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Monday 30 January 2012

Peter Rothwell: A Stratospheric Rise to a Giant of Neurology

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60662-4/fulltext
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The Lancet, Volume 377, Issue 9778, Page 1645, 14 May 2011
doi:10.1016/S0140-6736(11)60662-4Cite or Link Using DOI

Peter Rothwell: a dedicated flouter of fashion

Peter Rothwell, 1980—90: a lack of direction and an undistinguished career as a medical student. Peter Rothwell, 1991—2011: award-winning Director of the Stroke Prevention Research Unit at the University of Oxford, UK, and author of over 300 publications that have transformed the landscape of stroke prevention. He is a man who takes some figuring out. Reflecting on Rothwell's stratospheric rise to a giant of neurology, Charles Warlow, Rothwell's mentor and Professor of Medical Neurology at Edinburgh University, says simply, “he's a phenomenon”.
The past two decades have seen Rothwell show which patients benefit from carotid endarterectomy to prevent stroke, that there is a high risk of major stroke after transient ischaemic attack (TIA) and minor stroke, and that there are enormous benefits from urgent treatment to reduce this risk. This work called for greater urgency in investigating and treating minor stroke and TIA, which had previously been thought of as fairly benign conditions, so Rothwell developed a risk scoring system to enable clinicians to predict the likelihood of stroke in the first few days after TIA.
More recently, Rothwell has found that variability in blood pressure is at least as important as mean blood pressure for predicting the risk of stroke and that some of the most effective antihypertensive drugs reduce variability, as opposed to simply reducing mean blood pressure. Along the way, he has proved that the statistical basis of the “usual blood pressure hypothesis” approach to diagnosis and treatment of hypertension is invalid, and has still found time to show that aspirin can reduce mortality due to several major cancers.
Rothwell's record is extraordinary by any measure, but juxtaposed with his early years as a medical student it almost defies belief. Born to a 16-year-old single mother in a poor area of Liverpool and adopted and brought up by a family in Manchester, Rothwell got good grades at school. But, as the first person from his family to go to university, he had little sense of what kind of career he wanted. “I didn't have sufficient knowledge or originality to think of anything else to do, so I did medicine”, he says. Rothwell ended up at Edinburgh University, where he cheerfully admits to not being “particularly academic”. Far more interested in indulging his passion for mountaineering than attending medical lectures, “he was completely obscure as a student”, says Warlow. “And he became even more obscure when he went off to do his senior house officer [SHO] jobs in Middlesbrough.”
It was during his time working at the intensive therapy unit in Middlesbrough that Rothwell gathered data, largely unsupervised, on the endocrine response to critical illness, which he then wrote up for his MD. “That was extraordinary”, says Warlow. “I mean, no SHO collects data for an MD. Somehow or other, Pete just did it. And it's been just like that ever since. He just gets on and does it, and he does it at the most extraordinary speed.” A move back to Edinburgh as a clinical research fellow, and into Warlow's tutelage followed. “He got me interested in stroke and was an inspirational supervisor”, he says of Warlow. “And stroke has been my main focus since then”. His time with Warlow also laid the foundations for Rothwell's appreciation of the importance of asking the simple questions about how to best do medicine in the real world, and gave him the confidence to challenge the consensus. Louise Silver, Research Co-ordinator at the Stroke Prevention Research Unit, Oxford, which Rothwell established in 2000, explains that these are virtues that he is passing on to his own fellows. “His focus on clinical research, and how this can directly impact patient care, certainly gives myself and others a feeling that all our hard work has and will make a difference”, she says.
In an age when so many researchers fall over themselves to jump on the latest bandwagon, Rothwell is something of an iconoclast. “Medical research is so fashion conscious”, he says. “Everyone suddenly becomes geneticists, then 10 years later they're stem cell researchers.” By contrast, Rothwell's willingness to eschew fads has helped him reap a bumper crop of what he calls, for want of a better term, low-hanging fruit. “There's so much simple clinical research that should have been done 50 years ago but wasn't”, he explains. “The work we've done on working out the prognosis of TIAs and minor stroke should have been done years ago but wasn't.” The same can be said of his work on blood pressure variability and risk of stroke or the non-vascular effects of aspirin. “It's all simple stuff”, he insists.
For someone whose work has garnered such acclaim, Rothwell's modesty is striking. But beneath the softly spoken self-effacement, you get a sense of the kind of strength of character that has helped propel him so far, so fast. Moving to Oxford having been an undergraduate elsewhere certainly requires mental fortitude, and despite “still feeling like a new boy”, he has flourished. “He's quite tough you know, Pete”, Warlow attests. Still only 47, Rothwell is showing no signs of slowing down, and wants to carry on the Oxford Vascular Study, which he established in 2002, for another 20 years “to really understand what's happening to vascular disease over time”. He also expects variability in blood pressure to come further to the fore, especially in relation to dementia. And he hints that aspirin (he takes it) might still have a few new tricks up its sleeve. Considering what he has achieved in the past 20 years, the possibilities for the next 20 seem endless.

