Elsevier

The Lancet

Volume 387, Issue 10023, 12–18 March 2016, Pages 1057-1065
The Lancet

Articles
Invasive versus conservative strategy in patients aged 80 years or older with non-ST-elevation myocardial infarction or unstable angina pectoris (After Eighty study): an open-label randomised controlled trial

https://doi.org/10.1016/S0140-6736(15)01166-6Get rights and content

Summary

Background

Non-ST-elevation myocardial infarction (NSTEMI) and unstable angina pectoris are frequent causes of hospital admission in the elderly. However, clinical trials targeting this population are scarce, and these patients are less likely to receive treatment according to guidelines. We aimed to investigate whether this population would benefit from an early invasive strategy versus a conservative strategy.

Methods

In this open-label randomised controlled multicentre trial, patients aged 80 years or older with NSTEMI or unstable angina admitted to 16 hospitals in the South-East Health Region of Norway were randomly assigned to an invasive strategy (including early coronary angiography with immediate assessment for percutaneous coronary intervention, coronary artery bypass graft, and optimum medical treatment) or to a conservative strategy (optimum medical treatment alone). A permuted block randomisation was generated by the Centre for Biostatistics and Epidemiology with stratification on the inclusion hospitals in opaque concealed envelopes, and sealed envelopes with consecutive inclusion numbers were made. The primary outcome was a composite of myocardial infarction, need for urgent revascularisation, stroke, and death and was assessed between Dec 10, 2010, and Nov 18, 2014. An intention-to-treat analysis was used. This study is registered with ClinicalTrials.gov, number NCT01255540.

Findings

During a median follow-up of 1·53 years of participants recruited between Dec 10, 2010, and Feb 21, 2014, the primary outcome occurred in 93 (40·6%) of 229 patients assigned to the invasive group and 140 (61·4%) of 228 patients assigned to the conservative group (hazard ratio [HR] 0·53 [95% CI 0·41–0·69], p=0·0001). Five patients dropped out of the invasive group and one from the conservative group. HRs for the four components of the primary composite endpoint were 0·52 (0·35–0·76; p=0·0010) for myocardial infarction, 0·19 (0·07–0·52; p=0·0010) for the need for urgent revascularisation, 0·60 (0·25–1·46; p=0·2650) for stroke, and 0·89 (0·62–1·28; p=0·5340) for death from any cause. The invasive group had four (1·7%) major and 23 (10·0%) minor bleeding complications whereas the conservative group had four (1·8%) major and 16 (7·0%) minor bleeding complications.

Interpretation

In patients aged 80 years or more with NSTEMI or unstable angina, an invasive strategy is superior to a conservative strategy in the reduction of composite events. Efficacy of the invasive strategy was diluted with increasing age (after adjustment for creatinine and effect modification). The two strategies did not differ in terms of bleeding complications.

Funding

Norwegian Health Association (ExtraStiftelsen) and Inger and John Fredriksen Heart Foundation.

Introduction

During the past two decades, mortality from acute coronary syndrome has reduced because of the development of modern treatment strategies—ie, revascularisation, medical treatment, and risk factor reduction in the post-discharge management. These improvements have mainly been realised in younger people (median age of 65 years) and in men.1 According to the guidelines from the European Society of Cardiology, American Heart Association, and American College of Cardiology, patients with non-ST-elevation myocardial infarction (NSTEMI) and unstable angina pectoris should be stabilised medically and assessed for invasive treatment.2, 3, 4 NSTEMI and unstable angina are frequent causes of hospital admission in patients aged 80 years or older. However, these patients are less likely to receive invasive and medical treatment according to guidelines and are at a higher risk for adverse events than younger patients.1 In large randomised controlled trials of the effect of revascularisation versus medical treatment, patients aged 80 years or older are under-represented, making proper subanalysis of benefits and disadvantages uncertain.

The aim of the present randomised controlled trial was to investigate whether patients aged 80 years or older would benefit from an early invasive strategy versus a conservative strategy, in terms of a composite primary endpoint of myocardial infarction, need for urgent revascularisation, stroke, and death.

