A. J. Porsius

Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme

The use of angiotensin-converting-enzyme (ACE) inhibitors has been associated with increased insulin sensitivity in diabetic patients. Although such an effect could be beneficial in the treatment of hypertension or congestive heart failure in diabetic patients, it might also precipitate severe hypoglycaemia. To test this hypothesis we carried out a nested case-control study, using data in the Dutch PHARMO system (1986-92), among diabetic patients treated with insulin or with oral antidiabetic drugs, who were admitted to hospital with hypoglycaemia. We identified 94 patients who had been admitted with hypoglycaemia and selected 654 controls from the same cohort. With adjustment for a wide range of potential confounding factors, hypoglycaemia was significantly associated with current use of ACE inhibitors (odds ratio 2.8 [95% CI 1.4-5.7]). Both among users of insulin and among users of oral antidiabetic drugs, use of ACE inhibitors was significantly associated with an increased risk of hospital admission for hypoglycaemia (2.8 [1.2-6.4] and 4.1 [1.4-12.2], respectively). Although ACE inhibitors have several advantages over other antihypertensive drugs in diabetes, the risk of hypoglycaemia should be taken into account. Further investigation of the mechanism is needed since as many as 13.8% of all hospital admissions for hypoglycaemia might be attributable to use of ACE inhibitors.

Reducing prescribing of highly anticholinergic antidepressants for elderly people: randomised trial of group versus individual academic detailing.

Abstract Objective: To compare the effect of individual educational visits versus group visits using academic detailing to discuss prescribing of highly anticholinergic antidepressants in elderly people. Design: Randomised controlled trial with three arms (individual visits, group visits, and a control arm). Setting: Southwest Netherlands. Participants: 190 general practitioners and 37 pharmacists organised in 21 peer review groups were studied using a database covering all prescriptions to people covered by national health insurance in the area (about 240 000). Intervention: All general practitioners and pharmacists in both intervention arms were offered two educational visits. For physicians in groups randomised to the individual visit arm, 43 of 70 general practitioners participated; in the group visit intervention arm, five of seven groups (41 of 52 general practitioners) participated. Main outcome measures: Numbers of elderly people (60 years) with new prescriptions of highly anticholinergic antidepressants and less anticholinergic antidepressants. Results: An intention to treat analysis found a 26% reduction in the rate of starting highly anticholinergic antidepressants in elderly people (95% confidence interval —4% to 48%) in the individual intervention arm and 45% (8% to 67%) in the group intervention arm. The use of less anticholinergic antidepressants increased by 40% (6% to 83%) in the individual intervention arm and 29% (—7% to 79%) in the group intervention arm. Conclusions: Both the individual and the group visits decreased the use of highly anticholinergic antidepressants and increased the use of less anticholinergic antidepressant in elderly people. These approaches are practical means to improve prescribing by continuing medical education.

Drug-Induced lipid changes: a review of the unintended effects of some commonly used drugs on serum lipid levels.

Many drugs besides lipid-lowering drugs affect serum lipid levels in either a potentially harmful or beneficial way, and may therefore increase or decrease the risk of cardiovascular disease.Diuretics, β-blocking agents, progestogens, combined oral contraceptives containing ‘second generation’ progestogens, danazol, immunosuppressive agents, protease inhibitors and enzyme-inducing anticonvulsants adversely affect the lipid profile. They increase total cholesterol, low density lipoprotein cholesterol and triglycerides by up to 40, 50 and 300%, respectively, and decrease high density lipoprotein cholesterol by a maximum of 50%. Conversely, α-blocking agents, estrogens, hormone replacement therapy, combined oral contraceptives containing ‘third generation’ progestogens, selective estrogen receptor modulators, growth hormone and valproic acid show mostly beneficial effects on the lipd profile. Some drugs, for example, isotretinoin, acitretin and antipsychotics, mainly elevate triglyceride levels.Adverse or beneficial effects on serum cholesterol levels do not always translate into a higher or lower, respectively, incidence of cardiovascular disease, because these drugs may influence cardiovascular risk through multiple pathways. In some cases, excessive cholesterol levels occur, for example, with protease inhibitor therapy, and several cases of pancreatitis attributable to drug-induced hypertriglyceridaemia have been reported.Some general guidelines on the management of drug-induced dyslipidaemia can be given. Replacement of the dyslipidaemia-inducing drug by an equivalent alternative therapy is preferred. However, such alternatives are often difficult to find. If there is no equivalent alternative and treatment with the dyslipidaemia-inducing drug must be initiated, monitoring of serum lipid levels is important. If drug use is expected to be long term, the existing guidelines for the management of dyslipidaemia in the general population can be applied to drug-induced dyslipidaemia. In cases of extreme hyperlipidaemia, medication use should be reassessed.

