Comparative effectiveness of dopamine agonists and monoamine oxidase type-B inhibitors for Parkinson's disease: a multiple treatment comparison meta-analysis.

PURPOSE: To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. METHODS: We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. RESULTS: Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. CONCLUSIONS: Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.

New benzodiazepine and Z-hypnotic users and disability pension: an eight-year nationwide observational follow-up study.

OBJECTIVE: To compare how newly initiated treatment with benzodiazepines, Z-hypnotics or both associates with the reception of disability pension among 40,661 individuals of a working age. DESIGN: Prescription register study. SETTING: Norwegian nationwide prescriptions socio-economic and disability status data. METHODS: Cox regression analyses. SUBJECTS: New benzodiazepine or Z-hypnotic users. MAIN OUTCOME MEASURE: Time to receive disability pension given benzodiazepine or Z-hypnotic use or both. Additional analyses focused on the benzodiazepine first redeemed. RESULTS: Among new users 8.65% of Z-hypnotic users, 12.29% of benzodiazepines users and 13.96% of combined Z-hypnotic and benzodiazepine users became disability pensioners. Z-hypnotic users were weaker associated with becoming disability pensioners (HR = 0.78, CI: 0.73-0.84) and combined users were stronger associated (HR = 1.09, CI: 1.01-1.17), than benzodiazepine users. Women had higher risk than men for becoming disability pensioners. Higher age, lower education, previous drug use and psychiatrist as first prescriber were risk factors. Comparing first benzodiazepine redeemed; clonazepam initiators were stronger associated with becoming disability pensioners than diazepam initiators were (HR = 2.22, CI: 1.81-2.71). No differences between other benzodiazepine users were found. CONCLUSIONS: Adjusting for known risk factors gave lower risk for Z-hypnotic users compared to benzodiazepine users for receiving disability pension. Combined use increased the risk further. Clonazepam initiators are especially at risk. These findings may be helpful in prescribing situations to identify and guide individuals at risk for becoming disability pensioners.

Patterns of proton pump inhibitor utilization in gastroesophageal reflux disease and the effect of restrictions on reimbursement: a nationwide prescription database study.

OBJECTIVE: To assess the drug utilization patterns for proton pump inhibitors (PPIs) prescriptions dispensed in periods with and without restrictions on reimbursement in a public healthcare system. MATERIAL AND METHODS: Data on all PPI prescriptions dispensed for gastroesophageal reflux disease (GERD) was retrieved from the Norwegian Prescription Database (NorPD) from 1 January 2004 to 31 January 2008. PPI utilization patterns were studied in new and current users of PPI in periods affected and not affected by a change in prescription policy. RESULTS: The policy change resulted in 39% of esomeprazole patients discontinuing PPI therapy during a 12-month period while 23% discontinued PPI therapy during a period not affected by the policy change. The shift frequency to a different PPI was low, 5% and 7% respectively, during periods not affected by policy change. Despite a required shift in most esomeprazole patients, 64% still continued on esomeprazole. Among the 36% who shifted from esomeprazole to a different PPI, 25% subsequently shifted back to esomeprazole. In new PPI users, the proportion of esomeprazole users declined from 57% before to 20% after the introduction of the policy change. CONCLUSIONS: Despite GERD being a chronic disease in most patients, there was a high degree of alteration seen in the utilization patterns of PPIs. A high proportion discontinued PPI therapy indicating mild symptoms or remission. The switching between different PPIs was low indicating good efficacy and tolerability in most patients. The policy change was more effective in new PPI users compared with the mandated shift in ongoing esomeprazole users.

An approach to combining parallel and cross-over trials with and without run-in periods using individual patient data.

BACKGROUND: In active run-in trials, where patients may be excluded after a run-in period based on their response to the treatment, it is implicitly assumed that patients have individual treatment effects. If individual patient data are available, active run-in trials can be modelled using patient-specific random effects. With more than one trial on the same medication available, one can obtain a more precise overall treatment effect estimate. METHODS: We present a model for joint analysis of a two-sequence, four-period cross-over trial (AABB/BBAA) and a three-sequence, two-period active run-in trial (AB/AA/A), where the aim is to investigate the effect of a new treatment for patients with pain due to osteoarthritis. RESULTS: Our approach enables us to separately estimate the direct treatment effect for all patients, for the patients excluded after the active run-in trial prior to randomisation, and for the patients who completed the active run-in trial. A similar model approach can be used to analyse other types of run-in trials, but this depends on the data and type of other trials available. LIMITATIONS: We assume equality of the various carry-over effects over time. CONCLUSIONS: The proposed approach is flexible and can be modified to handle other designs. Our results should be encouraging for those responsible for planning cost-efficient clinical development programmes.

