Background
Background
Since the beginnings of the 1980 s, population-based registries of acute myocardial
infarction (AMI) and coronary deaths for the 35 to 64 year old inhabitants were established
as part of the WHO MONICA (multinational monitoring of trends and determinants in
cardiovascular disease) project [1]. Registries from 21 countries and 38 study regions have contributed to testing the
MONICA hypotheses [2]. The aim of the MONICA registries was a ten year long observation of the age and
sex-specific rates of acute coronary events (AMI attacks and CHD deaths) per 100,000
population and of the 28-day case-fatality (CF) per 100 coronary events [3]. At least two population-representative cardiovascular risk factor surveys were
conducted at the beginning and at the end of the 10-year MONICA study period (1984/85
to 1994/95). Ten-years time trends of risk factor prevalences were opposed to time
trends of the AMI rates to quantify the impact of changes in risk factor profile on
AMI occurrence within each study population.
Right from the start, the MONICA Augsburg registry was planned with four additional
special features:
(1) It was broadened to the 25 to 74 year old population for a better representation
of the AMI rates especially in the female population [4]. In Germany, only 10 % of all coronary deaths among women (men 25 %) occurred before
the age of 65 in the year 1985; up to the 75th year of age, the percentage of coronary deaths increased to 28 % in women and to
58 % in men.
(2) The Augsburg registry works on the basis of a written patient consent (response
> 95 %) which allows a re-identification of each registered person with a primarily
non-fatal MI. Therefore the possibility of a life-long follow-up for long-term survival
analyses is given [5].
(3) In cases of a CHD death, the last treating physicians and/or coroners are questioned
promptly through a written questionnaire for the cardiovascular history including
drug medication and circumstances of death (e. g. seen alive by a physician, place
of death) [6].
(4) Diabetes mellitus was added to the risk factor profile of the register cases for
a better explanation of differences in 28-day case-fatality and survival [7].
After the 10-years MONICA period from (1984/95), the Augsburg AMI registration was
continued as part of the KORA (Cooperative Health Research of the Region of Augsburg)
research program. Since 2000, the register is partly financed by the German Ministry
of Health and Social Security (BMGS) and is used as a data base for the German National
Health Report [8]. In addition to the core questions of the Augsburg registry further register-based
studies were implemented in cooperation with gsf-internal and -external partners:
(1) the register-based KORA Family Heart Study on genetic determinants of an AMI was
conducted in 1996/97 in cooperation with the University of Regensburg.
(2) Since 1999, the GSF-working group of air pollution health effects had focused their research on registered
AMI patients to study air pollution effects on cardiovascular health. The environmental
studies were co-financed by financial support from US [9] and from the European Union (see www.gsf.de/KORA).
(3) As a cooperation with the Medical School of Hannover, the medical care data of
the Augsburg AMI registry from the years 1985 to 2001 were made available for an international
comparison in the frame of the Technological Change in Health Care (TECH) Research
Network [10].
In the present paper selected sex-specific results of the MONICA/KORA registry based
on the four time intervals, 1985/87, 1990/92, 1995/97, and 2000/02 are presented.
The register-based CHD mortality is discussed in relation to the official mortality
statistics of Germany. Time trends of AMI attack rates subdivided into incident and
recurrent event rates per 100,000 population are shown. For hospitalized patients
with incident AMI, time trends of the cardiovascular risk profile, and the acute reperfusion
therapy are presented. Finally, time trends of the survival course after incident
AMI including pre-hospital deaths are reported. Possible explanations of the observed
trends are discussed from a public health point of view.
Material and methods
Material and methods
Case finding and data collection by the Augsburg registry
Clinically confirmed AMI cases (from 1985 to 1998 Q-wave and non-Q-wave AMI, since
1999 additionally ST-elevation and non-ST-elevation AMI) were identified during their
hospitalization contacting the treating physicians located primarily in up to 20 and
presently in 9 still existing hospitals within and surrounding the study region (Table
[1]).
