by The Welsh Aspirin Group

Peter Elwood, Gareth Morgan, Richard Adams, Christine Delon, Marcus Longley, Simon Noble, Janet Pickering, Majd Protty, John Watkins, Anna Yeatman Corresponding author: Gareth Morgan

ABSTRACT:  

Aspirin is a remarkable drug that has been shown in more than fifty years of research to be beneficial at low doses (300 mg or less daily) if included in the treatment of vascular disease and cancer, two of the most important sources of morbidity and mortality across the world. Although there are concerns about an increase in gastrointestinal bleeding, recent studies show that the risk of serious bleeding truly attributable to low-dose aspirin is low and is rarely – if ever – fatal.

This report presents evidence for aspirin’s role in in the management of both vascular disease and cancer treatment: its underuse worldwide and especially in low-income countries; and the need, on ethical grounds, for equal access to this easily affordable medication.

We strongly recommend the promotion of valid information about low-dose aspirin to healthcare professionals and to patients with vascular disease, and patients with cancer and their caregivers, to support informed decision taking based on valid evidence of its risks and benefits.

Aspirin and vascular disease:

The history of aspirin and vascular disease began with the study of platelets. While early microscopists dismissed platelets as cellular debris, in 1874 Sir William Osler described platelet pseudopodia, their adherence to fibrin, and their role in thromboembolism.¹ By 1985, it was evident that atheromatous plaque fissuring could lead to platelet adhesion, thrombus development, and myocardial infarction or ischaemic strokes.²

Beginning in 1965, Aneurin Hughes, a physician in North Wales, and Bob Tonks in Materia Medica in The Welsh National School of Medicine, published a long series of exquisite laboratory and clinical studies of platelets, salicylates, aspirin and ‘infarctoid cardiopathy’³  They linked platelet ‘clumping’ to diffuse myocardial necrosis and in 1966 they gave a presentation at an international conference in which they described the use of up to 5G. aspirin daily in the treatment of ‘more than 1,000 patients’.⁴

John O’Brien, a haematologist in Portsmouth, demonstrated that low-dose aspirin (150 mg daily) significantly reduced platelet aggregation and he persuaded the UK Medical Research Council in 1968 to conduct a randomised trial of 600 mg aspirin in the prevention of post-operative deep-vein thrombosis, diagnosed with the use I125-labelled fibrinogen in 303 patients undergoing surgery. The conclusion of the authors was:  ‘aspirin administration has not even a marginal effect on the frequency of DVT’.⁶

Despite this last, O’Brien persuaded Cochrane and Elwood, in a Medical Research Council research unit in Cardiff, to follow the work of Hughes and Tonks with a double-blind, placebo-controlled randomised trial of low-dose aspirin (300mg daily) in the reduction of death in 1,239 patients who had experienced a myocardial infarction.⁶  

The report of that trial⁶ in 1974went viral and appears to have stimulated a global research interest in aspirin and vascular disease.  However the global use of aspirin in the treatment of secondary vascular disease has been estimated as only 65% in high-income countries (71% in England) and only 25% in low-income countries.⁷

• Aspirin and the treatment of cancer:

Salicylates, the main component of aspirin, are widespread in plants. During the conduct of a vascular disease trial in Wales in the early 1970s, Elwood explored their role within plants, and he consulted Professor Stan Pierpoint, a leading expert on plant salicylates at Rothamsted Experimental Station. Pierpoint strongly supported the investigation into salicylates and human health but his advice to Elwood was: “Skip heart disease; go for cancer!” Later, Pierpoint wrote in a commentary on Plant Products and Mammalian Medicine: ‘The medicinal properties of salicylates would appear to be less fortuitous and simply a logical consequence of their role in plants.⁸

In 2002, Elwood partnered with Gareth Morgan, who had worked with the International Agency for Research on Cancer (IARC) and had contributed to a detailed review by IARC of aspirin, NSAIDs and cancer.⁹ Together, Elwood and Morgan published a comprehensive review of published evidence at that time on aspirin’s role in cancer,¹⁰ and in 2003 they set up a research group of colleagues in Wales who had recently published work on aspirin – the Welsh Aspirin Group (WAG). 

The first task WAG set itself was to draw up a list of key issues of relevance to the possible use of aspirin as an additional treatment of cancer, and during the following 15-20 years, the Group investigated each of these issues in detail, each commencing with a systematic literature search to identify publications relevant to an issue, followed by meta-analyses of relevant data extracted from all the relevant published studies.

