Elsevier

The Lancet

Volume 359, Issue 9314, 13 April 2002, Pages 1269-1275
The Lancet

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Effect of nicorandil on coronary events in patients with stable angina: the Impact Of Nicorandil in Angina (IONA) randomised triala

https://doi.org/10.1016/S0140-6736(02)08265-XGet rights and content

Summary

Background

In addition to its anti-ischaemic effects, the antianginal drug nicorandil is thought to have cardioprotective properties. We did a randomised trial to find out whether nicorandil could reduce the frequency of coronary events in men and women with stable angina and additional risk factors.

Methods

5126 patients were randomly assigned 20 mg nicorandil twice daily (n=2565) or identical placebo (n=2561) in addition to standard antianginal therapy. The primary composite endpoint was coronary heart disease death, non-fatal myocardial infarction, or unplanned hospital admission for cardiac chest pain. The secondary endpoint was the combined outcome of coronary heart disease death or nonfatal myocardial infarction. Other outcomes reported include all-cause mortality, all cardiovascular events, and acute coronary syndromes. Mean follow-up was 1·6 years (SD 0·5). Analysis was by intention to treat.

Findings

There were 398 (15·5%) primary endpoint events in the placebo group and 337 (13·1%) in the nicorandil group (hazard ratio 0·83, 95% Cl 0·72–0·97; p=0·014). The frequency of the secondary endpoint was not significantly different between the groups (134 events [5·2%] vs 107 events [4·2%]; 0·79, 0·61–1·02; p=0·068). The rate of acute coronary syndromes was 195 (7·6%) in the placebo group and 156 (6·1%) in the nicorandil group (0·79, 0·64–0·98; p=0·028), and the corresponding rates for all cardiovascular events were 436 (17·0%) and 378 (14·7%; 0·86, 0·75–0·98; p=0·027).

Interpretation

We showed a significant improvement in outcome due to a reduction in major coronary events by antianginal therapy with nicorandil in patients with stable angina.

Introduction

Stable angina affects 2·3–5·1% of men aged 40–59 years, and more than 10% of those older than 60 years.1 In the UK, 25% of all deaths are attributable to coronary heart disease, and 25% of all patients presenting with a first myocardial infarction have a history of stable angina.2 Therefore, stable angina is important, not only as a cause of disability, but also as a frequently observed marker for underlying coronary heart disease. Aspirin, angiotensin converting-enzyme (ACE) inhibitors, and statins reduce the risk of cardiovascular events in subgroups of patients with stable angina;3, 4, 5, 6, 7 however, the effect of specific antianginal treatment on morbidity and mortality in patients with stable angina remains unknown.

Nicorandil is a nicotinamide ester with a dual mechanism of action. Its distinctive pharmacological effect is to open ATP-sensitive potassium channels (KATP), thereby dilating peripheral and coronary resistance arterioles; but it also possesses a nitrate moiety which dilates systemic veins and epicardial coronary arteries. Thus, nicorandil increases coronary blood flow, reduces preload and after-load,8, 9, 10, 11 and has an antianginal efficacy and safety profile similar to that of oral nitrates, β-blockers, and calcium antagonists.12, 13, 14 However, in addition to relieving symptoms of ischaemia, nicorandil has potential cardioprotective effects. These effects are probably due to its ability to mimic the powerful ischaemic preconditioning phenomenon by opening KATP channels, as shown in clinical and preclinical studies.15, 16, 17, 18, 19

The objective of the Impact Of Nicorandil in Angina (IONA) study was to investigate whether or not cardioprotective effects of nicorandil could be shown in a large outcome study in stable angina.

Section snippets

Patients

The design and conduct of the IONA study has been reported in detail previously.20 Briefly, patients with a history of angina were recruited from centres in the UK. Angina could be recently diagnosed, but not unstable or chronic. Standard background antianginal therapy was not specified, but was to be optimum treatment as judged by the investigator for the individual patient. Such treatment could include one or more oral antianginal medications including β-blockers, calcium-channel blockers, or

Results

5126 patients were enrolled from 226 centres in the UK between May, 1998, and August, 2000. 2565 were randomly assigned nicorandil and 2561 placebo (figure 1). Patients were recruited in about equal numbers from primary care and hospital practices. The mean follow-up was 1·6 years (SD 0·5), with the final study visit in August, 2001. The baseline characteristics of randomised participants and the cardiovascular medications being taken at randomisation are listed in Table 1, Table 2,

Discussion

In the IONA study, we report a significant improvement in outcome from antianginal treatment in patients with stable angina. Outcome was defined as a combination of morbidity and mortality by a composite primary endpoint of coronary heart disease death, non-fatal myocardial infarction, or unplanned hospital admission for chest pain. Event rates in all components of the primary endpoint were lower in patients on nicorandil than on placebo and therefore each contributed to the significance of the

References (32)

  • HB Rubins et al.

    Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high density lipoprotein cholesterol

    N Engl J Med

    (1999)
  • T Chibana et al.

    Comparison of acute hemodynamic and coronary vasodilating effects between nicorandil and glyceryl trinitrate

    Arzneim-Forsh/Drug Res

    (1991)
  • N Treese et al.

    Acute hemodynamic effects of nicorandil in coronary artery disease

    J Cardiovasc Pharm

    (1992)
  • N Taira

    Similarity and dissimilarity in the mode and mechanism of action between nicorandil and classical nitrates: an overview

    J Cardiovasc Pharm

    (1987)
  • N Taira

    Nicorandil as a hybrid between nitrates and potassium channel activators

    J Cardiol

    (1989)
  • G Doring

    Antianginal and anti-ischemic efficacy of nicorandil in comparison with isosorbide-5-mononitrate and isosorbide dinitrate: results from two multicenter, double-blind, randomized studies with stable coronary heart disease patients

    J Cardiovasc Pharm

    (1992)
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