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Duration of antihypertensive drug use and risk of dementia: "Antihypertensive drug use was associated with 8% risk reduction of dementia per year of use for persons <75 years."
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A prospective cohort study
Neurology June 2009
M.D.M. Haag, PharmD, A. Hofman, PhD, P. J. Koudstaal, PhD, M. M.B. Breteler, PhD and B. H.C. Stricker, PhD
From the Departments of Epidemiology (M.D.M.H., A.H., M.M.B.B., B.H.C.S.), Neurology (P.J.K.), and Internal Medicine (B.H.C.S.), Erasmus Medical Center, Rotterdam; and Inspectorate for Health Care (B.H.C.S.), The Hague, The Netherlands.
Address correspondence and reprint requests to Dr. Bruno H.C. Stricker, Department of Epidemiology, Erasmus Medical Center, P.O Box 2040, 3000 CA Rotterdam, The Netherlands
"high blood pressure in midlife is associated with an increased risk of AD, Alzheimer disease...
...The pathologic processes through which hypertension is thought to influence dementia pathology are many. High blood pressure can result in severe atherosclerosis, leading to cerebral hypoperfusion.33 Changes in cerebral white matter can also occur as a result of sustained high blood pressure.34 Other than the blood pressure lowering effect of antihypertensive drugs, it has been suggested that certain antihypertensive drugs exert a more direct effect on dementia pathology. For example, the intracellular buildup of calcium in neurons can be neurotoxic and thus calcium channel blockers might result in neuroprotection.35 However, our findings do not support an advantage of one antihypertensive drug over another. Other studies have also investigated the different types of antihypertensive drugs in relation to dementia risk, but findings have been largely inconsistent. The types of antihypertensive drugs for which reductions were shown included ACE inhibitors, AT2 blockers, potassium-sparing diuretics, and dihydropyridine calcium channel blockers. The fact that, across both clinical and observational studies, various types of antihypertensive drugs have been identified as a having a particular beneficial effect on dementia suggests that this is the play of chance rather than that actual differences exist. Hence, we consider it more likely that effect of antihypertensive drugs on blood pressure in itself underlies the protective effect of these drugs. For future research, a more mechanistic approach, such as the use of imaging markers of cerebral pathology, would be desirable to understand the biologic basis of the association between antihypertensive drugs and dementia."
ABSTRACT
Background: The evidence from prospective observational research for a protective effect of antihypertensive drug use on the risk of dementia is far from uniform. Duration of follow-up was limited and relied mainly on baseline drug exposure data without information on duration of use. We investigated the association between the duration of antihypertensive use and risk of dementia.
Methods: We followed 6,249 participants (mean 68.4 years, 60% women) of a prospective, population-based cohort from baseline (1990-1993) until 2005 for incident dementia. Continuous data on filled prescriptions came from pharmacy records. Total cumulative duration of antihypertensive use was expressed in years. We subtracted a latent 4-year period before the date of dementia diagnosis in the quantification of exposure duration to avoid potential bias in antihypertensive prescription due to prodromal changes in blood pressure or cognition. With Cox regression models, we calculated crude and adjusted hazard ratios (HRs) of all dementia and Alzheimer disease (AD) with antihypertensive use vs never used.
Results: Compared to never used, antihypertensive use was associated with a reduced risk of all dementia (adjusted HR per year of use 0.95; 95% confidence interval [CI] 0.91-0.99). We observed an 8% (95% CI -15% to -1%) risk reduction per year of use for persons <75 years, whereas for persons >75 years this was 4% (95% CI -11% to 4%). Equivalent estimates were observed for AD. No apparent differences were observed among different types of antihypertensive drugs.
Conclusions: Antihypertensive drug use was associated with 8% risk reduction of dementia per year of use for persons <75 years.
Abbreviations: ACE = angiotensin-converting enzyme; AD = Alzheimer disease; AT2 = angiotensin-2; ATC = Anatomic Therapeutic Chemical; BMI = body mass index; BP = blood pressure; CCB = calcium channel blocker; CHD = coronary heart disease; CI = confidence interval; DBP = diastolic blood pressure; DHP = dihydropyridine; DM = diabetes mellitus; DSM = Diagnostic and Statistical Manual of Mental Disorders; GMS = Geriatric Mental State schedule; HR = hazard ratio; MI = myocardial infarction; MMSE = Mini-Mental State Examination; NINCDS-ADRDA = National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association; NINDS-AIREN = National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences; OR = odds ratio; RR = relative risk; SBP = systolic blood pressure.
