Post-stroke epilepsy and antiepileptic drug use in men and women.

Evidence-based recommendations for choice of antiepileptic drug (AED) in post-stroke epilepsy (PSE) are lacking. The aim of this study was to describe the use and persistence of AEDs when initiating treatment in men and women with PSE. An observational study based on individual-level patient data from a regional healthcare register in Stockholm, Sweden, was conducted. Adults (≥18 years) with a stroke diagnosis 2012-2016, a dispensed prescription of any AED within two years after the stroke, and with an epilepsy-related diagnosis were identified. Multinomial logistic regression and logistic regression were used to identify factors associated with choice of AED and discontinuation within 90 days, respectively. Of 9652 men and 9844 women with a stroke diagnosis, 287 men and 273 women had PSE and were dispensed AED. More than 60% of both men and women with PSE were treated with levetiracetam. Carbamazepine was the second most common drug followed by lamotrigine and valproic acid. There were significant differences in AED choice depending on for instance sex, age and renal impairment. Levetiracetam had the highest persistence in both men and women. Choice of AED, oral anticoagulant use and percutaneous endoscopic gastrostomy (PEG) showed an association with the persistence to therapy. We conclude that in both men and women with PSE, levetiracetam was the most used AED for initiation of treatment and also had the highest persistence.

Forecasting drug utilization and expenditure: ten years of experience in Stockholm.

BACKGROUND: Operating under constrained budgets, payers and providers globally face challenges in enabling appropriate and sustainable access to new medicines. Among payer initiatives aiming to improve preparedness of healthcare systems for the introduction of new medicines, drug utilization and expenditure forecasting has played an increasingly important role. This study aims to describe the forecasting model used in Region Stockholm and to evaluate the accuracy of the forecasts produced over the past decade. METHODS: In this repeated cross-sectional study, we compared the predicted pharmaceutical expenditure with actual expenditure during the entire available follow-up period (2007-2018) both for overall drug utilization and for individual therapeutic groups. All analyses were based on pharmaceutical expenditure data that include medicines used in hospitals and dispensed prescription medicines for all residents of the region. RESULTS: According to the forecasts, the total pharmaceutical expenditure was estimated to increase between 2 and 8% annually. Our analyses showed that the accuracy of these forecasts varied over the years with a mean absolute error of 1.9 percentage points. Forecasts for the same year were more accurate than forecasts for the next year. The accuracy of forecasts also differed across the therapeutic areas. Factors influencing the accuracy of forecasting included the timing of the introduction of both new medicines and generics, the rate of uptake of new medicines, and sudden changes in reimbursement policies. CONCLUSIONS: Based on the analyses of all forecasting reports produced since the model was established in Stockholm in the late 2000s, we demonstrated that it is feasible to forecast pharmaceutical expenditure with a reasonable accuracy. A number of factors influencing the accuracy of forecasting were also identified. If forecasting is used to provide data for decisions on budget allocation and agreements between payers and providers, we advise to update the forecast as close as possible prior to the decision date.

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study.

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36-1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350.

INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.

Cost-effectiveness analysis of newer anticholinergic drugs for urinary incontinence vs oxybutynin and no treatment using data on persistence from the Swedish prescribed drug registry.

UNLABELLED: Study Type - Therapy (cost effectiveness). Level of Evidence 2a. What's known on the subject? and What does the study add? Anticholinergic drugs are a common treatment alternative in urinary incontinence, which results in large costs for caregivers. So far, most cost-effectiveness analyses of anticholinergic drugs have focused on small putative differences between the newer anticholinergics. This study takes a novel approach by treating the clinical effects of the newer alternatives as similar and evaluating them as a group in relation to no treatment and oxybutynin (immediate release). It also uses registry data to account for persistence. OBJECTIVE: • To analyse the cost-effectiveness of newer anticholinergic drugs in relation to oxybutynin immediate release (IR) and no treatment for patients with urgency urinary incontinence. PATIENTS AND METHODS: • A decision analytic model was constructed. • Results were collected from randomized trials and combined with registry data on persistence of medicine use and estimated number of severe adverse events. • The setting corresponds to Swedish clinical practice. • The costs and effects of the treatment options were analysed over a period of 1 year. Costs included drug costs, treatment costs and costs for pad use. Patients' utilities were based on treatment effect and the lack or presence of adverse events. RESULTS: • No treatment was the least costly treatment but also resulted in the fewest number of quality adjusted life years (QALYs). • Treatment with newer anticholinergic drug medications is the most costly option but also the most efficient treatment. Sensitivity analyses showed that the results were robust. • Treatment with newer anticholinergics resulted in a cost per QALY gained of €21 045 compared with no treatment and no effect and €65 435 compared with no treatment and placebo effect. Compared with oxybutynin IR, the cost per QALY gained was €37 119. These calculations are based on relatively low pad costs, resulting in higher costs per QALY for the original drugs. CONCLUSIONS: • The newer anticholinergic medications are likely to be cost effective in relation to oxybutynin IR. • The cost-effectiveness of the newer anticholinergics compared with no treatment depends on assumptions of the effect of no treatment, the severity of the treated condition and the treated individual's risk of adverse events. • Treatment is less likely to be cost effective for elderly persons or for persons otherwise at higher risk for adverse events.

