Paul A. F. Jansen

Risk of cerebrovascular events in elderly users of antipsychotics.

It has been shown that elderly patients with dementia treated with atypical and conventional antipsychotics have a twofold increased risk of cerebrovascular adverse events (CVAEs). To investigate the temporal relationship between exposure to antipsychotics and the risk of CVAE, a case-control analysis nested within a cohort of 26,157 community-dwelling patients (mean age 76 ± 9.7) with at least one antipsychotic prescription was conducted. Data were used from Dutch community pharmacies and hospital discharge records. Five hundred and eighteen cases of hospital admission for CVAE were identified. For each case, four randomly selected controls matched by sex and age were sampled from the cohort. To evaluate the temporal relationship between antipsychotic use and the occurrence of CVAE, two measures were used: the first being a current, recent or past user, and the second for the current users, the duration of use up to the index date. In addition, the cumulative exposure was assessed. Current and recent exposure to antipsychotics were associated with an increased risk of CVAE compared with non-users (odds ratio [OR] 1.7, CI 1.4—2.2). A strong temporal relationship was found; the OR for a history of use less than a week is 9.9 (5.7—17.2). The risk decreases in time and is comparable to non-users after 3 months of use (OR 1.0, CI 0.7—1.3). Cumulative exposure was not associated with an increase in risk. The risk of CVAE in elderly patients associated with antipsychotics is elevated especially during the first weeks of treatment. This risk decreases over time and is back on base level after 3 months of treatment. Chronic use is not associated with CVAE.

Prescribing Optimization Method for Improving Prescribing in Elderly Patients Receiving Polypharmacy Results of Application to Case Histories by General Practitioners

BackgroundOptimizing polypharmacy is often difficult, and critical appraisal of medication use often leads to one or more changes. We developed the Prescribing Optimization Method (POM) to assist physicians, especially general practitioners (GPs), in their attempts to optimize polypharmacy in elderly patients. The POM is based on six questions: (i) is undertreatment present and addition of medication indicated; (ii) does the patient adhere to his/her medication schedule; (iii) which drug(s) can be withdrawn or which drugs(s) is/are inappropriate for the patient; (iv) which adverse effects are present; (v) which clinically relevant interactions are to be expected; and (vi) should the dose, dose frequency and/or form of the drug be adjusted?ObjectiveThe aim of this study was to evaluate the usefulness of the POM as a tool for improving appropriate prescribing of complex polypharmacy in the elderly.MethodsForty-five GPs were asked to optimize the medication of two case histories, randomly chosen from ten histories of geriatric patients admitted to a hospital geriatric outpatient clinic with a mean ± SD of 7.9±1.2 problems treated with 8.7±3.1 drugs. The first case was optimized without knowledge of the POM. After a 2-hour lecture on the POM, the GPs used the POM to optimize the medication of the second case history. The GPs were allowed 20 minutes for case optimization. Medication recommendations were compared with those made by an expert panel of four geriatricians specialized in clinical pharmacology. Data were analysed using a linear mixed effects model.ResultsOptimization was significantly better when GPs used the POM. The proportion of correct decisions increased from 34.7% without the POM to 48.1% with the POM (p=0.0037), and the number of potentially harmful decisions decreased from a mean ±SD of 3.3±1.8 without the POM to 2.4±1.4 with the POM (p=0.0046).ConclusionThe POM improves appropriate prescribing of complex polypharmacy in case histories.

Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case^control study using spontaneous reports

The aim of this study was to assess whether use of selective serotonin reuptake inhibitors (SSRIs) is associated with extrapyramidal syndromes (EPS). We analysed the spontaneous reports of adverse drug reactions (ADRs) collected by The Netherlands Pharmacovigilance Foundation Lareb in the period 1985–99 (n =24 263). The study population comprised all patients using an antidepressant drug at the time the ADR occurred. We calculated ADR-reporting odds ratios (ADR-OR) to estimate the association between SSRI-use and EPS, relative to other antidepressants. We identified 61 patients with EPS. SSRI-use was associated with spontaneous reporting of EPS compared to other antidepressants (adjusted ADR-OR 2.2; 95% confidence interval 1.2–3.9). This risk estimate appeared to be higher in patients concurrently using antipsychotic medication (6.9, 0.7–68.0), although the confidence interval was very wide. In conclusion, SSRI-use seems only to be moderately associated with EPS compared to other antidepressants. However, those concurrently using antipsychotic drugs or presenting with other risk factors may be more susceptible and should be closely monitored.

