Direct Oral Anticoagulants (DOACs). Dr GM Benson Director NI Haemophilia Comprehensive Care Centre and Thrombosis Unit BHSCT

Direct Oral Anticoagulants (DOACs). Dr GM Benson Director NI Haemophilia Comprehensive Care Centre and Thrombosis Unit BHSCT

OAC WARFARIN Gold standard DABIGATRAN RIVAROXABAN APIXABAN EDOXABAN BETRIXABAN HAVIN A LAUGH - ABAN

Profile of the ideal anticoagulant Minimal interactions with drugs or food Reversible Wide therapeutic window Oral administration and fixed dosing Reduced bleeding risk Rapid onset and offset of activity No laboratory monitoring Predictable dose response Furie & Furie. N Engl J Med 2008;359:938 949; Turpie. Eur Heart J 2007;29:155 165

NICE technology appraisal guidance on NOACs in VTE Apixaban Recommended as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults 1 Recommended as an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery 2 Rivaroxaban Recommended as an option for treating deep vein thrombosis and preventing recurrent deep vein thrombosis and pulmonary embolism after a diagnosis of acute deep vein thrombosis in adults 3 Recommended as an option for treating pulmonary embolism and preventing recurrent deep vein thrombosis and pulmonary embolism in adults 4 Recommended as an option for the prevention of venous thromboembolism in adults having elective total hip replacement surgery or elective total knee replacement surgery 5 Dabigatran Recommended as an option for the primary prevention of venous thromboembolic events in adults who have undergone elective total hip replacement surgery or elective total knee replacement surgery 6 Recommended as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults 7 Edoxaban Recommended as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults 8

Clinical pharmacology of NOACs Mechanism of action Oral bioavailability Apixaban 1,2 Rivaroxaban 1,3 Dabigatran 1,4 Edoxaban 5 Direct factor Xa inhibitor Direct factor Xa inhibitor Direct thrombin inhibitor Direct factor Xa inhibitor ~50% 80 100% ~6.5% ~62% Pro-drug No No Yes No Food effect No Yes (20 mg and 15 mg doses need to be taken with food) Renal clearance ~27% ~33 %* 85% 50% Mean half-life (t 1/2 ) 12 h 5 9 h (young) 11 13 h (elderly) No 12 18 h (patients) No 10 14 h T max 3 4 h 2 4 h 0.5 2 h 1 2 h

Rivaroxaban is increasingly used to treat patients with acute venous thromboembolism (VTE), a potentially life-threatening condition. Because absorption of rivaroxaban decreases from nearly 100% to 66% under fasting conditions, it is recommended that VTE patients take rivaroxaban with a meal. We describe a case of a compliant young patient who developed recurrent pulmonary embolism during rivaroxaban treatment. PK studies provided evidence that malabsorption of rivaroxaban 20 mg due to irregular intake of meals was the leading cause of recurrent pulmonary embolism. When the patient was instructed to take rivaroxaban with a regular meal, peak plasma concentrations increased from 115 to 318 ng ml 1 (+ 176%). Consequently, the importance of taking rivaroxaban with food may have a greater clinical relevance than data from preclinical PK studies suggest.

Warfarin only NVAF, acute and long term prevention DVT/ PE Warfarin experienced CrCl <15 Weight >120kg Acute venous thrombosis not involving the legs/ lung Drug interactions (CYP3A4 and P-gp inhibitors)

Aims Atrial fibrillation choice Acute VTE choice Prevention of recurrent VTE choice

Atrial fibrillation

DOACs: Stroke, systemic embolism vs warfarin SSE vs warfarin (ITT population) %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ¹ 1.11 1.71 0.65 (0.52-0.81) Dabigatran 110 mg ² 1.54 1.71 0.90 (0.74-1.10) Rivaroxaban ³ 2.1 2.4 0.88 (0.75-1.03) Apixaban 1.27 1.60 0.79 (0.66-0.95) SSE = stroke and systemic embolism 0.5 1 1.5 Favours new orals Favours warfarin No head to head studies have been conducted between any of the NOACs. Therefore, no conclusions about the relative efficacy or safety of any of these drugs should be drawn from these data 1.Connolly SJ et al. N Engl J Med 2009;361:1139 1151; 2.Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3.Patel MR et al. NEJM 2011;365:883 891 and Supplementary Appendix; 4.Granger et al. N Eng J Med 2011;365:981 992

