ESC GRAND DEBATE: Aspirin for life

One of the ESC Grand Debates revolved around whether or not aspirin should be used for primary and/or secondary CV prevention. Yes, there is a lot of evidence, but how valid is that evidence? This is an impression of this Grand Debate held at ESC 2017.

Positioning of the topic - Coronary artery disease: the aspirin story

Prof. Carlo Patrono (Rome, Italy)

A long trajectory of experimental research preceded the understanding of the mechanism between COX acetylation by acetylsalicylic acid and platelet function inhibition. Aspirin lead to prostaglandin intermediates, which are the precursor of thromboxane. Platelet activation occurs upon stimulation by thromboxane A2 of the TP receptor on the platelet membrane, similar to the action of ADP on the P2Y12 receptor. These two amplification loops are not redundant, which explains why targeting different receptors with various agents simultaneously can give added benefit.

A large post-MI study was published in 1980; it showed that 1 gram of aspirin per day did not significantly alter the death rate as compared with placebo. In the same year, Patrono’s group published a paper on a more sensitive and more specific method of measuring the antiplatelet effects of aspirin. This incited the interest to test a lower dose of aspirin. 30 mg/day of aspirin led to selective cumulative inhibition of platelet TXA2 within 7 days (now known to be an effect of platelet COX1 activity), while sparing the renal production of prostacyclin (as a result of constitutive renal expression of COX_2 in the kidney). Another study found aspirin doses in the range of 650-1300 to be ideal for anti-inflammatory and analgesic properties and reaching a maximum of inhibition of prostacyclin biosynthesis, an important antiplatelet agent.

ISIS-2 was a landmark study published in 1988 that tested the efficacy and safety of thrombolysis, antiplatelet therapy with aspirin, or both, by starting treating patients with acute myocardial infarction within 24 hours. Both treatments separately were about equally effective, and the two combined reduced vascular mortality by 40% vs. double placebo. According to Patrono, ISIS-2 showed 3 important concepts, namely that coronary atherothrombosis is a dynamic process, that the thromboxane -mediated amplification loop is important in this dynamic process, and thirdly, that aspirin is a life-saving drug.

In 1990, the results of the RISC study were published, in which low-dose aspirin (75 mg daily) in NSTEMI showed a remarkable benefit in reducing MI and death in the first 3 months and the first year (in addition to IV heparin). In total, there were at least four placebo-controlled trials testing doses ranging from 75 mg to 1300 mg daily, which showed a clear CV benefit of antiplatelet profylaxis independent of the dose of aspirin used.

Patrono did point out that these results need be put into the context of trials conducted in ‘80s; they were independent trials with public funding, but relatively small, although with a relatively high event rate. The placebo-arm at the time was a true placebo-arm, as there were no other effective anti-platelet agents. The quality of the design was adequate according to the requirements for FDA approval at the time.

In a NEJM editorial in 1994, Patrono wrote that ‘the recommendation of a single loading dose of 200 to 300 mg followed by a daily dose of 75 to 100 mg is based on findings that this dose is as clinically efficacious as higher doses and is safer than higher doses.” This concept was reinforced by the Antithrombotic Trialists’s Collaboration that concluded that there is a saturable clinical benefit of aspirin at low dose. Thus, Patrono concluded that a saturable and irreversible acetylation of COX-1 is responsible for complete suppression of thromboxane production, which explains the saturable reduction of vascular events by low-dose aspirin. He considers it a remarkable success story of development of a new drug mostly led by the medical scientific community, guided by mechanistic understanding of how aspirin works to inhibit platelet function, adequate clinical pharmacology of its desired effect and finally, a large number of independent trials in over 250000 subjects spanning the whole spectrum from healthy subjects to acute coronary syndrome, thus leading to a database of efficacy and safety data unparalleled by other antithrombotic agents.

Aspirin for life - PRO

Deepak Bhatt (Boston, MA, USA)

Atherothrombosis is the unhealthy coupling of atherosclerosis and thrombosis, which can affect the coronary, cerebral and peripheral arteries and manifest clinically or lie there asymptomatically. Atherosclerosis can affect multiple vascular beds; about 15% of patients have polyvascular disease. The platelet has an important function in preventing thrombus formation in response to vascular injury, hence the role of antiplatelet therapy in preventing platelet activation upstream, and platelet aggregation downstream. Numerous antiplatelet approaches exist. The data for ‘humble aspirin’ are extremely robust, Bhatt pointed out. Concerning efficacy of reducing CV death, MI and stroke, no difference is seen between lower and medium doses. The difference between doses lies in the rate of gastrointestinal (GI) bleeding, thus in general, the lower dose seems to be the way to go for chronic therapy.

