Is There Enough Evidence for Aspirin in High-Risk Groups?

PREVENTION AND EARLY DETECTION (N ARBER, SECTION EDITOR)

Is There Enough Evidence for Aspirin in High-Risk Groups?

Peter C. Elwood & Maribel Almonte & Mohammed Mustafa

Published online: 18 December 2012# Springer Science+Business Media New York 2012

Abstract There is convincing evidence of a reduction invascular disease by aspirin, and highly persuasive evidenceof a reduction in cancer, in particular colorectal cancer.Aspirin also increases the risk of gastrointestinal and cere-bral bleeding. However, overviews of randomised trial datasuggests that gastrointestinal bleeding attributable to aspirinis not the most serious, because there is no evidence of anyincrease in deaths from bleeding. The involvement of inad-equately treated hypertension in cerebral bleeding attribut-able to aspirin is uncertain. Aspirin is widely approved forvascular risk reduction but no regulatory body has yetapproved its use for reduction of cancer risk. Nevertheless,the risk–benefit balance of aspirin should be evaluated inrelation to both vascular disease and cancer reduction to-gether. Aspirin prophylaxis would seem to be of particularvalue as a complement to colorectal cancer screening.

Keywords Aspirin . Vascular disease . Cancer . Vasculardisease prevention . Colorectal cancer screening . Cancerprevention . Cancer treatment . Aspirin risks . Bleeding .

Haemorrhagic stroke . Blood pressure . Public health

Introduction

Much has been written recently about aspirin prophylaxis,but very little from a public health perspective. Vascular

disease and cancer together account for approximately70 % of deaths in “western” communities [1], yet whilecardiologists and others have written about the risk andbenefits of aspirin and vascular disease, oncologists andothers have written about aspirin and cancer. Furthermore,discussions about aspirin and cancer often focus on colorec-tal cancer, for which the evidence of benefit is most persua-sive, while ignoring the effect suggested in many reports ofreductions in cancers other than colorectal. Aspirin howeverseems to be unique in that it seems to affect a range ofbiological mechanisms relevant to vascular disease, to car-cinogenesis, to metastatic spread, and to frank clinical car-cinoma [2••]. There are highly effective alternativeprophylactics to aspirin, but although controversial [3] sta-tins probably do nothing for cancer [4, 5], and cancerscreening does nothing for vascular disease.

McKee and Raine [6], in a paper on issues in publichealth policy, wrote “First, choose your philosophy”. In thispaper we first consider some basic philosophical and generalissues relevant to public health, in particular responsibilityfor protection of health and the prevention of disease, andthen we consider the benefits and the risks of aspirin, andthe subject/patient groups for whom aspirin prophylaxis ismost appropriate.

The Rights and Responsibilities of Subjects

Lenaghan et al. [7] urged that decision makers at a local andnational level should take time and make an effort to obtaininformed comment from groups representative of the gen-eral public, and should not only listen to but should act onthe voice of the public. A Citizens’ Jury was held to giverepresentatives of the community opportunity to commenton the issue: “My Health—whose responsibility?” and low-dose aspirin was introduced as an example of a drug thatpreserves health [8•]. Sixteen jurors were selected by quotasampling to ensure representativeness of the community.

P. C. Elwood (*) :M. MustafaCochrane Institute of Primary Care and Public Health, CardiffUniversity, University Hospital of Wales, Cardiff CF14 4XN, UKe-mail: [email protected]

M. Mustafae-mail: [email protected]

M. AlmonteCochrane Institute of Primary Care and Public Health, CardiffUniversity, Cardiff CF14 5YS, UK

Curr Colorectal Cancer Rep (2013) 9:9–16DOI 10.1007/s11888-012-0149-y

Although, at the time of the jury (2006) the available evi-dence on the reduction of cancer by aspirin was only sug-gestive, the jurors stated that evidence on the risks andpossible benefit of aspirin in relation to cancer reductionshould be made available to the public “… even before thereis agreement amongst doctors” (our italics).

