Aspirin: 120 years of innovation. A report from the 2017 Scientific Conference of the International Aspirin Foundation, 14th September 2017, Charité, Berlin.
Walker J, Hutchison P, Ge J, Zhao D, Wang Y, Rothwell P, Gaziano M, Chan A, Burn J, Chia J, Langley R, O’Donnell V, Rocca B, Hawkey C, Patrono C, Badimon L.
Key words aspirin, inflammation, primary prevention, secondary prevention, tertiary prevention, Colorectal cancer (CRC), cardiovascular disease (CVD), stroke, bleeding, risk, benefit, Lynch syndrome, precision medicine, individualised choice, personalised medicine.
Acetylsalicylic acid, extracted from meadow sweet, was first synthesised by Dr FeIix Hoffman on August 10th 1897 and Aspirin was born. It quickly became the best known pain killer in the world and in the 120 years since this event aspirin has continued to attract interest, innovation and excitement. Set within the walls of the preserved ruins of Rudolf Virchow’s lecture hall at Charité, within Berlin’s Museum of Medical History, the International Aspirin Foundation’s 28th Scientific Conference served to facilitate international, multi-disease, multi discipline discussion about the current understanding of aspirin’s mechanisms of action and utility in modern medicine as well as ideas for future research into its multifaceted applications to enhancing global health.
In addition to the delegates in Berlin 300 medical doctors at the 19th Annual Scientific Congress of the Chinese Society of Cardiology were able to join the cardiology sessions from Taiyuan, Shangxi province via a live streaming link to and from China. This led to useful discussion and allowed a truly international perspective to the meeting.
The first session an update on cardiovascular disease (CVD) and stroke: East meets West was chaired by Professor Junbo Ge who expressed his delight at joining the conference and working together to tackle CVD which is now the number one killer in China.
The disease burden of CVD and the major strategy of primary prevention for CVD in China - Dr Dong Zhao
Dr Dong Zhao joined the meeting, via the live streaming link to the Chinese Society of Cardiology Congress in Taiyuan, and described the growing CVD burden in China and the primary prevention strategies used to tackle this. Dr Zhao is involved with the development of both chinese and international CVD prevention guidelines.
Cardiovascular disease (CVD) is currently the top cause of premature death in China. In line with the United Nation’s Sustainable development goals for 2030, China aims to reduce by a third all premature death from non-communicable causes1. In 2012 CVD was responsible for 41 % of all urban deaths and 39% of rural deaths2. This challenge is heightened by the fact that the rate of mortality from ischemic heart disease (IHD) has risen dramatically over the last 2 decades; it was the seventh leading cause of life lost in 1990 but by 2010 it had jumped up to be the second cause 3. This pattern is expected to continue with the estimated numbers of people with IHD in China more than doubling from 8.1 million in 2010 to 22.6 million in 20302,3,4. Stroke statistics show an improved survival rate and reduced disability, 3,5 however an increase in the number of people having a stroke is still expected to increase from 8.3 million in 2010 to 32 million in 2030. China ranks in the top three for premature deaths from stroke among the G20 countries, 3 whilst aging and population growth may account for at least half of the increase in CVD, lifestyle factors also play a key role in the current and future CVD epidemic.
Primary prevention of CVD is particularly important in China because in over 70% of individuals experiencing an initial Coronary Heart Disease (CHD) event death occurred outside of the hospital setting without a chance for secondary prevention 6. With cardiac arrest 74% of cases occurred at home. Primary prevention of CVD in China is therefore a top priority strategy for reducing these premature deaths especially the potential to influence lifestyle factors (e.g. smoking, diet, weight and activity levels) and reduce risk factors such as high blood pressure, high cholesterol and control diabetes.
It is usually doctors who perform CVD risk assessment because they are the decision makers for medical treatments in China. Dr Zhao explained that CVD risk assessment is important in order to identify those at high-risk in the Chinese population without current CVD and help them to understand the whole profile of their CVD risk factors in order to be able to provide an individualised CVD risk management plan. To be able to carry out CVD risk assessment a CVD risk predicted model based on long term observational studies and risk assessment tools are required as well as relevant recommendations in guidelines. Predictive models developed in one geographical area or ethnic population may not be suitable for other populations and regions. Risk assessment methods such as the Framingham CVD risk score which has a homogeneous nature to its study population cannot be simply extrapolated to other settings. Specific tools such as the Chinese Multi –provincial cohort study are required.
The 2012 China National Plan for Non-Communicable diseases [NCD] prevention and treatment7 has clear targets for CVD prevention. Both the 2016 China guidelines of dyslipidemia management and the 2017 Chinese guidelines for CVD prevention (soon to be published) have new recommendations for risk assessment in China.