Table 1 Cooperating institutions of the MONICA/KORA registry (status Nov. 2004)
| Regional Health departments: |
- City of Augsburg, Hoher Weg 8, 86 152 Augsburg
Leitende(r) Medizinaldirektor(in): Prof. Dr. Johannes Gostomzyk (1984 to 2002)
Dr. Traude Löscher, Dr. Claudia Schomann, Fr. Christine Brecheisen |
- Rural district of Augsburg, Prinzregentenplatz 4, 86150 Augsburg
Leitender Medizinaldirektor: Dr. Helmut Hübsch, Dr. Uta Warncke, Fr. Gabriele Bader |
- Rural district of Aichach-Friedberg, Schlossplatz 5, 86 551 Aichach
Leitende(r) Medizinaldirektor(in): Dr. Renate Deckart (1985 to 2004), Dr. Michael Hennig, Fr. Renate Klatz
|
| Regional hospitals: |
- Klinikum Augsburg, Stenglinstr. 2, 86 156 Augsburg
Chief physicians:
I. Med. Prof. Dr. H-Dietrich Bolte (1985 to 2000), Prof. Dr. Wolfgang von Scheidt, PD Dr. Bernhard Kuch
II. Med. Prof. Dr. Günter Schlimok,
III. Med. Prof. Dr. Helmut Messmann, Herzchirurgie Prof. Dr. Michael Beyer
Inst. für Labormedizin Prof. Dr. Werner Ehret
Zentralapotheke: Dr. Christian Bannert
|
- Klinikum Haunstetten, Sauerbruchstr. 6, 86 179 Augsburg
Chief physician Dr. Gerd Ziesing
|
- Krankenhaus Bobingen, Wertachstr. 55, 86 399 Bobingen
Chief physician Dr. Reiner Hoffmann
|
- Krankenhaus Schwabmünchen, Weidenhartstr. 35, 6 830 Schwabmünchen
Chief physician Dr. Peter Schmidt
|
- Kreiskrankenhaus Aichach, Krankenhausstr. 11, 86 551 Aichach
Chief physician Dr. Walter Remplik
|
- Krankenhaus Friedberg, Hergottsruhstr. 3, 86 316 Friedberg
Chief physician Dr. Alexander Stiebens
|
- Kreiskrankenhaus Krumbach, Mindelheimerstr. 69, 86 381 Krumbach
Chief physician Dr. Hanns Peter Otter
|
- Krankenhaus Schrobenhausen, Högenauer Weg 5, 86 637 Schrobenhausen
Chief physician Dr. Stefan Hüttl
|
- Kreiskrankenhaus Wertingen, Ebersberg 36, 86 637 Wertingen
Chief physician Dr. Wolf Kühl, OÄ Dr. Riemenschneider-Müller
|
- Ärztlicher Kreisverband (Head physician Dr. Kurt D. Reising)
mit ca. 1 139 niedergelassenen Ärzten und 907 Krankenhausärzten |
The study region comprises the city of Augsburg and the two adjacent more rural districts
of Augsburg and Aichach-Friedberg, all together with about 200,000 female and 200,000
male registered residents in the age group 25 to 74 years. All patients with a clinically
confirmed AMI were asked for their willingness for lifelong register participation.
Afterwards they were interviewed about their own AMI and family history including
drug medication, circumstances of the acute event and the pre-hospital supply. Medical
care data during hospitalization were collected by hospital chart review. In WHO MONICA,
clinically confirmed cases of non-fatal AMI (patients surviving the 28th-day) were
categorized in definite AMI (MD1), possible AMI (MD2), successful resuscitation without
signs of an definite or possible AMI (MD3), no AMI (MD4) using a defined algorithm.
The MONICA-algorithm for epidemiological comparability comprises the three diagnostic
criteria, acute symptoms (nitrate resistant chest pain lasting 20 minutes or longer),
elevated heart muscle specific enzymes (GOT, CPK, CK-MB, and troponin documented since
2001), and ECG signs (Q waves, ST-elevation) [11]. The MONICA ECG-variable based on Minnesota coding of up to 4 ECGs was realized
during the 10 years MONICA period. Additionally, the clinical ECG diagnosis (diagnostic
finding in at least one ECG) was also documented since 1985 to date and has built
the basis for long-term comparisons. It is of epidemiological relevance, that in 2000
the AMI diagnosis was clinically redefined as acute coronary syndrome (ACS) in which
patients with symptomatically angina and laboratory signs of ischemia (troponin positive)
without persistent ST-segment elevations in the ECG are included [12]. The Augsburg registry is able to use both definitions the old and the new one.
For long term-comparisons - presented in this paper - the clinical ECG diagnosis and
CPK/CK-MB values in combination with observed acute symptoms AMI are used as diagnostic
criteria; all non-fatal cases with MD1, MD2, and MD3 were included.
