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OPINION

Low-dose aspirin for the prevention of atherothrombosis across the cardiovascular risk continuum

Walker, Jaqui

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doi: 10.1097/CP9.0000000000000017
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Abstract

Introduction

The International Aspirin Foundation Symposium at the Oriental Congress of Cardiology (Shanghai, China) in May 2021 attracted 25,600 attendees and 120,000 on-line viewers. The wide-ranging program covered aspirin's mechanism of action, its use in primary prevention of cardiovascular disease (CVD), secondary prevention of stroke and peripheral arterial disease (PAD), as well as latest guidelines and improving bleeding safety. The symposium was chaired by Professor Junbo Ge (Fudan University, China). A number of international experts shared their recent research findings and opinions on the use of aspirin across the whole spectrum of CVD.

Mechanistic insights into how aspirin prevents atherothrombosis – professor Carlo Patrono (Catholic University, Rome, Italy)

Aspirin irreversibly inactivates prostaglandin H-synthase (PGHS), an enzyme with dual cyclooxygenase (COX) and peroxidase activities. PGHS converts arachidonic acid to prostaglandin G2 (PGG2) through COX activity and then reduces PGG2 to PGH2 through peroxidase activity. PGH2 is a common intermediate in the biosynthesis of different prostanoids through the action of tissue-specific isomerases and synthases[1].

Human cells express two PGHS isoforms: COX-1 and COX-2[1]. At low doses, aspirin selectively inhibits the COX-1 isoform in platelets; higher doses are needed to inhibit COX-2 in endothelial and inflammatory cells.

There are two important consequences of permanently inactivating COX-1 with aspirin – a long-lasting effect on platelet function and cumulative inhibition of platelet thromboxane (TXA2) upon repeated daily dosing[1]. With a single oral aspirin dose there is a log-linear relationship between dose and inhibition of platelet TXA2 production, with virtually complete suppression of platelet COX-1 activity at 100 mg[1]. Temporal profile of aspirin's action is consistent with irreversible inactivation of COX-1 throughout the entire lifespan of platelets (8–10 days). With a 30 mg daily dose for 4 weeks, platelet TXA2 is completely inhibited after one week and remains so throughout the treatment period, with time-dependent recovery of platelet COX-1 activity upon aspirin withdrawal[1].

The Antithrombotic Trialists’ Collaboration (ATC) showed no additional benefit at aspirin doses higher than 75 to 150 mg in high-risk patients[2]. These findings are consistent with saturability of platelet COX-1 inactivation and TXA2 suppression at low doses[3], and led Prof Patrono to conclude that maximal clinical efficacy could be achieved at low doses of aspirin.

The CURRENT-OASIS 7 trial was conducted in 25,000 patients with acute coronary syndromes (ACS), and found no difference in the primary outcome (cardiovascular [CV] death, myocardial infarction [MI] or stroke) between lower (75–100 mg) versus higher doses (300–325 mg)[4]. Similarly, the ADAPTABLE trial (15,000 patients with stable atherosclerotic CVD) found no difference between 81 versus 325 mg daily aspirin in the primary outcome (a composite of death from any cause, hospitalization for MI, or hospitalization for stroke)[5]. Together, CURRENT-OASIS 7 and ADAPTABLE demonstrated saturability of the antithrombotic effect of aspirin at low doses[6].

Due to inter-individual variability in COX-1 recovery during the 24-h dosing interval, a single dosing regimen may not be optimal for all. Patients with faster platelet turnover may require more frequent dosing. A recent study showed that a once-daily aspirin at 100 mg may be inadequate for most patients with essential thrombocythemia, a condition with accelerated platelet COX-1 renewal. In such patients, the antiplatelet response could be improved by using a shorter dosing interval of 12 h[7].

Prevention of serious vascular events by low-dose aspirin across the Cardiovascular continuum – professor J Michael Gaziano (Harvard University, Boston, USA)

The use of aspirin as secondary CVD prevention has been tested in over 400 trials. The ATC review of 287 trials found ∼ 22% reduction in serious vascular thrombotic events (non-fatal MI, non-fatal stroke or vascular death) in patients receiving aspirin (or other antiplatelet agents) versus placebo or other antiplatelet agents versus placebo. The risk of MI, stroke, and vascular death was reduced by 34%, 25%, and 15%, respectively[8].

