Eur Arch Psychiatry Clin Neurosci DOI 10.1007/s00406-014-0554-0
ORIGINAL PAPER
Risk of dementia in elderly patients with the use of proton pump inhibitors Britta Haenisch • Klaus von Holt • Birgitt Wiese • Jana Prokein • Carolin Lange • Annette Ernst • Christian Brettschneider • Hans-Helmut Ko¨nig • Jochen Werle • Siegfried Weyerer • Melanie Luppa Steffi G. Riedel-Heller • Angela Fuchs • Michael Pentzek • Dagmar Weeg • Horst Bickel • Karl Broich • Frank Jessen • Wolfgang Maier • Martin Scherer
•
Received: 19 May 2014 / Accepted: 11 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Drugs that modify the risk of dementia in the elderly are of potential interest for dementia prevention. Proton pump inhibitors (PPIs) are widely used to reduce gastric acid production, but information on the risk of dementia is lacking. We assessed association between the use of PPIs and the risk of dementia in elderly people. Data were derived from a longitudinal, multicenter cohort study in elderly primary care patients, the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe), including 3,327 community-dwelling persons aged C75 years. From follow-up 1 to follow-up 4 (follow-
For the AgeCoDe study group. B. Haenisch (&) K. von Holt F. Jessen W. Maier German Center for Neurodegenerative Diseases (DZNE), c/o Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany e-mail: [email protected] B. Haenisch K. Broich Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany B. Haenisch F. Jessen W. Maier Department of Psychiatry, University of Bonn, Bonn, Germany B. Wiese J. Prokein Institute for General Practice, Hannover Medical School, Hannover, Germany
up interval 18 months), we identified a total of 431 patients with incident any dementia, including 260 patients with Alzheimer’s disease. We used time-dependent Cox regression to estimate hazard ratios of incident any dementia and Alzheimer’s disease. Potential confounders included in the analysis comprised age, sex, education, the Apolipoprotein E4 (ApoE4) allele status, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease, and stroke. Patients receiving PPI medication had a significantly increased risk of any dementia [Hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04–1.83] and Alzheimer’s disease (HR 1.44, 95 % CI 1.01–2.06) compared with nonusers. Due to the major burden of dementia on public health and the lack of curative medication, this J. Werle S. Weyerer Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany M. Luppa S. G. Riedel-Heller Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany A. Fuchs M. Pentzek Institute of General Practice (IFAM), Medical Faculty of the Heinrich-Heine-University Du¨sseldorf, Du¨sseldorf, Germany D. Weeg H. Bickel Department of Psychiatry, Technical University of Munich, Munich, Germany
C. Lange A. Ernst M. Scherer Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany C. Brettschneider H.-H. Ko¨nig Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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finding is of high interest to research on dementia and provides indication for dementia prevention. Keywords Dementia Proton pump inhibitors Risk factor Elderly Prevention
Introduction Dementia is a progressive disorder characterized by deterioration in cognitive ability and capacity for independent living. It has a substantial and rising burden on patients, their families, and the healthcare system. Analyses of data from the German sick funds showed that the prevalence for dementia is about 1 % at the age of 65 and increases with age [1]. At the age of 90, about one-third of the population is affected [1]. The global prevalence of dementia will increase from about 35 million today to over 80 million patients worldwide by 2040 [2, 3]. The high demand on therapies and care because of cumulative cognitive decline combined with increasing numbers of patients has a remarkable socioeconomic impact. The estimated worldwide costs of dementia were US$604 billion in the year 2010 [4]. An effective procedure to obviate the burden dementia is expected to have on people and healthcare systems worldwide is dementia prevention in people at increased risk, i.e., in the elderly population. Therefore, often used drugs that potentially increase or decrease the risk of dementia in elderly people are highly interesting substances to examine in epidemiological studies the consequence of their long-term use on incidence of dementia. In the present study, we focus on the drug class of proton pump inhibitors (PPIs). PPIs are used for the treatment of gastrointestinal diseases where inhibition of gastric secretion is desired [5]. Gastroesophageal reflux disease causes distressing symptoms and is a risk factor for Barrett’s esophagus which can lead to esophageal adenocarcinoma [6]. PPI medication is also used in the management of gastric ulcers [7]. The use of PPIs has strongly increased during the last years, especially in the elderly [8, 9]. In Germany, the prescription rate of PPIs raised fourfold within the last 10 years [10]; in 2012, 2,885 million defined daily doses were prescribed [table 32.1 in 10]. Observational studies in the elderly population detected inappropriate use of PPIs without adequate documentation for a gastrointestinal diagnosis to be a common phenomenon [11, 12]. About 40–60 % of all PPI prescriptions were detected as inappropriate [11, 12]. These studies did not include analyses on the doses prescribed. There are hints that PPI use might influence cognition [13–15]. In a recent study, Lam et al. show a significant association of previous and current PPI use with the presence of vitamin B12 deficiency in a
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population-based sample [11]. Vitamin B12 deficiency has been described to be associated with cognitive decline [16]. Furthermore, PPIs were shown to potentially enhance amyloid beta peptide (Ab) levels in brain by directly affecting the enzymes b- and c-secretase which leads to increased Ab levels in mice [15] and by the modulation of degradation of Ab by lysosomes in microglia [17–20]. In the present study, we intend to examine whether there is a correlation between PPI use and developing dementia in the elderly population. The hypothesis is that the use of PPIs in elderly patients will be associated with an increased risk of dementia. We calculated a time-dependent Cox regression model with potential confounders as covariates, including age, sex, education, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease and stroke, and the Apolipoprotein E4 (ApoE4) allele status. The APOE locus in the human genome has frequently been shown to be the major susceptibility gene for Alzheimer’s disease (for review see 21). One APOE-e4 allele is associated with a twofold to threefold increased risk, two copies associated with a fivefold or more increase [21].
Methods Study design and procedures Data were derived from the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe) of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD). AgeCoDe is a longitudinal multicenter study in elderly primary care patients [22]. The study recruited subjects at six study sites in Germany (Bonn, Du¨sseldorf, Hamburg, Leipzig, Mannheim and Munich) by using general practitioners’ (GP) medical record registries [23]. Inclusion criteria comprised an age of 75 years or older, the absence of dementia at recruitment, and regular contact with the GP (at least once every 12 months). The lower age cutoff was part of the study design to select a high age-group of individuals. Subjects were excluded if they were consulted from the GP by home visits only or were a resident of a nursing home. While data were collected on several important risk factors, there are other factors that may contribute to the development of dementia that could not be considered in the course of the study. All subjects included in the study gave informed consent. The study protocol was approved by ethics committees at all sites. Collection of data started in 2003. Individuals were recruited by the GPs at the six sites. The GPs identified 22,701 patients aged 75 years or older [24]. Of those, 10,850 patients were eligible, meeting the
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inclusion criteria [24]. Among a randomly selected sample of 6,619 patients, 3,292 were not investigated because contact failed or they refused to participate [24]. At baseline, 3,327 participants were included in the study. A detailed description of the sampling and sample attrition is given elsewhere [24]. Baseline and subsequent follow-up assessments (18 months interval) including follow-up 1 to follow-up 4 are the timeframe for analysis of the present study. Data collection was performed by trained physicians and psychologists at the subjects’ home. Neuropsychological assessments included the Structured Interview for Diagnosis of Dementia of Alzheimer type, Multi-infarct Dementia and Dementia of other Aetiology according to DSM-IV and ICD-10 (SIDAM) [25]. The SIDAM contains a neuropsychological test battery [SIDAM cognitive (SISCO) score with 55 items, including the 30-item MiniMental State Examination (MMSE)], the assessment of activities of daily living (SIDAM ADL Scale), and the Hachinski–Rosen Scale. For participants who were unavailable for some reasons, information about his/her cognitive status was completed by interviewing an informant (e.g., a relative) using the structured Global Deterioration Scale [26] and the subscales ‘Changes in Performance of Everyday Activities’ and ‘Changes in Habits’ subscales from the Blessed Dementia Scale [27]. The Apolipoprotein E4 (ApoE4) genotype status was examined in the majority of the participants as described elsewhere [28]. Recording of medication was assessed within the interview using the name of the drug product or the unequivocal drug package code. This information was then used to identify the active substances and translate this into the Anatomical Therapeutic Chemical (ATC) code for further consideration. From baseline to follow-up 2, the presence or absence of a specific unequivocal drug package code and ATC code in the interview documentation was the only information to document medication use. From follow-up 3 onwards, additional questions focused on the drug use pattern by discriminating between ‘‘regular use’’ and ‘‘use if needed.’’ In addition, from follow-up 3 onwards, the frequency of drug use and pharmaceutical form is given. Dementia status was defined as described earlier [22]. In brief, dementia was diagnosed in consensus with the interviewer and an experienced geriatrician or geriatric psychiatrist according to DSM-IV criteria. This comprises a diagnostic algorithm in the SIDAM, comprising cognitive impairment defined by the SISCO and impairment of activities of daily living (C2 scores on the SIDAM ADL scale). For patients not interviewed personally, a score of C4 on the Global Deterioration Scale was used as criteria for dementia diagnosis. The diagnosis of Alzheimer’s disease was guided by the National Institute of Neurological
and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association criteria for probable Alzheimer’s disease [29]. Vascular dementia diagnosis was established according to the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche´ et l‘Enseignement en Neurosciences criteria [30] (i.e., the evidence of a cerebrovascular event and temporal association with cognitive decline). Mixed dementia was diagnosed in the absence of temporal association of the cerebrovascular event with cognitive decline. For analyses, subjects with mixed dementia and Alzheimer’s disease were combined because we lack imaging data for the patients and thus, cannot rule out vascular lesions. The group other dementia included patients with a dementia syndrome related to a specific reason, such as head trauma, normal pressure hydrocephalus, brain tumor as well as unspecified dementia cases, i.e., those cases in which an etiology could not be defined with sufficient certainty based on the available data. Statistical analyses We examined the effect on incident dementia by use of the PPIs omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, and dexlansoprazole (ATC code A02BC01-06) versus no use of these drugs. We used timedependent Cox regression to evaluate the association between use of the compounds in question and the risk of incident dementia (any dementia and dementia in the course of Alzheimer’s disease, respectively). Time-dependent Cox regression allows the status levels of the covariates to vary over time. The dependent variable was the occurrence of incident dementia. To address potential bias, we selected a priori a number of potential confounders that were plausible factors to modify the risk of incident dementia and for which information was available. We adjusted the Cox regression model for the following potential confounding factors which were incorporated as covariates: age, sex, education as defined by the CASMIN classification [31], the ApoE4 allele status, polypharmacy, and comorbidities: the presence of depression [32], as defined by the geriatric depression scale C6, as well as diabetes, ischemic heart disease, and stroke, all as diagnosed by GPs or specialists. The ApoE4 allele status was categorized in two classes, with and without the presence of the ApoE4 allele. We specified anticholinergic drug use as use of any anticholinergic drug according to the updated anticholinergic drug scale list (33 and personal communication; level 2 and 3). Polypharmacy was defined as taking five or more drugs, based on a definition commonly used in other studies [34, 35]. Exposure to PPIs and the presence of polypharmacy as well as the presence of comorbidities was modeled as a segmented time-dependent covariate to allow
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for status levels varying over time, i.e., from one follow-up to another. This means that the PPI user status was set for each follow-up interval separately, excluding PPI use after incident dementia. The drug use evaluated in the baseline interview and in each of the follow-up investigations was taken as the relevant exposure level during the subsequent period until the next follow-up. When, in a specific followup, information on medication was missing, the value of the preceding follow-up was taken, if that information was valid. This observation was taken as last observation carried forward. For visualization, we simplified the model and used Cox regression without time-dependent covariates: We defined the time from baseline to follow-up 2 as observation period for PPI use and evaluated for each individual if there was PPI use at any of the three different time points measured during this period (baseline, follow-up 1, follow-up 2). This value was used to calculate Cox regression for incident any dementia from follow-up 3 onwards as status variable (no confounders included). The resulting survival curves (Kaplan–Meier curves) are presented. All calculations were done using the SPSS statistical package (SPSS 21). We considered p \ 0.05 to be statistical significant.
