Page 100 - Haematologica May 2022

J.I. Zwicker et al.
(Table 2; hazard ratio [HR]: 5.83; 95% CI: 3.36-10.11; P<0.001). The risk of severe hemorrhage was significantly increased with the combination of aspirin plus anticoagu- lant compared with aspirin alone (HR: 7.49; 95% CI: 3.02- 18.62; P<0.001).
Influence of platelet count on rates of hemorrhage
In a time-dependent exposure Cox proportional hazards model, thrombocytosis was associated with an increased risk of total and severe hemorrhages. The cumulative expo- sure time for platelet count elevation (≥600×109/L) was 305.5 patient-years, controlled platelet count (100- 600×109/L) was 2,443.7 patient-years and thrombocytope- nia (below 100×109/L) was 21.7 patient-years. As shown in Table 2, thrombocytopenia (platelet count <100×109/L) was not statistically associated with an increased risk of hemor- rhage (HR: 1.72; 95% CI: 0.23-12.71; P=0.60) or severe hemorrhage (HR: 5.15; 95% CI: 0.65-40.75; P=0.12) when compared with periods when platelet count was between 100×109/L and 600×109/L. Thrombocytosis was associated with an increased risk of any hemorrhage (HR: 2.25; 95% CI: 1.16-4.38; P=0.02) but not severe hemorrhage (HR: 1.03; 95% CI, 0.24-4.52; P=0.97). Periods of modest thrombocy- tosis (i.e., platelet counts between 400x109/L to 600x109/L) were not associated with increased risk of hemorrhage compared to periods of platelet counts below 400x109/L (HR: 1.10; 95% CI: 0.59-2.05).
Comparison of aspirin with direct-acting oral anticoag- ulant or warfarin
Of the patients who received an anticoagulant, 73 received warfarin and 72 received a direct-acting oral anti- coagulant (DOAC). The DOAC group included rivaroxa- ban (n=50), apixaban (n=31) and dabigatran (n=6). In a time-dependent exposure model, the risk of severe hemor- rhage was significantly greater with warfarin with aspirin compared with aspirin alone (Table 2). The risk of severe hemorrhage was not statistically different with the use of aspirin plus DOACs versus aspirin plus warfarin.
Incidence of thrombosis
At the time of enrollment, 300 patients (18.7%) had a his- tory of thrombosis with 157 arterial events and 164 venous thromboembolic events. During the follow-up period, 61 patients experienced a thrombotic event. A numerically high- er proportion of patients receiving anticoagulant plus aspirin experienced a thrombotic event compared with those who were on aspirin alone (Figure 2). The 3-year cumulative inci- dence of thrombosis (arterial or venous) was 4.8% (95% CI: 3.57-6.20). In a Cox proportional hazards model with treat- ment as a two-level, time-dependent covariate (adjusting for age, sex, disease duration, history of thrombosis before enrollment), the use of aspirin with an anticoagulant was not associated with a lower rate of thrombosis compared with aspirin alone (HR: 1.97; 95% CI: 0.57-6.78; P=0.28).
AB
Figure 1. Cumulative incidence of hemorrhage in patients with polycythemia vera receiving aspirin with or without anticoagulants. The cumulative incidence of (A) any hemorrhage or (B) severe hemorrhage shown for patients receiving aspirin plus anticoagulant (blue) and aspirin alone (green).
Table 2. Cox proportional hazard ratios for risk factors contributing to hemorrhage in polycythemia vera.
Variable
Models 1 and 2* AC + ASA
Models 3 and 4*
Warfarin + ASA
DOAC + ASA
Other anticoagulants + ASA
Models 5 and 6* Platelet ≤100×109/L Platelet >600×109/L
All hemorrhages HR (95% CI)
5.83 (3.36-10.11)
4.44 (2.06-9.54) 3.97 (1.65-9.60) 9.26 (4.13-20.75)
1.72 (0.23-12.71) 2.25 (1.16-4.38)
P-value <0.001
<0.001 0.002 <0.0001
0.60
0.02
Severe hemorrhage HR (95% CI)
7.49 (3.02-18.62)
5.48 (1.81-16.61) 2.23 (0.50-9.96) 3.79 (0.86-16.68)
5.15 (0.65-40.75) 1.03 (0.24-4.52)
P-value <0.001
0.003
0.29 0.078
0.12
0.97
AC: anticoagulant; ASA: aspirin; CI: confidence interval; DOAC: direct-acting oral anticoagulant; HR: hazard ratio. *Models for all hemorrhage and severe hemorrhage were run separately, adjusting for variables of age, sex, disease duration and history of bleeding. Models 1 and 2: HR compared with aspirin alone. Models 3 and 4: all HR compared with aspirin alone. Models 5 and 6: HR compared with normal platelet range (100-600×109/L).
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