Haleh Bagheri

Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care

Several nonsteroidal anti‐inflammatory drugs (NSAIDs) have been withdrawn from the market because of hepatic adverse drug reactions (ADRs). Moreover, some cases of liver diseases have been reported in patients taking NSAIDs (arylcarboxylic NSAIDs, piroxicam, sulindac, nimesulide, etc.). Pharmacoepidemiological studies have shown a risk of hepatic ADRs with NSAIDs used in association with other hepatotoxic drugs. In contrast, other studies performed in hospitalized patients did not found any association. The aim of this study was to assess the hepatic risk associated with the use of NSAID in the setting of primary care. The study design was a case–control study where cases and controls were all recruited among patients seen in the context of medical community care. Eighty‐eight cases and 178 controls were included between January 1998 and December 2000. Cases used more drugs than controls in the 15u2003days before index day (2.9u2003±u20032.2 vs. 1.8u2003±u20031.8 different consumed drugs; Pu2003<u200310−4). After adjustment, we found a significant association between liver injury and NSAID exposure in women [odds ratio (OR)u2003=u20036.49 (1.67–25.16)] but not in men [ORu2003=u20031.06 (0.36–3.12)]. A total of 22 cases were exposed to NSAIDs. Of them, seven patients were exposed to salicylates, five to diclofenac, four to ibuprofen, four to ketoprofen, two to niflumic acid, one to flurbiprofen and one to meloxicam (two patients were simultaneously exposed to two different NSAIDs: salicylateu2003+u2003niflumic acid and salicylateu2003+u2003diclofenac). These patients suffered from hepatocellular (53.3%), cholestatic (20%) or mixed (26.7%) injury. In 18 cases, liver enzymes returned to normal values after discontinuation of drug. No case had a fatal outcome. This study shows the existence of a significant association between liver disturbances and NSAID use in women.

Overview of adverse reactions to nefopam: an analysis of the French Pharmacovigilance database

Nefopam is widely used for the relief of moderate acute pain. Its safety profile remains to be specified. The objective of the study was to review adverse reactions to nefopam spontaneously reported to the French Pharmacovigilance system. All cases of adverse drug reactions (ADRs) associated with nefopam, registered in the French Pharmacovigilance database from January 1, 1995 to December 31, 2004, were reviewed. For each reported ADR, information about patient (age, gender, medical history), drug exposure (suspected and concomitantly used drugs), characteristics of ADRs (imputability score, time of onset, seriousness, outcome) were collected. A total of 114 ADRs with an imputability rated from ‘plausible’ (I2) to ‘likely’ (I3) and ‘very likely’ (I4) was analysed. The most frequent ADRs included ‘expected’ ADRs such as sweating, nausea, tachycardia, malaise or vomiting; 61 ADRs were ‘unexpected. No overdose was reported; 26 ADRs (23%) were considered as ‘serious’. Most of them were ‘unexpected’, including neuropsychiatric (hallucinations, convulsions) or cutaneous (pruritus, erythema, urticaria) ADRs. Six cases of anaphylactic ADRs (two angioedema and four anaphylactic shocks) were reported, all occurring shortly after use of nefopam during the post‐operative period. Physicians should be aware of the possible occurrence of some serious ADRs when using nefopam such as convulsions and anaphylactic shocks, especially when the drug is used in special medical conditions, like post‐operative periods.

Detection and incidence of drug-induced agranulocytosis in hospital : a prospective analysis from laboratory signals