The 2016 China expert consensus advocates that for individuals with a ten year ASCVD8 risk of greater than or equal to 10%, aspirin should be used for the primary prevention of CVD. Doctors in China need to identify those with a high CVD risk in China and provide early treatment for their CVD risk factors. The updated protocol of CVD risk assessment in China has provided a reasonable tool to assist clinicians in achieving this. Busy clinics in China can sometimes stand in the way of finding time to carry out CVD risk assessment; the greatest challenge therefore will be finding ways to effectively implement these guidelines into CVD prevention practice in China.
Antiplatelet therapy for stroke prevention in China – Professor Yongjun Wang
Professor Yongjun Wang from Beijing Tiantan Hospital presented from China on antiplatelet therapy for stroke prevention in China. Stroke is a major burden in China; from 2010 stroke became a leading cause of death and disability in China and mortality from stroke is 5 times higher in China than it is in the USA3,9. According to a national population based survey in 2013, the prevalence of stroke in China was 1114.8 per 100, 000 people and its prevalence, incidence and mortality rates of stroke were significantly higher in rural areas compared with urban areas10. More than 70% patients have ischemic stroke or TIA10
The Chinese clinical guidelines for the secondary prevention of ischemic stroke and TIA recommend an optimal dosage of aspirin between 75 and 150 mg/day. A combination of aspirin and clopidogrel for 21 days is recommended to patients with minor stroke or high-risk TIA within 24 h of onset 11. These recommendations are based on the CHANCE trial12.
The rationale behind the randomised controlled CHANCE trial was to find the “sweet spot” or balance point of efficacy and safety for dual antiplatelet therapy in stroke. After three previous trials MATCH 2004, PRoFESS 2008 and SPS3 2012 had all failed to increase efficacy but had increased the risk of bleeding, CHANCE, which randomised 5170 patients from 114 hospitals focused on early, short-term, optimized dual antiplatelet therapy (within 24 hours) to reduce the risk of new stroke at 3 months for clopidogrel-aspirin treatment in acute minor stroke or high-risk TIA. After a big data analysis based on 90, 000 patients in other trials, several strategies were found that may improve the efficacy as well as decrease the risk of bleeding of antiplatelet therapy. This formed the rationale behind CHANCE;
- Intensive antiplatelet therapy should be conducted within 24 hours.
- High-risk non-disabling patients may have high risk of ischemic events but low risk of bleeding and are therefore the appropriate target population.
- An appropriate treatment strategy with a loading dose of clopidogrel 300g given as soon as possible and then dual antiplatelets for 21 days should be used.
The aim was that this early, short-term, optimized dual antiplatelet therapy could be an effective strategy with a low risk of bleeding13. CHANCE showed an early benefit of clopidogrel-aspirin treatment in reducing the risk of subsequent stroke which persisted for the duration of the 1-year of follow-up12. They also found in patients treated within 12 hours, the combination of clopidogrel and aspirin was more effective than aspirin alone in reducing the risk of recurrent ischemic stroke during the 90-day follow-up and did not increase the hemorrhagic risk 14. Clopidogrel-aspirin treatment may have a benefit of reducing stroke risk outweighing the potential risk of increased bleeding especially within the first 2 weeks compared with aspirin alone in patients with minor stroke or TIA15. In addition two-week combination therapy may be enough for minor stroke or high-risk TIA.
The CYP2C19 genotype and clopidpgrel responsiveness was also investigated in the CHANCE trial and it was discovered that the use of clopidogrel plus aspirin compared with aspirin alone reduced the risk of a new stroke only in the subgroup of patients who were not carriers of the CYP2C19 loss-of-function alleles. In CHANCE it was found that nearly 59% of patients were carriers of the CYP”C19 loss-of-function alleles 16. These findings support a role of the CYP2C19 genotype in the efficacy of this treatment. Precision individualised antiplatelet therapy according to geneotype will help target treatment in the future.
The efficacy of ticagrelor in however not affected by CYP2C19 and this led to the development of another RCT, the PRINCE trial, in order to assess 90-day platelet reactivity for ticagrelor-aspirin treatment, compared with clopidgorel-aspirin treatment in acute minor stroke or high-risk TIA within 24 hours after onset. The interim analysis suggests that looking at PRU (platelet reactivity units) and HOPR (high on-treatment platelet reactivity), there may be a positive trend for better efficacy for those treated with the ticagrelor and aspirin combination.
