Impaired cognitive function and compliance with antihypertensive drugs in elderly: the Rotterdam Study.

BACKGROUND: To our knowledge, there are no epidemiologic studies on the association between cognitive impairment and noncompliance with antihypertensive therapy. We studied compliance with antihypertensive treatment in elderly patients with cognitive impairment. METHODS: The Rotterdam Study is a prospective community-based cohort study of 7983 residents > or = 55 years old. We studied 1979 participants in the study who had 2 consecutive Mini Mental State Examination (MMSE) assessments in the period from 1991 to 1996, who did not have dementia at baseline, and who had received 3 or more consecutive antihypertensive prescriptions for at least 6 months. We compared persons with MMSE scores < or = 25 on both assessments to persons with MMSE scores > 25 on both occasions. Compliance was estimated by dividing the number of days the subjects took antihypertensive drugs by the follow-up period in days, and it was expressed as a ratio between 0 and 1. We defined patients as compliant if they had a compliance ratio > or = 0.80 and as noncompliant if they had a compliance ratio < or = 0.50 during the study period. RESULTS: We followed-up on 1573 patients (mean age, 68 years) during an average period of 1609 days. The risk of noncompliance in cognitively impaired elderly subjects was 2.0 (95% confidence interval, 1.4 to 2.8) after adjustment for age, sex, education, income, living situation, and smoking. Stratification by living situation showed that the risk increase predominantly occurred in those who lived alone (odds ratio, 2.9; 95% confidence interval, 1.2 to 7.5). CONCLUSIONS: Cognitive function is an independent predictor of compliance with antihypertensive drugs in elderly patients who are living alone.

Antihypertensive drugs and incidence of dementia: the Rotterdam Study.

There is increasing evidence that hypertension may contribute to the development of dementia. We investigated the relation of antihypertensive drug use and the risk of dementia in the cohort of the population based Rotterdam Study. The study cohort included 7046 elderly, free of dementia at baseline. Dementia was diagnosed in a stepwise procedure. Participants were first screened. Screen positives were further tested. Those suspected of dementia underwent a diagnostic work-up. Dementia and its subtypes were diagnosed according to prevailing criteria. A Cox proportional hazards model was used to estimate relative risks. After a mean follow-up of 2.2 years, subjects taking antihypertensive medication at baseline (n = 2015) had a reduced incidence of dementia (adjusted relative risk, 0.76; 95% confidence interval 0.52-1.12). This risk reduction was most pronounced for vascular dementia, (adjusted relative risk, 0.30; 95% confidence interval 0.11-0.99). For Alzheimer's disease the relative risk was 0.87, not significant. Dementia may be prevented by antihypertensive treatment. In order to confirm any relation in Alzheimer's disease larger observational studies with longer follow-up are needed.

Confounding by contraindication in a nationwide cohort study of risk for death in patients taking ibopamine.

BACKGROUND: Outcomes may differ in treated and untreated patients because of a contraindication for treatment in the latter that is independently associated with the outcome of interest. OBJECTIVE: To evaluate the effects of confounding by contraindication on risk factors for death in patients taking ibopamine after its use was restricted in early September 1995. DESIGN: Retrospective cohort study. SETTING: The Netherlands. PATIENTS: 1146 patients with congestive heart failure who were prescribed ibopamine at least once and for whom medication history and medical data were available. MEASUREMENTS: Cardiovascular risk factors, clinical characteristics, and medication use. Each patient was assigned an index date (the date of death, or a random date for patients still alive at the end of the study). RESULTS: In univariate analyses comparing patients with an index date before and those with an index date after 8 September 1995, the relative risk for death associated with current use of ibopamine was 3.02 (95% CI, 2.12 to 4.30) compared with 0.71 (CI, 0.53 to 0.96), respectively. In multivariate analyses, the risk for death was 2.62 (CI, 1.76 to 3.90) and 0.93 (CI, 0.84 to 1.02), respectively. CONCLUSION: The marked inversion of the relative risk estimate can be considered a practical example of confounding by contraindication.

Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease.

