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Myocardial infarction in Girona, Spain: Attack rate, mortality rate and 28-day case fatality in 1988
J CIinEpidemiolVol. 46, No. 10, pp. 1173-I179, Printedin GreatBritain.All rights reserved
0895-4356/93$6.00+ 0.00 Copyright0 1993Pcrgamon Press Ltd
1993
MYOCARDIAL INFARCTION IN GIRONA, SPAIN: ATTACK RATE, MORTALITY RATE AND 2%DAY CASE FATALITY IN 1988 G. PI&Z,’
J. MARRUGAT, I* J. SALA* and the REGICOR STUDY GROUP
‘Departament d’Epidemiologia i Salut Wblica, Institut Municipal d’Investigaci6 Mtiica, Barcelona and *Cardiologia i Unitat Coronaria, Hospital Josep Trueta, Girona, Spain (Received in revised form 22 April 1993)
study was conducted to establish the attack rate, mortality rate and 28&y case-fatality rates of acute myocardial infarction (AMI) occurring in Girona, Spain, between October 1987 and September 1988. The study was carried out using a
Abstract-This
population register of AMI, and took place in one central hospital, and eight county hospitals in Girona (in the autonomous community of Catalonia, northeast Spain). Subjects comprised 222 fatal cases selected from 4069 death certificates, and 210 non-fatal cases from hospital records, among subjects aged between 25 and 74 years (reference population 263,778). The age standardized attack rate was 105.6 per 100,000 inhabitants in the age group 35-64 (193.6 in men and 17.6 in women). The age standardized mortality rate was 36.3 per 100,000 inhabitants in the age group 35-64 (63.1 among men and 9.9 among women). The age standardized 28-day case-fatality was 34.6% in men and 50.1% in women in this same age group. Attack and mortality rates of AM1 in a region of Spain are presented for the first time. These rates are lower than in other developed countries, nevertheless the 28-day case-fatality is similar to that of these countries. Myocardial infarction Incidence Heart diseases Case fatality
Mortality
INTRODUCTION
Mortality rates of acute myocardial infarction have been extensively used as an approach to the magnitude of ischaemic heart disease (IHD) at population level [l-4]. Most of the published data rely on national vital statistics and do not provide accurate estimates of AM1 frequency. These shortcomings may be partially related with the changing state of medical knowledge and health care facilities, with inadequate coding of death certificates, with the occurrence of cases with insufficient
(AMI)
*All correspondence.should be addressed to: Jaume Marrugat, Departament d’Epidemiologia i Salut Pliblica, Institut Municipal d’Investigaci6 MBdica, Passeig Maritim, 25, 08003-Barcelona, Spain.
Registers
Epidemiology
clinical or laboratory data or with combinations of them [5]. Recent studies of mortality and morbidity based on registers or surveys have shown an increase in AM1 mortality rates in Eastern European countries as opposed to downward trends in Western industrialized countries [6]. In Spain, the AM1 mortality rate decreased between 1950 and 1967 [7j. After an abrupt increase of 49.5% that occurred between 1967 and 1976 [8], a slight decrease between 1978 and 1984 was observed 19, lo]. In 1987, the mortality for AM1 in the population aged 25-74 years was 60.4 per 100,000 (94.7 per 100,000 in men and 28.2 per 100,000 in women) [ll]. Data on incidence of AMI, however, are scarce in Spain.
1173
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G. Phz
The REGICOR group (“Registre Gironi de Coronariopaties”) [ 121started a population register of AM1 in 1987 in Girona, a region in northeastern Spain. The health care system in Girona is based on 8 local hospitals that are able to manage coronary emergencies that are referred to the only hospital with a Coronary Care Unit (CCU) in the area. Less than 5% of patients presenting with AM1 were sent to hospitals outside the studied region [ 131.These characteristics allowed AM1 patients to be traced easily through the medical resources of the region. After a 3-month pilot study, all AM1 occurring in-hospital or out-of-hospital were registered with the aim of determining the 12 month attack rate, mortality rate and 28-day case-fatality of AM1 among the reference population. This register follows the procedures for event registration of the WHO MONICA project [14]. The results of the first year of this AM1 population register are presented in this report. PATIENTS AND METHODS The
REGICOR register covers five counties in northern Spain, with a geographic extension of 4611 km*, an estimated mid-year population of 451,637 inhabitants in 1988, and a population MYOCARDIAL
. OUT- OF HOSPITAL
et al.
aged 25-74 of 263,778 (130,905 men and 132,873 women). Forty-seven percent of people live in towns and villages of less than 25,000 inhabitants. Only Girona city has more than 50,000 inhabitants. All suspected fatal and non-fatal coronary events occurring in residents in the study region, aged 25-74 years, in whom the onset of symptoms began at any time between October 1987 and September 1988, were registered. An event was considered as new in the same patient when more than 28 days had elapsed from any preceding event [14]. Medical records were screened for the diagnosis of AM1 in the reference hospital in Girona city, in the local hospitals and in the private medical centres (Fig. 1). All death certificates were screened for the presence of at least one of the following diagnoses or codes, from the 9th revision of the International Classification of Diseases (ICD-9), reported as immediate, main, antecedent or underlying causes of death [15]: diabetes (ICD code 250), hyperlipidaemia (ICD code 272), obesity (ICD code 278), hypertensive heart disease (ICD code 401-405), ischaemic heart disease (ICD code 410-414), other heart diseases (ICD code 420-429), stroke (ICD code 440447) and other ill-defined causes of death (ICD code 797-799). INFARCTION
Death
.
Physician or E-Room
I
I
Death
I 1
Alive
INHOSPITAL
Death Certificates l&dice1 records E-Room records
1
Medical records E-Room records Discharge records
Fig. 1. REGICOR sources of information and general data collection strategy in REGICOR AMI Registry, Girona, Spain (1988). E-ROOM: Emergency room. CCU: Coronary care unit.
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Epidemiology of Myocardial Infarction in Girona, Spain
The cause of every death was confirmed by interviewing the physicians who signed the selected death certificates, and the relatives or witnesses of the death. Data from all sources were linked by a quality control computer procedure, the results of which were visually verified. The events were classified according to the degree of certainty obtained with the MONICA algorithm [14] (which takes into account the different values of symptoms, ECG, cardiac enzymes and necropsy), into one of the following diagnostic categories:
Table 1. Distribution of surviving and deceased 25-74 year old patients in the MONICA diagnostic categories by sex in Girona, Spain (1988)
-Definite acute myocardial infarction (DC 1). -Possible acute myocardial infarction or coronary death (DC 2). -1schaemic cardiac arrest with successful resuscitation not fulfilling criteria for definite or possible myocardial infarction (DC 3). -No acute myocardial infarction nor coronary death (DC 4). -Insufficient data in fatal cases (DC 9).
