a INSERM U258, Hôpital Paul Brousse, Villejuif, France.
b MONICA-Toulouse, INSERM U558, Faculté de Médecine Purpan, Toulouse, France.
c MONICA-Lille, INSERM U508, Institut Pasteur de Lille, Lille, France.
d MONICA-Strasbourg, Laboratoire d'Epidémiologie et de Santé Publique, Strasbourg, France.
e Belfast-MONICA, Department of Epidemiology and Public Health, The Queen's University of Belfast, Belfast, UK.
Pierre Ducimetière, INSERM U258, Hôpital Paul Brousse,16 Avenue Paul Vaillant-Couturier, 94807 Villejuif Cedex, France. E-mail: ducimeti{at}vjf.inserm.
Abstract
Background The North-South gradient in myocardial infarction and coronary death rates in various western European regions has been described by the WHO MONICA Project over the last decade. The results of the 5-year follow-up of the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study reported here give the opportunity of extending the comparison to the incidence of angina pectoris in men aged 5059 living in four regions (Belfast, Lille, Strasbourg, Toulouse) which were covered by the MONICA Project.
Methods The PRIME Study is a multicentre cohort study with a common protocol and centralized event analysis. It included 10 600 men, of whom 9758 (7359 in France and 2399 in Belfast) were free of coronary disease at entry with 842 (496 in France and 346 in Belfast) having pre-existing coronary disease.
Results In France, subjects free of coronary heart disease at baseline developed 106 cases of myocardial infarction or coronary death (2.93/1000 subjects per year) and 94 cases of angina pectoris (2.61/1000). In Belfast, 61 developed myocardial infarction or coronary death (5.24/1000) and 60 angina pectoris (5.39/1000). Hazard rate ratios for Belfast in comparison to France were respectively 1.79 (95% CI : 1.302.47) and 2.07 (1.492.86) for each class of clinical complication.
Conclusion Rate ratios for angina pectoris incidence between Northern Ireland and France in the PRIME Study are comparable to those for myocardial infarction or coronary death reported by the WHO MONICA Project and suggest that the North-South gradient in Europe applies to different manifestations of coronary disease.
Keywords Incidence, angina pectoris, myocardial infarction, coronary artery disease, cohort study, men, France, Northern Ireland
Accepted 11 January 2001
Coronary heart disease is one of the main causes of premature death in industrialized countries,12 even though its incidence has been falling for more than a decade in most of them.3 Conversely, it appears to be increasing in many developing countries.4 France is characterized by low coronary mortality rates according to its national statistics: about one-third ofthat found in the UK, but these findings are mostly based on mortality data and thus open to biases which result in an imperfect picture of the true differences. For instance, medical treatment of myocardial infarction has greatly improved in recent years, along with a concomitant decrease in coronary mortality rates, as extensively described by the WHO MONICA Project.5 Thus, geographical variations in medical care may contribute to coronary mortality differences. Moreover, between-country mortality coding variations may play their part.
Most studies that reported coronary disease incidence data in various countries have only considered myocardial infarction and coronary death events. It is particularly the case with the registration procedures used by the MONICA Project.6 However, many subjects with coronary atherosclerosis in the population will develop angina pectoris without suffering myocardial infarction. Since the population incidence of angina pectoris may be of the same order of magnitude as that of myocardial infarction, incidence rates for myocardial infarction or coronary death alone may give an inaccurate measure of the true burden of coronary disease in a given country. Finally, diagnostic criteria for angina pectoris vary considerably across studies,789101112 and so between-country comparisons cannot easily be performed.
In this first analysis of prospective data in the PRIME Study, we compare 5-year frequency rates of first occurring angina events, together with myocardial infarction and coronary deaths, between two cohorts of men aged 5059 years in France and Northern Ireland, after exclusion of those with coronary history at entry, using common methodology and diagnostic criteria.
Patients and Methods
Cohort recruitment and examination methods have been described previously13 and only the main features are given below. However, the methods for follow-up and the protocol of the analysis of coronary events are detailed.
Population recruitment
The PRIME Study (Prospective Epidemiological Study of Myocardial Infarction) was established in 1991 in the populations of four collaborating WHO MONICA centres in Belfast (UK), Lille, Strasbourg and Toulouse (France). The target was to recruit 2500 men, aged 5059 years, in each centre and to follow them for a minimum of 5 years. The sample was recruited to broadly match the social class structure of the background population. The recruitment frame was based on industry and various employment groups, on health screening centres and general practice. Participation was voluntary. Subjects were informed of the aim of the study and those who agreed to take part were given a morning appointment and asked to fast for at least 12 hours.