For the registration of fatal cases, the following death certificate diagnoses (ICD
9) were suspected for an AMI or coronary death, if no other underlying cause of death
was diagnosed: Hypertension (401 - 405), ischemic heart disease (410 - 414), other
cardiovascular diseases (420 - 429), atherosclerosis (440 - 447), diabetes mellitus
(250), dyslipidemia (272), obesity (278), cardiac symptoms (797 - 799). All these
fatal cases were identified by weekly (city of Augsburg) or monthly (rural districts
of Augsburg, and of Aichach-Friedberg) checking of all death certificates within the
regional health departments and by sending a questionnaire to the last treating physician
and/or coroner. The physician questionnaire asks for socio-demographic data, cardiovascular
history, and circumstances of death. Using the information of the death certificate
and the physician questionnaires the register team reaches a decision to include the
case or not.
The MONICA diagnostic category of coronary deaths (MD1, MD2, MD9) is based on autopsy
result (only 2.3 % of the deceased), acute symptoms, and a positive history of CHD
(angina pectoris or previous MI or diagnosed coronary heart disease). Despite interviewing
physicians, about 31.0 % of fatal cases before or within 24 hours after hospitalization
(sudden cardiac deaths SCD) were unclassifiable. In fact, a coronary heart disease
could not be confirmed or excluded, and there is no information for another cause
of death [13]. In the WHO MONICA project those unclassifiable deaths (MD9) were included for calculation
of the AMI rates of the population, as a coronary death is the most plausible cause
of death as seen in autopsied deceased of some MONICA registries.
Long-term follow-up studies of 28-days-AMI survivors demanded information on the survival
status and the date and the region of death for deceased subjects. Cause of death
information came from the health departments of the Augsburg region.
Definitions
Definitions
The age- and gender-specific AMI attack rate per 100,000 population includes all incident
and recurrent cases of acute myocardial infarction (fatal and non-fatal) and all coronary
deaths divided by the mid-year population of the respective calendar year.
The age- and gender-specific incidence rate per 100,000 population includes all incident
cases of acute myocardial infarction (fatal and non-fatal) and all coronary deaths
(first ever events) divided by the mid-year population of the respective calendar
year(s).
The age- and gender-specific coronary deaths rate per 100,000 population includes
all fatal cases of acute myocardial infarction and all coronary deaths (incident and
recurrent) divided by the mid-year population of the respective calendar year.
The case fatality rate (in %) includes all fatal cases in the nominator divided by
all fatal and non-fatal cases (denominator) within a defined time interval: total
28-day case fatality, pre-hospital case fatality, 24-hour case-fatality of hospitalized
cases, 28-days case fatality of the 24 hour survivors were determined.
For comparisons by gender and/or over time the mean population rates (incidence, attack,
and death rate) with 95 % confidence intervals (CI) were age-standardized using the
age-specific weights of the German population 2002. Mean case-fatality rates were
age-standardized using the age-specific weights of all registered cases.
Patient characteristics (in %), e. g. cardiovascular risk factors, medication before
and during hospitalization, and at discharge from hospital, diagnostic and therapeutic
procedures during hospitalization, clinical complications, and survival status at
the 28th day after onset of symptoms were available.
For comparisons of patient characteristics mean percentages were age-adjusted by linear
logistic regression models. Age-stratified Mantel-Haenszel odds ratios with 95 % confidence
intervals (CI) were calculated to test case fatality differences for significance.
In general, a p-value less than 0.05 was considered as statistically significant.
Results
Results
From 1985 to 2002 a total of 17,884 (men 12,798, women 5,086) cases of acute myocardial
infarction including sudden cardiac death were registered. 9,886 of them (men 6,750,
women 3,136) died within 28 days.
Fig. [1] shows the sex-specific CHD-mortality rate per 100,000 population by 5-years age
groups from the German cause of death statistics in comparison to the registry based
rates for 1985/87 and 2000/02. At all ages, the register based CHD mortality rates
(1985/87 men 280, women 88; 2000/02 men 168, women 54) are slightly higher than the
official CHD-mortality rates (1985: men 259, women 80; 2002: men 138, women 45). Therefore
CHD mortality decrease was more pronounced in the official statistics (men 46 %, women
44 %) compared to the registry validated rates (men 40 %: women 38 %).
