Drugs, QTc prolongation and sudden cardiac death

__Abstract__ The term sudden cardiac death pertains to an unexpected death from cardiac causes within a short time period and has been described throughout history. The ancient Egyptians inscribed on the tomb of a nobleman some 4500 years ago that he had died suddenly and without apparent cause. Another early case of sudden death was Phidippides, the young Greek messenger, who collapsed and died after he ran 26.2 miles from Marathon to Athens to deliver the news of the Greek victory over the Persians in 460 BC. It has been hypothesised that Hippocrates in his writings provided the first medical description (approximately 400 BC) of sudden cardiac death: "Those who are subject to frequent and severe fainting attacks without obvious cause die suddenly". Sudden (cardiac) death was originally ascribed to supernatural causes. In the bible Ananias and his wife Sapphira were punished for their deceit by sudden death "WhenAnanias heard this, he fell down and died. And great fear seized all who heard what had happened. About three hours later his wife came in, not knowing what had happened. Peter asked her, "Tell me, is this the price you and Ananias got for the land?" "Yes," she said, "that is the price." Peter said to her, "How could you agree to test the Spirit of the Lord? Look! 1he feet of the men who buried your husband are at the door, and they will carry you out also. " At that moment she fell down at his feet and died. 1hen the young men came in and, .finding her dead, carried her out and buried her beside her husband. (ACTS 4:32-5:II). Even when medical science advanced to a stage where autopsies became available many sudden cardiac deaths remained unexplained. Only recently, it has been hypothesized that Napoleon might have died due cardiac arrhythmias induced by drugs the Emperor was using at that time

Number of Patients Studied Prior to Approval of New Medicines: A Database Analysis

Background: At the time of approval of a new medicine, there are few long-term data on the medicine's benefit-risk balance. Clinical trials are designed to demonstrate efficacy, but have major limitations with regard to safety in terms of patient exposure and length of follow-up. This study of the number of patients who had been administered medicines at the time of medicine approval by the European Medicines Agency aimed to determine the total number of patients studied, as well as the number of patients studied long term for chronic medication use, compared with the International Conference on Harmonisation's E1 guideline recommendations. Methods and Findings: All medicines containing new molecular entities approved between 2000 and 2010 were included in the study, including orphan medicines as a separate category. The total number of patients studied before approval was extracted (main outcome). In addition, the number of patients with long-term use (6 or 12 mo) was determined for chronic medication. 200 unique new medicines were identified: 161 standard and 39 orphan medicines. The median total number of patients studied before approval was 1,708 (interquartile range [IQR] 968-3,195) for standard medicines and 438 (IQR 132-915) for orphan medicines. On average, chronic medication was studied in a larger number of patients (median 2,338, IQR 1,462-4,135) than medication for intermediate (878, IQR 513-1,559) or short-term use (1,315, IQR 609-2,420). Safety and efficacy of chronic use was studied in fewer than 1,000 patients for at least 6 and 12 mo in 46.4% and 58.3% of new medicines, respectively. Among t

Spontaneous reports of vaccination errors in the European regulatory database EudraVigilance: A descriptive study

Background: Among all post-marketing medication error reports submitted to EudraVigilance, vaccines are the most frequently reported medicinal products. This study aims to describe the characteristics of vaccination errors submitted to Eudravigilance between 2001 and 2016. Methods: EudraVigilance is a spontaneous reporting database for adverse events maintained by the European Medicines Agency. We extracted Individual Case Safety Reports (ICSRs) submitted to EudraVigilance between 1 January 2001 and 31 December 2016. Reports were included for analysis if a vaccine was reported as interacting or suspect drug and at least one medication error term was listed as an adverse reaction. ICSRs were stratified by age and gender, by year of reporting, region of origin, reporter profession, seriousness of outcome, ATC, and type of error. Results: In total, 7097 ICSRs were included in the study. We observed a yearly increase in the reporting of vaccination errors, with the proportion to all vaccine ICSRs increasing from 0.4% to 4.0% between 2001 and 2016. The majority of reports was classified as serious (4248, 59.9%), but non-serious reports were increasingly reported since 2012. The mean age of patients was 24.1 years. The most frequently reported vaccines were influenza (13.5%), bacterial and viral combined (12.3%), and hepatitis vaccines (11.8%). A total of 8167 medication error terms were reported. The most frequently reported terms were “Inappropriate schedule of drug administration” (27.2%), “Incorrect route of drug administration” (12.5%) and “Drug administered to patient of inappropriate age” (10.0%). For infants and children, the error “Drug administered to patient of inappropriate age” was reported more often than for all other age categories. Discussion: Vaccination errors are increasingly submitted to EudraVigilance. Errors related to the schedule are the most common errors reported with vaccines. However, consequences of vaccination errors appear to be relatively mild

Isotretinoin exposure during pregnancy: A population-based study in the Netherlands

Objective: To estimate isotretinoin exposure in Dutch pregnant women despite the implemented pregnancy prevention programme (PPP) and second, to analyse the occurrence of adverse fetal or neonatal outcomes in these isotretinoin exposed pregnancies.Design: Population-based study.Setting: The Netherlands.Participants: A cohort of 203 962