Trials of aspirin as primary prevention have proved challenging due to lower event rate and reduced patient compliance over time. Nonetheless, a meta-analysis of 12 primary prevention aspirin trials showed a 12% reduction in vascular events[8,9].

The use of low-dose aspirin in older individuals has been an area of debate. In 2009, the ATC meta-analysis[8] found no difference for those <65 years and >65 years of age. However, lack of subjects in subjects >70 years of age led the United States Preventative Services Task Force (USPSTF) to conclude there was insufficient evidence to make recommendations for the ≥70 year-old age groups[9].

In the ASPREE trial, subjects ≥70 years of age (or ≥60 in minority groups) taking versus not taking aspirin did not differ in the composite primary end point (death, dementia, or persistent physical disability) between[10]. The inconsistent findings obtained in the ASPREE trial (compared to other trials) may represent an outlier effect due to the use of unconventional primary outcome.

The ARRIVE trial in high-risk individuals showed early separation of CVD event between aspirin and placebo, which then “drifted back” to a modest trend favoring aspirin[11]. Such a pattern was partly attributed by the authors to increasing non-compliance over time in the aspirin arm, as well as increasing use of aspirin over time in the placebo arm.

The TIPS-3 study in subjects with intermediate CV risk found lower risk of the primary outcome (death from CV causes, MI or stroke) in aspirin + polypill (statin + three Blood Pressure [BP] lowering agents) versus the placebo arm[12].

In summary, benefit of aspirin was demonstrated by the ARRIVE and TIPS-3 trials, but not by the ASPREE trial (for the combined outcome of dementia, disability or death). Placebo-controlled primary prevention trials in the 21st century is challenging, since many patients in the control arm of the trials are placed on aspirin once they develop early signs of atherosclerosis and prior to the actual events. Regardless, aspirin remains an important approach for primary prevention of CVD prevention, with more robust benefit when CVD risk is identified using CT imaging upon suspicion.

Prevention of serious vascular events by low-dose aspirin across the Cardiovascular continuum in China – professor Xiaoying Li, (Chinese PLA general hospital, Beijing, China)

Estimated 33% of adult men and 28% of adult women in China have a 10-year risk of fatal CVD at ≥ 10%, a figure considered among the highest in the world[13].

In the 2019 ACC/AHA guidelines on primary prevention of CVD, taking low-dose aspirin in high-risk patients is one of seven major recommended measures (others include cholesterol reduction, exercise, hypertension control, diabetes control, diet and smoking cessation)[14].

Decision making regarding aspirin use for primary CVD prevention should include consideration of family history of premature MI, inability to achieve lipid or BP targets, coronary artery calcification, as well as patient preferences. Aspirin is not routinely recommended for primary CVD prevention in those >70 years or with increased bleeding risk[14].

The 2019 Chinese guidelines on CVD risk assessment and management recommend aspirin for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in clearly defined patient populations[15]. Guidelines identify four measures prior to prescribing low-dose aspirin as primary CVD prevention:

  • Assess risk/benefit ratio and exclude those at high risk of bleeding; reassess during usage and solve issues in a timely manner.
  • Identify and treat Helicobacter pylori (H. pylori) infection in advance and consider prophylactic proton pump inhibitor (PPI) or H2 receptor agonists.
  • Adhere to a healthy lifestyle and control BP, blood glucose and lipids.
  • Communicate with patients and obtain consent.

The Chinese guidelines recommend low-dose aspirin (75–100 mg/day) as primary CVD prevention in adults aged 40 to 69 years if 10-year expected risk of ASCVD is ≥10% upon initial risk assessment as well as those with three or more uncorrected major risk factors after initial management[15]. According to 2017 Chinese guidelines for CVD prevention, main risk factors include hypertension, diabetes, dyslipidaemia, smoking, family history of premature CVD in first degree relative (<50 years), body mass index (BMI) > 28, coronary artery calcification score ≥100, and non-obstructive coronary artery stenosis (<50%)[16].

