Aspirin guidelines for patients at risk of ASCVD challenged in new study

1st March 2024

A new study challenges the ‘one size fits all’ approach to current aspirin guidelines for patients at risk of atherosclerotic cardiovascular disease (ASCVD).

The findings of three trials published in 2018 (ASPREE, ASCEND and ARRIVE), which assessed the effects of starting aspirin therapy versus a placebo on ASCVD outcomes in aspirin-naive adults, resulted in guidelines no longer recommending low-dose aspirin for the primary prevention of ASCVD.

The amended guidelines were motivated by findings showing an increased risk of significant bleeding for patients taking aspirin across the three trials; however, questions remain for patients who were already taking aspirin before the trials.

In a meta-analysis of a subset of the trial results, researchers from the University of Galway found that people who had been previously taking aspirin but had chosen to stop without consultation with their doctor faced a 28% increased risk of ASCVD.

The findings are published in the journal Circulation, and, in the absence of further data, the researchers suggest that patients already safely treated with low-dose aspirin for primary prevention of ASCVD can continue to do so.

The three original randomised trials involved over 47,140 patients from 10 countries, including the US, the UK and Australia.

In a previously published subgroup analysis, the ASPREE trial authors studied 1,714 participants taking aspirin at least twice weekly before enrolment.

In a randomised analysis, those who stopped taking aspirin and took a placebo had a trend to increased risk for ASCVD events compared with continuing aspirin (55 of 841 [6.5%] versus 44 of 873 [5.0%]). However, the findings have limitations since they were based on a small sample size of 99.

In the present investigation, trial-level meta-analyses were performed to study the subgroup of participants taking aspirin at baseline in both the ASPREE and ASCEND trials (n=7,222).

Data from the subset of patients revealed that there was a higher risk of both fatal or non-fatal ASCVD among baseline users who were randomised to stop aspirin and take a placebo versus those randomised to continue aspirin (450 of 3,609 [12.5%] versus 374 of 3,613 [10.4%]).

The hazard ratios in both subset meta-analyses (1.32 for the ASPREE data and 1.21 for the ASPREE and ASCEND combined analysis) suggest that although there is a potential trend towards increased risk for ASCVD events among those who stopped taking aspirin, the results are not statistically significant.

The Galway researchers found the difference in the risk of major bleeding was not statistically significant between baseline aspirin users randomised to discontinue aspirin and those who continued (123 out of 3609 [3.4%] versus 142 out of 3613 [3.9%]; hazard ratio, 0.86).

Professor John W. McEvoy from the University of Galway said the ‘results are hypothesis-generating’ and challenge the ‘one size fits all’ guidelines.

He said: ‘Our findings of the benefit of aspirin in reducing heart disease or stroke without an excess risk of bleeding in some patients could be due to the fact that adults already taking aspirin without prior bleeding problems are inherently lower risk for a future bleeding problem from the medication. Therefore, they seem to get more of the benefits of aspirin with less of the risks.’

Professor McEvoy explained that more research was needed but added: ‘Until further evidence becomes available, it seems reasonable that persons already safely treated with low-dose aspirin for primary prevention may continue to do so unless new risk factors for aspirin-related bleeding develop.’

A study published in March 2023 found that the benefits of aspirin use in myocardial infarction are offset by statin use in patients without ASCVD.

ESC: Survivors of MI discontinuing aspirin at higher risk of subsequent adverse cardiac events

25th August 2023

Survivors of a myocardial infarction (MI) who discontinue aspirin remain at an elevated risk of a subsequent infarction, stroke or even death over the next eight years compared to those who remain adherent to treatment.

These were the findings of a a study presented at the recent European Society of Cardiology (ESC) Congress 2023 in Amsterdam.

While the use of aspirin is no longer recommended for use as a primary preventative strategy, despite continued use, especially in the elderly, it remains an essential component of secondary prevention treatment.

Researchers used Danish nationwide health registries to look at patients aged 40 years and over who had a first MI and were prescribed aspirin during the first year after it. Their aim was to examine the extent to which MI survivors collected a prescription for aspirin over the next two, four, six and eight years and the clinical consequences of not taking the drug.

Adherence to aspirin at each of the four time points was assessed as the proportion of days patients had collected the drug over the preceding two years.

Non-adherence was defined when survivors used aspirin for 80% or less of the time and patients were excluded at each time point if they had experienced another heart attack, a stroke, died, or had been started on other anticoagulants or P2Y₁₂ inhibitors.