Study Design and Evaluation of Risk Minimization Measures: A Review of Studies Submitted to the European Medicines Agency for Cardiovascular, Endocrinology, and Metabolic Drugs

Introduction: Studies measuring the effectiveness of risk minimization measures (RMMs) submitted by pharmaceutical companies to the European Medicines Agency are part of the post-authorization regulatory requirements and represent an important source of data covering a range of medicinal products and safety-related issues. Their objectives, design, and the associated regulatory outcomes were reviewed, and conclusions were drawn that may support future progress in risk minimization evaluation. Methods: Information was obtained from risk management plans, study protocols, clinical study reports, and assessment reports of 157 medicinal products authorized for cardiovascular, endocrinology, and metabolic indications. We selected observational studies measuring, as outcomes o

Dissemination of Direct Healthcare Professional Communications on Medication Errors for Medicinal Products in the EU: An Explorative Study on Relevant Factors

Introduction: When serious medication errors (ME) are identified, communication to the field may be necessary. In the EU, communication of serious safety issues, such a

Fatal outcomes following immunization errors as reported to the EudraVigilance: A case series

Background: Serious adverse reactions after immunization are rare but do occur. In very rare instances, cases with fatal outcome have been reported. These reports can have a huge impact and even more so when due to an immunization error. The aim of this study is to systematically review immunization errors with fatal outcomes in EudraVigilance. Methods: This was a case-series analysis of Individual Case Safety Reports (ICSRs) reporting immunization errors and a fatal outcome. To determine the level of certainty of a causal association between the immunization errors and fatal outcomes two independent reviewers assessed all ICSRs using the WHO tool “Causality assessment of an Adverse Event Following Immunization (AEFI)”. In accordance with the tool, the ICSRs were classified as consistent, indeterminate, inconsistent/coincidental, or unclassifiable. In addition, we estimated the contribution of reported errors to the fatal outcomes as large, moderate, small, none, or unclassifiable using a classification developed f

Description of the Risk Management of Medication Errors for Centrally Authorised Products in the European Union

Introduction: Medication errors can have serious consequences for patients. To prevent the occurrence of medication errors in clinical practice, safety concerns may be included in the risk management plan and subsequently be addressed with routine and/or additional risk minimisation measures. Objective: This study aims to describe safety concerns around medication errors and the risk minimisation measures for centrally authorised products in the European Union. Methods: All safety concerns included in the risk management plans of originator centrally authorised products, authorised between 1 January, 2010 and 31 December, 2017, were collected from the European Public Assessment Report registry. Medication error safety concerns were categorised by Anatomical Therapeutic Classification code, year of authorisation, type of medication error and type of risk minimisation measure. Results: During the study period, 311 centrally authorised products were approved, of which 84 had at least one medication error safety concern. The proportion of centrally authorised products with medication error safety concerns showed variation between 2010 and 2017 ranging from 15.2% to 36.4%. In total, 95 medication error safety concerns were identified. The type of medication error was highly variable, drug administration error was listed most frequently (n = 17). For 27 out of 95 medication error safety concerns, corresponding to 23 centrally authorised products, additional risk minimisation measures were required. All additional risk minimisation measures consisted of educational material targeted at healthcare professionals (85.2%) and/or patients (51.9%). For 78.3% of centrally authorised products with additional risk minimisation measures for medication errors, studies to evaluate the effectiveness of the additional risk minimisation measures were agreed upon. Conclusions: Medication error safety concerns were listed for almost a quarter of centrally authorised products approved during the study period. Further research is needed to evaluate the effectiveness and continued need for additional risk minimisation measures for medication errors

Useful Interplay Between Spontaneous ADR Reports and Electronic Healthcare Records in Signal Detection

Background and Objective: Spontaneous reporting systems (SRSs) remain the cornerstone of post-marketing drug safety surveillance despite their well-known limitations. Judicious use of other available data source

Overanticoagulation is associated with renal function decline

Background: Recent studies suggest that overanticoagulation impairs renal function in patients on warfarin therapy, due to renal tubular obstruction from glomerular hemorrhage. Methods: Data from the Rotterdam Study (The Netherlands), a prospective population-based cohort study of patients 55 years and older, were used for this study. Information on vitamin K antagonist (VKA) therapy was obtained from the regional anticoagulation clinic, where prothrombin times were monitored every 1-6 weeks depending on target level and stability of the international normalized ratio (INR). Linear regression was performed to study the association between the cumulative number of instances of overanticoagulation (defined as a measurement of an INR >6.0) and the change in renal function between baseline and third examination round based on estimated glomerular filtration rate (CKD-EPI equation). Age, sex, baseline renal function, baseline and incident heart failure, and indication for VKA therapy were included as potential confounders. Results: Information was available for analysis on 2,802 study participants in whom overanticoagulation was significantly associated with a decline in renal function, after adjustment for confounding by age, sex, heart failure, baseline glomerular filtration rate and indication for VKA therapy (-0.180 ml/min per 1.73 m2 per year per event for INR >6.0, p = 0.030). Conclusions: Overanticoagulation (INR >6.0) is associated with a decline in renal function. Further studies are needed to evaluate the causal role of different degrees of overanticoagulation, including transient effects, in high-risk groups, and the association with the new oral anticoagulants