Long-Term Antithrombotic Treatments Prescribed for Cardiovascular Diseases in Patients with Hemophilia: Results from the French Registry

Abstract

Cardiovascular diseases (CVDs) are a major issue in aging patients with hemophilia (PWHs). Antithrombotic agents are widely used in the general population for CVD treatment, but this recommendation is not fully applicable to PWHs. To improve treatment strategies, a prospective case–control study (COCHE) that analyzed CVD management and follow-up (2 years/patient) in PWHs was performed in France from 2011 to 2018. In total, 68 PWHs (median age: 65 years [39–89]; 48 mild, 10 moderate, and 10 severe hemophilia) were included (n = 50 with acute coronary syndrome, n = 17 with atrial fibrillation, n = 1 with both). They were matched with 68 control PWHs without antithrombotic treatment. In our series, bleeding was significantly influenced by (1) hemophilia severity, with a mean annualized bleeding ratio significantly higher in COCHE patients than in controls with basal clotting factor level up to 20%, (2) antihemorrhagic regimen (on-demand vs. prophylaxis) in severe (hazard ratio [HR] = 16.69 [95% confidence interval, CI: 8.2–47.26]; p < 0.0001) and moderate hemophilia (HR = 42.43 [95% CI: 1.86–966.1]; p = 0.0028), (3) type of antithrombotic treatment in mild hemophilia, with a significantly higher risk of bleeding in COCHE patients than in controls for dual-pathway therapy (HR = 15.64 [95% CI: 1.57–115.8]; p = 0.019), anticoagulant drugs alone (HR = 9.91 [95% CI: 1.34–73.47]; p = 0.0248), dual antiplatelet therapy (HR = 5.31 [95% CI: 1.23–22.92]; p = 0.0252), and single antiplatelet therapy (HR = 3.76 [95% CI: 1.13–12.55]; p = 0.0313); and (4) HAS-BLED score ≥3 (odds ratio [OR] = 33 [95% CI: 1.43–761.2]; p = 0.0065). Gastrointestinal bleeding was also significantly higher in COCHE patients than in controls (OR = 15 [95% CI: 1.84–268]; p = 0.0141). The COCHE study confirmed that antithrombotic treatments in PWHs are associated with increased bleeding rates in function of hemophilia-specific factors and also of known factors in the general population.

Current Therapeutic Approach to Acute Myocardial Infarction in Patients with Congenital Hemophilia

“…DAPT doubled the incidence of bleeding events compared to SAPT. Important, the bleedings incidence was not influenced by the antithrombotic drug used, as aspirin and clopidogrel showed similar hemorrhagic risks when used in monotherapy [17]. During antiplatelet therapy, the highest bleeding incidence was noted in patients with severe hemophilia without concomitant prophylactic factor VIII/IX administration.…”

“…Before coagulation factor concentrates became available in the 1970s, the life expectancy of patients with hemophilia was no more than 30 years, with death caused by uncontrollable bleeding [17]. Therefore, atherosclerosis and its consequences had no clinical expression in those patients.…”

“…Therefore, atherosclerosis and its consequences had no clinical expression in those patients. Currently, due to the possibility of replacing the deficient coagulation factor (VIII or IX), life expectancy has increased significantly, approaching that of the general male population [1,2,17]. Age-related acute and chronic diseases not previously seen in this population emerged.…”

“…Infusion is preferred over bolus because acute thrombosis may occur due to a rapid increase in factor levels [16,56]. It was considered that within 24 h after PCI, trough levels should be around 50% [60], but recent data suggest that replacement coagulation factor therapy should aim for a peak level of at least 80% for 48 h after PCI [8,17,62,63,[80][81][82]. The amount of factor to be infused depends on the severity of the hemophilia.…”

“…To minimize the bleeding risk during DAPT, prophylactic administration of deficient coagulation factor and of proton pump inhibitors is indicated. A strong amount of evidence to support these indications is provided by the hemophilia French registry, a case-control study that prospectively collected data on the antithrombotic treatment received by hemophilic patients with coronary artery disease and/or atrial fibrillation (AF), including 20 ACS (3 STEMI, 16 NSTEMI, and 1 unstable angina) [17]. Bleeding events were more frequent in patients on antiplatelet drugs than in controls and in patients on DAPT than on single antiplatelet therapy (SAPT).…”