Results Of the 3,327 subjects of the AgeCoDe study participated at baseline, 251 subjects were excluded after quality control filtering (70 because of dementia at baseline, one because of missing value on dementia at baseline, 39 because of an age \75 years, 16 because of missing value dementia status at follow-up periods, 121 because of missing value on the ApoE4 status, and four because of missing or unknown medication information). Thus, 3,076 subjects were included in the following analysis. We detected 713 patients who received a PPI during the study period, i.e., at least one PPI drug at least at one assessment independent of dementia status (baseline to follow-up 4; Fig. 1). Sample characteristics of PPI users and nonusers are given in Table 1. In the AgeCoDe study, we have specification on regular drug use and drug use if required from follow-up 3 onwards. We observed regular drug use for 90.4 and 91.0 % of the PPI users in follow-up 3 and follow-up 4, respectively. The use of PPIs was associated with a significant increased risk of dementia [hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04–1.83; p = 0.02; Table 2]. Of the other factors, age, the presence of an ApoE4 allele, depression, diabetes, and stroke showed a significant increase in risk of incident dementia. For gender, education, polypharmacy, and ischemic heart disease, we did not detect significant effects on the risk of dementia (Table 2).
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Participants at baseline n= 3,327 Exclusion (n= 251)
Participants included for pharmacoepidemiological analysis incident any dementia n= 3,076
Dementia at baseline 70 Missing value on dementia at baseline 1 Age < 75 years 39 Missing value dementia status at follow-up periods 16 Missing value ApoE4 status 121 Missing value medication 4 Exclusion (n= 165)
Participants included for pharmacoepidemiological analysis incident Alzheimer dementia
Vascular Dementia Dementia, other
76 89
n= 2,911
Fig. 1 Sample for analysis
The inclusion of another specific drug class that can impact cognitive performance, into the model, namely anticholinergic drugs, resulted in comparable outcomes for PPI use (HR: 1.36, 95 % CI 1.03–1.81; p = 0.03) and for the other covariates (data not shown). As expected, anticholinergic drug use itself was a risk factor for incident dementia (HR 1.65, 95 % CI 1.23–2.21; p = 0.001). When the confounders were not included in the analysis, a similar result for the association between PPI use and incident any dementia was obtained (HR 1.44, 95 % CI 1.10–1.90, p = 0.008; Table 2). In a subgroup analysis, we explored the effect of PPI use on incident dementia in the course of Alzheimer’s disease (including mixed dementia, see methods). We obtained similar results as for incident any dementia. PPI use elevated the risk of Alzheimer’s disease (HR 1.44, 95 % CI 1.01–2.06; p = 0.04; Table 2). The increase in risk of Alzheimer’s disease by the presence of an ApoE4 allele was slightly higher compared with the HR for incident any dementia while diabetes and stroke did not show an elevated risk of Alzheimer’s disease. Exclusion of confounders did not clearly impact the effect of PPI use on Alzheimer’s disease (HR 1.45, 95 % CI 1.03–2.05; p = 0.03; Table 2). The association of PPI use and incident any dementia as well as Alzheimer’s disease was confirmed in the simplified Cox regression model without time-dependent covariates (HR 1.57, 95 % CI 1.14–2.15, p = 0.006 for incident any dementia, and HR 1.51, 95 % CI 1.03–2.21, p = 0.04 for Alzheimer’s disease; Table 3). Figure 2 shows the resulting Kaplan–Meier curves for incident any dementia.
Discussion The aim of the study was to examine the effect of PPIs on the risk of dementia in elderly patients. In the AgeCoDe
Eur Arch Psychiatry Clin Neurosci Table 1 Sample characteristics of PPI users and nonusers for Cox regression with time-dependent covariates (baseline–follow-up 4) Analysis any dementiaa No use PPI usec Aged Sexe
p valueb Use
2,363 (76.8 %) 79.7 (3.6)
Analysis Alzheimer’s diseasea No use
713 (23.2 %)
Use
2,238 (76.9 %)
79.6 (3.4)
0.51
490 (68.7 %)
0.02
1,440 (64.3 %)
0.89
1,512 (64.0 %)
p valueb
79.6 (3.6)
673 (23.1 %) 79.6 (3.4)
1.00
465 (69.1 %)
0.02
1,385 (61.9 %)
414 (61.5 %)
0.99
609 (27.2 %)
185 (27.5 %)
Education Low
1,467 (62.1 %)
436 (61.2 %)
Middle
642 (27.2 %)
197 (27.6 %)
High
254 (10.7 %)
80 (11.2 %)
244 (10.9 %)
74 (11.0 %)
ApoE4
511 (21.6 %)
129 (18.1 %)
0.04
473 (21.1 %)
125 (18.6 %)
0.15
Depressionf
482 (20.4 %)
204 (28.6 %)
\0.001
434 (19.4 %)
191 (28.4 %)
\0.001
Diabetes
795 (33.6 %)
281 (39.4 %)
0.005
750 (33.5 %)
262 (38.9 %)
0.01
Stroke
268 (11.3 %)
99 (13.9 %)
0.07
225 (10.1 %)
82 (12.2 %)
0.12
Ischemic heart disease
1,204 (51.0 %)
419 (58.8 %)
\0.001
1,126 (50.3 %)
394 (58.5 %)
\0.001
Polypharmacyg
1,634 (69.1 %)
659 (92.4 %)
\0.001
1,538 (68.7 %)
621 (92.3 %)
\0.001
509 (21.5 %)
139 (19.5 %)
0.24
460 (20.6 %)
118 (17.5 %)
0.09
Mortalityh a
Sample characteristics include demented and non-demented patients
b
Results of t test or Chi-square-test for group comparisons
c
PPI use at least at one study period assessment
d
In years (SD)
e
Female
f
Defined by Geriatric Depression Scale (GDS) score of C6
g
Defined as C5 drugs
h
Follow-up 1–follow-up 4
Table 2 Risk of incident any dementia and Alzheimer’s disease by PPI use Variable
Any dementia Hazard ratio (95 % CI)
Alzheimer’s disease p value
Hazard ratio (95 % CI)
p value
PPI usea,b
1.38 (1.04–1.83)
0.02
1.44 (1.01–2.06)
0.04
Agec
1.12 (1.10–1.15)
\0.001
1.15 (1.11–1.19)
\0.001
Sexd
1.00 (0.81–1.24)
1.00
0.77 (0.57–1.03)
0.08
Education Low
Reference
Middle
0.80 (0.64–1.00)
0.05
0.72 (0.53–0.97)
High
0.78 (0.55–1.10)
0.15
0.81 (0.52–1.28)
0.37
ApoE4
1.87 (1.52–2.31)
\0.001
2.25 (1.73–2.93)
\0.001
Depressione
2.28 (1.80–2.88)
\0.001
2.05 (1.50–2.81)
\0.001
Diabetes
1.30 (1.05–1.62)
0.02
1.21 (0.91–1.60)
0.20
Stroke
1.92 (1.38–2.67)
\0.001
0.99 (0.56–1.75)
0.98
Ischemic heart disease
1.10 (0.90–1.35)
0.35
1.06 (0.81–1.38)
0.66
Polypharmacyf
1.14 (0.92–1.42)
0.22
1.08 (0.82–1.42)
0.59
PPI usea,g
1.44 (1.10–1.90)
0.008
1.45 (1.03–2.05)
0.03
a
Reference 0.03
Use of PPI before the diagnosis of dementia
b
Calculation with potential confounding factors
c
In years
d
Female (reference)
e
Defined by Geriatric Depression Scale (GDS) score of C6
f
Defined as C5 drugs
g
Calculation without potential confounding factors
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Eur Arch Psychiatry Clin Neurosci Table 3 PPI users and nonusers for Cox regression without timedependent covariates Analysis any dementia
Analysis Alzheimer’s disease
Number of patients
Demented
Nondemented
Demented
Nondemented
PPI use
50
371
34
371
No PPI use
165
2,147
117
2,147
Hazard ratio (95 % CI); p value
1.57 (1.14–2.15); 0.006
1.51 (1.03–2.21); 0.04
PPI use: baseline–follow-up 2; observation period incident dementia: follow-up 3–follow-up 4
Fig. 2 Dementia-free survival by the use of PPIs. Baseline by followup 2 was defined as observation period for PPI use, and incident any dementia (follow-up 3 onwards) was set as outcome. The curves are not adjusted for confounders
sample, we detected that among primary care patients aged 75 years and older the use of PPIs was associated with a significant increase in the risk of incident dementia. Subanalyses of all dementia cases and dementia cases in the course of Alzheimer’s disease showed similar results. To our knowledge, this is the first epidemiological investigation showing that PPIs might have an impact on dementia risk. Although the use of PPIs is generally thought to cause few side effects, previous epidemiological studies have reported adverse effects of chronic PPI intake, including an increased risk of hip fracture and community acquired pneumonia [36, 37]. Our result of a significant enhanced risk of dementia by use of PPIs is in line with a study of Lam et al. [14] who recently describe a significant
