Janusz Jankowski et al comment on Peter Rothwell, Asprin & Cancer, 14 May 2011, The Lancet

reposted from: http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606661.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423 and Reply:
http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606703.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423

crabsallover highlights, key points, comments / links.

Janusz Jankowski, Hugh Barr, John deCaestecker, Peter Watson, Stephen Attwood, Paul Moayyedi


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 eff ects of low dose aspirin.

Additionally, meta-analysis of cardiac trials with reassess ment of causes of cancer deaths might have in advertently 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 trial 3 was specifi cally 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 proton-pump inhibitor [PPI], high-dose PPI, low-dose PPI with low-dose aspirin [300 mg], and high-dose PPI with low-dose aspirin). We need trials such as AspECT to report their preliminary findings of genetic stratification for response, as well as risk/benefi t, dose, and length of therapy.

JJ has a consultancy to AstraZeneca Oncology, which makes esomeprazole—one of the agents in the AspECT trial. JJ has also received grants in aid from AstraZeneca previously. All authors are co-investigators in the AspECT trial. *Janusz Jankowski, Hugh Barr, John deCaestecker, Peter Watson, Stephen Attwood, Paul Moayyedi j.a.jankowski@qmul.ac.uk Leicester Royal Infi rmary, Leicester LE7 7HH, UK (JJ, JdC); Gloucestershire Royal Hospital, Gloucester, UK (HB); Belfast Hospital Trust, Belfast, UK (PW); Northumbria Healthcare NHS Foundation Trust, Tyne and Wear, UK (SA); and Gastrointestinal Division, McMaster University Medical Centre, Hamilton, ON, Canada (PM)

1 Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Eff ect 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.
2 Jankowski J, Hunt R. Cyclooxygenase-2 inhibitors in colorectal cancer prevention: better the devil you know. Cancer Epidemiol Biomarkers Prevent 2008; 17: 1858–61.
3 Das D, Chilton AP, Jankowski JA. Chemoprevention of oesophageal cancer and the AspECT trial. Recent Results Cancer Res 2009; 181: 161–69.

Peter Rothwell Reply (full text)  - Risk of GI Bleeds
..
 Mark Nelson raises the issue of the risk of bleeding on aspirin. We deliberately made no specific recommendations about the widespread use of aspirin in healthy individuals, but we did discuss the issue of bleeding in some detail. Our analyses showed that taking aspirin daily for 5—10 years would reduce all-cause mortality (including any fatal bleeds) during that time by about 10% in relative terms. Subsequently, there would be further delayed reductions in risk of cancer death even if aspirin was stopped. In healthy middle-aged individuals, the risk of major bleeding on aspirin is relatively low (about 0·2 per 1000 patients per year—only a small proportion of which are fatal), and is already offset in many groups by the small reduction in risk of ischaemic vascular events. The reduction in risk of cancer is therefore additional to this existing balance in which the bleeding risk is already taken into account. However, the risk of bleeding on aspirin increases steeply with age and so we did not comment on use of aspirin in healthy individuals older than 75 years. The results of the ASPREE trial will be of great importance in this respect. 

Luca Mascitelli role of Aspirin in reducing Iron, Cancer effect, 14 May 2011, The Lancet

reposted from:

crabsallover highlights, key points, comments / links.
http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606703.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423
and http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606673.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423
Luca Mascitelli, Mark R Goldstein
Peter Rothwell and colleagues 1 provide new evidence that long-term daily aspirin lowers mortality from several common cancers. However, the mechanisms underlying this beneficial effect are not clearly understood. A plausible anti-tumour mechanism of long-term aspirin use that was not considered is aspirin-mediated chronic iron loss, as previously suggested.2

Loss of stored iron is known to be possible even in aspirin users with clinically undetectable occult gastric bleeding. Indeed, long-term aspirin use has been shown to be associated with roughly 20% lower serum ferritin concentrations—a good indicator of body iron stores—than in non-users;3 treatment with other non-steroidal anti-infl ammatory drugs had no signifi cant effect on serum ferritin concentrations.

