Elsevier

The Lancet

Volume 392, Issue 10152, 22–28 September 2018, Pages 1036-1046
The Lancet

Articles
Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(18)31924-XGet rights and content

Summary

Background

The use of aspirin in the primary prevention of cardiovascular events remains controversial. We aimed to assess the efficacy and safety of aspirin versus placebo in patients with a moderate estimated risk of a first cardiovascular event.

Methods

ARRIVE is a randomised, double-blind, placebo-controlled, multicentre study done in seven countries. Eligible patients were aged 55 years (men) or 60 years (women) and older and had an average cardiovascular risk, deemed to be moderate on the basis of the number of specific risk factors. We excluded patients at high risk of gastrointestinal bleeding or other bleeding, or diabetes. Patients were randomly assigned (1:1) with a computer-generated randomisation code to receive enteric-coated aspirin tablets (100 mg) or placebo tablets, once daily. Patients, investigators, and others involved in treatment or data analysis were masked to treatment allocation. The primary efficacy endpoint was a composite outcome of time to first occurrence of cardiovascular death, myocardial infarction, unstable angina, stroke, or transient ischaemic attack. Safety endpoints were haemorrhagic events and incidence of other adverse events, and were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00501059.

Findings

Between July 5, 2007, and Nov 15, 2016, 12 546 patients were enrolled and randomly assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites. Median follow-up was 60 months. In the intention-to-treat analysis, the primary endpoint occurred in 269 (4·29%) patients in the aspirin group versus 281 (4·48%) patients in the placebo group (hazard ratio [HR] 0·96; 95% CI 0·81–1·13; p=0·6038). Gastrointestinal bleeding events (mostly mild) occurred in 61 (0·97%) patients in the aspirin group versus 29 (0·46%) in the placebo group (HR 2·11; 95% CI 1·36–3·28; p=0·0007). The overall incidence rate of serious adverse events was similar in both treatment groups (n=1266 [20·19%] in the aspirin group vs n=1311 [20·89%] in the placebo group. The overall incidence of adverse events was similar in both treatment groups (n=5142 [82·01%] vs n=5129 [81·72%] in the placebo group). The overall incidence of treatment-related adverse events was low (n=1050 [16·75%] vs n=850 [13·54%] in the placebo group; p<0·0001). There were 321 documented deaths in the intention-to-treat population (n=160 [2·55%] vs n=161 [2·57%] of 6276 patients in the placebo group).

Interpretation

The event rate was much lower than expected, which is probably reflective of contemporary risk management strategies, making the study more representative of a low-risk population. The role of aspirin in primary prevention among patients at moderate risk could therefore not be addressed. Nonetheless, the findings with respect to aspirin's effects are consistent with those observed in the previously published low-risk primary prevention studies.

Funding

Bayer.

Introduction

The role of aspirin (acetylsalicylic acid) in inhibiting platelet aggregation has been well established in the secondary prevention of coronary and cerebrovascular diseases.1 The benefit of low-dose aspirin in patients with acute coronary syndromes or previous myocardial infarction, stroke, or transient ischaemic attacks is supported by more than 200 studies involving more than 200 000 patients.2 Numerous professional societies and governmental agencies recommend the use of 75–100 mg of aspirin in patient subgroups with overt cardiovascular disease with a 10-year risk of myocardial infarction or stroke that exceeds 20%.3, 4, 5

The role of aspirin in the primary prevention of myocardial infarction and stroke in groups with a moderate estimated risk of a first cardiovascular event has been controversial, despite 30 years of randomised trials. A major issue complicating the interpretation of these studies is a low but well described risk of bleeding, ranging from more common episodes of easy bruising and epistaxis, to less frequent but life-endangering gastrointestinal haemorrhage and haemorrhagic stroke. These deleterious effects of aspirin limit its use in people with low 10-year risk of myocardial infarction or stroke, or intolerance to aspirin. Six large randomised studies published from 1988 to 2005, included 100 000 participants who contributed 700 000 person-years of follow-up.6, 7, 8, 9, 10, 11 Most of these patients had a 10-year risk of less than 10%. The results of these studies were generally supportive of the use of 75–150 mg aspirin per day to prevent incident myocardial infarction and stroke. Since 2005, there have been six additional studies of aspirin (81–100 mg daily) in the primary prevention setting; four have been published.12, 13, 14, 15 These studies had less consistent results. This outcome has led to inconsistent guidelines, with recommendations both for and against aspirin use in primary prevention.4, 5, 16 Subsequently, a trend of decreasing aspirin use for primary prevention has been observed in the USA, including 10-year risk groups of both 10–20% and greater than 20%, presumably because of uncertainty of the risks and benefits of low-dose aspirin.17 Recent evidence about the potential benefits of aspirin in colon cancer prophylaxis also need to be considered in the overall benefit-risk assessment of low-dose aspirin use in the primary prevention setting.

Research in context

Evidence before this study

Numerous studies have investigated the benefits and risks of aspirin in the acute management of cardiovascular events and in longer-term secondary prevention among people with cardiovascular disease. Fewer large-scale trials were done in the primary prevention of cardiovascular disease before the design of the ARRIVE trial. There remains a gap in the understanding of benefits and risks of aspirin use in patients at moderate risk of cardiovascular disease. We considered six key aspirin primary prevention studies before doing this study (the only published large-scale trials), which showed a reduction in risk of cardiovascular disease, largely due to a reduction in the risk of myocardial infarction among people treated with aspirin. Four additional studies of aspirin (81–100 mg daily) in the primary prevention setting have been published since the initial design of ARRIVE. These studies, and the meta-analyses that followed, were also considered in the implementation of ARRIVE and for the interpretation of the ARRIVE findings.

