Reversal Agents, Safety Win Over Many DOAC Holdouts
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DOAC = direct-acting oral anticoagulant; OAC = oral anticoagulant, including DOACs and VKAs; PCC = prothrombin complex concentrate; RBC = red blood cell; VKA = vitamin K antagonist
∗Reversal/hemostatic agents include repletion strategies such as PCCs, plasma, vitamin K, and specific reversal agents for DOACs (e.g., idarucizumab for dabigatran; andexanet alfa for apixaban or rivaroxaban).
The shift from warfarin to direct-acting oral anticoagulants for atrial fibrillation treatment has been slower than expected at many healthcare system, including the VHA. Development of reversal agents has helped increase acceptance, as has research showing the benefit of DOAC treatment, which requires less monitoring and has fewer food and drug interactions, for a range of patients.
IOWA CITY, IA — Direct-acting oral anticoagulants have transformed the care of patients with atrial fibrillation since the first drug in the class gained U.S. Food and Drug Approval in 2010. The simplified, standardized dosing and elimination of the need for ongoing monitoring have led to significant increases in the number of patients with atrial fibrillation receiving guideline-concordant treatment with anticoagulant therapy to minimize the risk of stroke.
The American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines have recommended DOACs over warfarin for most patients with atrial fibrillation for a number of years. Despite the guidelines, many physicians remained leery of prescribing DOACs—apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban—because of fears that bleeds could not be controlled, despite the lower risk of bleeding associated with newer anticoagulants.
The approval of two specific agents has won over many of the holdouts. Idarucizumab, a reversal agent for dabigatran, received U.S. Food and Drug approval in 2015. Andexanet alfa, a novel modified recombinant human factor Xa, gained approval as a reversal agent for apixaban and rivaroxaban in 2018. The 2020 American College of Cardiology expert consensus decision pathway on managing bleeding in patients on oral anticoagulants also recommends administration of andexanet for patients on edoxaban and betrixaban who experience major bleeding events, although it has not received FDA approval for those indications.1
With standardized dosages, elimination of regular monitoring and development of reversal agents, DOACs have displaced warfarin in many contexts. The combined effect of multiple medications on comparative stroke and bleeding risk in DOACs and warfarin, however, has not been studied extensively, raising a question about the best choice of anticoagulant for these patients.
With more than 300,000 veterans in VHA care receiving anticoagulant therapy and a high percentage of patients with multiple comorbidities and consequently multiple medications, understanding the risks and benefits of various anticoagulants in this population is of great importance to the VA. Researchers at the Iowa City VAMC and the University of Iowa have undertaken several studies to learn more about the interaction of polypharmacy and anticoagulants.
In a recent study, Mary Vaughn Sarrazin, PhD, investigator, Center for Access and Delivery Research and Evaluation based at the Iowa City VAMC, and associate professor of internal medicine at the Roy and Lucille J. Carver College of Medicine at the University of Iowa and her colleagues examined the impact of polypharmacy on patients taking rivaroxaban, apixaban and warfarin.
“DOACs are believed to have fewer interactions with other drugs than warfarin, which may make them safer for patients with very complex medication regimens,” Sarrazin previously told U.S. Medicine. Much of the research on drug interactions with DOACs, however, comes from post hoc analyses of subgroups in the clinical trials submitted to the FDA in connection with the newer anticoagulants’ approvals. Both the ROCKET AF and ARISTOTLE trials for rivaroxaban an apixaban, respectively, excluded participants using strong CYP3A4 or P-GP inhibitors, which are often used to combat infections and cancer.
The Iowa-based team conducted a retrospective analysis of Medicare beneficiaries with a new diagnosis of atrial fibrillation between January 2015 and September 2017. The final study cohort included 22,042 patients. Of those, 3,838 patients started the standard dose of rivaroxaban, 6,985 initiated the full dose of apixaban, and 6,639 began warfarin. An additional 1,806 individuals started on a reduced dose of rivaroxaban and 2,774 were prescribed a half-dose of apixaban.