:: 168
Variables collected from the different sources were used to classify the cases in one of the diagnostic categories mentioned (symptoms, ECG and laboratory data, previous MI events), to match information from more than one source (diagnosis stated on death certificates, place of death, name and surname, date of birth, place of residence, date of death, necropsy diagnosis, hospital discharge diagnosis), to stratify the description of the cases (age, sex, place of treatment, vital status 28 days after onset of symptoms), and to calculate survival time when applicable (date of onset of symptoms, date of death). The rates of AM1 were established for the following diagnostic categories: on the one hand, definite and possible AM1 (DC 1 + 2) and, on the other, in addition to the former, fatal events with insufficient data (DC 1 + 2 + 9)
1161. 28-day case fatality is the proportion of fatal AM1 among all fatal and non-fatal AMI; and the attack rate (cumulative incidence rate) is the number of first and recurrent fatal and non-fatal events divided by the mid-year population. The mortality rate is the number of fatal events divided by the mid-year population. All ages are reported in years. AM1 attack and mortality rates were standardized using the SEGI World Standard Population Weights [17] for the 25-74 age interval: 25-34 (15/50), 35-44 (12/50), 45-54 (1 l/50), 55-64 (8/50), 65-74 (4/50).
Diagnostic categories Definite AMI Possible AMI Cardiac arrest No AMI Total Definite AM1 Possible AM1 No AM1 Insufficient data Total
No. of men 166 15 1 2 184
No. of women
Total W)
Non-fatal cases 23 189 (90.0) 2 17 (8.1) 0 1 (0.5) I 3 (1.4) 26 210
59 47
Fatal cases 14 73 17 64 52 15 33 8 54 222
(32.9) (28.8) (23.4) (14.9)
No: number. AMI: acute myocardiil infarction.
28-day case-fatality was standardized using the MONICA Data Centre Weights for the 35-64 age interval [18]: 35-44 (l/11), 45-54 (3/l 1) and 60-64 (7/l 1). Crude and age standardized rates per 100,000 inhabitants are presented in tables broken down by age groups and by sex for both groups of diagnostic categories (DC 1 + 2 and DC 1 + 2 + 9). Association between categorical variables was assessed with the chi-square test. Logistic regression was used to estimate the age-adjusted risk of gender for 28-day case-fatality. The level of significance accepted for two sided tests was 5%. The BMDP statistical package [19] was used for tables and bivariate contrasts, and EGRET (Seattle: Statistics and Epidemiology Research Corporation) for logistic regression modelling.
RESULTS
All death certificates (4069) corresponding to the deaths which occurred in Girona between October 1987 and September 1988 were reviewed. Among these, 1573 corresponded to subjects aged 25-74. 222 of them were selected for study. With regard to the information from hospitals, 224 records were examined. Information from death certificates and hospital records was cross-linked, and finally 432 cases were investigated (352 men and 80 women) of which 262 cases (60.6%) were classified as definite AMI, 81 (18.8%) as possible, 1 (0.2%) as ischaemic cardiac arrest, and 55 (12.8%) as no myocardial infarction. In the remaining 33 cases (7.6%) there were insufficient data to classify the
G. PI&Z et al.
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event (Table 1). Fourteen cases were detected by both hospital records and death certificates. There were 189 (43.7%) definite AM1 and 17 (3.9%) possible AM1 among non-fatal events, while 73 fatal cases (16.9%) were definite and 64 (14.8%) were possible AMI. The chi square for the distribution of definite and possible MI between fatal and non-fatal cases was statistically significant (p < 0.001). In 10 cases the same subject presented with more than one AM1 within the period of study, and 30 cases presented with a recurrent AM1 not previously registered in the period of study (for 115 patients this information could not be obtained). The crude attack rate in the 25-74 age interval was 129.6 per 100,000 (DC 1 + 2), and 142.2 when the diagnostic category of insufficient data (DC 9) was included, while the age standardized attack rates were 108.4 and 118.7 respectively. In the 35-64 age interval the standardized rate was 105.6 for definite and possible AMI, and 115.1 when patients with insuthcient data were included (see Table 2 for details on rates in subgroups of sex, age and diagnostic categories).
Table 2. AM1 attack rate per 100,000 inhabitants by sex and age in Girona, Spain (1988). MONICA diagnostic categories of AM1 definite, possible and insui%ient data Attack rate DC 1+2(n)
DC 1+2+9(n)
Men
Age Cvr) 25-34 35-44 45-54 55-64 65-74 25-74c 25-74’ 35-64s
17.5 (6) 63.3 (19) 185.0 (44) 400.8 (105) 654.0 (113) 218.3 (287) 190.3 193.6
17.5 (6) 70.0 (21) 193.4 (46) 431.4 (113) 729.3 (126) 237.3 (312) 206.2 207.1
Women
Age Olr) 25-34 3544 45-54 5-64 65-74 25-74’ 25-74’ 3Hi4’
0.0 (0)
3.5 (1) 21.4 15) 33.6 (9j 197.1 (41) 42.1 (56) 30.6 17.6
0.0 (0) 3.5 (1) 34.3 (8) 37.3 (10) 216.3 (45) 48.1 (64) 36.9 23.1
cCrude attack rate. ‘Age standardized attack rate. DC 1 + 2: Definite + possible myocardial infarctions. DC 1 + 2 + 9: Definite + possible myocardial infarctions + insufficient data. n: Number of cases.
