Joshua D. Lenchus, DO, RPh, FACP, SFHM Associate Professor of Medicine and Anesthesiology University of Miami Miller School of Medicine

Joshua D. Lenchus, DO, RPh, FACP, SFHM Associate Professor of Medicine and Anesthesiology University of Miami Miller School of Medicine

Antithrombotics Antiplatelets Aspirin Ticlopidine Prasugrel Dipyridamole Clopidogrel Ticagrelor Anticoagulants VKA Warfarin DTIs Lepirudin, argatroban, bivalirudin, desirudin, dabigatran FXaIs Fondaparinux, rivaroxaban, apixaban, edoxaban

P2Y 12 Inhibitors DRUG THIENO- PYRIDINE PLATELET INHIBITION MAJOR BLEEDING NOTES CLOPIDOGREL Yes Baseline Baseline Now available in generic formulation Contraindicated in patients with history of CVA/TIA PRASUGREL Yes Greater Greater Generally not recommended in patients >75 years (bleeding risk) Increased bleeding risk if body weight <60 kg Concomitant ASA dose should be <100 mg TICAGRELOR No (Reversible) Greater Similar Contraindicated if severe hepatic impairment Avoid use with strong CYP3A inhibitors* or inducers** *clarithromycin, ketoconazole, indinavir, itraconazole, etc. **rifampin, carbamazepine, dexamethasone, phenytoin, phenobarbital Based in part from Hamm CW, et al. Eur Heart J. 2011, as well as drug PIs and study protocols.

Contraindications? 1. History of GI bleeding 2. Predisposition to falls 3. Old age 4. History of intracranial hemorrhage 5. Prior stroke or TIA 6. Bleeding diatheses 7. Alcoholics 8. History of noncompliance

The Next Generation The ever-elusive ideal drug Ximelagatran v warfarin SPORTIF trials Newer treatment options (DOACs) Dabigatran Rivaroxaban Apixaban Edoxaban

Warfarin Decreases risk of CVA by 64% Aspirin reduced risk by 21% Limitations Narrow therapeutic window Individualized dosing Delayed onset of action Drug-drug interactions Drug-food interactions Pharmacogenetics

Factor Xa inhibitors Fondaparinux first DOACs next Rivaroxaban Apixaban Edoxaban

Direct thrombin inhibitors First, there was unfractionated heparin Then came those mainly for ACS Bivalirudin Desirudin Lepirudin *Argatroban Now, we have a DOAC Dabigatran

Dabigatran etexilate Oral prodrug Related to ximelagatran 1 st DOAC available for SPAF 150mg BID dose approved in US

Randomized Evaluation of Long-term anticoagulant therapy Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009;361(12):1139-1151.

RE-LY: A Non-inferiority Trial Atrial fibrillation 1 Risk Factor Absence of contra-indications 951 centers in 44 countries Blinded Event Adjudication. R Open Blinded Warfarin adjusted (INR 2.0-3.0) N=6000 Dabigatran Etexilate 110 mg BID N=6000 Dabigatran Etexilate 150 mg BID N=6000

Stroke or Systemic Embolism Dabigatran 110 vs. Warfarin Non-inferiority p-value <0.001 Superiority p-value 0.34 Dabigatran 150 vs. Warfarin <0.001 <0.001 Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Dabigatran better Warfarin better

Bleeding Dabi 110mg Dabi 150mg Warfarin Dabi 110mg vs. Warfarin Dabi 150mg vs. Warfarin Annual rate Annual rate Annual rate RR 95% CI p RR 95% CI p Total 14.6% 16.4% 18.2% 0.78 0.74-0.83 <0.001 0.91 0.86-0.97 0.002 Major 2.7 % 3.1 % 3.4 % 0.80 0.69-0.93 0.003 0.93 0.81-1.07 0.31 Life- Threatening major 1.2 % 1.5 % 1.8 % 0.68 0.55-0.83 <0.001 0.81 0.66-0.99 0.04 Gastrointestinal Major 1.1 % 1.5 % 1.0 % 1.10 0.86-1.41 0.43 1.50 1.19-1.89 <0.001

Conclusions Dabigatran 150 mg significantly reduced stoke compared to warfarin with similar risk of major bleeding Dabigatran 110 mg had a similar rate of stroke as warfarin with significantly reduced major bleeding Both doses markedly reduced intra-cerebral, lifethreatening and total bleeding Dabigatran had no major toxicity, but did increase dyspepsia and GI bleeding

Conclusions Both Dabigatran doses offer advantages over warfarin Dabigatran 150 is more effective and dabigatran 110 has a better safety profile There is potential to tailor therapy to individual patient characteristics

RE-COVER study group Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism N Engl J Med 2009. 361(24):2342-52.