Comparison of different methods to estimate prevalence of drug use by using pharmacy records

Several methods to estimate prevalence of drug use are available, which may complicate a valid comparison of these estimates. Standardization may contribute to more valid comparisons. We compared different methods to estimate prevalence of drug use by using pharmacy records. Data were obtained from the Dutch population-based PHARMO-database comprising medication histories of 300,000 subjects. Five point prevalences and a 1-year prevalence of cholesterol-lowering drug use were estimated in 1995. Four point prevalences differed in data handling before estimating prevalence (e.g., correction for irregular drug use or construction of episodes of drug use). The numerator of the fifth point prevalence estimate represented the number of defined daily doses (DDDs) instead of the number of patients filling a prescription. The first four point prevalences ranged from 11.0-12.1 per thousand. Prevalence ratio (male:female) was 1.2 for these methods. The fifth method resulted in an estimate similar to the other point prevalences (11.9 DDDs/1000 inhabitants). However, the prevalence ratio was 1.4 due to larger average number of DDDs prescribed to men. One year-prevalence was 4-5 per thousand higher than point prevalences. The comparison of these methods indicated that the choice of prevalence measure (point versus period prevalence) substantially influenced the prevalence estimate, whereas the influence of data handling was negligible. For standardization purposes in drug utilization research, we recommend estimating point prevalence instead of period prevalence. The various methods of data handling before estimating point prevalence yielded similar results and therefore we cannot recommend one specific method. However, defined daily doses should not be used to estimate (point) prevalences of drug use because this measure is significantly influenced by prescribed dosage regimens.

NON-COMPLIANCE IN ELDERLY PEOPLE : EVALUATION OF RISK FACTORS BY LONGITUDINAL DATA ANALYSIS

Studies on risk factors for drug non-compliance have not taken into account the possibility of correlated outcomes. We therefore conducted a study into risk factors for non-compliance by using analysis techniques that adjust for these correlations (longitudinal data analysis). Data were obtained from interviews and pharmacy records in a cross-sectional survey in Amsterdam. The subjects were 157 elderly people aged 70 years or older. Of these subjects, 37 were residents of a home for the elderly, 40 were community-dwelling elderly who needed to be visited regularly by a district nurse, and 80 were community-dwelling elderly who did not need to be visited by a distric nurse. Most drugs (78%) were used according to the directions; the remainder (22%) were not used as intended. Odds ratios (95% confidence intervals) for non-compliance for moderate and poor/wrong knowledge of the purpose of a drug as compared with good/correct knowledge were 2.8 (1.2–6.7) and 4.2 (1.5–12), respectively. Drug regimens of two times daily and more than two times daily were associated with odds ratios for non-compliance of 4.5 (1.6–12) and 4.2 (1.7–11), respectively, compared to a regimen of once daily. Compliance increased if a drug was prescribed by a specialist instead of a general practitioner [odds ratio 0.1 (0.04–0.4)]. There was no significant relation between compliance and the number of drugs prescribed to a patient, sex, age, living situation, patient group, or perceived effect. This study, which was based on longitudinal data analysis, demonstrates that in elderly people non-compliance with drug therapy is related to the knowledge of purpose of a drug, the complexity of a drug regimen, and the type of prescriber. The positive association between compliance and the number of drugs prescribed found in former studies was not confirmed.

Pharmacokinetics of lisinopril in hypertensive patients with normal and impaired renal function

SummaryThe pharmacokinetics of lisinopril was studied after administration of single and multiple doses of 5 mg to hypertensive patients with normal and impaired renal function.In patients with severe renal failure the peak concentrations were higher, the decline in serum concentration was slower and the time to peak concentration was extended. Accumulation of lisinopril was highly correlated with the creatinine clearance. The effective half-life was doubled and tripled in patients with mild and severe renal impairment, respectively, as compared to patients with a normal renal function. Lisinopril lowered blood pressure in all three groups over 24 h.It is suggested that smaller doses of lisinopril should be administered to patients with severe renal failure.

