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An early access pathway of conditional approval for potentially beneficial medicines is available within the European regulatory framework. However, marketing authorization does not necessarily result in recommendations for public funding by health technology assessment (HTA) agencies. As conditional approval goes along with less than complete data on benefits and risks of a treatment option for a high medical need, this raises the question how HTA decision-making is affected by these uncertainties.

BACKGROUND: Patients using higher dosages of inhaled or oral glucocorticoids (GCs) have an increased risk of hip/femur fractures. The role of the underlying disease in the aetiology of this increased risk has not been widely studied. OBJECTIVE: To evaluate the contribution of the underlying disease to the risk of hip/femur fracture in patients using inhaled or oral GCs. DESIGN AND SUBJECTS: A case-control study within the Dutch PHARMO-RLS database was conducted. Cases (n = 6763) were adult patients with a first hip/femur fracture during enrolment. Each case was matched to four controls by age, gender and region. RESULTS: The risk of hip/femur fracture increased with current use of inhaled GCs (crude OR 1.30, 95% CI:1.16-1.47) and with current use of oral GCs (crude OR 1.66, 95% CI: 1.46-1.90). After adjustment for disease severity, the risk of hip/femur fracture was no longer statistically significantly increased in inhaled GC users (adjusted OR 1.08, 95% CI: 0.91-1.27), whilst it remained elevated in oral GC users (adjusted OR 1.43, 95% CI: 1.22-1.67). Patients using inhaled GCs without any exposure to oral GCs had no increased risk of fracture (adjusted OR 0.98, 95% CI: 0.79-1.22). CONCLUSION: Inhaled GC users had no increased risk of femur/hip fracture after adjustment for underlying disease severity. Our data suggest that, even at higher dosages, inhaled GC use is not an independent risk factor for fracture. In contrast, oral GC use was associated with an increased risk of fracture, which was not fully explained by the underlying disease severity.

Aim-adrenoceptor blockers have been used with caution in patients with obstructive lung diseases such as asthma or chronic obstructive pulmonary disease (COPD), due to the potentially increased airway reactivity and risk of bronchial obstruction. Cardioselective -adrenoceptor blockers have a more beneficial profile than non-cardioselective -adrenoceptor blockers and can be safely prescribed to patients with both cardiovascular disease and COPD. We hypothesized that cardioselective -adrenoceptor blockers also affect pulmonary function. MethodsThis study was performed within the Rotterdam Study, a prospective population-based cohort study. Effects of cardioselective and non-cardioselective -adrenoceptor blockers on pulmonary function were analysed using regression techniques with multivariable adjustment for potential confounders. ResultsCurrent use of non-cardioselective -adrenoceptor blockers was significantly associated with a lower forced expiratory volume in 1s (FEV1) of -198ml (95% CI -301, -96), with a lower forced vital capacity (FVC) of -223ml (95% CI -367, -79) and with a decreased FEV1:FVC of -1.38% (95% CI -2.74, -0.13%). Current use of cardioselective -adrenoceptor blockers was significantly associated with a lower FEV1 of -118ml (95% CI -157, -78) and with a lower FVC of -167ml (95% CI -222, -111), but did n ConclusionIn our study both non-cardioselective and cardioselective -adrenoceptor blockers had a clinically relevant effect on both FEV1 and FVC. In contrast to cardioselective -adrenoceptor blockers, use of non-cardioselective -adrenoceptor blockers was associated with a significantly lower FEV1:FVC.

Background: Early treatment discontinuation will have a negative effect on a drug's benefit-risk profile if discontinuation occurs earlier in time than the positive effects of treatment. This non-persistence of therapy has been associated with an increased risk of adverse health outcomes. Objective: The aim of this study was to explore relationships between patient characteristics and reasons for and time to discontinuation of rimonabant therapy, focusing on psychiatric events, because these were the main safety concerns for rimonabant. Methods: A modified prescription-event monitoring (M-PEM) study was conducted for rimonabant. Descriptive statistics were used to describe the patient population. Rate ratios with 95% confidence intervals (CIs) were calculated to explore associations between patient characteristics and selected categories of reasons for stopping (RfS). Median times to discontinuation were compared using the Mann-Whitney U test. Results: The cohort comprised 10011 users of rimonabant, three of which were excluded from this analysis because of missing age or sex. A total of 7204 patients (72.0%) stopped using rimonabant (median observation time 323 days, interquartile range: 279-371 days). In addition, patients with a history of psychiatric illness were more likely to discontinue rimonabant therapy early for all reasons, but most pronounced due to psychiatric events (rate ratio 1.79; 95% CI 1.54, 2.09) than those without Conclusions: In this study, reasons for and time to discontinuation were associated with patient characteristics such as medical history. Patients discontinued treatment because of psychiatric events early after starting. In general, identification and characterization of early discontinuers, and increasing the understanding of reasons for stopping, may help healthcare professionals to develop targeted interventions to further improve treatment compliance, thereby optimizing treatment benefits a