The Responsibilities of Healthcare Workers

The responsibilities of healthcare workers follow from this.In relation to the treatment of disease, responsibilities areclear, and in the UK and many other countries, the rights ofpatients are enshrined in law. Responsibilities of healthcareworkers in relation to the protection of health and preventionof disease are less obvious, but they certainly include theprovision of evidence on prophylactic measures to subjectsand to the general community, including the avoidance ofsmoking, the benefits of regular exercise, etc. Issues relatingto prophylactic drugs are perhaps less obvious, yet theresponsibility of healthcare practitioners to provide evidenceof the risks and benefits of every evidence-based prophy-lactic measure, including drugs, seems irrefutable [9].

The Benefits of Aspirin Prophylaxis

There is little new on the vascular benefits of aspirin. Evi-dence from extensive overviews of randomised trials haveestablished low-dose aspirin as a cost-effective prophylacticand it is widely agreed that it should be prescribed forpatients with clinical evidence of vascular disease, togetherwith subjects who have a raised vascular risk score [10–13].

On the issue of aspirin prophylaxis for asymptomatic sub-jects, argument continues about the balance between the num-ber of vascular events likely to be prevented and the number ofbleeding episodes likely to be precipitated [14, 15]. Suchevaluations are based on the assumption that bleeding can beequated with heart attack or stroke.With regard to severity andsequelae this can be challenged, and a comment in one of themajor overviews of aspirin trials is apposite: “… the alterna-tive to primary prevention is deferral until some evidence ofocclusive disease is noted….. [but] the first manifestations ofdisease might be a disabling of fatal event” [11].

Debates about primary vascular prevention should considerthe reduction of cancer by aspirin and, as Rothwell andcolleagues point out, the benefits of aspirin on cancer risk“will tip the balance in favour of treatment” of asymptomaticolder subjects [16]. However, all this is prevention and nottreatment, and the last word should clearly lie with the indi-vidual, provided he/she has been adequately informed. Aspointed out by Kent and Shah [17]: “a decision on whetheror not a patient should take an aspirin requires a robustdiscussion of its benefits and harms…. [and] the elicitationof patient preferences”.

In relation to cancer, aspirin seems to be unique in that itengages with multiple mechanisms, affecting the carcino-genesis pathway from initiation through progression to clin-ically treated cancer [2••]. There is a large and growing bodyof evidence on prevention and this includes observationalcase-control and cohort studies [18–21, 22••] and evidencefrom randomised trials [22••, 23, 24, 25••, 26]. Taking allthis together, there is little doubt that aspirin reduces the riskof cancer, though the evidence is most convincing for colo-rectal cancer and less so for other cancers. Problems liehowever in the balance between the benefits and the risks,the main risks being gastrointestinal and cerebral bleeding.

Although the evidence from trials suggest a reduction inoverall cancer incidence of between perhaps 20 to 40 %, theeffect is likely to be less were the taking of aspirin to bepromoted in a community. In public health initiatives theeffects achieved are always smaller than those predictedfrom carefully controlled randomised trials, in part becauseof “dilution” by intermittent, or non-compliance in, drugtaking [27]. On the other hand, in a report of a long-termfollow-up of eight clinical trials the authors comment that“there were high rates of drop-outs from randomised treat-ment… about 40% of patients in the aspirin groups hadstopped treatment’ by the end of the follow-up, and hence ‘itis likely that we underestimated the benefit of long-termtreatment” [16].

A full evaluation of aspirin should also take account ofevidence of benefit from aspirin in the treatment of estab-lished cancer. In part this is because of a reduction inmetastatic spread [21, 24, 28•] However an increase insurvival and other evidence of benefit have been shownfor patients taking, or being given aspirin in addition toconventional chemotherapy. Thus, benefit has been shownin colorectal cancer [20, 29] in breast cancer [30], in oeso-phageal cancer [31], and in lung cancer [32].

