Apixaban in Patients With Sickle Cell Disease

There is not only significant morbidity associated with patients with SCD, but also costs
associated with the numerous hospitalizations. Small studies have been unable to show clear
benefit of the use of low dose anticoagulation in SCD due to limited sample size or the
inclusion of very specific populations. However, studies have shown a decrease in the level
of elevated prothrombotic markers with anticoagulation, and one study using full dose
anticoagulation in patients with a generally milder form of SCD (with high protective
hemoglobin) showed more rapid decrease in clinical pain with use of anticoagulation,
suggesting a possible benefit of such therapy. Due to the paucity of data to support
therapeutic dose LMWH in the more severe forms of SCD seen in the United States, we have
chosen prophylactic dose anticoagulation. This study proposal attempts to critically avoid
admissions by reducing daily pain scores and pain crisis as an outpatient by use of a novel
oral anticoagulant.

The development of novel anticoagulants such as oral direct factor Xa (FXa) inhibitors allows
the realistic use of daily prophylactic dosing as an outpatient. Past studies as detailed
earlier have been limited by attempts to use subcutaneous injections or frequent, close
monitoring for acenocoumarol treatment, both which are not ideal for chronic daily use.
Furthermore, the use of global assays such calibrated automated thrombography (CAT) have
shown further details about thrombin generation in a population which is hypercoagulable at
baseline.

This is a double blind, parallel group, placebo controlled feasibility study with an
enrollment target of 25 patients (12 per arm). All subjects that meet inclusion criteria as
an outpatient, following a 1 month observation, will be randomized to receive an oral
prophylactic dose factor Xa inhibitor (Apixaban 2.5mg po bid) or placebo for 6 months.
Subjects will return for a 30 day (+/- 5 days) follow-up visit after the End of Treatment
(EOT) visit. Initial randomization will occur by computerized randomization technique by the
investigational drug services (IDS) at Duke University Medical Center.

Inclusion Criteria:

- documented HgbSS, SC or HgbS-beta0 thalassemia,

- age ≥18 years old and ≤80,

- seen in outpatient clinic ≥2 times in past year

- seen for an acute care visit (hospitalization, emergency department, or day hospital
visit) for pain >2 times in the past year.

Exclusion Criteria:

- Hospitalization or day hospital visit for pain crisis within the past 2 weeks

- Patients with ≥10 acute care visits within the past year will be excluded

- Creatinine >3.0 mg/dL

- creatinine ≥1.5 mg/dL AND weight ≤60 kg

- chronic use of antiplatelet or anticoagulation medication

- Patients with known vasculopathy or Moya-Moya

- platelet count <100 X 109/L

- AST or ALT >3 times normal

- chronic red blood cell transfusions (scheduled transfusions)

- packed red blood cell transfusion within the past 2 months

- Use of CYP3A4 and P-gp inhibitor medications