Eibert R. Heerdink

Rate and determinants of 10-year persistence with antihypertensive drugs

Objective To assess the proportion of patients starting with antihypertensive drug treatment who continued treatment for at least 10 years. Design A retrospective cohort study. Setting The PHARMO record linkage system containing drug dispensing records from community pharmacies and linked hospital discharge records of approximately 950 000 subjects. Participants Patients who started using antihypertensive drugs (two or more prescriptions) in 1992 and did not receive a prescription for any antihypertensive drug in the 365 days preceding the first prescription. Main outcome measure Persistence with antihypertensive drugs until 10 years. Results Among a total of 2325 patients who started using antihypertensive drugs, 39% used continuously during the 10 years of follow-up. Approximately 22% temporarily discontinued and restarted treatment, whereas 39% of patients discontinued permanently. Older patients were more persistent than younger patients [20–39 years: odds ratio (OR) 2.08; 95% confidence interval (CI) 1.52–2.84; 40–59 years: (reference), ≥ 60 years: OR 0.69; 95% CI 0.54–0.89]. More patients who started with diuretics (reference) and beta blockers (OR 1.15; 95% CI 0.87–1.52) discontinued compared with those who started with dihydropyridine calcium antagonists (OR 0.54; 95% CI 0.34–0.84), and angiotensin-converting enzyme (ACE) inhibitors (OR 0.38; 95% CI 0.27–0.55). Patients who started with combination therapy (OR 0.29; 95% CI 0.14–0.54 compared with diuretics) or patients who were initially treated by a cardiologist (OR 0.82; 95% CI 0.61–0.97) or internist (OR 0.80; 95% CI 0.62–0.98 compared with general practitioners) also showed higher persistence. Conclusion Long-term persistence in daily practice is low compared with persistence observed in randomized clinical trials and should be considered in the choice of a first-line antihypertensive agent.

Effect of a pharmacist-led intervention on diuretic compliance in heart failure patients: a randomized controlled study

BACKGROUND Noncompliance is a major factor in the morbidity and unnecessary hospital readmissions for patients with heart failure. Several studies have aimed to reduce rehospitalizations in heart failure patients through a comprehensive, multidisciplinary approach. Medication compliance was rarely measured in these studies or, when it was measured, the method employed was seldom valid. We aimed at determining the effect of a pharmacist-led intervention on medication compliance in patients with heart failure. METHODS We conducted a randomized controlled trial into the effect of a pharmacist-led intervention on medication compliance in patients with heart failure (predominantly New York Heart Association [NYHA] II and III) treated with loop diuretics, presenting to a cardiology outpatient clinic or admitted to hospitals in The Netherlands. Patients in the intervention group received monthly consultations from their community pharmacist during a 6-month period. Patients in the control group received usual care. Primary endpoint was medication compliance, assessed with a medication event monitoring system, an electronic pill bottle that registers time of opening. Secondary endpoints were the number of rehospitalizations, death, and quality of life. RESULTS A total of 152 patients were randomized: 74 patients to the intervention arm and 78 patients to the usual care arm. Over the 6-month study period, patients in the intervention group had 140/7656 days without use of loop diuretics compared with 337/6196 days in the usual care group (relative risk 0.33 [confidence interval (CI) 95% 0.24-0.38]). Two consecutive days of nondosing occurred on 18/7656 days in the intervention group compared with 46/6196 days in the usual care group (relative risk 0.32 [CI 95% 0.19-0.55]). There were no significant differences in rehospitalizations, mortality, or disease-specific quality of life between groups. CONCLUSIONS A pharmacy-led intervention can improve medication compliance in patients with moderate to severe heart failure, even in those with relatively high compliance. Future interventions should also focus at less compliant patients.

Predicting mortality in patients with heart failure: a pragmatic approach.

Objective: To develop a comprehensive and easily applicable prognostic model predicting mortality risk in patients with moderate to severe heart failure. Design: Prospective follow up study. Setting: Seven general hospitals in the Netherlands. Patients: 152 outpatients with heart failure or patients admitted to hospital because of heart failure, who were included in a randomised trial to assess the impact of a pharmacist led intervention to improve drug compliance. Duration of follow up was at least 18 months. Main outcome measures: Multivariable logistic regression modelling was used to evaluate information from history, physical examination (for example, blood pressure), drug use, and quality of life questionnaires that independently contributed to the prediction of death. The area under receiver operating characteristic curves (AUC) was used to estimate the predictive ability of the prognostic models. Results: During the 18 months of follow up, 51 patients (34%) died. Independent predictors of mortality were diabetes mellitus, a history of renal dysfunction (or higher creatinine), New York Heart Association (NYHA) functional class III or IV, lower weight or body mass index, lower blood pressure, ankle oedema, and higher scores on a disease specific quality of life questionnaire. The use of β blockers was predictive of a better prognosis. These factors were used to derive various prediction formulas. A model based on medical history, weight, presence of oedema, and lower blood pressure had an AUC of 0.77. Addition of use of β blockers to this model improved the AUC to 0.80. Addition of NYHA class increased the AUC to 0.84. Data on quality of life did not improve the AUC further (AUC 0.85). Conclusions: A prognostic model produced on the basis of easily obtainable information from medical history and physical examination can adequately stratify heart failure patients according to their short term risk of death.