AimsOur objectives were to assess the detection and incidence of drug-induced agranulocytosis in two university hospitals using hematology laboratory data.MethodsA prospective study was undertaken at Toulouse University Hospital (France) and Navarra University Hospital (Spain) for 1xa0year (from 1 May 2004 to 30 April 2005). Using a computerized process and hematology laboratory data, all neutrophil counts with a value less than 500/mm3 were registered, allowing identification of inpatients suffering from agranulocytosis during the period of the study. Medical records of all selected patients were then consulted. Cytostatic drugs were excluded from this study.ResultsDuring the period of the study, 225,659 neutrophil counts were performed in both hospitals, of which 2,835 (1.26%) had a neutrophil count less than 500/mm3, corresponding to 739 patients. Seventeen patients were excluded because of lack of data, and 20 cases of infants younger than 3xa0months were excluded. Among the remaining patients (nu2009=u2009702), 23 cases of drug-induced agranulocytosis (excluding cytostatic drugs) were suspected. All cases were classified as “serious” since they led to death in 2 cases, hospitalization or prolongation of hospitalization in 19 cases and threatening of vital prognosis in 2 cases. Withdrawal of suspected drugs was done in all cases with regression of neutropenia in 21 cases. According to hospitalization data, the annual incidence of drug-induced agranulocytosis was 1.62 (1.0–2.6) per 10,000 inpatients in Toulouse University hospital (based on 534 cases) and 3.24 (0.9–8.3) per 10,000 inpatients in Navarra University Hospital (based on 168 cases). The involved drugs were mainly antibacterial (30.4%), immunosuppressive (17.4%), antithyroid (13.0%), antiplatelet (8.7%) and nonsteroidal anti-inflammatory (8.7%) ones. Only seven cases from Toulouse University Hospital were spontaneously reported by physicians during the same period. Thus, the underreporting coefficient (U) was 2.71 (63.2%) in France.ConclusionOur survey allowed us to identify the suspected drug-induced agranulocytosis through a prospective study in a large sample of inpatients using only laboratory data analysis. We also note an important underreporting rate of this serious adverse drug reaction (ADR) to the official French pharmacovigilance system. Laboratory data analysis could be used for identifying serious ADRs.

Atropinic burden of prescriptions forms in patients with Alzheimer disease: a cross-sectional study in a French PharmacoVigilance Database

AimAtropinic drugs in patients with Alzheimer disease (AD) can decrease the effects of anticholinesterase drugs and/or induce adverse drug reactions (ADRs). Several atropinic risk scales defining an atropinic burden of drugs were proposed but were little used in AD patients.MethodsAll ADRs’ notifications of AD patients registered in the Midi-Pyrénées PharmacoVigilance Database between 1999 and 2013 were analyzed using Anticholinergic Drug Scale (ADS) and Anticholinergic Duran’s list. The primary objective was to quantify atropinic burden in AD patients and the secondary one to investigate associated factors.ResultsAmong the 475 notifications, at least one atropinic drug was found in 282 notifications (59.4xa0%) according to ADS and 214 (45.1xa0%) according to Duran. Mean number of atropinics per notifications was 0.9u2009±u20090.9 (ADS) and 0.7u2009±u20090.9 (Duran). Mean atropinic burden per notifications was 1.2u2009±u20091.5 (ADS) and 0.9u2009±u20091.3 (Duran). Atropinic burdenu2009≥u20093 was found in 87 notifications (18.2xa0%) according to ADS and 50 (10.5xa0%) according to Duran. There was no association between atropinic burden and age of patients. The number of drugs is associated to a high atropinic burden.ConclusionThe present work found an association between an atropinic drug and an anticholinesterase agent in around 1 out of 2 AD patients and a clinically significant atropinic burden (≥3) in around 1 to 2 AD patients out of 10. The benefit harm balance of atropinic drugs must be discussed before each prescription in AD patients.

Hospital re-admission associated with adverse drug reactions in patients over the age of 65 years

ContextAdverse drug reactions (ADRs) are responsible for 5xa0% of hospital admissions, but hospital re-admission induced by ADRs remains poorly documented.ObjectiveThe aim of this study was to estimate the rate of hospital re-admission and the factors associated with re-admission in the patients over the age of 65xa0years. Secondary, we described the characteristics of cases of ADRs leading to re-admission for drugs other than chemotherapy agents.MethodsData were extracted from hospital discharge summaries provided by the Department of Medical Information of Toulouse University Hospital. All patients over the age of 65xa0years admitted to the hospital in 2010 for an ADR, identified from ICD-10 codes, were selected. All subsequent admissions of members of this cohort within 1xa0year of discharge following the index admission were reviewed retrospectively. The risk factors associated with hospital re-admission for ADRs were analyzed. Medical records were used for descriptive analysis of re-admission due to drugs other than chemotherapy agents.ResultsWe found that 553 of the 1000 patients admitted for ADRs in 2010 were re-admitted to hospital within 1xa0year. Among them, 87 cases were re-admitted for ADRs (estimated rate of 87/1000 re-admission for an ADR within 1xa0year). A comparison of the patients re-admitted for ADRs (nxa0=xa087) with those of patients re-admitted for other causes (nxa0=xa0410) suggested that only cancer increased the risk of re-admission for ADRs (ORxa0=xa07.69 [4.59–12.88] 95xa0% CI). ADRs due to the same drug combination were the suspected cause of repeat admission in half the cases (other than chemotherapy). Hospital re-admission was considered avoidable in four cases (22xa0%).ConclusionThis study shows an estimated rate of re-admission for an ADR around 87/1000 within 1xa0year, and the same drug combination were the suspected cause of repeat admission in half the cases. At least, 11xa0% of cases were avoidable.