Table 3. AM1 mortality rate per 100,000 by sex and age in Girona, Spain (1988). MONICA diagnostic categories of definite and possible AM1 and insuflicient data Mortality rate DC 1+2(n)
DC 1+2+9(n)
Mea Age tir) 25-34 35-44 45-54 55-64 65-74 25-74c 25-74’ 35-w
2.9 (1) 3.3 (1) 54.6 (13) 164.2 (43) 377.8 (48) 80.6 (106) 67.6 63.1
2.9 (1) 10.0 (3) 63.1 (15) 194.7 (51) 353.1 (61) 99.6 (131) 83.5 76.5
Women Age (_v) 25-34 354l 45-54 55-64 65-74 25-74c 25-74” 35-64’
0.0 (0) 0.0 (0) 17.1 (4) 14.9 (4) 110.6 (23) 23.3 (31) 17.2 9.9
0.0 (0) 0.0 (0) 30.0 (7) 18.6 (5) 129.8 (27) 29.4 (39) 22.5 15.4
‘Crude mortality rate. ‘Age standardized mortality. DC 1 + 2: Definite + possible myocardial infarctions. DC 1 + 2 + 9: Deft&e + possible myocardial infarctions + insufficient data. n: Number of cases.
The crude mortality rate in the 25-74 age interval was 5 1.8 per 100,000 while the age-standardized value was 41.6. When patients with insufficient data were included, the mortality rates increased to 64.3 and 51.9 respectively. In the 35-64 age interval, the standardized mortality rate was 36.3 in definite and possible AM1 (DC 1 + 2) and 45.8 when cases with insufficient data were added (see Table 3 for details on rates in subgroups of sex, age and diagnostic categories). The 28-day case fatality rate was 37.0% in men and 55.3% in women (DC 1 + 2) for subjects aged 25-74; the standardized 28-day case fatality rate was 34.6 and 50.1% respectively in the age group 35564 (Table 4). The 28-day case fatality rates increased with age and were significantly higher in women than in men after adjusting for age (likelihood ratio statistic on 3 df = 29.6, p < 0.001). Women had 1.9 times the risk of men of dying within 28 days after the onset of symptoms of AM1 (95% CI: 1.1, 3.4). From the 343 definite and possible AMI, 75 (21.8%) died out-of-hospital within 28 days after onset of symptoms, and 268 (78.1%) were admitted to a hospital (61.5% in the CCU,
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Epidemiology of Myocardial Infarction in Girona, Spain
Table 4. 28-Day case.-fatality (“X.)in men and women, by age and MONICA diagnostic categories in Girona, Spain (1988) Women
Men DC1+2 Age (yr) 25-34 3544 45-54 55-64 65-74 25-74 35-64’
DC1+2
DC 1+2+9
%
(n/N)
%
(n/N)
16.7 5.3 29.5 49.9 42.5 36.9 34.6
(l/6) (l/19) (13/44) (43/105) (48/113) (106/287)
16.7 14.3 32.6 45.1 48.4 41.9 38.9
(l/6) (3/21) (l5/46) (51/113) (61/126) (131/312)
%
DC 1+2+9
(n/N)
%
;t$ (4/9) i::;::;
0.0 87.5 50.0 z:
(n/N)
8::: 44.4 56.1 55.4 50.1
$; (5/l@ (27145) (39/64)
55:7
*Age standardized 28-day case-fatality. DC 1+ 2: Definite + possible myocardial infarctions. DC 1+ 2 + 9: Definite + possible myocardial infarctions + insutlicient data. n: Number of cases. N: Number of events.
15.0% in a local or private hospital and 1.7% of AM1 were transferred to a CCU out of the study area). Among all AM1 patients, 60.0% (206) were alive 28 days after the onset of symptoms. When only the 137 definite and possible fatal AM1 were considered, 54.5% (74) of deaths occurred out-of-hospital and 45.5% (62) in a hospital. In one case survival time was not available (see Table 5 for details on survival time). DISCUSSION
Attack and mortality rates, and 28-day casefatality of AM1 in a region of Spain (Girona) are presented for the first time. While the attack and mortality rates were lower than in other developed countries, the 28-day case-fatality was similar. In women, the attack rate showed an abrupt increase in the age group 65-74. The same applied to mortality rate, and the 28-day case-fatality. Women had less chance of surviving for 28 days after onset of symptoms than men. Although in our geographical area, women develop AM1 later in life than in other western industrialized countries [20,21], gender Table 5. Distribution of 136* fatal cases by survival period and place of death in definite and possible AMI MONICA diagnostic categories in Girona, Spain (1988) Out-of-hospital survival Period First hour > l-24 hours >24 hours-28 days Total
% 33.1 18.4 2.9 54.4
In-hospital
(n)
%
(45)
10.3 16.9 18.4 45.6
ii;) (74)
AMI: Acute myocardial infarction. n: Number of cases. *In one case survival time was not available. CE46110-H
(n) I::; I:;;
is an important risk factor for the AM1 28-day case-fatality. The cause for this remains unclear, although it has recently been pointed out that women suffering symptoms of coronary heart disease are less likely to undergo aggressive diagnostic and therapeutic procedures than men [22-241. Out-of-hospital deaths often occur suddenly [25] (within 24 hours after the onset of symptoms). The proportion of out-of-hospital definite and possible AM1 patients who died suddenly was higher than among in-hospital patients. It is worth noting that the proportion of definite AM1 among patients dying in-hospital is greater than among patients dying out-ofhospital. This finding may be related with the small number of post-mortem examinations carried out (8.8% were performed among the 137 definite and possible fatal AMI) [26]. When no autopsy had been done fatal cases were classified on the basis of the history of coronary disease. It is remarkable that the percentage of out-ofhospital deaths within the first hour was three times that of the in-hospital deaths. The delay in reaching and transferring acute AM1 patients to hospital is probably related to this high pre-hospita1 mortality. A combination of both definite AM1 and possible AM1 has been used in our study, since they are the most commonly used categories in other AM1 registers [l]. This combination of categories provides a realistic estimate of the actual attack and mortality rates of AMI. However, the diagnostic category “possible AMI” is mostly used among fatal cases; this diagnostic category may be interpreted in non-fatal cases as a particular expression for ischaemic heart
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disease 1271. However, an “upper limit” for these rates may be obtained by adding to the former the cases in the insufficient data category [28]. Inclusion of this category provides an approach to the worse possible rates which would result if all unclassified cases due to lack of information, turned out to be actual AMI. Fifteen percent of all events were included in the insufficient data category: this proportion is lower than that found in other studies using this category [la, 281. Our mortality and attack rate figures increased, similarly to other authors [18], when the insufficient data category was added to categories of definite and possible AMI. In the present study, the ischaemic cardiac arrest category has been used rarely. At the time of the study, no specific programs for pre-hospital care for this condition had been organized in the area; and, since the population of the region is spread across a large expanse, access to hospital care was difficult for many residents. However, detection of non-fatal and non-hospitalized AM1 events was based on the voluntary reporting by physicians of symptomatic cases treated at home. A letter was sent to all physicians (some 2000) in the area before and during the study, requesting their collaboration in reporting suspected cases whether hospitalized or not. As a matter of fact, most suspected cases of AM1 are hospitalized in Girona, although no quantification of the proportion is available. This limitation is shared by all AM1 registries
