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

doi:10.1016/S0140-6736(97)07201-2

The Lancet

Volume 350, Issue 9075, 9 August 1997, Pages 404-407

https://doi.org/10.1016/S0140-6736(97)07201-2 Get rights and content

Summary

Background

There is serological evidence for an association between Chlamydia pneumoniae and coronary heart disease. We investigated the hypothesis that an antichlamydial macrolide antibiotic, roxithromycin, can prevent or reduce recurrent major ischaemic events in patients with unstable angina.

Methods

The effect of roxithromycin was assessed in a double-blind, randomised, prospective, multicentre, parallel-group, placebo-controlled pilot study of 202 patients with unstable angina or non-Q-wave myocardial infarction. Patients were randomly assigned either roxithromycin 150 mg orally twice a day (n=102) or placebo orally twice a day (n=100). The treatment was for 30 days. Patients were followed up for 6 months. We report the primary clinical endpoints (cardiac ischaemic death, myocardial infarction, and severe recurrent ischaemia), assessed at day 31, in 202 patients on an intention-to-treat basis.

Findings

A statistically significant reduction in the primary composite triple endpoint rates was observed in the roxithromycin group; p=0·032. The rate of severe recurrent ischaemia, myocardial infarction, and ischaemic death was 5·4%, 2·2%, and 2·2% in the placebo group and 1·1%, 0%, and 0%, in the roxithromycin group, respectively. No major drug-related adverse effects were observed.

Interpretation

Antichlamydial antibiotics may be useful in therapeutic intervention in addition to standard medication in patients with coronary-artery disease. Large-scale trials are needed to confirm these preliminary observations.

Introduction

There has been renewed interest in the possibility of an association between coronary heart disease and infection, specifically with Chlamydia pneumoniae. This organism is now recognised as a common cause of respiratory-tract infection. Several investigators have documented an association between coronary heart disease and the presence of high titres of antibodies to C pneumoniae.1, 2, 3 The organism has also been detected in atherosclerotic plaques.⁴ Furthermore, it has been found that C pneumoniae might be involved both in atherogenesis and in plaque instability.⁵ We decided to test the hypothesis that treatment of patients with unstable angina with an antibiotic with antichlamydial activity, roxithromycin, in addition to conventional therapy, would reduce subsequent plaque instability and associated clinical events.

Section snippets

Patients and methods

This study was a double-blind, randomised, prospective, multicentre, parallel-group, placebo-controlled pilot study of patients with unstable angina or non-Q-wave myocardial infarction. Recruitment began in May, 1996, and was completed in March, 1997. A total of 205 patients, from eight coronary-care units in Argentina, were recruited into the study. At admission, all patients meeting the criteria for type

IIIb of Braunwald's classification for unstable angina⁶ and non-Q-wave myocardial

Results

Of the 205 patients recruited into the study, three failed to meet the inclusion criteria (figure). The remaining 202 eligible patients were randomly assigned roxithromycin (n=102) or placebo (n=100). A secondary analysis of patients who took the study treatment for at least 72 h (six doses) was done. Of the 202 patients nine patients of the roxithromycin-treated and seven patients of the placebo-treated group did not complete the minimum 72 h, because of the need for coronary artery bypass

Discussion

A substantial number of patients with unstable angina have an adverse clinical outcome despite the use of aspirin and heparin during the acute and chronic phases of angina.⁸ This loss of an initial benefit could be explained in part by the rebound activation of the coagulation system that follows the discontinuation of a heparin infusion and the continuing inflammatory process that persists for up to 6 months from the onset of a coronary event.

Data have shown that immunological and

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Patients with unstable angina related with C reactive protein and Chlamydia pneumoniae infection [suppl]
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Unstable angina: a classification
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Unstable angina: diagnosis and management
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There are more references available in the full text version of this article.

Cited by (544)