DOACs: Intracranial bleeding vs warfarin Intracranial bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ¹ 0.30 0.74 0.40 (0.27-0.60) Dabigatran 110 mg ² 0.23 0.74 0.31 (0.20-0.47) Rivaroxaban ³ 0.5 0.7 0.67 (0.47-0.93) Apixaban 0.33 0.80 0.42 (0.30-0.58) 0 1 2.0 Favours new orals Favours warfarin No head to head studies have been conducted between any of the NOACs. Therefore, no conclusions about the relative efficacy or safety of any of these drugs should be drawn from these data 1.Connolly SJ et al. N Engl J Med 2009;361:1139 1151; 2.Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3.Patel MR et al. NEJM 2011;365:883 891 and Supplementary Appendix; 4.Granger et al. N Eng J Med 2011;365:981 992

Definition of major bleeding Fatal bleeding, and/or Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome, and/or Bleeding causing a fall in hemoglobin level of 20 g L 1 or more, or leading to transfusion of two or more units of whole blood or red cells.

DOACs: Major bleeding vs warfarin Major bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ¹ 3.32 3.57 0.93 (0.81-1.07) Dabigatran 110 mg ² 2.87 3.57 0.80 (0.70-0.93) Rivaroxaban ³ 3.6 3.4 1.04 (0.90-1.20 Apixaban 2.13 3.09 0.69 (0.60-0.80) 0.5 1 Favours new orals Favours warfarin No head to head studies have been conducted between any of the NOACs. Therefore, no conclusions about the relative efficacy or safety of any of these drugs should be drawn from these data 1.Connolly SJ et al. N Engl J Med 2009;361:1139 1151; 2.Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3.Patel MR et al. NEJM 2011;365:883 891 and Supplementary Appendix; 4.Granger et al. N Eng J Med 2011;365:981 992 1.5

DOACs: Any bleeding vs warfarin Any bleeding vs warfarin %/yr Warfarin %/yr HR (95% CI) Dabigatran 150 mg ¹ 16.42 18.15 0.91 (0.86-0.97) Dabigatran 110 mg ² 14.62 18.15 0.78 (0.74-0.83) Rivaroxaban ³ 14.9 14.5 1.03 (0.96-1.11) Apixaban 18.1 25.8 0.71 (0.68-0.75) * major and non-major clinically relevant bleeding (excludes minimal bleeding) 0.5 1 Favours new orals Favours warfarin 1.5 No head to head studies have been conducted between any of the NOACs. Therefore, no conclusions about the relative efficacy or safety of any of these drugs should be drawn from these data 1.Connolly SJ et al. N Engl J Med 2009;361:1139 1151; 2.Connolly SJ et al. N Engl J Med 2010;363:1875 1876; 3.Patel MR et al. NEJM 2011;365:883 891 and Supplementary Appendix; 4.Granger et al. N Eng J Med 2011;365:981 992

Cumulative hazard AVERROES: Primary safety outcome -there was no statistically significant difference in the risk of MAJOR bleeding between apixaban and ASA 0.020 0.015 Apixaban 5mg BD (in 94% of patients) Apixaban ASA 0.010 0.005 0.000 0 3 6 9 12 18 Months HR 1.13 (95% CI: 0.74 1.75); p=0.57 No. at Risk Apixaban 2808 2759 2566 2120 1521 622 ASA 2791 2738 2557 2140 1571 642 Patients with 2 of the following received a reduced dose of 2.5 mg bd [6.4% of patients]: age 80 years, weight 60 kg, serum creatinine 1.5 mg/dl (133 μmol/l) Note: Per the SmPC, patients with the exclusive criterion of severe renal impairment (CrCl15 29 ml/min) should also receive the lower dose of apixaban 2.5 mg twice daily. This new criterion differs from the trial conduct. Adapted from Connolly et al. N Engl J Med 2011;364:806 17.. 17

