← Back

ARRIVE

Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease

Share Share Copied! Compare

Year of Publication: 2018

Authors: J Michael Gaziano, Carlos Brotons, Rosa Coppolecchia, ..., Gianni Tognoni; the ARRIVE Executive Committee

Journal: The Lancet

Citation: Lancet 2018; published online Aug 26. http://dx.doi.org/10.1016/S0140-6736(18)31924-X

Link: http://dx.doi.org/10.1016/S0140-6736(18)31924-X

PDF: https://www.ncbi.nlm.nih.gov/pmc/articles/7255888

Clinical Question

Does aspirin reduce the risk of first cardiovascular events in patients at moderate cardiovascular risk?

Study Overview

Objective

Evaluate the efficacy and safety of daily low-dose aspirin versus placebo for primary prevention of cardiovascular events in individuals with moderate cardiovascular risk.

Study Summary

In individuals with moderate estimated cardiovascular risk and no diabetes, daily aspirin 100 mg did not significantly reduce the risk of major cardiovascular events compared with placebo. Gastrointestinal bleeding, although mostly mild, was significantly more frequent with aspirin.

Intervention

Randomized, double-blind, placebo-controlled trial conducted in 7 countries. N=12,546 patients (men ≥55 years, women ≥60 years) with moderate CV risk but no diabetes. Randomized to:
Aspirin 100 mg enteric-coated tablet daily
Matching placebo Median follow-up: 60 months. Primary outcome: composite of MI, stroke, CV death, unstable angina, or TIA.

Bottom Line

Aspirin did not significantly reduce cardiovascular events in the enrolled population, which had lower event rates than expected, making it more representative of low-risk rather than moderate-risk patients.

        Major Points
        Large randomized, double-blind, placebo-controlled trial of 12,546 patients
Primary endpoint (cardiovascular death, MI, stroke, unstable angina, TIA) occurred in 4.29% aspirin vs 4.48% placebo (HR 0.96, p=0.6038)
Event rates were much lower than anticipated (550 vs 1488 expected events)
Gastrointestinal bleeding significantly increased with aspirin (HR 2.11, p=0.0007)
Per-protocol analysis showed trend toward benefit for myocardial infarction
Study became more representative of low-risk population due to contemporary risk management

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Patients, investigators, and others involved in treatment or data analysis were masked to treatment allocation

Enrollment Period: July 5, 2007 to November 15, 2016

Follow-up Duration: Median 60 months (5 years)

Centers: 501

Countries: Germany, Italy, Ireland, Poland, Spain, UK, USA

Sample Size: 12546

Analysis: Intention-to-treat and per-protocol analyses using Cox proportional hazards model, adjusted for country and sex

Inclusion Criteria

Men aged ≥55 years with 2-4 cardiovascular risk factors
Women aged ≥60 years with ≥3 cardiovascular risk factors
Risk factors: high cholesterol, current smoking, low HDL cholesterol, high blood pressure, receiving antihypertensive medication, positive family history of cardiovascular disease
Average cardiovascular risk (10-year risk of coronary heart disease 10-20%)

Exclusion Criteria

History of vascular events (stroke, MI, coronary procedures, relevant arrhythmias, heart failure)
Required antiplatelet therapy
High risk of gastrointestinal bleeding
History of gastric or duodenal ulcers or GI bleeding
Concomitant use of anticoagulants or frequent NSAID use
Diabetes mellitus

Baseline Characteristics

Characteristic	Control	Active
Mean age	63.9 years	63.9 years
Female	29.6%	29.5%
Current smokers	28.5%	28.8%
High total cholesterol	58.3%	58.2%
High LDL	45.7%	44.3%
Low HDL	13.9%	13.7%
High systolic BP	62.9%	62.5%
Taking antihypertensives	65.3%	64.4%
Mean Framingham 10-year CHD risk	14.1%	13.9%
Mean ACC/AHA 10-year ASCVD risk	17.4%	17.3%

Arms

Field	Aspirin group	Control
Intervention	Enteric-coated aspirin tablets 100 mg once daily	Placebo tablets once daily
Duration	Median 60 months	Median 60 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Composite of time to first occurrence of confirmed myocardial infarction, stroke, cardiovascular death, unstable angina, or transient ischaemic attack. The original protocol primary endpoint included only CV death, MI, and stroke; unstable angina and TIA were added by a later protocol amendment (to bind biologically related endpoints and compensate for selective withdrawals). The trial reported both the amended and original composites, with concordant null results (amended HR 0.96, p=0.6038; original CV death/MI/stroke HR 0.95, p=0.6190).	Primary	281/6276 (4.48%)	269/6270 (4.29%)	0.96	0.6038
Myocardial infarction (fatal or non-fatal)	Secondary	112/6276 (1.78%)	95/6270 (1.52%)	0.85	0.2325
Stroke (fatal or non-fatal)	Secondary	67/6276 (1.07%)	75/6270 (1.20%)	1.12	0.5072
Cardiovascular death	Secondary	39/6276 (0.62%)	38/6270 (0.61%)	0.97	0.9010
All-cause mortality	Secondary	161/6276 (2.57%)	160/6270 (2.55%)	0.99	0.9459
Gastrointestinal bleeding	Adverse	29/6276 (0.46%)	61/6270 (0.97%)	2.11	0.0007
Serious adverse events	Adverse	1311/6276 (20.89%)	1266/6270 (20.19%)

Subgroup Analysis

Subgroup analysis showed consistent results with overall findings for the primary endpoint, except for the lowest cardiovascular risk quartile which showed potential benefit (HR 0.58, 95% CI 0.35-0.97)

Criticisms

Event rate was much lower than expected, undermining the study's ability to address moderate-risk populations
High discontinuation rate (approximately 30% in both groups)
Study became time-driven rather than event-driven due to lower event rates
Potential undercounting of events due to pragmatic primary care setting
Compliance issues, particularly in UK subset possibly related to media coverage

Funding

Bayer

Based on: ARRIVE (The Lancet, 2018)