Low-dose aspirin is not recommended as primary CVD prevention in those <40 years or ≥70 years, and in people with greater risk of bleeding versus thrombosis. Additional conditions for which low-dose aspirin is not recommended for primary CVD prevention include high risk of bleeding due to medications, gastrointestinal (GI) bleeding, peptic ulcers or history of bleeding in other sites; thrombocytopenia, coagulopathy, severe liver disease, chronic kidney disease stage 4 to 5, uneradicated H. pylori; and uncontrolled hypertension.

The Chinese guidelines emphasized the need of reassessing risk/benefit ratio in individual patients during the course of management. The discussion session also suggested that, in addition to age cut-off, frailty status should also be considered (eg, a frail 65-year-old with 4-year life expectancy versus a fit 85-year-old with 10-year life expectancy).

Low-dose aspirin for the secondary prevention of stroke – professor Peter Rothwell (University of Oxford, UK)

The EXPRESS study demonstrated ∼80% reduction in 90-day risk of major recurrent stroke with urgent investigation/ treatment after transient ischaemic attack (TIA) or minor stroke[17–18]. Benefit was achieved by changing care from non-urgent general practice prescribing to urgent assessment and treatment with aspirin, other antiplatelet drugs in high-risk patients, BP-lowering drugs and statins. A pooled analysis of individual patient data from 12 trials of aspirin versus control as secondary prevention showed aspirin alone reduced 90-day risk of disabling recurrent stroke by 80% and all stroke by 60%[19]. The multifactorial interventions, however, made it uncertain which component reduced stroke. Based on acute major stroke and long-term prevention after TIA/minor stroke trials, the benefit of aspirin on recurrent stroke is considered modest by most experts.

To maximize the benefit of aspirin, current guidelines recommend immediate prescription of aspirin by first-line healthcare professionals (eg, paramedics and emergency physicians) prior to specialist assessment[20–22].

Based on the benefits of short-term dual treatment in clinical trials[22–25], patients with minor stroke and high-risk TIAs are commonly prescribed a second antiplatelet drug for a few weeks in addition to aspirin. Use of the ABCD[2] risk stratification score is recommended to identify high-risk TIA patients suitable for dual treatment[22,26–27].

Aspirin is recommended for life-long use as secondary prevention of vascular events, but clinical trials indicated that the benefits diminish over time due to withdrawal from treatment[19]. Nonetheless, the UK-TIA aspirin trial demonstrated cumulative benefit for at least three years in patients remaining on allocated treatment[28].

In a time-course analysis involving 12 trials, aspirin reduced the risk of early recurrent stroke following TIA and ischemic stroke (IS) in the first six weeks (P < 0.0001 vs. placebo) and 6 to 12 week period (P < 0.0001), but the benefit was no longer significant at > 12 weeks (P < 0.85)[19]. The aspirin arm also had decreased severity of recurrent ischaemic stroke (less major strokes, very disabling strokes and death and fewer symptoms after the event) at 6 to 12 weeks[19].

The Oxford Vascular Study (a population-based cohort study) found elevated risk of bleeding in elderly patients, and particularly in elderly frail populations[29]. Co-prescription of PPIs is encouraged if long-term use of aspirin is required in this population.

Addressing an audience question about dual antiplatelet therapy, Professor Rothwell highlighted the results of the Chinese CHANCE trial, namely significantly reduced recurrent stroke in the first 90 days with aspirin plus clopidogrel versus aspirin alone[23]. He also emphasized that optimal duration for dual treatment is three weeks, beyond which the risk of bleeding increases significantly, possibly exceeding the benefits.

Current guidelines recommend starting aspirin immediately and continuing lifelong, but no trials have examined when to stop aspirin treatment.

Dual-pathway inhibition for secondary antithrombotic prevention in CVD – professor Wei-Guo Fu (Fudan University, Shanghai, China)

PAD is often comorbid with CAD and CVD, and share common pathological bases. In the REACH registry, one out of six patients with CAD, CVD, or PAD had symptomatic involvement of one or two other arterial beds[30]. Also, patients with CAD and PAD have higher risk of CV events and death versus those with CAD alone[31].

PAD is estimated to affect 236 million people globally[32]. In China, where prevalence is 6.6% in adults >35 years, the level of awareness and the rate of revascularization and control are disappoiting[32]. The 2017 ESC PAD treatment guidelines reported that only one-fifth to one-third of the patients with lower extremity artery disease (LEAD) have intermittent claudication (IC) or other symptoms[33]. Together with the fact that most PAD symptoms are non-specific, imaging-based screening programs that identify high-risk groups are important.