2.1 The safety of aspirin: The first key issue examined by WAG was the relative safety of low-dose aspirin. It is unfortunate that the scientific literature on the issue of aspirin and bleeding appears to have been swamped by a plethora of statements about serious dangers from aspirin, most unsupported by any valid evidence while some are total misinterpretations. Probably the most misleading – and probably the most influential and destructive item on the web appears to have been a report issued by Reuters on the 14th June 2017, stating: ‘daily aspirin causes 3,000 deaths from bleeding in Britain every year’.¹¹ This claim was taken up and very widely and repeatedly publicised in the web and in the general media across the world.

The report by Reuters was however totally invalid, having been based on a prospective study of 3,166 older patients, all of whom (93–97%) were taking aspirin¹² and there were no control subjects not taking aspirin. Many of the bleeds attributed to aspirin will have been due to gastrointestinal pathology, including peptic ulcers and H.pylori infections. Furthermore, there have been reports of so-called ‘neurogenic’ bleeding in patients with acute ischaemic strokes. Thus, a report based on six thousand patients in the Fukuoka Stroke Registry, describes 89 patients (1.4%) who experienced a GI bleed within a week of admission for acute ischaemic stroke.¹³ O’Donnell et al. reported an incidence rate of 1.5% within a week of admission for acute ischaemic stroke, associated with a high rate of death¹⁴ and Davenport et al. estimated an incidence of 3%.¹⁵ In the study which led to the Reuters claim of 3000 deaths, 2000 (65%) of the patients had had a stroke. It is highly irresponsible therefore that the claim about aspirin and 3,000 deaths is still displayed repeatedly on the web and one cannot but lament that it has never been withdrawn.

Morgan appears to have been the first to raise the issue of the severity of GI bleeding attributable to aspirin,¹⁶ and together with the Group in Wales he conducted a systematic search of the published literature on aspirin and GI bleeding.¹⁷  They proposed that in this the proportion of bleeds that were fatal would be used as a measure of the severity of bleeding.  A systematic search of the literature identified eleven large randomised, placebo-controlled trials in which both total and fatal GI bleeds had been recorded.

• Table 1 Data from eleven randomised trials which had recorded fatal gastrointestinal (GI) bleeds ¹⁷

Incidence of all GI bleeds:      in 54,625 subjects on aspirin for 2.8 years     in 52,583 subjects on placebo for 2.8 years	8 per 1,000       5 per 1,000 RR 1.55(1.32, 1.83)
Proportion of GI bleeds that were fatal:      in subjects randomised to aspirin      in subjects randomised to placebo	4% 8% RR 0.45(0.25, 0.80)
Risk of a fatal GI bleed:      insubjects randomised to aspirin      in subjects randomised to placebo	3.7 per 10,000 4.7 per 10,000 RR 0.77(0.41, 1.43)

The table shows in the first row of data that during the conduct of the trials there had been an additional one GI bleed per year within every 1,000 subjects on aspirin. The mortality of the bleeds in subjects randomised to aspirin is however half that of the bleeds in subjects on placebo, implying that the overall severity of bleeds associated with aspirin taking is relatively low in comparison with bleeds attributable to GI pathology: peptic ulceration and gastric infection, and the final row confirms that there were no excess fatal bleeds in patients randomised to aspirin. 

The original report of this study ¹⁷ references several other overviews and meta-analyses which confirm these findings and show similar reductions in fatal bleeds truly attributable to aspirin. It is also worth noting that in the massive ASPREE trial of aspirin in 20,000 older patients there were only two fatal bleeds in a 4.7 year follow-up  –  both in patients randomised to aspirin.¹⁸  If however non-fatal GI bleeds are still a concern, co-prescription of a proton-pump inhibitor (a PPI) has been shown to reduce GI bleeding by 70-90%.¹²   

 Intracerebral bleeding is undoubtedly a most serious side effect of aspirin. Fortunately ir is a rare event, aspirin being associated with about one such bleed per year in every 10,000 patients given aspirin.¹⁹ However, the major factor in these bleeds is hypertension,  and in an RCT of aspirin based on more than 18,000 hypertensive patients – all of whom were receiving ‘optimal’ antihypertensive treatment – there were no additional cerebral bleeds in patients randomised to aspirin.²⁰

