Gabapentin and Pregabalin and Risk of Atrial Fibrillation in the Elderly: A Population-Based Cohort Study in an Electronic Prescription Database.

INTRODUCTION: Gabapentin and pregabalin are widely prescribed to elderly people, but data on their pharmacokinetics, safety, and efficacy in this population are scarce. Neurological adverse effects are common. Atrial fibrillation (AF) associated with their use has been described in several case reports and case series, but the incidence is unknown. OBJECTIVE: The aim of this study was to assess the association between exposure to gabapentin or pregabalin and AF in the elderly. METHODS: Patients ≥ 65 years of age starting treatment with either gabapentin or pregabalin between January 1 and March 31, 2015, free of cardiovascular disease, and who did not receive the alternate study medications were studied. They were compared with patients who initiated treatment with an analgesic opiate or with alprazolam or diazepam. The two primary outcome variables were a first claim of an oral anticoagulant plus an antiarrhythmic drug (OAC + AA), or of an oral anticoagulant or an antiplatelet agent plus an antiarrhythmic drug (OAC/APA + AA), in the 3 months after treatment initiation. RESULTS: Compared with opiate analgesics, both gabapentin and pregabalin were associated with an increased risk of initiating OAC/APA + AA. The incidence was 6 of 668 (9.0 per 1000 patients) with gabapentin, versus 12 of 3889 (3.1 per 1000) with opiates, relative risk (RR) 2.91 (95% confidence interval [CI] 1.10-7.73), and for pregabalin it was 6 of 698 (8.6 per 1000) RR 2.79 (95% CI 1.05-7.40). The comparison with alprazolam/diazepam gave similar results. The risks did not vary by age, sex, or co-treatment with NSAIDs, and they increased with dose. CONCLUSION: In elderly patients free of cardiovascular disease, an association between new exposure to gabapentin or pregabalin and initiating treatment for AF was found. These results should be confirmed in other studies.

Systematic Review and Meta-Analysis: Macrolides- and Amoxicillin/Clavulanate-induced Acute Liver Injury.

Antibacterials are frequently associated with idiosyncratic drug-induced liver injury (DILI). The objective of this study was to estimate the risk of macrolides and amoxicillin/clavulanate (AMC) on DILI. We conducted a systematic review (SR) and meta-analysis (MA) with studies retrieved from PubMed, Cochrane Library Plus, Web of Knowledge, clinicaltrials.gov, Livertox and Toxline (1980-2014). We searched for macrolides, AMC and MeSH and synonym terms for DILI. We included all study designs except case reports/series, all population ages and studies with a placebo/non-user comparator. We summarized the evidence with a random-effects MA. Quality of the studies was appraised with a checklist developed for SR of adverse effects. Heterogeneity and publication bias were assessed with different exploratory tools. We finally included 10 (two randomized clinical trials, six case-control, one cohort and one case-population studies) and 9 (case-population excluded) articles in the SR and MA, respectively. The overall summary relative risk of DILI for macrolides was 2.85 [95% confidence interval (CI) 1.81-4.47], p < 0.0001, I(2) = 57%. Three studies were perceived to be missing in the area of low statistical significance. Year of study and selected exposure window partly explained the variability between studies. For AMC, the risk of DILI was 9.38 (95% CI 0.65-135.41) p = 0.3, I2 = 95%. In conclusion, although spontaneous reports and case series have long established an association between macrolides and AMC with acute liver injury, these SR and MA have assessed the magnitude of this association. The low incidence of DILI and the therapeutic place of these antibiotics might tilt the balance in favour of their benefits.

Sales of macrolides, lincosamides, streptogramins, and amoxicillin/clavulanate in the in- and outpatient setting in 10 European countries, 2007-2010.

