A meta-analysis of effectiveness of real-world studies of antipsychotics in schizophrenia: Are the results consistent with the findings of randomized controlled trials?

Randomized controlled trials (RCTs) have been considered as gold standard for establishing the efficacy and safety of investigational new drugs; nonetheless, the generalizability of their findings has been questioned. To address this issue, an increasing number of naturalistic studies and real-world database analyses have been conducted. The question of how much information from these two approaches is congruent or discrepant with each other is of great importance for the clinical practice. To answer this question, we focused on data from the antipsychotic (AP) treatment of schizophrenia. Our aim was two-fold: to conduct a meta-analysis of real-world studies (RWS), and to compare the results of RWS meta-analysis with previously published meta-analyses of RCTs. The principal measure of effectiveness was all-cause treatment discontinuation for both RWS and RCTs (when not available, then drop out for RCTs). We included publications for 8 selected APs (oral formulations of amisulpride, aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and long-acting injectable (LAI) risperidone). We identified 11 RWS and 7 RCT meta-analyses for inclusion. Our results indicated that the RWS yielded statistically conclusive and consistent findings across individual investigations. For the overwhelming majority of the comparisons where both RWS and RCT meta-analyses were available, there was good congruency between the RWS and the RCT results. Our results support that RCTs, despite their limitations, provide evidence which is generalizable to real-world settings. This is an important finding for both regulators and clinicians. RWS can provide guidance for situations where no evidence is available from double-blind clinical trials.

A single centre phase II trial to assess the immunological activity of TroVax® plus pemetrexed/cisplatin in patients with malignant pleural mesothelioma - the SKOPOS trial.

Vaccines in combination with chemotherapy have been shown to be safe in different tumor types. We investigated the immunological activity of the TroVax® vaccine in combination with pemetrexed-cisplatin chemotherapy in malignant pleural mesothelioma (MPM). In this first line, open-label, single-arm, phase 2 study, patients with locally advanced or metastatic MPM were enrolled. Eligible patients received up to 9 intramuscular injections of TroVax®, starting two weeks before chemotherapy and continuing at regular intervals during and after chemotherapy to 24 weeks. The primary endpoint was the induction of cellular or humoral anti-5T4 immune response (defined as a doubling of either response at any of six follow-up time points), with a target response rate of 64%. Of 27 patients, enrolled between Feb 2013-Dec 2014, 23 (85%) received at least three doses of TroVax® and one cycle of chemotherapy and were included in the per-protocol analysis (PPA). 22/23 patients (95.6%) developed humoral or cellular immune response to 5T4. Thus, the study reached its primary endpoint. Disease control was observed in 87% of patients (partial response: 17.4%, stable disease: 69.6%). The median progression-free survival was 6.8 months and median overall survival 10.9 months. Treatment-related adverse events were comparable to those observed in patients with chemotherapy alone. Translational immunology studies revealed a circulating baseline immune signature that was significantly associated with long-term (>20 months in n = 8/23, 34.8%) survival. In this phase 2 trial, TroVax® with pemetrexed-cisplatin chemotherapy showed robust immune activity, acceptable safety and tolerability to warrant further investigation in a phase 3 setting.

Is stroke indeed a "Monday morning disease"?

BACKGROUND AND PURPOSE: The therapeutic time window of acute stroke is short. Decision on the use of intravenous thrombolysis is based on well-defined criteria. Any delay in the transport to a designated stroke centre decreases the odds of therapeutic success. In Hungary, the admission rate of stroke patients peaks on Monday, the number gradually decreasing by the end of the week. This phenomenon has long been suggested to be due to the lack of emergency care approach. According to the literature, however, returning to work following a holiday is a risk factor for acute stroke. A similar phenomenon is well-known in veterinary medicine, a condition in horses referred to as 'Monday morning disease'. In our study, we analysed the distribution of admissions due to acute stroke by the day of the week in 4 independent data sources. METHODS: The number of patients admitted to the Szent János Hospital, Budapest, Hungary with stroke and that of emergency ambulance transports in the whole city of Budapest due to acute stroke were analysed in the period between January 1 and March 31, 2009. The distribution of thrombolytic interventions reflecting hospitalizations for hyperacute stroke was analysed based on data of the Szent János Hospital in 2009-2012, and on national data from 2006-2012. Descriptive statistics was used to present the data. The variation between daily admission was compared by chi-square test. RESULTS: The proportion of daily admission of stroke patients admitted to the Szent János Hospital was the highest at the beginning of the week (18% on Monday, and 21% on Tuesday) and the lowest on the weekend (9% and 9% on Saturday and Sunday, respectively). The distribution of ambulance transports in Budapest due to acute stroke tended to be similar (15% and 15% on Monday and Tuesday, whereas 13% and 12% on Saturday and Sunday, respectively) on different days of the week. No such Monday peak could be observed in a single centre regarding thrombolytic interventions: 18% and 19% of the total of 80 thrombolytic interventions in the Szent János Hospital were performed on Monday and Sunday, respectively. At the national level the higher Monday rate is obvious: during a 7-year period 16.0%, 12.7%, and 13.5% of all thrombolytic interventions in Hungary were performed on Monday, Saturday and Sunday, respectively. CONCLUSION: Monday preference of stroke is not exclusively caused by the lack of emergency care approach, and the phenomenon is not consistent at the individual hospital level in cases undergoing thrombolysis.