REGICORprincipal investigators: J. Marrugat, R. Masil,
G. pkrezvJ. Sala.
REGZCOR investigators in this study: C. Ponsati, J. Roman (Hospital de Figueres); J. Bisbe, P. Cartes, A. Agusti (Hospital “Sant Jaume” dOlot); N. Constans, J. Valls (Hospital “Sant Jaume” de Blanes), J. Coderch, M. J. Marti (Hospital de Lloret de Mar), E. Ballesta, F. Basso (Hospital de Palamos), E. Clave, J. M. Torres (Servei d’Emergencies Mbdiques-SEM), X. Albert, J. Bassaganyes, M. J. Perez-Ayuso (Hospital Josep Trueta de Girona), P. Roset (Institut Municipal d’lnvestigacio Medica).
REFERENCES WHO MONICA Project. WHO MONICA Project: Assessing CHD mortality and morbidity. Int J Epidemiol 1989; 18 (Suppl. 1): S38-S45. Uemura K, Pisa Z. Recent trends in cardiovascular disease mortality in 27 industrialized countries. World Health Stat Q 1985; 38: 142-162. Stamler J. Opportunities and pitfalls in international comparisons related to patterns, trends and determinants of CHD mortality. Int J Epidemiol 1989; 18 (Suppl. 1): S3-Sl8. 4. Williams OD. Methodological issues in international comparisons. Int J Epidemiol 1989; 18 (Suppl. 3): S166S168. 5. The principal investigators of the MONICA Project. WHO MONICA Project: Geographic variation in mortality from cardiovascular diseases. World Health Stat Q 1987; 40: 171-184. World Health Organization. Mortality from ischaemic heart disease in industrialized countries. Wkly Epidem Ret 1987; 62: 233-240. Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialized countries since 1950. World Health Stat 0 1988: 41: 155-178.
PI. Both AM1 attack and mortality rates in Girona are far below the rates of northern Europe [29], U.S. [20] or Australia [30], and similar to those from other southern European countries [31]. Our figures, however, are also similar to those reported from Augsburg, Germany [18,32]. The present results provide further evidence that in southern Europe, particularly in the Mediterranean countries, the attack and the mortality rates of AM1 are low. Nevertheless the 28-day case-fatality rate in Girona is similar to that observed in countries with higher AM1 incidence rates [21,30,33]. Acknowledgements-The authors thank Marta Pulido, M. D. and David McFarlane for editorial assistance. We are also indebted to all Cardiologists and General Practitioners of Girona for their cooperation. Thanks also to Professor Ulrich Keil for the helpful comments on the final manuscript. This study was in part supported by a grant from the Associacio Catalana d’Ajut a la Cardiologia in 1985, and grant 90/0672 of the Fondo de Investigaciones Sanitaria%
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Sans S, Rod&A, And&J, Segura A, Balaguer Vintro I. Cardiovascular mortality trends 1968-77 in Spain. Em Heart J 1983; 4 (Suppl. E): 104. Banegas JR, Rodriguez Perez P, Rodriguez Artalejo F. Mortalidad por enfermedades cardiovasculares en Espatia: ihacia d&de vamos? Med Clia @areelonr) 1989; 93: 486489. Mortalidad por cardiopatia isquemica en Espatia. Bol Epidemiol Semanal 1989; 1821: 265-266. Instituto National de Estadistica. Defunciones segCln la causa de muerte 1987: Resultados basicos. Estadisticas de1 Movimiento natural de la Poblacih. Vol. I. Madrid: Instituto National de Estadistica; 1991. Marrugat J, Sala J, Ribaha A et al. Supcrvivencia a 10s 10 atios de una cohorte de 736 pacientes con un primer infarto de miocardio. LDiferencia entre sexos? Rev Esp Cardiol 1991; 44: 297-305. Navarro F, Caminal J, Oriol A et al. Registro de Infartos de Miocardio hospitalizados en Barcelona (II). La calidad de la asistencia comunitaria. Rev Esp Cardiol 1988; 41: 7&77. World Health Organisation: MONICA Manual version 1.1. Geneva: WHO; 1986. World Health Organization. International classification of diseases. Maaual of the Iateroatioaal Statistical Classification of Diseaseq Injuries and Causes of Death, Vol. 1, 9th revision. Geneva: World Health
Organization; 1977. 16. Lowe1 H, Keil U, Koenig W et al. Morbidity and mortality of myocardial infarction in the MONICA study area Augsburg in 1985. See PriIventIwned 1988; 33: 17-21. 17. Doll R et al., Eds. Caocer Iocideoce ia Five Continents. New York: Springer Verlag; 1970.
