MANAGING BLEEDING IN THE

MANAGING BLEEDING IN THE SETTING OF NEW ANTICOAGULANTS: HOW DO OLD METHODS MEASURE UP? Michelle Zeller MD Clinical Hematology Fellow November 5th, 2011

A FRIDAY NIGHT ON-CALL WITH DR. B. LUD Very keen first year resident on-call for Hematology Case 1: Ms. N. Pain, 65 yo W, presents to ER Extreme lower right quadrant abdo pain CT shows appendicitis Pt is on warfarin for Afib, INR 2.7; Hb 125; Plt 350 Gen Sx wants to operate in 2 hours! Case 2: Mr. M. Fine, 53 yo man Presented to ER with a localized rash from a cast placed following a recent knee surgery INR 2.1, PTT 43, Fibrinogen 0.52 ER calls for urgent cryoprecipitate Case 3: Mr. B. Leeding, 45 yo man Sustains numerous traumas following MVC On a new blood thinner for recent hip surgery. The patient is being air-lifted in and will arrive in 45 minutes. Dr. B. Lud needs a plan!

CASE 1: MS. N. PAIN 65 yo W: Extreme lower right quadrant abdo pain CT shows appendicitis Pt is on warfarin for Afib, INR 2.7; Hb 125; Plt 350 How should she be reversed for surgery? a. 4 units Fresh Frozen Plasma + Vit K IV b. Vit K PO and left over Halloween candies c. Hold warfarin for 5 days then operate d. Prothrombin Complex Concentrate + Vit K IV e. 2 units Fresh Frozen Plasma http://ohiosurgery.blogspot.com/2009_01_01_archive.html

CASE 2: MR. M. FINE 53 yo man: Presented to ER with a localized rash from a cast placed following a recent knee surgery INR 2.1, PTT 43, Fibrinogen 0.52 ER calls for urgent cryoprecipitate What should Dr. B. Lud do??? a. 10 unit of Cryoprecipitate b. Conduct a detailed history and physical exam c. 4 units FFP and Vit K IV d. PCC and Vit K IV e. Benadryl for the rash and repeat blood work

CASE 3: MR. B. LEEDING 45 yo man: Numerous traumas, MVC On new blood thinner for recent hip surgery. The patient is being air-lifted in and will arrive in 45 minutes. What should Dr. B. Lud recommend in addition to Initiating the Trauma Transfusion Pathway??? a. rfviia b. PCC c. rfviia & PCC d. Neither rfviia nor PCC e. Not sure. Digesting lunch.

THE PLAN Make a PLAN Background: Hemostasis Clotting cascade Anticoagulants: Old & New Mechanisms of Action Indications Bleeding Risks Effects on routine laboratory assays Review evidence of reversal with blood products Prothrombin Complex Concentrate (PCC) Recombinant Factor VIIa (rfviia)

BACKGROUND Hemostasis & Clotting Cascade

IN VITRO CASCADE MODEL

CELL BASED MODEL

INITIATION

PROPAGATION

FIBRINOLYSIS

Jonworth.eu ANTICOAGULANTS Old & New

ANTICOAGULANTS: WHERE THEY ACT

WHY DO WE NEW ANTICOAGULANTS??? The OLD: Narrow therapeutic window Frequent monitoring Drug interactions Inter-patient dose variation Intra-individual dose variation The NEW: Subcutaneous administration Predictable pharmacokinetics Wide therapeutic windows Fixed dose No monitoring

DABIGATRAN (PRADAX) FACTOIDS Oral reversible thrombin inhibitor developed for prevention and treatment of thromboembolic disease Prescribed as fixed dosing, no monitoring required Currently approved in Canada: Primary DVT prophylaxis following hip and knee surgery 110 mg PO BID for 28 35 days Prevention of stroke and central embolism in Nonvalvular AF 150 mg PO BID Half life 12-17 hr Renally excreted Major Trials: RE-LY, RECOVER, RENOVATE, REMODEL Connolly SJ et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139-1151

DABIGATRAN BLEEDING RISK Annual risk of any bleeding on treatment: 16.6% (1 in 6 patients) when taking 150 mg twice daily 14.7% (1 in 6.8 patients) taking 110 mg twice daily Compared to 18.4% (1 in 5.4 patients) for warfarin Annual risk of major bleeding 3.1% taking 150 mg twice daily 2.1% taking 110 mg twice daily Compared to 3.4% for warfarin Randomized Evaluation of Long-term anticoagulant therapy trial

DABIGARTRAN BLEEDING RISK Lower total bleeds with Dabigatran vs warfarin *2 Higher rate of major GI bleeds (1.6% vs 1.1%) vs warfarin * Similar rate of major bleeds (3.3% vs 3.6%) * http://www.pradaxapro.com/safety.jsp