Antipsychotic-induced hyponatraemia: a systematic review of the published evidence

Hyponatraemia is known to occur as a rare but clinically important adverse reaction to treatment with different psychotropic drugs, including selective serotonin reuptake inhibitors and antiepileptic drugs. In past decades, reports have been published that describe the development of hyponatraemia in association with antipsychotic drug treatment. Our objective was to systematically review the available evidence on antipsychotic-induced hyponatraemia, focussing on patient characteristics, drug dosage, polydipsia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).A search was carried out in the MEDLINE and EMBASE databases from January 1966 to 11 April 2009. Inclusion criteria were (i) hyponatraemia (serum sodium level <136 mmol/L) occurring after the start of treatment with an antipsychotic drug; and (ii) that the hyponatraemia potentially occurred as an adverse reaction to antipsychotic drug treatment in accordance with the WHO definition. Articles in languages other than English, Dutch, German, French and Spanish were excluded. Information on patient characteristics, medical and diagnostic data, pharmacological treatment, drug dechallenge and drug rechallenge were extracted from the publications whenever available. A causality assessment was performed on all case reports using Naranjo’s adverse drug reaction probability scale. Correlational analysis was performed to assess correlations between antipsychotic drug dosage and both serum sodium level and time to onset of hyponatraemia.We included four studies and 91 publications containing case reports and case series; no randomized controlled studies were identified. Data from the identified case reports were further analysed. The mean age of the patients was 46 years; 57% were male. The diagnosis was schizophrenia in 70% of the cases. A history of polydipsia was diagnosed as positive in 67% of the cases and negative in 23% of the cases. Polydipsia occurred in the remaining 10% of cases, although it was reported to be drug-induced (i.e. a severe increase in water intake was observed in relation to treatment with the suspected drug). Analysis of the case reports using the adverse drug reaction probability scale indicated possible causality in most cases (80%), probable causality in a significant amount of cases (19%) and unlikely causality in one case (1%). Overall correlational analysis yielded no significant correlations between defined daily dose-equivalent dosages and serum sodium or time to onset of hyponatraemia.The incidence of hyponatraemia induced by antipsychotics may be much higher than is currently thought. Both the newer atypical antipsychotics and the older drugs have been associated with the development of hyponatraemia. Physicians, psychiatrists and other healthcare workers should be aware of the possibility of hyponatraemia associated with the use of antipsychotics. Further studies are required to establish the risks of and risk factors associated with antipsychotic-induced hyponatraemia.

THE EFFECTS OF SODIUM VALPROATE ON DISTURBED BEHAVIOR IN DEMENTIA

responders and nonresponders concerning the mean dose. Determination of plasma levels of sodium valproate was performed in 6 patients (4 responders; 2 nonresponders). A positive relation was found between dose and plasma levels. Remarkably, plasma levels in 3 out of 4 responders were below the therapeutic window in epilepsy. The effects of sodium valproate in the 23 patients are shown in Table 1. In 26% of the patients, the disturbed behavior was completely abolished. Response defined as a long-term reduction of the type of disturbed behavior lasting until discharge was seen in 520/0 of the patients. No differences could be found in response between the various types of dementia nor between the stages of dementia. The apparent sex difference can largely be explained by the higher incidence of physical aggressive behavior in males in this study (M = 8; F = 1). This type of behavior showed the best response with sodium valproate. The effects of sodium valproate related to the various types of disturbed behavior are presented in Table 2. Restless behavior and physically aggressive and verbally aggressive behavior showed a good response. Two types of disturbed behavior were seen in 8 men and 2 women. Six of them were full responders. Two men had 3 types of disturbed behavior. In both cases, sodium valproate was effective on all 3 types of disturbed behavior.

Treatment of Chronic Pain in Older People Evidence-Based Choice of Strong-Acting Opioids

