Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial

doi:10.1016/S0140-6736(03)12706-7

The Lancet

Volume 361, Issue 9360, 8 March 2003, Pages 809-813

https://doi.org/10.1016/S0140-6736(03)12706-7 Get rights and content

Summary

Background

There is serological and epidemiological evidence of an association between Chlamydia pneumoniae infection and coronary artery disease. Results of previous smaller studies have indicated a reduction of recurrent ischaemic events in patients with acute coronary syndrome when given macrolide antibiotics. We aimed to assess whether short-term treatment with the macrolide antibiotic azithromycin reduces recurrent ischaemic events in patients admitted for unstable angina or myocardial infarction.

Methods

We assessed the effect of azithromycin in a multi-centre, double-blind randomised trial in 1439 patients with unstable angina or acute myocardial infarction. Patients were randomly allocated to receive 500 mg azithromycin on the first day after randomisation, followed by 250 mg daily for 4 days or placebo. Patients were followed up for 6 months. The primary endpoints were death, recurrent myocardial infarction, or recurrent ischaemia necessitating revascularisation. Analysis was done by intention to treat.

Findings

Treatment with azithromycin did not result in reduction of either individual endpoints or any of the primary endpoints. Of the 716 patients in the azithromycin group, 23 (3%) died, 17 (2%) developed myocardial infarction, 65 (9%) had recurrent ischaemia needing revascularisation, and 100 (14%) had one or more of these endpoints. In the placebo group (n=723) the corresponding numbers of patients were 24 (4%), 22 (3%), 59 (8%), and 106 (15%), respectively (p=0·664, 95% CI 0·72–1·24). 62 (9%) of patients in the azithromycin group and 59 (8%) in the placebo group reached the secondary endpoint of ischaemia or congestive heart failure necessitating admission (difference 0·5%, 95% CI 0·75–1·53; p=0·707). We recorded few side-effects.

Interpretation

Short-term treatment with azithromycin does not reduce development of recurrent events in patients with acute coronary syndrome.

Introduction

Acute coronary syndrome results from plaque disruption and superimposed platelet and fibrin thrombus formation, leading to occlusion of the coronary artery.¹ Despite widespread use of potent antiplatelet agents and statins, the rate of recurrent ischaemic events within the 2–6 months after an initial episode of acute myocardial infarction and unstable angina remains high, 12–20%.2, 3, 4 Vascular inflammation leading to plaque disruption and thrombus formation could be in part due to infection of the arterial wall, most notably with Chlamydia pneumoniae.⁵ Infection with this organism results in activation of prothrombotic and proinflammatory genes, such as tissue factor and adhesion molecules, creating a potential pathophysiological link between infection and acute coronary syndromes.6, 7 Results of initial studies, in which C pneumoniae was treated with azithromycin8, 9, 10 and roxithromycin¹¹ suggested that patients with acute coronary syndrome who were given antibiotics had either reduced serum concentrations of markers of inflammation, or a reduction in recurrent ischaemic events. The results were not conclusive because of the small number of patients included in the studies.

In the Azithromycin in Acute Coronary Syndrome (AZACS) study, we aimed to determine whether short-term treatment with azithromycin, initiated shortly after presentation with acute coronary syndrome, reduces the occurrence of recurrent ischaemic events and death during the following 6 months.

Section snippets

Patients

We recruited patients from seven centres in Europe, Israel, and the USA. Patients were eligible if they were aged 18 years or older and admitted with unstable angina or acute myocardial infarction. Unstable angina was defined as admission with chest pain or discomfort consistent with myocardial ischaemia lasting for at least 5 min that occurred at rest, at least one episode within 24 h of admission, and one of the following findings: substantial electrocardiographic evidence of ischaemia, new

Results

We enrolled 1439 consecutive patients; 716 were randomly allocated to azithromycin and 723 to placebo. Figure 1 shows the trial profile. The mean time between the qualifying diagnosis and randomisation was 2·9 days (SD 3·1). Table 1 shows the demographic and clinical characteristics of the patients.