Epidemiology of Myocardial Infarction in Girona, Spain 18. Liiwel H, Lewis M, Hiirmann A, Eberle E, Keil U. Morbidity and mortality of myocardiil infarction in the Augsburg MONICA study area in 1985, 1986 and 1987. Rev Epldemiol slate Publ 1990; 38: 411417. 19. Dixon WJ, Brown MB, Engelman L er al. BMDP Statistical Software 1981. Berkelev: Universitv of California Press; 1981. 20. Burke GL, Sprafka JM, Folsom AR, Luepker RV, Norsted SW, Blackbum H. Trends in CHD mortality, morbidity and risk factor levels from 1960 to 1986: the Minnesota Heart Survey. lot J Epidemiol 1989; 18 (Suppl.): S73-S8 1. 21. Evans AE, Patterson CC, Mathewson Z, McCrum EE, McIlmoyle EL. Incidence, delay and survival in Belfast MONICA project coronary event register. Rev Epidamiol Sant6 Pub1 1990; 38: 419427. 22. Steingart RM, Packer M, Hamm P et al. Sex differences in the management of coronary artery disease. N IQ@ J Med 1991; 325: 226-230. 23. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med‘ 1991; 325: 221-225. 24. Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274-275. 25. Goldberg RJ. Declining out-of-hospital sudden coronary death rates: additional pieces of the epidemiologic puzzle. Circulation 1989; 74: 1369-1373. 26. Wrez G, Marrugat J, Sunyer J er al. Mortalidad
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cardiaca stibita en las comarcas de Girona. Med Clin @arc&ma) 1992; 99: 489-492. Tunstall-Pedoe H. Diagnosis, measurement and surveillance of coronary events. lnt J Epidemini 1989; 18 (Suppl.): Sl69-S173. Liiwel H, Lewis M, Hiirmann A, Keil U. Case finding, data quality aspects and comparability of myocardial infarction registers: results of a South German Register Study. J Clin Epidemiol 1991; 44: 249-260. Wilhelmsen L, Johansson S, Ulvenstam G er al. CHD in Sweden: mortality, incidence and risk factors over 20 years in Gothenburg. Int J Epidemiol 1989; 18 (Suppl.): SlOl-S108. Dobson AJ, Gibberd EW, Leeder SR er al. Ischemic heart disease in the Hunter region of New South Wales, Australia, 1979-1985. Am J Epidemiol 1988; 128: 106-I 15. Nuttens MC, Arveiler D, Zafra Mpez S er al. L’infarctus du myocarde dans trois r&ions franqaises: comparaison de .~ ~~ I’incidence et de la mortalit en 1985. Rev Epidemiol Santh Pub1 1988; 36: 335-341. Greiser E, Joeckel KH. Giersienen K. MaschewskvSchneidei U, Zachcial k. Cardibvasciar disease riik factors, CHD morbidity and mortality in the Federal Republic of Germany. Int J Epidemiol 1989; 18 (Suppl.): Sl18Sl24. Beaglehole R, Bonita R, Jackson R, Stewart A, Sharpe M, Fraser GE. Trends in coronary heart disease event rates in New Zealand. Am J Epidemiol 1984; 120: 225-235.
0895-4356/93$6.00+ 0.00 Copyright0 1993Pcrgamon Press Ltd
1993
MYOCARDIAL INFARCTION IN GIRONA, SPAIN: ATTACK RATE, MORTALITY RATE AND 2%DAY CASE FATALITY IN 1988 G. PI&Z,’
J. MARRUGAT, I* J. SALA* and the REGICOR STUDY GROUP
‘Departament d’Epidemiologia i Salut Wblica, Institut Municipal d’Investigaci6 Mtiica, Barcelona and *Cardiologia i Unitat Coronaria, Hospital Josep Trueta, Girona, Spain (Received in revised form 22 April 1993)
study was conducted to establish the attack rate, mortality rate and 28&y case-fatality rates of acute myocardial infarction (AMI) occurring in Girona, Spain, between October 1987 and September 1988. The study was carried out using a
Abstract-This
population register of AMI, and took place in one central hospital, and eight county hospitals in Girona (in the autonomous community of Catalonia, northeast Spain). Subjects comprised 222 fatal cases selected from 4069 death certificates, and 210 non-fatal cases from hospital records, among subjects aged between 25 and 74 years (reference population 263,778). The age standardized attack rate was 105.6 per 100,000 inhabitants in the age group 35-64 (193.6 in men and 17.6 in women). The age standardized mortality rate was 36.3 per 100,000 inhabitants in the age group 35-64 (63.1 among men and 9.9 among women). The age standardized 28-day case-fatality was 34.6% in men and 50.1% in women in this same age group. Attack and mortality rates of AM1 in a region of Spain are presented for the first time. These rates are lower than in other developed countries, nevertheless the 28-day case-fatality is similar to that of these countries. Myocardial infarction Incidence Heart diseases Case fatality
Mortality
INTRODUCTION
Mortality rates of acute myocardial infarction have been extensively used as an approach to the magnitude of ischaemic heart disease (IHD) at population level [l-4]. Most of the published data rely on national vital statistics and do not provide accurate estimates of AM1 frequency. These shortcomings may be partially related with the changing state of medical knowledge and health care facilities, with inadequate coding of death certificates, with the occurrence of cases with insufficient
(AMI)
*All correspondence.should be addressed to: Jaume Marrugat, Departament d’Epidemiologia i Salut Pliblica, Institut Municipal d’Investigaci6 MBdica, Passeig Maritim, 25, 08003-Barcelona, Spain.
Registers
Epidemiology
clinical or laboratory data or with combinations of them [5]. Recent studies of mortality and morbidity based on registers or surveys have shown an increase in AM1 mortality rates in Eastern European countries as opposed to downward trends in Western industrialized countries [6]. In Spain, the AM1 mortality rate decreased between 1950 and 1967 [7j. After an abrupt increase of 49.5% that occurred between 1967 and 1976 [8], a slight decrease between 1978 and 1984 was observed 19, lo]. In 1987, the mortality for AM1 in the population aged 25-74 years was 60.4 per 100,000 (94.7 per 100,000 in men and 28.2 per 100,000 in women) [ll]. Data on incidence of AMI, however, are scarce in Spain.
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The REGICOR group (“Registre Gironi de Coronariopaties”) [ 121started a population register of AM1 in 1987 in Girona, a region in northeastern Spain. The health care system in Girona is based on 8 local hospitals that are able to manage coronary emergencies that are referred to the only hospital with a Coronary Care Unit (CCU) in the area. Less than 5% of patients presenting with AM1 were sent to hospitals outside the studied region [ 131.These characteristics allowed AM1 patients to be traced easily through the medical resources of the region. After a 3-month pilot study, all AM1 occurring in-hospital or out-of-hospital were registered with the aim of determining the 12 month attack rate, mortality rate and 28-day case-fatality of AM1 among the reference population. This register follows the procedures for event registration of the WHO MONICA project [14]. The results of the first year of this AM1 population register are presented in this report. PATIENTS AND METHODS The
REGICOR register covers five counties in northern Spain, with a geographic extension of 4611 km*, an estimated mid-year population of 451,637 inhabitants in 1988, and a population MYOCARDIAL
. OUT- OF HOSPITAL
et al.
aged 25-74 of 263,778 (130,905 men and 132,873 women). Forty-seven percent of people live in towns and villages of less than 25,000 inhabitants. Only Girona city has more than 50,000 inhabitants. All suspected fatal and non-fatal coronary events occurring in residents in the study region, aged 25-74 years, in whom the onset of symptoms began at any time between October 1987 and September 1988, were registered. An event was considered as new in the same patient when more than 28 days had elapsed from any preceding event [14]. Medical records were screened for the diagnosis of AM1 in the reference hospital in Girona city, in the local hospitals and in the private medical centres (Fig. 1). All death certificates were screened for the presence of at least one of the following diagnoses or codes, from the 9th revision of the International Classification of Diseases (ICD-9), reported as immediate, main, antecedent or underlying causes of death [15]: diabetes (ICD code 250), hyperlipidaemia (ICD code 272), obesity (ICD code 278), hypertensive heart disease (ICD code 401-405), ischaemic heart disease (ICD code 410-414), other heart diseases (ICD code 420-429), stroke (ICD code 440447) and other ill-defined causes of death (ICD code 797-799). INFARCTION
Death
.
