Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med 2012;367: DOI: /NEJMoa

2 Low-dose aspirin for preventing recurrent venous thromboembolism after a first unprovoked event: the ASPIRE trial Appendix Management Committee... 2 Outcomes Adjudication Committee... 2 Safety and Data Monitoring Commitee... 2 In addition to the authors, the following investigators participated in the ASPIRE study and randomised at least 1 patient randomized (principal investigator and site coordinator)... 2 Coordinating Centre Teams... 3 Webfigure 1. Study profile... 4 Webfigure 2. Effect of aspirin compared with placebo on primary and secondary outcomes in unadjusted analysis and analysis adjusted for age, sex, smoking, BMI, type of prior event, and time on prior anticoagulation therapy... 5 Webfigure 3. The effect of aspirin on first recurrent symptomatic deep-vein thrombosis or pulmonary embolism within pre-specified subgroups Webfigure 4. Kaplan-Meier curves of compliance with study medication (shown as time to permanent discontinuation of study medication) and cumulative risk curve of commencing other antiplatelet therapy or anticoagulation therapy by randomised treatment group Webtable 1. Serious adverse events leading to hospitalization by randomised treatment group Webtable 2. Permanent discontinuation of study medication by reason and randomised treatment group... 9 Page 1 of 9

3 Management Committee Executive Committee Members - T Brighton (Co-PI), J Eikelboom (Co-PI), W Hague, A Kirby, R Mister, J Simes (study chairman) Other - A Gallus, P Ockelford, R Baker, H Gibbs, P Coughlin, D Xavier, R Diaz, G Agnelli Outcomes Adjudication Committee H Gibbs (chairman), T Karplus, J Fletcher, A van Rij (former member) Safety and Data Monitoring Commitee Anthony Rogers (chairman), C Hayward, Graham Young (former member) In addition to the authors, the following investigators participated in the ASPIRE study and randomised at least 1 patient randomized (principal investigator and site coordinator) Australia- Canberra Hospital, ACT - P Crispin, J Slade (20); Royal North Shore Hospital, Sydney, NSW - C Ward, N Tadayon (21); Westmead Hospital, Sydney, NSW - J Koutts, L Fisher (2); Prince of Wales Hospital, Sydney, NSW - T Brighton, K McCardie, (42); Concord Hospital, Sydney, NSW - A Bianchi, J Trinh (12); St Vincent s Hospital Sydney, NSW - J Joseph, P Plenge (6); St George Hospital, Sydney, NSW - B Chong, S Davidson (28); Coffs Harbour Hospital, NSW - J Waites, P Cahill (1); Gosford Hospital, NSW - C Tiley, M Lacey (54); Lismore Base Hospital, NSW - D Jackson, J Boys (13); Calvary Mater Hospital, Newcastle, NSW - M Seldon, M Gambrill (18); St Vincent s Hospital Melbourne, Victoria - H Nandurkar, H Worland (2); Alfred Hospital, Melbourne, Victoria - H Salem, C Gollogly (2); Geelong Hospital, Victoria - P Campbell, I Marshall (10); Ballarat Health, Victoria - K Hamilton, C Goss (1); Box Hill Hospital, Melbourne, Victoria -, H Salem, L Poulton (34); Frankston Hospital, Victoria - M Jackson, T de Man (2); Monash Medical Centre, Melbourne, Victoria - E Gan, A Cummins (29); Maroondah Hospital, Victoria - M Leyden, C Sturtz (6); Royal Brisbane and Women s Hospital, Queensland - P Kubler, X Sansome (12), Princess Alexandra Hospital, Brisbane, Queensland - A McCann, C Downey (31); Redcliffe Hospital, Brisbane, Queensland - P Carroll, M Duroux (15); Nambour General Hospital, Queensland - S Hamwood, G Styles (8); Gold Coast Hospital, Queensland - N Buckmaster, T Schmidt (2); Wesley Medical Centre, Queensland D Colquhoun, A Jardim (1); Flinders Medical Centre, Adelaide, South Australia - A Gallus, J Osmond (23); Lyell McEwin Hospital, Adelaide, South Australia - W Jeffries, B Trezona (4); Page 2 of 9