Professor Wang concluded that antiplatelet therapy is easy to use, inexpensive and well tolerated; adherence however is not optimal with a decline in antiplatelet use from 81% at the time of hospital discharge to 66% post-stroke17.
Acute effects of aspirin in TIA and stroke – Professor Peter Rothwell
Professor Peter Rothwell, Head of the Centre for the Prevention of Stroke and Dementia in Oxford, UK took the delegates through the role of aspirin in acute TIA and minor stroke. There is an acute or early risk of a major stoke occurring after TIA or minor stroke of around 10% unless appropriate treatment is given 18,19,20,21. The first hours after a minor stroke or TIA are therefore considered an emergency. Unfortunately many patients after a TIA or minor stroke wait more than 24 hours to see their GP, the length of the delay depends on the day of the week, with weekends leading to a longer wait22.
Despite UK public education such as the FAST campaign (Face, Arms Speech, Time https://www.stroke.org.uk/take-action/recognise-signs-stroke). People are still not seeking medical attention soon enough 23. Unlike a suspected heart attack where the America Heart Association and British Heart Foundation advise self-medication with an aspirin, official website advice for a suspected TIA or stroke vary with either no recommendation or advice to check with a doctor before taking aspirin. Pre hospital self-administration of aspirin tends to be discouraged after stroke because of concerns about the possible risk of intracerebral haemorrhage. This fear is unfounded as haemorrhage is a rare cause of TIA symptoms and is responsible for less than 5% of minor strokes. People should be encouraged to seek immediate medical attention and with transient neurological symptoms self-administration of aspirin may also be appropriate especially where access to medical care maybe delayed.
There are few randomised trials on the effect of aspirin on the risk of early recurrent stroke after TIA and minor stroke and no data on severity. Observational studies do however suggest early substantial benefits.
The EXPRESS study which was not randomised but a before and after study showed an 80% reduction of recurrent stroke when patients were seen promptly and given aspirin, started on a statins and BP lowering agents 24,25. Of these aspirin is hypothesised to produce much of the acute benefit24. The severity of recurrent cerebral events was also reduced in EXPRESS.
Due to the absence of published randomised evidence, data was extracted and re-analysed from all available previous trials of aspirin versus placebo for secondary prevention after TIA or ischaemic stroke26. This showed that the acute benefits of aspirin have been underestimated. The researchers found if aspirin is give early after TIA and minor stroke there are less severe recurrent events as well as far fewer events. The patient is in a very thrombotic state after these events and aspirin reversed this substantially 26.
Professor Rothwell ended his presentation recommending that the general public should self-administer aspirin after TIA in the same way that they take aspirin for chest pain. Timely medical treatment with aspirin as a key intervention is important after all possible TIAs or minor stroke. Aspirin should be self-medicated after an unknown “funny turn”, it is widely available, costs virtually nothing and there is no major bleeding issue after transient events.
Primary prevention in the US and Europe and forthcoming trials – Professor Mike Gaziano
At the other end of the spectrum Professor Gaziano, a preventive cardiologist and internationally recognised chronic disease epidemiologist from Boston, USA, spoke of his work in aspirin primary prevention trials including the landmark Physicians Health Study (PHS), the large scale Women’s Health Study (WHS) and currently the ARRIVE trial.
Whilst the benefit of aspirin antiplatelet therapy has been clearly demonstrated for people with previous CVD27 this risk/benefit equation is more complex in primary prevention; where individuals are at risk of an initial cardiovascular disease but have not yet had an event.
The United States Preventative Services Task Force (USPSTF)28 has conducted a systematic review of the effect of aspirin in the primary prevention of CVD. It is worth noting the primary prevention trials were mostly in people of European descent and the risk to benefit ratio may differ in other populations. USPSTF used a series of scholarly works to underpin their decisions about aspirin in the primary prevention of CVD and colorectal cancer (CRC). They looked at the number of events prevented versus the number of events caused (e.g. fatal GI bleeding) and considered absolute number of events, all risk in net life years and quality of life years gained. This was a multiple risk strategy. Following their review the USPSTF has recommended initiating low dose aspirin use for the primary prevention of CVD and CRC in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at risk of bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for at least 10 years. They also state that in the 60-69 year age group the decision to initiate aspirin should be an individual one and that there is not enough available evidence to recommend, for or against, the use of aspirin in the prevention of CVD and CRC in those younger than 50 years and 70 years or above.
It is the action of aspirin on platelet function that works to prevent CVD events that is also responsible for its side effect of bleeding risk. This bleeding risk falls into two main categories; gastrointestinal (GI) bleeding and intracranial bleeding. Risk of bleeding can increase with a person’s age, gender, medication use and CVD risk factors29 .