Work on colorectal cancer is of interest in that Chan et al.[29] have shown that a reduction in mortality with aspirinwas confined to patients whose tumours overexpressedCOX-2 (HR 0.39, 95 % CI 0.20–0.76); no reduction wasobserved for those with weak of absent expression (HR1.22, 95 % CI 0.36–4.18). Chan and colleagues [33] havenow taken this further and shown that increased survival isassociated with a mutation in the PIK3CA gene, and thismutation may therefore serve as a predictive marker foradjuvant aspirin therapy. Whether or not this, or another,mutation is relevant to the effectiveness of aspirin therapy incancer has yet to be shown.

The Risks of Aspirin Prophylaxis

There are probably few clinical situations for which thereseems to be a greater difference between the perceived andactual risks found in clinical trials. It is unfortunate that

10 Curr Colorectal Cancer Rep (2013) 9:9–16

some statements about the risk of aspirin have been basedon studies of subjects for whom aspirin is clearly unsuitable,for example patients known to have a peptic ulcer [34] orclinical situations in which very large doses of aspirin areused, for example rheumatoid arthritis [35].

Gastrointestinal bleeding attributable to the aspirin islikely to be experienced by one or two subjects in every1,000 taking aspirin [36, 37], the risk increasing with age upto approximately four in every 1,000 subjects aged 70–79 years [38].

There is good evidence however that fatal bleedingamongst subjects in randomised trials are not increased byaspirin, suggesting that in the absence of gastric pathologybleeding caused by aspirin are not the most serious. Thus, insix aspirin trials there were four deaths per 100,000 subjectsper year in subjects randomised to aspirin and five per100,000 in subjects on placebo [39]. The report of theAntithrombosis Trialists meta-analysis [11] is consistentwith this: “ … there were actually fewer fatal bleeds inparticipants allocated to aspirin than in the controls (ninevs twenty)”. Further confirmation is given in an overview of51 trials: “ … case-fatality from major extracranial bleedswas also lower on aspirin than on control (8/203 vs 15/132;OR 0.32, 95 % CI 0.12–0.83, p00.009)” [23]. Finally, in anoverview of 25 randomised trials McQuaid and Laine [37]comment “the risk among aspirin users of any fatal bleed-ing, fatal GI bleeding, or fatal non-GI/non-intracranialbleeding was not significantly increased’.

The absence of any increase in fatal bleeding from aspirincould be attributed to the deliberate selection of healthysubjects at low risk of bleeding for inclusion in clinical trials[40], yet, if this is true the selection simply represents goodclinical care, and a similar level of care should be achievablethroughout the community if doctors and subjects are ade-quately informed. In any case, a nationwide estimate ofdeaths attributable to NSAID or aspirin use, based on hos-pital patients, was 15/100,000 [40] and the authors add thejudgement that one third of this rate was attributable to low-dose aspirin, resulting in a rate close to the five deaths per100,000 in the subjects in trials. A similar national study ofolder veterans with recent NSAID use made the same esti-mate of 5.5 deaths per 100,000 person years [41].

There is also evidence from trials that the incidence ofbleeding decreases with time. Garcia Rodriguez et al. [42] inan overview of 17 studies found that the risk of a GIbleeding was highest during the first month of aspirin use(RR 4.4; 3.2–6.1). Reduction over a much longer period oftime was reported in one of the long-term subsequent stud-ies by Rothwell [23]: the odds of bleeding in subjectsrandomised to aspirin was 1.95 (1.47–2.59) in the first threeyears on aspirin; lower in the next two years (OR 1.37;0.87–2.14), and five years after randomisation to aspirinthere was no significant excess (OR 0.63 0.34–1.16).

Although it can be argued that this reduction in bleedingover time could be because subjects who bleed stop theiraspirin, or take a gastric acid-suppressing drug along withthe aspirin, it can again be said that these measures are goodclinical practice and could be matched in the community ifdoctors and subjects are adequately informed.

Regarding the stopping of aspirin prophylaxis, it should berealised that an overview of studies in which aspirin had beenwithdrawn revealed an increased risk of myocardial infarc-tion. In an overview of three studies in which aspirin had beengiven for coronary artery disease, the OR of a major coronaryevent 8–10 days after withdrawal of the aspirin was 1.82(1.52–2.18) [43••]. More dramatic results come from a smallrandomised study in which subjects who bled while on low-dose aspirin were all given a PPI and then half were rando-mised on to aspirin again or to a placebo. All-cause mortalitywas 1.3 % among those put back on aspirin and 10.3 % inthose on placebo (HR 0.2; 0.05–0.90) [44••].