4 Queen Elizabeth Hospital, Adelaide, South Australia, S McRae, D King (16); Royal Perth Hospital, Western Australia - R Baker, K Courtley (26); Royal Hobart Hospital, Tasmania - R Kimber, L Oliver (10), Launceston General Hospital, Tasmania - A MacDonald, J Shepherd (3) New Zealand Auckland City Hospital - P Ockelford (NZ PI), M Hulton (69); Middlemore Hospital, Auckland - G Royle, L Haycock (38); North Shore Hospital, Auckland - D Simpson, K Yap (66); Palmerston North Hospital - B Baker, H McQuilkin (39); Wellington Hospital - J Carter, J Body (8) Singapore - Singapore General Hospital - L Lai Heng, M Tan (6); Tan Tock Seng Hospital - J Chin Tay, J Zou (9) Indian- St. John's Medical College, Bangalore - H Kumar Pandharpurkar, Remya.G (20); Christian Medical College Vellore, Tamil Nadu - E Stephen, A Benjamin (12); M.S. Ramaiah Medical College, Bangalore - S C Desai, R Singh (21); Bhagwan Mahaveer Jain, Bangalore - K R Suresh, Girija K R (4); Apollo Hospital, Chennai - S Natarajan, D Goel (14); Fortis Escorts Hospital, Rajasthan - R Gupta, B S Mishra (3); Sidhu Hospital Pvt.Ltd,Ludiana - G Sidhu, R Singh Sidhu (12); Sir Ganga Ram Hospital, New Delhi - R Parakh, R Sharma (12), Mahavir Hospital, Hyderabad, S Joshi, M Mahajan (1); Medanta The Medicity, New Delhi - T Grover, K Sharma (2); Ameya Clinic, Maharashtra - P Patel (17); Sahyadri Specialty Hospital, Maharashtra - A Kothurkar, P Ranade (6) Argentina - IIC Rosario, Rosario - J L Fedele, A C Cristófaro (1); CEDIC, Buenos Aires - E Gelersztein, M Gelersztein (4); Instituto de Investigaciones Clínicas Cipolletti Policlínico Modelo de Cipolletti, Rio Negro - A S Sánchez, L C Bowen (1), IIC San Nicolás, Buenos Aires - R O García Durán, F Cámpora (1); Consultorios Hematológicos SRL, Buenos Aires - H Héctor Ferro, M V Casais (2) Coordinating Centre Teams NHMRC Clinical Trials Centre, Sydney R Mister (project coordinator), A Kirby, K Mann (biostatisticians), C Van Holst Pellekaan, S Chinchen, A Lucas, W Hague, J Simes. Indian National Coordinating Office, St John s Medical College, Bangalore D Xavier, P Pais (PIs), A Sigamani, N Mathur, Anupama M, Deepthi KB. Argentine National Coordinating Office: ECLA, Rosario R Diaz (PI), C Chacon, R Rucci Page 3 of 9

5 Webfigure 1. Study profile Page 4 of 9

6 Analysis Unadjusted Placebo events (%pa) Aspirin events (%pa) Hazard ratio (95% CI) VTE 73 (6.5) 57 (4.8) 0.74 (0.52, 1.05) Major vascular events 88 (8.0) 62 (5.2) 0.66 (0.48, 0.92) Net clinical benefit 99 (9.0) 71 (6.0) 0.67 (0.49, 0.91) Clinically relevant bleeds 8 (0.6) 14 (1.1) 1.72 (0.72, 4.11) Cancer after randomisation 18 (1.5) 17 (1.3) 0.92 (0.47, 1.79) Adjusted VTE 73 (6.5) 57 (4.8) 0.72 (0.51, 1.01) Major vascular events 88 (8.0) 62 (5.2) 0.64 (0.46, 0.89) Net clinical benefit 99 (9.0) 71 (6.0) 0.64 (0.47, 0.87) Favors Aspirin Favors Placebo Webfigure 2. Effect of aspirin compared with placebo on primary and secondary outcomes in unadjusted analysis and analysis adjusted for age, sex, smoking, BMI, type of prior event, and time on prior anticoagulation therapy Page 5 of 9