Which DOAC to use in AF? Savelieva et al, Clin Cardiol 2014

Acute VTE NOAC trial exclusion criteria

NOAC trial designs in acute VTE treatment NOAC Trial Number of patients Design Parenteral required before NOAC? NOAC dosing Comparator Treatment length (months) Follow-up period Key inclusion criteria Apixab an AMPLIFY 1 5,395 DVT: 3,532 PE: 1,836 Double-blind No Apixab an 10 mg twiceda ily for 7d, then 5 mg twice daily Enoxaparin bridge to warfarin 6 30 days after study completion DVT/PE requiring treatment for 6 months Dabiga tran RE-COVER 2 2,539 DVT:1,749 PE: 786 RE-COVER II 3 2,568 DVT: 1,750 PE: 816 Double-blind Required for at least 5 days Dabigat ran 150 mg twice daily Enoxaparin bridge to warfarin 6 30 days after study completion DVT of the legs/pe requiring treatment for 6 months Rivaro xaban EINSTEIN-DVT 4 DVT: 3,449 Open-label No Rivarox aban 15 mg twice daily for 21d, then 20 mg once daily Enoxaparin bridge to VKA 3, 6, or 12* For duration of treatment DVT without PE EINSTEIN-PE 5 PE: 4,832 PE with or without DVT Edoxaba n Hokusai-VTE 6 8,240 DVT: 4,921 PE: 3,319 Double-blind Enoxaparin or UFH 5 days Edoxaban 60 mg once daily Enoxaparin bridge to warfarin 3 12 For duration of treatment DVT without PE PE with or without DVT There are no head-to-head studies between these agents. There are limitations such as differing patient populations, designs and outcomes, and caution should therefore be exercised when interpreting these findings. No conclusions about the relative efficacy or safety of any of these agents should be drawn from these data. Please refer to individual product SmPCs for further information

AMPLIFY: primary efficacy outcome and key safety outcomes The AMPLIFY trial was a double-blind, randomised trial comparing 6 months of apixaban treatment with enoxaparin bridging to warfarin therapy in patients with acute symptomatic DVT and/or PE Primary efficacy outcome* Recurrent VTE or VTErelated death, n (%) Safety outcomes# Apixaban (n=2,609) Enoxaparin/ warfarin (n=2,635) 59 (2.3) 71 (2.7) Apixaban (n=2,676) Enoxaparin/ warfarin (n=2,689) RR (95% CI) 0.84 (0.60 1.18) RR (95% CI) P Value <0.001 Noninferiority P Value Major bleeding, n (%) 15 (0.6) 49 (1.8) 0.31 (0.17 0.55) <0.001 Major or CRNM bleeding, n (%) 115 (4.3) 261 (9.7) 0.44 (0.36 0.55) <0.001 0 Favours apixaban 1 Favours 2 enoxaparin/warfarin Agnelli et al. N Engl J Med. 2013;369:799 808.

RE-COVER: primary efficacy outcome and key safety outcomes The RE-COVER trial was a double-blind, double-dummy, randomised trial comparing 6 months of dabigatran treatment (150 mg twice daily) with heparin* bridging to dose-adjusted warfarin therapy in patients with acute symptomatic DVT and/or PE Dabigatran (n=1,274) Heparin*/ warfarin (n=1,265) HR (95% CI) P Value Primary efficacy outcome# Recurrent VTE or VTErelated death, n (%) 30 (2.4) 27 (2.1) 1.10 (0.65 1.84) <0.001 Non-inferiority Dabigatran (n=1,273) Heparin*/ warfarin (n=1,266) HR (95% CI) P Value Safety outcomes Major bleeding, n (%) 20 (1.6) 24 (1.9) 0.82 (0.45 1.48) Data not available from publication Major or CRNM bleeding, n (%) 71 (5.6) 111 (8.8) 0.63 (0.47 0.84) 0.002 0 1 2 Favours dabigatran Favours warfarin Schulman et al. N Engl J Med. 2009;361:2342 2352.