Polypharmacy Intensity
All patients were stratified by polypharmacy intensity. The researchers categorized patients prescribed three or fewer drugs as low, those on four to eight drugs as medium, and patients on nine or more drugs as high polypharmacy. Three-way propensity score-matching created a subgroup of 10,287 patients with equal numbers of patients taking each drug at each level of polypharmacy.
“The prevalence of most comorbidities, including heart failure, coronary artery disease, diabetes mellitus, hypertension, and liver, kidney, and lung disease, increased with higher grades of polypharmacy in the three groups compared with lower grades of polypharmacy,” the authors noted. “In each polypharmacy category, warfarin users had the highest prevalence of most comorbidities.” Rivaroxaban users tended to be younger.
In patients taking three or fewer drugs, the analysis found no difference in the risk of ischemic stroke between the standard doses of the three anticoagulants. Apixaban provided a safety benefit in this group, with about half the risk of bleeding compared with warfarin. Both the ischemic stroke and bleeding risk rates were similar across the three anticoagulants in the moderate polypharmacy group.
In the high polypharmacy group, apixaban had more than twice the risk of ischemic stroke compared to warfarin and a nonsignificant difference in risk compared to rivaroxaban. All the anticoagulants had similar risks of bleeding in this population, including gastrointestinal and intracranial bleeding. Apixaban also had a higher risk of overall mortality compared with rivaroxaban in the high polypharmacy group.
“In our study, we found that apixaban is associated with a higher risk of ischemic stroke when compared with warfarin and a higher risk of mortality when compared with rivaroxaban,” the researchers said. “One potential explanation is that apixaban is dosed twice daily, while warfarin and rivaroxaban are dosed once daily.” Previous studies have shown that patients are less likely to take the recommended dose of medication when they must take a drug more than once a day.
“Our study suggests that, among patients with significant polypharmacy (>8 drugs), there may be a higher stroke and mortality risk with apixaban compared with warfarin and rivaroxaban,” the team concluded. They noted, however, that “differences were of borderline significance.”
Use of DOACs got another boost with a recent study find that they are associated with a lower risk of new-onset osteoporosis, not a greater risk than warfarin, which has been a concern.
The report in Thrombosis Research noted that oral anticoagulants have been shown to affect bone mineral density and cause osteoporosis. Salem, VA, VAMC-led researchers sought to compare the risk of osteoporosis in patients on warfarin vs. DOACs.2
To do that, they conducted a retrospective single-center cohort study among veterans who had warfarin or DOACs newly initiated between Jan. 1, 2012, to April 1, 2020, at their facility. Included were 1,526 patients on DOACs and 1,121 on warfarin; after propensity-matching, 943 patients were investigated in each arm.
The primary outcome was new-onset osteoporosis, with secondary outcomes comparing incidence of all clinical fractures, hip fractures, major bleeding and intracranial bleed between the treatments.
Results indicated that DOAC treatment was associated with lower incidence of new-onset osteoporosis vs. warfarin in matched cohort (aHR: 0.19, 95% CI: 0.10-0.36; p < 0.0001). Researchers determined that the risk of all clinical fracture and hip fracture was similar in patients receiving DOACs to those on warfarin (aHR: 1.18, 95% CI: 0.82-1.69; p = 0.3671). On the other hand, DOAC use was associated with lower risk of major bleed (aHR: 0.07, 95% CI: 0.03-0.15; p < 0.0001) and intracranial bleed (aHR: 0.14, 95% CI: 0.03-0.64; p = 0.0111).
“Overall, as compared to warfarin, prolonged use of DOACs is associated with lower risk of new-onset osteoporosis,” the authors concluded. “We hope that our study findings will enlighten current clinical practices assuring safe use of OAC in veteran patients.”
- Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC Expert Consensus Decision Pathway on Managing Bleeding in Patients on Oral Anticoagulants: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020 Aug; 76(5)594-622.
- Patil T, Hobson J. Risk of new-onset osteoporosis in single-center veteran population receiving direct oral anticoagulants versus warfarin. Thromb Res. 2021 Apr;200:56-63. doi: 10.1016/j.thromres.2021.01.019. Epub 2021 Jan 27. PMID: 33540293.