2009 - Aspirin & NSAID for cancer prevention: an international consensus statement

reposted from: http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70035-X/abstract
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The Lancet Oncology, Volume 10, Issue 5, Pages 501 - 507, May 2009
doi:10.1016/S1470-2045(09)70035-XCite or Link Using DOI

Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement

Prof Jack Cuzick PhD a Corresponding AuthorEmail AddressFlorian Otto MD b cProf John A Baron MD dProf Powel H Brown MD eProf John Burn PhD f,Peter Greenwald MD gProf Janusz Jankowski MD h iProf Carlo La Vecchia MD jProf Frank Meyskens MD kHans Jörg Senn MDb cProf Michael Thun MD l

Summary

Evidence clearly shows a chemopreventive effect for aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on colorectal cancer and probably other cancer types; however, data on the risk—benefit profile for cancer prevention are insufficient and no definitive recommendations can be made. Aspirin has emerged as the most likely NSAID for use in chemoprevention because of its known cardiovascular benefit and available safety and efficacy data. Other traditional NSAIDs, particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk of colorectal cancer, although these drugs do not provide cardioprotection. More studies of aspirin and cancer prevention are needed to define the lowest effective dose, the age at which to initiate therapy, the optimum treatment duration, and the subpopulations for which the benefits of chemoprevention outweigh the risks of adverse side-effects. Although it might be possible to answer some of these questions with longer follow-up of existing clinical trials, randomised controlled trials with new study designs will be needed. Future projects should investigate the effects of aspirin treatment on multiple organ systems. Cancers of interest are colorectal, breast, prostate, lung, stomach, and oesophageal. The main side-effect of aspirin is peptic ulcers; therefore coadministration of aspirin with a proton-pump inhibitor is an attractive option and is under investigation in the AspECT trial.
a Cancer Research UK Centre for Epidemiology, Mathematics, and Statistics, Queen Mary University of London, London UK
b Tumor Center ZeTuP, St Gallen, Switzerland
c Department of Hematology and Oncology, University Medical Center, Freiburg, Germany
d Dartmouth Medical School, Hanover, NH, USA
e Baylor College of Medicine, Houston, TX, USA
f Newcastle University, Institute for Human Genetics, Newcastle upon Tyne, UK
g Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
h University of Oxford, Oxford, UK
i Institute for Cellular and Molecular Sciences, Queen Mary's College, University of London, London UK
j Mario Negri Institute for Pharmacological Research and University of Milan, Milan, Italy
k Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Irvine, Orange, CA, USA
l Epidemiology and Surveillance Research, American Cancer Society, Atlanta, GA, USA
Corresponding Author Information Correspondence to: Prof Jack Cuzick, Cancer Research UK Centre for Epidemiology, Mathematics, and Statistics, Queen Mary University of London, Barts & The London School of Medicine and Dentistry, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK

Take aspirin daily - even for those at low cardiovascular risk

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60669-7/fulltext
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The Lancet, Volume 377, Issue 9778, Page 1651, 14 May 2011
doi:10.1016/S0140-6736(11)60669-7Cite or Link Using DOI