The long-term management goal for CAD and PAD is to reduce risk of adverse CV events as well as improving limb symptoms and reducing adverse limb events. Vascular protection strategies include healthy lifestyles (diet, physical activity and weight control), psychosocial support, antithrombotic treatments, and control of comorbidities (ie, hypertension, diabetes and hyperlipidemia).

Dual-pathway inhibition (DPI) antithrombosis, anticoagulation and antiplatelet therapy are synergistic in inhibiting atherothrombosis[34–35]. In the COMPASS trial, rivaroxaban 5 mg BDS plus aspirin 100 mg OD reduced major adverse cardiac events (MACE) by 28% and major adverse limb events (MALE) by 46% versus aspirin 100 mg alone[36].

Analysis of stroke outcomes in COMPASS showed nearly 50% reduction in ischemic/ cryptogenic events with DPI versus aspirin alone (HR 0.51; P < 0.0001)[36–37]. The overall risk of bleeding was higher in the DPI group, but there was no group difference in fatal bleeding, vital organ bleeding or intracranial haemorrhage[38]. Based on COMPASS, the 2019 ESC chronic coronary syndrome guidelines recommend rivaroxaban 2.5 BID plus aspirin for secondary prevention in diffuse multi vessel CAD and PAD in patients without high risk of bleeding[39].

In the VOYAGER trial of PAD patients undergoing lower-extremity revascularisation, subjects receiving rivaroxaban BID plus aspirin had significantly lower incidence of primary outcome (composite of acute limb ischemia, major amputation for vascular causes, MI, IS, or death from CV causes) than the patients receiving placebo plus aspirin (HR, 0.85, P = 0.009)[40] without increasing the risk of intracranial haemorrhage or fatal bleeding[40].

Together, the COMPASS and VOYAGER trials confirmed the benefit of rivaroxaban 2.5 mg BID in PAD patients irrespective of revascularisation. Both the CCS and PAD guidelines recommend rivaroxaban 2.5 mg BID plus low-dose aspirin in patients with high ischemic risk chronic CAD and PAD.

How to improve the gastrointestinal safety of low-dose aspirin – professor Andrew T Chan (Harvard University, Boston, USA)

Aspirin causes mucosal injury through prostaglandin-dependent topical and systemic mechanisms[41–42]. The injury is more dependent on higher doses than longer duration[43–44]. Both the ASPREE and ARRIVE trials found greater risk of bleeding in the aspirin versus placebo groups[11,45].

H. pylori infection is associated with increased risk of gastroduodenal damage in low-dose aspirin users, with higher GI bleeding in the Asian populations due to the high prevalence of H. pylori infection[46]. Other risk factors for aspirin/NSAID upper GI complications include smoking, history of ulcers, history of GI bleeding, ≥ two NSAIDs, concurrent use of corticosteroids or anticoagulants, older age, severe disease, and larger waist size[10–11,45,47].

GI bleeding risk did not differ among different P2Y12 inhibitors (eg, clopidogrel, ticagrelor and prasugrel) and aspirin alone[48–51], but the risk is magnified when these agents are taken together[52]. A meta-analysis of 10 trials indicated reduced risk of GI bleeding in patients taking a PPI together with aspirin (OR 0.27)[53]. The protection offered by PPIs seems to be greater than H2 blockers[54]. H. pylori eradication reduced aspirin-associated GI bleeding by approximately the same magnitude as PPI inhibitors[55].

Professor Chan advocates adding a PPI in people with one or more risks of bleeding, as well as eradication of H. pylori infection. Addressing a question on the safety of restarting antiplatelet therapy after GI bleeding, Professor Chan pointed out that withholding aspirin can be harmful due to increased CVD risk, and advocates comprehensive risk assessment that includes a thorough endoscopic investigation prior to resuming aspirin.

Conflict of interest statement

The author declares that there is no conflict of interest with regard to the content of this manuscript.

Acknowledgments

The International Aspirin Foundation thanks all who participated in the symposium.

References

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Keywords:

Cardiovascular Disease; Coronary artery disease; Peripheral arterial disease; Primary prevention; Secondary prevention; Stroke

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