Depressive symptoms in subjects with diagnosed and undiagnosed type 2 diabetes

Objective: To investigate if disturbed glucose homeostasis or known diagnosis of diabetes was associated with depressive symptoms. The reason for the increased prevalence of depression in patients with Type 2 diabetes mellitus (DM2) is unknown. Methods: Within the Utrecht Health Project, an ongoing longitudinal study among inhabitants of a residential area of a large city in The Netherlands, 4747 subjects (age: 39.4 ± 12.5 years) were classified into four mutually exclusive categories: normal fasting plasma glucose (FPG) (<5.6 mmol/l), impaired FPG (≥5.6 and <7.0 mmol/l), undiagnosed DM2 (FPG ≥7.0 mmol/l), and diagnosed DM2. Presence of depressive symptoms was defined as a score of ≥25 on the depression subscale of the Symptom Check List (SCL-90) or self-reported use of antidepressants. Results: Diagnosed DM2 was associated with an increased risk of depressive symptoms (odds ratio (OR) = 1.69; 95% confidence interval (CI) 1.06–2.72) after adjustment for demographic and lifestyle variables. Additional adjustment for number of chronic diseases reduced the OR to 1.36 (95% CI 0.83–2.23). Impaired fasting glucose and undiagnosed DM2 were not associated with depressive symptoms. Conclusions: Our findings suggest that disturbed glucose homeostasis is not associated with depressive symptoms. The increased prevalence of depressive symptoms among patients with diagnosed DM2 suggests that depressive symptoms might be a consequence of the burden of diabetes. The number of chronic diseases seems to explain part of the association between DM2 and depressive symptoms. DM2 = Type 2 diabetes mellitus; CI = confidence interval; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, fourth revision; FPG = fasting plasma glucose; OR = odds ratio; SCID = Structured Clinical Interview for DSM-IV; SCL-90 = Symptom Checklist; SD = standard deviation; SPSS = Statistical Package for the Social Sciences; UHP = Utrecht Health Project.

Application of the ATC/DDD methodology to monitor antibiotic drug use

In order to monitor the use of antibiotics, it is essential to have comprehensive data on drug consumption. The findings of drug utilisation studies can serve to describe the pattern of drug use in a particular population, to detect areas of concern, and to evaluate the impact of interventions taken to influence the use of drugs. In the present study, the Anatomical Therapeutical Chemical Classification/Defined Daily Doses (ATC/DDD) system developed by the World Health Organisation was evaluated. The system measures the amount of drug use independentof package size and sales price, which allows comparisons not only within an institution but also within a region, a country, or even internationally. Obviously, there can be no modifications of this system. To illustrate the method, the pattern of quinolone use in the general population, in long-term care facilities, and within a single institution was analysed. These drugs were widely used in long-term care facilities in the Nijmegen region of the Netherlands, accounting for about 30% of the antibiotics used in these settings, whereas in the general population as well as in the University Hospital Nijmegen, these drugs constitute only about 6% of the total antibiotics used. These differences are large enough to warrant closer analysis of patterns of antibiotic usage in different settings to identify the reasons for the use of quinolones and to identify measures that might be taken to rationalise the prescription of these drugs.

Initiation of antidepressant therapy: do patients follow the GP's prescription?

BACKGROUND The question whether patients actually start drug taking after having received a first antidepressant prescription is often overlooked. AIM To determine the incidence of patients who do not fill or fill only a single antidepressant prescription at the pharmacy, and to identify associated patient characteristics. DESIGN OF STUDY Retrospective study linking a general practice to a pharmacy dispensing database. SETTING General practice in the Netherlands. METHOD STUDY POPULATION patients who received a first-time antidepressant prescription from a GP. Three patient groups were identified: patients who did not fill the prescription (non-fillers); patients who filled only a single prescription (single Rx-fillers); and patients who filled at least two consecutive prescriptions. Non-fillers and single Rx-fillers were combined into a group of decliners. RESULTS Of all 965 patients, 41 (4.2%) did not fill the prescription, and 229 (23.7%) filled only a single prescription. Patients who consulted their GP for a non-specific indication, rather than for depression, anxiety, panic, or obsessive-compulsive disorder, were almost three times more likely (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.8 to 3.9) to decline treatment. Further, the risk of declining was almost fivefold higher (OR = 4.8, 95% CI = 2.1 to 11.3) in non-Western immigrants, and almost twofold higher (OR = 1.8, 95% CI = 1.2 to 2.8) in patients >60 years of age. CONCLUSION Over one in four patients who receive a first-time antidepressant prescription decline treatment; they either do not initiate drug taking or do not persist with antidepressant use for longer than 2 weeks.