2.2. Aspirin and metastatic cancer spread: A delay in the metastatic spread of cancerhas been shown with aspirin in a number of reports, and for a wide range of cancers.²¹This delay is of considerable importance. First, because much of the pain, many of the complications, and perhaps as many as 10% of deaths – are due to damage caused by the metastatic growths, rather than by the original tumour.^22,23 A further benefit of aspirin is that the delay with aspirin increases the opportunity for ‘early’ treatment – a highly beneficial effect in view of the increasing difficulties in cancer services in many countries.²⁴    

2.3 Aspirin and cancer mortality: The research group in Cardiff conducted three replicate systemic literature searches in 2016, 2018 and 2011 in order to identify deaths within observational studies of cohorts and case-control studies of patients with cancer, some of whom were taking aspirin.²⁵  The three searches together identified a total of 118 cohorts describing eighteen different cancers, and an overall meta-analysis showed that patients taking aspirin (250,000 patients in total) was associated with about a 20% reduction in cancer mortality. (Hazard Ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84 in 70 reports and a pooled odds ratio (OR): 0.67; 0.45, 1.00 in 11 other reports. Overall data for all-cause mortality showed closely similar reductions.

Table 2: Aspirin taking and mortality: meta-analysis of 118 published observational reports.²⁵

GROUP	Cancer mortality		All-cause mortality
	No. of studies	HRs (95% CIs) ORs (95% Cis)	No. of studies	HRs (95% CIs) ORs (95% Cis)
Colon cancer	24 One	HR 0,71 (0,62, 0.80) OR 0.78 (0.66, 0.93)	21 One	HR 0.81 (0.73, 0.91) OR 0.78 (0.65, 0.92)
Breast cancer	13 4	HR 0.84 (0.72, 0.98) OR 0.75 (0.36, 1.57)	9 None	HR 0.94 0.70, 1.25) –
Prostate cancer	15  One	HR 0.89 (0.78, 1.02) OR 1.02 (0.78, 1.34)	6 One	HR 1.00 (0.78, 1.27) OR 1.06 0.94, 1.19)
15 other cancers	18 5	HR 0.79 (0.70, 0.83) OR 0.49 (0.26, 0.95	21 5	HR 0.67 0.60, 0.75) OR 0.47 (0.26, 0.83)
All 18 cancers	70 11	HR0.79 (0.73, 0.84) OR 0.67 (0.45, 1.00)	56 7	HR 0.79 (0.74, 0.86) OR 0.57 (0.36, 0.89)

Note: a number of studies reported data on both Cancer and All-cause mortality

Publication bias, arising from the selective publication of positive findings for an intervention such as aspirin, is an important possible source of bias in observational studies such as the above.  However, a ‘trim and fill’ testing procedure which restores symmetry in forest plots was therefore applied extensively to the data, and although the benefits of aspirin were reduced, significance of almost all the reductions remained.²⁵

Of particular interest were the twenty-three cohorts of patients with less common cancers. In these, the table shows that aspirin taking was associated with an average reduction of about 21% in cancer deaths – almost identical to the reduction with aspirin in 52 cohorts of the three common cancers (20%),²⁵ suggesting that benefit from aspirin is likely in a very wide range, if not all, cancers.

All the above evidence comes from observational studies, and it is unfortunate that evidence on aspirin and cancer survival derived from randomised studies is both limited and inconsistent. Furthermore, some of the published randomised trials suffer from poor compliance, inadequate treatment duration, and/or insufficient statistical power. On this last Richard Peto, after publishing an overview of aspirin and vascular disease trials, highlighted the fact that underpowered trials are irresponsible as they risk dismissing crucial and important findings.

The most significant trial on aspirin and cancer deaths is undoubtedly the randomised trial by Burn et al. on aspirin and Lynch syndrome patients.²⁶ This trial showed a notable effect of aspirin on mortality (Hazard Ratio (HR) 0.41; 95% CI 0.19-0.86), leading NICE in the UK to recommend aspirin for patients with the syndrome.²⁷ Lynch syndrome, the most common hereditary cancer risk condition, accounts for at least 3% of colon and other cancers, and has an estimated prevalence within the general community of about 1 in every 300 individuals.²⁸