RIVAROXABAN (XARELTO) FACTOIDS Oral direct FXa inhibitor developed for prophylaxis and treatment of thromboembolic disease Prescribed as fixed daily dose & lab monitoring not necessary Currently approved in Canada: Primary prophylaxis post hip and knee surgery 10 mg PO OD for 28-25 days Half life: 7-11hr Excreted in urine and feces Major trials: RECORD, ROCKET-AF, MAGELLEN, ATLAS, EINSTEIN

RIVAROXABAN BLEEDING RISK Rivaroxaban vs enoxaparin: Major bleeding event rates reported in hip surgery studies were 0.2% vs 0.1% Any bleeding events were 6.1% vs 5.8%; Major bleeding events reported in the knee surgery study were 0.6% vs 0.5% Any bleeding events were 5.0% vs 4.9%. http://www.xareltohcp.com/xareltocontactus.html

BACK TO CASE 1: MS. N. PAIN 65 yo W: Extreme lower right quadrant abdo pain CT shows appendicitis Pt is on warfarin for Afib, INR 2.7; Hb 125; Plt 350 Pt was reversed with PCC and Vit K IV INR of 1.3 She had her surgery with no complications Her warfarin was restarted post op

WHY & HOW Measuring Anticoagulants

WHY MEASURE? Acute trauma Emergency surgery Overdose Bridging Drug interactions Compliance Renal Insufficiency Pregnancy Obesity

PT/INR APTT http://www.medicine.mcgill.ca/physio/vlab/bloodlab/pt_ptt. htm

EFFECTS ON PT & APTT ASSAYS Agent PT/INR aptt Warfarin Sensitive Prolongs, but less useful UFH Prolongs at [high] Sensitive LMWH No clinical effect No clinical effect Fondaparinox No clinical effect No clinical effect Dabigatran Prolongs, low sensitivity Prolongs, curvilinear, variable Rivaroxaban Prolongs, poor at [low] Prolongs, variable, low sensitivity Apixaban Prolongs, unknown variability Prolongs, unknown variability Edoxaban Prolongs, variable Prolongs, variable Ecarin Clotting Time (ECT) and Thrombin Clotting Time (TT) have strong linear relationship with dabigatran PT varies in a linear fashion, with plasma concentration with a correlation coefficient r = 0.98 when Neoplastin is used for the assay (xarelto.com)

CASE 2: MR. M. FINE 53 yo man: Presented to ER with a localized rash from a cast placed following a recent knee surgery INR 2.1, PTT 43, Fibrinogen 0.52 Dr. B. Lud conducted a thorough history and physical exam: Mr. Fine was healthy apart from a mild rash on his leg The patient was on Rivaroxaban following knee surgery He had no signs or symptoms of bleeding No clinical, historic or physical evidence to suggest DIC

REVIEW OF THE EVIDENCE REVERSAL WITH BLOOD PRODUCTS

BLOOD PRODUCTS FOR REVERSAL OF ANTICOAGULANTS FFP PCC rfviia Protein c & s FII, VII, IX, X +/- Heparin PCC http://www.frca.co.uk/article.aspx?articleid=100097 http://ajcp.ascpjournals.org/content/121/1/124.full.pdf

THE EVIDENCE...IN RATS 2 studies using rat models Van Ryn et al.: Used FVIIa (Novoseven) and PCC (Feiba) Measured tail bleeding time & aptt Bleeding time: Control = 125s; Dabigatran = 1455s FVIIa reduced to 135-186s PCC reduced to 146-174s aptt: Control = 7; Dabigatran = 58 FVIIa reduced to 27-31 PCC did not have effect on aptt Conclusions: Both FVIIa and PCC have potential reversal abilities for dabigatran. aptt might not correlate to in vivo activity of dabigatran

THE EVIDENCE... IN MICE Zhou, W et al. Mice received 2 doses of dabigatran (DE) followed injection that caused ICH, followed coags, MRI Mice were given one of: Saline PCC Murine FFP rfviia ICH size: Control = 7.8 mm3 vs 11-16 mm with increasing doses of DE 77% of max volume reached in 1hr; 86% in 3 hrs. Hematoma growth was prevented by administering PCC Mortality approached control in group treated with PCC Minimal or no effect with FFP or rviia Conclusion: PCC prevent excess expansion of ICH in murine model exposed to dabigatran

THE EVIDENCE... IN HUMANS Eerenberg at al.: Randomized, double blind, placebo controlled cross-over study in healthy subjects Twelve healthy male subjects Grp A: rivaroxaban 20 mg BID x 2.5 days Grp B: dabigatran 150 mg BID x 2.5 days PCC or placebo Wash out of eleven days Grp A: dabigatran 150 mg BID x 2.5 days Grp B: rivaroxaban 20 mg BID x 2.5 days PCC or placebo PCC (Cofact) FII, VII, IX, X, C, S & antithrombin (no heparin) 50 U PCC/kg Circulation 2011, 124:1573-1579

