granger, Christopher B., et al. "Apixaban versus warfarin in patients with atrial fibrillation." New England Journal of Medicine 365.11 (2011): 981-992.

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-2012.

Eerenberg, Elise S., et al. "Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate a randomized, placebo-controlled, crossover study in healthy subjects." Circulation 124.14 (2011): 1573-1579.

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 69.17 (2012): 1473-1484.

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): 525-529.

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): 300-306.

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 312.11 (2014): 1122-1135.

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): 983-992.

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 38.11 (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): 391-398.

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): 841-855.

Marlu, Raphael, et al. "Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban." Thromb Haemost

108.2 (2012): 217-224.