Lorna Hazell

A systematic review was performed to categorize the hERG (human ether‐a‐go‐go–related gene) liability of antihistamines, antipsychotics, and anti‐infectives and to compare it with current clinical risk of torsade de pointes (TdP). Eligible studies were hERG assays reporting half‐minimal inhibitory concentrations (IC50). A “hERG safety margin” was calculated from the IC50 divided by the peak human plasma concentration (free C_max). A margin below 30 defined hERG liability. Each drug was assigned an “uncertainty score” based on volume, consistency, precision, and internal and external validity of evidence. The hERG liability was compared to existing knowledge on TdP risk (www.credibledrugs.org). Of 1828 studies, 82 were eligible, allowing calculation of safety margins for 61 drugs. Thirty‐one drugs (51%) had evidence of hERG liability including 6 with no previous mention of TdP risk (eg, desloratadine, lopinavir). Conversely, 16 drugs (26%) had no evidence of hERG liability including 6 with known, or at least conditional or possible, TdP risk (eg, chlorpromazine, sulpiride). The main sources of uncertainty were the validity of the experimental conditions used (antihistamines and antipsychotics) and nonuse of reference compounds (anti‐infectives). In summary, hERG liability was categorized for 3 widely used drug classes, incorporating a qualitative assessment of the strength of available evidence. Some concordance with TdP risk was observed, although several drugs had hERG liability without evidence of clinical risk and vice versa. This may be due to gaps in clinical evidence, limitations of hERG/C_maxdata, or other patient/drug‐specific factors that contribute to real‐life TdP risk.

Patients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs. We systematically identified and reviewed cohort and case–control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison. The summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I 2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I 2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I 2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies). Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis. Use of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.

In 2005, spontaneous reporting of adverse drug reactions (ADRs) to the UK’s Yellow Card Scheme (YCS) was extended to include patient reports. Here, we investigate the potential pharmacovigilance impact of patient reporting.

Background: Intrinsa® is a transdermal testosterone patch that is indicated for use in hypoactive sexual desire disorder (HSDD) in women who have undergone bilateral oophorectomy and hysterectomy (surgically-induced menopause) receiving concomitant oestrogen therapy. Objective: To describe the utilization characteristics of the patients prescribed testosterone patch (Intrinsa®) based on an interim analysis of an ongoing Prescription-Event Monitoring study in England, and to assess, where possible, if the product is being used within the licensed therapeutic indication. Methods: In this interim analysis, patients were identified from dispensed prescriptions that had been issued by general practitioners (GPs) for Intrinsa® from March 2007. ‘Green form’ questionnaires were sent to GPs 6 months following the date of the first prescription for Intrinsa® for each individual patient, requesting information including age, sex, start and stop dates of treatment (if stopped), prescribing indication and reasons for stopping. Additional questions were asked regarding the patient’s menopausal status and use of concomitant oestrogen therapy. Results: The interim cohort consisted of 756 patients. The majority of patients were reported to be female (746 [98.7%]) with a median (interquartile range) age of 50 years (44–55 years). The most commonly reported indication was the licensed indication of HSDD in 580 patients (76.7%). Just under one-half of the patients (n=364 [48.1%]) were reported to have been hysterectomized and bilaterally oophorectomized (surgically-induced menopause) prior to starting Intrinsa®; 127 patients (16.8%) were naturally menopausal. For 222 patients (29.4%) the GP specified that the patient was not using concomitant oestrogen therapy. Overall, only 219 patients (29.0%) in the cohort were being prescribed Intrinsa® according to the manufacturer’s recommendations. Conclusions: This study has highlighted that some clinicians are prescribing this product outside the recommended terms of the licence, with less than 30% of patients receiving Intrinsa® according to prescribing guidelines. All events experienced by these patients will be analysed to detect any possible adverse events from using Intrinsa® outside of the licensed therapeutic indication. The findings support the ongoing postmarketing risk management of the product.

