Show Me the Outcomes! Real-World Safety Data on Oral Anticoagulants in Nonvalvular Atrial Fibrillation Gabby Anderson, PharmD PGY1 Pharmacy Resident anderson.gabrielle@mayo.edu Pharmacy Grand Rounds October 3 rd, 2017 2017 MFMER slide-1
80 Annual Prevalence of Oral Anticoagulant Use 70 60 Prevalence (%) 50 40 30 20 Warfarin 10 0 2008 2009 2010 2011 2012 2013 2014 Alalwan et al. Am J Health-Syst Pharm. 2017;74:1237-44 2017 MFMER slide-2
80 Annual Prevalence of Oral Anticoagulant Use 70 60 Prevalence (%) 50 40 30 20 Warfarin All DOACs 10 0 2008 2009 2010 2011 2012 2013 2014 DOACs: direct oral anticoagulants Alalwan et al. Am J Health-Syst Pharm. 2017;74:1237-44 2017 MFMER slide-3
80 Annual Prevalence of Oral Anticoagulant Use 70 60 Prevalence (%) 50 40 30 20 Warfarin All DOACs Dabigatran Rivaroxaban Apixaban 10 0 2008 2009 2010 2011 2012 2013 2014 DOACs: direct oral anticoagulants Alalwan et al. Am J Health-Syst Pharm. 2017;74:1237-44 2017 MFMER slide-4
Objectives Review landmark trials for the use of apixaban, dabigatran, and rivaroxaban in nonvalvular atrial fibrillation Discuss post-approval data for bleeding risk with oral anticoagulants Outline general recommendations for oral anticoagulation based on post-approval safety data 2017 MFMER slide-5
Dabigatran RE-LY Evaluation of stroke or SE Mean CHADS 2 = 2.1 CHADS 2 3 = 32% Prior stroke, SE, or TIA = 20.1% Warfarin time in therapeutic range = 64% Lower rates of stroke and SE with 150 mg Lower bleeding rates with 110 mg Similar bleeding rates with 150 mg SE: systemic embolism Connolly et al. N Engl J Med. 2009;361:1139-51 TIA: transient ischemic attack Patel et al. N Engl J Med. 2011;365:883-91 Granger et al. N Engl J Med. 2011;365:981-92 2017 MFMER slide-6
Dabigatran RE-LY Evaluation of stroke or SE Mean CHADS 2 = 2.1 CHADS 2 3 = 32% Prior stroke, SE, or TIA = 20.1% Warfarin time in therapeutic range = 64% Lower rates of stroke and SE with 150 mg Lower bleeding rates with 110 mg Similar bleeding rates with 150 mg Rivaroxaban ROCKET AF Evaluation of stroke or SE Mean CHADS 2 = 3.5 CHADS 2 3 = 87% Prior stroke, SE, or TIA = 54.9% Warfarin time in therapeutic range = 55% Noninferior to warfarin No significant difference in major bleeding risk SE: systemic embolism Connolly et al. N Engl J Med. 2009;361:1139-51 TIA: transient ischemic attack Patel et al. N Engl J Med. 2011;365:883-91 Granger et al. N Engl J Med. 2011;365:981-92 2017 MFMER slide-7
Dabigatran Rivaroxaban Apixaban RE-LY ROCKET AF ARISTOTLE Evaluation of stroke or SE Evaluation of stroke or SE Evaluation of stroke or SE Mean CHADS 2 = 2.1 CHADS 2 3 = 32% Prior stroke, SE, or TIA = 20.1% Warfarin time in therapeutic range = 64% Lower rates of stroke and SE with 150 mg Lower bleeding rates with 110 mg Similar bleeding rates with 150 mg Mean CHADS 2 = 3.5 CHADS 2 3 = 87% Prior stroke, SE, or TIA = 54.9% Warfarin time in therapeutic range = 55% Noninferior to warfarin No significant difference in major bleeding risk Mean CHADS 2 = 2.1 CHADS 2 3 = 30% Prior stroke, SE, or TIA = 19.2% Warfarin time in therapeutic range = 62.2% Superior to warfarin Less bleeding Lower mortality SE: systemic embolism Connolly et al. N Engl J Med. 2009;361:1139-51 TIA: transient ischemic attack Patel et al. N Engl J Med. 2011;365:883-91 Granger et al. N Engl J Med. 2011;365:981-92 2017 MFMER slide-8
AVERROES 5 Events per year (%) 4 3 2 1 p <0.001 1.6 3.7 Apixaban Aspirin 0 Stroke or SE Connolly et al. N Engl J Med. 2011;364:806-17 2017 MFMER slide-9
AVERROES 5 Events per year (%) 4 3 2 1 p <0.001 1.6 3.7 1.4 p = 0.57 1.2 Apixaban Aspirin 0 Stroke or SE Major Bleeding Connolly et al. N Engl J Med. 2011;364:806-17 2017 MFMER slide-10