Chlamydophila (Chlamydia) pneumoniae
2018, Principles and Practice of Pediatric Infectious Diseases
Infections, immunity and atherosclerosis: Pathogenic mechanisms and unsolved questions
2013, International Journal of Cardiology
The role of inflammation and immunity in the pathogenesis and clinical manifestations of atherosclerotic disease has been widely studied. Common infectious diseases can be associated with a chronic inflammatory state which is the hallmark of atherosclerosis, thus suggesting a possible link between the two pathological conditions. Therefore, a great number of studies have tested the “infection hypothesis”, but their results are conflicting. Nevertheless, several molecular and biological mechanisms possibly involved in the complex relationship between infections, immune response, vascular wall damage and atherosclerosis onset and progression have been described. The purpose of this article is to offer an overview of the principal mechanisms and molecular pathways that probably constitute the most relevant biological substrate on which the infection hypothesis is founded; some of these mechanisms are not fully understood yet. Nevertheless, their comprehension could be essential for the development of new preventive and therapeutic strategies.
Inflammation and atherothrombosis
2013, Clinical Immunology: Principles and Practice: Fourth Edition
Chlamydophila (Chlamydia) pneumoniae
2012, Principles and Practice of Pediatric Infectious Diseases, Fourth Edition
Effects in vitro of Chlamydia infection on monocitic-macrophagic cells and its relationship with lipid levels
2011, Clinica e Investigacion en Arteriosclerosis
La célula mononuclear-fagocítica es un elemento celular clave en el proceso aterogénico. El monocito forma parte trascendental del proceso inflamatorio característico del inicio y desarrollo de la placa de ateroma. Por otra parte, la infiltración celular es también un elemento que debe tenerse en cuenta en el proceso inflamatorio cuando se ha considerado la asociación entre arteriosclerosis e infección. En la teoría infecciosa los gérmenes más frecuentemente asociados a la patología vascular han sido Citomegalovirus, Helicobacter y Chlamydia. En el presente trabajo nos ha interesado evaluar las características del comportamiento celular en cultivos de células implicadas en el proceso aterogénico infectadas con Chlamydia.
Se han empleado células endoteliales humanas establecidas (células Hep-2), células mononucleares establecidas (células THP-1) y cultivos primarios de monocitos procedentes de sangre periférica de voluntarios.
Todos los cultivos celulares son fácilmente infectados por Chlamydia. No obstante, sus efectos son distintos dependiendo del tipo celular. Cuando se ha comparado el efecto de sueros normo e hiperlipidémicos en los cultivos de células mononucleares infectadas con Chlamydia, se ha podido comprobar que el efecto que provoca la infección es amortiguado por la existencia de valores elevados de lípidos plasmáticos.
The mononuclear-fagocitic cellular type is a key element during the atherogenic process. The monocyte takes a transcendental role in the inflammatory process that is relevant at the onset and subsequent development of atheroma plaque. Otherwise, the cellular infiltration is a key feature to consider during the inflammatory process that we can found related with the atherosclerosis/infection association. According with the infectious explanation of atherosclerosis, microorganism more frequent associated with vascular pathology has been: Citomegalovirus, Helicobacter and Chlamydia. In the present paper we are interested to evaluate the characteristics and cellular behaviour of cultures of cells related with atherogenic process that has been previously infected with Chlamydia.
We have analized established human endothelial cells (Hep-2 cells), established mononuclear cells (THP-1 cells) and primary cultures of monocytes from blood health volunteers.
All of cells types has been easily infected by Chlamydia. Nevertheless, the effects are different according with the different cells types. When we have compared the effect of normo or hyperlipidemic serum specimens over the cultures of infected mononuclear cells it is possible to show that the effect of infection is amortiguated by the presence of high serum levels of lipids.
Chlamydia pneumoniae IgG and IgA antibody titers and prognosis in patients with coronary heart disease: results from the CLARICOR trial
2010, Diagnostic Microbiology and Infectious Disease
The association observed between coronary heart disease (CHD) and Chlamydia (Chlamydophila) pneumoniae antibodies prompted, during the 1990s, several primary and secondary prevention trials with various antibiotics. In our CLARICOR trial, a randomized placebo-controlled trial in 4372 patients with stable CHD, a brief clarithromycin regimen was followed, unexpectedly, by increased long-term mortality. We now compare C. pneumoniae antibody levels at entry with population levels, with the patients' individual histories, and with their subsequent outcomes. IgG antibody levels were somewhat raised, but elevated IgA and IgG titers were unrelated to entry data (including prior acute myocardial infarction), except for an association with smoking and with not using statins. Hazards of mortality and of other outcomes tended to slightly increase with IgA and decrease with IgG titers, but the unfavorable clarithromycin effect was unrelated to antibody levels and remains unexplained. Smoking-related lung disease probably underlies the link between heart disease and increased IgG titers.

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: Other members of the ROXIS Study Group are listed at the end of the paper

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The Lancet

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients and methods

Results

Discussion

References (18)

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

Lancet

Increased incidence of Chlamydia species within the coronary arteries of patients with symptomatic atherosclerosis versus other forms of cardiovascular disease

J Am Coll Cardiol

Immunological and microbiological factors in the pathogenesis of atherosclerosis

Clin Immunol Immunopathol

Chlamydia pneumoniae-specific circulating immune complexes in patients with chronic coronary heart disease

Circulation

Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease

JAMA

Patients with unstable angina related with C reactive protein and Chlamydia pneumoniae infection [suppl]

Eur Heart J

Unstable angina: a classification

Circulation

Unstable angina: diagnosis and management

Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q wave myocardial infarction

Circulation

Cited by (544)

Chlamydophila (Chlamydia) pneumoniae

Infections, immunity and atherosclerosis: Pathogenic mechanisms and unsolved questions

Inflammation and atherothrombosis

Chlamydophila (Chlamydia) pneumoniae

Effects in vitro of Chlamydia infection on monocitic-macrophagic cells and its relationship with lipid levels

Chlamydia pneumoniae IgG and IgA antibody titers and prognosis in patients with coronary heart disease: results from the CLARICOR trial

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

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients and methods

Results

Discussion

Lancet

J Am Coll Cardiol

Clin Immunol Immunopathol

Chlamydia pneumoniae-specific circulating immune complexes in patients with chronic coronary heart disease

Circulation

Association of prior infection with Chlamydia pneumoniae and angiographically demonstrated coronary artery disease

JAMA

Patients with unstable angina related with C reactive protein and Chlamydia pneumoniae infection [suppl]

Eur Heart J

Unstable angina: a classification

Circulation

Unstable angina: diagnosis and management

Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q wave myocardial infarction

Circulation

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