Physician or E-Room
I
I
Death
I 1
Alive
INHOSPITAL
Death Certificates l&dice1 records E-Room records
1
Medical records E-Room records Discharge records
Fig. 1. REGICOR sources of information and general data collection strategy in REGICOR AMI Registry, Girona, Spain (1988). E-ROOM: Emergency room. CCU: Coronary care unit.
1175
Epidemiology of Myocardial Infarction in Girona, Spain
The cause of every death was confirmed by interviewing the physicians who signed the selected death certificates, and the relatives or witnesses of the death. Data from all sources were linked by a quality control computer procedure, the results of which were visually verified. The events were classified according to the degree of certainty obtained with the MONICA algorithm [14] (which takes into account the different values of symptoms, ECG, cardiac enzymes and necropsy), into one of the following diagnostic categories:
Table 1. Distribution of surviving and deceased 25-74 year old patients in the MONICA diagnostic categories by sex in Girona, Spain (1988)
-Definite acute myocardial infarction (DC 1). -Possible acute myocardial infarction or coronary death (DC 2). -1schaemic cardiac arrest with successful resuscitation not fulfilling criteria for definite or possible myocardial infarction (DC 3). -No acute myocardial infarction nor coronary death (DC 4). -Insufficient data in fatal cases (DC 9).
:: 168
Variables collected from the different sources were used to classify the cases in one of the diagnostic categories mentioned (symptoms, ECG and laboratory data, previous MI events), to match information from more than one source (diagnosis stated on death certificates, place of death, name and surname, date of birth, place of residence, date of death, necropsy diagnosis, hospital discharge diagnosis), to stratify the description of the cases (age, sex, place of treatment, vital status 28 days after onset of symptoms), and to calculate survival time when applicable (date of onset of symptoms, date of death). The rates of AM1 were established for the following diagnostic categories: on the one hand, definite and possible AM1 (DC 1 + 2) and, on the other, in addition to the former, fatal events with insufficient data (DC 1 + 2 + 9)
1161. 28-day case fatality is the proportion of fatal AM1 among all fatal and non-fatal AMI; and the attack rate (cumulative incidence rate) is the number of first and recurrent fatal and non-fatal events divided by the mid-year population. The mortality rate is the number of fatal events divided by the mid-year population. All ages are reported in years. AM1 attack and mortality rates were standardized using the SEGI World Standard Population Weights [17] for the 25-74 age interval: 25-34 (15/50), 35-44 (12/50), 45-54 (1 l/50), 55-64 (8/50), 65-74 (4/50).
Diagnostic categories Definite AMI Possible AMI Cardiac arrest No AMI Total Definite AM1 Possible AM1 No AM1 Insufficient data Total
No. of men 166 15 1 2 184
No. of women
Total W)
Non-fatal cases 23 189 (90.0) 2 17 (8.1) 0 1 (0.5) I 3 (1.4) 26 210
59 47
Fatal cases 14 73 17 64 52 15 33 8 54 222
(32.9) (28.8) (23.4) (14.9)
No: number. AMI: acute myocardiil infarction.
28-day case-fatality was standardized using the MONICA Data Centre Weights for the 35-64 age interval [18]: 35-44 (l/11), 45-54 (3/l 1) and 60-64 (7/l 1). Crude and age standardized rates per 100,000 inhabitants are presented in tables broken down by age groups and by sex for both groups of diagnostic categories (DC 1 + 2 and DC 1 + 2 + 9). Association between categorical variables was assessed with the chi-square test. Logistic regression was used to estimate the age-adjusted risk of gender for 28-day case-fatality. The level of significance accepted for two sided tests was 5%. The BMDP statistical package [19] was used for tables and bivariate contrasts, and EGRET (Seattle: Statistics and Epidemiology Research Corporation) for logistic regression modelling.
RESULTS
All death certificates (4069) corresponding to the deaths which occurred in Girona between October 1987 and September 1988 were reviewed. Among these, 1573 corresponded to subjects aged 25-74. 222 of them were selected for study. With regard to the information from hospitals, 224 records were examined. Information from death certificates and hospital records was cross-linked, and finally 432 cases were investigated (352 men and 80 women) of which 262 cases (60.6%) were classified as definite AMI, 81 (18.8%) as possible, 1 (0.2%) as ischaemic cardiac arrest, and 55 (12.8%) as no myocardial infarction. In the remaining 33 cases (7.6%) there were insufficient data to classify the
G. PI&Z et al.
1176
event (Table 1). Fourteen cases were detected by both hospital records and death certificates. There were 189 (43.7%) definite AM1 and 17 (3.9%) possible AM1 among non-fatal events, while 73 fatal cases (16.9%) were definite and 64 (14.8%) were possible AMI. The chi square for the distribution of definite and possible MI between fatal and non-fatal cases was statistically significant (p < 0.001). In 10 cases the same subject presented with more than one AM1 within the period of study, and 30 cases presented with a recurrent AM1 not previously registered in the period of study (for 115 patients this information could not be obtained). The crude attack rate in the 25-74 age interval was 129.6 per 100,000 (DC 1 + 2), and 142.2 when the diagnostic category of insufficient data (DC 9) was included, while the age standardized attack rates were 108.4 and 118.7 respectively. In the 35-64 age interval the standardized rate was 105.6 for definite and possible AMI, and 115.1 when patients with insuthcient data were included (see Table 2 for details on rates in subgroups of sex, age and diagnostic categories).