Hypertension is a risk factor for cerebrovascular disease and consequently for vascular dementia. The association between hypertension and Alzheimer disease (AD) is less clear.1 Follow-up studies generally showed that high blood pressure in midlife is associated with an increased risk of AD.2 In contrast, high blood pressure later in life appears to lower the risk of AD.3 It was also suggested that in the preclinical stage of AD blood pressure declines, possibly due to imminent disease.4
Evidence from observational research for a protective effect of antihypertensive drugs on the risk of dementia has been far from uniform (table 1). With the exception of two studies,5,6 a major shortcoming of previous observational studies was the availability of merely baseline data on antihypertensive treatment. This considerably increases the chance of exposure misclassification during follow-up and, moreover, prohibits investigation of treatment duration. The intricate relation between blood pressure, age, and dementia risk can also be responsible for the variance in the observed relationships. Furthermore, prodromal changes in blood pressure and cognitive decline could lead to changes in antihypertensive prescription or drug intake, both leading to bias.4,7 Hence, the years immediately preceding clinical onset of dementia may not provide the relevant risk period to investigate the effect of antihypertensive drugs on dementia risk.
DISCUSSION
In the general population, we found that antihypertensive drug use was associated with decreased risk of all dementia and AD with 8% per year of use for people 75 years of age. No apparent differences were observed among the various types of antihypertensive drugs.
Strengths of our study design included its prospective design, large number of participants, a general population-based setting, and the long follow-up period of over 8 years average. Moreover, we used pharmacy records for the assessment of antihypertensive drug use. This greatly reduces the chance of exposure misclassification as opposed to baseline exposure data or periodic reassessment of drug use and allows for an accurate estimation of exposure duration. In an earlier study, we demonstrated that there was a high concordance between pharmacy filling data of cardiovascular drugs and actual use according to a patient interview.19 Moreover, we were able to subtract 4 years from the date of clinical diagnosis of dementia to avoid potentially biased risk estimates as a result of changes in antihypertensive prescription due to blood pressure changes or cognitive decline in the prodromal phase of dementia. Nevertheless, some issues warrant consideration. First, the 4-year period is an average estimation of the prodromal period based on the available data from literature. There is, however, limited longitudinal data on the course of blood pressure before clinical dementia. Data from the Kungsholmen Project shows that blood pressure markedly decreases over a 3-year period preceding diagnosis of dementia.20 The Goteborg longitudinal study revealed that a decline in systolic blood pressure between age 70 and 75 was the only predictor of dementia with onset at age 75 to 79.21 Likewise, estimations of the intervals between cognitive decline and dementia vary from 1.5 years to up to 10 years, but generally suggest a more rapid decline in the last 2 to 3 years before diagnosis.22-24 In a sensitivity analysis, we also investigated the association of antihypertensive drug use and dementia subtracting only 2 years from the date of diagnosis for quantification of exposure duration, and also the date of diagnosis itself. Though protective effects of antihypertensive drug use on dementia risk were still observed, the attenuation of the protective effect in these analyses suggests that, at least in part, the protective effect of antihypertensive drugs may be obscured in the prodromal phase of dementia. Second, we have to consider potential bias due to confounding by indication, since the indication for antihypertensive drug use, i.e., hypertension, is associated with the outcome of interest, i.e., dementia.7 However, given the complex association between hypertension and dementia, it is difficult to predict the direction of this effect. If hypertension increases the risk of dementia,2 than our estimates would underestimate the true protective effect. Instead, if hypertension would protect against dementia in persons above <75 years of age,3 then confounding by indication could lead to a spurious protective effect on dementia for antihypertensive drugs. However, this is refuted by our finding of no benefit of antihypertensive drug use on dementia risk for persons >75 years. Finally, our analyses for the separate types of antihypertensive drugs must be interpreted in light of low numbers within the different antihypertensive drug categories. Since some antihypertensive drugs are preferred when certain comorbidities apply, the differences observed among the various antihypertensive drugs, though small, may be explained by differences in underlying comorbidity rather than by a true difference in physiologic effect. No data are available on the indication for drug use. Low numbers also prohibited further investigation across strata of age in the analyses of the separate antihypertensive drugs.