Clopidogrel has been demonstrated to be more effective than aspirin in reducing event rate and the rate of rehospitalization in patients with recent ischemic stroke, MI or symptomatic PAD, in the CAPRIE trial. Antiplatelet therapy is used in higher risk patients, but guidelines still recommend aspirin (continued indefinitely, IA recommendation) in patients with stable ischemic heart disease, and clopidogrel is only mentioned in second instance (IB recommendation), if aspirin is contraindicated in these patients.

Bhatt noted that aspirin for primary prevention is a bit more controversial. The Physicians’ Health Study and the Women’s Health Study did show CV risk reductions with aspirin as compared with placebo, but it should be noted that concomitant therapies may be have changed since those data were collected. In the Women’s Health Study, aspirin mostly reduced ischemic events. A meta-analysis of randomized controlled trials showed an overall reduction in MI in men, but not in women, thus sex was concluded to possibly act as an effect modifier.

When using antiplatelet therapy, ACC/AHA consensus guidance recommends to assess GI bleeding risk. If a patient is at risk of GI bleeding, additional treatment with a proton pump inhibitor is indicated. This may be the same for aspirin monotherapy.

Back to secondary prevention; in diabetic patients antiplatelet therapy is strongly indicated to reduce the risk of vascular events; there is no controversy. But, something is going on with platelet function in diabetic persons: platelet aggregation is higher on aspirin treatment in patients with diabetes than in non-diabetics. Dosing twice daily might be useful, the biological rationale having to do with the circadian release of platelets into the bloodstream from bone marrow. Aspirin resistance has been proposed to occur, but Bhatt thinks this phenomenon is overrated. He suspects problematic treatment adherence might have something to with it. Indeed, analysis of REACH registry data revealed that established therapies, including antiplatelets and lipid-lowering therapy, are consistently underused in various patient types.

An ‘aspiringuide’ application has been developed by researchers of the Brigham and Women’s Hospital, and aims to help decide whether or not a person is a candidate to take low-dose aspirin for primary prevention, by balancing the benefits of preventing atherosclerotic CVD against the risk of developing (GI) bleeding. This app follows a practical algorithm that facilitates the shared decision-making process between doctors and patients.

In this debate, data of the COMPASS trial, also presented at this ESC congress, should also be mentioned. The COMPASS trial compared rivaroxaban on top of aspirin and versus aspirin, and showed a clear risk reduction of the composite of CV death, stroke and MI with combination therapy as compared with aspirin monotherapy. Interesting for this debate is that the arm with rivaroxaban treatment alone did not beat the aspirin arm; ‘humble aspirin is holding its own’. With regard to bleeding, aspirin performed better than rivaroxaban.

Then a remark on aspirin and cancer risk; aspirin does not seem to have an effect on non-GI cancer including breast, advanced prostate and lung cancer, but it might reduce GI cancers, including colorectum and maybe gastroesophagus cancer.

Thus, Bhatt concluded by noting that aspirin is strongly indicated for secondary prevention (and everyone knows it), and aspirin is an essential part of DAPT. He added that we now learn that it is an essential part of the winning COMPASS arm. In primary prevention, it can be used in selected patients, in those with high ischemic risk at low bleeding risk. Trials are ongoing to find out who these patients are, and risk calculators can be employed.

Bhatt is convinced: aspirin is effective, cheap and familiar: so aspirin is not going away.

Aspirin for life – CON

Marco Valgimigli (Bern, Switzerland)

Valgimigli felt less comfortable defending his position, and he started with an apology to Carlo Patrono, whom he called the father of aspirin, about the upcoming impossible mission. He compared this debate to the fight between David and Goliath, in which Goliath is aspirin, and he is David with the 5 stones. Valgimigli used the five stones to point out that we know less than we think we know about aspirin.

