A Multicenter, Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Oral Anticoagulation in Systemic...

The SPHInX study is the first-ever randomized controlled trial (RCT) seeking to inform an area of equipoise regarding the efficacy of oral anticoagulation as adjunct therapy in systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). The SPHInX study was an Australian multicenter, double-blind Phase III RCT of 1:1 oral apixaban 2.5 mg twice daily versus placebo over 3 years, as additional therapy in patients with SSc-PAH. The primary end-point was time to clinical worsening (TtCW), or death. A sample size of 85 per arm was required to show a two-fold reduction in TtCW. Participants experiencing clinical worsening events continued in the study, allowing for assessment of exploratory endpoints (including physical function and quality of life measures) up until 3 years of treatment. Among 11 SSc-PAH participants assigned apixaban treatment and 14 participants assigned placebo, apixaban demonstrated no benefit compared to placebo for TtCW from commencement until 30 days after discontinuation of study drug, Cox proportional hazard ratio 0.92 (95% confidence interval 0.32-2.66), p = 0.88. There was no difference between treatment groups in event-free survival, all-cause mortality, or exploratory endpoints. New iron deficiency anemia occurred in 9 (81.8%) apixaban treated participants compared to 4 (28.6%) controls. Although strict selection criteria in a complex disease meant recruitment was insufficient for the primary efficacy endpoint, the SPHInX RCT showed no signal for benefit with anticoagulation as adjunct therapy, with a high frequency of iron deficiency anemia suggesting that even at low doses, risk may outweigh benefit with anticoagulation in SSc-PAH. Trial Registration: Australian New Zealand Clinical Trials Registry Registration Number: ACTRN12614000418673 (http://www.ANZCTR.org.au/ACTRN12614000418673.aspx).