Early identification of long-term poor adherence in ambulatory patients.
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Aged↗
Biomedical subjects
Antoine C G Egberts
Publications and source records attributed to Antoine C G Egberts.
The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice.
PURPOSE: This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. METHODS: The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. RESULTS: For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. CONCLUSIONS: CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.
Antidepressive Agents↗
Potential bias in pharmacoepidemiological studies due to the length of the drug free period: a study on antidepressant drug use in adults in the Netherlands.
PURPOSE: The aim of this study was to evaluate the effect of the length of the drug free period on incidence measurements as well as on cohort characteristics in users of antidepressants. METHODS: The study population consisted of patients aged 18 years or older who filled a prescription for an antidepressant drug in the Netherlands, between October 2001 and September 2002. One-year incidence of antidepressant drug use was estimated using drug free periods varying in length from 1 month to 9 years. In addition, we evaluated what effect the drug free period has on cohort characteristics by comparing a cohort of first time antidepressant drug users defined using a 9-year drug free period with cohorts using 6, 12 and 24 months drug free period. RESULTS: When using a 6-month drug free period the measured incidence was about 32 per 1,000 individuals (95%CI: 31.3, 32.6) while the measured incidence was 27.5 (95%CI: 26.9, 28.1), 23.5 (95%CI: 22.9, 24.0) and 17.2 (95%CI: 16.7, 17.7) per 1,000 individuals when using a 12-month, 24 month respectively a 9-year drug free period. Furthermore, the prevalence of characteristics in inception cohort studies changes when using different drug free periods. CONCLUSION: Altering the drug free period from a short to a longer one results in decreased incidence. Furthermore, for inception cohorts where first time drug use is an inclusion criterion the drug free period can influence the prevalence of cohort characteristics and for short drug free periods give biased estimates.
Adolescent↗
VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation.
OBJECTIVE: Our objective was to assess the effects of VKORC1 and CYP2C9 genotypes on severe overanticoagulation and time to achieve stability and their contributions to dose requirement during the initial phase of acenocoumarol treatment. METHODS: A prospective follow-up study was conducted at 2 anticoagulation clinics in The Netherlands. We assessed the CYP2C9 genotype (CYP2C9*2 and CYP2C9*3 polymorphisms) and the VKORC1 C1173T genotype of the subjects and collected data on international normalized ratio, dose, comedication, and comorbidity. RESULTS: Of the 231 patients in the cohort, 150 (64.9%) had a VKORC1 C1173T polymorphism and 84 (36.4%) had a CYP2C9*2 or CYP2C9*3 allele. Only carriers of a combination of a CYP2C9 polymorphism and a VKORC1 polymorphism had an increased risk of severe overanticoagulation compared with subjects with no polymorphism or only 1 polymorphism (hazard ratio, 3.83 [95% confidence interval, 1.62-9.05]). The time to achieve stability was associated with the possession of the CYP2C9 genotype, not with the VKORC1 genotype (hazard ratio for CYP2C9*3 allele compared with CYP2C9 wild type, 0.59 [95% confidence interval, 0.40-0.87]). Patients with a VKORC1 polymorphism required significantly lower doses than VKORC1 CC wild-type patients. A larger part of the variability in dose requirement was explained by the VKORC1 genotype than by the CYP2C9 genotype (21.4% and 4.9%, respectively). CONCLUSION: Being a carrier of a combination of polymorphisms of VKORC1 and CYP2C9, rather than of one of these polymorphisms, is associated with severe overanticoagulation. The time to achieve stability is mainly associated with the CYP2C9 genotype.
Acenocoumarol↗
The association between cytochrome P450-2D6 genotype and prescription of antiparkinsonian drugs in hospitalized psychiatric patients using antipsychotics: a retrospective follow-up study.
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Antiparkinson Agents↗
Drug-induced thrombocytopenia: a population study.