EINSTEIN-PE: primary efficacy outcome and key safety outcomes The EINSTEIN-PE trial was an open-label, randomised trial comparing rivaroxaban treatment (15 mg twice daily for 21d, then 20 mg once daily for 3, 6 or 12 months) with enoxaparin bridging to VKA therapy in patients with acute symptomatic PE with or without symptomatic DVT Rivaroxaban (n=2,419) Enoxaparin/ VKA (n=2,413) Primary efficacy outcome* (mean study duration: ~9 months) HR (95% CI) P Value Recurrent VTE, n (%) 50 (2.1) 44 (1.8) 1.12 (0.75 1.68) 0.003 Non-inferiority Rivaroxaban (n=2,412) Enoxaparin/ VKA (n=2,405) HR (95% CI) P Value Safety outcomes# Major or CRNM bleeding, n (%) 249 (10.3) 274 (11.4) 0.90 (0.76 1.07) 0.23 Major bleeding, n (%) 26 (1.1) 52 (2.2) 0.49 (0.31 0.79) 0.003 0 Favours rivaroxaban 1 Favours 2 enoxaparin/vka The EINSTEIN-PE Investigators. N Engl J Med. 2012;366:1287 1297.

HOKUSAI-VTE: primary efficacy outcome and key safety outcomes The HOKUSAI-VTE trial was a randomised, double-blind, non-inferiority trial comparing edoxaban treatment (60 mg once daily for 3 to 12 months)* with warfarin in patients with acute symptomatic DVT or symptomatic PE with or without DVT Edoxaban (n=4,118) Warfarin (n=4,122) HR (95% CI) P Value Primary efficacy outcome# (efficacy evaluated at 12 months regardless of treatment duration) Recurrent VTE or VTE-related death, n (%) 130 (3.2) 146 (3.5) 0.89 (0.70 1.13) <0.001 Non-inferiority Edoxaban (n=4,118) Warfarin (n=4,122) HR (95% CI) P Value Safety outcomes First major or CRNM bleeding, n (%) 349 (8.5) 423 (10.3) 0.81 (0.71 0.94) 0.004 Major bleeding, n (%) 56 (1.4) 66 (1.6) 0.84 (0.59 1.21) 0.35 0 Favours edoxaban 1 Favours warfarin 2 Büller et al. N Engl J Med. 2013;369:1406 1415.

Higher recurrence rates in unprovoked VTE Cumulative incidence of recurrent VTE (%) 30 25 20 15 10 5 0 28.4% 20.5% Provoked VTE Unprovoked VTE 0 1 2 3 4 5 6 7 8 9 10 Years after first VTE p<0.001 Data from patients with non-active cancer Adapted from Martinez et al. Thromb Haem 2014; 112. epub ahead of print. Martinez et al. Thromb Haem 2014;112. epub ahead of print.

ACCP guidance 2012 In patients with an unprovoked PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration In patients with a first VTE that is unprovoked proximal and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy. In patients with a first VTE that is unprovoked and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy.

Age >65 Age >75 Previous bleeding Cancer Metastatic cancer Renal failure Liver failure Thrombocytopenia Diabetes Anaemia Antiplatelet therapy Poor anticoagulant control Comorbidity and reduced functional capacity Recent surgery Frequent falls Alcohol abuse Previous stroke Estimated absolute risk of major bleeding Categorisation of risk of Low(Zero risk factors) Moderate (1 risk factor) High (>2 risk factors) bleeding Anticoagulation 0-3 months Baseline risk(%) 0.6 1.2 4.8 Increased risk (%) 1.0 2.0 8.0 Total risk (%) 1.6 3.2 12.8 Anticoagulation beyond 3 months Baseline risk (%/year) 0.3 0.6 >2.5 Increased risk (%/year) 0.5 1.0 >4.0 Total risk (%/year) 0.8 1.6 >6.5