Whilst hundreds of trials have been carried out on the role of aspirin in acute treatment and the secondary prevention of CVD there are relatively few in the area of primary prevention. This is because of the large scale required for these studies and the need for long term follow up. Several ongoing primary prevention trials are however now under way and will come to fruition over the next few years which will help to give more insight into the use of aspirin in populations where the risk of CVD is higher than the general population. ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events) tests aspirin 100mg daily in those with moderate to high risk of a CVD event results are expected 2018. ARRIVE is being conducted mainly in Europe. ASPREE Aspirin in Reducing Events in the Elderly looks at patients over 70 years and is being conducted in Australia and the United States, ASCEND is a study based in the UK testing low dose aspirin in diabetics without known CVD and ACCEPT-D tests low dose aspirin and simvastatin in diabetics. These trials will provide critical information to round up recommendations for different segments of the population.
People should be encouraged to talk with their clinician about starting low dose aspirin. Providers also need education on how to apply risk assessment tools and make calculations regarding the use of low dose aspirin. In this age of empowerment patients can help with this dialogue. Tools are emerging that help patients own more of their health data and contribute to decisions about their treatment. An assessment of CVD risk, total mortality, cancer risk and bleeding risks are necessary when considering aspirin in primary prevention. Therefore, unlike acute care, where a more parental role is used to recommend treatment, in primary prevention we need to empower patients to make the decision. In an acute event the patient can see the benefit of the therapy and understands the risk but in primary prevention the patient often feel well and yet their blood pressure and cholesterol are raised. They might need to take a statin, aspirin and blood pressure medication. All of which requires active participation from the patient. “The person wont thank you for the heart attack or stroke they didn’t have but they will blame you for a bleed whilst on aspirin”. This is a difficult paradigm and a complex construct for the clinician to manage.
Professor Gaziano called for a consideration for wider use of low dose aspirin in both primary and secondary prevention which could potentially save hundreds of thousands of lives annually and prevent millions of CVD and cancer events around the world.
During the discussion time the question of what is low dose aspirin in primary prevention was raised. Overall there is a lack of data to agree an exact dose but when using aspirin for primary prevention compliance over a long time period needs to be considered and it is therefore better to be within an effective dose range rather than on the margin of the dose range; 100 mg a day seems to be effective for most people. However a one dose fits all approach may not be right. There is currently no tailoring to weight and physical characteristics and this is probably what is needed especially where compliance is an issue leading to an intermittent rather than continuous antithrombotic effect. Personalised medicine will probably be the future with precise targeting of medication. This is an area of active research currently.
Stopping aspirin for surgery was also discussed. This is done more for surgeons benefit as the operation will be approximately 10% shorter but is not usually necessary for the patient. Surgery puts the patient into a very prothrombotic state so stopping aspirin is not helpful.
Delegates asked how long patient should be on aspirin. It was felt overall that in primary care in general there should be ongoing dialogue regarding CVD risk, cancer risk, life expectancy and bleeding risks on aspirin as these all change over time. Therefore at fairly regular intervals medications need to be reviewed with the patient in order to update where the patient is on the risk to benefit spectrum.
The oncology session, chaired by Dr Ruth Langley, looked at the evidence for aspirin in cancer prevention and treatment and the challenges in communicating the benefits and risks of aspirin to the wider population. The concept of therapeutic chemoprevention for cancer is relatively novel, people ‘don’t want to take tablets’; it may be that a measurable cancer biomarker analogous to cholesterol or blood pressure in cardiovascular disease is needed for therapeutic cancer prevention to be successful. Other issues include the fact that aspirin is not considered to be an oncology drug and that meetings and conferences are arranged by tumour site which may be a challenge for chemoprevention. Understanding the anti-cancer mechanism(s) of action of aspirin will be crucial to maximising its clinical utility in the future.
Aspirin for the Primary Prevention of Colorectal Cancer- Professor Andrew Chan
Professor Andrew Chan, who heads the Clinical and Translational Epidemiology Unit at Massachusetts General Hospital and is a Professor of Medicine at Harvard Medical School, spoke about the role of aspirin for the primary prevention of colorectal cancer (CRC). He explained that in some ways this should be a public health consideration in the context of aspirins role in multiple diseases rather than any single individual disease. An improved identification of those in whom the protective effect of aspirin outweighs any harms will be important and this precision medicine approach may emerge as further understanding of aspirins mechanism of action become clearer.
