Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome

Abstract

Antiphospholipid antibody syndrome (APS) is an acquired thrombophilic disorder in which vascular thrombosis (venous or arterial) and pregnancy losses may occur in the presence of persistent antiphospholipid antibodies (aPLs) (14). Although different pathogenic mechanisms have been described, long-term anticoagulation with vitamin K antagonists (VKAs), rather than immunosuppression, remains the standard treatment for secondary prevention of thrombosis. Despite the use of dose-adjusted warfarin, the annual risk for recurrent thrombosis ranges from 2% to 5% (59), with half the cases occurring when the international normalized ratio (INR) is below the predetermined target range (5). In recent years, anticoagulation management has been a matter of debate, with arguments for and against high-intensity anticoagulation (INR, 3.1 to 4.0). Two randomized controlled trials demonstrated that standard-intensity anticoagulation (INR, 2.0 to 3.0) was noninferior to high-intensity treatment (5, 6). Maintaining optimized anticoagulation to prevent recurrent thrombosis and bleeding remains a therapeutic challenge. Rivaroxaban is an orally active, direct factor Xa inhibitor that provides more consistent and predictable anticoagulation than warfarin. Currently, it is licensed for the treatment and secondary prevention of venous thromboembolism (10) and stroke prevention in patients with nonvalvular atrial fibrillation (11). So far, several case reports, case series, cross-sectional studies, and randomized controlled trials have provided conflicting data on the efficacy of rivaroxaban in APS (1219). Two randomized controlled trials comparing rivaroxaban with warfarin suggested that rivaroxaban may be efficacious in patients with previous venous thromboembolism who are receiving standard-intensity anticoagulation (INR, 2.0 to 3.0) (20) but showed an increased thrombotic risk in those with triple-positive aPLs (21). Results from these studies must be interpreted with caution in view of their limitations, which include the use of a laboratory surrogate marker as a primary outcome and premature termination due to an excess of study events (20, 21). Thus, we conducted a randomized controlled comparative effectiveness trial to test whether rivaroxaban is noninferior to dose-adjusted VKAs for preventing thrombotic events in patients with APS. Methods Design Overview This multicenter, randomized, open-label, phase 3 noninferiority clinical trial was conducted at 6 university hospitals in Spain. The study recruited patients from March 2013 to December 2014. Follow-up was completed in December 2017. Vall d Hebron Hospital (VHH) coordinated the trial, managed the database, and performed the primary analyses independently. The original research protocol and a summary of protocol changes are in Supplement 1. The local ethics committees approved the study, and all participants provided written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice principles. The full list of study investigators is shown in Supplement 2, Appendix 1. Supplement. Study Protocol (Supplement 1) and Supplemental Appendices (Supplement 2) Setting and Participants Adult patients fulfilling the international consensus criteria for APS (3) were recruited from internal medicine and rheumatology clinics. Eligible patients included those with objectively confirmed arterial or venous thrombosis and a positive result on aPL testing on 2 occasions at least 3 months apart. Testing for aPL was performed locally and confirmed by the central laboratory (VHH). Acceptable candidates included those with lupus anticoagulant or moderate to high titers (40 GPL [IgG phospholipid] units) of IgG anticardiolipin, anti2-glycoprotein I antibodies, or both, measured in accordance with international guidelines (3, 22). Patients with only IgM subtypes were not eligible. All patients with systemic lupus erythematosus were classified according to the revised criteria of the American College of Rheumatology (23). Patients were excluded if they had clinically significant bleeding diathesis (such as refractory thrombocytopenia with a platelet count 50109 cells/L); had intracranial hemorrhage, stroke, or gastrointestinal bleeding within the previous 3 months; were pregnant or lactating; had severe renal impairment (creatinine clearance, calculated with the CockcroftGault formula, 30 mL/min/1.73 m2 [24]); had an alanine aminotransferase level more than twice the upper limit of normal; had ChildPugh class B or C cirrhosis; were nonadherent to their warfarin regimen; or were receiving cytochrome P450 3A4 inducers. Complete eligibility criteria are shown in Supplement 2, Appendix 2. Randomization and Interventions The randomized list, stratified by center and presence of systemic lupus erythematosus, was created at VHH by using computer-generated random-number sequences (C4-Study design pack software [GlaxoSmithKline]) in blocks