Fig. 1 Time trends of mortality from Coronary Heart Disease (CHD) per 100,000 population
by age and sex based on the official statistics of Germany (full lines) 1985 and 2002
and based on the MONICA/KORA Augsburg Registry of Acute Myocardial infarction (dotted
lines) 1985/87 and 2000/02.
The MONICA/KORA registry based time trends of age-standardized AMI attack rates subdivided
into rates of incident and recurrent AMI are presented by sex in Fig. [2] for four time intervals each including three years.
Fig. 2 Age-standardized rates of incident and recurrent acute myocardial infarction (fatal
and non-fatal) per 100,000 population by sex. MONICA/KORA Augsburg Registry of Acute
Myocardial Infarction 1985/87, 1990/92, 1995/97, and 2000/02.
From 1985/87 to 2000/02, the total age-standardized AMI attack rate per 100,000 population
decreased from 541 to 404 acute coronary events (- 25 %) in men. In women, an initial
increase of the attack rate from 171 to 193 coronary events was observed with a subsequent
decrease to 123 AMI cases in 2000/02. The age-standardized rate of first ever AMI
of the male population decreased continuously from 377 to 299 in 1995/97 followed
by a not yet significant re-increase to 313 incident cases in 2000/02. In the female
population incidence rates increased from 135 (1985/87) to 149 cases in 1990/92, and
subsequently decreased continuously to 100 incident cases per 100,000 population in
2000/02. In contrast, the rates of recurrent AMI cases per 100,000 population show
a remarkably changing trend from 164 to 91 in men (- 44 %), and an increase from 36
to 44, followed by a decrease to 23 in women (overall decrease: - 35 %).
As shown in Table [2] the hospitalized patients with an incident AMI were characterized by high and mostly
increasing proportions of hypertension, dyslipidemia, and diabetes mellitus. Against
the background of the decreasing AMI morbidity, the decrease of a positive history
of angina pectoris from 41 to 15 % in men and from 52 to 18 % in women with an acute
coronary event has to be emphasized. Of further great importance is the falling proportion
of never smokers among female AMI patients.
Table 2 History of cardiovascular risk profile of 25 - 74 year old hospitalized patients (%
and 95 % Confidence Interval, age adjusted). MONICA/KORA Augsburg Registry of Acute
Myocardial Infarction 1985/87, 1990/92, 1995/97, and 2000/02
|
1985/87 |
1990/92 |
1995/97 |
2000/02 |
| men |
n = 834 |
n = 759 |
n = 755 |
n = 1 115 |
| employed |
37 (35; 40) |
35 (33; 37) |
33 (31; 35) |
29 (27; 31) |
cigarette smoking
present smokers
never smokers |
37 (34; 41)
25 (22; 28) |
35 (31; 38)
25 (22; 28) |
38 (34; 41)
28 (25 32) |
30 (28; 33)
24 (21; 26) |
| hypertension |
44 (40; 48) |
48 (44; 52) |
58 (54; 61) |
70 (67; 73) |
| angina pectoris |
41 (37; 44) |
19 (16; 23) |
15 (12; 18) |
15 (13; 18) |
| dyslipidemia |
36 (32; 39) |
60 (56; 64) |
56 (52; 60) |
75 (72; 77) |
| diabetes mellitus |
19 (16; 22) |
21 (18; 25) |
23 (20; 27) |
31 (28; 34) |
| stroke |
6 (4; 8) |
6 (4; 8) |
2 (1; 4) |
9 (7; 11) |
| women |
n = 269 |
n = 304 |
n = 268 |
n = 359 |
| employed |
21 (16; 26) |
18 (14; 22) |
17 (13; 21) |
18 (15; 22) |
cigarette smoking
present smokers
never smokers |
23 (18; 28)
58 (52; 64) |
30 (25; 35)
53 (48; 58) |
33 (27; 38)
52 (46; 57) |
29 (25; 33)
43 (38; 48) |
| hypertension |
66 (60; 72) |
61 (56; 67) |
66 (60; 72) |
79 (75; 83) |
| angina pectoris |
52 (46; 58) |
28 (23; 33) |
17 (12; 21) |
18 (14; 22) |
| dyslipidemia |
40 (34; 47) |
65 (60; 70) |
60 (54; 66) |
77 (73; 81) |
| diabetes mellitus |
33 (27; 38) |
26 (21; 31) |
32 (27; 38) |
35 (30; 40) |
| stroke |
8 (3; 10) |
5 (3; 8) |
5 (3; 8) |
11 (8; 15) |
From 1985 to 2002 a tremendous increase of evidence-based drug medication (acetyl
salicylic acid [ASA], beta-blockers, ACE inhibitors, lipid lowering drugs, especially
statines, and thrombolytic drugs) and an invasive reperfusion therapy of occluded
coronary arteries (PCI percutaneous coronary interventions, stenting, coronary artery
bypass surgery) became clinical standard. Fig. [3] gives an impression of the use of different procedures of reperfusion therapy over
time.