BACKGROUND: Drug-induced immune thrombocytopenia, excluding heparin-induced thrombocytopenia, is a rare adverse drug reaction for which the evidence about frequency, relative risk and risk factors mainly originates from case reports and case studies. This study aims to quantify the risk for thrombocytopenia following exposure to drugs that are most often reported to cause thrombocytopenia in the general population. METHODS: A retrospective, case-control study was conducted within the PHARMO record linkage system. Cases were defined as patients hospitalised for thrombocytopenia in the period 1 January 1990 to 31 December 2002. For each case, up to four controls were matched based on age, sex and geographical area. Exposure on the index date to anticonvulsants, beta-lactam antibacterials, cinchona alkaloids, disease modifying antirheumatic drugs (DMARDs), diuretics, NSAIDs, sulfonamide antibacterials and tuberculostatics was assessed and categorised into mutually exclusive groups of current, recent, past and non-use. The risk was quantified with multivariate conditional logistic regression analysis. RESULTS: The study population comprised 705 cases and 2658 controls. Current use of beta-lactam antibacterials was associated with an increased risk for thrombocytopenia (adjusted odds ratio 7.4, 95% CI 1.8, 29.6). Increased risk estimates, although not significant, were found for current exposure to DMARDs and the sulfonamide antibacterial cotrimoxazole (trimethoprim/sulfamethoxazole). No increased risk was found for anticonvulsants, cinchona alkaloids, diuretics, NSAIDs or tuberculostatics. CONCLUSION: More evidence for an increased risk for thrombocytopenia in current use of beta-lactam antibacterials in the general population was provided. The expected increase in risk could not be confirmed for the other drugs investigated, which is possibly a result of the limited statistical power. Future studies including more patients and with laboratory data should confirm our findings before drawing definite conclusions.
Anti-Infective Agents↗
Clinical risk management in Dutch community pharmacies: the case of drug-drug interactions.
BACKGROUND: The prevention of drug-drug interactions requires a systematic approach for which the concept of clinical risk management can be used. The objective of our study was to measure the frequency, nature and management of drug-drug interaction alerts as these occur in daily practice of Dutch community pharmacies. METHODS: In total, 63 Dutch pharmacies collected all drug-drug interaction alerts during 153 research days (on average 2.4 days/pharmacy), as well as variables related to these alerts, such as involved medicines, first time or recurrent drug-drug interaction, same or different prescribers, patient data (age, sex) and information about the management of drug-drug interactions by the pharmacy. The latter was discriminated into internal procedures only and external action, such as communication with the patient, the prescriber or the anticoagulation clinic and prescription modification. All drug-drug interactions were classified into categories of clinical relevance (A-F) and available evidence (0-4). RESULTS: A total of 43,129 prescription-only medicines were dispensed during the study period. On average, 16.8 interaction alerts per day per pharmacy were collected. Approximately 6% of all prescriptions generated a drug-drug interaction alert. Of all alerts (n = 2572), 31.1% occurred for the first time and with 21% two different prescribers were involved. The 20 most frequently occurring drug-drug interaction alerts accounted for approximately 76% of all alerts. Cardiovascular drugs, NSAIDs, oral contraceptives and antibacterials were most frequently involved. External action was taken in response to 27.3% of the alerts, meaning either a modification of one of the concerned prescriptions (n = 65; 9.3%), communication with the prescriber or anticoagulation clinic (n = 90; 12.8%) or communication with the patient or a relative (n = 547; 77.9%). Where there was no external action (n = 1860; 72.3%), pharmacists concluded in about two-thirds of cases that the drug-drug interaction had been managed in the past. Other reasons not to intervene externally were for instance: incorrect alert; acceptable drug-drug interaction; or outcome of the interaction considered irrelevant. Adjusted for several variables, a first alert was found to be a main determinant for external action. After stratifying for first alerts no other significant determinants were found. CONCLUSIONS: A high frequency of drug-drug interaction alerts was found. Most concerned recurrent alerts, which were the main reason not to act externally. Concerning the assessment phase in the risk-management process, drug-drug interactions with no or low evidence/relevance should be reconsidered. Concerning the management of drug-drug interactions in pharmacies, the opportunity to actively suppress alerts for a certain period of time should be studied in more detail. There are indicators that the management of patient-orientated advice could be improved and a greater degree of consistency developed for the management of first and recurrent interaction alerts.
Adolescent↗
Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: comparison with officially recommended doses.