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association of previous and current PPI use with the presence of vitamin B12 deficiency (odds ratio 1.65, 95 % CI 1.58–1.73) in a population-based setting. Poor vitamin B12 status has been linked to cognitive decline and neurological damage, probably due to impaired DNA synthesis, methylation, and homocysteine neurotoxicity [38, 39]. Lam et al. [14] mention that the association between PPI use and the presence of vitamin B12 deficiency decreased with age. However, it is known that vitamin B12 deficiency often remains undetected in the elderly population [40, 41]. Another aspect how PPI use may influence cognition is by directly interacting with brain enzymes. Interestingly, in a recent study by Badiola et al. [15], PPIs like lansoprazole were shown to augment amyloid beta peptide (Ab) levels in an amyloid cell model and in mouse brain. The authors suggest that PPIs might act as inverse c-secretase modulators and by increasing the activity of the b-secretase BACE1 and, thus, cause an accumulation of Ab [15]. Ab peptides are one of the major pathological signs of dementia in the course of Alzheimer’s disease and are cytotoxic to endothelial cells as well [42]. A further functional aspect of enrichment of Ab levels by PPIs might involve the modulation of degradation of Ab by lysosomes in microglia [17]. Clearance of fibrillar Ab by microglia is pH-dependent and induced by acidification of lysosomes. This acidification was reported to be mediated by the V-ATPase proton pump [18]. PPIs exhibit inhibitory properties at V-ATPases [19] which may contribute to inhibition of acidification, reduced Ab degradation, and thus, enhanced Ab levels [20]. The clinical impact of our finding is supported by studies that report PPIs (e.g., lansoprazole, omeprazole) to cross the blood brain barrier [43, 44]. Therefore, this class of drugs is able to exert effects in the brain. Of the covariates included in the study, the known risk factors depression, the ApoE4 allele status, stroke, and age were found to significantly elevate the risk of any dementia and/or Alzheimer’s disease. Depression (HR 2.28, 95 % CI 1.80–2.88; p \ 0.001) and ApoE4 (HR 2.25, 95 % CI 1.73–2.93; p \ 0.001) had the highest hazard ratios of the covariates in the model for the development of any dementia and Alzheimer’s disease, respectively. An important strength of the study is that the results are based on the detailed and rigorous data from a prospective cohort study (AgeCoDe). Furthermore, our study covered a 6-year period of longitudinal data. A particular strength of the AgeCoDe study is the comprehensive documentation of cognitive performance, medical history and medication. Furthermore, we were able to adjust for a wide range of possible confounders, including genetic data, polypharmacy, and comorbidities with possible impact on the outcome.
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The present study has limitations. Specific information on the drug use pattern (regularly or if required) in the AgeCoDe study is available only from follow-up 3 onwards. We detected a constant regular PPI use of over 90 % of PPI users in follow-up 3 and 4. We cannot rule out differences in baseline to follow-up 2, but it seems to be a constant high rate of regular PPI use pattern in the sample. Another fact is that we can only show the statistical association between PPI use and risk of dementia, as this is an epidemiological study. The underlying causal biological mechanisms are to be investigated in detail in further studies. Randomized, prospective trials are needed to establish direct cause and effect relationships between PPI use and incident dementia in the elderly. In conclusion, this is the first epidemiological investigation showing evidence that PPI use might have an impact on dementia risk. Our findings suggest PPI intake to be of harm for elderly patients by increasing the risk of dementia. Avoidance of PPI use in the elderly could be a substantial element of dementia prevention. Acknowledgments This study is part of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD) and was funded by the German Federal Ministry of Education and Research (Grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; Grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716). Conflict of interest The authors declare that they have no conflicts of interest.
Appendix: Members of the AgeCoDe Study Group Principal Investigators*: Wolfgang Maier and Martin Scherer Heinz-Harald Abholz, Christian Brettschneider, Cadja Bachmann, Horst Bickel, Wolfgang Blank, Hendrik van den Bussche, Sandra Eifflaender-Gorfer, Marion Eisele, Annette Ernst, Angela Fuchs, Kathrin Heser, Frank Jessen, Hanna Kaduszkiewicz, Teresa Kaufeler, Mirjam Ko¨hler, Hans-Helmut Ko¨nig, Alexander Koppara, Carolin Lange, Tobias Luck, Melanie Luppa, Manfred Mayer, Edelgard Mo¨sch, Julia Olbrich, Michael Pentzek, Jana Prokein, Anna Schumacher, Steffi Riedel-Heller, Janine Stein, Susanne Steinmann, Franziska Tebarth, Michael Wagner, Klaus Weckbecker, Dagmar Weeg, Jochen Werle, Siegfried Weyerer, Birgitt Wiese, Steffen Wolfsgruber, Thomas Zimmermann. *Hendrik van den Bussche (2002–2011) We want to thank both all participating patients and their general practitioners for their good collaboration.
GPs participating at the time of Follow-up V Bonn Claudia Adrian, Hanna Liese, Inge Bu¨rfent, Johann von Aswege, Wolf-Dietrich Honig, Peter Gu¨lle, Heribert Schu¨tzendorf, Elisabeth Benz, Annemarie Straimer, Arndt Uhlenbrock, Klaus-Michael Werner, Maria Go¨bel-Schlatholt, Hans-Ju¨rgen Kaschell, Klaus Weckbecker, Theodor Alfen, Markus Stahlschmidt, Klaus Fischer, Wolf-Ru¨diger Weisbach, Martin Tschoke, Ju¨rgen Dorn, Helmut Menke, Erik Sievert, Ulrich Kro¨ckert, Gabriele Salingre´, Christian Mo¨rchen, Peter Raab, Angela Baszenski, Cla¨rli Loth, Christian Knaak, Peter Ho¨tte, Jo¨rg Pieper, Dirk Wassermann, Hans Josef Leyendecker, Gerhard Gohde, Barbara Simons, Achim Bru¨nger, Uwe Petersen, Heike Wahl, Rainer Tewes, Doris Junghans-Kullmann, Angela GrimmKraft, Harald Bohnau, Ursula Pinsdorf, Thomas Busch, Gisela Keller, Susanne Fuchs-Ro¨mer, Wolfgang Beisel. Du¨sseldorf Birgitt Richter-Polynice, Florinela Cupsa, Roland Matthias Unkelbach, Gerhard Schiller, Barbara Damanakis, Michael Frenkel, Klaus-Wolfgang Ebeling, Pauline Berger, Kurt Gillhausen, Uwe Hellmessen, Helga Hu¨mmerich, Hans-Christian Heede, Boguslaw- Marian Kormann, Wolfgang Josef Peters, Ulrich Schott, Dirk Matzies, Andre Schumacher, Tim Oliver Flettner, Winfried Thraen, Harald Siegmund, Claus Levacher, Tim Blankenstein, Eliane Lamborelle, Ralf Hollstein, Edna Hoffmann, Ingeborg Ghane, Regine Claß, Stefan-Wolfgang Meier, Leo W. Moers, Udo Wundram, Klaus Schmitt, Rastin Missghian, Karin Spallek, Christiane Schlo¨sser. Hamburg Kathrin Groß, Winfried Bouche´, Ursula Linn, Gundula Bormann, Gerhard Schulze, Klaus Stelter, Heike Gatermann, Doris Fischer-Radizi, Otto-Peter Witt, Stefanie Kavka, Gu¨nther Klo¨tzl, Karl-Christian Mu¨nter, Michael Baumho¨fener, Maren Oberla¨nder, Cornelia Schiewe, Jo¨rg Hufnagel, Anne-Marei Kressel, Michael Kebschull, Christine Wagner, Fridolin Burkhardt, Martina Hase, Matthias Bu¨ttner, Karl-Heinz Houcken, Christiane Zebidi, Johann Bro¨han, Christiane Russ, Frank Bethge, Gisela Rughase-Block, Margret Lorenzen, Arne Elsen, Lerke Stiller, Angelika Giovanopoulos, Daniela Korte, Ursula Jedicke, Rosemarie Mu¨llerMette, Andrea Richter, Sanna Rauhala-Parrey, Constantin Zoras, Gabriele Pfeil-Woltmann, Annett Kno¨ppel-Frenz, Martin Kaiser, Johannes Bruns, Joachim Homann, Georg Gorgon, Niklas Middendorf, Kay Menschke, Hans Heiner Sto¨ver, Hans H. Bayer, Ru¨diger Quandt, Gisela RughaseBlock, Hans-Michael Ko¨llner, Enno Strohbehn, ThomasHaller, Nadine Jesse, Martin Domsch, Marcus Dahlke. Leipzig Thomas Lipp, Ina Lipp, Martina Amm, Horst Bauer, Gabriele Rauchmaul, Hans Jochen Ebert, Angelika Gabriel-Mu¨ller, Hans-Christian Taut, Hella Voß, Ute Mu¨hlmann, Holger Schmidt, Gabi Mu¨ller, Eva Hager,
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Bettina Tunze, Barbara Bra¨utigam, Thomas Paschke, Heinz-Michael Assmann, Ina Schmalbruch, Gunter Ka¨ssner, Iris Pfo¨rtzsch, Brigitte Ernst-Brennecke, Uwe Rahnefeld, Petra Striegler, Marga Gierth, Anselm Kru¨gel, Margret Boehm, Dagmar Harnisch, Simone KornischKoch, Birgit Ho¨ne, Lutz Scho¨nherr, Frank Hambsch, Katrin Meitsch, Britta Kra¨gelin-Nobahar, Cornelia Herzig, Astrid Georgi, Erhard Schwarzmann, Gerd Schinagl, Ulrike Pehnke, Mohammed Dayab, Sabine Mu¨ller, Jo¨rgFriedrich Onnasch, Michael Brosig, Dorothea Frydetzki, Uwe Abschke, Volkmar Sperling, Ulrich Gla¨ser, Frank Lebuser, Detlef Hagert. Mannheim Gerhard Arnold, Viet-Harold Bauer, Hartwig Becker, Hermine Becker, Werner Besier, Hanna Bo¨ttcherSchmidt, Susanne Fu¨llgraf-Horst, Eniko¨ Go¨ry, Hartmut Grella, Hans Heinrich Grimm, Petra Heck, Werner Hemler, Eric Henn, Violetta Lo¨b, Grid Maaßen-Kalweit, Manfred Mayer, Hubertus Mu¨hlig, Arndt Mu¨ller, Gerhard Orlovius, Helmut Perleberg, Brigitte Radon, Helmut Renz, Carsten Rieder, Michael Rosen, Georg Scheer, Michael Schilp, Angela Schmid, Matthias Schneider, Christian Schneider, Ru¨diger Stahl, Christian Uhle, Ju¨rgen Wachter, Necla Weihs, Brigitte Weinga¨rtner, Monika Werner, Hans- Georg Willhauck, Eberhard Wochele, Bernhard Wolfram. Munich Andreas Hofmann, Eugen Allwein, Helmut Ruile, Andreas Koeppel, Peter Dick, Karl-Friedrich Holtz, Gabriel Schmidt, Lutz-Ingo Fischer, Johann Thaller, Guntram Bloß, Franz Kreuzer, Gu¨nther Holthausen, Karl Ludwig Maier, Walter Krebs, Christoph Mohr, Heinz Koschine, Richard Ellersdorfer, Michael Speth, Maria Kleinhans, Panagiota Koutsouva-Sack, Gabriele Staudinger, Johann Eiber, Stephan Thiel, Cornelia Gold, Andrea Nalbach, Kai Reichert, Markus Ru¨ckgauer, Martin Neef, Viktor Fleischmann, Natalija Mayer, Andreas Spiegl, Fritz Renner, Eva Weishappel-Ketisch, Thomas Kochems, Hartmut Hunger, Marianne Hofbeck, Alfred Neumeier, Elfriede Goldhofer, Thomas Bommer, Reinhold Vollmuth, Klaus Lanzinger, Simone Bustami-Lo¨ber, Ramona Pauli, Jutta Lindner, Gerlinde Brandt, Otto Hohentanner, Rosita Urban-Hu¨ttner, Peter Porz, Bernd Zimmerhackl, Barbara Naumann, Margarete Vach, Alexander Hallwachs, Claudia Haseke, Andreas Ploch, Paula Bu¨rkle-Grasse, Monika Swobodnik, Corina Tro¨ger, Detlev Jost, Roman Steinhuber, Renate Narr, Gabriele Nehmann-Ho¨rwick, Christiane Eder, Helmut Pillin, Frank Loth, Beate Ru¨cker, Nicola Fritz, Michael Rafferzeder, Dietmar Zirpel.