Fig. 3 Time trends in reperfusion therapy (PCI = Percutaneus Coronary interventions, CABS
= Coronary artery bypass surgery) after incident acute myocardial infarction by sex
(age-standardized using the weights of the total registered cases) in percent. MONICA/KORA
Augsburg Registry of Acute Myocardial Infarction 1985/87, 1990/92, 1995/97, and 2000/02.
At the beginning of the MONICA Project, thrombolytic drug treatment started at a low
level of less than 10 % in 1985/87 and increased to 47 % in male and 39 % in female
AMI patients in 1995/97. After a timely delay, in 2000/02 about 50 % of all incident
AMI cases were provided with a PCI and most of them with a coronary stent; finally
25 % of the male and 14 % of the female cases needed a coronary artery bypass surgery.
Therefore, the lower rate of reperfusion therapy in women (70 %, 95 % CI 65; 75) compared
to men (79 %, 95 % CI 76; 81) resulted from a less often conducted ACVB surgery. For
secondary prevention, in 2000/02 51 % of men (95 % CI 48; 55) and 56 % of women after
an incident AMI (95 % CI 51; 62) received a concomitant treatment with ASA, beta-blockers,
ACE-inhibitors and statins at discharge; three of the drug groups were prescribed
to 35 % (95 % CI 32; 38) of male and 33 % (95 % CI 28; 38) of female survivors of
an incident AMI (data not shown in a table). Actually, less then 10 % of the cases
were discharged with one or none of the designated cardiovascular drug groups; in
1985/87 about one third of the incident AMI survivors received none of the four drug
groups (men 33 %, 95 % CI 29; 37; women 31 % 95 % CI 25; 37). In contrast, cardiovascular
drug medication before the incident AMI has remained suboptimal. In 2000/02 55 % (95
% CI 52; 58) of male and 45 % (95 % CI 40; 50) of female patients received none of
the four CVD drug groups relevant for prevention of an incident AMI; only 8 % of men
and 11 % of female patients were pre-treated with three or four of the drug groups.
In Fig. [4] the survival structure of the registered incident cases is compared between the
four time intervals. From 1985/87 to 1995/97, neither in men nor in women significant
changes could be observed.
Fig. 4 Age-standardized course of survival within 28 days (PHT prehospital death; KHT death
during the first 24 hours after hospitalization, KHE death during 2nd to 28th day after acute onset; KHL 28 day survivors) per 100 incident cases, age 25 - 74
years by sex. MONICA/KORA Augsburg Registry of Acute Myocardial Infarction 1985/87,
1990/92, 1995/97, and 2000/02.
Compared to men, between 1985 and 1997 a higher percentage of female cases died before
hospitalization, whereas no significant gender differences were observed in the percentage
of in-hospital deaths. A statistically significant lower percentage of 28-day survivors
were observed in women than in men (Mantel-Haenszel age-weighted odds ratio men to
women: 1985/87 OR 1.52, 95 % CI 1.24 - 1.86; 1990/92 OR 1.24, 95 % CI 1.02 - 1.50;
1995/97 OR 1.74 95 % CI 1.44 - 2.11). But in 2000/02, a significantly reduced percentage
of pre-hospital (men 26 %, women 27 %) and early in-hospital (men and women 12 %)
deaths were seen in both, men and women. The percentage of 28-day-survivors increased
to 57 % in men and 56 % in women, from now on without gender differences (OR 1.04;
95 % CI 0.85; 1.27).