Personal history and examination
Self-administered questionnaires related to demographic, socioeconomic factors and diet were completed at home by the participants and checked by the technician with the subject at the clinic. Data on educational level, occupational activity, personal and family history, tobacco and alcohol consumption, drug intake and physical activity were collected by the technician. During the examination, the questionnaire on personal medical history was completed along with the London School of Hygiene Cardiovascular (Rose) Questionnaire for Chest Pain on Effort and Possible Infarction,14 and a standard 12-lead electrocardiogram was recorded. Questionnaires were designed in French and rigorously translated into English. Anthropometric measurements included height and weight without shoes, and blood pressure was measured on two occasions in the sitting position with the same automatic device (Spengler SP9).
Subjects were considered free of coronary disease at entry if no criterion among the following three was met: (1) reported myocardial infarction and/or angina pectoris diagnosed by a physician; (2) electrocardiographic evidence of myocardial infarction, defined as major or moderate Q waves coded using the Minnesota system;14 (3) a positive answer to the Rose Questionnaire. As no retrospective checking with data from doctors and clinics was possible, a strict definition was chosen in order to exclude any subject with suspicion of disease.
Follow-up
Subjects were contacted annually by letter and asked to complete a clinical event questionnaire to be returned to the centre in a pre-paid envelope. If the subject did not comply, phone contact was established with him or with his general practitioner. For all subjects reporting a possible event, clinical information was sought directly from the hospital or general practitioner notes. All details of electrocardiograms, hospital admissions, enzymes, surgical operations, angioplasty, treatment, etc., were collected. Death certificates were checked for supporting clinical and post-mortem information on cause of death. Whenever necessary, the circumstances of death were obtained from the practitioner or the family.
A Medical Committee was established, comprising one member from each PRIME Centre, including the Co-ordinating Centre, and three independent cardiologists (two from France and one from the UK). Its task was to provide an independent validation of coronary events in the PRIME Study. The Committee met on four occasions during the 5-year follow-up period. All medical information, including electrocardiograms related to all available events, was sequentially displayed by each Centre's representative and the Committee assigned a code for each according to a strict protocol.
Myocardial infarction was defined by one of the following sets of conditions: (1) new diagnostic Q wave or other fresh typical electrocardiographic sign of necrosis; (2) typical or atypical pain symptoms and new (or increased) ischaemia and myocardial enzyme levels higher than twice the upper limit; (3) post-mortem evidence of fresh myocardial infarction or thrombosis.
Definite coronary death was defined as death with a documented coronary event. Sudden death was defined as death occurring within one hour following symptoms without explanation. However, when significant coronary atheroma was present at autopsy, the death was considered as definite coronary death. When a coronary death was suspected, with no other documentation or explanation, it was labelled possible coronary death. The three death categories were grouped together as coronary deaths.
Hard coronary cases were subjects who had at least one non-fatal myocardial infarction event or who died from coronary disease during follow-up.
Angina pectoris was defined by the presence of chest pain at rest and/or on exertion and one of the following criteria: (1) angiographic stenosis over 50%; or (2) a positive scintigraphy (if no angiographic data); or (3) positive exercise stress test (if no angiographic or scintigraphic data); or (4) electrocardiogram changes at rest (if no angiographic, scintigraphic or exercise stress test data), but without myocardial infarction and no evidence of a non-coronary cause in the clinical history. Unstable angina was defined as a crescendo pain (change in frequency or severity of chest pain on exertion or appearance of chest pain at rest following pre-existing pain on exertion) or chest pain at rest, with either enzyme changes or electrical changes. In the absence of enzyme or electrical data, the diagnosis was not upheld.
Total coronary cases were defined as all subjects with at least one of the categories of coronary death, non-fatal myocardial infarction or angina pectoris.
Statistical analysis
Statistical analysis was conducted using SAS (SAS Institute, Cary, USA) software. Mean annual incidence rates in men free of coronary disease at entry were computed using the number of person-years of follow-up in each centre or country. Hard coronary events were counted only once, whether or not preceded by a diagnosis of angina. However, when detailed events are reported (Table 2), the total number of coronary deaths is given regardless of any previous diagnosis. Conversely, angina pectoris events were counted once (stable or unstable according to the first occurring event), but not when they developed after a myocardial infarction. Results were expressed as mean ± SD or as a percentage and (number of subjects). Statistical significance was assessed for P < 0.05.