Added value of this study

Findings of the ARRIVE trial add to our understanding of the use of aspirin in primary prevention in several ways. First, the study was designed to assess the benefit of 100 mg per day of enteric-coated aspirin versus placebo in the reduction of incident myocardial infarction, stroke, and related cardiovascular conditions in people considered to be at moderate risk, with the exclusion of patients with diabetes. An additional objective of ARRIVE was to assess the safety and tolerability of aspirin in these patients in the setting of decreasing population-wide cardiovascular risk. Finally, ARRIVE assessed the role of aspirin with a background of modern preventive and therapeutic strategies. The findings of ARRIVE are generally consistent with the collective results of the previous primary prevention studies.

Implications of all the available evidence

While ARRIVE sought to add relevant information about the cardiovascular benefits and bleeding risks of aspirin among people at moderate cardiovascular risk, it shows some of the challenges of doing long-term prevention studies in the current era. Findings from ARRIVE are generally consistent with many other studies that tended to show aspirin's ability to lower the risk of first non-fatal myocardial infarction without affecting the risk of total stroke. With respect to safety, as expected, rates of gastrointestinal bleeding events and some other minor bleeding events were higher in the aspirin treatment group, but there was no difference in the incidence of fatal events. The use of aspirin remains a decision that should involve a thoughtful discussion between a clinician and a patient, given the need to weigh the cardiovascular as well as possible cancer prevention benefits against the bleeding risks, patient preferences, cost, and other factors. ARRIVE contributes useful information in relation to the efficacy and safety of aspirin in the intermediate term. The ARRIVE study adds additional relevant data to the body of evidence that can help the clinician with the decision as to when to use aspirin. The ARRIVE data must be interpreted in the context of other studies, which have tended to demonstrate a reduction primarily in myocardial infarction, but less of an effect on total stroke (including both ischaemic and haemorrhagic stroke). The overall decision to use aspirin should be based on individual patient–physician discussion.

We designed the Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) study to investigate the efficacy of 100 mg enteric-coated aspirin daily versus placebo in the reduction of incident myocardial infarction, stroke, and related cardiovascular conditions in people at moderate risk (defined as 10–20% 10-year coronary heart disease, with the exclusion of patients with diabetes). An additional objective of ARRIVE was to assess the safety and tolerability of aspirin in these patients in the setting of decreasing population-wide cardiovascular risk.

Section snippets

Study design and participants

The ARRIVE study is a randomised, double-blind, placebo-controlled, multicentre primary prevention study done in seven countries (Germany, Italy, Ireland, Poland, Spain, the UK, and the USA). The study setting was largely primary care offices.

Eligible male patients were aged 55 years and older and had between two and four risk factors; eligible female patients were aged 60 years or older and had three or more risk factors. Risk factors were high cholesterol (total cholesterol >200 mg/dL [5·180

Results

Between July 5, 2007, and Nov 15, 2016, 12 546 participants were enrolled and assigned to receive aspirin (n=6270) or placebo (n=6276) at 501 study sites (figure 1). Each participant completed up to a total of nine visits over an approximate 6-year period. Over the course of the study, which lasted 60 months on average (median follow-up 1858 days; IQR 1475–2209), 29·6% of patients terminated the study prematurely (1843 [29·4%] in the aspirin group and 1875 [29·9%] in the placebo group). The

Discussion

In the ARRIVE study, we aimed to address the role of aspirin in primary prevention of cardiovascular disease in patients at moderate risk of a first cardiovascular event, in a pragmatic, primary care-based randomised trial. The findings add important information to the body of evidence and are generally consistent with previous primary prevention studies. This study also showed the challenges of doing long-term primary prevention studies in an era of aggressive management of risk factors among

Data sharing

Availability of the data underlying this publication will be determined according to Bayer's commitment to the EFPIA/PhRMA principles for responsible clinical trial data sharing. This pertains to scope, timepoint, and process of data access. As such, Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the

References (22)

  • L Hansson et al.

    Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial

    Lancet

    (1998)
  • N Raju et al.

    Updated meta-analysis of aspirin in primary prevention of cardiovascular disease

    Am J Med

    (2016)
  • JM Guirguis-Blake et al.

    Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force

    Ann Intern Med

    (2016)
  • Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials

    Lancet

    (2009)
  • SC Smith et al.

    World Heart Federation and the Preventive Cardiovascular Nurses Association. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation

    Circulation

    (2011)
  • K Bibbins-Domingo

    Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement

    Ann Intern Med

    (2016)
  • MF Piepoli et al.

    2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR)

    Eur Heart J

    (2016)
  • R Peto et al.

    Randomised trial of prophylactic daily aspirin in British male doctors

    Br Med J (Clin Res Ed)

    (1988)
  • Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group

    N Engl J Med

    (1989)
  • Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk

    Lancet

    (1998)
  • Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice

    Lancet

    (2001)
  • Cited by (586)

    • Refining the classification of cardiovascular prevention

      2024, Revista Portuguesa de Cardiologia
    View all citing articles on Scopus
    View full text