BACKGROUND: Previous studies have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may help to prevent Alzheimer's disease. The results, however, are inconsistent. METHODS: We studied the association between the use of NSAIDs and Alzheimer's disease and vascular dementia in a prospective, population-based cohort study of 6989 subjects 55 years of age or older who were free of dementia at base line, in 1991. To detect new cases of dementia, follow-up screening was performed in 1993 and 1994 and again in 1997 through 1999. The risk of Alzheimer's disease was estimated in relation to the use of NSAIDs as documented in pharmacy records. We defined four mutually exclusive categories of use: nonuse, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use), and long-term use (24 months or more of cumulative use). Adjustments were made by Cox regression analysis for age, sex, education, smoking status, and the use or nonuse of salicylates, histamine Hz-receptor antagonists, antihypertensive agents, and hypoglycemic agents. RESULTS: During an average follow-up period of 6.8 years, dementia developed in 394 subjects, of whom 293 had Alzheimer's disease, 56 vascular dementia, and 45 other types of dementia. The relative risk of Alzheimer's disease was 0.95 (95 percent confidence interval, 0.70 to 1.29) in subjects with short-term use of NSAIDs, 0.83 (95 percent confidence interval, 0.62 to 1.11) in those with intermediate-term use, and 0.20 (95 percent confidence interval, 0.05 to 0.83) in those with long-term use. The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia. CONCLUSIONS: The long-term use of NSAIDs may protect against Alzheimer's disease but not against vascular dementia.

Hormone replacement therapy and peripheral arterial disease: the Rotterdam study.

BACKGROUND: As the number of elderly women increases in Western society, peripheral arterial disease (PAD) is likely to become an increasing problem. Hormone replacement therapy, suggested to protect against coronary atherosclerosis, might also inhibit the development of PAD. METHODS: The association between hormone replacement therapy and the presence of PAD was studied in a population-based study consisting of 2196 naturally menopausal women aged 55 to 80 years living in a suburban area of Rotterdam, the Netherlands. Peripheral arterial disease was defined as an ankle/arm systolic blood pressure index (ratio of the systolic blood pressure at the ankle to the systolic blood pressure at the arm) lower than 0.9. RESULTS: Hormone replacement therapy for 1 year or longer was associated with a 52% decreased risk of PAD (odds ratio, 0.48 [95% confidence interval, 0.24-0.85]), while no association was found for therapy duration shorter than 1 year (odds ratio, 0.97 [95% confidence interval, 0.58-1.63) after adjustment for age, smoking, and socioeconomic status. Additional adjustment for body mass index, age at menopause, total cholesterol and high-density lipoprotein cholesterol, alcohol intake, and frequency of visits to health care facilities did not change the results. CONCLUSION: The findings of this population-based study suggest that hormone replacement therapy given for a year or more is associated with a decreased risk of PAD among postmenopausal women.

Hormone replacement therapy and intima-media thickness of the common carotid artery: the Rotterdam study.

BACKGROUND AND PURPOSE: Observational data suggest that hormone replacement therapy (HRT) reduces morbidity and mortality from cardiovascular disease in healthy postmenopausal women. The mechanisms underlying this protection are not entirely clear but may include inhibition of the atherosclerotic process. METHODS: We studied the association between ever use of HRT and intima-media thickness (IMT) of the common carotid artery in 1103 naturally menopausal women, aged 55 to 80 years, in the Rotterdam Study, a community-based cohort study in a suburban area of Rotterdam, Netherlands. Mean and maximum IMT of the common carotid artery were measured noninvasively with B-mode ultrasound. RESULTS: Ever use of HRT for >/=1 year was associated with a decreased mean and maximum IMT compared with never users (mean IMT, 0.719 mm [SE 0.01] versus 0. 742 mm [SE 0.004], P=0.03; maximum IMT, 0.952 mm [SE 0.015] versus 0. 983 mm [SE 0.006], P=0.04), after adjustment for age, smoking, educational level, systolic blood pressure, and body mass index. No association was found for use <1 year (mean IMT, 0.739 mm [SE 0.013] versus 0.742 mm [SE 0.004], P=0.69; maximum IMT, 0.990 mm [SE 0.019] versus 0.983 mm [SE 0.006], P=0.75). Additional adjustment for diabetes, frequency of visits to healthcare facilities, or total and HDL cholesterol did not change these results. CONCLUSIONS: The findings of this population-based study show that ever use of HRT is associated with a decreased IMT in the common carotid artery in elderly women.

[The need for 'postmarketing surveillance']. / Noodzaak van 'postmarketing surveillance'.

Postmarketing surveillance of medicines includes two activities: pharmacovigilance and pharmaco-epidemiology. Despite the importance of postmarketing surveillance, too few surveillance studies are performed. The studies carried out by the pharmaceutical industry predominantly consist of 'seeding trials': offering prescribing physicians financial rewards if they prescribe a particular product, thus trying to change the prescription habits. The results of such trials are scientifically worthless. These activities cast a shadow on sincere postmarketing surveillance. A recent nationwide cohort study by the Inspectorate for Health Care on mortality in users of ibopamine demonstrates that Dutch medical doctors and pharmacists are very co-operative if further studying of a particular adverse reaction is warranted.