Purpose Real-life experience with anti-obesity drugs has shown that psychiatric and cardiovascular diseases may be reported as adverse drug reactions. For adequate risk assessment of these drugs knowledge on baseline risks of patients starting anti-obesity drugs and insight in patterns of use is needed. The aim was to assess whether baseline characteristics of patients starting anti-obesity drugs differ from those not being prescribed these drugs, and to study patterns of anti-obesity drug use. Methods A population-based cohort study was conducted in the IPCI database (1995-2007). The index cohort comprised all persons who started an anti-obesity drug. The reference cohort comprised up to six randomly sampled patients from the same GP practice with same index date. Baseline characteristics were assessed for both cohorts. The index cohort was followed for 1 year to study patterns of drug use. Unconditional logistic regression was used to calculate crude odds ratios and 95% confidence intervals. Results The index and reference cohort comprised 1471 and 8736 persons, respectively. Both cardiovascular and psychiatric co-morbidities were more prevalent among starters compared to non-starters. 77.7% of the patients stopped using anti-obesity drugs within 90 days. Users of amphetamine-like drugs differed from patients using orlistat or sibutramine, whereas users of orlistat and sibutramine were highly comparable. Conclusions The increased prevalence of co-morbidities constitutes a baseline risk which may translate in higher occurrence of psychiatric and cardiovascular diseases during use of anti-obesity drugs, independent of the drugs. The limited period of use might reduce possible cardiovascular benefits of weight reduction induced by these drugs. Copyright (C) 2009 John Wiley & Sons, Ltd.

Objective. To determine the prevalence, incidence and average duration of use of selective serotonin-reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in the Netherlands in 1992-2001, as well as the incidence of prolonged SSRI use and the possible determinants thereof in the years 1991-1997. Design. Descriptive. Method. On the basis of pharmacy data in the PHARMO-database on approximately 850,000 patients, a calculation of the prevalence (number of users of an antidepressant per 1000 persons on an arbitrary day) and the incidence (number of new users per 1000 persons per year) was made for each year. Prolonged use was defined as the uninterrupted use of an antidepressant during at least 12 months. The relative risk for prolonged use was calculated and corrected for possible determinants with the aid of Poisson and Cox regression analysis. Results. Both the prevalence (2.2 to 17.1 per 1000 persons) and the incidence (3-7 to 14.5 per 1000 persons per year) of the use of SSRIs increased in the period 1992-2001 while the use of TCAs remained stable. An increasing number of the 9857 SSRI-users who were included in the follow-up study became long-term users (n = 2909) during the treatment (a total of 30%). Female gender, advanced age, prior use of benzodiazepines and treatment by a psychiatrist were associated with an increased risk of becoming a long-term user. Conclusion. Both the prevalence and the incidence of the use of SSRIs increased during the 1990s. This can be explained by both the larger number of patients starting on an antidepressant and the longer continuation of the treatment. During the follow-up period, 30% of the patients became a long-term user at one time or another.

(B)ackground: Several studies have indicated that type 2 diabetes mellitus is more common among schizophrenic patients than in the general population. In this study, we investigated whether the use of antipsychotic drugs in patients with diabetes leads to worsening of glycemic control. Method: In this cohort study, patients with newly diagnosed type 2 diabetes were selected from the PHARMO Record Linkage System, which comprises pharmacy records for all 320,000 residents of 6 Dutch cities. In total, we identified 2585 patients with incident cases of type 2 diabetes who began treatment with oral hypoglycemic agents between 1991 and 1997 and had a medication history of at least 2 years after diagnosis of diabetes. A change in treatment from oral hypoglycemic agents alone to insulin therapy (with or without continuation of oral hypoglycemic agents) was considered a proxy for deterioration of beta-cell function. We compared the incidence of initiation of insulin therapy between users and nonusers of antipsychotic drugs by performing a Cox proportional hazards model analysis. Results: We found an increased risk for initiation of insulin therapy at 2 years after diagnosis of diabetes in users of antipsychotics compared with nonusers; the relative hazard (hazard ratio) was 2.0 (95% CI = 1.2 to 3.3), which did not change after adjustment for potential confounders. The risk decreased in the years after diagnosis of diabetes. Conclusion: It seems that use of antipsychotics by patients with type 2 diabetes mellitus is associated with initiation of insulin therapy (i.e., "secondary failure"), especially in the first 2 years of the disease.