Colon cancer is one of the most preventable cancers in the developed world however the current methods of prevention do have limitations 30. There is however a substantial weight of evidence supporting aspirin in CRC prevention starting with research carried out in the 1980s and continuing through to the current day. The data includes case control and cohort studies as well as some randomised controlled trials (RCTs). Current cancer screening methods are successful but there are limitations and they are resource intensive, limiting its potential in many populations. To investigate the potential for precision medicine, Professor Chan’s team leveraged data from two large population based cohorts. From a pooled-analysis of ten cohort and case-control studies aspirin was shown to reduce the risk of CRC by 29%31. Further data has come from a secondary analysis of RCTs; a meta-analysis of four RCTs suggested that aspirin treatment for five or more years at doses of at least 75mg daily reduced long-term CRC risk by 24%32. It appeared that a significant reduction in risk was not observed until at least a decade of use. Aspirin use is however associated with clear hazards – especially gastrointestinal bleeding and therefore there is a critical need for a precision medicine approach.
The weight of the evidence is so strong that the influential USPSTF released a recommendation which incorporates CRC prevention into the rationale for recommending routine aspirin use among patients with cardiovascular risk factors. Although this guideline doesn’t speak to a recommendation in the absence of CVD prevention, it is a milestone in that, other than tamoxifen in high risk breast patients, this is the first medication recommended for cancer prevention.
Professor Chan explained that a definitive RCT testing long term daily aspirin at a range of doses for its effect on CRC is difficult to carry out due to the large number of subjects and the length of follow up that would be required. Instead RCTs designed to test the effect of aspirin on colorectal adenomas, the precursor to most CRCs, have been carried out and have provided positive data for aspirin in chemoprevention. These include the Aspirin/Folate Polyp Prevention Study (AFPPS), Association pour la Prévention parl’Aspirine du Cancer Colorectal (APACC), Cancer and Leukemia Group B (CALGB), the United Kingdom Colorectal Adenoma Prevention (ukCAP) trial and the Japan Colorectal Aspirin Polyps Prevention (j-CAPP) trial.
In future years additional RCTs such as ARRIVE, ASCOLT, ASPIRED, ASPREE, CAPP3, SeAFOod and the continued collection of long term outcome data from completed trials are expected to add to the growing weight of evidence supporting the use of aspirin for the prevention of CRC.
Professor Chan proposed that aspirin probably works via an integrative multi-pathway model rather than any single dominant pathway for its mode of action. As our understanding of aspirin’s anti-cancer mechanism grows it may be possible to develop molecular biomarkers (using tissue, urinary or genetic biomarkers) that will help to stratify those most likely to benefit from taking long term aspirin. Pathways for finding potential biomarkers include the inhibition of prostaglandin-endoperoxide synthase (PTGs), the Wnt/b-catenin signalling axis, aspirins anti-inflammatory properties (including host immune response modulation) and platelet mediated effects.
As well as these effects on cancer initiation, aspirin may also inhibit cancer progression. A number of studies have shown aspirin use to lower cancer specific CRC mortality in patients with CRC 33,34,35,36,37,38,39. This action may be explained by aspirin’s effect on PG synthesis or Wnt signalling or other mechanisms such as the PIK3CA mutant. Biomarkers such as the PIK3CA mutant may be able to be used in the future to predict responsiveness to aspirin treatment.
Professor Chan concluded that there is overwhelming evidence to support the chemopreventative benefit of aspirin on CRC. Hazards associated with long-term aspirin use such as GI bleeding make strategies for risk stratification important and work around aspirins mechanisms of action may help to target its application to specific groups. Aspirin has an integrative multi-pathway model for its mode of action and it may be possible to use these pathways to develop mechanistic biomarkers for personalized risk stratification. Molecular and generic markers in prostaglandin and inflammatory pathways hold promise. Such biomarkers could then be translated clinically to predict who will benefit from aspirin chemoprevention and treatment and fulfil the promise of a precision medicine approach.
Lynch syndrome and experience of implementing secondary prevention – Professor Sir John Burn
Lynch syndrome is an important area of investigation for aspirin and its cancer preventative effects because it provides a genetical sub group of people who can be specifically treated with the aim of benefiting them and informing the research into aspirin’s mechanism in cancer prevention as a whole.
Professor Sir John Burn presented an analysis of cancer rates carried out at the tenth year of the CAPP2 trial which showed aspirin to have a protective effect against cancer 40. A secondary analysis of the impact of obesity revealed those that individuals who had the genetic predisposition for cancer and were overweight were more than twice as likely to develop CRC. This effect was partially abrogated in the aspirin arm of the study when compared with placebo possibly due to the anti-inflammatory role of the 600mg dose used in the study. The ten year blinded follow up of this study 41 confirms that there is a protective effect from aspirin use and that this effect is a truly preventative effect rather than suppressing tumours which may then later emerge. In most cases the aspirin was discontinued in CAPP2 before the impact on cancer incidence. This suggests an impact on precancerous legions (possibly by enhanced apoptosis or immune clearance of defective stem cells) rather than a direct effect on malignant cells.