RE-COVER: A Non-inferiority Trial Parenteral anticoagulation 10 days Acute venous thromboembolism Absence of contra-indications 228 centers in 29 countries R Blinded Warfarin adjusted (INR 2.0-3.0) + Dabigatran like placebo N=1265 Blinded Dabigatran Etexilate 150 mg BID + Warfarin like placebo N=1274

Recurrent VTE or Related Death Dabigatran Warfarin Event Rate 2.4 2.1 HR (95% CI): 1.10 (0.65, 1.84) P-value Non-Inferiority: <0.001 N Engl J Med 2009. 361(24):2342-52.

First event of Major Bleeding or any Bleeding Event Rate Dabigatran Warfarin Major bleeding 1.6 1.9 Major + CRNM bleeding 5.6 8.8 HR (95% CI): 0.71 (0.59, 0.85) P-value:< 0.001 (any) HR (95% CI): 0.82 (0.45, 1.48) P-value: 0.38 (major) N Engl J Med 2009. 361(24):2342-52.

Conclusions For the treatment of acute VTE... Fixed dose dabigatran is as effective as warfarin Safety profile is similar to that of warfarin Does not require laboratory monitoring N Engl J Med 2009. 361(24):2342-52.

Reversal Effects of Idarucizumab on Active Dabigatran (REVERSE-AD) N Engl J Med 2015;373:511-20.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/761025lbl.pdf

Rivaroxaban Selective, competitive, direct factor Xa inhibitor

Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med 2011;365(10):883-891.

Study Design Atrial Fibrillation Risk Factors CHF Hypertension At least 2 or Age 75 3 required* Diabetes OR Stroke, TIA or Systemic embolus Rivaroxaban 20 mg daily 15 mg for Cr Cl 30-49 ml/min Randomize Double Blind / Double Dummy (n ~ 14,000) Warfarin INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-cns Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

Primary Efficacy Outcome Stroke and non-cns Embolism Cumulative event rate (%) Event Rate Rivaroxaban Warfarin 1.71 2.16 Warfarin Rivaroxaban HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001 No. at risk: Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634 Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655 Event Rates are per 100 patient-years Based on Protocol Compliant on Treatment Population Days from Randomization

Major >2 g/dl Hgb drop Transfusion (> 2 units) Critical organ bleeding Bleeding causing death Primary Safety Outcomes Rivaroxaban Event Rate or N (Rate) 3.60 2.77 1.65 0.82 0.24 Warfarin Event Rate or N (Rate) 3.45 2.26 1.32 1.18 0.48 HR (95% CI) 1.04 (0.90, 1.20) 1.22 (1.03, 1.44) 1.25 (1.01, 1.55) 0.69 (0.53, 0.91) 0.50 (0.31, 0.79) P- value 0.576 0.019 0.044 0.007 0.003 Intracranial Hemorrhage 55 (0.49) 84 (0.74) 0.67 (0.47, 0.94) 0.019 Intraparenchymal 37 (0.33) 56 (0.49) 0.67 (0.44, 1.02) 0.060 Intraventricular 2 (0.02) 4 (0.04) Subdural 14 (0.13) 27 (0.27) 0.53 (0.28, 1.00) 0.051 Subarachnoid 4 (0.04) 1 (0.01) Event Rates are per 100 patient-years Based on Safety on Treatment Population

Efficacy: Summary Rivaroxaban was non-inferior to warfarin for prevention of stroke and non-cns embolism. Rivaroxaban was superior to warfarin while patients were taking study drug. By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority. Safety: Similar rates of bleeding and adverse events. Less ICH and fatal bleeding with rivaroxaban. Conclusion: Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

EINSTEIN study group Oral Rivaroxaban for Symptomatic Venous Thromboembolism N Engl J Med 2010. 363:2499-510.