RESULTS OF LABORATORY ASSAYS Rivaroxaban Pre PCC Rivaroxaban Post PCC PT Significantly prolonged Completely normalized ETP Decreased Normalized Dabigatran Pre PCC Dabigatran Post PCC ETPlt Prolonged No change aptt Significantly prolonged No change TT Immeasurable (>120 sec) No change ECT Significantly prolonged Further increased! ETP: Endogenous thrombin potential (lt = lag time) ECT: Ecarin clotting time

STUDY CONCLUSIONS First study in human investigating the effects of PCC in reversing new anticoagulants PCC neutralizes anticoagulant laboratory effect of rivaroxaban but had no effect on dabigatran Numerous study limitations makes applying these results to bleeding patients in clinical practice difficult.

BACK TO CASE #3 Mr. B. Leeding arrived with multiple injuries and was initiated on the transfusion trauma pathway. He was taking Dabigatran Unfortunately, he continued to bleed... What should Dr. B. Lud recommend in addition to continuing along the pathway??? a. rfviia b. PCC c. rfviia & PCC d. Neither rfviia, nor PCC

REVERSAL OF RIVAROXABAN Activated charcoal to reduce absorption Supportive treatment: mechanical compression, surgical interventions, fluid replacement hemodynamic support, blood product or component transfusion If life-threatening bleeding cannot be controlled by the above measures, administration of recombinant Factor VIIa may be considered. PCC s might play a role in limiting bleeding and reversing anticoagulant activity Protamine sulfate and vitamin K are not useful No evidence to support use of systemic haemostatics desmopressin, aprotinin, tranexamic acid Not dialyzable - high plasma protein binding http://www.xarelto.com/en/information-on-xarelto/xarelto-in-practice/?user=hcp

REVERSAL OF DABIGATRAN Activated charcoal to reduce absorption Supportive treatment: mechanical compression, surgical interventions, fluid replacement hemodynamic support, blood product or component transfusion Dialysis: studies have shown it can remove ~60% PCC and rfviia might have beneficial role in reversal Protamine sulfate and vitamin K are not useful No evidence to support use of systemic haemostatics desmopressin, aprotinin, tranexamic acid

FOOD FOR THOUGHT: Dabigatran & Rivaroxaban are becoming more widely used These medications effect coagulation assays There is insufficient evidence to support use of rfviia & PCC in reversal but they may have a role in the future

QUESTIONS?

REFERENCES Battinelli EM. Reversal of new anticoagulants. Circulation. 2011, 124:1508-1510 Calatzis A, Peetz D, Haas S, Spannagl M, Rudin K, Wilmer M. Prothrombinase-induced clotting time assay for determination of the anticoagulant effects of unfractionated and low-molecular-weight heparins, fondaparinux, and thrombin inhibitors. Am J Clin Pathol. 2008 Sep;130(3):446-54. Eerenberg ES. Et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo controlled, crossover study in healthy subjects. Circulation. 2011, 124:1573-1579 Hillarp, A et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. Journal of Thrombosis and Haemostasis. 2010;9:133-139 Lindahl, TL et al. Effects of the oral, direct thrombin inhibito dabigatran on five common coagulation assays. 2011. Thrombosis and Haemostasis105: 371-8 Samama MM and Guinet C. Laboratory assessment of new anticoagulants. Clin chem Eikelboom, JW (31 May 2011). "Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the Randomized Evaluation of Long- Term Anticoagulant Therapy (RE-LY) Trial Connolly, SJ; Ezekowitz, MD; Yusuf, S et al. (September 2009). "Dabigatran versus warfarin in patients with atrial fibrillation" (PDF). N Engl J Med 361 (12): 1139 51. http://vte.pradaxa.com/content/dam/internet/pm/vte/com_en/documents/pradaxa_spc_emea.pdf http://www.fiercebiotech.com/press-releases/bayers-xarelto-approved-canada Tinel H, Huetter J, Perzborn E. RECOMBINANT FACTOR VIIA PARTIALLY REVERSES THE ANTICOAGULANT EFFECT OF HIGH-DOSE RIVAROXABAN A NOVEL, ORAL, DIRECT FACTOR XA INHIBITOR IN RATS. J Thromb Haemost 2007; 5 Supplement 2: P-W-652 Van Ryn et al. Dabigatran Etexilate a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversa lof anticoagulant activity. Thrombosis and Hemostasis. 2010 Van Ryn J. Et al. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran by recombinant factor VIIa or activated prothrombin complex concenetrate. Haematologica 2008; 93(s1):148 Zhou, W et al. Hemostatic therapy in experimental intracerebral hemorrhage associated with the direct thrombin inhibitor dabigatran. Stroke, 2011;42