OBJECTIVE: To determine the doses of haloperidol as a comparator drug in randomized controlled trials (RCTs) with atypical antipsychotics in patients with schizophrenia and to compare these doses with the officially recommended doses for haloperidol in the United States and the United Kingdom. DATA SOURCES: We searched for RCTs conducted and published in English in full before January 2005 in which atypical antipsychotics were compared with haloperidol for the treatment of schizophrenia. We searched for Cochrane Reviews in which 1 of the following atypical antipsychotics was evaluated for the treatment of patients with schizophrenia, schizophreniform psychosis, or other primary psychosis: amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone. For the gap between the end point of inclusion of the studies in the Cochrane Reviews and January 2005, we electronically searched the Cochrane Central Register of Controlled Trials for any further RCTs in which atypical antipsychotics were compared with haloperidol for the same indication. Search terms used were haloperidol and schizophren and haloperidol and psychotic, as well as the names of the selected atypical antipsychotics for the years that were not covered by the Cochrane Reviews. For each study, the required dose and mean dose of haloperidol were compared with officially recommended doses of haloperidol in U.S. (Food and Drug Administration) and U.K. (British National Formulary) guidelines. DATA SYNTHESIS: In all of the included studies (N = 49), the midpoints of the required doses were above the midpoint of the official recommended doses in the United States and United Kingdom for moderately ill patients. In 94% (U.S.) and 80% (U.K.) of the studies, they were above the upper border of the recommended doses. Compared with recommended doses for severely ill patients in both the United Kingdom and United States (range, 6-15 mg daily), in 17 studies (35%) the mean actual used dose was above the upper dose border for severely ill patients (15 mg daily). CONCLUSIONS: Nearly all randomized clinical trials used haloperidol in doses that were higher than the official recommended doses for moderately ill or even severely ill patients. Therefore, it is probable that the results of the RCTs were affected by the high dose of haloperidol, hampering the interpretation of the effects of atypical anti-psychotics in their comparison with haloperidol.
Antipsychotic Agents↗
Disease and intolerability documentation in electronic patient records.
BACKGROUND: Documentation of diseases and intolerabilities in electronic patient records (EPRs) in pharmacies is needed to produce an alert in case a contraindicated medicine is prescribed. Limited research is available concerning EPRs in pharmacies. OBJECTIVE: To study the prevalence and quality of documentation of diseases and intolerabilities in EPRs in a sample of Dutch community pharmacies. METHODS: Each participating pharmacy (N = 79) collected data on one day in May 2003 for each patient enrolled into the study (N = 687) concerning demographics, drug use, and documentation of diseases and intolerabilities. RESULTS: In 57.4% of the EPRs, at least one disease and, in 7.9%, at least one intolerability was documented. Higher age, number of drugs used, and chronic disease score were associated with any documentation of a disease/intolerability in the EPR. The highest sensitivity scores (completeness) were found for diabetes (84.7%), asthma/chronic obstructive pulmonary disease (strict definition: 75.9%), and hypothyroidism (75.0%). Rather low values were found for prostatic hyperplasia (55.6%) and heart failure (29.4%). The positive predictive value (reliability) was high for hypothyroidism (100%) and diabetes (87.1%). CONCLUSIONS: In a selection of Dutch pharmacies, at least one documented disease and/or intolerability was found in the EPR of almost 60% of the patients. Certain diseases were documented to a relatively high degree; others had poorer levels of documentation. For optimal surveillance of drug-disease interactions in pharmacies, the frequency and quality of disease and intolerability documentation need further improvement.
Community Pharmacy Services↗
Risk of hip/femur fractures in patients using antipsychotics.
The objective of our study was to investigate whether use of antipsychotics is associated with hip/femur fractures and whether pharmacological differences between antipsychotics are related to the occurrence of fractures. A case-control study was conducted, in which cases were defined as patients with a hip/femur fracture. Each patient was matched to one control patient. The association between use of antipsychotics and the occurrence of hip/femur fractures was evaluated using conditional logistic regression. The study included 44,500 patients from 683 general practices from different geographical areas in the UK, registered within the General Practice Research Database (GPRD). Exposure to antipsychotics was categorized as "no use", "current use" and "prior use". Both current and prior use of antipsychotics were associated with an approximately two-fold increased risk of fractures. After adjustment for possible confounders, a small significant effect remained (Odds Ratios (OR) of 1.3). We did not find an association between dose of antipsychotics, or between the degree of blockade of the alpha-1 adrenoceptor or histamine-1 receptor and risk of fractures. The total number of days of antipsychotic use was significantly associated with an increased risk of hip/femur fractures. We conclude that there is a small increased risk of hip/femur fractures associated with the use of antipsychotics. This risk increases with long-term use.
Adolescent↗
The impact of hospitalisation on the initiation and long-term use of benzodiazepines.