Adverse drug reactions in an emergency medical dispatching centre

PurposeThe purpose of this study is to assess the incidence of adverse drug reactions (ADR) leading to call an emergency medical dispatching centre.MethodsA prospective, observational, monocentric clinical study performed over a 2-year period (2011–2012) in a French prehospital emergency dispatching centre, the Service dAide Médicale Urgente (SAMU) covering 1,156,000 inhabitants. All adult patients (ageu2009≥u200918) who called for any cause were included. We created an electronic trigger ‘iatrogenic event’ implemented by the dispatching physician for each suspected case of ADR, then we completed the analyses of all the cases with a chief complain represented in more than 1xa0% of the triggered cases. The primary outcome variable was the occurrence of any possible ADR. We then used the French method of causal relationship assessment.ResultsThe SAMU dispatched 339,915 calls during the study. In total, 1,467 ADRs were identified, representing 0.95xa0% (CI 95xa0% 0.90–1.00xa0%) of cases. ADRs were as serious (SADR) in 51.06xa0% (CI 95xa0% 48.45–53.67xa0%) of cases. The major ADR observed was haemorrhage, (42.81xa0% (CI 95xa0% 40.62–45.00xa0%), nu2009=u2009628) followed by allergy, hypoglycaemia, vomiting, dizziness and drowsiness. The class of drugs most frequently involved was antithrombotic (43.69xa0% (CI 95xa0% 41.45–45.93xa0%), nu2009=u2009641), followed by insulin (17.98xa0% (CI 95xa0%:17.06–18.90xa0%), nu2009=u2009264).ConclusionsEmergency calls concerning ADRs were estimated as 9/1,000, and one out of two is serious.

Hemorrhagic effects of oral anticoagulants: a comparative study between vitamin K antagonists (VKA) and direct oral anticoagulants (DOA)

Clinical trials described differences in anatomical localizations of bleedings between vitamin K antagonists (VKA) and direct oral anticoagulants (DOA) [1]. RE-LY trial did not evidence differences in major bleedings but found more gastrointestinal and less intracranial hemorrhages with dabigatran [2]. However, clinical trials are conducted in standardized conditions far from the real world [3]. In order to verify these conclusions in real life, we compared anatomical localizations of bleedings reported with VKA and DOA as spontaneous notifications in a pharmacovigilance center. The study was performed into the French Pharmacovigilance Database [previously described [4]] that registers adverse drug reactions (ADRs) reported by health professionals or patients. All ADRs registered inMidi-Pyrenees area (SouthWest France, 3 million inhabitants) with VKA or DOA (Bsuspect^ drugs) between January 2009 (first marketing of dabigatran) and August 2014 were included. Cases with more than one anticoagulant were excluded. Comparisons used chi-square and Z tests and adjusted logistic regression models. A multivariate logistic regression was used to compare risk of bleedings. Adjustment variables were gender and age (4 classes: 220 mg daily, 1 apixaban), and 503 (75.1%) with VKA (364 fluindione, 126 warfarin, 13 acenocoumarol). There was no significant difference in mean age and sex ratio. BSerious^ ADRs were significantly more frequent with VKA than with DOA, without any difference in the number of reported deaths. There were more muscular bleedings with VKA than with DOA without any difference in other sites (Table 1). When analysis of bleedings was restricted to atrial fibrillation indication, similar results were found (not shown). Adjusted analysis on age and gender did not find any difference in total or digestive bleedings (not shown). We cannot conclude on delay of occurrence since VKA are marketed for much longer time than DOA. In contrast to clinical trials, this study was unable to describe any difference in main anatomical sites of bleedings between the two classes of oral anticoagulants. Ruff’s metaanalysis of randomized trials found fewer strokes or systemic embolic events (and more gastrointestinal bleedings) [5]. However, these differences in clinical trials come from analyses of secondary and not primary endpoints. There are relatively few data about hemorrhagic ADRs during post-marketing use. Hernandez reported more bleedings (whatever the anatomical site), especially gastrointestinal ones with less intracranial hemorrhage with dabigatran [6]. In patients ≥65 years with non-valvular atrial fibrillation, there was less ischemic stroke and intracranial hemorrhage and more major gastrointestinal bleedings with dabigatran than with warfarin [7]. Since the risk of gastrointestinal bleedings was only significant in patients ≥75 years, we investigated in an adjusted analysis the role of age and gender and were * J. L. Montastruc jean-louis.montastruc@univ-tlse3.fr

