title: Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol.
abstract: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12-15% of patients with SSc and accounts for 30-40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc-PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH.
  
  
  
  This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken.
  
  
  
  Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.
  
  
  
  ACTRN12614000418673, Pre-results.
authors.affiliation: Department of Rheumatology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
authors.forename: Alicia
authors.initials: A
authors.lastname: Calderone
authors.affiliation: Department of Rheumatology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
authors.forename: Wendy
authors.initials: W
authors.lastname: Stevens
authors.affiliation: Department of Cardiology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.|The University of Melbourne Department of Medicine at St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Prior
authors.affiliation: The University of Melbourne Department of Medicine at St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.|Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
authors.forename: Harshal
authors.initials: H
authors.lastname: Nandurkar
authors.affiliation: The University of Notre Dame, Fremantle, Western Australia, Australia.|Institute for Respiratory Health, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
authors.forename: Eli
authors.initials: E
authors.lastname: Gabbay
authors.affiliation: Department of Rheumatology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia.|University of Adelaide Discipline of Medicine at Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia.
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Proudman
authors.affiliation: Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Monash University, Prahran, Victoria, Australia.
authors.forename: Trevor
authors.initials: T
authors.lastname: Williams
authors.affiliation: Department of Cardiology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Celermajer
authors.affiliation: Department of Rheumatology, Monash Health and Monash University, Clayton, Victoria, Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Sahhar
authors.affiliation: Mid-North Coast Arthritis Clinic, Coffs Harbour, New South Wales, Australia.|Faculty of Medicine, Rural Clinical School, University of New South Wales, Coffs Harbour, New South Wales, Australia.
authors.forename: Peter K K
authors.initials: PK
authors.lastname: Wong
authors.affiliation: Department of Rheumatology, Liverpool Hospital, Liverpool, New South Wales, Australia.|School of Medicine, University of Western Sydney, Penrith, New South Wales, Australia.
authors.forename: Vivek
authors.initials: V
authors.lastname: Thakkar
authors.affiliation: Department of Cardiology, Royal Hobart Hospital, Hobart, Tasmania, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Dwyer
authors.affiliation: Advanced Lung Disease Unit, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wrobel
authors.affiliation: Institute for Respiratory Health, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
authors.forename: Weng
authors.initials: W
authors.lastname: Chin
authors.affiliation: Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, The Alfred Centre, Melbourne, Victoria, Australia.
authors.forename: Danny
authors.initials: D
authors.lastname: Liew
authors.affiliation: Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, The Alfred Centre, Melbourne, Victoria, Australia.|Monash Department of Clinical Epidemiology, Cabrini Institute, Cabrini Health, Suite 41 Cabrini Medical Centre, Malvern, Victoria, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Staples
authors.affiliation: Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, The Alfred Centre, Melbourne, Victoria, Australia.|Monash Department of Clinical Epidemiology, Cabrini Institute, Cabrini Health, Suite 41 Cabrini Medical Centre, Malvern, Victoria, Australia.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Buchbinder
authors.affiliation: Department of Rheumatology, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.|The University of Melbourne Department of Medicine at St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia.
authors.forename: Mandana
authors.initials: M
authors.lastname: Nikpour
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000925:Anticoagulants / Q000627:therapeutic use*; D001777:Blood Coagulation; D002985:Clinical Protocols; D003362:Cost-Benefit Analysis; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D011658:Pulmonary Fibrosis / Q000209:etiology; D011720:Pyrazoles / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D012107:Research Design; D012595:Scleroderma, Systemic / Q000150:complications*
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban
keywords: Apixaban; Pulmonary arterial hypertension; Randomised controlled trial; Systemic sclerosis