BACKGROUND: Inappropriate (long-term) use of benzodiazepines (BZDs) is a reason for concern. Several studies have suggested that hospitalisation may be a determinant for initiation of BZD use as well as for long-term use. However, the available evidence is conflicting. OBJECTIVE: To determine whether hospitalisation induces initiation of BZD use and subsequent long-term use. METHODS: A retrospective follow-up study was conducted. Randomly, 10,000 patients who had been hospitalised were selected (index date). Non-hospitalised patients, matched on age and gender, were sampled from the same living region and assigned the same index date as the corresponding hospitalised patient. Patients were included if adequate medication data were available from 18 months before to 18 months after the index date. Initiation of BZD use was defined as a prescription for a BZD or BZD-related hypnotic without a prescription for any of these drugs during the prior 6 months. Long-term use was defined as a period of consecutive use for at least 6 months following initiation. RESULTS: In this study, 8,681 hospitalised patients and an equal number of non-hospitalised patients were finally included. Overall, the relative risk for initiation of BZD use was almost twice as high [IDR 1.97 (95%CI 1.84-2.10)] among hospitalised patients as in non-hospitalised patients. This relative risk was most clearly elevated during the time window from 3 months before to 3 months after hospitalisation [IDR 4.81 (95%CI 4.08-5.67)]. The relative risk for long-term use during the entire 36-month observation period was not higher [IDR 1.04 (95%CI 0.95-1.13)] among hospitalised patients than among non-hospitalised patients. Within the time window of 3 months before and after hospitalisation, the relative risk for long-term use was significantly lower for the hospitalised group [RR 0.82 (CI 0.69-0.98)]. CONCLUSION: Our results confirm that hospitalisation is associated with an increased risk for initiation of BZD use; the risk is highest during the 3 months just before and after hospitalisation. However, hospitalisation appeared not to be a determinant for long-term use of BZDs.
Age Factors↗
Methylphenidate: use in daily practice.
OBJECTIVE: With the aim of getting more insight into compliance of children using methylphenidate, we studied the day-to-day use of the drug. In addition, the efficacy and side effects of treatment, stopping, switching to other drugs and the use of additional psychoactive drugs in daily practice were studied. METHOD: On the basis of pharmacy records, the use of methylphenidate by 52 children was studied. Two parameters for compliance were calculated. By means of a questionnaire, parents were asked about their children's compliance with the use of methylphenidate as well as about their experience with treatment. MAIN OUTCOME MEASURE: Compliance, use of methylphenidate in weekends and holidays, self-reported efficacy, side effects, stopping and switching to other drugs. RESULTS: Depending on the parameter calculated, the percentage of children with a good compliance varied from 25 to 47%. About 65% of the children used less or no methylphenidate in the weekends and holidays. Sixty-five percent of the parents reported to pass over a dose once in a while. According to 61% of the parents (n = 28) the efficacy of methylphenidate was good or very good. Nine (33%) of 28 children stopped using methylphenidate. Seven children stopped using the drug because of side-effects or lack of efficacy. Seven children switched to other psychoactive drugs. Fifty-seven percent of all children used additional psychoactive drugs. CONCLUSION: The percentage of children having a good compliance calculated on the basis of pharmacy records is rather low. This is partly the result of the decreased use of methylphenidate in the weekends and holidays.
Adolescent↗
The association between cytochrome P450 2D6 genotype and prescription patterns of antipsychotic and antidepressant drugs in hospitalized psychiatric patients: a retrospective follow-up study.
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Antidepressive Agents↗
Impaired glucose homeostasis after imipramine intake in a diabetic patient.
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Antidepressive Agents, Tricyclic↗
Effect of low-intensity acenocoumarol on frequency and severity of migraine attacks.
OBJECTIVE: To investigate the effect of low-intensity acenocoumarol treatment (target INR 1.5 to 2.0) on the frequency and severity of migraine attacks. BACKGROUND: The positive effect of anticoagulation on migraine has been described in case reports and observational studies. METHODS: We conducted a randomized, open, crossover study in migraine patients. After a run-in period of 8 weeks, all patients received acenocoumarol or propranolol during a period of 12 weeks and, after a washout period of 2 weeks, propranolol or acenocoumarol during a second period of 12 weeks. RESULTS: Nineteen patients fulfilling the criteria were included. In 12 patients with complete data collection, only one good responder could be noted. In the other patients, treatment with low-intensity acenocoumarol did not show improvement of migraine symptoms compared with the run-in period. Treatment with propranolol showed a trend towards improvement compared with the run-in period. No serious adverse events were observed. CONCLUSIONS: Overall, low-intensity acenocoumarol treatment has no prophylactic effect in migraine patients.