Adjunctive treatment with mianserin enhances effects of raclopride on cortical dopamine output and, in parallel, its antipsychotic-like effect.

Clinical studies indicate that adjunctive treatment with the antidepressant drug mianserin, a 5-hydroxytryptamine (5-HT)(2A/C) receptor antagonist and an alpha(2)- and alpha(1)-adrenoceptor antagonist, may enhance the effect of conventional antipsychotic drugs in schizophrenia, in particular on negative symptoms such as withdrawal retardation, akathisia, and some aspects of cognitive impairment. Here, we have examined the effect of mianserin in combination with the selective dopamine (DA) D(2/3) receptor antagonist raclopride on conditioned avoidance response (CAR), a preclinical test of antipsychotic efficacy with high predictive validity; catalepsy, a preclinical test of extrapyramidal side effect liability; and DA output in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), respectively. Mianserin (5 mg/kg intraperitoneal) significantly enhanced the suppressant effect of a low dose of raclopride (0.1 mg/kg subcutaneous) on CAR without any increase in catalepsy. Administration of raclopride to rats pretreated with mianserin resulted in a large enhancement of DA output in the mPFC and, at the same time, a small but significant reduction in the raclopride-induced DA output in the NAC. These experimental results indicate that adjunctive treatment with mianserin to a typical D(2) antagonist generates an atypical antipsychotic profile.

Adjunctive treatment with mianserin enhances effects of raclopride on cortical dopamine output and, in parallel, its antipsychotic-like effect.

Clinical studies indicate that adjunctive treatment with the antidepressant drug mianserin, a 5-hydroxytryptamine (5-HT)(2A/C) receptor antagonist and an alpha(2)- and alpha(1)-adrenoceptor antagonist, may enhance the effect of conventional antipsychotic drugs in schizophrenia, in particular on negative symptoms such as withdrawal retardation, akathisia, and some aspects of cognitive impairment. Here, we have examined the effect of mianserin in combination with the selective dopamine (DA) D(2/3) receptor antagonist raclopride on conditioned avoidance response (CAR), a preclinical test of antipsychotic efficacy with high predictive validity; catalepsy, a preclinical test of extrapyramidal side effect liability; and DA output in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), respectively. Mianserin (5 mg/kg intraperitoneal) significantly enhanced the suppressant effect of a low dose of raclopride (0.1 mg/kg subcutaneous) on CAR without any increase in catalepsy. Administration of raclopride to rats pretreated with mianserin resulted in a large enhancement of DA output in the mPFC and, at the same time, a small but significant reduction in the raclopride-induced DA output in the NAC. These experimental results indicate that adjunctive treatment with mianserin to a typical D(2) antagonist generates an atypical antipsychotic profile.

Noradrenaline reuptake inhibition enhances the antipsychotic-like effect of raclopride and potentiates D2-blockage-induced dopamine release in the medial prefrontal cortex of the rat.

We have previously observed that addition of an alpha(2)-adrenoceptor antagonist to a selective dopamine (DA) D(2) receptor antagonist enhances the antipsychotic-like effect of the D(2) blocker and also selectively increases DA output in the medial prefrontal cortex (mPFC) in rats. These data also correlate well with previous clinical trials showing augmentation by an equivalent drug combination in schizophrenia. Since the selective noradrenaline reuptake inhibitor reboxetine was found to cause similar effects on the mesolimbocortical DA system as alpha(2)-adrenoceptor antagonists, the present study was undertaken to explore whether also reboxetine might augment the effect of the DA D(2) receptor antagonist raclopride in the same preclinical model of antipsychotic activity, the conditioned avoidance response (CAR) test. We also investigated the effect of this combination in the catalepsy test for extrapyramidal side effect liability, as well as on DA output in the mPFC and the nucleus accumbens, respectively. Reboxetine (6 mg/kg, i.p.) significantly enhanced the suppressant effect of raclopride (0.1 mg/kg, s.c.) on CAR without affecting catalepsy. Administration of raclopride (0.1 mg/kg, s.c.) to rats pretreated with reboxetine (6 mg/kg, i.p.) resulted in a greatly enhanced effect on DA output in the mPFC but not in the nucleus accumbens when compared with raclopride alone. Consequently, these results suggest that noradrenaline reuptake inhibition may provide means of augmenting the efficacy of classical D(2)-antagonists in the treatment of schizophrenia, and, in principle, to generate an atypical antipsychotic drug profile.