Firstly, there is no evidence in favor of life-long aspirin; only very few studies on aspirin have had a treatment duration longer than a year. Importantly, many of these studies were conducted 30-50 years ago. Concerning meta-analyses he noted that what goes in, must come out. In a meta-analysis on individual patient data from randomized trials, not much difference was seen between the relative risk reductions of aspirin as primary or secondary prevention of major coronary events; the difference lies in the yearly absolute difference. But, overall the data are very limited. Of note, the vast majority of aspirin trials included patients aged 60 years or less. Moreover, very few trials included information on bleeding events; the focus was put on ischemic events. An exception is the Oxford vascular study, with 10 years of follow-up. 50% of patients were at least 75 years old. Bleeding risk increased with age, with the oldest group (>85) showing an annual rate of bleeding of up to 7%. Thus, ‘it is fair to say that the bleeding risk associated to long-term aspirin has been largely underestimated in aspirin trials’, said Valgimigli.

Then, how about the estimates for the ischemic benefit conferred by aspirin across available studies? They are likely much more reliable than the ones for bleeding, but it should be noted that concomitant therapy used then is now totally outdated. For instance, no revascularization was done, and it was not reported, or only a low percentage of patients was treated with betablockers. Valgimigli does not believe that the benefit of aspirin is the same now, considering contemporary management. All-cause mortality and ischemic event rates were much higher then, which naturally affects the number needed to treat.

Moreover, the standards for setting up, conducting, analyzing and reporting studies was very different. As an example Valgimigli showed results of the Canadian Multicenter Trial on Aspirin in unstable angina. At the time, it was concluded that the findings provided strong evidence for a beneficial effect of aspirin in these patients. Applying the intention-to-treat protocol to the findings, would render it no longer significant (P=0.07). According to today’s standards this study should be seen as negative. This is what happened with the SOCRATES trial, in which a P for superiority of 0.07 led to the conclusion that it was a negative study, despite the fact that all numbers were numerically in favor of aspirin. Valgimigli argued that in the old days, this study may have most likely have been claimed to be highly positive.

In the CAPRIE trial, clopidogrel showed a small benefit over aspirin, without a difference in safety. At the time aspirin was much cheaper, but that is no longer the case. So why should we now not use clopidogrel, since it was better, Valgimigli wondered out loud. And in the MATCH study, addition of aspirin to clopidogrel led to more intracranial and major bleedings in patients with recent stroke or TIA, as compared with either clopidogrel or placebo. These data thus disfavor addition of aspirin on top of clopidogrel.

The WOEST trial even showed a mortality benefit when dropping aspirin. Dropping aspirin is already a class 2 recommendation, now also strengthened by the results of the reDUAL-PCI, in which not adding aspirin reduced bleeding complication, without increasing events.

Valgimigli also referred to the COMPASS data in his defense; when looking at the Kaplan-meier curves of aspirin vs rivaroxaban, it can be seen that they separate from 1.5 year onwards. From that moment on the curve of rivaroxaban monotherapy is getting closer to the curve for rivaroxaban plus aspirin. The trial was prematurely stopped, so one can wonder what would have happened to the results if we had a longer follow-up?

Thus, plenty of reasons for Valgimigli to conclude that the value of aspirin in terms of risks and benefits in contemporary practice remains unclear. The bleeding risks have been underestimated due to the inclusion of relatively young patients and an ascertainment bias justified by lack of awareness of the importance of bleeding on outcome. Moreover, the lack of true long-term studies is a problem. The effect on ischemia, on the other hand, may have been overestimated, due to lack of concomitant proper CAD management, very high event rates leading to unrealistically low numbers needed to treat, and due to lack of proper control treatment at the time.

Aspirin for life - Rebuttal PRO

Deepak Bhatt (Boston, MA, USA)

Bhatt said he was not convinced about the proposed effect of stopping the COMPASS trial early; ‘you don’t need an RCT for every question’. He also stated that Valgimigli made a classic mistake, in that it is a fallacy to think that clopidogrel generic is as cheap as aspirin. In a global sense, thinking in terms of public health, in terms of cost-effectiveness, you can’t beat aspirin. Doctors’ and patients’ familiarity of aspirin should also be considered: many patients actually want to take it.