Comparison of the antiatherogenic effects of isradipine and ramipril in cholesterol-fed rabbits. I: Effect on progression of atherosclerosis and endothelial dysfunction

This study was designed to compare the effects of a calcium antagonist (isradipine) and a converting enzyme inhibitor (ramipril) on progression and regression of atherosclerosis in hypercholesterolemic rabbits. Sixty rabbits in three groups were fed a 0.3% cholesterol diet for 4 weeks. After this induction period, group II received the 0.3% cholesterol diet, group III received cholesterol diet with isradipine (0.33 mg/kg/day), and group IV received cholesterol with ramipril (0.33 mg/kg/day) for 12 more weeks. A group of 20 rabbits received a standard diet throughout the study (group I). After 16 weeks, 10 rabbits were randomly chosen from each group and used in the progression study. The other rabbits were placed on a standard diet and remained on their respective drug regimen for 12 more weeks. In the progression phase of the study, ramipril significantly attenuated the percentage of aortic lesions in group IV (35 +/- 6%) as compared with group II (56 +/- 6%, p < 0.05), whereas isradipine had no effect. Acetylcholine (ACh)-induced maximum endothelium-dependent relaxations (EDR) of aortic rings were significantly reduced by the atherogenic diet to 37 +/- 4 versus 77 +/- 2% in group I (p < 0.05). Treatment with ramipril significantly improved maximum EDR to 53 +/- 3% (p < 0.05 vs. group II). Isradipine had no significant effect on impaired EDR. Aortic rings with endothelium from group II developed supersensitivity to sodium nitroprusside (SNP) and had significantly reduced basal cyclic GMP levels as compared with those of group I. Both drugs prevented development of supersensitivity to SNP and blunted the cholesterol-induced reduction in basal cyclic GMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of antiparkinsonian drugs in pharmacy records as a marker for Parkinson's disease

Aim: The aim of this study was to determine whether use of antiparkinsonian drugs in pharmacy records can be used as a marker for patients with Parkinsons disease (PD). Method: Data were obtained from the Rotterdam Study, a community‐based prospective cohort study among people aged 55 years or older who were all screened for PD. For 5510 persons, of whom 74 had PD, pharmacy records were available. Stepwise logistic regression analysis was used to evaluate whether age, sex and use of the antiparkinsonian drugs amantadine, anticholinergics, dopamine agonists, levodopa and selegiline, were predictive variables for PD. For each individual a probability for having PD was calculated. Sensitivity, specificity and positive predictive value (PPV) were calculated at different cut‐off values based on calculated probabilities. Results: More than 90% of the users of levodopa, bromocriptine, selegiline, and users of at least two different antiparkinsonian drugs had PD. Age, use of amantadine, anticholinergics, bromocriptine, levodopa, and selegiline were predictive variables for PD. After application of different cut‐off values, sensitivity was at most 66.2%, and specificity was at least 99.8%. A PPV of higher than 90% was obtained at higher probabilities.Conclusion: Based on the high PPV of our predictive model, antiparkinsonian drugs can be used as a reliable marker for PD in pharmacy records. Because sensitivity is low, pharmacy records cannot be used to estimate prevalence of PD.

Use of prevalence and incidence measures to describe age-related prescribing of antidepressants with and without anticholinergic effects

To evaluate whether physicians avoid prescribing highly anticholinergic antidepressants (AAD) in the elderly, a population-based retrospectively data analysis was performed using databases from a Dutch health insurance company. Data collected on approximately 240,000 persons covered the period from 1 July 1993 to 1 January 1996. The prevalence and the incidence (number of new starters) of antidepressant use was measured over 1994 and 1995. Use of AAD was proportionally higher in the elderly in terms of both prevalence and incidence rates; the ratio of starters of AAD versus starters of non-AAD in 1994 increased steadily with age (from 0.54 in the age group 20-29 to 1.15 in the age group 60-69). In 1995 these incidence ratios decreased (0.41 to 0.99, respectively); however, the decrease was higher in the younger age groups. The data indicate that in the population studied, physicians do not refrain from prescribing highly anticholinergic agents to older patients despite their potential adverse drug reactions in this age group. This study also indicates that prevalence and incidence rates can be extracted from reimbursement data and give insight into actual prescribing practices.

Do the research goal and databases match? A checklist for a systematic approach

To test the appropriateness of a given database for specific research questions, we designed a checklist starting with the definition of an ideal database. This ideal database contains all relevant data on patients, providers and services. It is safe and accessible, input is always accurate, continuity is guaranteed and linkage with other information is easy. Of course no such database exists. Still these features are often taken for granted, but highly influenced by organizational processes in healthcare and prioritization. Starting with the characteristics of an ideal database, one can systematically list the required aspects for research goals and compare these with the available systems. This checklist is used to address important aspects of administrative database research and ethical issues. The increasing possibility to misuse sensitive data needs to be discussed by researchers, administrators, individuals and society. This checklist can also be valuable to others to design or interpret studies based on claims databases.