In the treatment of chronic malignant and non-malignant pain, opioids are used as strong analgesics. Frail elderly patients often have multiple co-morbidities and use multiple medicines, leading to an increased risk of clinically relevant drug-drug and drug-disease interactions. Age-related changes and increased frailty may lead to a less predictable drug response, increased drug sensitivity, and potential harmful drug effects. As a result, physicians face a complex task in prescribing medication to elderly patients. In this review, the appropriateness of the strong-acting opioids buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone and tapentadol is determined for use in elderly patients. Evidence-based recommendations for prescribing strong opioids to the frail elderly are presented. A literature search was performed for all individual drugs, using a validated and published set of 23 criteria concerning effectiveness, safety, pharmacokinetics and pharmacodynamics, experience, and convenience in elderly patients. First, information on the criteria was obtained from pharmaceutical reference books and a MEDLINE search. The information obtained on the individual drugs in the class of opioids was compared with the reference drug morphine. Evidence-based recommendations were formulated on the basis of the pros and cons for the frail elderly. Using the set of 23 criteria, no differentiation can be made between the appropriateness of buprenorphine, fentanyl, hydromorphone, morphine and oxycodone for use in elderly patients. Methadone has strong negative considerations in the treatment of chronic pain in the frail elderly. Methadone has a high drug-drug interaction potential and is associated with prolongation of the QT interval and a potential risk of accumulation due to a long elimination half-life. In addition, methadone is difficult to titrate because of its large inter-individual variability in pharmacokinetics, particularly in the frail elderly. Because of a lack of empiric knowledge, the use of tapentadol is not recommended in frail elderly persons. Nevertheless, tapentadol may prove to be a useful analgesic for the treatment of chronic pain in frail elderly persons because of its possible better gastrointestinal tolerability. In the treatment of chronic pain in the frail elderly, the opioids of first choice are buprenorphine, fentanyl, hydromorphone, morphine and oxycodone. In order to improve the convenience for elderly patients, the controlled-release oral dosage forms and transdermal formulations are preferred.

Statin Prescribing in the Elderly in the Netherlands A Pharmacy Database Time Trend Study

AbstractIntroduction There is some evidence that the beneficial effects of HMG-CoA reductase inhibitors (statins) in the elderly are at least comparable to the effects in middle-aged people. However, several studies have shown prescription rates of statins to be significantly lower in the elderly than in younger populations. Objective The aim of the present study was to monitor statin prescribing trends in the elderly in the Netherlands over time in terms of prevalence, incidence, type of statin, dose prescribed and adherence to clinical guidelines. Methods The database of a community pharmacy in Utrecht, which includes prescription data for approximately 11 000 people, was analysed to investigate trends in statin prescriptions from January 1999 to December 2008. The 1-year prevalence and incidence of statin use stratified by age were determined for each calendar year. Rate ratios (RRs) and 95% confidence intervals were calculated with 1999 as the reference year. Furthermore, the following trends of interest were calculated for each calendar year: the percentage of statin users prescribed simvastatin or atorvastatin, the median dose of simvastatin and atorvastatin prescribed, and the percentage of simvastatin users prescribed a dosage of 40 mg/day (which is recommended by the Dutch multidisciplinary guideline). Results The 1-year prevalence of statin use in medication users aged ≥50 years increased from 13.9% in 1999 to 22.8% in 2008 (RR 1.6; 95% CI 1.4, 1.9; p<0.001). Overall, the lowest prevalence (5.1% in 1999 and 15.2% in 2008) and incidence rates (3.2% in 2000 and 4.2% in 2008) were found in patients aged ≥80 years. Before 2006, simvastatin was the most commonly prescribed statin, but the number of users declined as the percentage of patients with new simvastatin prescriptions decreased (from 43.4% in 2000 to 36.5% in 2005) and the percentage of patients treated with new atorvastatin prescriptions increased (from 37.7% in 2000 to 47.3% in 2005). As from 2006, when the Dutch multidisciplinary guideline for Cardiovascular Risk Management was introduced, recommending treatment with a daily simvastatin dose of 40 mg, the number of simvastatin users increased again and most treatment-naive patients were started on simvastatin (62.3% in 2006, increasing to 66.7% in 2008). The median simvastatin dose increased from 10 mg in 1999 to 20 mg in 2001, remaining at the same dose until 2008, and appeared to be related to the patient’s age. From 2006, patients aged ≥80 years were the least likely group to receive the recommended dose of 40 mg simvastatin daily (10.0–20.0% of simvastatin users aged ≥80 years compared with 32.5–36.9% of simvastatin users aged 60–69 years). Conclusion Despite the benefits of statin treatment previously reported in older patients, the prevalence and incidence of statin use were lower in elderly patients compared with younger patients. In addition, lower dosages of statins were prescribed. These findings suggest the beneficial effects of statins in the elderly observed in clinical trials may not be achieved in everyday practice.