Aspirin in the prevention of cancer

That aspirin can help to prevent cancer1 has caught the public's attention. How does this benefit compare with the rather modest benefit in lessening cardiovascular events previously reported in those at low cardiovascular risk? In a previous study of such patients,2 the prevention was only three events in women and four in men among 1000 people studied over 6·4 years. The cost was 2·5 major bleeds per 1000 per 5 years in women and three in men, so the overall benefit was truly modest. By contrast, the cancer prevention rates in the study by Rothwell and colleagues1 included 15 gastrointestinal cancer deaths per 1000 people over 5 years. These benefits vastly outweighed the risk of major bleeds.
In view of these new facts, we should no longer be reserved about recommending aspirin even for those at low cardiovascular risk. However, we are still lacking firm data on when aspirin should be started in those at low risk, and at which dose. The doses of aspirin protecting from cancer in Peter Rothwell and colleagues' study1 were in the range of 75—300 mg daily. My guess is to start at a low dose—say 75 mg—in the early 50s.
I delare that I have no conflicts of interest.

References

1 Rothwell PMFowkes FGBelch JFOgawa HWarlow CPMeade TWEffect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsLancet 201137731-41Summary | Full Text | PDF(502KB) |CrossRef | PubMed
2 Berger JSRoncaglioni MCAvanzini FPangrazzi ITognoni GBrown DLAspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trialsJAMA 2006295306-313CrossRef |PubMed
a Hatter Cardiovascular Research Institute, University of Cape Town Medical School, Observatory, Cape Town 7925, South Africa

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 effects on cancer outcomes will dominate the overall risk/benefit equation, particularly when the delayed effects on cancer death beyond the end of the trials is also factored in.

Iron loss as mechanism for reduction of cancer deaths with aspirin

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60667-3/fulltext
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The Lancet, Volume 377, Issue 9778, Page 1650, 14 May 2011
doi:10.1016/S0140-6736(11)60667-3Cite or Link Using DOI

Aspirin in the prevention of cancer

Peter Rothwell and colleagues1 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-inflammatory drugs had no significant effect on serum ferritin concentrations.
A protective effect of iron loss on cancer mortality was confirmed in a randomised trial in which patients were randomly assigned to reduction in iron stores by calibrated phlebotomies or to observation. Over 4·5 years, the risk of new cancers was significantly lower in the iron reduction group than in controls.4 Furthermore, in patients with new cancers, those with iron reduction had highly significantly lower cancer-specific 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 effects 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 conflicts of interest.

References

1 Rothwell PMFowkes FGBelch JFOgawa HWarlow CPMeade TWEffect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsLancet 201137731-41Summary | Full Text | PDF(502KB) |CrossRef | PubMed
2 Mascitelli LPezzetta FSullivan JLAspirin-associated iron loss as an anticancer mechanismMed Hypotheses 20107478-80.CrossRef | PubMed
3 Milman NOvesen LByg KGraudal NIron status in Danes updated 1994, I: prevalence of iron deficiency and iron overload in 1332 men aged 40-70 years. Influence of blood donation, alcohol intake, and iron supplementationAnn Hematol 199978393-400CrossRef | PubMed
4 Zacharski LRChow BKHowes PS, et alDecreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trialJ Natl Cancer Inst 2008100996-1002CrossRef | PubMed
5 Mascitelli LGoldstein MRInhibition of iron absorption by polyphenols as an anti-cancer mechanismQJM 2011104459-461.CrossRef | PubMed
a Medical Service, Comando Brigata alpina “Julia”, Via S Agostino 8, 33100 Udine, Italy
b Fountain Medical Court, Bonita Springs, FL, USA

Luca Mascitelli and Mark Goldstein raise the issue of the possible effect 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 insufficient 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.

Aspirin in the prevention of cancer - Jankowski v Rothwell

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60666-1/fulltext
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The Lancet, Volume 377, Issue 9778, Pages 1649 - 1650, 14 May 2011
doi:10.1016/S0140-6736(11)60666-1Cite or Link Using DOI

Aspirin in the prevention of cancer

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 low-dose 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 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/benefit, 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.