Purpose The objective of this study was to determine the association between different antihypertensive drug therapies and lower extremity amputations (LEAs) in type 2 diabetes patients. Methods Data were obtained from the PHARMO Record Linkage System comprising pharmacy records and data on hospitalisations for all 450 000 residents of eight Dutch cities. In a nested case-control study among 12 140 type 2 diabetes patients who used antihypertensive drugs, 26 cases with a first LEA and 94 controls without a LEA matched on age, sex and calendar time were identified. Logistic regression was used to estimate the relative risk of LEA and to adjust for potential confounding factors. Results Among type 2 diabetes patients who used antihypertensive drugs, subjects who used thiazide diuretics, alone or in combination, had a higher risk of LEA compared to subjects who used Angiotensin Converting Enzyme (ACE) inhibitor monotherapy (crude odds ratio (OR): 6.11 [95% confidence interval (CI): 1.32-28.27]). The use of thiazide diuretics was also associated with an increased risk of LEA when compared to the use of any non-thiazide antihypertensive drug (adjusted OR: 7.04 [1.10-45.30]). The increased risk of LEA associated with the use of thiazides compared to the use of non-thiazides depended on the duration of use (adjusted ORless than or equal to365 days, 4.82 [0.61-38.34] and adjusted OR>365 days, 26.16 [1.02-674.02], p-trend = 0.01). Conclusions Treatment with thiazide diuretics compared to treatment with other antihypertensive drugs was associated with excess amputations in type 2 diabetes patients. Due to several limitations of this study, our findings do not preclude the use of thiazides in type 2 diabetes mellitus patients as yet. Copyright (C) 2004 John Wiley Sons, Ltd.

Background: The aim of our study was to determine which factors are associated with switching from oral hypoglycaemic agents to insulin therapy in patients with type 2 diabetes mellitus in general practice. Methods: Longitudinal, observational study in a Dutch general healthcare centre. All pharmacologically treated patients with type 2 diabetes mellitus were included (n=152). Comorbidity, laboratory results and medication use were obtained from the general practitioners' files. Results: A total of 31 (20.4%) patients switched from oral hypoglycaemic agents to insulin therapy; they were significantly younger at the onset of diabetes, 50.5 versus 57.7 years. Fasting blood glucose levels and HbA(IC) values were significantly higher after the switch compared with patients on oral treatment, 10.0 mmol/l versus 8.4 mmol/l and 8.8 versus 7.9%, respectively. Concerning comorbidity, they suffered more frequently from acute myocardial infarction, lipid disorders, depression, retinopathy and atrial fibrillation. Cardiovascular disease in general was more often present in patients who switched over to insulin, 77.4% versus 52.9% (OR 3.1; CI 1.2-7.6). Conclusions: Patients who switch over to insulin therapy are younger at diagnosis, suffer from more health problems besides diabetes, especially cardiovascular disease, and have worse metabolic control, compared with users of oral hypoglycaemic agents.

Although patients with type 2 diabetes mellitus and cardiovascular disease share common risk factors, the link between these diseases remains largely unexplained. In this case-control study, the earlier use of cardiovascular drugs (before the diagnosis of diabetes) was investigated among cases with type 2 diabetes mellitus and controls without diabetes. Using the PHARMO database, we identified 4,864 patients who were prescribed oral hypoglycaemic agent (OHA) therapy between 1985-1998 in the Netherlands. For each case, two controls matched on age, sex and pharmacy were randomly selected. Controls had not received insulins or OHA therapy. There were 2,656 (55.0%) cases compared with 2,727 (28.1%) controls who used cardiovascular drugs at the start of OHA therapy. Cases had a 3.5-fold increased risk of cardiovascular drug use (OR95% CI = 3.5 [3.2-3.8]) compared to controls. Differences in cardiovascular drug use were noted as early as 7 years before the start of OHA therapy, distinguishing cases from controls. Our finding that patients with type 2 diabetes mellitus were more likely to receive treatment for cardiovascular disease several years before they start diabetes therapy supports the hypothesis of a common underlying mechanism of these two disorders and stresses the importance of the pre-diabetic state. (C) 2002 Elsevier Science Inc. All rights reserved.