Table 2. AM1 attack rate per 100,000 inhabitants by sex and age in Girona, Spain (1988). MONICA diagnostic categories of AM1 definite, possible and insui%ient data Attack rate DC 1+2(n)
DC 1+2+9(n)
Men
Age Cvr) 25-34 35-44 45-54 55-64 65-74 25-74c 25-74’ 35-64s
17.5 (6) 63.3 (19) 185.0 (44) 400.8 (105) 654.0 (113) 218.3 (287) 190.3 193.6
17.5 (6) 70.0 (21) 193.4 (46) 431.4 (113) 729.3 (126) 237.3 (312) 206.2 207.1
Women
Age Olr) 25-34 3544 45-54 5-64 65-74 25-74’ 25-74’ 3Hi4’
0.0 (0)
3.5 (1) 21.4 15) 33.6 (9j 197.1 (41) 42.1 (56) 30.6 17.6
0.0 (0) 3.5 (1) 34.3 (8) 37.3 (10) 216.3 (45) 48.1 (64) 36.9 23.1
cCrude attack rate. ‘Age standardized attack rate. DC 1 + 2: Definite + possible myocardial infarctions. DC 1 + 2 + 9: Definite + possible myocardial infarctions + insufficient data. n: Number of cases.
Table 3. AM1 mortality rate per 100,000 by sex and age in Girona, Spain (1988). MONICA diagnostic categories of definite and possible AM1 and insuflicient data Mortality rate DC 1+2(n)
DC 1+2+9(n)
Mea Age tir) 25-34 35-44 45-54 55-64 65-74 25-74c 25-74’ 35-w
2.9 (1) 3.3 (1) 54.6 (13) 164.2 (43) 377.8 (48) 80.6 (106) 67.6 63.1
2.9 (1) 10.0 (3) 63.1 (15) 194.7 (51) 353.1 (61) 99.6 (131) 83.5 76.5
Women Age (_v) 25-34 354l 45-54 55-64 65-74 25-74c 25-74” 35-64’
0.0 (0) 0.0 (0) 17.1 (4) 14.9 (4) 110.6 (23) 23.3 (31) 17.2 9.9
0.0 (0) 0.0 (0) 30.0 (7) 18.6 (5) 129.8 (27) 29.4 (39) 22.5 15.4
‘Crude mortality rate. ‘Age standardized mortality. DC 1 + 2: Definite + possible myocardial infarctions. DC 1 + 2 + 9: Deft&e + possible myocardial infarctions + insufficient data. n: Number of cases.
The crude mortality rate in the 25-74 age interval was 5 1.8 per 100,000 while the age-standardized value was 41.6. When patients with insufficient data were included, the mortality rates increased to 64.3 and 51.9 respectively. In the 35-64 age interval, the standardized mortality rate was 36.3 in definite and possible AM1 (DC 1 + 2) and 45.8 when cases with insufficient data were added (see Table 3 for details on rates in subgroups of sex, age and diagnostic categories). The 28-day case fatality rate was 37.0% in men and 55.3% in women (DC 1 + 2) for subjects aged 25-74; the standardized 28-day case fatality rate was 34.6 and 50.1% respectively in the age group 35564 (Table 4). The 28-day case fatality rates increased with age and were significantly higher in women than in men after adjusting for age (likelihood ratio statistic on 3 df = 29.6, p < 0.001). Women had 1.9 times the risk of men of dying within 28 days after the onset of symptoms of AM1 (95% CI: 1.1, 3.4). From the 343 definite and possible AMI, 75 (21.8%) died out-of-hospital within 28 days after onset of symptoms, and 268 (78.1%) were admitted to a hospital (61.5% in the CCU,
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Epidemiology of Myocardial Infarction in Girona, Spain
Table 4. 28-Day case.-fatality (“X.)in men and women, by age and MONICA diagnostic categories in Girona, Spain (1988) Women
Men DC1+2 Age (yr) 25-34 3544 45-54 55-64 65-74 25-74 35-64’
DC1+2
DC 1+2+9
%
(n/N)
%
(n/N)
16.7 5.3 29.5 49.9 42.5 36.9 34.6
(l/6) (l/19) (13/44) (43/105) (48/113) (106/287)
16.7 14.3 32.6 45.1 48.4 41.9 38.9
(l/6) (3/21) (l5/46) (51/113) (61/126) (131/312)
%
DC 1+2+9
(n/N)
%
;t$ (4/9) i::;::;
0.0 87.5 50.0 z:
(n/N)
8::: 44.4 56.1 55.4 50.1
$; (5/l@ (27145) (39/64)
55:7
*Age standardized 28-day case-fatality. DC 1+ 2: Definite + possible myocardial infarctions. DC 1+ 2 + 9: Definite + possible myocardial infarctions + insutlicient data. n: Number of cases. N: Number of events.
15.0% in a local or private hospital and 1.7% of AM1 were transferred to a CCU out of the study area). Among all AM1 patients, 60.0% (206) were alive 28 days after the onset of symptoms. When only the 137 definite and possible fatal AM1 were considered, 54.5% (74) of deaths occurred out-of-hospital and 45.5% (62) in a hospital. In one case survival time was not available (see Table 5 for details on survival time). DISCUSSION
Attack and mortality rates, and 28-day casefatality of AM1 in a region of Spain (Girona) are presented for the first time. While the attack and mortality rates were lower than in other developed countries, the 28-day case-fatality was similar. In women, the attack rate showed an abrupt increase in the age group 65-74. The same applied to mortality rate, and the 28-day case-fatality. Women had less chance of surviving for 28 days after onset of symptoms than men. Although in our geographical area, women develop AM1 later in life than in other western industrialized countries [20,21], gender Table 5. Distribution of 136* fatal cases by survival period and place of death in definite and possible AMI MONICA diagnostic categories in Girona, Spain (1988) Out-of-hospital survival Period First hour > l-24 hours >24 hours-28 days Total
% 33.1 18.4 2.9 54.4
In-hospital
(n)
%
(45)
10.3 16.9 18.4 45.6
ii;) (74)
AMI: Acute myocardial infarction. n: Number of cases. *In one case survival time was not available. CE46110-H
(n) I::; I:;;
is an important risk factor for the AM1 28-day case-fatality. The cause for this remains unclear, although it has recently been pointed out that women suffering symptoms of coronary heart disease are less likely to undergo aggressive diagnostic and therapeutic procedures than men [22-241. Out-of-hospital deaths often occur suddenly [25] (within 24 hours after the onset of symptoms). The proportion of out-of-hospital definite and possible AM1 patients who died suddenly was higher than among in-hospital patients. It is worth noting that the proportion of definite AM1 among patients dying in-hospital is greater than among patients dying out-ofhospital. This finding may be related with the small number of post-mortem examinations carried out (8.8% were performed among the 137 definite and possible fatal AMI) [26]. When no autopsy had been done fatal cases were classified on the basis of the history of coronary disease. It is remarkable that the percentage of out-ofhospital deaths within the first hour was three times that of the in-hospital deaths. The delay in reaching and transferring acute AM1 patients to hospital is probably related to this high pre-hospita1 mortality. A combination of both definite AM1 and possible AM1 has been used in our study, since they are the most commonly used categories in other AM1 registers [l]. This combination of categories provides a realistic estimate of the actual attack and mortality rates of AMI. However, the diagnostic category “possible AMI” is mostly used among fatal cases; this diagnostic category may be interpreted in non-fatal cases as a particular expression for ischaemic heart