Numerous studies have investigated the association between antihypertensive drug use and the risk of dementia. Thus far, findings have been inconsistent. Considerable methodologic differences exist among studies. Clinical trials mainly included patients >60 years of age with, in four out of five trials, a systolic blood pressure of 160 mm Hg.25-30 Some trials had a significant number of patients who were lost to follow-up31 or allowed for usual antihypertensive treatment other than the study drug in the placebo group,28,31 which further complicates the interpretation of their findings. The null findings in four out of five trials have also been attributed to the limited duration of follow-up.25,28-30 Nonetheless, in the Syst-EUR trial, antihypertensive treatment reduced the risk of dementia by no less than 50% after a mere 2 years of follow-up26 and again in an open-label extension of the same trial after 3.9 years of follow-up.27 However, as with most of the studies previously performed, the Syst-Eur trial had a small number of dementia endpoints. Besides the limited duration of follow-up, most observational studies relied on baseline data on antihypertensive treatment, which can lead to considerable misclassification of drug exposure during follow-up (table 1). Furthermore, only two out of eight of the prospective observational studies investigated whether associations depended on duration of antihypertensive drug use.6,32 In the Cache County Study, the protective effect of antihypertensive drugs was observed regardless of duration of use as assessed at baseline.32 In a cohort of Japanese men, the risk of dementia was reduced by 6% with each additional year of antihypertensive treatment, based on self-reported duration of drug use at the final examination.6 Considerable differences in both setting and design hamper a direct comparison of these findings to our study. Nevertheless, both studies suggest that the protective effect depends on the duration of antihypertensive drug use. Our observation of a stronger protective effect for people <75 years of age corresponds with the view that an increased blood pressure earlier in life increases the risk of dementia, whereas high blood pressure in older persons may not necessarily put persons at higher risk for dementia.1
The pathologic processes through which hypertension is thought to influence dementia pathology are many. High blood pressure can result in severe atherosclerosis, leading to cerebral hypoperfusion.33 Changes in cerebral white matter can also occur as a result of sustained high blood pressure.34 Other than the blood pressure lowering effect of antihypertensive drugs, it has been suggested that certain antihypertensive drugs exert a more direct effect on dementia pathology. For example, the intracellular buildup of calcium in neurons can be neurotoxic and thus calcium channel blockers might result in neuroprotection.35 However, our findings do not support an advantage of one antihypertensive drug over another. Other studies have also investigated the different types of antihypertensive drugs in relation to dementia risk, but findings have been largely inconsistent. The types of antihypertensive drugs for which reductions were shown included ACE inhibitors, AT2 blockers, potassium-sparing diuretics, and dihydropyridine calcium channel blockers. The fact that, across both clinical and observational studies, various types of antihypertensive drugs have been identified as a having a particular beneficial effect on dementia suggests that this is the play of chance rather than that actual differences exist. Hence, we consider it more likely that effect of antihypertensive drugs on blood pressure in itself underlies the protective effect of these drugs. For future research, a more mechanistic approach, such as the use of imaging markers of cerebral pathology, would be desirable to understand the biologic basis of the association between antihypertensive drugs and dementia.
Given the established benefit of antihypertensive drugs on prevention of cardiovascular disease, current evidence constitutes a limited basis for advocating a universal antihypertensive treatment policy for the sole purpose of dementia prevention. Further insight on the association between blood pressure and dementia and the effect of antihypertensive drugs on this association could nonetheless provide important information on pathologic pathways leading to dementia.
RESULTS
In total, 6,249 persons were included in the analysis. In table 2, baseline characteristics of the study population are given. Persons were followed up to 13.3 years (average 8.0 years), with a total of 49,829 person-years of follow up. During follow-up, 527 persons developed dementia, of whom 432 were diagnosed with AD, 50 with vascular dementia, and 45 with other types of dementia. The total number of filled antihypertensive prescriptions during follow-up was 54,584. Of the 527 persons who developed dementia, 264 persons had used antihypertensive drugs during follow-up, whereas 263 persons never used antihypertensive drugs.