OBJECTIVE - To investigate cardiovascular drug use and hospitalizations attributable to type 2 diabetes from I year before until 6 years after the start of oral antidiabetic therapy. RESEARCH DESIGN AND METHODS - In this cohort study, 2,584 patients With type 2 diabetes were selected from the PHARMO Record Linkage System, comprising pharmacy records and hospitalizations for all 320,000 residents of six Dutch Cities. Patients with type 2 diabetes were identified as incident oral antidiabetic drug users between 1992 and 1997, Nondiabetic subjects were 1:1-matched for age, sex, pharmacy, and index date and received no insulin, oral antidiabetic drugs, or glucose-testing supplies, RESULTS - Patients with type 2 diabetes were more likely to use cardiovascular drugs (RR 1.28 [95% CI 1.23-1.34]) and to be hospitalized because of cardiovascular diseases (1.54 [1.33-1.78]) after the start of oral antidiabetic therapy than nondiabetic subjects, Differences between patients with type 2 diabetes and nondiabetic subjects lessened from I year before until 6 years after the start of oral antidiabetic therapy, reflected by decreasing attributable risks lot, diuretics, beta -blockers, calcium channel blockers, and cardiac and antithrombotic drugs. The difference in use of angiotensin-converting enzyme inhibitors and lipid-lowering drugs increased. Cardiovascular hospitalizations attributable to type 2 diabetes were similar to 50% in the years close to the start of oral antidiabetic treatment and decreased to similar to 33% in the following),cars. CONCLUSIONS - Although cardiovascular drug use and hospitalizations remained increased in patients with type 2 diabetes after the start of oral antidiabetic therapy, cardiovascular drug use attributable to type 2 diabetes decreased after the start of oral antidiabetic therapy, especially beta -blockers, whereas cardiovascular hospitalizations First decreased and then stabilized.

Aim: To compare the risk of extrapyramidal syndromes (EPS) between patients using risperidone and those using low-potency conventional antipsychotic drugs (APDs) in outpatient clinical practice, as measured by the use of anticholinergic medication. We tried to replicate results from previous clinical trials that compared risperidone with high-potency APDs. Method: Data was obtained from the PHARMO database containing filled prescriptions of 450,000 community-dwelling people in The Netherlands from 1986 to 1998. From the patients aged 15-54 years who had been newly treated with APDs, we defined mutually exclusive cohorts according to the APD first prescribed to a patient. APD exposure was followed until the first prescription of anticholinergic medication and was censored when APD prescribing was interrupted or switched. We estimated relative risks between risperidone and commonly used low-potency and high-potency APDs using Cox proportional hazards models, adjusting for age, gender, dose and other potential confounders. Results: In 4094 patients who had been newly prescribed antipsychotic drugs, the overall incidence rate of anticholinergic drug therapy was 556 per 1000 person-years, which was dose dependent. Prescribed doses of all antipsychotics were low. While, in accordance with previous trials, risperidone showed a lower risk of EPS than the high potency APDs such as haloperidol (RR 0.26; 95% CI 0.10-0.64), we did not observe a lower EPS rate than low-potency APDs (risperidone vs thioridazine RR 1.73, 95% CI 0.49-6.13; risperidone vs pipamperone RR 2.50, 95% CI 0.78-8.04). Conclusion: The reduced EPS rates observed when comparing risperidone with high-potency antipsychotics such as haloperidol may not apply to comparisons with low-potency drugs.

To study possible selective prescribing ('channelling') we compared characteristics of patients using the SSRI sertraline with patients using longer available SSRIs.An observational cohort study in 1251 patients being prescribed an SSRI.In contrast to other studies, we found no evidence for channeling of sertraline. Sertraline was mainly prescribed for the labelled indication (depressive disorder), while older SSRIs were more often prescribed also for other indications. Time on the market was inversely associated to the proportion of patients treated for depressive disorder.We found no evidence for channeling of sertraline compared with prescribing patterns of older SSRIs.