The drugs taken by patients were much the same in the two groups at randomisation and at 6 months' follow-up (table 2). Fewer than 1% of patients had missing information for any drug.

The number of

Discussion

Our results over 6 months show that an early 5-day course of azithromycin after an acute coronary syndrome did not reduce the number of people who died or developed myocardial infarction, or ischaemic episodes needing percutaneous coronary intervention or coronary artery bypass graft. Similarly, the frequency of recurrent ischaemia or congestive heart failure needing admission was also not affected by treatment with azithromycin.

Treatment with azithromycin also did not reduce adverse clinical

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A number of large clinical trial including the Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD), the Azithromycin in Acute Coronary Syndromes (AZACS), the Azithromycin and Coronary Events Study (ACES), and the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE-IT-TIMI22) have investigated the effectiveness of different antibiotics and therapeutic regimens on the risk of CVD in patients with ischemic heart disease with or without serological evidence of C. pneumoniae infection. The evidence of a short-term reduction in the risk of CVD was weak and there was no evidence of a long-term reduction in these trials [21,45–47]. Antibiotic treatment for Helicobacter pylori infection was again inconsistent [48].
Atherosclerosis is the leading global cause of mortality, morbidity, and disability. Heat shock proteins (HSPs) are a highly conserved family of proteins with diverse functions expressed by all cells exposed to environmental stress. Studies have reported that several HSPs may be potential risk markers of atherosclerosis and related cardiovascular diseases, or may be directly involved in the atherogenic process itself. HSPs are expressed by cells in atherosclerotic plaque and anti-HSP has been reported to be increased in patients with vascular disease. Autoimmune responses may be generated against antigens present within the atherosclerotic plaque, including HSP and may lead to a cycle of ongoing vascular injury. It has been suggested that by inducing a state of tolerance to these antigens, the atherogenic process may be limited and thus provide a potential therapeutic approach. It has been suggested that anti-HSPs are independent predictors of risk of vascular disease. In this review, we summarize the current understanding of HSP in cardiovascular disease and highlight their potential role as diagnostic agents and therapeutic targets.
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The Lancet

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

References (18)

Serologic evidence of an association of a novel chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction

Lancet

Randomised trial of roxithromycin in non-Q-wave coronary syndromes: ROXIS pilot study

Lancet

Coronary plaque rupture

Circulation

Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease

Lancet

Comparison of early invasive and conservative strategies in patients with unstable coronary syndrome treated with glycoprotein IIb/IIIa inhibitor tirofiban

N Engl J Med

Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes

JAMA

Chlamydial and human heat shock protein localizes in human atheroma and regulates macrophage tumor necrosis factor- and matrix metalloproteinase expression

Circulation

Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology

Circulation

Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction

Circulation

Cited by (136)

Extrinsic and Intrinsic Responses in the Development and Progression of Atherosclerosis

Non-anti-infective effects of antimicrobials and their clinical applications: A review

Vaccine for atherosclerosis

Macrolides, Clindamycin, and Ketolides

Heat shock proteins and cardiovascular disease

Infections, immunity and atherosclerosis: Pathogenic mechanisms and unsolved questions

ArticlesEffect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Lancet

Lancet

Coronary plaque rupture

Circulation

Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease

Lancet

Comparison of early invasive and conservative strategies in patients with unstable coronary syndrome treated with glycoprotein IIb/IIIa inhibitor tirofiban

N Engl J Med

Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes

JAMA

Chlamydial and human heat shock protein localizes in human atheroma and regulates macrophage tumor necrosis factor- and matrix metalloproteinase expression

Circulation

Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology

Circulation

Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction

Circulation

Articles
Effect of short-term treatment with azithromycin on recurrent ischaemic events in patients with acute coronary syndrome in the Azithromycin in Acute Coronary Syndrome (AZACS) trial: a randomised controlled trial