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
Probability of Rebleeding Over Time
To estimate the decrease in rebleeding risk over time, we searched the Medline database for systematic reviews of recurrent bleeding following UGIB using the strategy detailed in the Supplemental Appendix. Using the interval rates of rebleeding we identified, we calculated implied daily rates of rebleeding at the midpoint of each interval. For example, 39.5% of rebleeding events occurred within three days of hemostasis, implying a daily rate of approximately 13.2% on day two (32 of 81 events over a three-day period). We repeated this process to estimate daily rates at the midpoint of each reported time interval and fitted an exponential decay function.26 Our exponential fitted these datapoints quite well, but we lacked sufficient data to test other survival functions (eg, Gompertz, lognormal, etc.). Our fitted exponential can be expressed as:
P rebleeding = b 0 *exp(b 1 *day)
where b0 = 0.1843 (SE: 0.0136) and b1 = –0.1563 (SE: 0.0188). For example, a mean of 3.9% of rebleeding episodes will occur on day 10 (0.1843 *exp(–0.1563 *10)).
Relative Risks of Events with Anticoagulation
For patients resuming warfarin, the probabilities of each event were adjusted based on patient-specific daily INR. All INRs were assumed to be 1.0 until the day of warfarin reinitiation, after which interpolated trajectories of postinitiation INR measurements were sampled for each patient from an earlier study of clinical warfarin initiation.27 Relative risks of ischemic stroke and hemorrhagic events were calculated based on each day’s INR.
For patients taking apixaban, we assumed that the medication would reach full therapeutic effect one day after reinitiation. Based on available evidence, we applied the relative risks of each event with apixaban compared with warfarin.25
Future Disability and Mortality
Each event in our simulation resulted in hospitalization. Length of stay was sampled for each diagnosis.28 The disutility of hospitalization was estimated based on length of stay.8 Inpatient mortality and future disability were predicted for each event as previously described.8 We assumed that recurrent episodes of UGIB conferred morbidity and mortality identical to extracranial major hemorrhages more broadly.29,30
