Pascale Tubert-Bitter

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Background— The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results— This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (⩽20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions— Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France

An increased incidence of narcolepsy in children was detected in Scandinavian countries where pandemic H1N1 influenza ASO3-adjuvanted vaccine was used. A campaign of vaccination against pandemic H1N1 influenza was implemented in France using both ASO3-adjuvanted and non-adjuvanted vaccines. As part of a study considering all-type narcolepsy, we investigated the association between H1N1 vaccination and narcolepsy with cataplexy in children and adults compared with matched controls; and compared the phenotype of narcolepsy with cataplexy according to exposure to the H1N1 vaccination. Patients with narcolepsy-cataplexy were included from 14 expert centres in France. Date of diagnosis constituted the index date. Validation of cases was performed by independent experts using the Brighton collaboration criteria. Up to four controls were individually matched to cases according to age, gender and geographic location. A structured telephone interview was performed to collect information on medical history, past infections and vaccinations. Eighty-five cases with narcolepsy-cataplexy were included; 23 being further excluded regarding eligibility criteria. Of the 62 eligible cases, 59 (64% males, 57.6% children) could be matched with 135 control subjects. H1N1 vaccination was associated with narcolepsy-cataplexy with an odds ratio of 6.5 (2.1-19.9) in subjects aged<18 years, and 4.7 (1.6-13.9) in those aged 18 and over. Sensitivity analyses considering date of referral for diagnosis or the date of onset of symptoms as the index date gave similar results, as did analyses focusing only on exposure to ASO3-adjuvanted vaccine. Slight differences were found when comparing cases with narcolepsy-cataplexy exposed to H1N1 vaccination (n=32; mostly AS03-adjuvanted vaccine, n=28) to non-exposed cases (n=30), including shorter delay of diagnosis and a higher number of sleep onset rapid eye movement periods for exposed cases. No difference was found regarding history of infections. In this sub-analysis, H1N1 vaccination was strongly associated with an increased risk of narcolepsy-cataplexy in both children and adults in France. Even if, as in every observational study, the possibility that some biases participated in the association cannot be completely ruled out, the associations appeared robust to sensitivity analyses, and a specific analysis focusing on ASO3-adjuvanted vaccine found similar increase.

Trends in Spontaneous Adverse Drug Reaction Reports to the French Pharmacovigilance System (1986—2001)

AbstractBackground: The French pharmacovigilance system is based on a network of 31 regional centres located in teaching hospitals and coordinated by the French Medicines Agency (‘Agence Francaise de Securite Sanitaire des Produits de Santé’ [Afssaps]). Since 1984, they have shared a common database of adverse drug reactions (ADRs) that are spontaneously reported by healthcare professionals. The objective of this study is to describe the characteristics of the reports and the reporting trends in the French pharmacovigilance spontaneous reporting database from 1986 to 2001. Methods: All the reports from January 1986 to December 2001 were included. Drugs and ADRs were translated to anatomical therapeutic chemical (ATC) codes and MedDRA classifications, respectively. Results: The total number of reports was 197 580 over the 16-year period, with linearly increase over time. The median (interquartile range [IQR]) age of the patients was 53 (34–70) and the male/female ratio was 0.82. The median (IQR) time between the date of occurrence of the ADR and the date of report was 73 days (34–166). The reporter was a specialist in 74% of the reports and a general practitioner in 17%. The annual rate of reporting according to medical demography strongly increased for the specialists, especially since 1994. At least one ADR was considered as serious in 44.8% of the reports. The ADRs were most frequently related to nervous system drugs (23%), followed by cardiovascular drugs (19%) and systemic anti-infectives (17%). The latter class had the fastest progression mostly due to antiretroviral therapy since 1996. According to the Medical Dictionary for Regulatory Activities (MedDRA) coding, the system organ most often reported was skin and subcutaneous tissue disorders (29%), followed by nervous system disorders (19%), gastrointestinal disorders (12%), blood and lymphatic system disorders (12%), vascular disorders (12%) and general disorders and administration site conditions (12%). Discussion: All spontaneous reporting systems are affected by under-reporting. One of their goals is to generate early signals, which might be more affected by reporting bias than by under-reporting. Some improvements should be made in the design of the French database, but data collected since 1986 constitute an essential tool for the routine work of the 31 pharmacovigilance centres. Conclusion: This first description of the data of the French pharmacovigilance database involving all drugs and ADRs shows an increasing tendency to reporting over time, especially in specialists and for systemic anti-infective drugs. The database that uses hierarchical international classifications for drugs and adverse reactions may be used for further studies and could be the basis for an automatic signal generation system.

Evaluation of statistical association measures for the automatic signal generation in pharmacovigilance

Pharmacovigilance aims at detecting the adverse effects of marketed drugs. It is generally based on the spontaneous reporting of events thought to be the adverse effects of drugs. Spontaneous Reporting Systems (SRSs) supply huge databases that pharmacovigilance experts cannot exhaustively exploit without data mining tools. Data mining methods; i.e., statistical association measures in conjunction with signal generation criteria, have been proposed in the literature but there is no consensus regarding their applicability and efficiency, especially since such methods are difficult to evaluate on the basis of actual data. The objective of this paper is to evaluate association measures on simulated datasets obtained with SRS modeling. We compared association measures using the percentage of false positive signals among a given number of the most highly ranked drug-event combinations according to the values of the association measures. By considering 150 drugs and 100 adverse events, these percentages of false positives, among the 500 most highly ranked drug-event couples, vary from 1.1% to 53.4% (averages over 1000 simulated datasets). As the measures led to very different results, we could identify which measures appeared to be the most relevant for pharmacovigilance.