Monitoring the use of antibiotics is relevant due to the public health impact of microbial resistance, adverse effects, and costs. We present data on the consumption of macrolides, lincosamides, streptogramins and amoxicillin/clavulanate (AMC) between 2007 and 2010 in the in-and outpatient healthcare setting in 10 European countries provided by IMS Health. Antibiotics were classified according to the anatomical therapeutic chemical classification and consumption was expressed in defined daily doses/1000 inhabitants/day (DIDs). We analysed the number of prescriptions by diagnostic codes between 2008 and 2010, based on the International Classification of Diseases, 10th revision (ICD-10). These ICD-10 codes were grouped into four main categories: respiratory infections, genitourinary infections, other infections and other diagnoses. In 2010, the consumption of macrolides and lincosamides ranged from 0.45 DIDs (Sweden) to 5.46 DIDs (Italy), and from 0.04 DIDs (Denmark) to 1.00 DID (Germany), respectively. Streptogramins were available in France, Germany, Italy, Norway, Spain and United Kingdom with a consumption of <0.001 DID exclusively in the hospital setting. The consumption of AMC ranged from <0.001 DIDs (Norway) to 11.67 DIDs (Spain). During the study period, the consumption of macrolides decreased, the consumption of AMC increased in most of European countries, and lincosamides varied very slightly. Macrolides and AMC were mainly prescribed for respiratory infections in all countries but United Kingdom, where most of the prescriptions were assigned to diagnostic codes not clearly related with an infection. Lincosamides were prescribed for the respiratory infections and other infections groups. There was a wide inter-country variability in the percentage of the prescriptions assigned to each of the diagnostic categories. The inter-country differences in the consumption of these antibiotics and their prescription by diagnostic categories point to an inappropriate use of antibiotics.

[Pharmacoepidemiology: lights and shadows]. / La pharmaco-épidémiologie: ombres et lumières.

Adverse drug reactions are a major cause of illness and death. They cause 5-10% of general practice consultations and 5 to 10% of hospital admissions and would be the third or fourth cause of death (after heart attack, stroke and cancer). It is a failure of contemporary medicine. The purpose of pharmacoepidemiology is the study of drug use in populations and its impact on public health. The author describes the four stages of the recent history of pharmacovigilance. The first, spontaneous reporting, has identified many adverse drug reactions but cannot provide with incidence or risk estimates. Observational epidemiological research has shaped second generation pharmacovigilance, providing incidence and relative and absolute risks which are essential for public health decision taking. The meta-analysis of clinical trials would be third-generation pharmacovigilance: it has contributed to the understanding of relatively common adverse drug reactions with great impact on public health. Research on big data will surely be the basis of the fourth generation of pharmacovigilance.

Sources of European drug consumption data at a country level.

OBJECTIVES: This study aimed at outlining the characteristics of nationwide administrative databases monitoring drug consumption in Europe. METHODS: Internet and bibliographic databases (April 2010) were searched and experts in drug utilization (DU) research interviewed to find nationwide administrative medicines consumption databases in Europe, with data for the out- and inpatient healthcare sector. A questionnaire was developed to gather additional information. We collected data providers, websites, accessibility, data sources, healthcare settings, population coverage, medicines-related data, patient and prescriber data, periods covered, and linkage to other databases. RESULTS: Thirty-one administrative nationwide medicine consumption databases in 25 countries were identified. Questionnaires were responded for 20 databases. Eleven provided wholesalers' sales data, 11 on reimbursed, 5 on prescribed, and 4 on dispensing medicines. Fifteen databases provided inpatient drug consumption data, mainly wholesalers' sales. CONCLUSIONS: Nationwide administrative databases are of value to all stakeholders involved in the conduct and interpretation of post-marketing safety studies, and in the conduct of DU research. The endorsement of the anatomical therapeutic chemical/defined daily dose methodology by these databases contributes to data harmonization. However, there is still a lack of information on inpatient medicines consumption at a patient-level.

A compilation of research working groups on drug utilisation across Europe.

BACKGROUND: The assessment of the benefit-risk of medicines needs careful consideration concerning their patterns of utilization. Systems for the monitoring of medicines consumption have been established in many European countries, and several international groups have identified and described them. No other compilation of European working groups has been published. As part of the PROTECT project, as a first step in searching for European data sources on the consumption of five selected groups of medicines, we aimed to identify and describe the main characteristics of the existing collaborative European working groups. FINDINGS: Google and bibliographic searches (PubMed) of articles containing information on databases and other sources of drug consumption data were conducted. For each working group the main characteristics were recorded.Nineteen selected groups were identified, focusing on: a) general drug utilisation (DU) research (EuroDURG, CNC, ISPE'S SIG-DUR, EURO-MED-STAT, PIPERSKA Group, NorPEN, ENCePP, DURQUIM), b) specific DU research: b.1) antimicrobial drugs (ARPAC, ESAC, ARPEC, ESGAP, HAPPY AUDIT), b.2) cardiovascular disease (ARITMO, EUROASPIRE), b.3) paediatrics (TEDDY), and b.4) mental health/central nervous system effects (ESEMeD, DRUID, TUPP/EUPoMMe). Information on their aims, methods and activities is presented. CONCLUSIONS: We assembled and updated information on European working groups in DU research and in the utilisation of five selected groups of drugs for the PROTECT project. This information should be useful for academic researchers, regulatory and health authorities, and pharmaceutical companies conducting and interpreting post-authorisation and safety studies. European health authorities should encourage national research and collaborations in this important field for public health.

