Direct Oral Anticoagulant Use in Older Adults Brian Skinner, PharmD

Transcription

1 Direct Oral Anticoagulant Use in Older Adults Brian Skinner, PharmD Dr. Skinner serves as an Assistant Professor of Pharmacy Practice at Manchester University, and he is one of three Internal Medicine Clinical Pharmacy Specialists at St. Vincent Indianapolis Hospital. This presentation will expose clinicians to various considerations when treating obese and end-stage renal disease patients with direct oral anticoagulants. The objective is to identify the place in therapy for direct oral anticoagulants and apply this knowledge to care for older adults. *This speaker has no conflicts of interest to disclose

2 Disclosures This speaker has indicated there are no relevant financial relationships to be disclosed. 2

3 Anticoagulant Use in the United States 3 Am J Med. 2015;128(12):

4 Obesity in the Older Adult Population Increased Vd for lipophilic drugs Increased glomerular filtration rate Decreased total drug exposure Shank BR. 2016;Chapter 1. NCHS Data Brief. 2012;106:1-8.

5 Direct Oral Anticoagulants (DOACs) 5 Lexicomp TM J Thromb Thrombolylsis. 2016;41:

6 J Thromb Haemostasis. 2016;14: Clinical Trial Data Dabigatran Increased risk of VTE in patients 100kg (RR 2.04; 95% CI ) Factor Xa inhibitors No significant differences in efficacy noted between weight classes Risk of GI bleed may be less in obese patients taking apixaban

7 Pharmacokinetic Studies Dabigatran Rivaroxaban Apixaban Edoxaban Comparator kg vs 70-80kg vs 65-85kg vs Groups 100kg >120kg 120kg No Studies 31% lower Findings peak and 21% lower No meaningful 23% lower trough in differences total drug obese group detected exposure in No Studies obese group Subgroup Mean 137kg Patient Mean ± analysis of Range 120- Population 9.9 (SD) RE-LY trial 175kg No Studies 7 J Am Coll Cardiol. 2014;63(4):321-8 Br J Clin Pharmacol. 2013; 76(6): J Clin Pharmacol. 2007;47(2): J Thromb Haemostasis. 2016;14:

8 J Thromb Haemostasis. 2016;14: International Society on Thrombosis and Haemostasis Recommendations We suggest that DOACs should not be used in patients with a BMI of >40kg/m 2 or a weight of >120kg, because there are limited clinical data available for patients at the extreme of weight, and the available PK/PD evidence suggests that decreased drug exposures, reduced peak concentrations and shorter half- lives occur with increasing weight, which raises concerns about underdosing in the population at the extreme of weight.

9 J Thromb Haemostasis. 2016;14: International Society on Thrombosis and Haemostasis Recommendations If DOACs are used in a patient with a BMI of >40kg/m 2 or a weight of >120 kg, we suggest checking a drug- specific peak and trough level. If the level falls within the expected range, continuation of the DOAC seems reasonable. However, if the drug- specific level is found to be below the expected range we suggest changing to a VKA rather than adjusting the dose of the DOAC.

10 Summary for Use in Obesity Pharmacokinetic changes in obesity may result in increased renal clearance and decreased total drug exposure in obesity The use of the DOACs in obesity has not been well studied A small portion of participants in clinical trials were >100kg There is no available data on patients at weight extremes (i.e. >200kg) The ISTH suggests avoiding the use of DOACs in patients weighing >120kg

11 Renal Impairment Dabigatran Rivaroxaban Apixaban Edoxaban Mechanism of Action Direct thrombin inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Factor Xa Inhibitor Renal Elimination 80% 33% 25% 50% Venous Thrombo- 15mg BID x 21days; Not 10mg studied BID x 150mg in CrCl 15-50: CrCl < 30: BID CrCl <30: 60mg daily embolism VTE Renal (VTE) Dose 20mg daily pts 7days; with 5mg SCr >2.5 BID 30mg daily AVOID AVOID Not or CrCl studied <25in CrCl CrCl <15: 15-50: AVOID CrCl < 30: CrCl <30: VTE Renal Dose pts 2.5mg with BID SCr if >2.5 at 30mg daily CrCl AVOID 15-30: CrCl AVOID 15-50: or CrCl 15-50: least CrCl 2: <25 CrCl <15: AVOID 75mg BID 15mg daily 30mg daily Atrial AF Renal Fibrillation Dose Age 80yo 150mg BID 20mg daily Wt 5mg 60kg BID 60mg daily (AF) CrCl <15: AVOID CrCl <15: AVOID CrCl <15: AVOID SCr 1.5mg/dL 2.5mg BID if at CrCl 15-30: CrCl 15-50: CrCl 15-50: least 2: 75mg BID 15mg daily 30mg daily AF Renal Dose Age 80yo CrCl <15: AVOID CrCl <15: AVOID Wt 60kg SCr 1.5mg/dL CrCl <15: AVOID Lexicomp TM J Thromb Thrombolylsis. 2016;41:

12 Rivaroxaban and Dabigatran in ESRD Patients 12 Following dabigatran s release into the market, 45 days later it was used in a dialysis patient Event rate of major bleeding was higher in both dabigatran and rivaroxaban users than warfarin users 83.1 events/100 patient years (Dabigatran) 68.4 events/100 patient years (Rivaroxaban) 35.9 events/100 patients years (Warfarin) No statistically significant differences in rates of embolic events 10.6 events/100 patient years (Dabigatran) 11.2 events/100 patient years (Rivaroxaban) 6.2 events/100 patients years (Warfarin) Circulation. 2015;131(11):

13 Apixaban in ESRD Patients 13 J Clin Pharmacol. 2016;56(5):628-36

14 Summary for Use in ESRD Rivaroxaban and dabigatran have been found to significantly increase the risk of major bleeding in ESRD patients The use of the edoxaban in ESRD has not been study Only apixaban has recommendations for use in ESRD when used for the treatment of atrial fibrillation The design of this study limits it s ability to be utilized Warfarin should be the drug of choice for patients on hemodialysis

15 Final Thoughts As time progresses, the use of the DOACs is bound to increase Limited data evaluates the safety and efficacy of these drugs in both the obese population and in patient with ESRD Clinicians should critically evaluate the appropriateness of DOAC therapy in their patients to ensure safe use When in doubt, warfarin is still a viable option for most patients

16 Bibliography 1. Barnes GD et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12): Shank BR, Zimmerman DE. Demystifying drug dosing in obese patients. Bethesda, MD: American Society of Health- system Pharmacists. 2016;Chapter Fakhouri THI, et al. Prevalence of obesity among older adults in the United States, National Center for Health Statistics Data Brief. 2012;106: Lexi- Comp Online TM, Lexi- Drugs Online, Hudson, Ohio: Lexi- Comp, Inc.; Accessed: Jan 19, Burnett AE et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolylsis. 2016;41: Martin K et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemostasis. 2016;14:

17 Bibliography 7. Reilly PA et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE- LY Trial (Randomized Evaluation of Long- Term Anticoagulation Therapy. J Am Coll Cardiol. 2014;63(4): Kubitza D et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY ) in healthy subjects. J Clin Pharmacol. 2007;47(2): Upreti VV et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol. 2013; 76(6): Chan KE et al. Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation. 2015;131(11): Wang X et al. Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end- stage renal disease on hemodialysis. J Clin Pharmacol. 2016;56(5):

18 Direct Oral Anticoagulant Use in Older Adults Brian Skinner, PharmD *This speaker has no conflicts of interest to disclose