It is important to distinguish ‘ad hoc’ studies, conducted to test a prior hypothesis, from opportunistic trials based upon the re-analysis of data collected for some other purpose. An ad hoc trial (ASCOLT) conducted in patients with colorectal cancer²⁹ given aspirin (200 mg daily for 3 years after completion of standard adjuvant therapy, was well tolerated but did not significantly improve disease-free survival (HR after 60 months 0.91; CI 0.73,1.13)..  Another ad hoc randomised trial (the ABC trial) which had been set up to test 5 years of 300 mg aspirin daily in 3,021 patients with advanced, high-risk breast cancer.³⁰  However the trial was prematurely ended after only 20 months when aspirin was associated with a non-significant 25% increase in mortality (HR 1.27; 95% CI 0.99-1.63). Although compliance with allotted treatment is said to have been high, there were important compromises in treatment allocation during the trial. Thus there was a cross-over in the treatment actually taken, and 10% of patients  allotted to placebo actually took aspirin, and 45% of trial subjects discontinued their allotted treatment. For these last, the cessation of aspirin could have increased their risk of death.³¹   

These ad hoc trials had however been preceded by reports of four small randomised trials and a later pooled examination of these yielded a non-significant HR of 0.68; in 722 patients.²⁵ An opportunistic trial of aspirin and prostate cancer, conducted within the US Physicians study, yielded a reduction in prostate deaths (HR 0.68; 95% CI 0,52, 0,90 in cancer deaths and HR 0.72; 0.61, 0.90 in all cause deaths).³²

A highly commendable series of long-term follow-up studies conducted by Rothwell and colleagues of patients who had already participated in more than 50 earlier randomised trials of aspirin and vascular disease. These patients who had already been randomised to aspirin or placebo were followed-up for up to 20 years after conclusion of the vascular trials. The medical records of the individual patients were examined for later evidence of incident cancer.Consistently, in seven reports based upon separate groups of original vascular trials there was evidence of a reduction in cancer incidence and in cancer deaths associated with aspirin. For example: odds ratio (OR) 0.58; 95% CI 0.44, 0.78 in a pooling of follow-up data from six previous vascular trial cohorts³³  and OR 0.84; 0.75, 0.94 in an follow-up of subjects from 51 prior vascular trials).³⁴

Using much the same approach, a research group in Canada⁵⁵ included data on non-vascular deaths in eleven randomised trials and reported a meta-analysis on pooled cancer deaths. There was a total of 162 cancer deaths (2.02%) in the aspirin group and 210 cancer deaths (2.60%) in the control groups (RR 0.77: 95% CI, 0.63-0.94), during an average follow-up time of 2.8 years.

Using a quite different strategy, a group in Liverpool extracted extensive baseline data, including aspirin taking, from the records for 44,000 patients with colon cancer. Within a subset of these they constructed a formula giving predicted estimates of survival,³⁶  which, if applied to the remainder of the patients gives increases in survival attributable to aspirin taking, of about five years in males and about four years for a woman.²⁵

Yet another approach to evaluate associations is Mendelial Randomisation. This is based on the fact that a mutation which mimics the effect(s) of a preventive measure or a drug such as aspirin, will have occurred at random within a population. Several studies using this strategy have yielded evidence favourable to aspirin in the treatment of cancer.^10,37,38 

Finally, support for the validity of aspirin as a treatment of cancer follows from the known effects of aspirin upon biological mechanisms of cancer initiation, growth and development, and clinical outcomes of cancer,³⁶ providing a reasonable basis for an expectation of clinical benefit(s) in cancer.  One such report led The Royal Society, in a commentary entitled ‘Aspirin; the wonder drug against cancer?’  to refer to a ‘harmony’ between the effects of aspirin on biological mechanisms and its effects upon the clinical outcomes of cancer.³⁹

With all this background evidence from randomised and quazi-randomised studies, one wonders how many new randomised trials, in how many different cancers will be required to resolve the uncertainties some express about the evidence on mortality already available from observational cohort studies of patients with cancer.²⁵ Furthermore, are the other benefits of aspirin –  the delay in metastatic spread, and the reduction in vascular complications – to be withheld while new RCTs are completed?

 In a number of studies covering a wide range of cancer sites, patients with cancer have been shown to be at increased risks of dying from cardiovascular disease, including coronary artery disease, stroke, and both arterial and venous thrombosis.^40,41 Aspirin has been shown to reduce the incidence and overall mortality of these and other vascular complications of cancer,  and the biological mechanisms through which this is achieved have been  described. Guidelines issued by the American Society of Clinical Oncology recommend appropriate vascular prophylactic and treatment measures for all hospitalized cancer patients,⁴².and most recently, the need for cardioprotective therapies has been shown to be particularly great in patients undergoing chemotherapy.⁴³

Discussion:

Perhaps the most crucial issue in relation to the treatment of cancer by aspirin is: who should evaluate and make the final decision whether or not to take aspirin and what rights do cancer patients themselves have? In 2010, a challenge was published in the BMJ: “The debate about aspirin has consumed the medical profession for over 30 years” [now, 50 years!] “yet public participation or consultation has been minimal”.⁴⁴

In response, a three-day inquiry – a ‘Citizens’ Jury’ – was held in Cardiff entitled: “My Health – whose responsibility?” ⁴⁵ Sixteen members of the public with no relevant vested interest convened as jurors. They heard from experts, including “experts by experience,” and they debated the issues, including the indecision about aspirin as a potential cancer treatment. On this last, the jurors unanimously judged that patients and the public should be more involved in research evaluation and the relevance of findings to clinical practice and to public health policy – ‘even before there is agreement between doctors’.⁴⁵

A basic principle in clinical care is that patients have a right to be involved in discussion about their treatment and have a right to make informed decisions about their care.⁴⁶  One wonders how patients can make an informed decision about the safety of aspirin and its possible benefits with regard to their own case, let alone make an informed comment about the role of aspirin in the general community, when they have been frequently misinformed bn the world-wide web, in news-papers, and in published journal articles etc. of the dangers of aspirin, even at low doses. 

We would also assert that the basic principle of justice demands the active promotion of low-dose aspirin within poorer countries. One in every six deaths worldwide is due to cancer, giving an estimated 9.6 million deaths in 2018, with around 70% of the deaths in low- and middle-income countries. WHO points out that most cancers in the poorer countries are diagnosed at a very late stage, when most treatments are no longer effective – even if treatments were available, which they are not in many countries.⁴⁷ Against that background the promotion of aspirin would be of enormous benefit if promoted within developing countries, and, as one oncologist has predicted: ‘a global impact [upon cancer] could be realised.⁴⁸

In fact, even the established benefits of aspirin in vascular disease should be more effectively promoted.  A recent analysis of the use of aspirin in secondary prevention across 51 countries showed that only 40% of individuals with a history of cardiovascular disease used aspirin, and in low-income countries, the figure was just 17%.⁷ Thus, any increase in the use of low-dose aspirin would be likely to substantially reduce mortality from both cancer and cardiovascular disease worldwide.

Conclusions: Low-dose aspirin is a uniquely affordable and effective drug with significant potential to combat the world’s leading causes of morbidity and mortality: vascular disease and cancer. Despite extensive research and advocacy efforts—including public lectures, collaborations with cancer charities, and online reports,⁴⁹ the clinical use of aspirin remains limited. The Welsh Aspirin Group continues to work towards ensuring that both patients and healthcare providers have access to evidence based information, allowing for informed discussions on aspirin’s role in cancer treatment.

However, the medical community remains divided. While some consider the current evidence compelling – NICE’s recommendation of low-dose aspirin for a subgroup of subjects at high risk of colon and other cancers; its role in delaying metastasis; in reducing vascular complications of cancer; and in influencing key biological mechanisms. Yet others insist that further randomized controlled trials are needed to secure its place in cancer treatment. This ongoing debate raises an important question: why is a safe, widely available, and low-cost medication not being routinely recommended or prescribed? Hence the aspirin paradox!

Beyond its established benefits, aspirin’s potential extends to other areas of medicine, including its role in Hughes Syndrome, in preeclampsia, and in pregnancy-related complications. Further research is essential to determine optimal dosages, its impact on different cancers, and its relative effectiveness in patients with genetic mutations such as PIK3CA. However, increasing difficulties in raising research funding and the closure of the International Aspirin Foundation raise concerns that profit-driven priorities may be overshadowing public health interests.

To unlock aspirin’s full potential, a coordinated effort among healthcare providers, policymakers, and researchers is essential. Covering the gaps in scientific evidence, ensuring equitable access, and prioritizing further investigation could establish aspirin as a cornerstone of global health strategies, ultimately improving and saving countless lives.

ACKNOWLEDGEMENTS

No financial support was sought or received for any of the work undertaken in Wales.  The authors will be every grateful to colleagues in Wales and beyond who collaborated and encouraged the work described, including the following:

Beswick AD, Burr ML, Cochrane AL, Chia JWK, Dolwani S, Duthie GG, Galante J, Hughes J, Gallacher AM, Gallacher JE, Gaziano JM, Kelson M, Lanas A, Mason M, Morris D, Mur LAJ, Phillips CJ, Renton R, Roberts S, Soon SS, Steward W, Sweetnam PM, Watkins A, Weightman AL Welsby E, Williams G, Woollard M

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