The case-population study design: an analysis of its application in pharmacovigilance.

BACKGROUND: The case-population approach or population-based case-cohort approach is derived from the case-control design and consists of comparing past exposure to a given risk factor in subjects presenting a given disease or symptom (cases) with the exposure rate to this factor in the whole cohort or in the source population of cases. In the same way as the case-control approach, the case-population approach measures the disproportionality of exposure between cases of a given disease and their source population expressed in the form of an odds ratio approximating the ratio of the risks in exposed and not-exposed populations (relative risk). OBJECTIVE: The aim of this study was to (i) present the case-population principle design in a way understandable for non-statisticians; (ii) propose the easiest way of using it for pharmacovigilance purposes (mainly alerting and hypothesis testing); (iii) propose simple formulae for computing an odds ratio and its confidence interval; (iv) apply the approach to several practical and published examples; and (v) discuss its pros and cons in the context of real life. METHODS: The approach used is derived from that comparing two rates expressed as person-time denominators. It allows easy computation of an odds ratio and its confidence interval under several hypotheses. Results obtained with the case-population approach were compared with those of case-control studies published in the literature. RESULTS: Relevance and limits of the proposed approach are illustrated by examples taken from published pharmacoepidemiological studies. The odds ratio (OR) reported in a European case-control study on centrally acting appetite suppressants and primary pulmonary hypertension was 23.1 (95% CI 6.9, 77.7) versus 31 (95% CI 16.2, 59.2) using the case-population approach. In the European case-control studies SCAR (Severe Cutaneous Adverse Reactions) and EuroSCAR on the risk of toxic epidermal necrolysis associated with the use of medicines, the OR for cotrimoxazole was 160 and 102, respectively, versus 44.4 using the case-population approach. Similarly, these two case-control studies found ORs of 12 and 72 for carbamazepine versus 24.4 using the case-population approach, 8.7 and 16 for phenobarbital versus 21.9, 12 for piroxicam (analysed in the SCAR study only) versus 14.5, and 5.5 and 18 for allopurinol versus 3.4 using the case-population approach. CONCLUSIONS: Being based on the estimate derived from sales statistics of the total exposure time in the source population of cases, the method can be used even when there is no information about the actual number of exposed subjects in this population. Although the case-population approach suffers from limitations stemming from its main advantage, i.e. impossibility to control possible confounders and to quantify the strength of associations due to the absence of an ad hoc control group, it is particularly useful to use in routine practice, mainly for purposes of signal generation and hypothesis testing in drug surveillance.

Paracetamol in therapeutic dosages and acute liver injury: causality assessment in a prospective case series.

BACKGROUND: Acute liver injury (ALI) induced by paracetamol overdose is a well known cause of emergency hospital admission and death. However, there is debate regarding the risk of ALI after therapeutic dosages of the drug.The aim is to describe the characteristics of patients admitted to hospital with jaundice who had previous exposure to therapeutic doses of paracetamol. An assessment of the causality role of paracetamol was performed in each case. METHODS: Based on the evaluation of prospectively gathered cases of ALI with detailed clinical information, thirty-two cases of ALI in non-alcoholic patients exposed to therapeutic doses of paracetamol were identified. Two authors assessed all drug exposures by using the CIOMS/RUCAM scale. Each case was classified into one of five categories based on the causality score for paracetamol. RESULTS: In four cases the role of paracetamol was judged to be unrelated, in two unlikely, and these were excluded from evaluation. In seven of the remaining 26 cases, the RUCAM score associated with paracetamol was higher than that associated with other concomitant medications. The estimated incidence of ALI related to the use of paracetamol in therapeutic dosages was 0.4 per million inhabitants older than 15 years of age and per year (99%CI, 0.2-0.8) and of 10 per million paracetamol users-year (95% CI 4.3-19.4). CONCLUSIONS: Our results indicate that paracetamol in therapeutic dosages may be considered in the causality assessment in non-alcoholic patients with liver injury, even if the estimated incidence of ALI related to paracetamol appears to be low.

Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting.