Lung cancer drug therapy in Hungary - 3-year experience.

Hungary is a world leader in lung cancer deaths, so it is of crucial importance that patients have access to modern treatments. The aim of our analysis was to explore how drug treatments are used in Hungary and how they are compatible with international practice. The inpatient and prescription database of the National Health Insurance Fund Administration of Hungary was used to study the frequency of certain chemotherapy protocols and duration of therapies during a 3-year period (2008-2010). During the study period, 12,326 lung cancer patients received first-line chemotherapy, a third of those (n=3,791) received second-line treatment, and a third of the latter (n=1,174) received third-line treatment. The average treatment duration was between 3 and 4 months. The first-line treatment of non-small-cell lung carcinoma mainly consisted of platinum treatment in combination with third-generation cytotoxic agents. A downward trend of gemcitabine, still the most common combination compound, was observed, in parallel with a significantly increased use of paclitaxel, and as a consequence carboplatin replaced cisplatin. Among the new agents, the use of pemetrexed and bevacizumab increased. Pemetrexed appeared mainly in second-line treatment, while erlotinib appeared also in second-line but mostly in third-line treatments. The first-line treatment of small-cell lung carcinoma consisted of a platinum-etoposide combination, while in the second-line setting topotecan was the most commonly used drug. According to our results, the chemotherapeutic combinations and sequencing are in accordance with international and national recommendations. Further detailed analysis of the available data may help to obtain a more accurate picture of the efficacy of lung cancer treatments as well.

Real-world effectiveness of antipsychotic monotherapy vs. polypharmacy in schizophrenia: to switch or to combine? A nationwide study in Hungary.

BACKGROUND: Leading guidelines recommend antipsychotic (AP) monotherapy for schizophrenia, nonetheless the combination of antipsychotics (polypharmacy) is common practice worldwide. We conducted a nationwide population-based study to investigate the comparative effectiveness of monotherapy versus polypharmacy in schizophrenia and other psychotic disorders. METHODS: Data was collected from the Hungarian National Health Insurance Fund's database and a non-interventional retrospective-prospective parallel arm study was designed with a monotherapy arm (MA, switch to a new antipsychotic after >60 days of monotherapy, N=5480) and a polypharmacy arm with two APs (PA, addition of a second antipsychotic after >60 days of monotherapy, N=7901). The analyses focused on therapy changers, who started a new monotherapy or added a new AP to the existing one. Polypharmacy combinations with more than two APs were not investigated. Fourteen APs were investigated representing the majority of marketed antipsychotics of Hungary in the period of 1/2007-12/2009. The principal endpoint was the time to all-cause treatment discontinuation during a one-year observation period. Kaplan-Meier survival analysis and Cox proportional hazards model were applied with propensity score adjustment. RESULTS: The principal outcome measure time to all-cause discontinuation indicated superiority for monotherapy over polypharmacy for the majority of (oral and depot) second generation APs (SGAs). For first generation APs (FGAs), oral formulations did not show a difference between monotherapy and polypharmacy, while depot formulations exhibited polypharmacy advantage. For the four most frequently used oral SGAs, the median times to all-cause discontinuation for monotherapy and polypharmacy, respectively, were 192 and 100 days for aripiprazole; 222 and 86 days for olanzapine; 176 and 91 days for quetiapine; and 157 and 93 days for risperidone. For mortality and hospitalization, a significant overall advantage of polypharmacy was detected. CONCLUSIONS: Our study provides evidence for the superiority of monotherapy over polypharmacy for SGAs in terms of all-cause treatment discontinuation in schizophrenia. Polypharmacy, however, was associated with a lower likelihood of mortality and hospitalizations. The finding that MA is superior to PA for long-term sustained treatment whereas polypharmacy has advantage in mortality and psychiatric hospitalizations suggests that combination treatments may be more efficacious during exacerbation of psychotic symptoms.

[Analysis of drug therapy of lung cancer in Hungary]. / A tüdorák hazai gyógyszeres kezelésének elemzése.

Hungary is a world leader in lung cancer deaths, so it is particularly important that patients could have access to modern treatments. The aim of our analysis was to find how drug treatments are used in Hungary and how they are compatible with international practice. The in-patient and prescription database of the National Health Insurance Fund for three years (2008-2010) was used to study the frequency of certain chemotherapy protocols, the duration of therapies, and the changes in the individual protocols and drugs used for lung cancer treatment (ICD: C33H0-C34) during the reviewed period. We did not differentiate between neoadjuvant and adjuvant treatment and therapy after progression. During the study period 12326 lung cancer patients received first-line chemotherapy, one third of those (n=3791) received second-line, and one third of those (n=1174) third-line treatment. The average treatment duration was between 3 and 4 months. The first-line treatment of NSCLC mainly consisted of platinum treatment in combination with third generation cytotoxic agents. A downward trend of gemcitabine, still the most common combination compound, was observed, in parallel with the increased use of paclitaxel, and as a consequence carboplatin replaced cisplatin. Among new agents the use of pemetrexed and bevacizumab has increased. Pemetrexed appeared mainly in second-line treatment, while erlotinib also in second, but mostly in third line. The first-line treatment of SCLC consisted of a platinum-etoposide combination, and in second-line setting topotecan was the most commonly used drug. According to our results the chemotherapeutic combinations and sequencing are in accordance with international and national recommendations. Further detailed analysis of the available data may help to obtain more accurate picture of the efficacy of lung cancer treatments as well.