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Population characteristics
In total, 10 600 men, aged 5059, entered the PRIME Study from April 1991 to January 1994: 9758 free of coronary disease at entry (7359 in France and 2399 in Northern Ireland) and 842 (496 in France and 346 in Northern Ireland) with coronary disease. The prevalence of myocardial infarction (clinical history or isolated Q waves at entry) was higher in Belfast than in France (6.4% versus 1.9%, P = 0.01), but that of angina pectoris (clinical history or positive Rose questionnaire with the exclusion of myocardial infarction) did not differ significantly (6.2% versus 4.4%).
The characteristics of the cohorts are summarized in Table 1. Subjects who could not be contacted at the fifth year of surveillance or who refused to participate any longer in the study at any time of follow-up, represented 12/1000 of the total cohort, slightly more men without than with coronary disease (12.6 versus 7.1), and more men in France than in Belfast (14.0 versus 6.9). Lost-to-follow-up subjects in France were more numerous in Toulouse than in the two other centres. Over the whole period, 239 men died (2.3%), a higher proportion in Belfast than in France (2.9% versus 2.0%). Death rates were higher in men with than without pre-existing coronary disease (5.0% versus 2.0%) and the lowest total mortality was observed in Toulouse.
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The first incidence results from the PRIME Study clearly demonstrate a hazard ratio for angina pectoris as high as for myocardial infarction or coronary death between Northern Ireland and France, a finding which is unavailable from the registry data on acute events as defined by the MONICA Project. These results, however, were observed in the setting of a cohort study and the issue of representativeness of the population samples from France and Northern Ireland was introduced in a previous paper.13 It described in detail the selection and screening procedures of the samples and gave some assurance that they were generally representative of the populations from which they were drawn. The prospective results reported here permit new insights to be gained on the validity of comparing the two cohorts, at least for the specific purposes of the PRIME Study.
5-year mortality and hard coronary events
Some healthy worker effect in both populations was expected from the recruitment methods that were used. As for any medical examination on a voluntary basis, acutely ill people and those with a bad prognosis were not recruited in the PRIME Study. This effect can easily be checked with the 5-year mortality experience of the cohorts. From both countries, simple computations from the official death rates according to age in the years 19911993 in the four regions under study yielded an estimate of a 6.3% death rate in 5 years in Northern Ireland and 6.1% in the French regions for the same age group. However, the observed rates in the PRIME cohorts were 2.9% and 2.0% respectively, thus representing between one-third and one-half of the expected rates. A large between-country difference in the way the effect might operate in the selection scheme can, however, be ruled out.
More importantly, the level of coronary heart disease incidence in the two PRIME cohorts can be compared, at least for hard coronary events, with the data observed in the MONICA registers in the same regions.6 Definitions for these events are largely consistent with those followed by the PRIME Medical Committee. We can remark that, in both studies, silent myocardial infarction cases were excluded as no follow-up examination of the population was available. We used the incidence of three diagnostic categories by 5-year age groups over the period 1991 1993 in men without a history of coronary disease (unpublished data) in order to estimate the expected corresponding incidence in the PRIME cohorts. Table 4 gives the expected incidence rates for (a) definite myocardial infarction (MONICA category 1) and possible coronary deaths (fatal category 2); (b) the same as (a) plus possible myocardial infarction (non-fatal category 2 when clinicians gave a diagnosis of myocardial infarction); (c) the same as (a) plus insufficiently documented death which comprises mostly sudden death (MONICA category 9). Incidence rates were surprisingly similar to those actually observed, which are reported in Table 3
, at least for Belfast and France (as a whole). Some discrepancies may be observed for specific rates in Toulouse and Lille, with a reverse ranking across the three French regions. No explanation can be presently given for this finding, considering the fact that classical risk factor levels were generally lower in the Toulouse sample than in the other French centres.13 The risk ratio for hard coronary disease incidence of 1.79 between Belfast and France is not far from the 1.82.0 range estimated from MONICA.
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In Table 2, if we look at detailed numbers, the distribution of sudden death appears very different in France and Belfast: only 1 case in Belfast versus 11 in France. From the individual medical reports, it was clear that three deaths in Belfast were coded as coronary deaths because they fulfilled the conditions of sudden death, but with an autopsy showing coronary atheroma; this was not observed in the French cohort. This confirms that comparable between-region diagnosis of coronary death is dependent upon the autopsy rate in the regions and that grouping of coronary, possible coronary and sudden deaths is necessary for any valid comparison.
