- Email: [email protected]
Aspirin in the prevention of cancer
Correspondence
Aspirin in the prevention of cancer Peter Rothwell and colleagues, in their meta-analysis of randomised trials (Jan 1, p 31),1 show that low-dose long-term aspirin use reduces the risk of several cancers. Before this information was available, the balance of benefit and harm in taking aspirin in the primary prevention of coronary heart disease and stroke (cardiovascular disease [CVD]) was uncertain. The new data on cancer help to clarify the net benefit of aspirin, particularly if aspirin were included with a statin and bloodpressure-lowering drugs in a combined formulation (Polypill). The table shows the estimated number of first CVD events and cancer deaths prevented in England and Wales in 1 year on the basis of a Polypill (composed of three blood-pressurelowering drugs at half standard dose and a statin at standard dose such as simvastatin 40 mg), with or without aspirin. In people aged 55–89 years, for example, 186 000 CVD events and cancer deaths would be prevented. The table shows that 120 such outcomes would be prevented in 1000 people over a period of 20 years (or 170 per 1000 over 35 years).2–6 Aspirin causes substantially fewer major extracranial bleeds that require a blood transfusion than the number of CVD events and cancer deaths prevented (table). However, the risk of an aspirin-induced major extracranial bleed increases with age.4 The estimates for such bleeds shown in the table among people aged 55 years over a period of 20 years are based on observed data and are likely to be accurate, but the numbers in people older than 75 years are uncertain— they would be twice those shown if the age trend to 75 years continues to 90 years. Given the results published by Rothwell and colleagues,1 the balance of the evidence is in favour of including aspirin in a Polypill strategy to prevent CVD and cancer. www.thelancet.com Vol 377 May 14, 2011
Polypill including Polypill excluding aspirin aspirin
Aspirin alone
Effect of adding aspirin to polypill
Number of CVD events and cancer deaths prevented* Among people aged 55–74 years in 1 year
80 000
60 000
30 000
20 000
Among people aged 55–89 years in 1 year
186 000
141 000
68 000
45 000
Among 1000 people aged 55 years over 20 years
120
90
40
30
Among 1000 people aged 55 years over 35 years
170
120
50
50
Number of aspirin-induced major extracranial bleeds Among 1000 people aged 55 years over 20 years
6
0
5
5
Among 1000 people aged 55 years over 35 years
8
0
8
8
CVD incidence rates taken from reference 2 (assuming 10% of strokes occur in people who have already had an ischaemic heart disease [IHD] event and vice versa); cancer mortality rates taken from reference 3. Relative risks associated with aspirin: IHD 0·77,4 stroke 0·95,4 cancer (after 5 years of use) 0·66.5 Relative risks associated with statins: IHD (only after 3 years of use) 0·39,5 stroke 0·87,5 cancer 1·00. Relative risks associated with three blood-pressure-lowering agents: IHD 0·64,6 stroke 0·37,6 cancer 1·00. Aspirin-induced major extracranial bleeds=three per 10 000 per year.4 *Rounded to the nearest 1000 and nearest 10.
Table: Estimated number of cardiovascular disease (CVD) events and cancer deaths prevented in England and Wales in 1 year according to Polypill use, with and without aspirin, number of such events prevented in 1000 people aged 55 years over periods of 20 years and 35 years, and corresponding number of asprin-induced major extracranial bleeds
NW and ML hold a European and Canadian patent (pending in the USA) for the Polypill, filed in April 2000.
*N J Wald, J K Morris, M R Law [email protected] Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK 1
2
3
4
5
6
Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377: 31–41. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Health Technol Assess 2003; 7: 31. Office for National Statistics. Mortality statistics: deaths registered in 2009. London: Stationery Office, 2010. http://www.statistics.gov.uk/ downloads/theme_health/dr2009/dr-09.pdf (accessed April 27, 2011). Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849–60. Law MR, Wald NJ, Rudnicka AR. Quantifying the effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423–27. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419–23.
