International Aspirin Foundation Senior Science Award Ceremony 2016
Pippa Hutchison Executive Director of the International Aspirin Foundation Pippa welcomed the attendees and introduced the Senior Science Awards evening which, this year, honours the work of three world class Professors from Boston, Massachusetts for their dedication to aspirin research. The Foundation began in 1974 with the aim of increasing the knowledge and understanding of aspirin and owes its existence to the vision of Nick Henderson. Nick remains active as President of the Foundation and sent his best wishes to the winners and attendees of the awards evening. Pippa announced that Tom Smith, the Foundation s medical writer, is stepping down after many years of dedicated service. He is passing the role to Jaqui Walker (GPN and medical writer) and the executive team has been further strengthened with the addition of Laura Sutherland in PR & communications and Douglas Hutchison as a fellow director. In her opening speech Pippa highlighted the importance of aspirin, explaining that the World Health Organisation (WHO) classifies aspirin as an essential medicine (one that is needed to satisfy the priority healthcare needs of the population) due to the value aspirin has made to human health; its ease of use and its low cost. The Scientific Meeting and presentation of the Senior Science Award not only honours the significant contribution that this year s winners have made to research into the role of aspirin, but aims to encourage and stimulate future work into aspirin s potential, as it continues to surprise with new important indications for use within healthcare. The International Aspirin Foundation continues to have ambitious plans and attracts international interest. At the award ceremony Pippa welcomed visitors from North America, China and Europe. In September 2017, the Foundation will hold a special scientific conference in Berlin to celebrate 120 years since the synthesis of acetylsalicylic acid. The International Aspirin Foundation is also extremely honoured to be guided by a Scientific Advisory Board of international key opinion leaders whose Chair, Peter Rothwell, introduced the Scientific Meeting and presented the Senior Science Award. International Aspirin Foundation Scientific Advisory Board
Professor Rothwell noted that the award was incredibly well deserved and presented the Professors with their award which included a framed certificate and a pair of crystal tumblers engraved with the crest of the International Aspirin Foundation.
Professor Peter Rothwell Chair of the Scientific Advisory Board of the International Aspirin Foundation Professor Rothwell introduced the scientific meeting and gave a speech on behalf of Professor Peter Elwood (who was unable to attend) on the history of both the Senior Science Award and the origins of aspirin. The Senior Science Award is a very prestigious award that aims to recognise and support contributions to aspirin research and development from around the globe. The award has an impressive pedigree of previous winners who have all made significant contributions to the development of aspirin. The winners of this years award are Professor Julie Buring, Professor Michael Gaziano and Professor Nancy Cook for their work to increase the understanding of the role of aspirin as a preventative strategy in both cardiovascular disease (CVD) and for certain cancers. Presentations by both Professor John Michael Gaziano and Professor Nancy Cook later in the evening described this work in more depth. Julia Buring is Professor of Medicine in the Division of Preventative Medicine at Brigham and Women s Hospital and Harvard Medical School. The main focus of her research has been on the epidemiology of chronic diseases such as CVD and cancer in women. She is principle investigator (PI) on the Women s Health Study (WHS) and its observational follow up and showed the vision to develop the cohort into a rich resource of phenotypic, biomarker and genetic data which has benefited many other studies. Professor Rothwell took the attendees back in time to the first recorded use of plants containing salicylate (the natural component that aspirin is derived from) such as willow, meadowsweet and cumin. This fascinating historical journey moved the audience through ancient times when salicylates use for pain and fever was discovered, with for example the Egyptians in 1500 BC, Hypocrates 300 BC, to a 1763 letter to the Royal Society by The Revd Edward Stone describing its use for rheumatic fever. We moved forward to the acetylation of aspirin in the mid to late 1800s which led to its launch by Bayer at the turn of the century. Next the seminal trials of the sixties and seventies were discussed, these trials showed the role of aspirin as an antithrombotic and paved the way for the long term prevention studies that are now influencing the recommendations in prevention guidelines today. The Food and Drug Administration (FDA) gave approval for the use of aspirin to reduce the risk of stroke after transient ischaemic attack (TIA) in 1980 and as a preventative post myocardial infarction (MI) in 1985. The work of Peter Elwood, Charles Warlow, Richard Doll and Richard Petro in the prophylactic use of aspirin for preventing CVD events led on to the development in the USA of the Physicians Health Study and Women s Health Study the data from which has led to the wider ranging guidance for aspirin in primary prevention of both CVD and colorectal cancer (CRC).