7 Subgroup Gender Females Males 25 (4.5) 48 (8.6) 21 (3.7) 36 (5.8) Prior time on anticoagulation 0-6 months 6-9 months >=9 months Age 22 (7.6) 30 (5.0) 21 (8.8) 13 (3.6) 34 (6.0) 10 (3.8) <50 years years >=65 years BMI 16 (3.6) 29 (7.4) 28 (9.8) 16 (3.6) 15 (4.0) 26 (7.1) Normal Overweight Obese QE event 15 (5.0) 28 (6.5) 30 (7.8) 9 (3.2) 23 (5.3) 25 (5.4) DVT only PE +/- DVT 40 (6.8) 33 (6.2) 30 (4.6) 27 (5.1) Placebo events (%pa) Aspirin events (%pa) Hazard ratio (95% Overall Webfigure 3. The effect of aspirin on first recurrent symptomatic deep-vein thrombosis or pulmonary embolism within pre-specified subgroups. There was no evidence of heterogeneity of treatment effect within subgroups (each interaction p-value >0.6) Page 6 of 9

8 1 Drop outs: HR 0.79, 95% CI (0.62, 1.01), p= Aspirin Proportion Drop ins: HR 0.70, 95% CI (0.49, 1.00), p=0.05 Placebo 0.2 Placebo No. at risk: Drop out Placebo 411 Aspirin 411 No. at risk: Drop in Placebo Aspirin Years since randomization Aspirin Webfigure 4. Kaplan-Meier curves of compliance with study medication - shown as time to permanent discontinuation of study medication (drop out) and cumulative risk curve of commencing other antiplatelet therapy or anticoagulation therapy (drop in) by randomised treatment group. Page 7 of 9

9 Webtable 1. Serious adverse events leading to hospitalization by randomised treatment group. Number of patients (%)* with at least one hospitalization within each category. Reason for hospitalization Placebo Aspirin n=411 n=411 Other cardiovascular events (excluding primary/secondary study outcomes) 15 (3.6) 15 (3.6) Accident/Trauma 10 (2.4) 15 (3.6) Cancer 9 (2.2) 11 (2.7) Endocrine 4 (1.0) 3 (0.7) Gastrointestinal 15 (3.6) 22 (5.4) Genitourinary 9 (2.2) 10 (2.4) Musculoskeletal 19 (4.6) 13 (3.2) Neurological 7 (1.7) 4 (1.0) Respiratory 15 (3.6) 16 (3.9) Other 45 (10.9) 34 (8.3) Total patients hospitalized 117 (28.5) 102 (24.8) Page 8 of 9

10 Webtable 2. Permanent discontinuation of study medication by reason and randomised treatment group Reason for discontinuation Placebo Aspirin n=411 n=411 Clinical 61 (14.8) 49 (11.9) Indication for thromboprophylaxis 1 32 (7.8) 21 (5.1) Other hospitalisations 4 (1.0) 5 (1.2) Bleeding 2 0 (0) 6 (1.5) GI toxicity 2 (0.5) 8 (1.9) Other clinical reason 3 23 (5.6) 9 (2.2) Patient choice 67 (16.3) 65 (15.8) Other 4 (1.0) 3 (0.7) Total discontinuations 132 (32.1) 117 (28.5) 1 Stopped study medication AND commenced antiplatelet or anticoagulant therapy either following cardiovascular events (excluding primary / secondary outcomes) or for other clinical reason considered at increased risk for thrombotic / ischemic events (eg: thrombophlebitis, TIA, angina, pregnancy) 2 6 discontinuations were due to bleeding (1 major and 5 other clinically relevant), all of which were included in all analyses of bleeding including Table Other reasons included cancer, pregnancy, rash and possible allergy. Page 9 of 9