Heribert Schu¨tzendorf, Manfred Marx, Annemarie Straimer, Arndt Uhlenbrock, Klaus-Michael Werner, Maria Go¨bel-Schlatholt, Eberhard Prechtel, Hans-Ju¨rgen Kaschell, Klaus Weckbecker, Theodor Alfen, Jo¨rg EimersKleene, Klaus Fischer, Wolf- Ru¨diger Weisbach, Martin Tschoke. Du¨sseldorf Birgitt Richter-Polynice, Michael Fliedner, Binjamin Hodgson, Florinela Cupsa, Werner Hamkens, Roland Matthias Unkelbach, Gerhard Schiller, Barbara Damanakis, Angela Ackermann, Michael Frenkel, KlausWolfgang Ebeling, Bernhard Hoff, Michael Kirsch, Vladimir Miasnikov, Pauline Berger, Kurt Gillhausen, Uwe Hellmessen, Helga Hu¨mmerich, Hans-Christian Heede, Boguslaw-Marian Kormann, Dieter Lu¨ttringhaus, Wolfgang Josef Peters, Ulrich Schott, Dirk Matzies, Andre Schumacher, Tim Oliver Flettner, Winfried Thraen, Clemens Wirtz, Harald Siegmund. Hamburg Kathrin Groß, Bernd-Uwe Krug, Petra Hu¨tter, Dietrich Lau, Gundula Bormann, Ursula Schro¨der-Ho¨ch, Wolfgang Herzog, Klaus Weidner, Doris Fischer-Radizi, Otto-Peter Witt, Stefanie Kavka, Gu¨nther Klo¨tzl, Ljudmila Titova, Andrea Moritz. Leipzig Thomas Lipp, Ina Lipp, Martina Amm, Horst Bauer, Gabriele Rauchmaul, Hans Jochen Ebert, Angelika Gabriel-Mu¨ller, Hans-Christian Taut, Hella Voß, Ute Mu¨hlmann, Holger Schmidt, Gabi Mu¨ller, Eva Hager, Bettina Tunze, Barbara Bra¨utigam, Sabine Ziehbold, Thomas Paschke, Heinz-Michael Assmann, Ina Schmalbruch, Gunter Ka¨ssner. Mannheim Gerhard Arnold, Viet-Harold Bauer, Werner Besier, Hanna Bo¨ttcher-Schmidt, Hartmut Grella, Ingrid Ludwig, Manfred Mayer, Arndt Mu¨ller, Adolf Noky, Gerhard Orlovius, Helmut Perleberg, Carsten Rieder, Michael Rosen, Georg Scheer, Michael Schilp, Gerhard Kunzendorf, Matthias Schneider, Ju¨rgen Wachter, Brigitte Weinga¨rtner, Hans- Georg Willhauck. Munich Helga Herbst, Andreas Hofmann, Eugen Allwein, Helmut Ruile, Andreas Koeppel, Peter Friedrich, Hans-Georg Kirchner, Elke Kirchner, Luitpold Knauer, Peter Dick, Karl- Friedrich Holtz, Elmar Schmid, Gabriel Schmidt, Lutz-Ingo Fischer, Johann Thaller, Guntram Bloß, Franz Kreuzer, Ulf Kahmann, Gu¨nther Holthausen, Karl Ludwig Maier, Walter Krebs, Christoph Mohr, Heinz Koschine, Richard Ellersdorfer, Michael Speth.
GPs who participated at baseline
GPs who used to participate in the study
Bonn Heinz-Peter Romberg, Hanna Liese, Inge Bu¨rfent, Johann von Aswege, Wolf-Dietrich Honig, Peter Gu¨lle,
Bonn Heinz-Peter Romberg, Eberhard Prechtel, Manfred Marx, Jo¨rg Eimers-Kleene, Paul Reich, Eberhard Stahl,
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Reinhold Lunow, Klaus Undritz, Bernd Voss, Achim Spreer, Oliver Brenig, Bernhard G. Mu¨ller, Ralf Eich, Angelika Vossel, Dieter Leggewie, Angelika Schmidt, Nahid Aghdai-Heuser, Lutz Witten, Michael Igel. Du¨sseldorf Michael Fliedner, Benjamin Hodgson, Werner Hamkens, Angela Ackermann, Bernhard Hoff, Michael Kirsch, Vladimir Miasnikov, Dieter Lu¨ttringhaus, Clemens Wirtz, Rolf Opitz, Ju¨rgen Bausch, Dirk Mecking, Friederike Ganßauge, Elmar Peters, Alfons Wester. Hamburg Werner Petersen, Martin Daase, Martin Ru¨sing, Christoph von Sethe, Wilmhard Borngra¨ber, Brigitte Colling-Pook, Ullrich Weidner, Peter Rieger, Lutz Witte, Hans-Wilhelm Busch, Ju¨rgen Unger, Angela Preis, Michael Mann, Ernst Haeberle, Horst Ko¨hler, Ruth Scha¨fer, Helmut Sliwiok, Volker L. Bru¨hl, Hans Heiner Sto¨ver, Harald Deest, Margret Ackermann-Ko¨rner, Dieter Reinstorff, Christamaria Schlu¨ter, Henrik Heinrichs, Ole Dankwarth, Michael Bo¨se, Ulricke Ryll, Reinhard Bauer, Dieter Mo¨ltgen, Sven Schnakenbeck, Karin Beckmann, Annegret Callsen, Ewa Schiewe, Holger Gehm, Volker Lambert, Karin Hinkel-Reineke, Carl-Otto Stolzenbach, Peter Berdin, Friedhelm Windler. Leipzig Sabine Ziehbold, Sabine Weidnitzer, Erika Rosenkranz, Norbert Letzien, Doris Klossek, Martin Liebsch, Andrea Zwicker, Ulrike Hantel, Monika Pilz, Volker Kirschner, Rainer Arnold, Ulrich Poser. Mannheim Wolfgang Barthel, Fritz Blechinger, Marcus Fa¨hnle, Reiner Walter Fritz, Susanne Ju¨nemann, Gabriele Kirsch, Ju¨rgen Kulinna, Gerhard Kunzendorf, Andreas LegnerGo¨rke, Christa Lehr, Wolfgang Meer, Adolf Noky, Christina Panzer, Achim Raabe, Helga Schmidt- Back, Ralf Schu¨rmann, Hans-Gu¨nter Stieglitz, Marie-Luise von der Heide. Munich Helga Herbst, Peter Friedrich, Hans-Georg Kirchner, Elke Kirchner, Luitpold Knauer, Elmar Schmid, Ulf Kahmann, Jo¨rg Kastner, Ulrike Janssen, Albert Standl, Clemens Go¨ttl, Marianne Franze, Gerhard Moser, Almut Blu¨mm, Petra Weber, Wolfgang Poetsch, Heinrich Puppe, Thomas Bommer, Gerd Specht, Leonard Badmann, May Leveringhaus, Michael Posern, Andreas Ploch, Ralph Potkowski, Christiane Eder, Michael Schwandner, Rudolf Weigert, Christoph Huber.