of 10. Sequentially numbered, concealed envelopes containing group assignments were provided to the investigators. After written informed consent was obtained, the envelopes were opened in sequence and patients were randomly assigned in a 1:1 ratio to receive rivaroxaban (20 mg/d, or 15 mg/d for patients with a creatinine clearance of 30 to 49 mL/min/1.73 m2) (24) or to continue receiving the adjusted dosage of VKAs (target INR, 2.0 to 3.0, or 3.1 to 4.0 for those with a history of recurrent thrombosis). The trial was open label to ensure optimum VKA dosing and monitoring, and because bleeding management differs between VKAs and rivaroxaban. The transition from VKAs to rivaroxaban involved an intermediate step to therapeutic low-molecular-weight heparin. In brief, VKA therapy was discontinued; then, heparin administration (1 mg/kg per 12 hours) began when the INR was 2 or less, and it was continued for 48 hours. Finally, rivaroxaban treatment was started (Supplement 2, Appendix 3. During the study, the rivaroxaban dosage could be modified in relation to changes in creatinine clearance (24). Adherence in the rivaroxaban group was evaluated by self-reported questionnaire and residual pill count at each visit. Patients exiting the study were not considered in the adherence calculation. The use of additional aspirin, antimalarial drugs, or immunosuppressive agents was allowed at the investigator s discretion (Supplement 2, Appendix 3). Outcomes and Follow-up The primary efficacy end point was the proportion of patients who had a new thrombotic event during the study, confirmed by adjudication. Diagnosis of venous and arterial thrombosis was based on objective imaging techniques. The primary safety end point was the proportion of patients with a major bleeding episode. Secondary efficacy end points included time to thrombosis, type of thrombotic event, cardiovascular death, and changes in levels of selected biomarkers (D-dimer, von Willebrand factor, and platelet factor 4) (2527). Secondary safety end points included any adverse event and nonmajor bleeding. An independent committee blinded to the clinical end points applied protocol definitions to adjudicate suspected cases of thrombosis, death, and bleeding events that contributed to the prespecified end points (see outcome definitions in Supplement 2, Appendix 4. Patients were evaluated monthly for the first 3 months and every 3 months thereafter. Follow-up was 36 months, regardless of events. The study treatment could be discontinued early because of unacceptable serious adverse or thrombotic events, any change in the patient s condition that justified discontinuation, consent withdrawal, pregnancy, or lack of adherence to the protocol. In the VKA group, doses were monitored and INR was measured at local hematologic clinics. International normalized ratio was checked every 2 to 6 weeks as necessary, but every 4 weeks on average. Unscheduled INR measurements during a thrombotic episode were obtained from the patient s clinical record. If the INR was not measured on the day of the episode, the reported INR was the value at the last scheduled visit before diagnosis of the episode. Patients were instructed to go to the local emergency department if they had recurrent thrombosis or major bleeding. Results of any objective diagnostic tests were forwarded to VHH. Temporary drug withdrawal due to bleeding, surgery, or invasive procedures was carried out according to established protocols. Reasons for premature discontinuation of treatment were recorded. The following laboratory tests were performed at each visit: complete blood count; renal and liver function tests; standard coagulation tests; urinalysis; 24-hour protein collection; and tests for antidouble-stranded DNA antibodies, antinuclear antibodies, complement levels, lupus anticoagulant, IgG and IgM anticardiolipin, and anti2-glycoprotein I antibodies. Additional samples were obtained at baseline and every 6 months for further measurement of thrombotic risk biomarkers (D-dimer, von Willebrand factor, and platelet factor 4). At randomization, Global Anti-Phospholipid Syndrome Score (28) also was assessed (see Supplement 2, Appendix 5 for study measures). Reports of serious adverse events and serious adverse reactions were reviewed by external, independent, medically qualified staff and classified according to MedDRA (Medical Dictionary for Regulatory Activities), version 12 (available at www.meddra.org). Statistical Analysis The study was designed and powered to determine whether rivaroxaban was noninferior to VKAs by 36 weeks for the primary efficacy outcome. No clinical trials comparing rivaroxaban and warfarin in APS were available when the study was designed. Thus, to define the noninferiority margin, we considered meta-analysis data comparing warfarin with placebo with regard to stroke incidence in patients with atrial fibrillation (29), in whom the relative risk for stroke reduction was estimated as