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Whatever happened to the polypill?

BMJ 2017; 356 doi: https://doi.org/10.1136/bmj.j1474 (Published 27 March 2017) Cite this as: BMJ 2017;356:j1474

Rapid Response:

The polypill – not just for cardiovascular disease?

The recent article on the polypill focussed exclusively on cardiovascular benefits (and the risk of toxicity). Yet a number of the candidates for inclusion in such a formulation, such as aspirin and metformin, have, in recent years, shown anti-cancer activity.

Randomised trials demonstrate that aspirin prevents the development of colorectal cancer[1, 2] and long-term follow-up from vascular trials suggests that aspirin prevents the development of a range of cancers, as well as preventing metastases[3, 4]. This latter hypothesis is being evaluated in several ongoing randomised trials which will evaluate both cancer and vascular outcomes[5]. Similarly, metformin is being evaluated as a treatment for both breast and prostate cancer[6, 7].

In 2015, the U.S. Preventive Services Task Force judged the evidence sufficient to recommend daily low-dose aspirin for primary prevention of cardiovascular disease and colorectal cancer in individuals aged 50-59 years with a moderate risk of cardiovascular disease and no increased risk of bleeding[8]. This approach factors in both potential benefits, cardiovascular and cancer outcomes, as well as age which is associated with toxicity (gastrointestinal bleeding).

Whilst aspirin does increase bleeding, significant events are rarer than generally appreciated. The Anti-thrombotic Trialists’ Collaboration estimated 3.6 additional serious extra-cranial bleeding events (requiring transfusion or resulting in death) per 10,000 people treated for a year with aspirin; intracranial haemorrhage was rarer still (0.8 additional events)[9].

Instead of “Whatever happened to the polypill?” perhaps we should be asking “How can we update our thinking about a potential polypill?“. We agree with Professor Viera that more evidence, including from the trials mentioned above, is needed before aspirin or an aspirin-containing polypill is recommended more widely. Evidence of anti-cancer effects may shift the balance of risks and benefits for some individuals. A more individualised approach, in which all of the possible benefits, as well as risks, are assessed is likely to be appropriate and may help the idea to “slowly but surely” continue to gain ground.

References
1. Cook NR, Lee IM, Zhang SM, et al. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159(2):77-85.
2. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet 2012;378(9809):2081-7.
3. Rothwell PM, Price JF, Fowkes FG, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet 2012;379(9826):1602-12.
4. Rothwell PM, Wilson M, Price JF, et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012;379(9826):1591-601.
5. Coyle C, Cafferty FH, Rowley S, et al. ADD-ASPIRIN: A phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours. Contemp Clin Trials 2016;51:56-64.
6. Goodwin PJ, Parulekar WR, Gelmon KA, et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J Natl Cancer Inst 2015;107(3)
7. Gillessen S, Gilson C, James N, et al. Repurposing Metformin as Therapy for Prostate Cancer within the STAMPEDE Trial Platform. Eur Urol 2016;70(6):906-08.
8. Bibbins-Domingo K, on behalf of the USPSTF. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.s. preventive services task force recommendation statement. Annals of Internal Medicine 2016;164(12):836-45.
9. Antithrombotic Trialists C, Baigent C, Blackwell L, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373(9678):1849-60.

Competing interests: No competing interests

11 May 2017
Fay H Cafferty
Senior Statistician
Ruth E Langley
MRC Clinical Trials Unit at UCL
Institute of Clinical Trials Methodology, Aviation House, 125 Kingsway, London WC2B 6NH, UK