Intended for healthcare professionals


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

BMJ 2008; 337 doi: (Published 16 October 2008) Cite this as: BMJ 2008;337:a1840
  1. Jill Belch, professor of vascular medicine1,
  2. Angus MacCuish, consultant diabetologist2,
  3. Iain Campbell, professor of diabetic medicine3,
  4. Stuart Cobbe, Walton professor of cardiology4,
  5. Roy Taylor, professor of medicine and metabolism5,
  6. Robin Prescott, professor of health technology assessment8,
  7. Robert Lee, research associate8,
  8. Jean Bancroft, senior research nurse1,
  9. Shirley MacEwan, honorary senior research fellow1,
  10. James Shepherd, professor of pathological biochemistry6,
  11. Peter Macfarlane, professor of electrocardiology7,
  12. Andrew Morris, professor of diabetic medicine9,
  13. Roland Jung, consultant physician (endocrine and diabetes) and honorary professor of medicine10,
  14. Christopher Kelly, consultant diabetologist11,
  15. Alan Connacher, consultant diabetologist and endocrinologist12,
  16. Norman Peden, consultant diabetologist13,
  17. Andrew Jamieson, consultant physician14,
  18. David Matthews, consultant physician15,
  19. Graeme Leese, consultant endocrinologist,
  20. John McKnight, consultant physician and honorary senior lecturer16,
  21. Iain O’Brien, consultant diabetologist17,
  22. Colin Semple, consultant physician18,
  23. John Petrie, reader in diabetes9,
  24. Derek Gordon, consultant physician19,
  25. Stuart Pringle, professor of cardiology20,
  26. Ron MacWalter, consultant stroke physician1,
  27. Prevention of Progression of Arterial Disease and Diabetes Study Group, Diabetes Registry Group, and Royal College of Physicians Edinburgh
  1. 1Institute of Cardiovascular Research, University of Dundee, Ninewells Hospital, Dundee DD1 9SY
  2. 2Diabetes Centre, Glasgow Royal Infirmary
  3. 3Department of Medicine, Royal Victoria Hospital, Kirkcaldy
  4. 4British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow
  5. 5Royal Victoria Infirmary, Newcastle upon Tyne
  6. 6Department of Biochemistry, Glasgow Royal Infirmary
  7. 7Department of Medical Cardiology, Glasgow Royal Infirmary
  8. 8Medical Statistics Unit, University of Edinburgh
  9. 9Diabetes Research Centre, Ninewells Hospital
  10. 10Diabetes and Endocrinology, Ninewells Hospital
  11. 11Diabetes Centre, Stirling Royal Infirmary
  12. 12Diabetes Centre, Perth Royal Infirmary
  13. 13Diabetes Centre, Falkirk and District Royal Infirmary, Falkirk
  14. 14Diabetes Centre, Queen Margaret Hospital, Dunfermline
  15. 15Diabetes Centre, Monklands Hospital, Airdrie
  16. 16Metabolic Unit, Western General Hospital, Edinburgh
  17. 17Wishaw General Hospital, Wishaw
  18. 18Southern General Hospital NHS Trust, Glasgow
  19. 19Medical Unit B, Stobhill NHS Trust, Glasgow
  20. 20Cardiology Department, Ninewells Hospital
  1. Correspondence to: J Belch J.J.F.Belch{at}
  • Accepted 19 August 2008


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

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

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

Participants 1276 adults aged 40 or more with type 1 or type 2 diabetes and an ankle brachial pressure index of 0.99 or less but no symptomatic cardiovascular disease.

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

Main outcome measures Two hierarchical composite primary end points of death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, or amputation above the ankle for critical limb ischaemia; and death from coronary heart disease or stroke.

Results No evidence was found of any interaction between aspirin and antioxidant. Overall, 116 of 638 primary events occurred in the aspirin groups compared with 117 of 638 in the no aspirin groups (18.2% v 18.3%): hazard ratio 0.98 (95% confidence interval 0.76 to 1.26). Forty three deaths from coronary heart disease or stroke occurred in the aspirin groups compared with 35 in the no aspirin groups (6.7% v 5.5%): 1.23 (0.79 to 1.93). Among the antioxidant groups 117 of 640 (18.3%) primary events occurred compared with 116 of 636 (18.2%) in the no antioxidant groups (1.03, 0.79 to 1.33). Forty two (6.6%) deaths from coronary heart disease or stroke occurred in the antioxidant groups compared with 36 (5.7%) in the no antioxidant groups (1.21, 0.78 to 1.89).

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

Trial registration Current Controlled Trials ISRCTN53295293.


  • We thank Bayer for donating the aspirin and placebo tablets, Scotia Pharmaceuticals (formerly Cardinal) for the anitioxidant capsules and matching placebo, and the study nurse team of the prevention of progression of arterial disease and diabetes trial. Members of the Prevention of Progression of Arterial Disease and Diabetes Study Group. Medical Research Council steering committee: JBel (principal investigator), IC, SC, AMacC (chair), RT, and representatives of the Medical Research Council (various). Data and safety monitoring committee: Keith Fox, Desmond G Johnston, Gordon Murray, and JS (chair). End points committee: PM (chair), SMcE, JMcK, SP, RMacW, JBan, and Mairi Stirling. Contributing centres: Dundee—GL, RJ, AM, and Ray Newton (Ninewells Hospital); Dunfermline—AJ (Queen Margaret Hospital); Edinburgh West—JMcK (Western General Hospital); Falkirk—J Doig and NP (Falkirk and District Royal Infirmary); Glasgow—CS (Southern General Hospital), DG (Stobhill), Colin Kesson (Victoria Infirmary), and JP (Royal Infirmary); East Kilbride—Susan Benbow (Hairmyres and Stonehouse); Kirkcaldy—IC (Royal Victoria Hospital); Livingstone—Stuart Gray (St John’s Hospital); Perth—AC (Perth Royal Infirmary); Monklands—DM (Monklands Hospital); Motherwell and Wishaw—IO’B (Wishaw General); Stirling—Sheila Reith and CK (Stirling Royal Infirmary). Nursing staff: JBan (senior research nurse). Royal College of Physicians Edinburgh Diabetes Registry Group, and West of Scotland clinicians: JBel, IC, John Chalmers, Joycelin Chalmers, AC, John Doig, David Fraser, Stuart Gray, Victor Hawthorne, RJ, RL (study statistician), GL, Susan Lewis, Derreck McCullough, SMcE, Margaret MacLeod, John McKnight, David Matthews, Andrew Morris, Ray Newton, NP, RP (study statistician), Sheila Reit, Mary Scott, Tanya Siann, Alan Smith, and James Walker.

  • Contributors: All authors were members of the Royal College of Physicians Edinburgh and as such helped in the development and completion of the protocol and the project. The writing committee consisted of JBel, RP, and RL but all authors had input into the written document.

  • Funding: This work was supported by the Medical Research Council grant number G9534799. All researchers were independent of the funder.

  • Competing interests: None declared.

  • Ethical approval: This work was approved by the local research ethics committees of all participating centres and by a multiresearch ethics committee.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

View Full Text