The association between antidepressant use and disturbances in glucose homeostasis: evidence from spontaneous reports.

ObjectivesDepression is common in patients with diabetes, and the use of antidepressants may impair glycaemic control. We assessed the association between antidepressant use and hyper- and hypoglycaemia.MethodsBased on spontaneous reports listed in the World Health Organization (WHO) Adverse Drug Reaction Database, a case-control study was conducted. The study base consisted of all adverse drug reactions (ADRs) ascribed to antidepressants, antipsychotics and benzodiazepines between 1969 and 2005. Cases were defined as reported ADRs classified as hyper- or hypoglycaemia and separated in different study populations. All other reports were considered as controls. Exposure to antidepressants was the primary determinant investigated. Benzodiazepines and antipsychotics were chosen as reference groups. Potential confounding factors, namely, age, gender, use of antidiabetic medication, use of hyper- or hypoglycaemia-inducing comedication and reporting year, were determined on the index date. Multivariate logistic regression was used to evaluate the strength of the association, which was expressed as reporting odds ratios (RORs) with 95% confidence intervals (95% CI).ResultsOverall, the use of antidepressants was associated with hyperglycaemia [ROR 1.52 (95% CI: 1.20–1.93)] and of hypoglycaemia [ROR 1.84 (95% CI: 1.40–2.42)]. The association with hyperglycaemia was most pronounced for antidepressants with affinity for the 5-HT2c receptor, histamine-1 receptor and norepinephrinic (NE) reuptake transporter. The association with hypoglycaemia was most pronounced for antidepressants with affinity for the serotonin reuptake transporter.ConclusionThe results of this study strengthen the findings in individual case reports that the use of antidepressants is associated with disturbances in glucose homeostasis.

Generic Substitution of Antihypertensive Drugs: Does it Affect Adherence?

Background: Generic substitution is an important opportunity to reduce the costs of pharmaceutical care. However, pharmacists and physicians often find that patients and brand-name manufacturers have doubt about the equivalence of the substituted drug. This may be reflected by decreased adherence to therapy. Objective: To assess the association between generic substitution and nonadherence to antihypertensive drugs. Methods: We conducted a matched cohort study between January 1, 1999, and December 31, 2002. Data were obtained from PHARMO, a record linkage system containing drug-dispensing records from community pharmacies and linked hospital discharge records of approximately 950 000 people in the Netherlands. Residents of 30 medium-sized cities who initiated antihypertensive drug therapy were potential subjects. Refill adherence with antihypertensive drugs after substitution was determined; those with refill adherence below 80% were considered nonadherent. Results: Four hundred sixty-three patients with a substitution in therapy and 565 controls, matched on age, gender, therapy start date, duration of use, and generic product code, were identified. Of the patients who switched from brand-name to generic formulations (“substituted”), 13.6% were nonadherent, and of the non-substituted patients (those who did not switch to generic), 18.7% were nonadherent (OR 0.68; 95% aph.1G163CI 0.48 to 0.96). The association was absent in males. None of the patients discontinued the medication. No differences in hospitalizations for cardiovascular disease in the 6 months after the substitution were observed. Conclusions: Generic substitution of antihypertensive drugs does not lead to lower adherence or more discontinuation and cardiovascular disease–related hospitalizations compared with brand-name therapy. When a less-expensive antihypertensive generic equivalent becomes available, generic substitution should be considered to achieve economic benefits.

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.

Impact of coaching by community pharmacists on drug attitude of depressive primary care patients and acceptability to patients; a randomized controlled trial.

OBJECTIVE To investigate whether an intervention by Dutch community pharmacists improves the drug attitude of depressive patients, who are prescribed a nontricyclic antidepressant by their general practitioner (GP). METHOD A randomized controlled trial with a 3-month follow-up was conducted among consecutive general practice patients who go to 19 pharmacists for antidepressants. The trial consisted of a control group (n=79) that received usual care and an intervention group (n=69) that received three drug coaching contacts at the pharmacy and a 25-min take-home video on the background of depression and the effects of medication. OUTCOME MEASURE Drug attitude (DAI). RESULTS At the baseline measurement there were no significant differences between the intervention and control group on any demographic and health status variables or on clinical symptoms. At the 3-month follow-up intervention patients had a better drug attitude (P=0.03) than their controls and evaluated the coaching of their pharmacist as more positive. They also felt the video to be useful. It had changed their ideas about medication. CONCLUSIONS Coaching by community pharmacists is an effective way to improve drug attitude of depressive primary care patients and it is acceptable to them.