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ORIGINAL PAPER
Risk of dementia in elderly patients with the use of proton pump inhibitors Britta Haenisch • Klaus von Holt • Birgitt Wiese • Jana Prokein • Carolin Lange • Annette Ernst • Christian Brettschneider • Hans-Helmut Ko¨nig • Jochen Werle • Siegfried Weyerer • Melanie Luppa Steffi G. Riedel-Heller • Angela Fuchs • Michael Pentzek • Dagmar Weeg • Horst Bickel • Karl Broich • Frank Jessen • Wolfgang Maier • Martin Scherer
•
Received: 19 May 2014 / Accepted: 11 October 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Drugs that modify the risk of dementia in the elderly are of potential interest for dementia prevention. Proton pump inhibitors (PPIs) are widely used to reduce gastric acid production, but information on the risk of dementia is lacking. We assessed association between the use of PPIs and the risk of dementia in elderly people. Data were derived from a longitudinal, multicenter cohort study in elderly primary care patients, the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe), including 3,327 community-dwelling persons aged C75 years. From follow-up 1 to follow-up 4 (follow-
For the AgeCoDe study group. B. Haenisch (&) K. von Holt F. Jessen W. Maier German Center for Neurodegenerative Diseases (DZNE), c/o Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany e-mail: [email protected] B. Haenisch K. Broich Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany B. Haenisch F. Jessen W. Maier Department of Psychiatry, University of Bonn, Bonn, Germany B. Wiese J. Prokein Institute for General Practice, Hannover Medical School, Hannover, Germany
up interval 18 months), we identified a total of 431 patients with incident any dementia, including 260 patients with Alzheimer’s disease. We used time-dependent Cox regression to estimate hazard ratios of incident any dementia and Alzheimer’s disease. Potential confounders included in the analysis comprised age, sex, education, the Apolipoprotein E4 (ApoE4) allele status, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease, and stroke. Patients receiving PPI medication had a significantly increased risk of any dementia [Hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04–1.83] and Alzheimer’s disease (HR 1.44, 95 % CI 1.01–2.06) compared with nonusers. Due to the major burden of dementia on public health and the lack of curative medication, this J. Werle S. Weyerer Central Institute of Mental Health, Medical Faculty Mannheim/ Heidelberg University, Mannheim, Germany M. Luppa S. G. Riedel-Heller Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany A. Fuchs M. Pentzek Institute of General Practice (IFAM), Medical Faculty of the Heinrich-Heine-University Du¨sseldorf, Du¨sseldorf, Germany D. Weeg H. Bickel Department of Psychiatry, Technical University of Munich, Munich, Germany
C. Lange A. Ernst M. Scherer Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany C. Brettschneider H.-H. Ko¨nig Department of Health Economics and Health Services Research, Hamburg Center for Health Economics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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finding is of high interest to research on dementia and provides indication for dementia prevention. Keywords Dementia Proton pump inhibitors Risk factor Elderly Prevention
Introduction Dementia is a progressive disorder characterized by deterioration in cognitive ability and capacity for independent living. It has a substantial and rising burden on patients, their families, and the healthcare system. Analyses of data from the German sick funds showed that the prevalence for dementia is about 1 % at the age of 65 and increases with age [1]. At the age of 90, about one-third of the population is affected [1]. The global prevalence of dementia will increase from about 35 million today to over 80 million patients worldwide by 2040 [2, 3]. The high demand on therapies and care because of cumulative cognitive decline combined with increasing numbers of patients has a remarkable socioeconomic impact. The estimated worldwide costs of dementia were US$604 billion in the year 2010 [4]. An effective procedure to obviate the burden dementia is expected to have on people and healthcare systems worldwide is dementia prevention in people at increased risk, i.e., in the elderly population. Therefore, often used drugs that potentially increase or decrease the risk of dementia in elderly people are highly interesting substances to examine in epidemiological studies the consequence of their long-term use on incidence of dementia. In the present study, we focus on the drug class of proton pump inhibitors (PPIs). PPIs are used for the treatment of gastrointestinal diseases where inhibition of gastric secretion is desired [5]. Gastroesophageal reflux disease causes distressing symptoms and is a risk factor for Barrett’s esophagus which can lead to esophageal adenocarcinoma [6]. PPI medication is also used in the management of gastric ulcers [7]. The use of PPIs has strongly increased during the last years, especially in the elderly [8, 9]. In Germany, the prescription rate of PPIs raised fourfold within the last 10 years [10]; in 2012, 2,885 million defined daily doses were prescribed [table 32.1 in 10]. Observational studies in the elderly population detected inappropriate use of PPIs without adequate documentation for a gastrointestinal diagnosis to be a common phenomenon [11, 12]. About 40–60 % of all PPI prescriptions were detected as inappropriate [11, 12]. These studies did not include analyses on the doses prescribed. There are hints that PPI use might influence cognition [13–15]. In a recent study, Lam et al. show a significant association of previous and current PPI use with the presence of vitamin B12 deficiency in a
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population-based sample [11]. Vitamin B12 deficiency has been described to be associated with cognitive decline [16]. Furthermore, PPIs were shown to potentially enhance amyloid beta peptide (Ab) levels in brain by directly affecting the enzymes b- and c-secretase which leads to increased Ab levels in mice [15] and by the modulation of degradation of Ab by lysosomes in microglia [17–20]. In the present study, we intend to examine whether there is a correlation between PPI use and developing dementia in the elderly population. The hypothesis is that the use of PPIs in elderly patients will be associated with an increased risk of dementia. We calculated a time-dependent Cox regression model with potential confounders as covariates, including age, sex, education, polypharmacy, and the comorbidities depression, diabetes, ischemic heart disease and stroke, and the Apolipoprotein E4 (ApoE4) allele status. The APOE locus in the human genome has frequently been shown to be the major susceptibility gene for Alzheimer’s disease (for review see 21). One APOE-e4 allele is associated with a twofold to threefold increased risk, two copies associated with a fivefold or more increase [21].
Methods Study design and procedures Data were derived from the German Study on Aging, Cognition and Dementia in Primary Care Patients (AgeCoDe) of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD). AgeCoDe is a longitudinal multicenter study in elderly primary care patients [22]. The study recruited subjects at six study sites in Germany (Bonn, Du¨sseldorf, Hamburg, Leipzig, Mannheim and Munich) by using general practitioners’ (GP) medical record registries [23]. Inclusion criteria comprised an age of 75 years or older, the absence of dementia at recruitment, and regular contact with the GP (at least once every 12 months). The lower age cutoff was part of the study design to select a high age-group of individuals. Subjects were excluded if they were consulted from the GP by home visits only or were a resident of a nursing home. While data were collected on several important risk factors, there are other factors that may contribute to the development of dementia that could not be considered in the course of the study. All subjects included in the study gave informed consent. The study protocol was approved by ethics committees at all sites. Collection of data started in 2003. Individuals were recruited by the GPs at the six sites. The GPs identified 22,701 patients aged 75 years or older [24]. Of those, 10,850 patients were eligible, meeting the
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inclusion criteria [24]. Among a randomly selected sample of 6,619 patients, 3,292 were not investigated because contact failed or they refused to participate [24]. At baseline, 3,327 participants were included in the study. A detailed description of the sampling and sample attrition is given elsewhere [24]. Baseline and subsequent follow-up assessments (18 months interval) including follow-up 1 to follow-up 4 are the timeframe for analysis of the present study. Data collection was performed by trained physicians and psychologists at the subjects’ home. Neuropsychological assessments included the Structured Interview for Diagnosis of Dementia of Alzheimer type, Multi-infarct Dementia and Dementia of other Aetiology according to DSM-IV and ICD-10 (SIDAM) [25]. The SIDAM contains a neuropsychological test battery [SIDAM cognitive (SISCO) score with 55 items, including the 30-item MiniMental State Examination (MMSE)], the assessment of activities of daily living (SIDAM ADL Scale), and the Hachinski–Rosen Scale. For participants who were unavailable for some reasons, information about his/her cognitive status was completed by interviewing an informant (e.g., a relative) using the structured Global Deterioration Scale [26] and the subscales ‘Changes in Performance of Everyday Activities’ and ‘Changes in Habits’ subscales from the Blessed Dementia Scale [27]. The Apolipoprotein E4 (ApoE4) genotype status was examined in the majority of the participants as described elsewhere [28]. Recording of medication was assessed within the interview using the name of the drug product or the unequivocal drug package code. This information was then used to identify the active substances and translate this into the Anatomical Therapeutic Chemical (ATC) code for further consideration. From baseline to follow-up 2, the presence or absence of a specific unequivocal drug package code and ATC code in the interview documentation was the only information to document medication use. From follow-up 3 onwards, additional questions focused on the drug use pattern by discriminating between ‘‘regular use’’ and ‘‘use if needed.’’ In addition, from follow-up 3 onwards, the frequency of drug use and pharmaceutical form is given. Dementia status was defined as described earlier [22]. In brief, dementia was diagnosed in consensus with the interviewer and an experienced geriatrician or geriatric psychiatrist according to DSM-IV criteria. This comprises a diagnostic algorithm in the SIDAM, comprising cognitive impairment defined by the SISCO and impairment of activities of daily living (C2 scores on the SIDAM ADL scale). For patients not interviewed personally, a score of C4 on the Global Deterioration Scale was used as criteria for dementia diagnosis. The diagnosis of Alzheimer’s disease was guided by the National Institute of Neurological
and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association criteria for probable Alzheimer’s disease [29]. Vascular dementia diagnosis was established according to the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche´ et l‘Enseignement en Neurosciences criteria [30] (i.e., the evidence of a cerebrovascular event and temporal association with cognitive decline). Mixed dementia was diagnosed in the absence of temporal association of the cerebrovascular event with cognitive decline. For analyses, subjects with mixed dementia and Alzheimer’s disease were combined because we lack imaging data for the patients and thus, cannot rule out vascular lesions. The group other dementia included patients with a dementia syndrome related to a specific reason, such as head trauma, normal pressure hydrocephalus, brain tumor as well as unspecified dementia cases, i.e., those cases in which an etiology could not be defined with sufficient certainty based on the available data. Statistical analyses We examined the effect on incident dementia by use of the PPIs omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole, and dexlansoprazole (ATC code A02BC01-06) versus no use of these drugs. We used timedependent Cox regression to evaluate the association between use of the compounds in question and the risk of incident dementia (any dementia and dementia in the course of Alzheimer’s disease, respectively). Time-dependent Cox regression allows the status levels of the covariates to vary over time. The dependent variable was the occurrence of incident dementia. To address potential bias, we selected a priori a number of potential confounders that were plausible factors to modify the risk of incident dementia and for which information was available. We adjusted the Cox regression model for the following potential confounding factors which were incorporated as covariates: age, sex, education as defined by the CASMIN classification [31], the ApoE4 allele status, polypharmacy, and comorbidities: the presence of depression [32], as defined by the geriatric depression scale C6, as well as diabetes, ischemic heart disease, and stroke, all as diagnosed by GPs or specialists. The ApoE4 allele status was categorized in two classes, with and without the presence of the ApoE4 allele. We specified anticholinergic drug use as use of any anticholinergic drug according to the updated anticholinergic drug scale list (33 and personal communication; level 2 and 3). Polypharmacy was defined as taking five or more drugs, based on a definition commonly used in other studies [34, 35]. Exposure to PPIs and the presence of polypharmacy as well as the presence of comorbidities was modeled as a segmented time-dependent covariate to allow
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for status levels varying over time, i.e., from one follow-up to another. This means that the PPI user status was set for each follow-up interval separately, excluding PPI use after incident dementia. The drug use evaluated in the baseline interview and in each of the follow-up investigations was taken as the relevant exposure level during the subsequent period until the next follow-up. When, in a specific followup, information on medication was missing, the value of the preceding follow-up was taken, if that information was valid. This observation was taken as last observation carried forward. For visualization, we simplified the model and used Cox regression without time-dependent covariates: We defined the time from baseline to follow-up 2 as observation period for PPI use and evaluated for each individual if there was PPI use at any of the three different time points measured during this period (baseline, follow-up 1, follow-up 2). This value was used to calculate Cox regression for incident any dementia from follow-up 3 onwards as status variable (no confounders included). The resulting survival curves (Kaplan–Meier curves) are presented. All calculations were done using the SPSS statistical package (SPSS 21). We considered p \ 0.05 to be statistical significant.
