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
Disutilities
We used a multiplicative model for disutility with baseline utilities conditional on age and sex.31 Each day after resumption of anticoagulation carried a disutility of 0.012 for warfarin or 0.002 for apixaban, which we assumed to be equivalent to aspirin in disutility.32 Long-term disutility and life expectancy were conditional on modified Rankin Score (mRS).33,34 We discounted all QALYs to day zero using standard exponential discounting and a discount rate centered at 3%. We then computed the average discounted QALYs among the cohort of patients that resumed anticoagulation on each day following the index UGIB.
Sensitivity Analyses and Metamodel
To assess sensitivity to continuously varying input parameters, such as discount rate, the proportion of extracranial major hemorrhages that are upper GI bleeds, and inpatient mortality from extracranial major hemorrhage, we constructed a metamodel (a regression model of our microsimulation results).35 We tested for interactions among input parameters and dropped parameters that were not statistically significant predictors of discounted QALYs from our metamodel. We then tested for interactions between each parameter and day resuming anticoagulation to determine which factors may impact the optimal day of reinitiation. Finally, we used predicted marginal effects from our metamodel to assess the change in optimal day across the ranges of each input parameter when other parameters were held at their medians.
RESULTS
Resuming warfarin on day zero produced the fewest QALYs. With delay in reinitiation of anticoagulation, expected QALYs increased, peaked, and then declined for all scenarios. In our base-case simulation of warfarin, peak utility was achieved by resumption 41 days after the index UGIB. Resumption between days 32 and 51 produced greater than 99.9% of peak utility. In our base-case simulation of apixaban, peak utility was achieved by resumption 32 days after the index UGIB. Resumption between days 21 and 47 produced greater than 99.9% of peak utility. Results for warfarin and apixaban are shown in Figures 1 and 2, respectively.
The optimal day of warfarin reinitiation was most sensitive to CHA2DS2-Vasc scores and varied by around 11 days between a CHA2DS2-Vasc score of one and a CHA2DS2-Vasc score of six (the 5th and 95th percentiles, respectively) when all other parameters are held at their medians. Results were comparatively insensitive to rebleeding risk. Varying Rockall score from two to seven (the 5th and 95th percentiles, respectively) added three days to optimal warfarin resumption. Varying other parameters from the 5th to the 95th percentile (including HAS-BLED score, sex, age, and discount rate) changed expected QALYs but did not change the optimal day of reinitiation of warfarin. Optimal day of reinitiation for warfarin stratified by CHA2DS2-Vasc score is shown in Table 2.
Sensitivity analyses for apixaban produced broadly similar results, but with greater sensitivity to rebleeding risk. Optimal day of reinitiation varied by 15 days over the examined range of CHA2DS2-Vasc scores (Table 2) and by six days over the range of Rockall scores (Supplemental Appendix). Other input parameters, including HAS-BLED score, age, sex, and discount rate, changed expected QALYs and were significant in our metamodel but did not affect the optimal day of reinitiation. Metamodel results for both warfarin and apixaban are included in the Supplemental Appendix.