NOAC trial designs for prevention of recurrent VTE Study drug Trial Number of patients Treatment before randomisation Study drug dosing Comparator Treatment length (months) Apixaban AMPLIFY-EXT 1 2,482 6 12 months of standard therapy or apixaban Apixaban 2.5 mg or 5 mg twice daily* Placebo 12 Dabigatran RE-SONATE 2 1,343 6 18 months of VKA or dabigatran Dabigatran 150 mg twice daily Placebo 6 Rivaroxaban EINSTEIN- EXT 3 1,196 6 or 12 months of VKA or rivaroxaban Rivaroxaban 20 mg once daily Placebo 6 or 12 Edoxaban HOKUSAI- VTE 4 8,240 No preceding anticoagulation Edoxaban 60 mg Warfarin 3 to 12 once daily # Dabigatran RE-MEDY 2 2,856 3 12 months of VKA or dabigatran Dabigatran 150 mg twice daily Warfarin INR 2.0 3.0 6 36 There are no head-to-head studies between these agents. There are limitations such as differing patient populations, designs and outcomes, and caution should therefore be exercised when interpreting these findings. No conclusions about the relative efficacy or safety of any of these agents should be drawn from these data. Please refer to individual product SmPCs for further information 1. Agnelli et al. N Engl J Med. 2013;368:699 708; 2. Schulman et al. N Engl J Med. 2013;368:709 718; 3. The EINSTEIN Investigators. N Engl J Med. 2010;363:2499 510; 4. Büller et al. N Engl J Med. 2013;369:1406 1415.

AMPLIFY-EXT: apixaban had a comparable rate of major bleeding compared to placebo Patients with event (%) 4.0 Major bleeding RR (95% CI) 0.49 (0.09 2.64) p value not calculated Major or CRNM bleeding RR (95% CI) 1.20 (0.69 2.10) p value not calculated 3.0 27/840 22/829 2.0 1.0 0.0 2/840 4/829 Apixaban2.5 Primary safety Placebo endpoint mg BD Major Apixaban or CRNM Placebo bleeding 2.5 mg BD Agnelli et al. N Engl J Med 2013; 368:699 708.

NOAC dosing regimens across each stage of VTE treatment Initial VTE treatment Ongoing VTE Treatment Prevention of Recurrent VTE Apixaban 1 10 mg BD Day 1 7 5 mg BD Day 8 onwards for at least 3 months* 2.5 mg BD Following completion of 6 months of treatment with apixaban 5 mg BD or another oral anticoagulant Rivaroxaban 2 15 mg BD with food Day 1 21 20 mg OD with food Day 22 onwards for at least 3 months* Dabigatran 3 Parenteral anticoagulant For at least 5 days (not to be taken concomitantly with dabigatran) 150 mg BD For at least 3 months* (Dose adjustments to 110 mg BD in patients 80 years, patients on concomitant verapamil, and those at high risk of bleeding) Edoxaban 4 Parenteral anticoagulant For at least 5 days (not to be taken concomitantly with edoxaban) 60 mg OD For at least 3 months* (Dose adjustment required to 30 mg OD in patients with CrCl 15 50 ml/min or body weight 60 kg or with concomitant use of the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin or ketoconazole. Refer to edoxaban SmPC for further information) 1. Apixaban SmPC. July 2014; 2. Rivaroxaban SmPC. August 2014; 3. Dabigatran SmPC. June 2014; 4. Edoxaban SmPC. July 2015.

Summary AF, prescribe for stroke prevention reduction and low bleeding risk. Acute VTE, low risk, DOAC appropriate, outpatient based If in patient, do not rush to start DOAC Acute VTE, high risk, haemodynamic compromise, SoC?long term prevention of recurrence beyond 3 months