The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease

doi:10.1136/bmj.a1840

Published 16 October 2008, doi:10.1136/bmj.a1840
Cite this as: BMJ 2008;337:a1840

Research

The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease

Jill Belch, professor of vascular medicine¹, Angus MacCuish, consultant diabetologist², Iain Campbell, professor of diabetic medicine³, Stuart Cobbe, Walton professor of cardiology⁴, Roy Taylor, professor of medicine and metabolism⁵, Robin Prescott, professor of health technology assessment⁸, Robert Lee, research associate⁸, Jean Bancroft, senior research nurse¹, Shirley MacEwan, honorary senior research fellow¹, James Shepherd, professor of pathological biochemistry⁶, Peter Macfarlane, professor of electrocardiology⁷, Andrew Morris, professor of diabetic medicine⁹, Roland Jung, consultant physician (endocrine and diabetes) and honorary professor of medicine¹⁰, Christopher Kelly, consultant diabetologist¹¹, Alan Connacher, consultant diabetologist and endocrinologist¹², Norman Peden, consultant diabetologist¹³, Andrew Jamieson, consultant physician¹⁴, David Matthews, consultant physician¹⁵, Graeme Leese, consultant endocrinologist, John McKnight, consultant physician and honorary senior lecturer¹⁶, Iain O’Brien, consultant diabetologist¹⁷, Colin Semple, consultant physician¹⁸, John Petrie, reader in diabetes⁹, Derek Gordon, consultant physician¹⁹, Stuart Pringle, professor of cardiology²⁰, Ron MacWalter, consultant stroke physician¹, Prevention of Progression of Arterial Disease and Diabetes Study Group, Diabetes Registry Group, and Royal College of Physicians Edinburgh

¹ Institute of Cardiovascular Research, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, ² Diabetes Centre, Glasgow Royal Infirmary, ³ Department of Medicine, Royal Victoria Hospital, Kirkcaldy, ⁴ British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, ⁵ Royal Victoria Infirmary, Newcastle upon Tyne, ⁶ Department of Biochemistry, Glasgow Royal Infirmary, ⁷ Department of Medical Cardiology, Glasgow Royal Infirmary, ⁸ Medical Statistics Unit, University of Edinburgh, ⁹ Diabetes Research Centre, Ninewells Hospital, ¹⁰ Diabetes and Endocrinology, Ninewells Hospital, ¹¹ Diabetes Centre, Stirling Royal Infirmary, ¹² Diabetes Centre, Perth Royal Infirmary, ¹³ Diabetes Centre, Falkirk and District Royal Infirmary, Falkirk, ¹⁴ Diabetes Centre, Queen Margaret Hospital, Dunfermline, ¹⁵ Diabetes Centre, Monklands Hospital, Airdrie, ¹⁶ Metabolic Unit, Western General Hospital, Edinburgh, ¹⁷ Wishaw General Hospital, Wishaw, ¹⁸ Southern General Hospital NHS Trust, Glasgow, ¹⁹ Medical Unit B, Stobhill NHS Trust, Glasgow, ²⁰ Cardiology Department, Ninewells Hospital

Correspondence to: J Belch J.J.F.Belch{at}dundee.ac.uk

Objective To determine whether aspirin and antioxidant therapy,combined or alone, are more effective than placebo in reducingthe development of cardiovascular events in patients with diabetesmellitus and asymptomatic peripheral arterial disease.

Design Multicentre, randomised, double blind, 2x2 factorial,placebo controlled trial.

Setting 16 hospital centres in Scotland, supported by 188 primarycare groups.

Participants 1276 adults aged 40 or more with type 1 or type2 diabetes and an ankle brachial pressure index of 0.99 or lessbut no symptomatic cardiovascular disease.

Interventions Daily, 100 mg aspirin tablet plus antioxidantcapsule (n=320), aspirin tablet plus placebo capsule (n=318),placebo tablet plus antioxidant capsule (n=320), or placebotablet plus placebo capsule (n=318).