Compared to never used, antihypertensive use was associated with a reduced risk of all dementia. HRs for AD were nearly equivalent (table 3). There was an evident duration-response relationship as the risk of all dementia decreased with longer duration of cumulative use, resulting in a 5% risk reduction per year of use (table 3). Correspondingly, the strongest risk reduction was observed with long-term use of antihypertensive drugs (>5.3 years), whereas short-term use of antihypertensive drugs (<1.6 years) was not associated with a reduced risk of dementia or AD.
The association between antihypertensive use and dementia was modified by age (pinteraction = 0.003). For people aged <75 years, antihypertensive drugs reduced the risk of dementia with 8% per year of use (table 4). For people aged >75 years, we observed a risk reduction of 4% per year of use.
Although the protective effect of antihypertensive drugs on dementia risk seemed stronger for carriers of an APOE-4 allele, numbers across strata were low and the interaction between APOE-e4 and antihypertensive drug use was not significant (pinteraction = 0.9) (data not shown).
No apparent differences among the various types of antihypertensive drugs were observed. Adjusted HRs of all dementia per year of use were as follows: 0.97 (95% CI 0.90-1.05) for thiazide diuretics; 0.89 (95% CI 0.78-1.01) for high ceiling diuretics; 0.93 (95% CI 0.87-1.00) for ß-blockers; 1.00 (95% CI 0.91-1.09) for calcium channel antagonists; 1.07 (95% CI 0.99-1.09) for ACE inhibitors, 0.85 (95% CI 0.44-1.66) for AT2 antagonists; and 1.04 (95% CI 0.88-1.24) for other antihypertensive drugs. Similar estimates were found for AD risk.
In the sensitivity analyses, estimates for risk of dementia gradually attenuated if shorter prodromal periods were considered. We observed a 4% risk reduction (0% to 7%, p = 0.03) if 2 years were subtracted from the date of diagnosis to 3% (0% to 6%, p = 0.03) per year of antihypertensive use if the original date of diagnosis was used.
METHODS
Study population. The Rotterdam Study is a prospective, population-based cohort study of age-related disorders.9 The medical ethics committee at Erasmus MC, Rotterdam, the Netherlands, approved the study. Between 1990 and 1993, all persons aged >55 years living in Ommoord, a district of Rotterdam, were invited to participate. Of 10,275 eligible persons, 7,983 (78%) signed informed consent. Of these, 7,528 (94%) were screened for dementia and 7,046 were free of dementia at baseline.10 Follow-up examinations, including screening and clinical workup for dementia, were conducted in 1993-1994, 1997-1999, and 2000-2004. In addition, the cohort was continuously monitored for major disease outcomes and death through linkage with records of general practitioners, the Regional Institute for Outpatient Mental Health Care, and bimonthly updates from the municipality records. This resulted in a virtually complete follow-up for dementia until January 1, 2005.
Nearly all persons (99.7%) were registered at one or more of seven automated pharmacies serving the Ommoord area. Records of all filled prescriptions were available from January 1, 1991. To ensure at least 6 months medication history, we excluded persons for whom follow-up ended before July 1, 1991.
Assessment of drug exposure. Complete data on filled prescriptions were available on a day-to-day basis from the pharmacy prescription database in automated form. This included the product name, international non-proprietary name, Anatomic Therapeutic Chemical (ATC) code, total number of delivered units (e.g., tablets/capsules), prescribed daily number of units, date of delivery, and drug dosage. The duration of a prescription is calculated as the number of delivered units divided by the prescribed daily number of units.
In addition to overall antihypertensive use, we distinguished among the most commonly used types of antihypertensive drugs in the Netherlands, as classified by ATC code. These included ß-blocking agents, thiazides and high ceiling diuretics, calcium-channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin-2 (AT2) antagonists, and other antihypertensive drugs (centrally acting sympathicolytics, peripheral acting sympathicolytics, and agents acting on arteriolar smooth muscle).