Pulmonary hypertension associated with benfluorex exposure

Benfluorex was marketed in France until 2009, despite its similar pharmacological properties with fenfluramine and its derivatives known to be a cause of pulmonary arterial hypertension (PAH). The aim of this study is to report clinical and haemodynamic characteristics for patients suffering from pulmonary hypertension (PH) associated with benfluorex exposure that had been identified by the French PAH Network. 85 cases of PH associated with benfluorex exposure were identified by the French PAH Network from June 1999 to March 2011. Of these, 70 patients had confirmed pre-capillary PH. The median duration of exposure was 30 months, with a median of 108 months between start of exposure and diagnosis of the pulmonary vascular disease. 33% of all patients also had prior exposure to fenfluramine or dexfenfluramine, and an additional risk factor for PH was identified in 20 (30%) out of 70 patients with pre-capillary PH. A quarter of patients in this current series showed coexisting PH and mild-to-moderate cardiac valve involvement. The results of our study, together with the accumulated data regarding the known toxic effects of fenfluramine and dexfenfluramine, strongly suggest that benfluorex exposure is a potent trigger for PAH.

False Discovery Rate Estimation for Frequentist Pharmacovigilance Signal Detection Methods

Pharmacovigilance systems aim at early detection of adverse effects of marketed drugs. They maintain large spontaneous reporting databases for which several automatic signaling methods have been developed. One limit of those methods is that the decision rules for the signal generation are based on arbitrary thresholds. In this article, we propose a new signal-generation procedure. The decision criterion is formulated in terms of a critical region for the P-values resulting from the reporting odds ratio method as well as from the Fishers exact test. For the latter, we also study the use of mid-P-values. The critical region is defined by the false discovery rate, which can be estimated by adapting the P-values mixture model based procedures to one-sided tests. The methodology is mainly illustrated with the location-based estimator procedure. It is studied through a large simulation study and applied to the French pharmacovigilance database.

Bayesian pharmacovigilance signal detection methods revisited in a multiple comparison setting

Pharmacovigilance spontaneous reporting systems are primarily devoted to early detection of the adverse reactions of marketed drugs. They maintain large spontaneous reporting databases (SRD) for which several automatic signalling methods have been developed. A common limitation of these methods lies in the fact that they do not provide an auto-evaluation of the generated signals so that thresholds of alerts are arbitrarily chosen. In this paper, we propose to revisit the Gamma Poisson Shrinkage (GPS) model and the Bayesian Confidence Propagation Neural Network (BCPNN) model in the Bayesian general decision framework. This results in a new signal ranking procedure based on the posterior probability of null hypothesis of interest and makes it possible to derive with a non-mixture modelling approach Bayesian estimators of the false discovery rate (FDR), false negative rate, sensitivity and specificity. An original data generation process that can be suited to the features of the SRD under scrutiny is proposed and applied to the French SRD to perform a large simulation study. Results indicate better performances according to the FDR for the proposed ranking procedure in comparison with the current ones for the GPS model. They also reveal identical performances according to the four operating characteristics for the proposed ranking procedure with the BCPNN and GPS models but better estimates when using the GPS model. Finally, the proposed procedure is applied to the French data.

Pharmacovigilance Data Mining With Methods Based on False Discovery Rates: A Comparative Simulation Study

The early detection of adverse reactions caused by drugs that are already on the market is the prime concern of pharmacovigilance efforts; the methods in use for postmarketing surveillance are aimed at detecting signals pointing to potential safety concerns, on the basis of reports from health‐care providers and from information available in various databases. Signal detection methods based on the estimation of false discovery rate (FDR) have recently been proposed. They address the limitation of arbitrary detection thresholds of the automatic methods in current use, including those last updated by the US Food and Drug Administration and the World Health Organizations Uppsala Monitoring Centre. We used two simulation procedures to compare the false‐positive performances for three current methods: the reporting odds ratio (ROR), the information component (IC), the gamma Poisson shrinkage (GPS), and also for two FDR‐based methods derived from the GPS model and Fishers test. Large differences in FDR rates were associated with the signal‐detection methods currently in use. These differences ranged from 0.01 to 12% in an analysis that was restricted to signals with at least three reports. The numbers of signals generated were also highly variable. Among fixed‐size lists of signals, the FDR was lowered when the FDR‐based approaches were used. Overall, the outcomes in both simulation studies suggest that improvement in effectiveness can be expected from use of the FDR‐based GPS method.

Comparing the toxicity of two drugs in the framework of spontaneous reporting: A confidence interval approach

Spontaneous reporting remains the most frequently used technique in post-marketing surveillance. Decision-making usually depends on comparisons between the number of adverse drug reactions (ADRs) reported for two drugs on the basis of an equivalent number of prescriptions. The validity of such comparisons is expected to be jeopardized by probable underreporting ADR cases. This problem is accentuated when it cannot be assumed that the magnitude of underreporting is the same for the both drugs. Differences in reporting ratios can overemphasize, cancel, or reverse the conclusions of a statistical comparison based on the number of reports. We propose a single method for (1) calculating confidence intervals for relative risks estimated in the context of spontaneous reporting and (2) deriving the range of reporting ratios for which the conclusion of the statistical comparison remains statistically valid.

Drugs induced pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature, resulting in elevated pulmonary vascular resistance and premature death. According to the current classification, PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressant drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used but are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, in part reversible after its withdrawal. Recently several studies raised the potential endothelial dysfunction that could be induced by interferon, and few cases of PAH have been reported with interferon therapy. Other possible risk factors for PAH include: nasal decongestants, like phenylpropanolamine, dietary supplement - L-Tryptophan, selective serotonin reuptake inhibitors, pergolide and other drugs that could act on 5HT2B receptors. Interestingly, PAH remains a rare complication of these drugs, suggesting possible individual susceptibility and further studies are needed to identify patients at risk of drugs induced PAH.