Meta-regression analysis of paroxetine clinical trial data: does reporting scale matter?

OBJECTIVES: It is unknown to which degree the effect of antidepressant drugs are related to baseline degree of depression, dose level, patient's age, or type of questionnaire used. We explored this for paroxetine. METHODS: We used placebo-controlled published and unpublished randomized, double-blind, clinical trials of paroxetine that included moderate to severely depressed patients in an outpatient setting. We specified random-effect models for the Hamilton 17-item and Hamilton 21-item studies separately and jointly. RESULTS: Among 35 studies retrieved, we considered 26 appropriate for a pooled analysis. Paroxetine (placebo) was given to 2958 (2123) patients. We found that the effects of paroxetine, the differences between score reduction in drug versus placebo group, are smaller in Hamilton 17 (3.8%) than in Hamilton 21 studies (7.0%). The mean difference is 3.2% (95% confidence interval, 0.94%-5.42%), statistically significant by meta-regression analysis. Treatment effects did not change with mean age of patients, early or late studies, baseline score value, or maximal daily dose. CONCLUSIONS: We forward 2 hypotheses for explanation. The Hamilton 21 studies had better selection of patients, thereby smaller effect of regression to the mean than the Hamilton 17 studies, meaning the Hamilton 21 studies reveal true somewhat higher treatment effects. Alternatively, the study groups contained some patients with psychotic symptoms tested for with the Hamilton 21-item questionnaire and thereby becoming decisive for the outcome. If so, paroxetine would have an antipsychotic effect. This is in accordance with some experimental and clinical observations.

Time until Need for Levodopa among New Users of Dopamine Agonists or MAO-B Inhibitors.

OBJECTIVE: To investigate the use of dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors in the Norwegian population, between 1 July 2006 and 31 December 2016. Our primary endpoint was time until need for levodopa among new monotherapy users of dopamine agonists and MAO-B inhibitors. METHODS: A prospective cohort study including all patients, aged 50 years or above, who had at least one prescription for a dopamine agonist or a MAO-B inhibitor dispensed in the study period. We used data from the Norwegian Prescription Database (NorPD). As we wished to focus on new Parkinson patients, we excluded patients who had levodopa dispensed less than 180 days prior to their first dopamine agonist or MAO-B inhibitor redemption. We explored the demographics and the time until monotherapy was insufficient treatment (defined as need for levodopa prescription). RESULTS: We included 22958 new monotherapy users. Of these, 22108 used dopamine agonists and 850 used MAO-B inhibitors. The mean number of days until the first prescription of levodopa was dispensed was higher among the dopamine agonist users (621 days) compared to the MAO-B inhibitor users (352 days). The proportion of dopamine agonist users who started levodopa treatment during the study period was less than 7%, while the corresponding proportion of MAO-B inhibitor users was almost 59%. CONCLUSIONS: We found that new dopamine agonist users had a much greater delay in the need for levodopa than new MAO-B inhibitor users. It seems to be beneficial to initiate treatment with dopamine agonists when starting pharmacological treatment for new Parkinson patients.

Incident users of antipsychotic agents and future use of cholesterol-lowering drugs: an observational, pharmacoepidemiologic study.

OBJECTIVE: Antipsychotic agents have serious metabolic adverse effects, among them dyslipidemia, which may necessitate secondary prophylaxis with cholesterol-lowering drugs. Second-generation antipsychotics (SGAs), particularly clozapine and olanzapine, are known to confer a higher risk of metabolic adverse effects than first-generation antipsychotics (FGAs). However, little is known regarding the real-life number of antipsychotic-treated patients receiving statins. METHOD: By extracting data from the Norwegian prescription database, all patients 18-69 years old that started treatment with an antipsychotic during 2004-2012 formed the basis for analysis (n = 301,713). The primary outcome measure was the proportion of FGA and SGA users prescribed with cholesterol-lowering agent during the same period. We used Cox proportional hazards regression to evaluate the risk of redeeming a cholesterol-lowering drug for formerly antipsychotic drug-naive patients (n = 147,218). RESULTS: Statin prescription rates in patients receiving antipsychotic agents were lower (5.3%) than comparable rates in studies covering the general population (34%) and lower than would be expected based on the recognized negative impact of antipsychotics on serum lipids. Statin prescription rates were affected by patient age, antipsychotic dose, and the number of antipsychotic agents prescribed, but rates were only 5% elevated in patients receiving SGAs compared to patients receiving FGAs (P = .048). CONCLUSIONS: Our results may support the notion that patients treated with antipsychotic agents receive suboptimal care with regard to metabolic adverse effects.