Professor J Michael Gaziano Professor of Medicine at Harvard Medical School, Chief of the Division of Aging at Brigham and Women s Hospital and Principal Investigator, Million Veteran Program, VA Boston Healthcare System in Boston Professor Gaziano has a significant clinical practice, runs a major academic department and is a world renowned researcher on the epidemiology of vascular disease, large-scale clinical trials and preventative cardiology. Professor Gaziano expressed his honour to be at the awards meeting with Nancy Cook and on behalf of Julie Buring who have between them led the Boston teams responsible for the two largest randomised controlled trials to look at the impact aspirin has in the prevention of CVD and other pathologies (e.g. cancer). Professor Gaziano reviewed both the history and the future direction of what he described as the spectacular opportunity presented by these two population studies: Physicians Health Study (PHS) Women s Health Study (WHS) Professor Gaziano commenced and concluded his presentation with a patient with multiple risk factors and asked the audience to reflect upon whether or not this patient should be given aspirin. He emphasised the importance of ensuring prevention studies have a focus on the patient and the use of the intervention in real life. Patient with Multiple Risk Factors for CVD 56-year-old male No history of CVD or diabetes Father died at age 45 of MI Nonsmoker BP: 144/89 mm Hg (treated) BMI 28 Lipid parameters > Total cholesterol: 243 mg/dl > LDL-C: 172 mg/dl > HDL-C: 39 mg/dl > Triglycerides: 158 mg/dl Should he be on ASA? What is his CVD Risk?
His presentation took the audience through the story of aspirin in preventative medicine but also looked at the important role aspirin has played in the evolution of epidemiology trials. He divided clinical trial development into four stages: > Descriptive phase - which is about numbers > Pre-analytic phase- when associations are made > Analytic phase - case control studies, cohort studies, RCTs > Super analytic phase - mega biobanks, genetics, phenotype, environment There are over 400 trials for the use of aspirin in secondary prevention working on the hypothesis that platelet inhibition with aspirin will lower the risk of subsequent vascular events in those with prior MI, stroke, CAD, TIA or peripheral artery disease. A collaboration of the results from these antithrombotic trials showed an overall 22% risk reduction in vascular events. This led on to the hypothesis that aspirin could potentially also prevent a first CVD event. The trials of aspirin in primary prevention were longer trials, the event rates are lower in this population and yet the complication rate (gastric bleeds) remains the same as for secondary prevention. The duration of time required for such a study is quite a challenge. The US Physicians Health Study (PHS) commenced in 1982 and continues today. It is a 2x2 factorial design, randomised, double-blind, placebocontrolled, observational cohort study. The trial recruited 22071, male physicians between the ages of 40-84 years. The trial tested the effects of low dose aspirin (325mg on alternate days) in the primary prevention of CVD and beta-carotene (50mg on alternate days) in the prevention of cancer. Doctors were chosen because it was felt they could report events, consent and understand and complete forms by mail. A calendar pack of drugs taken on alternate days were sent out. Participants were proud to be part of such an important study and took photographs of themselves with their calendar packs from all around the globe. There has been excellent long term follow up. The results were very positive showing a 44% reduction in first MI due to aspirin. Death in old age is inevitable but death before old age is not. Richard Doll The US Women s Health Study (WHS) commenced in 1999 with a similar design. It enrolled 39876, female health professionals aged 45 years and over and its aim was to study the effect of alternate day low dose (100mg) aspirin and alternate day vitamin E (600mg). Like the PHS it was a postal study. MI in the Physicians Health Study number of MIs 250 200 150 100 50 0 239 Placebo (n=11,034) 44% in the first MI due to aspirin 139 Aspirin (n=11,037) Professor Gaziano has also led progress in embedding research into health care systems by establishing the Massachusetts Veterans Epidemiology Research and Information Centre (MAVERIC) and is Director for the Million Veteran Program which will be important for future discovery in genetics and epidemiology. Work in large scale trials to look at aspirin in higher than average risk populations is ongoing. The ARRIVE trial looking at initial CVD events will finish this year and report in early 2017. The ASCEND trial looks at cardiovascular risk in patients with diabetes and ASPREE aims to reduce cardiovascular events in the elderly. Professor Gaziano summarised by explaining that in secondary prevention aspirin clearly prevents
further CVD events in a wide range of high risk patients with a low risk of haemorrhagic stroke and at a dose of 75-150mg daily. The US FDA has provided indications for acute and prior MI and stroke, angina, PVD or other forms of vascular disease. Primary prevention with aspirin is effective at reducing the risk of a major first CVD event among both men and women but it is also important to consider baseline risks and look carefully at the sort of patient profiles who would most benefit from primary prevention e.g. patients with multiple risk factors for CVD. Even though bleeding with aspirin is rare, in order to optimise the benefit to risk ratio of low dose aspirin therapy careful discussion needs to be had at a clinical level with the patient. He explained; The paradox with preventative medicine is that the patient will blame you for their GI bleed but won t thank you for the stroke or MI you have silently prevented. It is estimated aspirin has the potential to save hundreds of thousands of lives through primary and secondary prevention of CVD around the world each year. It may also help prevent cancer. Guidelines recommend low-dose aspirin in those with a 10- year CVD risk of 10% or more. At the end of his talk Professor Gaziano took us back to the patient profile and asked if we would put that patient on aspirin for prevention of a CVD event. The majority of the audience appeared to support this. Key discussion points. How to assemble the cohort and maintain commitment? Calendar packs helped but also a test period was used to check commitment. Professor Gaziano found 33000 willing to participate but only 22000 passed muster when it came to adhering to the trial protocol. He felt that you can achieve a longer connection by mail but you need to ensure that you are maximising compliance. It is important to remember that preventative therapy lowers risk but it doesn t totally eliminate the risk. There may also be a delay in the time to the first event. Professor Gaziano advised that preventative medicine presents a very different paradigm to managing acute situations. In prevention; you need to work with the person to empower them to own and control their disease, risk and lifestyle. It is important to explain short term risks and benefits as well as long term benefits such as cancer risk reduction. These long term benefits should be seen more as an extra bonus.