EINSTEIN: A Non-inferiority Trial Acute DVT without PE Age > 18 years old N = 3449 R Open-label Exclusion criteria Another indication for VKA Clinically significant liver disease Cr clearance > 30 ml/min Endocarditis Active bleeding Pregnancy Non controlled HTN Concomitant use of cyt.450 3A4 inh Enoxaparin-VKA adjusted (INR 2.0-3.0) 3,6 or 12 months N=1718 Rivaroxaban 15 mg BID x 3 weeks + 20 mg daily 3,6 or 12 months N=1731 Primary outcome: Recurrent venous thromboembolism (DVT or PE)

EINSTEIN: Recurrent VTE Rivaroxaban Enoxaparin-VKA Event Rate 2.1 3 HR (95% CI): 0.68 (0.44, 1.04) P-value Non-Inferiority: <0.001

EINSTEIN: Major or CRNM bleeding Rivaroxaban Enoxaparin-VKA Event Rate 8.1 8.1 HR (95% CI): 0.97 (0.76, 1.22) P-value: 0.77

Conclusions For the treatment of acute VTE... Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation

Apixaban Selective, competitive, direct factor Xa inhibitor

Apixaban for Reduction In STroke and Other ThromboemboLic Events in atrial fibrillation Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med 2011;365(11):981-992.

Atrial Fibrillation with at Least One Additional Risk Factor for Stroke Inclusion risk factors Age 75 years Prior stroke, TIA, or SE HF or LVEF 40% Diabetes mellitus Hypertension Randomize double blind, double dummy (n = 18,201) Major exclusion criteria Mechanical prosthetic valve Severe renal insufficiency Need for aspirin plus thienopyridine Apixaban 5 mg oral twice daily (2.5 mg BID in selected patients) Warfarin (target INR 2-3) Warfarin/warfarin placebo adjusted by INR/sham INR based on encrypted point-of-care testing device Primary outcome: stroke or systemic embolism Hierarchical testing: non-inferiority for primary outcome, superiority for primary outcome, major bleeding, death

Primary Outcome Stroke (ischemic or hemorrhagic) or systemic embolism P (non-inferiority)<0.001 21% RRR Apixaban 212 patients, 1.27% per year Warfarin 265 patients, 1.60% per year HR 0.79 (95% CI, 0.66 0.95); P (superiority)=0.011 No. at Risk Apixaban 9120 8726 8440 6051 3464 1754 Warfarin 9081 8620 8301 5972 3405 1768

Major Bleeding ISTH definition 31% RRR Apixaban 327 patients, 2.13% per year Warfarin 462 patients, 3.09% per year HR 0.69 (95% CI, 0.60 0.80); P<0.001 No. at Risk Apixaban 9088 8103 7564 5365 3048 1515 Warfarin 9052 7910 7335 5196 2956 1491

Summary Treatment with apixaban as compared to warfarin in patients with AF and at least one additional risk factor for stroke: Reduces stroke and systemic embolism by 21% (p=0.01) Reduces major bleeding by 31% (p<0.001) Reduces mortality by 11% (p=0.047) with consistent effects across all major subgroups and with fewer study drug discontinuations on apixaban than on warfarin, consistent with good tolerability.

Conclusion In patients with atrial fibrillation, apixaban is superior to warfarin at preventing stroke or systemic embolism, causes less bleeding, and results in lower mortality.

AMPLIFY study group Oral Apixaban for the Treatment of Acute Venous Thromboembolism N Engl J Med 2013. 369:799-808

AMPLIFY: A Non-inferiority Trial Acute venous thromboembolism Age > 18 years old N = 5395 R Double blind Exclusion criteria Another indication for VKA If less than 6 months of treatment was planned Cancer and long term heparin treatment was planned Active bleeding or high risk or other contraindication Concomitant use of cyt.450 3A4 inh or antiplatelet therapy Hb < 9 g/dl, Pt < 100.000 or Cr clearance < 25 ml/min. Enoxaparin-VKA adjusted (INR 2.0-3.0) 6 months N= 2704 Apixaban 10 mg BID x 7d + 5 mg BID 6 months N=2691 Primary outcome: Recurrent venous thromboembolism (DVT or PE)

Recurrent VTE or death Apixaban Enoxaparin-VKA Event Rate 2.3 2.7 RR (95% CI): 0.84 (0.60, 1.18) P-value Non-Inferiority: <0.001

Major Bleeding Apixaban Enoxaparin-VKA Event Rate 0.6 1.8 RR (95% CI): 0.31 (0.17, 0.55) P-value : < 0.001 for superiority

Conclusions For the treatment of acute VTE... A fixed-dose regimen of apixaban alone was noninferior to conventional therapy It was associated with significantly less bleeding

Edoxaban Selective, competitive, direct factor Xa inhibitor

ENGAGE AF-TIMI study group Edoxaban versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2013 Nov 28;369(22):2093-104