Acenocoumarol↗
Association of risk of abnormal bleeding with degree of serotonin reuptake inhibition by antidepressants.
BACKGROUND: Serotonin plays a role in platelet aggregation. Because antidepressants influence blood serotonin levels, their use may be associated with an increased risk of abnormal bleeding. However, previous studies were inconclusive regarding this association. The aim of this study was to estimate the risk of abnormal bleeding associated with the use of antidepressants and to establish the relationship between serotonin reuptake inhibition and the risk of bleeding. METHODS: We used data collected from 1992 through 2000 to conduct a nested case-control study of a cohort of more than 64 000 new antidepressant users. Cases were identified as all patients hospitalized for a primary diagnosis of abnormal bleeding, and they were matched with controls for age and sex. We classified exposure according to the degree (high, intermediate, or low) of serotonin reuptake inhibition and performed logistic regression analysis to calculate odds ratios. RESULTS: There were 196 cases of abnormal bleeding. The risk of hospitalization increased with the use of inhibitors providing intermediate (odds ratio, 1.9; 95% confidence interval, 1.1-3.5) and high degrees of serotonin reuptake inhibition (odds ratio, 2.6; 95% confidence interval, 1.4-4.8). CONCLUSIONS: In a large population of new antidepressant users we found a significant association between degree of serotonin reuptake inhibition by antidepressants and risk of hospital admission for abnormal bleeding as the primary diagnosis. An increased risk of abnormal bleeding was strongly associated with the degree of serotonin reuptake inhibition.
Antidepressive Agents↗
The risk of cancer in users of statins.
PURPOSE: Several preclinical studies suggested a role for 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) in the treatment of cancer. The objective of this study was to compare the risk of incident cancer between users of statins and users of other cardiovascular medication. METHODS: Data were used from the PHARMO database, containing drug dispensing records from community pharmacies and linked hospital discharge records for residents of eight Dutch cities. The study base included all patients with one or more prescriptions for cardiovascular drugs in the period between January 1, 1985 and December 31, 1998. Cases were identified as patients in the study base with a diagnosis of incident cancer and matched with four to six controls on sex, year of birth, geographic region, duration of follow-up, and index date. The analysis was adjusted for diabetes mellitus; prior hospitalizations; comorbidity; and use of diuretics, angiotensin-converting enzyme inhibitors, calcium-channel blockers, nonsteroidal anti-inflammatory drugs, sex hormones, and other lipid-lowering drug therapies. RESULTS: In the study base, 3129 patients were identified and matched to 16976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91). CONCLUSION: This observational study suggests that statins may have a protective effect against cancer.
Aged↗
Incidence and determinants of long-term use of antidepressants.
OBJECTIVES: The use of antidepressants has increased over the years, which may be due to more new antidepressant users, but also may be due to a longer duration of use. We aimed to assess the prevalence, incidence and average duration of selective serotonin reuptake inhibitor (SSRI) and tricyclic antidepressant (TCA) use in the Netherlands during 1992-2001. In addition, we assessed the incidence of long-term use of SSRIs and identified possible determinants of long-term use. METHODS: We assessed prevalence (number of current users of an antidepressant per 1000 persons assessed on a single day) and incidence (number of new users per 1000 persons per year) of antidepressant use for each year in the PHARMO record linkage system. Long-term use was defined as the consecutive use of any antidepressant for at least 12 months. Relative risks and hazard ratios were calculated and adjusted for possible determinants using Poisson and Cox regression analyses. RESULTS: Both prevalent and incident use of SSRIs increased during 1992-2001, while TCA use remained stable. A total of 9857 patients using SSRIs were included in a follow-up study. During the follow-up period, more patients became long-term users, either directly after the start of the initial SSRI or anytime during follow-up (29.5%). The average number of days before start of long-term use decreased from 595 days in 1991 to 19 days in 1997. Female patients, older age, previous use of benzodiazepines and being treated by a psychiatrist increased the probability of becoming a long-term user. CONCLUSION: Both prevalent and incident use of SSRIs increased during the 1990s, implicating an increased number of patients starting SSRIs, but also a longer duration of use of antidepressant therapy. Over the entire follow-up period, almost 30% of the patients became long-term users at anytime during the follow-up period.
Adolescent↗