CAPP3 a randomised dose non-inferiority trial will compare the 600mg dose of aspirin, shown to be effective in CAPP2, with a 300mg and 100mg daily dosing schedule. Results should be available from 2023 with an adverse events assessment in 2020. In addition a biobank will assess frame shift peptide antibody titres as possible biological surrogates for cancer development.
Aspirin for cancer prevention and cure – Is the time now? Professor John Chia
Professor Chia described the twin challenges of cardiovascular disease and cancer facing Asia with its current burgeoning populations. Over the coming decades the economic burden of these two major diseases is expected to cost in excess of a trillion dollars 42.
Professor Chia reviewed past and ongoing trials of aspirin in cancer and asked if the widespread adoption of aspirin as a chemo preventative agent in Asia, is an idea whose “time has come.”
As well as a primary prevention and treatment role for CRC aspirin is also creating interest for its role in tertiary cancer prevention via its synergy with immunotherapy. The 2017 ESMO conference was dominated by immune oncology and headline press currently are the immune check point inhibitors such as pembrolizumab and nivolumab. Immunotherapy is set to become the fourth pillar of cancer therapy along with surgery, radiotherapy and chemotherapy.
Aspirin now also has a story to tell in combination with these new compounds as it appears to have a synergistic effect with them. Aspirin in combination with immunotherapy is of key interest and it is being included in some immune check point inhibitor trials. Aspirin also potentially enhances adoptive T cell therapy and this unfolding story is thought to be due to the fact platelets potentially stop T cells from killing cancer cells. Aspirin appears to allow the immune system access to kill cancer cells. These examples of aspirin’s exciting and potentially synergistic role in cancer immune therapy created a lot of discussion among the delegates at the meeting.
Discussion about clinical implications – Dr Ruth Langley
The discussion focused on how best to communicate aspirins benefits and risks and its role in primary, secondary and even tertiary prevention and treatment of cancer to a wider population. It was felt that, particularly in primary prevention, this was a fairly complex concept for people to grasp as aspirins effect takes about 10 years to come to fruition. The challenge of explaining the risks and benefits to patients was discussed and it was felt that the future development of biomarkers to identify those who would benefit the most would be helpful.
The group agreed that these complicated messages with many factors to communicate represented a major challenge to getting aspirins benefits out to patients. Social media with its short punchy lines would not be not so easy to use for communication with aspirin. Instead it was felt that primary care clinicians should be a major target for education and the risk and benefits of aspirin should be disseminated to them. Others however felt that in the modern 21 century we need to get away from a professional telling you what to do and that people need to make the decision to take aspirin themselves. The evidence is there, it has been 30 years in making and individuals can decide to reduce their CVD and cancer risk in exchange for a small risk of side effects.
The science session chaired by Professor Lina Badimon explored some of the excellent work currently being carried out to enhance our understanding of aspirins mode of action and pharmacological profile.
The aspirin-sensitive platelet lipidome: beyond thromboxane A2 – Professor Valerie O’Donnell
Valerie O’Donnell is a Professor of Biochemistry and Co-Director of the Systems Immunity Research Institute in Cardiff. Professor O’Donnell uses new generation mass spectrometry to characterise cellular lipidomes. Aspirin’s cardioprotective effects result from it blocking cyclooxygenase-1 (COX-1) dependent generation of the pro-thrombotic lipid, thromboxane A2 (TXA2). In her work Professor O’Donnell uses high resolution mass spectrometry techniques to gain insight into the behaviour of cellular lipidomes in health and disease. By defining the aspirin sensitive platelet lipidome and investigating how platelet lipids change with aspirin treatment we can further enhance the diagnosis and treatment of patients. In particular Professor O’Donnell has set out to gain answers to the following question:
- How many lipids do platelets contain?
- Can we use this information to discover new bioactive lipids from platelets?
- How do lipids vary over time in the same people?
- What is the effect of gender on platelet lipids?
- How variable are aspirin responses in the same people over time?
Understanding the total diversity and number of individual lipids in cells as well as how they alter during activation of cells and differ between individuals will help improve the understanding of lipid biochemistry and help find new targets for drug therapy and improve the identification of lipid biomarkers in cohort samples. In particular this work will help to identify bioactive lipids that are usually present in very small amounts and therefore not routinely detected.
