Dabigatran and other NOAC in the treatment of DVT Dr Khalid AlHashmi MD, FRCSPC Internal Medicine/Hematology/Medical Oncology

VTE - The third most common cause of vascular death after myocardial infarction and stroke. - The current standard treatment is rapidly acting parenteral anticoagulation for 5 to 7 days followed by at least 3 months of treatment with a vitamin K antagonist.

Incidence of VTE - Estimated to affect 350,000 to 600,000 Americans annually. • Contributing to at least 100,000 deaths per year • increases with ageing population.

Boulay, F. et al. BMJ 2001;323:601-602

Thrombophilia and risk FII MUTATIO FVL PROTEIN S PROTEIN C ANTITHROMBIN DEFECT 2-4 2.10 0.7-2.3 0.4-4.0 0.02 Prevalence *3-4 *4-5 *10 Risk of VTE increased by Increased? Increased Not Increased Thromboembolism Increased risk for VTE by 30-140 Neonatel Purpura Fulminans Often Lethal Homozygous form

NEW ORAL ANTICOAGULANTS VS WARFARIN New Agents Warfarin Features rapid slow onset fixed variable Dosing same indications no yes Food effect Drug interaction Monitoring short long Half-life antidote

Some of the New Anticoagulants O:Oral, P:Parenteral Anti-FXa Anti-Flla (anti-thrombin) Rivaroxaban (o) Apixaban (o) Edoxaban (o) Otamixaban (p) LY-517717 (o) DX-9065a (p) Betrixiban (o) TK-442 (o) Dabigatran (o) Odiparcil (o) Flovagatran (p) Pegmusirudin (p) Peg-hirudin (p) Desirudin (p)

Thrombin (IIa) inhibition -Important : - The last enzymatic step in coagulation. - Thrombin also involved in platelet activation. - Activates fibrinogen. - Activates thrombomodulin. - back-activation of F XI, F V and F VIII

The New Oral Anticoagulants: Similar Yet Different DABGATRAN Etexilate APIXABAN RIVARXABAN FEATURES IIa Xa Target 628 460 436 Molecular Weight Yes No Prodrug 6 50 80 Bioavailability % 2 3 Time to peak 12-17 9-14 9 Half-life (h) 25 65 Renal excretion (%) none antidote

NOAC DVT Prophylaxis. VTE treatment. Post surgical prophylaxis. Stroke prevention in AF. ACS.

Dabigatran Etexilate Pradaxa® Specific, competitive, reversible univalent thrombin inhibitor Rapid onset within 2 hours Low protein binding Half life 12-17 hours Renal clearance as glucuronic acid conjugate: 85% Metabolized by esterase catalyzed hydrolysis and P-gp transport mechanisms

Dabigatran: Clinical Development ACS Stroke prevention in AF DVT Treatment Postsurgical prophylaxis of DVT RE-DEEM Unpublished RE-LY RE-COVER RE-MODEL RE-MEDY RE-MOBIZE RE-SONATE RE-NOVATE RE-NOVATE 2

-228 clinical centers in 29 countries -228 clinical centers in 29 countries. - Recurrent thromboembolism: -30/1274 ((2.4%) dabigatran - 27/1265 (2.1%) warfarin . P value <0.001. -Major bleeding -20 (1.6%) dabigatran -24 (1.9%) warfarin. HR 0.84 -The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism Sam Schulman, RE-COVER Study Group N Engl J Med 2009; December 10, 2009

RE-COVER

RE-COVER

RE-COVER

RE-COVER

RE-COVER

-completed at least 3 initial months of therapy In the active-control study, Recurrent venous thromboembolism : -26 of 1430 patients in the dabigatran group (1.8%) -18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44). Major bleeding : -13 patients in the dabigatran group (0.9%) -25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54). Acute coronary syndromes -13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). ================================================ In the placebo-control study, Recurrent venous thromboembolism - 3 of 681 patients in the dabigatran group (0.4%) - 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; P<0.001). Major or clinically relevant bleeding -36 patients in the dabigatran group (5.3%) - 12 patients in the placebo group (1.8%) (hazard ratio, 2.92). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism -Sam Schulman, -completed at least 3 initial months of therapy -N Engl J Med 2013; 368:709-718 -RE-MEDY and the RE- SONATE Trials