Landmark Trial Conclusions Clinical efficacy of DOACs similar to warfarin Apixaban and dabigatran (150 mg) superior to warfarin Apixaban and dabigatran (110 mg) associated with significantly lower rates of major bleeding All others non-inferior to warfarin Limitations: Poor adherence/high discontinuation rates Numerous exclusion criteria Applicability to general population 2017 MFMER slide-11
Patient Case AB is a 68-year-old female who presents with new-onset nonvalvular atrial fibrillation for 72 hours. She will be started on oral anticoagulation. Past medical history: hypertension, diabetes mellitus, history of stroke CHADS 2 score = 4 2017 MFMER slide-12
Question #1 Based on the landmark trials, which drug would you select for this patient? Apixaban Dabigatran Rivaroxaban Warfarin 2017 MFMER slide-13
Question #2 In your opinion, which oral anticoagulant has the highest bleeding risk in post-approval data? Apixaban Dabigatran Rivaroxaban Warfarin 2017 MFMER slide-14
Warfarin vs DOAC Methods Large U.S. administrative claims database Time Period July 1 st, 2006 to June 30 th, 2016 Population Outcomes 107,373 new adult users ( 18 years) of oral anticoagulants for nonvalvular atrial fibrillation Warfarin, apixaban, dabigatran, or rivaroxaban Inpatient admission for one of the following: Stroke (efficacy) Major bleeding (safety) Noseworthy et al. Int J Cardiol. 2017;245:174-7 2017 MFMER slide-15
60 50 Baseline Characteristics: CHA 2 DS 2 -VASc * Patients (%) 40 30 20 * Warfarin Apixaban Dabigatran Rivaroxaban 10 0 3 4 5 CHA 2 DS 2 -VASc Noseworthy et al. Int J Cardiol. 2017;245:174-7 2017 MFMER slide-16
40 Baseline Characteristics: HAS-BLED Patients (%) 35 30 25 20 15 10 * * Warfarin Apixaban Dabigatran Rivaroxaban 5 0 0,1 2 3 4 HAS-BLED Noseworthy et al. Int J Cardiol. 2017;245:174-7 2017 MFMER slide-17
Oral Anticoagulant Efficacy and Safety Ischemic stroke or SE Major bleeding 14 12 11.7 Event incidence (%) 10 8 6 4 3.5 5.4 7.0 8.2 2 2.3 2.1 2.3 0 Warfarin Apixaban Dabigatran Rivaroxaban Noseworthy et al. Int J Cardiol. 2017;245:174-7 2017 MFMER slide-18
6 Oral Anticoagulant Efficacy Warfarin Apixaban Dabigatran Rivaroxaban 5.5 Ischemic stroke or SE (%) 5 4 3 2 1 1.8 1.3 1.8 1.0 3.1 1.9 1.1 2.6 4.1 3.4 4.4 0 3 4 5 CHA 2 DS 2 -VASc Noseworthy et al. Int J Cardiol. 2017;245:174-7 2017 MFMER slide-19
25 Oral Anticoagulant Safety Warfarin Apixaban Dabigatran Rivaroxaban 20 19.6 Major bleeding (%) 15 10 9.7 7.2 7.4 14.3 8.5 7.9 10.3 9.1 13.2 13.3 5 5.3 3.0 4.5 3.8 0 1.2 0,1 2 3 4 HAS-BLED Noseworthy et al. Int J Cardiol. 2017;245:174-7 2017 MFMER slide-20
Real-World Comparison: Warfarin vs DOAC Similar efficacy among agents Major bleeding risk: Highest with warfarin Lowest with apixaban Increased stroke or systemic embolism risk with higher CHA 2 DS 2 -VASc score Increased major bleeding risk with higher HAS-BLED score 2017 MFMER slide-21
DOAC vs DOAC Methods Large U.S. administrative claims database Time Period October 1 st, 2010 to February 28 th, 2015 Population Outcomes Adult users ( 18 years) of apixaban, dabigatran, or rivaroxaban for nonvalvular atrial fibrillation 3 propensity-score-matched cohorts: Rivaroxaban vs dabigatran (n = 31,574) Apixaban vs dabigatran (n = 13,084) Apixaban vs rivaroxaban (n = 13,130) Median CHA 2 DS 2 -VASc = 4 Median HAS-BLED = 2 Stroke and systemic embolism (efficacy) Major bleeding (safety) Noseworthy et al. CHEST. 2016;150:1302-12 2017 MFMER slide-22
Stroke or Systemic Embolism Event rate per 100 person-years Rivaroxaban vs Dabigatran 1.12 1.03 Favor Rivaroxaban Apixaban vs Dabigatran 1.22 1.17 Favor Dabigatran Hazard ratio p value 1.00 0.99 0.82 0.41 Apixaban vs Rivaroxaban 1.21 1.03 Favor Apixaban Favor Apixaban Favor Dabigatran Favor Rivaroxaban 1.05 0.85 Noseworthy et al. CHEST. 2016;150:1302-12 2017 MFMER slide-23