Cerebral bleeding is a very serious outcome and two orthree additional subjects in every 10,000 on aspirin are likelyto experience a haemorrhagic stroke each year [11, 37, 45].Inadequately treated hypertension is a major factor in this, andin one overview there was a doubling of haemorrhagic strokesfor a 20 mmHg increase in blood pressure [12]. On the otherhand, the hypertensive optimal treatment (HOT) trial wasbased on adequately treated patients with hypertension, andthe number of haemorrhagic strokes in 9,399 subjects onaspirin (seven fatal and 12 non-fatal) was similar to that in9,391 subjects on placebo (eight fatal, and 12 non-fatal) [46].The incidence of haemorrhagic stroke was however high inthis trial (approx. 5 per 10,000 per year) confirming theadditional risk of cerebral bleeding in hypertensive patients.

Nevertheless, an overview of vascular disease in hyper-tensive patients [47] concluded that, apart from secondaryvascular disease prevention, any vascular benefit from aspi-rin is negated by an increase in major haemorrhage. Thiswould seem to lead to two conclusions:

& first, that the blood pressure of every person who decidesto take aspirin long-term should be checked, and, if ele-vated, should be treated to achieve the criteria set in recentguidelines, namely: <150 mmHg systolic and <90 mmHgdiastolic [48]; and

& second, if a subject has no evidence of vascular disease,aspirin should be considered only if there is convincingevidence of an increased risk of cancer which might “tipthe balance” in favour of prophylaxis.

The Appropriate Dose of Aspirin

The ideal dose of aspirin for prophylaxis is uncertain anddifficulties arise both in relation to the benefits, and thehazards of the drug.

Curr Colorectal Cancer Rep (2013) 9:9–16 11

Dose for Vascular Disease Reduction

Studies of the platelet response to aspirin suggest that max-imum inhibition of platelet aggregation is achieved with adose of approximately 30 mg [49], and clinical studies giveno evidence of any increase in the reduction of vasculardisease events with doses above approximately 75 mg onceper day [50].

Yet an intensive study showed that for some subjectsthere can be an unusually rapid recovery of thromboxaneafter a single dose of aspirin, and this may explain bothaspirin “resistance”, and uncertainties about vascular pro-tection by aspirin for diabetic subjects [51, 52].

Rocca et al. [53] have, however, shown that giving100 mg aspirin twice a day led to a complete reversal ofthe rapid recovery of thromboxane after a single dose.

The Dose for Cancer Reduction

The reductions in cancer reported from the long-termfollow-up studies of Rothwell et al. [16] “did not appearto increase at aspirin doses greater than 75 mg daily”. Onthe other hand, in the report of the trial in patients with theLynch syndrome, the authors comment that the reductions inboth colorectal and other cancers were suggestive of a dose–response relationship [25••].

However, it is uncertain whether it is primarily the doseor the frequency of aspirin taking which is critical. Withinthe Nurses’ Health Study [54] there was a trend (P<0.005)in the relative risk of death from cancer reducing withincreasing numbers of tablets to 0.77 (0.68–0.87) with 20or more per week, and the trend (P<0.02) with colorectalcancer deaths there was again a trend (P<0.02), with anincrease in the reduction to 0.61 (0.41–0.90) with 20 ormore tablets per week. In another study of 626 patients withcolon cancer there was again a significant trend (P<0.03) inthe reduction in deaths with increasing frequency of aspirintaking, the HR for colorectal cancer deaths was 0.57 (0.33–0.99) for those using 0.5 to five tablets per week and 0.46(0.17–1.26) for those using six or more tablets per week[29]. The increase in benefit, whether from different doses/or different frequencies of aspirin taking, should be exam-ined in further randomised trials.