A protective effect of iron loss on cancer mortality was confi rmed in a randomised trial in which patients were randomly assigned to reduction in iron stores by calibrated phlebo tomies or to observation. Over 4·5 years, the risk of new cancers was signifi cantly lower in the iron reduction group than in controls.4 Furthermore, in patients with new cancers, those with iron reduction had highly signifi cantly lower cancerspecifi c and all-cause mortality than controls. These findings are plausible in view of the growing number of published studies on the role of iron in carcinogenesis.2 In this setting, we have also proposed that lower stored iron concentrations mediated by inhibition of iron absorption by polyphenols present in the diet might exert an anti-cancer mechanism.5 Future studies of aspirin action should therefore include assessment of the eff ects of the intervention on iron status. If iron loss is found to be a mechanism, this consequence of aspirin use can be clinically replicated by other methods without incurring the risk of major aspirin-induced haemorrhage.2

We declare that we have no confl icts of interest. *Luca Mascitelli, Mark R Goldstein lumasci@libero.it Medical Service, Comando Brigata alpina “Julia”, Via S Agostino 8, 33100 Udine, Italy (LM); and Fountain Medical Court, Bonita Springs, FL, USA (MRG)

1 Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Eff ect 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.
2 Mascitelli L, Pezzetta F, Sullivan JL. Aspirin-associated iron loss as an anticancer mechanism. Med Hypotheses 2010; 74: 78–80.
3 Milman N, Ovesen L, Byg K, Graudal N. Iron status in Danes updated 1994, I: prevalence of iron defi ciency and iron overload in 1332 men aged 40-70 years. Infl uence of blood donation, alcohol intake, and iron supplementation. Ann Hematol 1999; 78: 393–400.
4 Zacharski LR, Chow BK, Howes PS, et al. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 2008; 100: 996–1002.
5 Mascitelli L, Goldstein MR. Inhibition of iron absorption by polyphenols as an anti-cancer mechanism. QJM 2011; 104: 459–61.

Peter Rothwell Reply
Luca Mascitelli and Mark Goldstein raise the issue of the possible eff ect of aspirin treatment on iron loss as a mechanism for the reduction in cancer deaths. We deliberately did not review the many suggested mechanisms by which aspirin might reduce the risk of death due to cancer, but it is possible that reduced iron stores might contribute. There are currently insuffi cient data on the associations between iron stores and cancer risk to determine whether their pattern closely mirrors that of the effects of aspirin on deaths due to the specific cancers that we noted.

Mark Nelson, risk of bleeding with Asprin, Peter Rothwell reply

reposted from: http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606703.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423
and http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606685.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423

crabsallover highlights, key points, comments / links.

Mark Nelson

Although Peter Rothwell and colleagues 1 provide the strongest evidence to date for the effect of aspirin in cancer prevention, they do not consider the well known adverse effects of aspirin, and focused on one potential benefit of aspirin in a study largely confined to middle-aged men.

Risk and benefit increase with age.2 Although the results look impressive when presented in proportional reduction terms, they are less so in “real” terms (14 000 people took aspirin for at least 4 years for a saving of about 100 cancer deaths). It is important, therefore, to be aware that a small proportion of those who develop serious adverse events, such as haemorrhagic stroke and major gastrointestinal bleeding, could reduce or reverse the benefi t.2–4

In older people, for whom serious adverse events are much more common and their consequences potentially more serious, the risk/benefi t equation will probably be different. The ASPirin in Reducing Events in the Elderly (ASPREE) trial5 examines whether the benefits of daily aspirin outweigh the risks in people aged 70 years or older. The ASPREE primary endpoint is extension of life free from dementia and disability. The trial will be able to show the true overall benefi t of routine use of aspirin in older people for primary prevention beyond simply counting individual adverse events.

