Giselle Sarganas

Epidemiology of symptomatic drug-induced long QT syndrome and torsade de pointes in Germany

AIMS Drug-induced long QT syndrome (diLQTS) leading to Torsade de Pointes (TdP) is a potentially lethal condition, which has led to several post-marketing drug withdrawals in the past decade. The true incidence of diLQTS/TdP is largely unknown. One explanation is under-reporting of this potentially life-threatening adverse event by physicians and other medical staff to pharmacovigilance agencies. To gain more insight into the incidence of diLQTS and TdP, the Berlin Pharmacovigilance Center (PVZ-FAKOS) has actively and prospectively identified patients who developed this particular type of drug-induced adverse event. Here, the basic characteristics of the affected patients are summarized and suspected drugs are discussed. Furthermore, an extrapolation of the Berlin incidence rates to the German Standard Population is presented. METHODS AND RESULTS Using a Berlin-wide network of 51 collaborating hospitals (>180 clinical departments), adult patients presenting with long QT syndrome (LQTS/TdP) between 2008 and 2011 were identified by active surveillance of these hospitals. Drug exposures as well as other possible risk factors were obtained from the patients files and in a face-to-face interview with the patient. One-hundred and seventy patients of possible LQTS/TdP were reported to the Pharmacovigilance Center of whom 58 cases were confirmed in a thorough validation process. The majority (66%) of these cases were female and 60% had developed LQTS/TdP in the outpatient setting. Thirty-five (60%) of 58 confirmed cases were assessed as drug-related based on a standardized causality assessment applying the criteria of the World Health Organization. Drugs assessed as related in more than two cases were metoclopramide, amiodarone, melperone, citalopram, and levomethadone. The age-standardized incidence of diLQTS/TdP in Berlin was estimated to be 2.5 per million per year for males and 4.0 per million per year for females. CONCLUSION While European annual reporting rates based on spontaneous reports suggest an annual diLQTS/TdP incidence of 0.26 per million in Germany, we estimated a considerably higher incidence of diLQTS/TdP in an active surveillance approach. Further measures are warranted to better sensitize physicians against this potentially life-threatening drug-induced adverse event.

Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patients death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity.

Drug-induced liver injury: results from the hospital-based Berlin Case–Control Surveillance Study

AIM Drug-induced liver injury (DILI) is often responsible for acute liver failure, drug withdrawal, boxed warnings or drug non-approval. Therefore, we conducted a case-control study to determine the hepatotoxic risk of a wide range of drugs. METHODS The Berlin Case-Control Surveillance Study FAKOS included all 51 Berlin hospitals in a hospital network. Between 2002 and 2011, 198 patients with acute idiopathic hepatitis, 377 inpatient controls and 708 outpatient controls were ascertained. Case patients were thoroughly validated using anamnestic, clinical, laboratory and histological data. Drug exposure was obtained in a face-to-face interview. A possible drug aetiology was assessed in individual patients by applying the updated Council for International Organizations of Medical Sciences (CIOMS) scale. Drug risks were further quantified [odds ratios (OR) with 95% confidence intervals (CI)] in a case-control design with unconditional logistic regression analysis. Drug intake in the last 28 days before index date was considered for the analysis. RESULTS The study corroborated hepatotoxic risks for a number of drugs, including phenprocoumon (OR 3.3, 95% CI 1.5, 6.7), amiodarone (OR 5.5, 95% CI 1.3, 21.2), clozapine (OR 34.6, 95% CI 2.8, 824.9) and flupirtine (OR 40.2, 95% CI 5.5, 856.9). Increased risks were also suggested for less commonly reported substances such as angiotensin II receptor blockers, atypical antipsychotics and for biperiden, a drug never before reported to be hepatotoxic. CONCLUSIONS Our study identified a large number of drugs as possible causes of hepatotoxicity. The observed risk for seldom reported substances highlights the need for further post-authorization safety studies not exclusively focusing on drugs already labelled as potentially hepatotoxic.

Pharmacoepidemiology of common colds and upper respiratory tract infections in children and adolescents in Germany

BackgroundMedicines to treat common colds (CC) and upper respiratory tract infections (URTI) are widely used among children, but there are only few data about treatments actually applied for these diseases. In the present study we analyze the prevalence and correlations of self-medicated and prescribed drug use for the treatment of CCs and URTIs among children and adolescents in Germany.MethodsMedicine use during the week preceding the interview was recorded among 17,450 children (0–17 years) who participated in the drug interview of the 2003–2006 German Health Interview and Examination Survey for Children and Adolescents (KiGGS). The definition of CCs and URTIs in the present study included the WHO-ICD-10 codes J00, J01.0, J01.9, J02.0, J02.9, J03.0, J03.9, J04.0, J06.8, J06.9, J11.1, J11.8, R05 and R07.0. Using the complex sample method, the prevalence and associated socio-demographic factors of self-medication, prescribed medicines and antibiotics were defined.Results13.8% of the participating girls and boys use drugs to treat a CC or an URTI. About 50% of this group use prescribed medications. Among the users of prescribed medication, 11.5% use antibiotics for the treatment of these diseases. Looking at all prescribed medicines we find associations with younger age, immigration background, and lower social status. Antibiotic use in particular is associated with female sex, higher age, residency in the former East Germany and immigration background.ConclusionsThe use of medicines to treat CCs or URTIs is widespread among children and adolescents in Germany. Thus, longitudinal studies should investigate the risks associated with this drug use. Differences in socio-demographic variables regarding exposure to antibiotic use indicate that there could be an implausible prescribing behavior among physicians in Germany.