Risk factors for mortality in users of ibopamine.

AIMS: In September 1995, the indication for the oral dopamine agonist ibopamine was restricted in the Netherlands and in several other European countries to patients with NYHA-class II heart failure as a result of an interim analysis of the PRIME-II trial. This trial demonstrated an increased risk of mortality in patients with NYHA-class III/IV heart failure on ibopamine. In September 1995, we initiated an assessment of the effects of ibopamine under everyday circumstances in a cohort of users of ibopamine in all NYHA-classes. METHODS: In a nationwide retrospective cohort study all 2147 community pharmacies and drug dispensing general practitioners received a request to list all patients to whom they had dispensed ibopamine in the preceding years. All responding drug dispensing outlets (DDO) received a questionnaire on cardiovascular risk factors and mortality for the general practitioner of a random sample of these patients. DDO were also requested to send an anonymised printout of the complete medication record. On the end-date of follow-up, February 15th 1996, mortality rates were compared across categories of ibopamine use, adjusted for potential confounders. To assess medication use, drug exposure was compared in a 3 months' period before date of death in the deceased, and before a random date in those patients who were still alive. RESULTS: In patients with NYHA-class III/IV heart failure, multivariate analysis indicated that current use of ibopamine was significantly associated with mortality (RR 1.37;95% CI: 1.15-1.64). In patients with NYHA-class I/II heart failure, however, multivariate analysis showed a 2.03 (95% CI: 1.10-3.72) risk of mortality in current users of ibopamine. Apart from current use of ibopamine, male gender and increased serum creatinine were also independent risk factors for mortality in all NYHA-classes. No statistically significant association was found between mortality and current use of amiodarone or use of amiodarone at baseline. CONCLUSIONS: The increased risk of mortality in patients with NYHA-class III and IV heart failure on ibopamine seems to confirm the main finding of the recently published PRIME-II trial. However, our results indicate that also patients with NYHA-class I/II heart failure may be at an increased risk of mortality when using ibopamine. Additional research on the effects of ibopamine in these patients is warranted and the use of ibopamine in NYHA-class II heart failure patients may have to be reconsidered.

NSAIDs and incident Alzheimer's disease. The Rotterdam Study.

Recent studies suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk for Alzheimer's disease (AD). We investigated the relation of NSAID use over a 10-year period and the risk for incident AD using a nested case-control design in the population-based Rotterdam Study. The study was performed in 306 subjects; 74 Alzheimer patients diagnosed according to NINCDS-ADRDRA criteria and 232 age and sex-matched controls. NSAID use was abstracted from general practitioners' medical records and expressed as cumulative prescription days. The relative risk for AD associated with long-term use (> or = 2 months) was 0.95 (95% CI: 0.46-1.99) as compared to nonusers, after controlling for possible confounders. In a separate examination, subjects who had more than 6 months of prescription days had a reduced relative risk for AD (RR = 0.74 (95% CI: 0.20-2.72). In an age-stratified analysis the effect in long-term users was evident in those aged 85 and under; 0.53 (95% CI: 0.15-1.77). All risk estimates were lower when the last 2 years of exposure were excluded from the analyses. Our point estimates in subjects younger than 85 years and in subjects using NSAIDs for 6 months or more are consistent with the hypothesis that long-term use of NSAIDs reduces the risk for AD. However, overall there was no association between NSAID use and the risk for incident AD.

Fever attributed to the use of hydroxyurea.

We report on three patients who developed fever after starting treatment with the anti-neoplastic agent, hydroxyurea. Fever occurred within 5 days to 3 weeks after starting treatment. In all cases the causal relationship between fever and use of hydroxyurea was demonstrated by spontaneous recovery after drug withdrawal and was confirmed by recurrence of fever after rechallenge. Other causes were excluded. Fever was accompanied by rash, gastro-intestinal and pulmonary symptoms, and arthralgia. Physicians should be aware of the fact that unexplained fever may be caused by hydroxyurea.

[Hypersensitivity reactions to use of mebeverine]. / Overgevoeligheidsreacties bij gebruik van mebeverine.

Twenty-one cases of adverse reactions to mebeverine use were reported to the Inspectorate for Health Care in the Netherlands since 1978. In 12 patients (five men and seven women) this was an immunological hypersensitivity reaction. All patients recovered after drug withdrawal. The time between start and onset of symptoms varied from several minutes to 14 days. Most reactions consisted of urticaria or maculopapular rash, sometimes accompanied by fever, polyarthritis, thrombopenia or angioedema. In contradiction to the manufacturer's claims adverse reactions to the use of mebeverine do occur.