5-year incidence of angina pectoris
Few cohort studies have given precise results on the population incidence of coronary disease other than the so-called hard events. We report here incidence data in France and Northern Ireland for angina pectoris occurring as a first coronary event and diagnosed according to a standardized protocol which used the case description made by the clinician. It defined angina pectoris as the association of chest pain at rest or on exertion with one positive finding from a cardiovascular examination, such as angiography, scintigraphy, exercise testing or resting ischaemic electrical change. The experience of the Medical Committee was that exercise testing was common diagnostic practice in both countries and effort angina pectoris diagnosis was ruled out when negative. Angina pectoris as a first coronary event in Belfast was approximately twice that in France (5.39/1000 years versus 2.61). These numbers are higher than those reported for men of Japanese origin,10 but lower than those found in US7 or Swedish11 cohorts of similar age. Those data, however, were obtained in the early 1980s and a comparison of the diagnostic criteria used is nearly impossible. In particular, about 25% of the angina events reported in Table 2 were classified as unstable angina by the PRIME Medical Committee, but we could not find any published population cohort data for any comparison. It is likely that some unstable angina diagnoses might be in fact non Q-wave myocardial infarctions, but such a distinction was practically impossible. In both PRIME cohorts, overall we found an incidence of first angina events of the same order of magnitude as for hard events, which is in agreement with data from some other studies.789 The congruence of between-country risk ratios (about 2.0) for both types of clinical complications is striking and underscores the fact that the higher risk of myocardial infarction and coronary death in Belfast than in France indicates a higher overall risk for the coronary atherosclerotic disease burden (excluding silent myocardial infarction) in that population.
In conclusion, the 5-year follow-up data of the PRIME Study confirm the higher incidence of myocardial infarction and coronary death in Belfast than in France, at least in middle-aged men, and the results extend to another important clinical form of the disease: angina pectoris. Although the results were obtained only in men aged 5059 at baseline in two countries, they suggest that the North-South European gradient of the disease demonstrated by the MONICA Project may be valid for a large spectrum of clinical complications of coronary heart disease including angina pectoris. The impact of the distribution of cardiovascular risk factors on this geographical gradient are currently under investigation in the PRIME Study.
Appendix
The PRIME Study Group
The Strasbourg MONICA Project, Department of Epidemiology and Public Health, Faculty of Medicine, Strasbourg, France (D Arveiler, B Haas). The Toulouse MONICA Project, INSERM U558, Department of Epidemiology, Paul Sabatier-Toulouse Purpan University, Toulouse, France (J Ferrières, JB Ruidavets, P Marques-Vidal). The Lille MONICA Project, INSERM U508, Pasteur Institute, Lille, France (P Amouyel, M Montaye). The Department of Epidemiology and Public Health, The Queen's University of Belfast, Belfast, Northern Ireland (A Evans, J Yarnell). The Department of Atherosclerosis, SERLIAINSERM U325, Lille, France (G Luc, JM Bard). The Laboratory of Haematology, La Timone Hospital, Marseilles, France (I Juhan-Vague). The Laboratory of Endocrinology, INSERM U326, Toulouse, France (B Perret). The Vitamin Research Unit, The University of Bern, Bern, Switzerland (F Gey). The Trace Element Laboratory, Department of Medicine, The Queen's University of Belfast, Belfast, Northern Ireland (D McMaster). The DNA Bank, INSERM U525/SC7, Paris, France (F Cambien). The Coordinating Center, INSERM U258, Villejuif, France (P Ducimetière, PY Scarabin, A Bingham).
KEY MESSAGES
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The PRIME Study was supported by grants from the Merck, Sharp and Dohme-Chibret Laboratory. We thank the following organizations which allowed the recruitment of the PRIME subjects: the Health screening centres organized by the Social Security of Lille (Institut Pasteur), Strasbourg, Toulouse and Tourcoing; Occupational Medicine Services of Haute-Garonne; the Urban Community of Strasbourg; the Association Inter-entreprises des Services Médicaux du Travail de Lille et environs; the Comité pour le Développement de la Médecine du Travail; the Mutuelle Générale des PTT du Bas-Rhin; the laboratoire d'Analyses de l'Institut de Chimie Biologique de la Faculté de Médecine de Strasbourg. Thanks are also due to DHSS (Northern Ireland) and the Northern Ireland Chest, Heart and Stroke Association. We thank Pr Louis Guize, Dr Caroline Morrison and Dr Marie-Thérèse Guillanneuf for their invaluable participation in the PRIME Medical Committee sessions and their constructive advice in defining the selection criteria for the coding of new cases observed during the follow-up phase of the Study. We also gratefully acknowledge the teams of the Belfast, Lille, Strasbourg and Toulouse Centres for their dedicated work and relentless energy in following-up their cohorts.
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