Results Of the 3,327 subjects of the AgeCoDe study participated at baseline, 251 subjects were excluded after quality control filtering (70 because of dementia at baseline, one because of missing value on dementia at baseline, 39 because of an age \75 years, 16 because of missing value dementia status at follow-up periods, 121 because of missing value on the ApoE4 status, and four because of missing or unknown medication information). Thus, 3,076 subjects were included in the following analysis. We detected 713 patients who received a PPI during the study period, i.e., at least one PPI drug at least at one assessment independent of dementia status (baseline to follow-up 4; Fig. 1). Sample characteristics of PPI users and nonusers are given in Table 1. In the AgeCoDe study, we have specification on regular drug use and drug use if required from follow-up 3 onwards. We observed regular drug use for 90.4 and 91.0 % of the PPI users in follow-up 3 and follow-up 4, respectively. The use of PPIs was associated with a significant increased risk of dementia [hazard ratio (HR) 1.38, 95 % confidence interval (CI) 1.04–1.83; p = 0.02; Table 2]. Of the other factors, age, the presence of an ApoE4 allele, depression, diabetes, and stroke showed a significant increase in risk of incident dementia. For gender, education, polypharmacy, and ischemic heart disease, we did not detect significant effects on the risk of dementia (Table 2).
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Participants at baseline n= 3,327 Exclusion (n= 251)
Participants included for pharmacoepidemiological analysis incident any dementia n= 3,076
Dementia at baseline 70 Missing value on dementia at baseline 1 Age < 75 years 39 Missing value dementia status at follow-up periods 16 Missing value ApoE4 status 121 Missing value medication 4 Exclusion (n= 165)
Participants included for pharmacoepidemiological analysis incident Alzheimer dementia
Vascular Dementia Dementia, other
76 89
n= 2,911
Fig. 1 Sample for analysis
The inclusion of another specific drug class that can impact cognitive performance, into the model, namely anticholinergic drugs, resulted in comparable outcomes for PPI use (HR: 1.36, 95 % CI 1.03–1.81; p = 0.03) and for the other covariates (data not shown). As expected, anticholinergic drug use itself was a risk factor for incident dementia (HR 1.65, 95 % CI 1.23–2.21; p = 0.001). When the confounders were not included in the analysis, a similar result for the association between PPI use and incident any dementia was obtained (HR 1.44, 95 % CI 1.10–1.90, p = 0.008; Table 2). In a subgroup analysis, we explored the effect of PPI use on incident dementia in the course of Alzheimer’s disease (including mixed dementia, see methods). We obtained similar results as for incident any dementia. PPI use elevated the risk of Alzheimer’s disease (HR 1.44, 95 % CI 1.01–2.06; p = 0.04; Table 2). The increase in risk of Alzheimer’s disease by the presence of an ApoE4 allele was slightly higher compared with the HR for incident any dementia while diabetes and stroke did not show an elevated risk of Alzheimer’s disease. Exclusion of confounders did not clearly impact the effect of PPI use on Alzheimer’s disease (HR 1.45, 95 % CI 1.03–2.05; p = 0.03; Table 2). The association of PPI use and incident any dementia as well as Alzheimer’s disease was confirmed in the simplified Cox regression model without time-dependent covariates (HR 1.57, 95 % CI 1.14–2.15, p = 0.006 for incident any dementia, and HR 1.51, 95 % CI 1.03–2.21, p = 0.04 for Alzheimer’s disease; Table 3). Figure 2 shows the resulting Kaplan–Meier curves for incident any dementia.
Discussion The aim of the study was to examine the effect of PPIs on the risk of dementia in elderly patients. In the AgeCoDe
Eur Arch Psychiatry Clin Neurosci Table 1 Sample characteristics of PPI users and nonusers for Cox regression with time-dependent covariates (baseline–follow-up 4) Analysis any dementiaa No use PPI usec Aged Sexe
p valueb Use
2,363 (76.8 %) 79.7 (3.6)
Analysis Alzheimer’s diseasea No use
713 (23.2 %)
Use
2,238 (76.9 %)
79.6 (3.4)
0.51
490 (68.7 %)
0.02
1,440 (64.3 %)
0.89
1,512 (64.0 %)
p valueb
79.6 (3.6)
673 (23.1 %) 79.6 (3.4)
1.00
465 (69.1 %)
0.02
1,385 (61.9 %)
414 (61.5 %)
0.99
609 (27.2 %)
185 (27.5 %)
Education Low
1,467 (62.1 %)
436 (61.2 %)
Middle
642 (27.2 %)
197 (27.6 %)
High
254 (10.7 %)
80 (11.2 %)
244 (10.9 %)
74 (11.0 %)
ApoE4
511 (21.6 %)
129 (18.1 %)
0.04
473 (21.1 %)
125 (18.6 %)
0.15
Depressionf
482 (20.4 %)
204 (28.6 %)
\0.001
434 (19.4 %)
191 (28.4 %)
\0.001
Diabetes
795 (33.6 %)
281 (39.4 %)
0.005
750 (33.5 %)
262 (38.9 %)
0.01
Stroke
268 (11.3 %)
99 (13.9 %)
0.07
225 (10.1 %)
82 (12.2 %)
0.12
Ischemic heart disease
1,204 (51.0 %)
419 (58.8 %)
\0.001
1,126 (50.3 %)
394 (58.5 %)
\0.001
Polypharmacyg
1,634 (69.1 %)
659 (92.4 %)
\0.001
1,538 (68.7 %)
621 (92.3 %)
\0.001
509 (21.5 %)
139 (19.5 %)
0.24
460 (20.6 %)
118 (17.5 %)
0.09
Mortalityh a
Sample characteristics include demented and non-demented patients
b
Results of t test or Chi-square-test for group comparisons
c
PPI use at least at one study period assessment
d
In years (SD)
e
Female
f
Defined by Geriatric Depression Scale (GDS) score of C6
g
Defined as C5 drugs
h
Follow-up 1–follow-up 4
Table 2 Risk of incident any dementia and Alzheimer’s disease by PPI use Variable
Any dementia Hazard ratio (95 % CI)
Alzheimer’s disease p value
Hazard ratio (95 % CI)
p value
PPI usea,b
1.38 (1.04–1.83)
0.02
1.44 (1.01–2.06)
0.04
Agec
1.12 (1.10–1.15)
\0.001
1.15 (1.11–1.19)
\0.001
Sexd
1.00 (0.81–1.24)
1.00
0.77 (0.57–1.03)
0.08
Education Low
Reference
Middle
0.80 (0.64–1.00)
0.05
0.72 (0.53–0.97)
High
0.78 (0.55–1.10)
0.15
0.81 (0.52–1.28)
0.37
ApoE4
1.87 (1.52–2.31)
\0.001
2.25 (1.73–2.93)
\0.001
Depressione
2.28 (1.80–2.88)
\0.001
2.05 (1.50–2.81)
\0.001
Diabetes
1.30 (1.05–1.62)
0.02
1.21 (0.91–1.60)
0.20
Stroke
1.92 (1.38–2.67)
\0.001
0.99 (0.56–1.75)
0.98
Ischemic heart disease
1.10 (0.90–1.35)
0.35
1.06 (0.81–1.38)
0.66
Polypharmacyf
1.14 (0.92–1.42)
0.22
1.08 (0.82–1.42)
0.59
PPI usea,g
1.44 (1.10–1.90)
0.008
1.45 (1.03–2.05)
0.03
a
Reference 0.03
Use of PPI before the diagnosis of dementia
b
Calculation with potential confounding factors
c
In years
d
Female (reference)
e
Defined by Geriatric Depression Scale (GDS) score of C6
f
Defined as C5 drugs
g
Calculation without potential confounding factors
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Eur Arch Psychiatry Clin Neurosci Table 3 PPI users and nonusers for Cox regression without timedependent covariates Analysis any dementia
Analysis Alzheimer’s disease
Number of patients
Demented
Nondemented
Demented
Nondemented
PPI use
50
371
34
371
No PPI use
165
2,147
117
2,147
Hazard ratio (95 % CI); p value
1.57 (1.14–2.15); 0.006
1.51 (1.03–2.21); 0.04
PPI use: baseline–follow-up 2; observation period incident dementia: follow-up 3–follow-up 4
Fig. 2 Dementia-free survival by the use of PPIs. Baseline by followup 2 was defined as observation period for PPI use, and incident any dementia (follow-up 3 onwards) was set as outcome. The curves are not adjusted for confounders
sample, we detected that among primary care patients aged 75 years and older the use of PPIs was associated with a significant increase in the risk of incident dementia. Subanalyses of all dementia cases and dementia cases in the course of Alzheimer’s disease showed similar results. To our knowledge, this is the first epidemiological investigation showing that PPIs might have an impact on dementia risk. Although the use of PPIs is generally thought to cause few side effects, previous epidemiological studies have reported adverse effects of chronic PPI intake, including an increased risk of hip fracture and community acquired pneumonia [36, 37]. Our result of a significant enhanced risk of dementia by use of PPIs is in line with a study of Lam et al. [14] who recently describe a significant