We write with regard to the Article by Peter Rothwell and colleagues,1 which indicates that low-dose aspirin might prevent cancer. Although we strongly endorse Rothwell and colleagues’ publication, we urge caution. If we presume that aspirin does have a chemoprotective role, it clearly does
not work for everyone since at best 25% of people are estimated to get a cancer prevention benefit but this figure could be as low as 20%. This “aspirin resistance” in patients seems to be present widely in the population so we do not know who should respond.2 Genetic studies such as those undertaken by the Esophageal Adenocarcinoma Genetic Linkage (EAGLE) consortia are needed to assess which individuals will respond best to the chemopreventive effects of lowdose aspirin. Additionally, meta-analysis of cardiac trials with reassessment of causes of cancer deaths might have inadvertently introduced bias. For example, the number of cases of gastrointestinal cancer death in Rothwell and colleagues’ study was 182 out of almost 20 000 cases. In particular there were only 23 oesophageal cancers. Patients in these trials, especially those using aspirin, might have had complications that resulted in earlier presentation. The AspECT chemoprevention trial3 was specifically designed to look at the effect of aspirin on oesophageal cancer development but will also give information on effects on colon cancer development as well as on cardiac deaths. To date, the data monitoring team and the trial steering team have not divulged any obvious trend between the four groups of this trial (low-dose
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1649
Aspirin in the prevention of cancer Peter Rothwell and colleagues, in their meta-analysis of randomised trials (Jan 1, p 31),1 show that low-dose long-term aspirin use reduces the risk of several cancers. Before this information was available, the balance of benefit and harm in taking aspirin in the primary prevention of coronary heart disease and stroke (cardiovascular disease [CVD]) was uncertain. The new data on cancer help to clarify the net benefit of aspirin, particularly if aspirin were included with a statin and bloodpressure-lowering drugs in a combined formulation (Polypill). The table shows the estimated number of first CVD events and cancer deaths prevented in England and Wales in 1 year on the basis of a Polypill (composed of three blood-pressurelowering drugs at half standard dose and a statin at standard dose such as simvastatin 40 mg), with or without aspirin. In people aged 55–89 years, for example, 186 000 CVD events and cancer deaths would be prevented. The table shows that 120 such outcomes would be prevented in 1000 people over a period of 20 years (or 170 per 1000 over 35 years).2–6 Aspirin causes substantially fewer major extracranial bleeds that require a blood transfusion than the number of CVD events and cancer deaths prevented (table). However, the risk of an aspirin-induced major extracranial bleed increases with age.4 The estimates for such bleeds shown in the table among people aged 55 years over a period of 20 years are based on observed data and are likely to be accurate, but the numbers in people older than 75 years are uncertain— they would be twice those shown if the age trend to 75 years continues to 90 years. Given the results published by Rothwell and colleagues,1 the balance of the evidence is in favour of including aspirin in a Polypill strategy to prevent CVD and cancer. www.thelancet.com Vol 377 May 14, 2011
Polypill including Polypill excluding aspirin aspirin
Aspirin alone
Effect of adding aspirin to polypill
Number of CVD events and cancer deaths prevented* Among people aged 55–74 years in 1 year
80 000
60 000
30 000
20 000
Among people aged 55–89 years in 1 year
186 000
141 000
68 000
45 000
Among 1000 people aged 55 years over 20 years
120
90
40
30
Among 1000 people aged 55 years over 35 years
170
120
50
50
Number of aspirin-induced major extracranial bleeds Among 1000 people aged 55 years over 20 years
6
0
5
5
Among 1000 people aged 55 years over 35 years
8
0
8
8
CVD incidence rates taken from reference 2 (assuming 10% of strokes occur in people who have already had an ischaemic heart disease [IHD] event and vice versa); cancer mortality rates taken from reference 3. Relative risks associated with aspirin: IHD 0·77,4 stroke 0·95,4 cancer (after 5 years of use) 0·66.5 Relative risks associated with statins: IHD (only after 3 years of use) 0·39,5 stroke 0·87,5 cancer 1·00. Relative risks associated with three blood-pressure-lowering agents: IHD 0·64,6 stroke 0·37,6 cancer 1·00. Aspirin-induced major extracranial bleeds=three per 10 000 per year.4 *Rounded to the nearest 1000 and nearest 10.
Table: Estimated number of cardiovascular disease (CVD) events and cancer deaths prevented in England and Wales in 1 year according to Polypill use, with and without aspirin, number of such events prevented in 1000 people aged 55 years over periods of 20 years and 35 years, and corresponding number of asprin-induced major extracranial bleeds
NW and ML hold a European and Canadian patent (pending in the USA) for the Polypill, filed in April 2000.
*N J Wald, J K Morris, M R Law [email protected] Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK 1
2
3
4
5
6
Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 2011; 377: 31–41. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Health Technol Assess 2003; 7: 31. Office for National Statistics. Mortality statistics: deaths registered in 2009. London: Stationery Office, 2010. http://www.statistics.gov.uk/ downloads/theme_health/dr2009/dr-09.pdf (accessed April 27, 2011). Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849–60. Law MR, Wald NJ, Rudnicka AR. Quantifying the effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423–27. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419–23.
We write with regard to the Article by Peter Rothwell and colleagues,1 which indicates that low-dose aspirin might prevent cancer. Although we strongly endorse Rothwell and colleagues’ publication, we urge caution. If we presume that aspirin does have a chemoprotective role, it clearly does
not work for everyone since at best 25% of people are estimated to get a cancer prevention benefit but this figure could be as low as 20%. This “aspirin resistance” in patients seems to be present widely in the population so we do not know who should respond.2 Genetic studies such as those undertaken by the Esophageal Adenocarcinoma Genetic Linkage (EAGLE) consortia are needed to assess which individuals will respond best to the chemopreventive effects of lowdose aspirin. Additionally, meta-analysis of cardiac trials with reassessment of causes of cancer deaths might have inadvertently introduced bias. For example, the number of cases of gastrointestinal cancer death in Rothwell and colleagues’ study was 182 out of almost 20 000 cases. In particular there were only 23 oesophageal cancers. Patients in these trials, especially those using aspirin, might have had complications that resulted in earlier presentation. The AspECT chemoprevention trial3 was specifically designed to look at the effect of aspirin on oesophageal cancer development but will also give information on effects on colon cancer development as well as on cardiac deaths. To date, the data monitoring team and the trial steering team have not divulged any obvious trend between the four groups of this trial (low-dose
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1649