The researchers analysed whether patients who did not take aspirin as prescribed had a higher risk of the composite outcome of recurrent heart attack, stroke or death compared with those who consistently took aspirin.

Survivors and aspirin adherence

The study included 40,114 patients with a first-time MI. Adherence to aspirin progressively declined with each time point, from 90% at two years post-MI, to 84% at four years, 82% at six years and 81% at eight years.

At each of the time-points, adherence to aspirin was associated with a reduced risk of the composite outcome. For example, when compared to adherent patients, non-adherent patients had a 29%, 40%, 31% and 20% higher likelihood of recurrent heart attack, stroke or death at two, four, six and eight years post-MI, respectively.

Commenting on the findings, study author Dr Anna Meta Kristensen of Bispebjerg and Frederiksberg Hospital, Frederiksberg, Denmark, said: ‘Our findings suggest that not taking aspirin as prescribed after a heart attack is linked to a higher risk of having another heart attack, a stroke or dying.‘

However, she added: ‘Our results should be interpreted with caution because they show an association but do not establish causality. Since the study is registry-based, we do not have information about the specific reasons as to why patients did not take their aspirin.

‘Furthermore, our findings cannot be generalised to all patients who experience a heart attack, as our study specifically focused on those who received treatment with a coronary stent and were not taking other medications to prevent blood clot formation.

‘With that in mind, the results support current guidelines recommending long-term aspirin after a heart attack.‘

Cardiopulmonary events not reduced in symptomatic outpatients with COVID-19

21st October 2021

Cardiopulmonary events were unaffected by antithrombotic therapy in symptomatic outpatients with COVID-19 but the trial was terminated early.

The level of cardiopulmonary events such as symptomatic deep vein thrombosis, pulmonary embolism, myocardial infarction and ischaemic stroke are not affected by the use of antithrombotic therapy. This was the conclusion of a randomised, double-blind, placebo-controlled trial among symptomatic outpatients infected with COVID-19 undertaken by a group from the Brigham and Women’s Hospital, Boston, Massachusetts, US. The risks of thromboembolic events in patients with covid-19 are high and associated with a greater risk of death. While there is some evidence indicating that the use of heparins among non-critically ill hospitalised patients with Covid-19 increases  the probability of survival, there is a paucity of data on the use of antithrombotic therapy among symptomatic outpatients.

The ACTIV-4B COVID-19 Outpatient Thrombosis Prevention Trial was designed to explore whether patients infected with COVID-19 but who were not sufficiently unwell to require hospitalisation, could benefit from anti-platelet or anticoagulant (i.e., antithrombotic) therapy, as a means of slowing disease progression. Patients aged between 40 and 80 years of age with a PCR or antigen confirmed diagnosis of COVID-19 were eligible for inclusion in the study. All were randomised in a 1:1:1:1 fashion to aspirin 81 mg daily (and matching placebo), apixaban 2.5 mg twice daily, apixaban 5 mg twice daily or placebo twice daily for a period of 45 days. The primary outcome of interest was a composite of cardiopulmonary outcomes including symptomatic deep vein thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, ischaemic stroke, hospitalisation for cardiovascular or pulmonary events and all-cause mortality, for up to 45 days.

Findings

In total, 657 patients with a median age of 54 years (59.1% women) were randomised to one of the four arms and the median time from diagnosis to randomisation was 7 days and 3 days between randomisation and the start of therapy. During this period of time, some patients were hospitalised and complete follow-up were available for only 556 individuals. Unfortunately, the incidence of cardiopulmonary events was low, with only 5 events; 1 deep vein thrombosis in the aspirin group, 3  cardiopulmonary events (all hospitalisations), 2 in the apixaban 5 mg group, 1 in apixaban 2.5 mg group) and one hospitalisation in the placebo group. While the event rate was very low, the authors also noted that there were no major bleeding events reported during the trial and there were no deaths. However, there were 4 suspected non-major bleeds in the aspirin group with 6 and 4 in the low and high apixaban groups respectively.

The authors reported that the trial was terminated early due to the low event rate. They concluded that while among clinically stable symptomatic outpatients, treatment with aspirin or apixaban did not reduce the rate of clinical outcomes. However, the generalisability of this conclusion is limited because of the low incidence of primary events.

Citation

Connors JM et al. Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19. The ACTIV-4B Randomized Clinical Trial. JAMA 2021

Aspirin use associated with improved survival but only for bladder and breast cancer

18th January 2021

The protective effects of aspirin in older patients with a range of different cancers has been poorly studied prompting researchers to examine the benefits for a range of different cancers.