Professor Nancy R Cook Professor of Biostatistics in the Department of Medicine at Harvard Medical School and Professor of Epidemiology at Harvard School of Public Health Professor Cook described how observational cohort studies had indicated that aspirin may reduce cancer incidence, especially CRC. This was supported by several meta-analyses looking at cancer outcomes within trials of aspirin and cardiovascular disease, primarily conducted by Professor Rothwell. A low dose (75-300mg) of daily aspirin in a meta-analysis of three trials showed the impact on CRC was a latent effect emerging after 7-10 years. At this point Professor Cook was chief statistician for WHS which had cancer as one of its primary outcomes. In the WHS just under 40,000 women age 45 and over took 100mg of aspirin every other day. The active intervention for this study ended in 2004 with a median of 10 years follow up. The results showed no reduction in cancer at the end of the active intervention part of the study. However, after eight additional years of post-trial follow-up there was a statistically significant reduction in CRC in those that had been in the active arm of the study. This latent, post-trial effect has a hazard ratio of 0.57 and is highly significant, with a clear difference in effect over time. A similar effect is seen when looking at all GI cancers. Cook et al, Ann Intern Med 2013 Professor Cook used statistical modelling to ensure these results were not due to differences in the women opting in for long term follow-up, or for differing characteristics in the women taking aspirin post-trial. The modelling work also ensured that interventions such as colonoscopy or polyp removal did not influence the results. No differences were found. Reference Cook NR, Lee I-M, Zhang SM, Moorthy MV, Buring JE. Alternate-day low-dose aspirin and cancer risk: Long-term observational follow-up of a randomized trial. Ann Intern Med 2013; 159:77-85
Adverse events did occur but in low numbers. Appropriate weighting of the adverse bleeding events in relation to GI cancer, MI and Stroke suggested a small benefit overall, with a larger benefit among women over the age of 65 years. This work contributed to the current USPSTF recommendations for aspirin in primary prevention of CVD and CRC. Professor Cook concluded that to fully understand the role of aspirin as a preventative strategy in the general population, prediction models for adverse as well as beneficial effects are required. Aspirin may not be appropriate for everyone in general population due to the increased risk of modest bleeds including ulcers, increased medical expenses and reduced quality of life. Understanding and targeting those at higher risk of CVD and CRC may be an important first step in getting aspirin used in clinical practice and increasing benefit for primary prevention of CVD and GI cancers. Key discussion points. Confounding factors may strongly influence the results from observational studies. For example, those who have GI side effects may stop taking aspirin but these effects could be related to a GI cancer. Aspirin use is associated with behaviours that are both beneficial and with those that increase risk. Those who exercise, have a healthy diet, and/or a family history of CVD or CRC may be more likely to take aspirin. Compliance is a big issue; will we only ever get a small subset of the population compliant over ten years? While compliance in both the PHS and WHS trials was very high, in the general population it may be more of a problem to adhere to using aspirin in the long term. It is important to advise patient s how to improve compliance. A lot of people will need to take aspirin for a small number to benefit. It may be best to present aspirin use to patients as a way to delay events rather than total prevention. It is important to focus on the individual s risks of CVD and CRC as well as GI bleeds. Professor Cook emphasised; Julie E Buring Professor in the Department of Epidemiology at Brigham and Women s Hospital Division of Preventive Medicine and Professor of Medicine at the T.H. Chan School of Public Health, Harvard University. Risk benefit discussion with higher risk patients needs to be embedded into clinical care so that people can benefit from the disease prevention capabilities of aspirin.
International Aspirin Foundation Senior Science Award Ceremony Professor Peter Rothwell took the opportunity to ask questions and discuss both the Physicians Health Study and Women s Health Study trials in depth with the world class professors. The full interview with both Professor Mike Gaziano and Professor Nancy Cook lasts for 17 minutes and can be seen using the following link: https://youtu.be/i4fdu1dbwks
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