AIMS: Despite progress in anti-emetic treatment, many patients still suffer from chemotherapy-induced nausea and vomiting (CINV). This is a pilot, randomized, double-blind, placebo-controlled phase II clinical trial designed to evaluate the tolerability, preliminary efficacy, and pharmacokinetics of an acute dose titration of a whole-plant cannabis-based medicine (CBM) containing delta-9-tetrahydrocannabinol and cannabidiol, taken in conjunction with standard therapies in the control of CINV. METHODS: Patients suffering from CINV despite prophylaxis with standard anti-emetic treatment were randomized to CBM or placebo, during the 120 h post-chemotherapy period, added to standard anti-emetic treatment. Tolerability was measured as the number of withdrawals from the study during the titration period because of adverse events (AEs). The endpoint for the preliminary efficacy analysis was the proportion of patients showing complete or partial response. RESULTS: Seven patients were randomized to CBM and nine to placebo. Only one patient in the CBM arm was withdrawn due to AEs. A higher proportion of patients in the CBM group experienced a complete response during the overall observation period [5/7 (71.4%) with CMB vs. 2/9 (22.2%) with placebo, the difference being 49.2% (95% CI 1%, 75%)], due to the delayed period. The incidence of AEs was higher in the CBM group (86% vs. 67%). No serious AEs were reported. The mean daily dose was 4.8 sprays in both groups. CONCLUSION: Compared with placebo, CBM added to standard antiemetic therapy was well tolerated and provided better protection against delayed CINV. These results should be confirmed in a phase III clinical trial.

Reporting randomised clinical trials of analgesics after traumatic or orthopaedic surgery is inadequate: a systematic review.

BACKGROUND: Several randomised clinical trials (RCTs) of analgesics in postoperative pain after traumatic or orthopaedic surgery (TOS) have been published, but no studies have assessed the quality of these reports. We aimed to examine the quality of reporting RCTs on analgesics for postoperative pain after TOS. METHODS: Reports of RCTs assessing analgesics in postoperative pain after TOS were systematically searched from electronic databases. The quality of reports was assessed using the CONSORT checklist (scoring range from 0 to 22). The quality was considered poor when scoring was 12 or lesser. The publication year and the impact factor of journals were recorded. RESULTS: A total of 92 reports of RCTs were identified and 69 (75%) scored 12 or lesser in CONSORT checklist (range 5-17). The mean (SD) CONSORT score of all reports was 10.6 (2.7). Missing CONSORT items included primary and secondary outcome measures (11%), the specific objectives and hypothesis definition (12%), the sample size calculation (12%), the dates defining the periods of recruitment (12%), the discussion of external validity of findings (14%), the allocation sequence generation (24%), and the interpretation of potential bias or imprecision of results (25%). There was a little improvement in CONSORT scores over time (r = 0.62; p < 0.001) and with impact factor of journals (r = 0.30; p < 0.001). CONCLUSION: Quality of reporting RCTs on analgesics after TOS is poor. Reporting of those RCTs should be improved according to methodological standard checklists in the next years.

Epidemiology of aplastic anemia: a prospective multicenter study.

BACKGROUND: Aplastic anemia is a rare and severe disease. Its incidence varies considerably worldwide. We aimed at describing the epidemiology of this disease, including the incidence, mortality and survival trends, in a well-defined population. DESIGN AND METHODS: Since 1980, a case-control surveillance study of aplastic anemia has been carried out by a cooperative group, in the metropolitan area of Barcelona. Inclusion is dependent on the patient having at least two of the following features: white blood cell count < or = 3.5 x 10(9)/L, platelet count < or = 50 x 10(9)/L, hemoglobin <10 g/L or hematocrit of <30%; when only one of these last two criteria is fulfilled, a reticulocyte count of < or = 30 x 10(9)/L is also required. The bone marrow biopsy has to be compatible with the diagnosis of aplastic anemia. RESULTS: Between 1980 and 2003, a total of 235 cases of aplastic anemia were identified. The overall incidence was 2.34 per million inhabitants per year and the incidence increased with age. Most of the cases were classified as severe or very severe aplastic anemia. Survival rates at 3 months, and at 2 and 15 years after the diagnosis were 73%, 57%, and 51%, respectively. Advanced age and more severe disease at the time of diagnosis were associated with a lower survival rate. There was a trend to a better 2-year survival rate among patients treated with bone marrow transplantation. Forty-nine cases (20.8%) were exposed to drugs reported to be associated with aplastic anemia, and 21 (8.9%) to toxic agents. CONCLUSIONS: The incidence of aplastic anemia in Barcelona is low but the case fatality rate is high. Advanced age and severe disease at the time of diagnosis were associated with decreased survival.