Diagnosis of AD. The diagnosis of dementia was made following a three-step protocol. Screening was done with the Mini-Mental State Examination (MMSE) and Geriatric Mental State schedule (GMS) organic level for all persons.11,12 Screen-positives (MMSE score <26 or GMS organic level >0) underwent the Cambridge examination for mental disorders of the elderly.13 Persons who were suspected of having dementia underwent more extensive neuropsychological testing. When available, imaging data were used. In addition, the total cohort was continuously monitored for incident dementia through computerized linkage between the study database and digitalized medical records from general practitioners and the Regional Institute for Outpatient Mental Health Care. The diagnosis of dementia was made in accordance with internationally accepted criteria for dementia (DSM-III-R), AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association), and vascular dementia (National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche en l'Enseignement en Neurosciences) by a panel of a neurologist, neurophysiologist, and research physician, blinded to drug exposure of the study population.14-16
Other covariates. Covariates included age, sex, education level, systolic and diastolic blood pressure, current smoking, total serum cholesterol, body mass index, diabetes mellitus, and cardiovascular and cerebrovascular disease. Education was assessed at the baseline interview and dichotomized into low education (primary education only or low vocational training) and high education (intermediate-level vocational training, secondary education, or university). Smoking status was also self-reported and categorized as ever or never. Total serum cholesterol was measured in nonfasting blood drawn at baseline. Sitting blood pressure was measured on the right upper arm using a random-zero sphygmomanometer. The average of two measurements at one occasion was used. Diabetes mellitus was defined as a nonfasting or 2-hour post load glucose level of 11.1 mmol/L or antidiabetic medication use at baseline. Cardiovascular disease included myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, and atrial fibrillation. Cerebrovascular disease included TIA and stroke. Both prevalent and incident cardiovascular and cerebrovascular events were taken into account. APOE genotyping was performed on coded DNA samples, and participants were classified by presence of an APOE-4 allele.
Statistical analyses. We calculated the hazard ratio (HR) and 95% confidence intervals (CI) of the risk of all dementia and AD associated with antihypertensive use using a Cox proportional hazards model with antihypertensive use as time-dependent covariate. Calendar time was used as the time-axis in the model to account for changes in prescription guidelines and availability of antihypertensive drugs over time. For all subjects, we calculated the duration of follow-up between start of study and diagnosis of dementia, death, or end of the study period, whichever came first. Because lowering of blood pressure and changes in cognition occur during the latent phase of disease, physicians might change antihypertensive treatment in the prodromal period of dementia. Calculating the cumulative exposure until the date of diagnosis would not take into account such disease-related changes in prescription and this might bias our risk estimates. To avoid this type of bias, we subtracted a potential latent period from the date of diagnosis, for quantification of exposure duration.8 Based on the current knowledge regarding the course of blood pressure1 and cognition in the latent phase of dementia,17 we considered a 4-year prodromal phase for our main analysis. Consequently, at each date of diagnosis minus 4 years we determined cumulative duration of drug until that date for both the person who developed dementia as well as for all persons in the remainder of the cohort. Total cumulative duration of antihypertensive use was expressed in years and as categorical variable based on tertiles of total use at end of follow-up being no use, <1.6 year use, from 1.6 to 5.3 years use, and >5.3 years use. Never use of antihypertensive drugs was the reference in all analyses. In a sensitivity analysis we investigated whether associations differed if we subtracted 2 years from the date of diagnosis or if we used the original date of diagnosis.
We anticipated that the association might be modified by age, since the association between blood pressure and dementia appears to be different at older age. Therefore, we reperformed the analyses for persons <75 years and >75 years of age. Likewise, we investigated whether the associations were different for carriers and noncarriers of an APOE-4 allele, by adding an interaction term to a model, and by stratified analyses.18 Using the same exposure definitions, we also investigated the association between separate types of antihypertensive drugs and risk of dementia. A cohort member could contribute person-time to more than one class of antihypertensive drug if a person had used more than one antihypertensive drug during follow-up.
All analyses were adjusted for age, sex, and systolic and diastolic blood pressure (model I). To adjust for potential confounders we additionally included smoking, total serum cholesterol, education, body mass index, diabetes mellitus, and cardiovascular and cerebrovascular disease (model II). Missing values for continuous variables were imputed with linear regression analyses using sex, age, and dementia outcome as determinants. For categorical variables we used a missing indicator for missing values. Analyses were performed with SPSS 16.0 and SAS 9.1 software.
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