1178
G. PEREZet al.
disease 1271. However, an “upper limit” for these rates may be obtained by adding to the former the cases in the insufficient data category [28]. Inclusion of this category provides an approach to the worse possible rates which would result if all unclassified cases due to lack of information, turned out to be actual AMI. Fifteen percent of all events were included in the insufficient data category: this proportion is lower than that found in other studies using this category [la, 281. Our mortality and attack rate figures increased, similarly to other authors [18], when the insufficient data category was added to categories of definite and possible AMI. In the present study, the ischaemic cardiac arrest category has been used rarely. At the time of the study, no specific programs for pre-hospital care for this condition had been organized in the area; and, since the population of the region is spread across a large expanse, access to hospital care was difficult for many residents. However, detection of non-fatal and non-hospitalized AM1 events was based on the voluntary reporting by physicians of symptomatic cases treated at home. A letter was sent to all physicians (some 2000) in the area before and during the study, requesting their collaboration in reporting suspected cases whether hospitalized or not. As a matter of fact, most suspected cases of AM1 are hospitalized in Girona, although no quantification of the proportion is available. This limitation is shared by all AM1 registries
REGICORprincipal investigators: J. Marrugat, R. Masil,
G. pkrezvJ. Sala.
REGZCOR investigators in this study: C. Ponsati, J. Roman (Hospital de Figueres); J. Bisbe, P. Cartes, A. Agusti (Hospital “Sant Jaume” dOlot); N. Constans, J. Valls (Hospital “Sant Jaume” de Blanes), J. Coderch, M. J. Marti (Hospital de Lloret de Mar), E. Ballesta, F. Basso (Hospital de Palamos), E. Clave, J. M. Torres (Servei d’Emergencies Mbdiques-SEM), X. Albert, J. Bassaganyes, M. J. Perez-Ayuso (Hospital Josep Trueta de Girona), P. Roset (Institut Municipal d’lnvestigacio Medica).
REFERENCES WHO MONICA Project. WHO MONICA Project: Assessing CHD mortality and morbidity. Int J Epidemiol 1989; 18 (Suppl. 1): S38-S45. Uemura K, Pisa Z. Recent trends in cardiovascular disease mortality in 27 industrialized countries. World Health Stat Q 1985; 38: 142-162. Stamler J. Opportunities and pitfalls in international comparisons related to patterns, trends and determinants of CHD mortality. Int J Epidemiol 1989; 18 (Suppl. 1): S3-Sl8. 4. Williams OD. Methodological issues in international comparisons. Int J Epidemiol 1989; 18 (Suppl. 3): S166S168. 5. The principal investigators of the MONICA Project. WHO MONICA Project: Geographic variation in mortality from cardiovascular diseases. World Health Stat Q 1987; 40: 171-184. World Health Organization. Mortality from ischaemic heart disease in industrialized countries. Wkly Epidem Ret 1987; 62: 233-240. Uemura K, Pisa Z. Trends in cardiovascular disease mortality in industrialized countries since 1950. World Health Stat 0 1988: 41: 155-178.
PI. Both AM1 attack and mortality rates in Girona are far below the rates of northern Europe [29], U.S. [20] or Australia [30], and similar to those from other southern European countries [31]. Our figures, however, are also similar to those reported from Augsburg, Germany [18,32]. The present results provide further evidence that in southern Europe, particularly in the Mediterranean countries, the attack and the mortality rates of AM1 are low. Nevertheless the 28-day case-fatality rate in Girona is similar to that observed in countries with higher AM1 incidence rates [21,30,33]. Acknowledgements-The authors thank Marta Pulido, M. D. and David McFarlane for editorial assistance. We are also indebted to all Cardiologists and General Practitioners of Girona for their cooperation. Thanks also to Professor Ulrich Keil for the helpful comments on the final manuscript. This study was in part supported by a grant from the Associacio Catalana d’Ajut a la Cardiologia in 1985, and grant 90/0672 of the Fondo de Investigaciones Sanitaria%
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Epidemiology of Myocardial Infarction in Girona, Spain 18. Liiwel H, Lewis M, Hiirmann A, Eberle E, Keil U. Morbidity and mortality of myocardiil infarction in the Augsburg MONICA study area in 1985, 1986 and 1987. Rev Epldemiol slate Publ 1990; 38: 411417. 19. Dixon WJ, Brown MB, Engelman L er al. BMDP Statistical Software 1981. Berkelev: Universitv of California Press; 1981. 20. Burke GL, Sprafka JM, Folsom AR, Luepker RV, Norsted SW, Blackbum H. Trends in CHD mortality, morbidity and risk factor levels from 1960 to 1986: the Minnesota Heart Survey. lot J Epidemiol 1989; 18 (Suppl.): S73-S8 1. 21. Evans AE, Patterson CC, Mathewson Z, McCrum EE, McIlmoyle EL. Incidence, delay and survival in Belfast MONICA project coronary event register. Rev Epidamiol Sant6 Pub1 1990; 38: 419427. 22. Steingart RM, Packer M, Hamm P et al. Sex differences in the management of coronary artery disease. N IQ@ J Med 1991; 325: 226-230. 23. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med‘ 1991; 325: 221-225. 24. Healy B. The Yentl syndrome. N Engl J Med 1991; 325: 274-275. 25. Goldberg RJ. Declining out-of-hospital sudden coronary death rates: additional pieces of the epidemiologic puzzle. Circulation 1989; 74: 1369-1373. 26. Wrez G, Marrugat J, Sunyer J er al. Mortalidad
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