The Dose and Adverse Effects

Studies have reported greater incidence of GI bleeding withdoses of aspirin above 300 mg/day [42] but below this dosethe evidence of differences between doses is equivocal [37,50] and even the difference in bleeding with 30 and 283 mgwas found to be non-significant (HR 0.84; 0.53–1.3) [55].

Therefore, the optimum dose of aspirin for prophylaxis isuncertain. For cancer protection it might be 600mg used in the

trial of patients with the Lynch syndrome [25••] or the 20tablets per week described by Chan [54] in a population ataverage cancer risk. There seems to be sufficient uncertaintyto justify the testing in future studies of different doses, orfrequency of aspirin, together with, it is hoped, randomisationof intervention to reduce bleeding, for example a proton pumpinhibitor (PPI) or Helicobacter pylori eradication.

Alternative Preventives to Aspirin

Statins are not only a highly effective alternative to aspirinin vascular disease reduction [56], and there are suggestionsthat they may reduce the risk of spontaneous gastrointestinaland cerebral bleeding [57]; however, although controversial[3] statins probably do nothing for cancer [4, 5].

Colorectal screening by flexible sigmoidoscopy is a high-ly effective procedure, even with only a single screening[58]. Logan et al. [59••] report that cancer was detected atfirst colonoscopy following a positive faecal occult bloodtest in 10 % of subjects aged 60–69 years and a further 10 %had “high risk” polyps. Overall, screening is likely to reducecolorectal mortality by approximately 25 % in those whoaccept screening, but the acceptance rate is only approxi-mately 50 % and this reduces the population effectiveness ofscreening to approximately 16 % [59••]. More seriousaspects of colonoscopy include bleeding for approximately0.9 to 6.4 per 1,000 colonoscopies, and perforation of thecolon for 4–12 per 10,000 [59••, 60–63].

There are several reasons why aspirin prophylaxis shouldbe considered alongside screening. First, because there is onlya 50 % acceptance of screening [59••]. Second, aspirin seemsto be of especially effective in reducing cancer in the proximalcolon [22••, 64]. Although taking low-dose aspirin may in-crease false positive results from the guaiac-based faecal occultblood (FOB) test, the sensitivity of immunochemical FOBtests is said to be “markedly increased” for subjects takinglow-dose aspirin [65]. Furthermore, a serious ethical issuearises with subjects who have a positive faecal test but refusecolonoscopy. These subjects must surely be given an alterna-tive and must be fully informed about aspirin prophylaxis.

At the same time, if subjects are adequately informed aboutaspirin prophylaxis, refusal of screening may well increase.While probably inevitable, this would be unfortunate, not justbecause there is 5–10 year delay before a reduction by aspirincommences, but also because the first colonoscopy is ofparticular value in detecting and dealing with prevalent neo-plastic lesions, and even a single examination by flexiblesigmoidoscopy has been shown to reduce mortality [58].

Aspirin for Subjects at High Risk

Questions immediately arise about how greatly increasedthe disease risk must be for recommendation of daily aspirin


to be reasonable. Clearly, the risk–benefit balance is highlydependent on both the frequency and seriousness of thevarious possible outcomes. Although much discussion(and disagreement) has focused on aspirin prophylaxis invascular disease, what ultimately matters both for publichealth and for the “man in the street” is disease-free surviv-al, and, therefore, the full value of aspirin prophylaxis is itscombined effect on vascular disease and cancer. Aspirinmay therefore be judged appropriate for subjects at a lowlevel of risk of vascular disease if there is, at the same time,a risk for cancer which tips the risk–benefit balance infavour of prophylaxis, and vice-versa.

It would be ideal if all subjects at high risk of vasculardisease or cancer who would benefit from aspirin could beidentified genetically [2••]. Although this might becomepossible for some cancers, it is limited at present to patientswith the Lynch syndrome, and to subjects known to havefamilial hypercholesterolaemia.

Vascular Disease

In addition to subjects with hypercholesterolaemia, allpatients who have evidence of vascular disease, or a highrisk score [12] should be strongly advised to take daily low-dose aspirin.