Research in context

Evidence before this study

We searched PubMed on April 10, 2015, for manuscripts published in English between Jan 1, 2000, and April 10, 2015, with the terms “non ST-elevation myocardial infarction in the elderly” and “acute coronary syndrome in the elderly”. We had no specific inclusion or exclusion criteria for the studies searched.

A meta-analysis of the FRISC II, ICTUS, and RITA-3 trials suggested that patients older than 75 years benefit from a routine invasive strategy, but data are not available for patients aged 80 years or older. Median age in these trials was less than 65 years whereas it is older in community populations. Consequently, these trials do not have adequate sample sizes to enable subgroup analysis in patients older than 80 years. The Italian Elderly Acute Coronary Syndrome study, with 196 patients older than 80 years, is the only exception, but this trial was underpowered. An early invasive strategy in selected patients aged 80 years or more with non-ST-elevation myocardial infarction (NSTEMI) or unstable angina pectoris was associated with a reduction in endpoints (a composite of myocardial infarction, stroke, death, bleeding complications, and length of hospital stay) in the 2003–10 Nationwide Inpatient Sample database and the GRACE registry. In the most cited trials, the population aged 80 years and older is under-represented or missing, making proper subanalysis of benefits and disadvantages uncertain. This difficulty explains why references targeting this population are scarce in the guidelines and also why the European Society of Cardiology, American Heart Association, and American College of Cardiology have called for trials in this age group.

Added value of this study

The After Eighty study is the first randomised controlled trial to be specifically designed for the very elderly population (aged 80 years or older) with NSTEMI and unstable angina, which are frequent causes of hospital admission in this age group. In the present randomised controlled trial, 457 patients aged 80 years or older with NSTEMI or unstable angina were randomly assigned to an invasive strategy (including early coronary angiography with immediate assessment for percutaneous coronary intervention, coronary artery bypass graft, and optimum medical treatment) or to a conservative strategy (optimum medical treatment only). The primary outcome was a composite of myocardial infarction, need for urgent revascularisation, stroke, and death. The results show that an invasive strategy is superior to a conservative one. However, a dilution of the efficacy occurred with increasing age, and for patients older than 90 years the merit of the invasive strategy was not clear. Bleeding complication rates did not differ between the two strategies.

Implications of all the available evidence

Previous randomised trials suggest an invasive strategy is beneficial after NSTEMI and unstable angina. The results from the After Eighty study support use of an invasive strategy in patients aged 80 years or older. However, a dilution of the efficacy occurred with increasing age, and for patients older than 90 years we cannot conclude if an invasive strategy is beneficial.

Section snippets

Study design

The After Eighty study was an open-label, randomised, controlled multicentre trial. Between Dec 10, 2010, and Feb 21, 2014, patients admitted to 16 academic and teaching hospitals without percutaneous coronary intervention facilities in the South-East Health Region of Norway were included.

The protocol was approved by the relevant institutional review boards and the regional board of research ethics and is published online on the Oslo University Hospital website. No interim analysis was done.

Participants

The

Results

The median follow-up of this dynamic trial was 1·53 years. During the inclusion period, 4187 patients aged 80 years or older were admitted to the participating hospitals with the diagnosis NSTEMI or unstable angina (figure 1). 2214 (53%) of these patients met the exclusion criteria whereas 1973 (47%) patients were candidates for inclusion. 457 (23%) of the candidates for inclusion gave written consent and were randomly assigned to the invasive group (229 patients) or the conservative group (228

Discussion

The results of this open-label, randomised, controlled, multicentre study show that an invasive strategy including early coronary angiography and subsequent treatment with percutaneous coronary intervention, coronary artery bypass graft, or optimum medical treatment is superior to a conservative strategy of optimum medical treatment alone in the reduction of composite events in clinically stable patients aged 80 years or more after presenting with NSTEMI or unstable angina. The primary outcome

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