Major Bleeding Event rate per 100 person-years Rivaroxaban vs Dabigatran 3.77 2.58 Favor Rivaroxaban Apixaban vs Dabigatran 2.06 3.25 Favor Dabigatran Hazard ratio p value 1.30 <0.01 0.50 <0.001 Apixaban vs Rivaroxaban 2.01 4.55 Favor Apixaban Favor Apixaban Favor Dabigatran Favor Rivaroxaban 0.39 <0.001 Noseworthy et al. CHEST. 2016;150:1302-12 2017 MFMER slide-24
Intracranial Bleeding Event rate per 100 person-years Rivaroxaban vs Dabigatran 0.53 0.26 Favor Rivaroxaban Apixaban vs Dabigatran 0.25 0.34 Favor Dabigatran Hazard ratio p value 1.79 0.02 0.65 0.36 Apixaban vs Rivaroxaban 0.25 0.43 Favor Apixaban Favor Apixaban Favor Dabigatran Favor Rivaroxaban 0.56 0.23 Noseworthy et al. CHEST. 2016;150:1302-12 2017 MFMER slide-25
DOAC vs DOAC: Gastrointestinal Bleed Methods Large U.S. administrative claims database Time Period October 1 st, 2010 to February 28 th, 2015 Population Adult users ( 18 years) of apixaban, dabigatran, or rivaroxaban for nonvalvular atrial fibrillation 3 propensity-score-matched cohorts: Rivaroxaban vs dabigatran (n = 31,574) Apixaban vs dabigatran (n = 13,084) Apixaban vs rivaroxaban (n = 13,130) Median CHA 2 DS 2 -VASc = 4 Median HAS-BLED = 2 Outcome Gastrointestinal bleed Abraham et al. Gastroenterology. 2017;152;1014-22 2017 MFMER slide-26
Gastrointestinal Bleeding Events Hazard Ratio Apixaban vs dabigatran (n = 13,084) Overall 0.39 Age 18-64 years 0.38 Age 65-74 years 0.25 Age 75 years 0.45 p <0.05 Abraham et al. Gastroenterology. 2017;152;1014-22 2017 MFMER slide-27
Gastrointestinal Bleeding Events Hazard Ratio Apixaban vs dabigatran (n = 13,084) Apixaban vs rivaroxaban (n = 13,130) Overall 0.39 0.33 Age 18-64 years 0.38 0.38 Age 65-74 years 0.25 0.18 Age 75 years 0.45 0.39 p <0.05 Abraham et al. Gastroenterology. 2017;152;1014-22 2017 MFMER slide-28
Gastrointestinal Bleeding Events Hazard Ratio Apixaban vs dabigatran (n = 13,084) Apixaban vs rivaroxaban (n = 13,130) Rivaroxaban vs dabigatran (n = 31,574) Overall 0.39 0.33 1.20 Age 18-64 years 0.38 0.38 2.03 Age 65-74 years 0.25 0.18 1.44 Age 75 years 0.45 0.39 1.06 p <0.05 Abraham et al. Gastroenterology. 2017;152;1014-22 2017 MFMER slide-29
Real-World Comparison: DOAC vs DOAC Similar efficacy Major, intracranial, and gastrointestinal bleeding risk: Rivaroxaban > Dabigatran > Apixaban Limitations: Reliance on pharmacy claims data and billing codes Potential residual confounding 2017 MFMER slide-30
1 st Apixaban Lowest major bleeding risk Lowest gastrointestinal bleeding risk Chronic kidney disease 2017 MFMER slide-31
1 st Apixaban Lowest major bleeding risk Lowest gastrointestinal bleeding risk 2 nd Dabigatran Lower major bleeding risk than rivaroxaban and warfarin Reversal agent Chronic kidney disease 2017 MFMER slide-32
3 rd Rivaroxaban Highest major bleeding risk among DOACs Highest gastrointestinal bleeding risk among DOACs Compliance issues 2017 MFMER slide-33
3 rd Rivaroxaban Highest major bleeding risk among DOACs Highest gastrointestinal bleeding risk among DOACs Compliance issues Warfarin Chronic kidney disease Compliance issues Reversal agents Valves 2017 MFMER slide-34
Question #3 AB develops a GI bleed on rivaroxaban therapy and requires a change in oral anticoagulant therapy. Which alternative agent would you select for her? Apixaban Dabigatran Warfarin 2017 MFMER slide-35
Questions & Discussion 2017 MFMER slide-36
Acquisition Costs Drug Mayo Clinic Acquisition Cost Warfarin $0.04 Apixaban $4.54 Dabigatran $5.20 Rivaroxaban $9.06 2017 MFMER slide-37