ENGAGE AF-TIMI: A Non-inferiority Trial Moderate to high risk Afib. patients CHADS2 risk assessment 2 N = 21,105 R Double blind Double dummy Exclusion Criteria Afib due to reversible disorder Cr clearance < 30 ml/min High risk of bleeding Dual antipletelet therapy Modere to severe mitral stenosis. Other indication for anticoagulation therapy ACS, coronary revasc. or stroke < 30 days before randomization Warfarin adjusted (INR 2.0-3.0) N= 7036 Edoxaban 60 mg daily N= 7035 Edoxaban 30 mg daily N= 7034 Primary outcome: Stroke or systemic embolism

Stroke or systemic embolism Edoxaban Low dose Edoxaban High dose Warfarin Event Rate 1.61 1.18 1.5 HR High dose (97.5% CI): 0.79 (0.63, 0.99) P < 0.001 for non-inferiority P = 0.02 for superiority HR Low dose (97.5% CI): 1.07 (0.87, 1.31) P = 0.005 for non-inferiority P = 0.44 for superiority

Major Bleeding Bleeding (%) Low dose Edoxaban High-dose Edoxaban Warfarin Gastrointestinal 0.82 1.51 1.23 Life-threatening 0.25 0.4 0.78* Intracranial 0.26 0.39 0.85* Major 1.61 2.75 3.43* Major + CRNM 7.97 11.1 13.02* *P < 0.001 for comparison of warfarin with each dose of edoxaban

Conclusions For the prevention of stroke or systemic embolism in patients with AF... Edoxaban was noninferior to warfarin; high dose showed superiority Edoxaban was associated with significantly lower rates of death from CV causes and bleeding, except GI

HOKUSAI-VTE study group Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism N Engl J Med 2013;369: 1406-1415

HOKUSAI-VTE: A Non-inferiority Trial Acute venous thromboembolism N = 8,292 439 centers, 37 countries R Double blind Double dummy Exclusion Criteria Contraindication for anticoagulation Have received heparin or VKA < 48 h before randomization. Another indication for VKA Cancer and long term heparin treatment was planned Concomitant use of aspirin or dual antiplatelet therapy Cr clearance < 30 ml/min. Initial heparin + Warfarin adjusted (INR 2.0-3.0) 3 to 12 months N= 4149 Initial heparin + Edoxaban 60 mg daily (30 mg if CrCl 30-50 ml/min or body weight < 60 kg) 3 to 12 months N= 4143 Primary outcome: Recurrent acute venous thromboembolism

Recurrent acute VTE Edoxaban Warfarin Event Rate 3.2 3.5 HR (95% CI): 0.89 (0.70, 1.13) P-value non-inferiority: <0.001

First Major or CRNM bleeding Edoxaban Warfarin Event Rate 8.5 10.3 HR (95% CI): 0.81 (0.71, 0.94) P-value: 0.004 for superiority

Conclusions For the prevention of recurrent VTE... Edoxaban was noninferior to standard therapy Edoxaban caused significantly less bleeding in patients with VTE, including those with severe PE

N Engl J Med 2015;373:2413-24.

Bottom line vs warfarin 1. Dabigatran Equivalent mortality Less life-threatening, but more GI, bleeding 2. Rivaroxaban Non-inferior Equal rates of major bleeding More transfusion-requiring, less critical/fatal 3. Apixaban Reduced all-cause mortality & major bleeding 4. Edoxaban Non-inferior Less bleeding, except GI with high dose

Comparison of Pharmacologic Features of the Direct Oral Anticoagulants (DOACs) Characteristic Dabigatran Rivaroxaban Apixaban Edoxaban Target Thrombin Factor Xa Factor Xa Factor Xa Dosing 150mg BID 20mg QHS 5 or 2.5mg BID 30-60mg QD Prodrug Yes No No No Bioavailability 3 7% 80 100% for the 10-mg dose 50% for doses up to 10 mg 62% t-1/2 12 17 hrs 5 13 hrs 8 14 hrs 6 11 hrs ESRD +/- HD (CrCl < 15mL/min) AVOID AVOID 2.5mg BID? N/A

Anticoagulation: Bottom Line Fear of hemorrhagic complications is greater than the real risk Close monitoring of INR if using warfarin Consider newer anticoagulants Patient participation in anticoagulation decision Encourage compliance

Questions? Joshua D. Lenchus, DO, RPh, FACP, SFHM jlenchus@med.miami.edu Off: 305-243-1960 Cel: 954-817-5684