Conclusion
Conclusion
In Germany, the decrease of CHD mortality and AMI morbidity among the middle-aged
population observed during the 10-year WHO MONICA period continued to date. Similar
trends were also reported from many other industrialized countries within and outside
Europe [14]
[15]
[16]
[17]
[18]. Morbidity of recurrent AMI decreased to a higher extent as the rates of incident
AMI, because more effort was observed concerning intensified drug treatment for secondary
prevention after AMI than in treatment of high risk individuals before incident AMI
among the Augsburg population. In the time period 2000/02, an increase of non-fatal
AMI was observed in the Augsburg region. On the one hand this could be the result
of the reported intensified and more effective acute coronary care, but on the other
hand it could also be the result of the changed definition of AMI. As a consequence
of the new definition, symptomatic patients with elevated concentrations of the heart-specific
marker troponin, and without typical ECG changes (NSTEMI) are admitted to hospital
at an earlier stage of the acute event [9]. Possibly, this fact could result in an improved prevention of recurrent AMI due
to the aggressive invasive treatment during their first acute event, as recently also
reported from France [19]. The still high risk profile of the patients with an incident AMI in combination
with an ongoing low level of preventive drug medication before their incident event
highlighted the great potentials of primary prevention.
On the other hand, the observed large increase of therapy with thrombolytic agents
and other cardiovascular drug combinations was clearly associated with an increase
of 28-day-survival of the hospitalized 24 hour survivors and a decrease of recurrent
events per 100,000 population. The population-based Augsburg registry has shown, that
- for the first time - the since 2000 implemented strategy of a very early coronary
stenting was associated with a decrease of the 24 hour case-fatality, and therefore
a 10 %-point increase of 28-day survival; this high impact of declined early case-fatality
on the overall CHD mortality of the population was also reported from the FINAMI study
[20]. Presumably, a further decrease of recurrent event morbidity per population might
be expected in the future. The strength of hospital-based registers is the standardized
quality control of the implementation of evidence-based therapy for the welfare of
the patients. However, only population-based registries including clinically confirmed
AMI cases and validated CHD deaths inside and outside a hospital can quantify the
public health consequences of intensified acute coronary care strategies.
Future planning
Future planning
The population-based registration of AMI cases and CHD deaths in the study region
of Augsburg will be continued, and long-term survival analyses will be performed with
special regard to medical care effects.
Furthermore, studies of a possible inflammatory effect of air pollution on cardiovascular
health will be continued and flanked by the measurement of special properties of ambient
particles by the newly established GSF monitoring station located in the city of Augsburg.
Another still important challenge of the Augsburg registry is the identification of
clinical outcomes among the MONICA/KORA cohort members as basis for the long-term
prediction of AMI and diabetes mellitus in primary healthy individuals.
The GSF Institute of Health Economics and Health Care Management is testing the opportunity
to get individual data on long-term health care utilization and expenditure (related
as well as unrelated) of the registered AMI patients by contacting the relevant health
security institutions, in order to explore the trends of costs and cost-effectiveness
in health services delivered to these patients.
In the years 2005/06 a follow-up examination on sub-clinical outcomes in participants
of the KORA-Family Heart Study from 1996/97 is planned, again in close cooperation
with cardiologists of the University of Regensburg.
All together the Augsburg registry builds an important base for further cooperative
investigations on positive or critical developments of the AMI risk in the population
and for AMI survivors from the public health point of view.
Acknowledgement
Acknowledgement
The authors wish to thank all the participants of the MONICA/KORA registry during
the 20 year long study time. We specifically would like to thank all our partner institutions
(see Table [1]) and to the registry team: Dorothea Lukitsch, Anita Schuler (management of the registration
procedures), Gabriele Zimmermann, Christine Winter, Petra Heilander, Gabriele Orlik
(patient interview and medical record reviewing), Walter Huss (data bank programming),
Ursula Kaup (data handling and data analyses). Last but not least, we are thankful
to Prof. Dr. med Ulrich Keil, PhD, the principal investigator of the WHO MONICA Augsburg
project.
The MONICA/KORA registry has been supported by GSF and grants from BMBF - Federal
Ministry of Education and Research (01 EG 9405/8, FKZ 01ER 9502/0, and NGFN: 01GS0499),
BMGS - Federal Ministry of Health and Social Security (AZ 317-123 002/18, Fe 76212),
DFG - Deutsche Forschungsgemeinschaft (HO 1073/8-1, SCHW 490/2-1//490/2-2) and EU
- European Union (S12.292277/ 2000CVG3-508, QLK4-CT2000-00708, QLG2 CT-2002-01254,
QLRT-2000-02236, S12.292277/ 2003118).
The article refers specifically to the following contributions of this special issue
of Das Gesundheitswesen: [21]
[22]
[23]
[24]
[25]
[26].
