Page 99 - Haematologica May 2022

Anticoagulants and hemorrhage in PV
Methods
Study design
REVEAL is a multicenter, non-interventional, prospective, observational study of patients with PV (clinicaltrials gov. Identifier: NCT02252159). Details regarding study design, patient eligibility and study conduct were previously described.8 The study enrolled 2,510 patients with a diagnosis of PV from 227 sites in the United States over a 24-month period (July 22, 2014 to August 3, 2016) followed by an observation period up to 3 years from the date of last patient enrollment. Eligibility criteria included age ≥18 years old and a clinical diagnosis of PV. Patients were excluded if they had a life expectancy <6 months; diagnosis of myelofibrosis, acute myeloid leukemia or myelodysplastic syn- drome; underwent (or were planning to undergo) an allogeneic transplant; or were status post-splenectomy. Data pertaining to PV-directed treatment, concomitant medications, adverse events, laboratory values and other relevant clinical measures were col- lected for at least 6 months before enrollment and during the fol- low-up period. The study was conducted in accordance with the Declaration of Helsinki. Approval of all study materials was obtained by a central Institutional Review Board (Sterling IRB, Atlanta, GA, USA) and local Institutional Review Boards of partic- ipating centers. All patients provided written informed consent.
Bleeding events
Hemorrhagic events occurring before enrollment were identi- fied from the patient’s medical history collected at the time of enrollment. Hemorrhagic events during the follow-up period were determined from prospectively collected adverse events. Post- enrollment events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 by treating physicians.9 Grade 3 or 4 hemorrhagic events were classi- fied as severe hemorrhages. Use of anticoagulant medications and aspirin was determined based on concomitant medications data collected at baseline and prospectively throughout the study. Medication start dates and end dates were used to determine whether patients were receiving an anticoagulant concomitantly with aspirin. Rivaroxaban, apixaban and dabigatran were com- bined into a direct-acting oral anticoagulants (DOAC) group.
Statistical analysis
In order to assess cumulative incidence rates and exposure- adjusted event rates, patients were assigned to groups based on their treatment at enrollment (aspirin or aspirin plus anticoagu- lant). If a patient changed their treatment group, then time was censored on the last day in the original treatment group. If a patient died or discontinued the study, time was censored at date of death or discontinuation, respectively. Time was censored at the last visit for patients who continued to be enrolled in the study without any events. The risk of hemorrhage associated with aspirin plus anticoagulant versus aspirin alone was assessed with a
Cox proportional hazards model adjusting for age, sex, duration of PV, history of hemorrhage and platelet count ranges. Platelet counts were included in the models as three-level categorical vari- ables: ≤100×109/L; >100×109/L and ≤600×109/L; >600×109/L based on the estimated thresholds for increased hemorrhage in the Primary Thrombocythemia study.10 For the time-dependent covariate analysis, linear interpolation was used to determine lab- oratory values at time points between observed values. Missing data were not imputed. Observed P-values were assessed at a=0.05 level for statistical significance. The P-values were not adjusted for multiple tests.
Results
Of the 2,510 enrolled patients, 1,602 patients with PV received aspirin and were included in the analysis (Table 1). The median time from PV diagnosis to enrollment was 4 years (range, 0-39.2 years). At the time of enrollment, 103 patients (6.4%) were receiving the combination of aspirin plus anticoagulant and 1,499 patients (93.6%) were receiv- ing aspirin alone. Median follow-up of patients from enroll- ment to the time of analysis was 2.4 years (range, 0-3.6 years).
Overall incidence of hemorrhage
Sixty-nine patients developed one or more hemorrhagic events after enrollment. The exposure-adjusted rate of all hemorrhages was 1.71 per 100 patient-years (95% confi- dence interval [CI]: 1.27-2.15), and the overall cumulative incidence of hemorrhage at 3 years was 4.70% (95% CI: 3.47-6.15). Among those with hemorrhage, the most com- mon sites were gastrointestinal (n=30, 43.5%), cutaneous (n=19, 27.5%), central nervous system (n=10, 14.5%) and genitourinary (n=7, 10.1%).
Severe hemorrhagic events occurred in 25 patients with an exposure-adjusted rate of 0.55 events per 100 patient- years (95% CI: 0.30-0.80). The most common sites of severe hemorrhage were gastrointestinal (n=11, 44%) and central nervous system (n=9, 36%). Of those with severe hemorrhagic events, there were five fatal events with all but one involving a central nervous system bleed.
Risk of hemorrhage associated with aspirin alone or with anticoagulants
Aspirin alone was associated with 1.4 hemorrhagic events per 100 patient-years (95% CI: 0.99-1.82), whereas the combination of aspirin with anticoagulation was asso- ciated with 6.75 hemorrhagic events per 100 patient-years (95% CI: 3.04-10.46). The cumulative incidence of hemor- rhage at 3 years in patients receiving aspirin alone was 3.6% (95% CI: 2.64-4.84) and 19.8% (95% CI: 9.78-32.45) for those receiving aspirin with an anticoagulant as shown in Figure 1A. The rate of severe hemorrhage was relatively higher among those who received aspirin with an anticoag- ulant (1.46 events per 100 patient-years; 95% CI: 0-3.21) compared with those who received aspirin alone (0.49 events per 100 patient-years; 95% CI: 0.25-0.74). The cumulative incidence rate of severe hemorrhage at 3 years was 3.7% (95% CI: 0.96-9.50) for patients who had aspirin with an anticoagulant and 1.2% (95% CI: 0.74-2.00) for patients who had aspirin alone (Figure 1B).
In a Cox proportional hazards model, the use of aspirin plus anticoagulant was associated with a greater than 5-fold increased risk of hemorrhage compared with aspirin alone
Table 1. Baseline characteristics. Characteristic
Median (range) age, years
Women, n (%)
Median (range) disease duration, years
History of hypertension, n (%)
History of hemorrhagic events, n (%)
History of thrombotic events, n (%) Arterial
Venous
N=1,602
67 (22-95)
734 (45.8) 4.0 (0.0-39.2) 916 (57.2) 103 (6.4)
300 (18.7) 157 (9.8) 164 (10.2)
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