Renal function assessment in older adults

AIMS The Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD) and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formulae are often used to estimate glomerular filtration rate (GFR). The objective was to determine the best method for estimating GFR in older adults. METHODS A cross-sectional study was conducted at the geriatric wards of two hospitals in The Netherlands. Patients aged 70 years or above with an estimated (e)GFR below 60 ml min⁻¹  1.73 m⁻² were included. The CG, CG calculated with ideal bodyweight (IBW), MDRD and CKD-EPI formulae were compared with a criterion standard, sinistrin clearance. Renal function was classified into five stages according to the National Kidney Foundation Disease Outcomes Quality Initiative chronic kidney disease classification, as follows (in ml min⁻¹  1.73 m)⁻²: stage 1, eGFR ≥ 90; stage 2, eGFR of 60-89; stage 3, eGFR of 30-59; stage 4, eGFR of 15-29; and stage 5, eGFR < 15. RESULTS Sixteen patients, 50% male, with a mean age of 82 years (range 71-87 years) and mean body mass index 26 kg m⁻² (range 18-36 kg m⁻²), were included. On average, all formulae slightly overestimated GFR, as follows (in ml min⁻¹  1.73 m⁻²: CG +0.05 [95% confidence interval (CI) -28 to +28]; CG with IBW +0.03 (95% CI -20 to +20); MDRD +9 (95% CI -16 to +34); and CKD-EPI +5 (95% CI -20 to +29). They classified kidney disease correctly in 68.8% (CG), 75% (CG with IBW), 43.8% (MDRD) and 68.8% (CKD-EPI) of the participants, respectively. CONCLUSIONS The CG, CG with IBW, MDRD and CKD-EPI formulae estimate the mean GFR of a population rather well. In individual cases, all formulae may misclassify kidney disease by one stage.

The course of behavioral problems in elderly nursing home patients with dementia when treated with antipsychotics

BACKGROUND Although antipsychotic treatment of behavioral problems in dementia is common, studies investigating the course of these symptoms in nursing homes are scarce. Our primary objective is therefore to describe the course of behavioral problems during antipsychotic treatment in a large sample of elderly nursing home patients with dementia. METHODS The course of behavioral problems during antipsychotic treatment was studied by comparing the characteristics of patients before, during and after antipsychotic treatment. The study was conducted using the VURAIDB, a database with over 40,000 assessments of over 10,000 nursing home residents in the Netherlands. We used the Challenging Behavior Profile (CBP) to measure an overall behavior score. RESULTS In total, 556 patients starting with antipsychotics were studied. Of these, 101 (18.2%) improved and 260 (46.8%) deteriorated at three months on the behavior score, compared with their scores before therapy (z = -7.955; P<0.0001). Patients with severe challenging behavior showed improvement more often than patients with mild disturbances. The course of behavioral symptoms after withdrawal was evaluated in 520 patients. Of these patients, 352 (68%) remained stable or improved at 3 months compared with their scores before withdrawal (z = -0.697; p = 0.486), this figure was 58% at 6 months after withdrawal (z = -2.77; p = 0.006). CONCLUSIONS During treatment of nursing home residents with dementia with antipsychotics the severity of most behavioral problems continues to increase in most patients, with only one out of six patients showing improvement. After withdrawal of antipsychotics, behavioral problems remained stable or improved in 58% of patients.

Prevalence of hyponatremia on geriatric wards compared to other settings over four decades: A systematic review

Aim of the study was to analyze temporal trends in prevalence of hyponatremia over four decades in different settings. A systematic review of the literature from 1966 to 2009 yielded prevalences of hyponatremia, with standard errors (SE) and pooled estimated means (PEM), calculated by year and setting (geriatric, ICU, other hospital wards, psychiatric hospitals, nursing homes, outpatients). 53 studies were included. Prevalence of hyponatremia was stable from 1976 to 2006, and higher on geriatric wards accept for ICU: e.g. PEM prevalence of mild hyponatremia (serum sodium <135 mM) was 22.2% (95%CI 20.2-24.3) on geriatric wards, 6.0% (95%CI 5.9-6.1) on other hospital wards and 17.2% (SE 7.0) in one ICU-study; for severe hyponatremia (serum sodium<125 mM) these figures were 4.5% (95%CI 3.0-6.1), 0.8% (95%CI 0.7-0.8) and 10.3% (SE 5.6). In nursing homes PEM prevalence of mild hyponatremia was 18.8% (95%CI 15.6-22.2). The higher prevalence on geriatric wards could partly be explained by age-related changes in the regulation of serum sodium. Other underlying factors can be the presence of multiple diagnoses and the use of polypharmacy.