Following some innovative research work using mass spectrometry, informatics, statistics and the development of some in house software to manage data, Professor O’Donnell and her team began to characterize the platelet aspirin-sensitive lipidome and use this to uncover lipidomic networks43. They found that the human platelet lipidome is complex and that major changes occur following the ingestion of aspirin. They found large numbers of lipids appeared on activation and of these in excess of 70% were sensitive to aspirin. There is a lot of potential discovery science in finding new lipids and this represents an important opportunity for the future.
After an initial pilot in 3 genetically different donors a current project is underway looking at 30 volunteers over a six month period during which they were given repeated aspirin. The results of this work are expected soon. The research is still at the stage of trying to understand what goes on in healthy people rather than exploring effects in disease.
PK/PD determinants of the interindividual variability in the antiplatelet response: aspirin “resistance” revisited – Professor Bianca Rocca
Professor Bianca Rocca from the pharmacology department of the Catholic University School of Medicine in Rome discussed the pharmacokinetic (PK) and pharmacodynamics (PD) determinants of the interindividual variability in the antiplatelet response and aspirin “resistance”.
She explained the prescribed dose of a drug differs from that actually administered, which differs again from the dose/drug concentration at the site of action and the intensity of pharmacological effect and clinical outcome. Many factors play a part in this; physiological (e.g. age, renal function etc.), pathological factors (e.g. kidney or liver dysfunctions), genetic variation, drug-drug interactions and the development of resistance or tolerance.
Considerable interindividual variation in response to drugs remains after the concentration of the drug in plasma has been adjusted to a target value. Understanding what causes variability and reducing interindividual variability can help improve a drug’s effectiveness in real world settings. If reliable biomarkers can be found a greater understanding of drug variability can be developed with personalised, precision or stratified medicine. Serum TXB2 ex vivo is for example a pharmacodynamics biomarker that can be used to check the efficacy of new aspirin formulations 44.
Interindividual variability in response applies to aspirin and seems to be associated with its PD and/or metabolic disposition, using the correct assay appears crucial for identifying determinants of variability and designing new regimens. Identifying determinants of variability in aspirin response is relevant in hypothesizing and testing new ways of administering an ‘old’, effective (and cheap) drug in selected clinical conditions.
Shortening the dosing interval rescues the impaired antiplatelet effect of low-dose aspirin in acute or chronic settings of high platelet turnover. A reduced bioavailability may benefit from doubling the once daily dose. The clinical translation of these PD/PK findings will need adequately sized randomised trials comparing improved versus conventional regimens.
Essential thrombocythemia (ET) (a myeloproliferative neoplasm which causes increased platelet generation and an increased risk of thrombotic complications) is one example where the dose of aspirin may need to be altered and algorithms for treating ET at intermediate and high risk of thrombosis have been developed with twice daily aspirin being considered for certain patients45.
Another area where aspirin dose may require alteration is when aspirin is used before and early after cardiac surgery for CABG, unless the bleeding risk is higher than the thrombotic risk, work has now shown that a twice daily low dose aspirin regimen may be required 46.
The global obesity epidemic is another issue for drug pharmacokinetics with a multitude of changes take place and a speeding up of absorption, distribution, metabolism and excretion. The net effect of which on a single drug is variable and unpredictable especially for lipophilic drugs. Aspirin is lipophilic and body weight has been shown to reduce aspirin efficacy 47,48. The area of obesity and drug pharmacokinetics is currently a big gap in knowledge especially in those with a BMI above 35 or 40 kg/m2.
Interindividual variability in response to aspirin is an important issue and is associated with its pharmacodynamics and pharmacokinetics. Research into this area of pharmacology using the correct assays will be crucial in order to identify the determinants of this variability and design new regimens.
The final session of the day chaired by Professor Carlo Patrono focussed on increasing our understanding of the bleeding risk with aspirin and what can be done to minimise this important side effect.
What is the risk of bleeding? – Professor Peter Rothwell
Professor Rothwell explored the risk of bleeding in the secondary prevention setting where lifelong antiplatelet treatment is recommended after a vascular event. Antiplatelet drugs increase the risk of a patient experiencing a major bleed in particular upper-gastrointestinal (GI) bleeding49 . These potential harms include haemorrhagic stroke and GI bleeding. The risk of haemorrhagic stroke is largely offset by the reductions in ischaemic stroke and the HOT trial showed that optimising blood pressure control can help to minimise the haemorrhagic strokes caused by aspirin. In the case of GI bleeding the majority of people do not have serious sequelae with this if they are under the age of 65 years. Proton pump inhibitors (PPI) do however reduce the risk of a GI bleed by 70-90%50 but co-prescription is not currently routine practice. Secondary prevention clinical guidelines make no recommendations on PPI use and although some consensus statements do advocate GI protection in “high risk” patients the definition of who is high risk varies. The low uptake of PPI use may be due to concerns about long-term harm from PPIs and variability in the definition of who the “high risk” population for bleeding on aspirin constitutes. The evidence behind antiplatelet therapy in secondary prevention is based on early randomised trials in patients under 75 years. The mean age for a myocardial infarction is however 75 years with the mean age for TIA and stroke 65 years. It is estimated that 50% of patients taking antiplatelets are now age 75 and older.