Comparative effectiveness of depot and oral second generation antipsychotic drugs in schizophrenia: a nationwide study in Hungary.

We conducted a nationwide, full-population based investigation to evaluate the comparative effectiveness of all marketed second generation antipsychotic drugs (SGA) prescribed for outpatients with the diagnosis of schizophrenia in Hungary. Using the national central register, our observational follow-up study included all patients with schizophrenia or related disorder between 01/01/2006 and 30/06/2008. The study cohort comprised 9567 patients who started new SGA during the inclusion period (01/07/2007-30/06/2008). All-cause medication discontinuation of 8 SGAs (1 depot and 7 oral formulations) marketed during the inclusion period, and the time to all-cause discontinuation were the main outcomes. Statistical models included the Kaplan-Meier and the Cox proportional hazards models with propensity score adjustment. Patients treated with a depot formulation risperidone had the longest time to discontinuation with a median of 215 days (95%CI:181-242 days), which was statistically significantly different compared to patients treated with the rest of the medications: olanzapine (136 days, 95%CI:121-153 days), aripiprazole (102 days, 95%CI:81-126 days), ziprasidone (93 days, 95%CI:82-119 days), quetiapine (89 days, 95%CI:81-100 days), clozapine (76 days, 95%CI:54-92 days), amisulpride (73 days, 95%CI:62-85 days), and risperidone (55 days, 95%CI: 41-63 days). Our results in Hungary are partly similar to those of a recent register-based study in Finland with patients who were discharged from their first hospitalization for schizophrenia (Tiihonen et al., 2006, 2011); namely the median times to all-cause medication discontinuation were <120 days for the majority of the oral SGA. In terms of medication differences, our data support the superior effectiveness of the depot formulation regarding all-cause discontinuation, followed by olanzapine at the efficacy rank order.

[The prevalence of atrial fibrillation in Hungary]. / A pitvarfibrilláció prevalenciája Magyarországon.

UNLABELLED: To estimate the prevalence and incidence of atrial fibrillation in the entire population of Hungary. METHODS: Analysis of the National Health Insurance Fund Administration database between 2007 and 2009 considering data from 2002. We assumed that patients with atrial fibrillation would turn to health care providers at least once either as outpatients or inpatients in a 5-year period. The National Health Insurance Patient Registry was used to assess the true number of patient visits. RESULTS: The prevalence of atrial fibrillation in Hungary is between 2.37-2.67%. Each year, only about half of these patients seek medical advice. CONCLUSIONS: Our survey seems to be the first epidemiological study that aims at estimating the prevalence of atrial fibrillation in the total population of our country. Using a time frame of five to seven years, the prevalence of atrial fibrillation in the total population is significantly higher than it was estimated earlier. However, by using a mathematical model, an even higher prevalence rate of atrial fibrillation (2.95%) was calculated for the total population of Hungary.

Persistence of initial oral antidiabetic treatment in patients with type 2 diabetes mellitus.

BACKGROUND: Adequate persistence of oral antidiabetic treatment is highly important to achieve proper glycemic control in patients with type 2 diabetes. The aim of this study was to evaluate the persistence of initial treatment with metformin and/or sulphonylureas in patients with type 2 diabetes. MATERIAL/METHODS: The study was performed among diabetic patients (n=256,384) who were with newly prescribed oral antidiabetic drugs (metformin and/or sulphonylureas) between 2007 and 2009. For making comparison, patients with newly prescribed statin or clopidogrel therapy (with and without percutaneous coronary intervention) were investigated. The database of the Hungarian National Health Insurance Fund Administration was used. RESULTS: The 1-year persistence of initial treatment with metformin, sulphonylureas or metformin/sulphonylurea combination was 47.7%, 45.4% and 55.8%, respectively, which was significantly better than the persistence of statin therapy (26.3%) but worse than that of clopidogrel therapy in patients undergoing coronary intervention (73.2%). Within the sulphonylurea group there was a tendency of better persistence of treatment with the "modified-release" tablets at 12 months compared to the conventional sulphonylureas (47.8 vs. 42.2%). The persistence of therapy using metformin 1000 mg - 60 tablets was significantly better (60.4%) at 12 months than that of other forms of metformin therapy with lower doses and smaller boxes (with fewer tablets) analyzed together (47.7%). CONCLUSIONS: The persistence of initial treatment with metformin and/or sulphonylureas is far from optimal. Better diabetic care and continuous patient education should be encouraged to achieve higher persistence of oral antidiabetic treatment in patients with type 2 diabetes.