RE-MEDY and the RE-SONATE Trials

RE-MEDY and the RE-SONATE Trials

RE-MEDY and the RE-SONATE Trials

RE-MEDY and the RE-SONATE Trials

2589 patients with acute VTE treated with low-molecular-weight or unfractionated heparin for 5 to 11 days. Patients were assigned in a 1:1 ratio to receive active fixed-dose dabigatran 150 mg twice daily and warfarin-like placebo or active warfarin and dabigatran-like placebo The primary outcome, recurrent symptomatic, objectively confirmed VTE and related deaths during 6 months : 30 of the 1279 dabigatran patients (2.3%) 28 of the 1289 warfarin patients (2.2%) hazard ratio, 1.08; 95%; P<0.001 major bleeding, 15 patients receiving dabigatran (1.2%) 22 receiving warfarin (1.7%) hazard ratio, 0.69; 95% CI, 0.36–1.32). Deaths, adverse events, and acute coronary syndromes were similar in both groups. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. More Asian Circulation. 2014 Feb 18;129(7):764-72 Sam Schalman RE-COVER II

Recover -II

RECOVER -II

RECOVER-II

RECOVER-II - Dabigatran was noninferior to warfarin for the prevention of recurrent or fatal VTE (P<0.001 for both hazard ratio and difference in absolute risk criteria). - The incidence of different categories of adverse events was similar in the 2 treatment groups. - Dyspepsia was the only drug related adverse event that was more common in the dabigatran group (1.0%).

Xarelto® Rivaroxaban Direct, specific, competitive factor Xa inhibitor Rapid onset within 2-4 hours High bioavailability of >80% Metabolized via the CYP3A4, CYP211, and P-gp transport mechanisminteractions with drugs using the same metabolic pathways Renal and fecal elimination

Rivaroxaban: Clinical Development ACS STROKE Prevention in AF DVT TREATEMNT POST SURGICAL PROPHYLAXIS ATLAS ROCKET-AF EINSTEIN-DVT ODIXa-KNEE ROCKET-J EINSTEIN-EXT ODIXa-HIP EINSTEIN-PE RECORD-1 RECORD-2 RECORD-3 RECORD-4

EINSTEIN

EINSTEIN

EINSTEIN

Noninferiority study rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) VS subcutaneous enoxaparin followed by a vitamin K antagonist (either warfarin or acenocoumarol). - 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. - Rivaroxaban (36 events/ 1730) (2.1%). - Enoxapain/warfarin (51 events/1718 )(3.0%] HR 0.68; P<0.001. Oral Rivaroxaban for Symptomatic Venous Thromboembolism The EINSTEIN Investigators N Engl J Med 2010; 363:2499-2510 December 23, 2010

EINSTEIN

Direct, reversible FXa inhibitor Rapid onset, peak within 3 hrs Apixaban Eliquis Direct, reversible FXa inhibitor Rapid onset, peak within 3 hrs Bioavailability of 51-85% Long half life, slightly longer in elderly (15 hrs) Multiple elimination pathways 25% renal 75% biliary Metabolism via CYP3A4, SULT1AA pathways

Apixaban: Clinical Development ACS Stroke Prevention In AF DVT Treatment Post surgical Prophylaxis of DVT APPRAISE-1 ARISTOTOLE Botticelli DVT Dose ranging study APROPOS APPRAIS-2 Terminated-bleedin AVERROES AMPLIFY ADVANCE-1 APPRAISE-Japan terminated ADVANCE-2 ADVANCE-3

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In the continued-treatment study (had been treated for 6 or 12 months with a vitamin K antagonist or rivaroxaban were randomly assigned to receive continued treatment with rivaroxaban or placebo) -602 patients in the rivaroxaban group -594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). - Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11

Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism Noninferiority trail Recurrent venous thrombosis: Rivaroxaban group (2.1%) Standard-therapy group ( (1.8%) (hazard ratio, 1.12) Major bleeding: (1.1%) in the rivaroxaban (2.2%) standard-therapy group (hazard ratio, 0.49) The EINSTEIN–PE Investigators N Engl J Med 2012