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association of previous and current PPI use with the presence of vitamin B12 deficiency (odds ratio 1.65, 95 % CI 1.58–1.73) in a population-based setting. Poor vitamin B12 status has been linked to cognitive decline and neurological damage, probably due to impaired DNA synthesis, methylation, and homocysteine neurotoxicity [38, 39]. Lam et al. [14] mention that the association between PPI use and the presence of vitamin B12 deficiency decreased with age. However, it is known that vitamin B12 deficiency often remains undetected in the elderly population [40, 41]. Another aspect how PPI use may influence cognition is by directly interacting with brain enzymes. Interestingly, in a recent study by Badiola et al. [15], PPIs like lansoprazole were shown to augment amyloid beta peptide (Ab) levels in an amyloid cell model and in mouse brain. The authors suggest that PPIs might act as inverse c-secretase modulators and by increasing the activity of the b-secretase BACE1 and, thus, cause an accumulation of Ab [15]. Ab peptides are one of the major pathological signs of dementia in the course of Alzheimer’s disease and are cytotoxic to endothelial cells as well [42]. A further functional aspect of enrichment of Ab levels by PPIs might involve the modulation of degradation of Ab by lysosomes in microglia [17]. Clearance of fibrillar Ab by microglia is pH-dependent and induced by acidification of lysosomes. This acidification was reported to be mediated by the V-ATPase proton pump [18]. PPIs exhibit inhibitory properties at V-ATPases [19] which may contribute to inhibition of acidification, reduced Ab degradation, and thus, enhanced Ab levels [20]. The clinical impact of our finding is supported by studies that report PPIs (e.g., lansoprazole, omeprazole) to cross the blood brain barrier [43, 44]. Therefore, this class of drugs is able to exert effects in the brain. Of the covariates included in the study, the known risk factors depression, the ApoE4 allele status, stroke, and age were found to significantly elevate the risk of any dementia and/or Alzheimer’s disease. Depression (HR 2.28, 95 % CI 1.80–2.88; p \ 0.001) and ApoE4 (HR 2.25, 95 % CI 1.73–2.93; p \ 0.001) had the highest hazard ratios of the covariates in the model for the development of any dementia and Alzheimer’s disease, respectively. An important strength of the study is that the results are based on the detailed and rigorous data from a prospective cohort study (AgeCoDe). Furthermore, our study covered a 6-year period of longitudinal data. A particular strength of the AgeCoDe study is the comprehensive documentation of cognitive performance, medical history and medication. Furthermore, we were able to adjust for a wide range of possible confounders, including genetic data, polypharmacy, and comorbidities with possible impact on the outcome.
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The present study has limitations. Specific information on the drug use pattern (regularly or if required) in the AgeCoDe study is available only from follow-up 3 onwards. We detected a constant regular PPI use of over 90 % of PPI users in follow-up 3 and 4. We cannot rule out differences in baseline to follow-up 2, but it seems to be a constant high rate of regular PPI use pattern in the sample. Another fact is that we can only show the statistical association between PPI use and risk of dementia, as this is an epidemiological study. The underlying causal biological mechanisms are to be investigated in detail in further studies. Randomized, prospective trials are needed to establish direct cause and effect relationships between PPI use and incident dementia in the elderly. In conclusion, this is the first epidemiological investigation showing evidence that PPI use might have an impact on dementia risk. Our findings suggest PPI intake to be of harm for elderly patients by increasing the risk of dementia. Avoidance of PPI use in the elderly could be a substantial element of dementia prevention. Acknowledgments This study is part of the German Research Network on Dementia (KND) and the German Research Network on Degenerative Dementia (KNDD) and was funded by the German Federal Ministry of Education and Research (Grants KND: 01GI0102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 01GI0434; Grants KNDD: 01GI0710, 01GI0711, 01GI0712, 01GI0713, 01GI0714, 01GI0715, 01GI0716). Conflict of interest The authors declare that they have no conflicts of interest.
Appendix: Members of the AgeCoDe Study Group Principal Investigators*: Wolfgang Maier and Martin Scherer Heinz-Harald Abholz, Christian Brettschneider, Cadja Bachmann, Horst Bickel, Wolfgang Blank, Hendrik van den Bussche, Sandra Eifflaender-Gorfer, Marion Eisele, Annette Ernst, Angela Fuchs, Kathrin Heser, Frank Jessen, Hanna Kaduszkiewicz, Teresa Kaufeler, Mirjam Ko¨hler, Hans-Helmut Ko¨nig, Alexander Koppara, Carolin Lange, Tobias Luck, Melanie Luppa, Manfred Mayer, Edelgard Mo¨sch, Julia Olbrich, Michael Pentzek, Jana Prokein, Anna Schumacher, Steffi Riedel-Heller, Janine Stein, Susanne Steinmann, Franziska Tebarth, Michael Wagner, Klaus Weckbecker, Dagmar Weeg, Jochen Werle, Siegfried Weyerer, Birgitt Wiese, Steffen Wolfsgruber, Thomas Zimmermann. *Hendrik van den Bussche (2002–2011) We want to thank both all participating patients and their general practitioners for their good collaboration.
GPs participating at the time of Follow-up V Bonn Claudia Adrian, Hanna Liese, Inge Bu¨rfent, Johann von Aswege, Wolf-Dietrich Honig, Peter Gu¨lle, Heribert Schu¨tzendorf, Elisabeth Benz, Annemarie Straimer, Arndt Uhlenbrock, Klaus-Michael Werner, Maria Go¨bel-Schlatholt, Hans-Ju¨rgen Kaschell, Klaus Weckbecker, Theodor Alfen, Markus Stahlschmidt, Klaus Fischer, Wolf-Ru¨diger Weisbach, Martin Tschoke, Ju¨rgen Dorn, Helmut Menke, Erik Sievert, Ulrich Kro¨ckert, Gabriele Salingre´, Christian Mo¨rchen, Peter Raab, Angela Baszenski, Cla¨rli Loth, Christian Knaak, Peter Ho¨tte, Jo¨rg Pieper, Dirk Wassermann, Hans Josef Leyendecker, Gerhard Gohde, Barbara Simons, Achim Bru¨nger, Uwe Petersen, Heike Wahl, Rainer Tewes, Doris Junghans-Kullmann, Angela GrimmKraft, Harald Bohnau, Ursula Pinsdorf, Thomas Busch, Gisela Keller, Susanne Fuchs-Ro¨mer, Wolfgang Beisel. Du¨sseldorf Birgitt Richter-Polynice, Florinela Cupsa, Roland Matthias Unkelbach, Gerhard Schiller, Barbara Damanakis, Michael Frenkel, Klaus-Wolfgang Ebeling, Pauline Berger, Kurt Gillhausen, Uwe Hellmessen, Helga Hu¨mmerich, Hans-Christian Heede, Boguslaw- Marian Kormann, Wolfgang Josef Peters, Ulrich Schott, Dirk Matzies, Andre Schumacher, Tim Oliver Flettner, Winfried Thraen, Harald Siegmund, Claus Levacher, Tim Blankenstein, Eliane Lamborelle, Ralf Hollstein, Edna Hoffmann, Ingeborg Ghane, Regine Claß, Stefan-Wolfgang Meier, Leo W. Moers, Udo Wundram, Klaus Schmitt, Rastin Missghian, Karin Spallek, Christiane Schlo¨sser. Hamburg Kathrin Groß, Winfried Bouche´, Ursula Linn, Gundula Bormann, Gerhard Schulze, Klaus Stelter, Heike Gatermann, Doris Fischer-Radizi, Otto-Peter Witt, Stefanie Kavka, Gu¨nther Klo¨tzl, Karl-Christian Mu¨nter, Michael Baumho¨fener, Maren Oberla¨nder, Cornelia Schiewe, Jo¨rg Hufnagel, Anne-Marei Kressel, Michael Kebschull, Christine Wagner, Fridolin Burkhardt, Martina Hase, Matthias Bu¨ttner, Karl-Heinz Houcken, Christiane Zebidi, Johann Bro¨han, Christiane Russ, Frank Bethge, Gisela Rughase-Block, Margret Lorenzen, Arne Elsen, Lerke Stiller, Angelika Giovanopoulos, Daniela Korte, Ursula Jedicke, Rosemarie Mu¨llerMette, Andrea Richter, Sanna Rauhala-Parrey, Constantin Zoras, Gabriele Pfeil-Woltmann, Annett Kno¨ppel-Frenz, Martin Kaiser, Johannes Bruns, Joachim Homann, Georg Gorgon, Niklas Middendorf, Kay Menschke, Hans Heiner Sto¨ver, Hans H. Bayer, Ru¨diger Quandt, Gisela RughaseBlock, Hans-Michael Ko¨llner, Enno Strohbehn, ThomasHaller, Nadine Jesse, Martin Domsch, Marcus Dahlke. Leipzig Thomas Lipp, Ina Lipp, Martina Amm, Horst Bauer, Gabriele Rauchmaul, Hans Jochen Ebert, Angelika Gabriel-Mu¨ller, Hans-Christian Taut, Hella Voß, Ute Mu¨hlmann, Holger Schmidt, Gabi Mu¨ller, Eva Hager,