Patients with diabetes have a raised vascular risk, andalso an increased risk of colon cancer [66]. Diabetic patientsshould therefore be told of the equivocal results of aspirin inthe reduction of vascular disease in diabetic subjects andthey should also be fully informed of the recent evidencesuggestive of benefit from two aspirin doses each day [53].They should therefore be encouraged to make their owninformed decision about aspirin prophylaxis.

Aspirin has been recommended [67, 68] and challenged[69] for all men over the age of about 50 years, and womenover the age of about 55 years, and Rothwell et al. [16] pointout that the steeply increasing risk of cancer after the age ofabout 50 years tips the balance in favour of aspirin prophy-laxis from the age of approximately 45 years. All suchsubjects should be informed of the evidence and are proba-bly best left to make their own informed decision.

Cancer

Patients known to have the Lynch syndrome should bestrongly advised to submit to regular colonoscopy, and totake regular daily aspirin. Despite the findings of protectionfrom low-dose aspirin [22••], it would be difficult not torecommend the 600 mg daily found to be effective in the adhoc trial [25••].

Persons with familial adenomatous polyposis have a veryhigh life-time risk of cancer, believed to be more than 95 %,with progression to cancer by the age of 35–40 years [70].

Aspirin prophylaxis should be considered for such subjectsfrom an early age.

Persons found at colorectal screening to have adenomashould be informed of the benefits and the risk of aspirin.Persons who are invited, but decline screening raise specialproblems. It can reasonably be maintained that an invitationto be screened is a declaration of possible increased risk. Itwould seem therefore to be only reasonable to inform allsubjects who refuse screening about alternative preventives.An unequivocal ethical imperative arises for any subjectwho cooperates in a colon cancer screening procedure andwhose faecal sample is found to contain blood, but thendeclines colonoscopy. Aspirin should certainly be stronglyrecommended to all such.

Colorectal screening has been shown to be cost effective[71], but in most countries the strategy is limited at presentto a very narrow age range. For most old people, difficultdecisions arise therefore in relation to cancer prophylaxis.The most powerful predictive factor for cancer, after a veryfew genetic mutations, is age, and this is true for bothvascular disease and cancer. Evidence from post-mortemexaminations indicates the presence of polyps in approxi-mately one third of persons aged 50 years, rising to approx-imately half in persons aged 70 years [72] and, perhaps,approximately 20 % of old people are found at first colo-rectal screening to have neoplastic colon lesions [59••].“Risk scores” have been devised for colon cancer, basedon age, gender, family history, alcohol use, smoking, andBMI and it seems possible to select persons at increased riskup to approximately 15-fold [73, 74]. Use of such riskscores should be helpful with individual patients in a clinicalsetting, but it is difficult, however, to see how any suchselection could be incorporated into a public health strategy.

Conclusion

There is currently intense disagreement among expertsabout whether or not the community generally, and oldpeople in particular, should be advised, or even just in-formed, about the results of research on aspirin prophylaxis[14, 15, 75]. Nevertheless, over a third of subjects aged50 years and over in the UK have made their decision andare taking aspirin regularly [76]; in the USA the estimatesare somewhat higher [77, 78].

Although individual physicians and oncologists are free totake action with individual patients and/or subjects, the bot-tom line in relation to any public health initiative is that noregulatory authority has yet approved aspirin for use in cancerprevention. Nevertheless, what is urgently required, is:

1. large-scale, population-based observation studies inwhich the uptake of aspirin prophylaxis is monitored,


with detailed clinical assessment of the involvement ofgastric pathology in GI bleeding attributable to aspirinand the effect of untreated hypertension in cerebralhaemorrhage attributable to aspirin; and

2. large-scale randomised studies of possible measures toreduce the risk of gastrointestinal bleeding, for exampleadministration of a PPI or elimination of H. pyloriinfection, and possible measures to reduce cerebralbleeding attributable to aspirin, and, in particular, thedetection and adequate treatment of hypertension.

Disclosure No potential conflicts of interest relevant to this articlewere reported.

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Is There Enough Evidence for Aspirin in High-Risk Groups?

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