SDSHP ANNUAL MEETING CLINICAL PEARLS APRIL 7 TH, 2017 USE OF DIRECT ORAL ANTICOAGULANTS IN OBESITY STEFFANIE DANLEY, PHARM D, BCPS, CACP DISCLOSURE I have had no financial relationship over the past 12 months with any commercial sponsor with a vested interest in this presentation. 1
LEARNING OBJECTIVES Pharmacist: Summarize the evidence from Phase III DOAC trials regarding effective and safe use in obese patients. Technician: Identify the weight levels at which DOACs are not recommended, according to the International Society of Thrombosis and Haemostasis. BACKGROUND Direct Oral Anticoagulants (DOACs): Direct Thrombin Inhibitor dabigatran Factor Xa Inhibitors rivaroxaban apixaban edoxaban SUMMARY OF EVIDENCE 2
SUMMARY OF EVIDENCE: ATRIAL FIBRILLATION ( AFIB) TRIALS DRUG TRIAL WEIGHT NUMBER OF OBESE PTS (%) Dabigatran RE-LY 100 kg 3099/18113 (17.1) Rivaroxaban ROCKET-AF > 90 kg 2035/7131 (28.5) 972/7131 (13.6) Apixaban ARISTOTLE None Edoxaban ENGAGE AF TIMI 48 None AFIB TRIALS: CLINICAL EFFICACY OUTCOMES DRUG TRIAL WEIGHT CATEGORY Rivaroxaban ROCKET-AF > 90 kg DOAC vs. VKA RELATIVE RISK (CI) 0.90 (0.67-1.43) 0.82 (0.45-1.50) AFIB TRIALS: CLINICAL SAFETY OUTCOMES DRUG TRIAL WEIGHT CATEGORY Rivaroxaban ROCKET-AF > 90 kg DOAC vs. VKA RELATIVE RISK (CI) 0.9 (0.56-1.44) 0.82 (0.45-1.52) 3
SUMMARY OF EVIDENCE: VENOUS THROMBOEMBOLISM (VTE) TRIALS DRUG TRIAL WEIGHT NUMBER OF OBESE PTS (%) Dabigatran RE-COVER I 100 kg BMI 35 RE-COVER II 100 kg 502/2539 (20) 306/2539 (12) 438/1280 (34.2) 302/1280 (23.6) RE-MEDY 100 kg 299/1430 (20.9) RE-SONATE 100 kg 122/681 (17.9) Rivaroxaban EINSTEIN DVT > 100 kg 245/1731 (14.2) EINSTEIN PE > 100 kg 345/2419 (14.3) EINSTEIN EXT > 100 kg 85/602 (14.1) Apixaban AMPLIFY 100 kg 522/2691 (19.4) 349/2691 (13.0) Edoxaban HOK USAI VTE > 100 kg 611/4118 (14.8) VTE TRIALS: CLINICAL EFFICACY OUTCOMES PER WEIGHT DRUG TRIAL DOAC vs. VKA RELATIVE RISK (CI) Dabigatran RE-COVER II 1.16 (0.58-2.29) Rivaroxaban EINSTEIN DVT 0.99 (0.43-2.26) EINSTEIN PE 1.28 (0.56-2.90) Apixaban AMPLIFY 0.61 (0.29-1.28) Edoxaban HOK USAI VTE 1.02 (0.58-1.82) Overall 0.98 (0.72-1.35) VTE TRIALS: CLINICAL EFFICACY OUTCOMES PER BMI DRUG TRIAL DOAC vs. VKA RELATIVE RISK (CI) Dabigatran RE-COVER II 1.53 (0.56-4.15) Rivaroxaban EINSTEIN PE 1.02 (0.45-2.33) Apixaban AMPLIFY 0.56 (0.22-1.41) Overall 0.94 (0.56-1.59) 4
VTE TRIALS: CLINICAL EFFICACY OUTCOMES IN OBESE VS. NORMAL WEIGHT PATIENTS DRUG TRIAL OBESE vs NORMAL RELATIVE RISK (CI) Dabigatran RE-COVER II 2.04 (1.19-3.51) Rivaroxaban EINSTEIN DVT 1.28 (0.58-2.82) EINSTEIN PE 1.03 (0.52-2.06) Apixaban AMPLIFY 0.96 (0.50-1.66) Edoxaban HOK USAI VTE 1.17 (0.74-1.83) Overall 1.28 (0.98-1.67) VENOUS THROMOEMBOLISM TRIALS: CLINICAL SAFETY OUTCOMES DRUG TRIAL DOAC vs. VKA RELATIVE RISK (CI) Rivaroxaban EINSTEIN DVT 0.78 (0.50-1.23) EINSTEIN PE 1.09 (0.79-1.52) Edoxaban HOK USAI VTE 1.07 (0.75-1.54) Overall 1.01 (0.81-1.25) SUMMARY OF EVIDENCE: LIMITATIONS Efficacy Inconsistencies across studies Weight categories vary between studies BMI categorization only in select studies Published data is limited regarding absolute weight of patients Limited number of patients at extremes of weight No data on number of patients with BMI > 40 kg/m 2 Safety Only half of the studies included safety analysis by weight Weight categories vary between studies Safety outcomes varied between studies 5
SUMMARY OF EVIDENCE: PHARMACOKINETIC/ PHARMACODYNAMIC DATA Dabigatran: patients >100 kg 21% lower trough concentrations Rivaroxaban: patients >100 kg Similar peak concentrations Similar half-lives 0.8% decrease in volume of distribution/kg of body weight for patients <56 kg Apixaban: Patients >120 kg and BMI 30 kg/m 2 31% lower peak concentration 24% higher volume of distribution 23% lower drug exposure Mean half-life 3.2 hours shorter Edoxaban: no PK studies SUMMARY OF GUIDELINES: ANTICOAGULATION FORUM: VTE Mean weight in DOAC VTE trials: 84 kg (60-100 kg) Patients <50-60 kg: 2-13% of patients Patients >100 kg: 14-19% Pending further evidence in patients at extremes of weight (<50 kg, >120 kg or BMI 35 kg/m 2 ) it is advisable to limit DOAC use to situations where vitamin K antagonists cannot be used. SUMMARY OF GUIDELINES: S C I E N T I F I C A N D S TA N DA R D I Z AT I O N C O M M I T T E E A N D I N T E R N AT I O N A L S O C I E T Y O F T H R O M B O S I S A N D H A E M O S TA S I S Standard dosing of DOACs in patients with a BMI 40 kg/m 2 and weight 120 kg Avoid DOACs in patients with a BMI of > 40 kg/m 2 or a weight of > 120 kg, due to limited clinical data. If DOACs are used with a BMI of > 40 kg/m 2 or a weight of > 120 kg, consider checking a drug-specific peak and trough level. 6
CLINICAL APPLICATION Consider using DOACs at standard dosing up to weight of 120 kg. If a patient weighs > 120 kg, used shared-decision making with the patient to discuss the risks vs. benefits of DOAC therapy vs. warfarin. LEARNING ASSESSMENT Pharmacist: Of the four Phase III atrial fibrillation DOAC trials, identify which trials did not include a weight-based efficacy analysis. Please select all that apply: A. RE-LY B. ROCKET-AF C. ARISTOTLE D. ENGAGE AF TIMI-48 LEARNING ASSESSMENT Technician: According to the International Society of Thrombosis and Haemostasis, DOACs are not recommended for patients with a weight greater than: A. 60 kg B. 100 kg C. 120 kg D. 150 kg 7
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