The risk-benefit ratio for the use of aspirin in older adults is still unclear though some secondary analyses of randomised trials have indicated that aspirin can reduce the incidence and mortality due to colorectal cancer. Given this uncertainty, a team from the Division of Cancer Prevention, National Cancer Institute, Maryland, US, decided to focus their investigation on a post hoc analysis of older individuals in the prostate, lung, colorectal and ovarian cancer screening trial (PLCO).

PLCO was a large trial to determine the effects of screening on cancer-related mortality and secondary endpoints in people aged 55 to 74 years of age. The researchers limited their analysis to individuals at least 65 years of age after enrolment and whose baseline questionnaire contained information on aspirin use. Individuals who had a history of any of the cancers studied were excluded. The use of aspirin was then categorised as either less than or more than three-times/week. The aim of the study was to evaluate whether use of aspirin had an impact on the incidence and survival from bladder, breast, oesophageal, gastric, pancreatic and uterine cancers among individuals 65 years of age and older. The original PLCO data collection was completed in 2009 after 13 years of follow-up but for the current study, data collection continued until 2014, among individuals who consented to further follow-up or 2009 in those unwilling to be followed.

Findings
The eligible study population included 139,896 individuals with a mean age at baseline of 66.4 years (51.4% female). A total of 32,580 incident cancers were recorded during the follow-up period. The use of aspirin at least three times per week not associated with the incident risk of any of the included cancers. However, the researchers did find that after adjustment for co-morbidities, aspirin use (i.e., at least three times per week) was associated with a significantly increased survival compared to no use of the drug for bladder (hazard ratio, HR = 0.67, 95% CI 0.51–0.88, p = 0.003) and breast cancer (HR = 0.75, 95% CI 0.59–0.96, p = 0.02) only. In addition, any use of aspirin was also associated with a reduced risk of death from both bladder (HR = 0.75, 95% CI 0.58 – 0.98) and breast cancer (HR = 0.79, 95% CI 0.63–0.99) but again, not for any of the other cancers.

Unfortunately, the authors were unable to account for their findings and concluded that further work is needed to consider the relative benefits and harms associated with longterm use of aspirin.

Citation
Loomans-Kropps HA, Pinksky P, Umar A. Evaluation of aspirin use with cancer incidence and survival among older adults in the prostate, lung, colorectal, and ovarian cancer screening trial. JAMA Netw Open 2021

Ticagrelor and aspirin superior to aspirin alone in ischaemic stroke

20th November 2020

It is known that only a quarter of patients who experience an ischaemic stroke with a disability will improve over time and are at an increased risk of subsequent death.

Thus any intervention that is able to reduce disability by reducing a subsequent ischaemic stroke is a major objective of immediate therapy. Although the use of aspirin in combination with clopidogrel has been shown to reduce the risk of further stroke and myocardial infarction, to date, evidence for a beneficial effect from adding ticagrelor to aspirin in terms of a reduction in the burden of disability after a stroke is lacking.

In an analysis, researchers from the Department of Neurology and Stroke Center, University of Paris, France, sought to examine whether combing both drugs reduced the 30-day risk of disabling stroke or death. Disability was measured using the modified Rankin Scale (mRS) which ranges from 0 to 6, in which 0-1 represents no disability, 2-5 increasing disability and 6, death. Patients were enrolled if they were 40 years of age and older, with a non-cardioembolic acute ischaemic stroke and a stroke scale score of 5 or less (higher scores indicate more severe stroke). They were randomised to ticagrelor or matching placebo 1:1 and a loading dose of 180mg was given as soon as possible after randomisation, followed by a daily dose of 180mg (90mg twice daily). In addition, all patients received 300 to 325 mg of aspirin on the first day, followed by 75 to 100mg until day 30. The main outcome measure was the time to the occurrence of disabling stroke or death within 30 days, measured by the mRS scale.

Findings
A total of 11,016 patients with a mean age of 68.1 years (42.6% female) were included in the study. A primary end point with a mRS > 1 at day 30 (that is. disabling stroke or death) occurred in 221 (4.0%) of patients taking ticagrelor and in 260 (4.7%) of those taking placebo. This provided a number needed to treat of 133. In other words, treating 133 patients with ticagrelor and aspirin for 30 days, avoided 1 disabling stroke or death at day 30. Furthermore, disability burden (based on the mRS scale) was reduced by 23%.

Reference
Amarenco P et al. Ticagrelor added to aspirin in acute ischemic stroke
or transient ischemic attack in prevention of disabling stroke: A randomized clinical trial. JAMA Neurol doi:10.1001/jamaneurol.2020.4396