Main outcome measures Two hierarchical composite primary endpoints of death from coronary heart disease or stroke, non-fatalmyocardial infarction or stroke, or amputation above the anklefor critical limb ischaemia; and death from coronary heart diseaseor stroke.

Results No evidence was found of any interaction between aspirinand antioxidant. Overall, 116 of 638 primary events occurredin the aspirin groups compared with 117 of 638 in the no aspiringroups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval0.76 to 1.26). Forty three deaths from coronary heart diseaseor stroke occurred in the aspirin groups compared with 35 inthe no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). Amongthe antioxidant groups 117 of 640 (18.3%) primary events occurredcompared with 116 of 636 (18.2%) in the no antioxidant groups(1.03, 0.79 to 1.33). Forty two (6.6%) deaths from coronaryheart disease or stroke occurred in the antioxidant groups comparedwith 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89).

Conclusion This trial does not provide evidence to support theuse of aspirin or antioxidants in primary prevention of cardiovascularevents and mortality in the population with diabetes studied.

Trial registration Current Controlled Trials ISRCTN53295293 [controlled-trials.com] .

Add to CiteULike CiteULike Add to Complore Complore Add to Connotea Connotea Add to Del.icio.us Del.icio.us Add to Digg Digg Add to Reddit Reddit Add to StumbleUpon StumbleUpon Add to Technorati Technorati What's this?

Find additional patient-related information at:

: http://www.diabetes.org/

Relevant Articles

Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials: Giorgia De Berardis, Michele Sacco, Giovanni F M Strippoli, Fabio Pellegrini, Giusi Graziano, Gianni Tognoni, and Antonio Nicolucci
BMJ 2009 339: b4531. [Abstract] [Full Text] [PDF]

Don’t stop taking aspirin: Peter Elwood
BMJ 2008 337: a2581. [Extract] [Full Text]

Time for a proper study of aspirin after a vascular event?: John G F Cleland
BMJ 2008 337: a2583. [Extract] [Full Text]

Aspirin for prevention of cardiovascular events: William R Hiatt
BMJ 2008 337: a1806. [Extract] [Full Text]

Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients: Antithrombotic Trialists' Collaboration
BMJ 2002 324: 71-86. [Abstract] [Full Text] [PDF]

Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis: Sheena Derry and Yoon Kong Loke
BMJ 2000 321: 1183-1187. [Abstract] [Full Text] [PDF]

ABC of arterial and vascular disease: Secondary prevention of peripheral vascular disease: Sean Tierney, Fiona Fennessy, and David Bouchier Hayes
BMJ 2000 320: 1262-1265. [Extract] [Full Text] [PDF]

Association of upper gastrointestinal toxicity of non-steroidal anti-inflammatory drugs with continued exposure: cohort study: T M MacDonald, S V Morant, G C Robinson, M J Shield, M M McGilchrist, F E Murray, and D G McDevitt
BMJ 1997 315: 1333-1337. [Abstract] [Full Text]

This article has been cited by other articles:

De Berardis, G., Sacco, M., Strippoli, G. F M, Pellegrini, F., Graziano, G., Tognoni, G., Nicolucci, A. (2009). Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 339: b4531-b4531 [Abstract] [Full text]
(2009). Aspirin for primary prevention of cardiovascular disease?. DTB 47: 122-125 [Abstract] [Full text]
Berger, J. S., Krantz, M. J., Kittelson, J. M., Hiatt, W. R. (2009). Aspirin for the Prevention of Cardiovascular Events in Patients With Peripheral Artery Disease: A Meta-analysis of Randomized Trials. JAMA 301: 1909-1919 [Abstract] [Full text]
Tousoulis, D., Briasoulis, A., Dhamrait, S. S, Antoniades, C., Stefanadis, C. (2009). Effective platelet inhibition by aspirin and clopidogrel: where are we now?. Heart 95: 850-858 [Full text]
Tavintharan, S., Ning Cheung, , Su Chi Lim, , Tay, W., Shankar, A., Shyong Tai, E., Wong, T. Y. (2009). Prevalence and risk factors for peripheral artery disease in an Asian population with diabetes mellitus. Diabetes and Vascular Disease Research 6: 80-86 [Abstract]
Angiolillo, D. J. (2009). Antiplatelet Therapy in Diabetes: Efficacy and Limitations of Current Treatment Strategies and Future Directions. Diabetes Care 32: 531-540 [Full text]
O'Connor, P. J., Sperl-Hillen, J. M. (2009). The Role of Diabetes Educators in the Medical Home. Diabetes Spectr. 22: 124-126 [Full text]
Elasy, T. A. (2009). Diabetes Quality Improvement: Rigor and Ridicule. Clin. Diabetes 27: 49-51 [Full text]
Tay, K. H., Lane, D. A., Lip, G. Y. H. (2009). Challenges facing anticoagulation among the elderly and frail. Age Ageing 38: 140-142 [Full text]
Miller, E. R III, Guallar, E. (2009). Vitamin E supplementation: what's the harm in that?. Clin Trials 6: 47-49
Elwood, P. (2008). Don't stop taking aspirin. BMJ 337: a2581-a2581 [Full text]
Cleland, J. G F (2008). Time for a proper study of aspirin after a vascular event?. BMJ 337: a2583-a2583 [Full text]
(2008). Aspirin or Antioxidants for Primary Prevention? Not so Fast!. Journal Watch Cardiology 2008: 3-3 [Full text]
(2008). No Benefit for Aspirin in Diabetic Patients Without Symptomatic CVD. JWatch General 2008: 2-2 [Full text]
Nicolucci, A. (2008). Aspirin for Primary Prevention of Cardiovascular Events in Diabetes: Still an Open Question. JAMA 300: 2180-2181 [Full text]

Rapid Responses:

Read all Rapid Responses

Aspirin ineffective in diabetic patients with PAD: it is not a novelty!: Massimo Milani MD
bmj.com, 18 Oct 2008 [Full text]
Will you trust guidelines again ?: Paul Heath
bmj.com, 19 Oct 2008 [Full text]
Re: Aspirin ineffective in diabetic patients with PAD: it is not a novelty!: Jill JF Belch
bmj.com, 20 Oct 2008 [Full text]
The POPADAD study: Peter Elwood
bmj.com, 21 Oct 2008 [Full text]
POPADAD Trial only shows that Aspirin can be given in too low a dose: Michael A JAMES
bmj.com, 22 Oct 2008 [Full text]
Re: The POPADAD study: Jill JF Belch
bmj.com, 24 Oct 2008 [Full text]
Aspirin for Priamary Prevention in Diabetes: Richard L. Kennedy, et al.
bmj.com, 26 Oct 2008 [Full text]
Practising evidence-based medicine: people with or at risk of atherosclerotic disease should not receive long-term aspirin.: John GF Cleland
bmj.com, 28 Oct 2008 [Full text]
Time of Taking Aspirin Can Have an Effect on the Frequency of Occurrence of Cardiovascular Events: Balint Vas, et al.
bmj.com, 5 Nov 2008 [Full text]
Why is the dose of aspirin 100mg?: Margaret Warlow
bmj.com, 6 Nov 2008 [Full text]
Diabetes, blood viscosity and the POPADAD trial: Leslie O Simpson
bmj.com, 8 Nov 2008 [Full text]
Re: Why is the dose of aspirin 100mg?: Jill J Belch
bmj.com, 11 Nov 2008 [Full text]
Re: Diabetes, blood viscosity and the POPADAD trial: Jill J Belch
bmj.com, 11 Nov 2008 [Full text]
Re: Re: Diabetes, blood viscosity and the POPADAD trial: Les O. Simpson
bmj.com, 13 Nov 2008 [Full text]
Time of taking aspirin, blood pressure and cardiovascular events: Martin S Knapp
bmj.com, 13 Nov 2008 [Full text]
Antiplatelet drugs for the prevention of cardiovascular events in patients with peripheral arterial disease � the confusion reaches new levels with the POPADAD trial: Eric Wahlberg
bmj.com, 24 Nov 2008 [Full text]