Torsade de pointes tachycardia in a patient on dronedarone therapy.

Dronedarone is a promising, relatively new antiarrhythmic agent characterized by structural similarities to amiodarone but without amiodarones severe organ toxicity. The proarrhythmic potential of dronedarone, however, is of increasing concern. We describe a 76‐year‐old woman who had been receiving dronedarone 400 mg twice/day to prevent recurrent atrial tachycardia with rapid ventricular response. Several months later, she came to the emergency department with decompensated congestive heart failure and episodes of atrial tachycardia; digoxin 0.5 mg and furosemide 40 mg were administered intravenously. Thereafter nonsustained torsade de pointes (TdP) tachycardia occurred. She was transferred to the intensive care unit where a dose of amiodarone 150 mg was administered intravenously by mistake. Thereafter, the patient showed sustained TdP necessitating cardiac resuscitation. Dronedarone was discontinued, and digoxin and amiodarone were not administered again. Under dronedarone a relevant QT prolongation was documented that was additionally augmented after concomitant treatment with digoxin and amiodarone. Use of the Naranjo adverse drug reaction probability scale indicated a probable adverse drug reaction to dronedarone (score of 7). To our knowledge, this is the first case report of a patient who experienced TdP tachycardias while receiving dronedarone therapy in connection with a worsening of heart failure and possible drug interactions with digoxin and amiodarone. Clinicians should be aware of this potential adverse drug reaction and perform repeated heart rate–corrected QT (QTc) interval measurements as well as screening for congestive heart failure in patients receiving dronedarone therapy.

Primary prevention in general practice - views of German general practitioners: a mixed-methods study.

BackgroundPolicy efforts focus on a reorientation of health care systems towards primary prevention. To guide such efforts, we analyzed the role of primary prevention in general practice and general practitioners’ (GPs) attitudes toward primary prevention.MethodsMixed-method study including a cross-sectional survey of all community-based GPs and focus groups in a sample of GPs who collaborated with the Institute of General Practice in Berlin, Germany in 2011. Of 1168 GPs 474 returned the mail survey. Fifteen GPs participated in focus group discussions. Survey and interview guidelines were developed and tested to assess and discuss beliefs, attitudes, and practices regarding primary prevention.ResultsMost respondents considered primary prevention within their realm of responsibility (70%). Primary prevention, especially physical activity, healthy eating, and smoking cessation, was part of the GPs’ health care recommendations if they thought it was indicated. Still a quarter of survey respondents discussed reduction of alcohol consumption with their patients infrequently even when they thought it was indicated. Similarly 18% claimed that they discuss smoking cessation only sometimes. The focus groups revealed that GPs were concerned about the detrimental effects an uninvited health behavior suggestion could have on patients and were hesitant to take on the role of “health policing”. GPs saw primary prevention as the responsibility of multiple actors in a network of societal and municipal institutions.ConclusionsThe mixed-method study showed that primary prevention approaches such as lifestyle counseling is not well established in primary care. GPs used a selective approach to offer preventive advice based upon indication. GPs had a strong sense that a universal prevention approach carried the potential to destroy a good patient-physician relationship. Other approaches to public health may be warranted such as a multisectoral approach to population health. This type of restructuring of the health care sector may benefit patients who are unable to afford specific prevention programmes and who have competing demands that hinder their ability to focus on behavior change.

Constraints, synergies and avenues for scaling up breastfeeding, antibiotics for pneumonia and IMCI interventions in the Cusco region, Peru

Objective: The purpose of this qualitative case study was to assess the feasibility of scaling up exclusive breastfeeding for 6 months, antibiotics for pneumonia and integrated management of childhood illness (IMCI) child interventions in three districts of the Cusco region, Peru. Methods: During field visits, constraints, synergies and solutions to the implementation of the selected interventions were collected through observational recording and interviews of mothers, health workers, and health managers/decision makers. Results are presented for each intervention according to the health system level where they occurred: mother/community, health worker, health centre, and political/managerial levels. Findings: This case study demonstrates that it is feasible to scale up exclusive breastfeeding, antibiotics for pneumonia and IMCI interventions in poverty-stricken rural areas of a low-income country. Factors that helped and hindered the implementation were identified for each intervention. Conclusions: The need for a coherent multi-sector approach that includes regulation, implementation and monitoring of health policies and education of all involved stakeholders was apparent. This study also demonstrates that global health interventions need to undergo local adaptation. Identifying local constraints and facilitating factors in a systematic way as proposed in this study is a useful step to increase their effectiveness and reach at the local level and to identify areas for improvement in the original intervention policies.