Resuming Anticoagulation following Upper Gastrointestinal Bleeding among Patients with Nonvalvular Atrial Fibrillation—A Microsimulation Analysis
BACKGROUND: Among patients with nonvalvular atrial fibrillation (NVAF) who have sustained an upper gastrointestinal bleed (UGIB), the benefits and harms of oral anticoagulation change over time. Early resumption of anticoagulation increases recurrent bleeding, while delayed resumption exposes patients to a higher risk of ischemic stroke. We therefore set out to estimate the expected benefit of resuming anticoagulation as a function of time after UGIB among patients with NVAF.
METHODS: We created a decision-analytic model estimating discounted quality-adjusted life-years when patients with NVAF resume anticoagulation on each day following UGIB. We simulated from a health system perspective over a lifelong time horizon.
RESULTS: Peak utility for warfarin was achieved by resumption 41 days after hemostasis from the index UGIB. Resumption between days 32 and 51 produced greater than 99.9% of the peak utility. Peak utility for apixaban was achieved by resumption 32 days after the index UGIB. Resumption between days 21 and 47 produced greater than 99.9% of the peak utility. Of input parameters, results were most sensitive to underlying stroke risk. Specifically, across the range of CHA2DS2-Vasc scores, the optimal day of resumption varied by around 11 days for patients resuming warfarin and by around 15 days for patients resuming apixaban. Results were less sensitive to underlying risk of rebleeding.
CONCLUSIONS: For patients with NVAF following UGIB, warfarin is optimally restarted approximately six weeks following hemostasis, and apixaban is optimally restarted approximately one month following hemostasis. Modest changes to this timing based on probability of thromboembolic stroke are reasonable.
© 2019 Society of Hospital Medicine
Anticoagulation is commonly used in the management of atrial fibrillation to reduce the risk of ischemic stroke. Warfarin and other anticoagulants increase the risk of hemorrhagic complications, including upper gastrointestinal bleeding (UGIB). Following UGIB, management of anticoagulation is highly variable. Many patients permanently discontinue anticoagulation, while others continue without interruption.1-4 Among patients who resume warfarin, different cohorts have measured median times to resumption ranging from four days to 50 days.1-3 Outcomes data are sparse, and clinical guidelines offer little direction.5
Following UGIB, the balance between the risks and benefits of anticoagulation changes over time. Rebleeding risk is highest immediately after the event and declines quickly; therefore, rapid resumption of anticoagulation causes patient harm.3 Meanwhile, the risk of stroke remains constant, and delay in resumption of anticoagulation is associated with increased risk of stroke and death.1 At some point in time following the initial UGIB, the expected harm from bleeding would equal the expected harm from stroke. This time point would represent the optimal time to restart anticoagulation.
Trial data are unlikely to identify the optimal time for restarting anticoagulation. A randomized trial comparing discrete reinitiation times (eg, two weeks vs six weeks) may easily miss the optimal timing. Moreover, because the daily probability of thromboembolic events is low, large numbers of patients would be required to power such a study. In addition, a number of oral anticoagulants are now approved for prevention of thromboembolic stroke in atrial fibrillation, and each drug may have different optimal timing.
In contrast to randomized trials that would be impracticable for addressing this clinical issue, microsimulation modeling can provide granular information regarding the optimal time to restart anticoagulation. Herein, we set out to estimate the expected benefit of reinitiation of warfarin, the most commonly used oral anticoagulant,6 or apixaban, the direct oral anticoagulant with the most favorable risk profile,7 as a function of days after UGIB.
METHODS
We previously described a microsimulation model of anticoagulation among patients with nonvalvular atrial fibrillation (NVAF; hereafter, we refer to this model as the Personalized Anticoagulation Decision-Making Assistance model, or PADMA).8,9 For this study, we extended this model to incorporate the probability of rebleeding following UGIB and include apixaban as an alternative to warfarin. This model begins with a synthetic population following UGIB, the members of which are at varying risk for thromboembolism, recurrent UGIB, and other hemorrhages. For each patient, the model simulates a number of possible events (eg, thromboembolic stroke, intracranial hemorrhage, rebleeding, and other major extracranial hemorrhages) on each day of an acute period of 90 days after hemostasis. Patients who survive until the end of the acute period enter a simulation with annual, rather than daily, cycles. Our model then estimates total quality-adjusted life-years (QALYs) for each patient, discounted to the present. We report the average discounted QALYs produced by the model for the same population if all individuals in our input population were to resume either warfarin or apixaban on a specific day. Input parameters and ranges are summarized in Table 1, a simplified schematic of our model is shown in the Supplemental Appendix, and additional details regarding model structure and assumptions can be found in earlier work.8,9 We simulated from a health system perspective over a lifelong time horizon. All analyses were performed in version 14 of Stata (StataCorp, LLC, College Station, Texas).