The Oxford Vascular Study (OXVASC) is a prospective, population based study of all incident and recurrent acute vascular events including TIA, ischaemic stroke and myocardial infarction (MI). It is based on a population of 92,728 people. In OXVASC 3166 patients of which 1094 had an MI and 2072 had a TIA/ischaemic stroke were studied and all were treated with antiplatelet medication. At one year 2301 (89%) were on antiplatelet treatment and 852 (33%) were taking a PPI or H2 antagonist. Half (1582 (50%)) of the patients were 75 years or older. The study found that during 13,509 years of patient follow-up there were 405 first bleeding events and of these 162 were upper GI51. The risk of having a major bleed increased steeply with age and was more severe and more sustained at older ages. The study group found the estimated NNT for routine PPI use to prevent one disabling/fatal upper-GI bleed over 5 years fell from 338 at ages less than 65 years to 25 at aged 85 years or older.
Professor Rothwell concluded that the long- term risks and severity of bleeding on aspirin-based antiplatelet treatment in secondary prevention increase steeply with age51. For those under 75 years the risks are comparable with those reported in RCTs. In patients under 75 years the bleeding risk is more front loaded to the first year and flattens after this time period. In those 75 years or older the risks of bleeding are higher, more severe and more sustained and the functional outcomes are far worse. In patients 75 years or older upper GI bleeds tend to be major disabling or fatal bleeding events. This study gave real life data on bleeding risks with aspirin. Professor Rothwell recommended routine PPI use to prevent upper-GI bleeds in patients age 75 years or over is considered for inclusion in future secondary prevention guidelines.
Causes of bleeding and strategies for prevention – Professor Chris Hawkey
Professor Hawkey explained that in contrast to non-steroidal anti-inflammatory drugs (NSAIDS) there is a clear clinical and epidemiological evidence that patients with the bacteria Helicobacter Pylori (H.Pylori) who are also taking aspirin have an increased risk of ulcer development and bleeding52 . This may be due to the fact one of the main actions of aspirin is to abrogate haemostasis and promote bleeding in lesions caused by another agent, e.g. H.pylori, whilst with NSAIDS it is their intrinsic ulcerogenic activity which is the important factor.
Therefore two main strategies are proposed to protect against aspirin associated ulceration and ulcer bleeding;
- Use of an ulcer healing agent
- H.pylori eradication
Ulcer healing agent: in a meta-analysis of ten RCTs involving 8780 participants PPIs were found to be superior to both H2 receptor antagonists and gefarnate in preventing ulceration or bleeding50. There are concerns about the risk of long term use of PPIs53. It is interesting therefore that a recent trial has found famotidine (H2 receptor antagonist) to have equal efficacy to a PPI54 .
The association between H.pylori and ulcer bleeding in people taking low-dose aspirin raises the question as to whether the main effect of the aspirin is to enhance bleeding from the ulcer caused by H pylori and would therefore the eradication of the H.pylori reduce or eliminate upper GI bleeding on aspirin? HEAT is an ongoing study designed to test whether H.pylori eradication will reduce the incidence of bleeding peptic ulcers in patients taking aspirin55. HEAT is an outcomes study and uses cost saving innovations in the way the data and resources are utilised in order to save money and make it affordable. The trial is expected to complete in 2020.
Professor Hawkey concluded that inducing ulcer bleeding is a most common side effect from aspirin use and reformulating the aspirin does not work to prevent this. PPIs are effective but a H2 receptor antagonist a reasonable option if a PPI cannot be used. Aspirin is anti-haemastatic rather than ulcerogenic .
Concluding remarks: Professor Carlo Patrono
Professor Patron thanked everyone involved for a fantastic and very stimulating day of science. The presentations have illuminated aspects of the past history of aspirin but also most importantly its exciting potential in the future.
“As I take over chair from Professor Rothwell I look forward to the Foundation being an instrument for a joint venture from all interested parties into a global strategy for disease prevention using aspirin and investigation into its multifaceted actions.”
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