Importantly; it is safe. Adding a PPI may make it even safer. This will add some costs, but multiple generic versions are available. Since gastric symptoms may lead to non-adherence, PPI may even improve adherence. As an indication of its effectiveness Bhatt showed a list of clinical scenario’s: as monotherapy for secondary and primary prevention, as part of DAPT for stents, ACS, post-MI, and in COMPASS regimen for stable CAD and PAD. He concluded ‘whatever the future, aspirin will be part of thrombocardiology’.

Aspirin for life - Rebuttal CON

Marco Valgimigli (Bern, Switzerland)

Valgimigli admitted that is was happy to loose the debate. He agreed with Bhatt that aspirin is here to stay. But, he wanted to add, we cannot keep adding anti-thrombotics on top of statin, because then we will never be able to understand the true independent value, concerning both risks and benefits. Fortunately, relevant studies are ongoing, thus there are more relevant data to come. We should keep our eyes wide open. Based on those results, the debate should be repeated.

Aspirin for life - Chairperson's conclusion

Prof. Eugene Braunwald (Boston, MA, USA)

Professor Braunwald started by showing a timeline, on which the discovery of aspirin was marked at 1897: ‘It has been used for even longer than my life’, he noted. Willow bark was already used to treat fever in 1763. It took until 1967 to discover its antiplatelet function.

He showed a complex cartoon with five arrows of where aspirin acts on endothelial functions, with some of the effects going in opposite directions. He noted that it is very simple to take, and achieve multiple effects.

Diabetes was brought up; this is relevant as a large part of the patient population is now diabetic, and this will only increase. The 2017 recommendation of the American Diabetes Association, in Braunwald’s words ‘a very conservative group’ say use aspirin for secondary prevention, and consider it for primary prevention (this would be a 2A recommendation) in those at increased CV risk. The guideline says it should not be considered for primary prevention in adults with diabetes at low atherosclerotic CVD risk.

He pointed out that we have better methods now to determine risk, for instance calcium testing, which shows actual disease. That raises the question whether acting based on calcium testing is primary prevention, or secondary prevention. Braunwald thinks of it as 1.5th prevention.

In his last slide he referred to another conservative group: the US Preventive Services Task Force, in relation to cancer. They conclude that 20-year cancer mortality was reduced among patients assigned to aspirin, with RR: 0.67 and a P-value ‘out of sight. This was studied over very long periods of time, with the reduction of cancer mortality beginning 10-19 years after initiation.

He ended his reflection by saying that he agreed with both speakers. Dr. Bhatt based his presentation on today’s evidence, and Braunwald thinks the current guidelines he showed, should be followed.

On the other hand, what Valgimigli introduced, is that everything is up for questioning. We have been wrong in medicine many times. Thus, we have to remain skeptic; the idea of staying open-minded is extremely important. Reinterpretation of old data is extremely welcome. And indeed, concerning pulling back on aspirin: some trials will give important insights.

Discussion with the audience

Before moving to questions of the audience, the moderator asked Bhatt whether aspirin being cheap and familiar is good enough. Bhatt replied that no, it is not enough, but based on current data he said that. Indeed it is not always the right argument, as was demonstrated by another presentation at this ESC Congress: oxygen is cheap and familiar but DETO2X-AMI showed it doesn’t work.

Patrono noted that if you drop aspirin, you need something to replace it with. But we do not have data. There are primary prevention trials with 10 years follow-up on aspirin use. There may be additional non-CV benefits. Where are we going to get similar data from an alternative to replace aspirin?

Somebody in the audience noted that when trying to intensify antithrombotic treatment, the real question we need to address is how to reduce the risk of bleeding, so that we can intensify more. That is more important than choosing one over the other. Bhatt thinks that adding PPIs already improves safety a lot, and can help with adherence. He added that hopefully the COMPASS results will give some reassurance to public and regulatory bodies that the side-effects (such as cognitive effects) are no issue. The ESC guidelines recommend to use PPIs liberally (studies show it is effective, and those at high risk of GI bleeding were excluded).

In the discussion it was also noted that P2Y12 inhitor monotherapy is not sufficient to keep platelet reactivity low. Platelet thromboxane activity is quite intact upon treatment with P2Y12 inhibition. Addition of aspirin is therefore needed to keep thromboxane activity down. Braunwald added that there are many receptors (about 50) that can be targeted to block platelet function. We may need to block two simultaneously, but not too many, in light of the risk of massive