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
Synthetic Population
To generate a population reflective of the comorbidities and age distribution of the US population with NVAF, we merged relevant variables from the National Health and Nutrition Examination Survey (NHANES; 2011-2012), using multiple imputation to correct for missing variables.10 We then bootstrapped to national population estimates by age and sex to arrive at a hypothetical population of the United States.11 Because NHANES does not include atrial fibrillation, we applied sex- and age-specific prevalence rates from the AnTicoagulation and Risk Factors In Atrial Fibrillation study.12 We then calculated commonly used risk scores (CHA2DS2-Vasc and HAS-BLED) for each patient and limited the population to patients with a CHA2DS2-Vasc score of one or greater.13,14 The population resuming apixaban was further limited to patients whose creatinine clearance was 25 mL/min or greater in keeping with the entry criteria in the phase 3 clinical trial on which the medication’s approval was based.15
To estimate patient-specific probability of rebleeding, we generated a Rockall score for each patient.16 Although the discrimination of the Rockall score is limited for individual patients, as with all other tools used to predict rebleeding following UGIB, the Rockall score has demonstrated reasonable calibration across a threefold risk gradient.17-19 International consensus guidelines recommend the Rockall score as one of two risk prediction tools for clinical use in the management of patients with UGIB.20 In addition, because the Rockall score includes some demographic components (five of a possible 11 points), our estimates of rebleeding risk are covariant with other patient-specific risks. We assumed that the endoscopic components of the Rockall score were present in our cohort at the same frequency as in the original derivation and are independent of known patient risk factors.16 For example, 441 out of 4,025 patients in the original Rockall derivation cohort presented with a systolic blood pressure less than 100 mm Hg. We assumed that an independent and random 10.96% of the cohort would present with shock, which confers two points in the Rockall score.
The population was replicated 60 times, with identical copies of the population resuming anticoagulation on each of days 1-60 (where day zero represents hemostasis). Intermediate data regarding our simulated population can be found in the Supplemental Appendix and in prior work.
Event Type, Severity, and Mortality
Each patient in our simulation could sustain several discrete and independent events: ischemic stroke, intracranial hemorrhage, recurrent UGIB, or extracranial major hemorrhage other than recurrent UGIB. As in prior analyses using the PADMA model, we did not consider minor hemorrhagic events.8
The probability of each event was conditional on the corresponding risk scoring system. Patient-specific probability of ischemic stroke was conditional on CHA2DS2-Vasc score.21,22 Patient-specific probability of intracranial hemorrhage was conditional on HAS-BLED score, with the proportions of intracranial hemorrhage of each considered subtype (intracerebral, subarachnoid, or subdural) bootstrapped from previously-published data.21-24 Patient-specific probability of rebleeding was conditional on Rockall score from the combined Rockall and Vreeburg validation cohorts.17 Patient-specific probability of extracranial major hemorrhage was conditional on HAS-BLED score.21 To avoid double-counting of UGIB, we subtracted the baseline risk of UGIB from the overall rate of extracranial major hemorrhages using previously-published data regarding relative frequency and a bootstrapping approach.25