OBJECTIVES: To examine the safety of tadalafil as used in general practice in England, and to compare the mortality rate due to ischaemic heart disease (IHD) in tadalafil users with that in the male population in England. PATIENTS AND METHODS: Patients in this observational cohort study were identified from dispensed prescriptions for tadalafil issued by general practitioners (GPs) from February 2003 to November 2004. Demographic and outcome data (clinical events) were requested from patients’ GPs using a postal questionnaire. A standardized mortality ratio (SMR) was calculated using indirect standardization for deaths from IHD in the cohort (where age was known) over a 1‐year observation period compared to that in the English male population (2003). A sensitivity analysis was carried out to investigate the effects of missing data for age and cause of death. RESULTS: Clinical information was obtained for 16 129 patients (median age 60 years, interquartile range 52–67); the age was not specified for 3212 (19.9%) patients. At least a third of the patients had diabetes mellitus and 29% had hypertension. Comparison of the mortality rate due to IHD for the patients of known age with that in the English male population provided an SMR of 0.57 (95% confidence interval 0.38–0.83) indicating fewer observed deaths in the cohort than expected. The results of the sensitivity analyses investigating the effect of missing data for age and cause of death produced similar SMR estimates. One confirmed case of non‐arteritic anterior ischaemic optic neuropathy (NAION) was reported during tadalafil therapy in a patient with other risk factors for this condition. CONCLUSION: The results from this prescription‐event monitoring study suggest that tadalafil is generally well tolerated when used in general practice in England. The most frequently reported adverse clinical events were in keeping with clinical trial data and include headache, dyspepsia and back pain. There was no evidence of a greater mortality rate due to IHD in the tadalafil cohort than in the general male population. However, these results are limited by the use of an external comparator group and might be explained by a ‘healthy cohort effect’. One event of NAION was reported, and although a causal relationship was not established it indicates that NAION occurs rarely in patients prescribed tadalafil.

OBJECTIVE: To examine the cardiovascular safety of tadalafil, a phosphodiesterase type‐5 inhibitor used for treating erectile dysfunction in patients prescribed this drug by general practitioners (GPs) in England in 2003, focusing on mortality due to ischaemic heart disease (IHD). PATIENTS AND METHODS: Patients in this observational cohort study were identified from dispensed prescriptions for tadalafil issued by GPs from February to November 2003. Demographic and outcome data were requested from patients’ GPs using a postal questionnaire. A standardized mortality ratio (SMR) was calculated using indirect standardization for all deaths from IHD or myocardial infarction (MI) in male patients who were prescribed tadalafil, regardless of whether they were taking tadalafil at the time, compared to those in the English male population (2002). RESULTS: Clinical information was obtained for 6266 patients; patient sex could not be confirmed for 37 but in the remaining 6229 the median age was 61 years (interquartile range 53–68). The age was not specified for 2361 (37.7%) of the patients. Excluding patients not taking tadalafil at the time of the event, cardiovascular events included chest pain in 20, angina in 18, MI in 15 (including six fatal) and IHD in 11 (including five fatal). There were also six deaths where the cause was not ascertained; five of these patients were known to be male. Comparison of mortality due to IHD or MI for men with those in the English male population (2002) provided an SMR of 0.91 (95% confidence interval 0.50–1.48). CONCLUSIONS: The results from this study suggest a similar incidence of death due to IHD or MI in men prescribed tadalafil to that in the male English population. However, due to possible under‐reporting and the limitations of using an external comparator, these results should be interpreted in context with other studies on the cardiovascular effects and safety of tadalafil.

The purpose of this review was to estimate the extent of under-reporting of adverse drug reactions (ADRs) to spontaneous reporting systems and to investigate whether there are differences between different types of ADRs. A systematic literature search was carried out to identify studies providing a numerical estimate of under-reporting. Studies were included regardless of the methodology used or the setting, e.g. hospital versus general practice. Estimates of under-reporting were either extracted directly from the published study or calculated from the study data. These were expressed as the percentage of ADRs detected from intensive data collection that were not reported to the relevant local, regional or national spontaneous reporting systems. The median under-reporting rate was calculated across all studies and within subcategories of studies using different methods or settings. In total, 37 studies using a wide variety of surveillance methods were identified from 12 countries. These generated 43 numerical estimates of under-reporting. The median under-reporting rate across the 37 studies was 94% (interquartile range 82–98%). There was no significant difference in the median under-reporting rates calculated for general practice and hospital-based studies. Five of the ten general practice studies provided evidence of a higher median under-reporting rate for all ADRs compared with more serious or severe ADRs (95% and 80%, respectively). In comparison, for five of the eight hospital-based studies the median under-reporting rate for more serious or severe ADRs remained high (95%). The median under-reporting rate was lower for 19 studies investigating specific serious/severe ADR-drug combinations but was still high at 85%. This systematic review provides evidence of significant and widespread under-reporting of ADRs to spontaneous reporting systems including serious or severe ADRs. Further work is required to assess the impact of under-reporting on public health decisions and the effects of initiatives to improve reporting such as internet reporting, pharmacist/nurse reporting and direct patient reporting as well as improved education and training of healthcare professionals.