References

1 Rothwell PMFowkes FGBelch JFOgawa HWarlow CPMeade TWEffect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsLancet 201137731-41Summary | Full Text | PDF(502KB) |CrossRef | PubMed
2 Jankowski JHunt RCyclooxygenase-2 inhibitors in colorectal cancer prevention: better the devil you knowCancer Epidemiol Biomarkers Prevent 2008171858-1861PubMed
3 Das DChilton APJankowski JAChemoprevention of oesophageal cancer and the AspECT trialRecent Results Cancer Res2009181161-169PubMed
a Leicester Royal Infirmary, Leicester LE7 7HH, UK
b Gloucestershire Royal Hospital, Gloucester, UK
c Belfast Hospital Trust, Belfast, UK
d Northumbria Healthcare NHS Foundation Trust, Tyne and Wear, UK
e Gastrointestinal Division, McMaster University Medical Centre, Hamilton, ON, Canada

We thank Janusz Jankowski and colleagues for their comments. However, our estimate of the effect of aspirin on death due to oesophogeal cancer was based on 68 events and not 23 as Jankowski and colleagues state. The 20-year risk of death due to adenocarcinoma of the oesophagus, the predominant histological subtype in Barretts' oesophagus, was substantially reduced by allocation to aspirin in the trials (hazard ratio 0·36, 95% CI 0·21—0·63, p=0·0001).
It is difficult to conceive of how this estimate might have been biased by inclusion of some trials that included patients with established vascular disease, as Jankowski and colleagues suggest. Moreover, the effect was significant in both of the large randomised trials of daily aspirin versus control in primary prevention that we studied—ie, the Thrombosis Prevention Trial1(0·42, 0·22—0·78, p=0·004) and the British Doctors Aspirin Trial2 (0·45, 0·19—0·99, p=0·04). The figure shows a pooled analysis of the effect in these two trials.
Additionally, our estimates of the effect of aspirin on risk of death due to gastrointestinal cancers as a whole were based on more than 500 deaths and not on 182 as stated by Jankowski and colleagues, with a highly statistically robust reduction in 20-year mortality (0·65, 0·53—0·78, p<0·0001).
2 Peto RGray RCollins R, et alRandomised trial of prophylactic daily aspirin in British male doctorsBMJ 1988296313-331.CrossRef | PubMed

Risk of GI bleed with Aspirin

reposted from: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60668-5/fulltext
crabsallover highlightskey pointscomments / links.

The Lancet, Volume 377, Issue 9778, Pages 1650 - 1651, 14 May 2011
doi:10.1016/S0140-6736(11)60668-5Cite or Link Using DOI

Aspirin in the prevention of cancer

Although Peter Rothwell and colleagues1 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 benefit.2—4
In older people, for whom serious adverse events are much more common and their consequences potentially more serious, the risk/benefit 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 benefit 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.

References

1 Rothwell PMFowkes FGBelch JFOgawa HWarlow CPMeade TWEffect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trialsLancet 201137731-41Summary | Full Text | PDF(502KB) |CrossRef | PubMed
2 Hernandez-Diaz SRodriguez LAIncidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studiesJ Clin Epidemiol 200255157-163CrossRef | PubMed
3 He JWhelton PKVu BKlag MJAspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials.JAMA 19982801930-1935CrossRef | PubMed
4 Pirmohamed MJames SMeakin S, et alAdverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patientsBMJ 200432915-19CrossRef | PubMed
5 Nelson MRReid CMAmes D, et alFeasibility of conducting a primary prevention trial of low-dose aspirin for major adverse events in the elderly in Australia: ASPirin in Reducing Events in the Elderly (ASPREE)Med J Aust 2008189105-109PubMed
a Menzies Research Institute/University of Tasmania, Private Bag 23, Hobart, Tasmania 7001, Australia

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 offset 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.
3 Antithrombotic Trialists' (ATT) CollaborationAspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trialsLancet 20093731849-1860Summary | Full Text | PDF(329KB) CrossRef | PubMed