I have received travel support from Bayer Healthcare—a manufacturer of aspirin. This company is also providing aspirin for ASPREE, of which I am a principal investigator. Mark Nelson mark.nelson@utas.edu.au Menzies Research Institute/University of Tasmania, Private Bag 23, Hobart, Tasmania 7001, Australia

1 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.
2 Hernandez-Diaz S, Rodriguez LA. Incidence of serious upper gastrointestinal bleeding/ perforation in the general population: review of epidemiologic studies. J Clin Epidemiol 2002; 55: 157–63.
3 He J, Whelton PK, Vu B, Klag MJ. Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials. JAMA 1998; 280: 1930–35

Peter Rothwell Reply
Mark Nelson raises the issue of the risk of bleeding on aspirin. We deliberately made no specific recommendations about the widespread use of aspirin in healthy individuals, but we did discuss the issue of bleeding in some detail. Our analyses showed that taking aspirin daily for 5–10 years would reduce all-cause mortality (including any fatal bleeds) during that time by about 10% in relative terms. Subsequently, there would be further delayed reductions in risk of cancer death even if aspirin was stopped. In healthy middle-aged individuals, the risk of major bleeding on aspirin is relatively low (about 0·2 per 1000 patients per year—only a small proportion of which are fatal),3 and is already off set in many groups by the small reduction in risk of ischaemic vascular events.3 The reduction in risk of cancer is therefore additional to this existing balance in which the bleeding risk is already taken into account. However, the risk of bleeding on aspirin increases steeply with age and so we did not comment on use of aspirin in healthy individuals older than 75 years. The results of the ASPREE trial will be of great importance in this respect.

We agree with L H Opie that, in individuals without previous vascular events, both the relative and absolute reductions in risk of death due to cancer on aspirin versus control are larger than the equivalent reductions in risk of fatal vascular events, and that eff ects on cancer outcomes will dominate the overall risk/benefi t equation, particularly when the delayed eff ects on cancer death beyond the end of the trials is also factored in.

I have received honoraria for talks, advisory boards, and clinical trial committees from several pharmaceutical companies with an interest in antiplatelet agents, including AstraZeneca, Bayer, Boehringer Ingelheim, Sanofi -Aventis/ Bristol-Myers Squibb, and Servier.
Peter M Rothwell, on behalf of all authors peter.rothwell@clneuro.ox.ac.uk Stroke Prevention Research Unit, University Department of Clinical Neurology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK

1 Medical Research Council’s General Practice Research Framework. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41.
2 Peto R, Gray R, Collins R, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ 1988; 296: 313–31.
3 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.

Lancet Correspondence on Peter Rothwell studies on Aspirin & Cancer, 14 May 2011

This is an important series of 4 letters published May 2011 about Peter Rothwells work on Aspirin and Cancer followed by a comment by Peter Rothwell.

reposted from: http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606661.pdf
and Peter Rothwells comments: http://download.thelancet.com/pdfs/journals/lancet/PIIS0140673611606703.pdf?id=e16241398b8eb460:3c68b886:1306b6f6506:38b41307479634423

crabsallover highlights, key points, comments / links.

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). Aspirin causes substantially fewer major extracranial bleeds that require a blood transfusion than the number of CVD events and cancer deaths prevented (table).

Aspirin in the prevention of cancer, N J Wald, J K Morris, M R Law
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-pressure lowering 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.


NW and ML hold a European and Canadian patent (pend ing in the USA) for the Polypill, filed in April 2000.


 *N J Wald, J K Morris, M R Law n.j.wald@qmul.ac.uk Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK 
1 Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Eff ect 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. 
2 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. 
3 Offi ce for National Statistics. Mortality statistics: deaths registered in 2009. London: Stationery Offi ce, 2010. http://www.statistics.gov.uk/ downloads/theme_health/dr2009/dr-09.pdf (accessed April 27, 2011). 
4 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. 
5 Law MR, Wald NJ, Rudnicka AR. Quantifying the eff ect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423–27. 
6 Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419–23.


Author’s reply 
We agree with N J Wald and colleagues that our results and their analyses do suggest that aspirin should be included in Polypill regimens, although the balance of risk and benefit is less certain in older individuals owing to the increase in risk of bleeding with age.