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Bettina Tunze, Barbara Bra¨utigam, Thomas Paschke, Heinz-Michael Assmann, Ina Schmalbruch, Gunter Ka¨ssner, Iris Pfo¨rtzsch, Brigitte Ernst-Brennecke, Uwe Rahnefeld, Petra Striegler, Marga Gierth, Anselm Kru¨gel, Margret Boehm, Dagmar Harnisch, Simone KornischKoch, Birgit Ho¨ne, Lutz Scho¨nherr, Frank Hambsch, Katrin Meitsch, Britta Kra¨gelin-Nobahar, Cornelia Herzig, Astrid Georgi, Erhard Schwarzmann, Gerd Schinagl, Ulrike Pehnke, Mohammed Dayab, Sabine Mu¨ller, Jo¨rgFriedrich Onnasch, Michael Brosig, Dorothea Frydetzki, Uwe Abschke, Volkmar Sperling, Ulrich Gla¨ser, Frank Lebuser, Detlef Hagert. Mannheim Gerhard Arnold, Viet-Harold Bauer, Hartwig Becker, Hermine Becker, Werner Besier, Hanna Bo¨ttcherSchmidt, Susanne Fu¨llgraf-Horst, Eniko¨ Go¨ry, Hartmut Grella, Hans Heinrich Grimm, Petra Heck, Werner Hemler, Eric Henn, Violetta Lo¨b, Grid Maaßen-Kalweit, Manfred Mayer, Hubertus Mu¨hlig, Arndt Mu¨ller, Gerhard Orlovius, Helmut Perleberg, Brigitte Radon, Helmut Renz, Carsten Rieder, Michael Rosen, Georg Scheer, Michael Schilp, Angela Schmid, Matthias Schneider, Christian Schneider, Ru¨diger Stahl, Christian Uhle, Ju¨rgen Wachter, Necla Weihs, Brigitte Weinga¨rtner, Monika Werner, Hans- Georg Willhauck, Eberhard Wochele, Bernhard Wolfram. Munich Andreas Hofmann, Eugen Allwein, Helmut Ruile, Andreas Koeppel, Peter Dick, Karl-Friedrich Holtz, Gabriel Schmidt, Lutz-Ingo Fischer, Johann Thaller, Guntram Bloß, Franz Kreuzer, Gu¨nther Holthausen, Karl Ludwig Maier, Walter Krebs, Christoph Mohr, Heinz Koschine, Richard Ellersdorfer, Michael Speth, Maria Kleinhans, Panagiota Koutsouva-Sack, Gabriele Staudinger, Johann Eiber, Stephan Thiel, Cornelia Gold, Andrea Nalbach, Kai Reichert, Markus Ru¨ckgauer, Martin Neef, Viktor Fleischmann, Natalija Mayer, Andreas Spiegl, Fritz Renner, Eva Weishappel-Ketisch, Thomas Kochems, Hartmut Hunger, Marianne Hofbeck, Alfred Neumeier, Elfriede Goldhofer, Thomas Bommer, Reinhold Vollmuth, Klaus Lanzinger, Simone Bustami-Lo¨ber, Ramona Pauli, Jutta Lindner, Gerlinde Brandt, Otto Hohentanner, Rosita Urban-Hu¨ttner, Peter Porz, Bernd Zimmerhackl, Barbara Naumann, Margarete Vach, Alexander Hallwachs, Claudia Haseke, Andreas Ploch, Paula Bu¨rkle-Grasse, Monika Swobodnik, Corina Tro¨ger, Detlev Jost, Roman Steinhuber, Renate Narr, Gabriele Nehmann-Ho¨rwick, Christiane Eder, Helmut Pillin, Frank Loth, Beate Ru¨cker, Nicola Fritz, Michael Rafferzeder, Dietmar Zirpel.
Heribert Schu¨tzendorf, Manfred Marx, Annemarie Straimer, Arndt Uhlenbrock, Klaus-Michael Werner, Maria Go¨bel-Schlatholt, Eberhard Prechtel, Hans-Ju¨rgen Kaschell, Klaus Weckbecker, Theodor Alfen, Jo¨rg EimersKleene, Klaus Fischer, Wolf- Ru¨diger Weisbach, Martin Tschoke. Du¨sseldorf Birgitt Richter-Polynice, Michael Fliedner, Binjamin Hodgson, Florinela Cupsa, Werner Hamkens, Roland Matthias Unkelbach, Gerhard Schiller, Barbara Damanakis, Angela Ackermann, Michael Frenkel, KlausWolfgang Ebeling, Bernhard Hoff, Michael Kirsch, Vladimir Miasnikov, Pauline Berger, Kurt Gillhausen, Uwe Hellmessen, Helga Hu¨mmerich, Hans-Christian Heede, Boguslaw-Marian Kormann, Dieter Lu¨ttringhaus, Wolfgang Josef Peters, Ulrich Schott, Dirk Matzies, Andre Schumacher, Tim Oliver Flettner, Winfried Thraen, Clemens Wirtz, Harald Siegmund. Hamburg Kathrin Groß, Bernd-Uwe Krug, Petra Hu¨tter, Dietrich Lau, Gundula Bormann, Ursula Schro¨der-Ho¨ch, Wolfgang Herzog, Klaus Weidner, Doris Fischer-Radizi, Otto-Peter Witt, Stefanie Kavka, Gu¨nther Klo¨tzl, Ljudmila Titova, Andrea Moritz. Leipzig Thomas Lipp, Ina Lipp, Martina Amm, Horst Bauer, Gabriele Rauchmaul, Hans Jochen Ebert, Angelika Gabriel-Mu¨ller, Hans-Christian Taut, Hella Voß, Ute Mu¨hlmann, Holger Schmidt, Gabi Mu¨ller, Eva Hager, Bettina Tunze, Barbara Bra¨utigam, Sabine Ziehbold, Thomas Paschke, Heinz-Michael Assmann, Ina Schmalbruch, Gunter Ka¨ssner. Mannheim Gerhard Arnold, Viet-Harold Bauer, Werner Besier, Hanna Bo¨ttcher-Schmidt, Hartmut Grella, Ingrid Ludwig, Manfred Mayer, Arndt Mu¨ller, Adolf Noky, Gerhard Orlovius, Helmut Perleberg, Carsten Rieder, Michael Rosen, Georg Scheer, Michael Schilp, Gerhard Kunzendorf, Matthias Schneider, Ju¨rgen Wachter, Brigitte Weinga¨rtner, Hans- Georg Willhauck. Munich Helga Herbst, Andreas Hofmann, Eugen Allwein, Helmut Ruile, Andreas Koeppel, Peter Friedrich, Hans-Georg Kirchner, Elke Kirchner, Luitpold Knauer, Peter Dick, Karl- Friedrich Holtz, Elmar Schmid, Gabriel Schmidt, Lutz-Ingo Fischer, Johann Thaller, Guntram Bloß, Franz Kreuzer, Ulf Kahmann, Gu¨nther Holthausen, Karl Ludwig Maier, Walter Krebs, Christoph Mohr, Heinz Koschine, Richard Ellersdorfer, Michael Speth.
GPs who participated at baseline
GPs who used to participate in the study
Bonn Heinz-Peter Romberg, Hanna Liese, Inge Bu¨rfent, Johann von Aswege, Wolf-Dietrich Honig, Peter Gu¨lle,
Bonn Heinz-Peter Romberg, Eberhard Prechtel, Manfred Marx, Jo¨rg Eimers-Kleene, Paul Reich, Eberhard Stahl,
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Reinhold Lunow, Klaus Undritz, Bernd Voss, Achim Spreer, Oliver Brenig, Bernhard G. Mu¨ller, Ralf Eich, Angelika Vossel, Dieter Leggewie, Angelika Schmidt, Nahid Aghdai-Heuser, Lutz Witten, Michael Igel. Du¨sseldorf Michael Fliedner, Benjamin Hodgson, Werner Hamkens, Angela Ackermann, Bernhard Hoff, Michael Kirsch, Vladimir Miasnikov, Dieter Lu¨ttringhaus, Clemens Wirtz, Rolf Opitz, Ju¨rgen Bausch, Dirk Mecking, Friederike Ganßauge, Elmar Peters, Alfons Wester. Hamburg Werner Petersen, Martin Daase, Martin Ru¨sing, Christoph von Sethe, Wilmhard Borngra¨ber, Brigitte Colling-Pook, Ullrich Weidner, Peter Rieger, Lutz Witte, Hans-Wilhelm Busch, Ju¨rgen Unger, Angela Preis, Michael Mann, Ernst Haeberle, Horst Ko¨hler, Ruth Scha¨fer, Helmut Sliwiok, Volker L. Bru¨hl, Hans Heiner Sto¨ver, Harald Deest, Margret Ackermann-Ko¨rner, Dieter Reinstorff, Christamaria Schlu¨ter, Henrik Heinrichs, Ole Dankwarth, Michael Bo¨se, Ulricke Ryll, Reinhard Bauer, Dieter Mo¨ltgen, Sven Schnakenbeck, Karin Beckmann, Annegret Callsen, Ewa Schiewe, Holger Gehm, Volker Lambert, Karin Hinkel-Reineke, Carl-Otto Stolzenbach, Peter Berdin, Friedhelm Windler. Leipzig Sabine Ziehbold, Sabine Weidnitzer, Erika Rosenkranz, Norbert Letzien, Doris Klossek, Martin Liebsch, Andrea Zwicker, Ulrike Hantel, Monika Pilz, Volker Kirschner, Rainer Arnold, Ulrich Poser. Mannheim Wolfgang Barthel, Fritz Blechinger, Marcus Fa¨hnle, Reiner Walter Fritz, Susanne Ju¨nemann, Gabriele Kirsch, Ju¨rgen Kulinna, Gerhard Kunzendorf, Andreas LegnerGo¨rke, Christa Lehr, Wolfgang Meer, Adolf Noky, Christina Panzer, Achim Raabe, Helga Schmidt- Back, Ralf Schu¨rmann, Hans-Gu¨nter Stieglitz, Marie-Luise von der Heide. Munich Helga Herbst, Peter Friedrich, Hans-Georg Kirchner, Elke Kirchner, Luitpold Knauer, Elmar Schmid, Ulf Kahmann, Jo¨rg Kastner, Ulrike Janssen, Albert Standl, Clemens Go¨ttl, Marianne Franze, Gerhard Moser, Almut Blu¨mm, Petra Weber, Wolfgang Poetsch, Heinrich Puppe, Thomas Bommer, Gerd Specht, Leonard Badmann, May Leveringhaus, Michael Posern, Andreas Ploch, Ralph Potkowski, Christiane Eder, Michael Schwandner, Rudolf Weigert, Christoph Huber.
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