Overview of Pharmacovigilance System in Vietnam: Lessons Learned in a Resource-Restricted Country

Drug safety issues in developing countries are complex and sensitive, and health authorities cannot always simply implement decisions from developed countries because the health system, disease patterns, and lists of marketed drugs all differ. A system for proactive and effective surveillance of drugs in each nation is needed to identify and manage the exact drug-related problems faced by patients in these countries. Vietnam launched its university-based National Drug Information and Adverse Drug Reaction Monitoring Centre (NDIADRMC) in 2009, a significant step towards catching up with international trends. Although the center is still in its infancy and has limited resources, it has attained some achievements and largely met the minimum World Health Organization requirements for a functional pharmacovigilance center. The number of reports has increased rapidly, with some important signals generated from the national database leading to regulatory actions at a national level. In addition, this system can help detect drug-quality problems that are less common in developed countries. The success of the quantity and quality of reporting, risk assessment, and communication is still limited compared with more developed systems. A number of opportunities remain to enhance the system, particularly in risk communication and evaluation of the impact of pharmacovigilance, and to apply reporting outcomes to reduce drug-related risks throughout the country. More internal and external support is needed to develop a stronger and more comprehensive pharmacovigilance system.

First cases of calcium pyrophosphate deposition disease after zoledronic acid therapy

A number of medications promote the development of calcium pyrophosphate deposition disease (CPDD). We report 2 cases of acute CPDD after intravenous zoledronic acid therapy. Case #1: a 63-year-old female was admitted for vertebroplasty at the site of an osteoporotic fracture. She received an intravenous infusion of zoledronic acid 5mg on the day after the procedure. Acute CPDD developed in her right knee 24hours later. Findings from joint aspiration and standard radiography confirmed the diagnosis. Case #2: this 79-year-old woman had a history of CPDD was on glucocorticoid and hydroxychloroquine therapy for lupus. She was given an intravenous infusion of zoledronic acid 5mg as prophylaxis of glucocorticoid-induced osteoporosis. Joint pain and a fever developed later on the same day. After 5xa0days, she had arthritis of the right wrist, laboratory evidence of systemic inflammation, and hypocalcemia. Radiographs showed evidence of CPDD. A Medline search identified 6xa0cases of bisphosphonate-related CPDD, including 2 due to pamidronate, 2 to etidronate, 1 to alendronic acid, and 1 to neridronic acid. The features were similar to those in our patients, with a short time to onset, systemic inflammation in many cases, a tendency toward hypocalcemia, and radiographs that often showed evidence of CPDD. Bisphosphonate-induced CPDD is a rare eventuality that should nevertheless be borne in mind by rheumatologists. Also, in patients with CPDD while taking bisphosphonate therapy, a role for the drug in the symptoms should be considered.

Comment on: “Drug-Induced Hyperglycaemia and Diabetes”

We read with great interest the paper from Fathallah et al.’s Tunisian group [1] on drug-induced hyperglycaemia and diabetes. As underlined by the authors, the topic is important because of the frequency of diabetes mellitus and the high number of drugs potentially involved in this adverse drug reaction (ADR). However, as clinical pharmacologists, we would add two comments. The first concerns the words ‘hyperglycaemia’ and ‘diabetes’. These are not synonyms because from a medical point of view, diabetes includes not only hyperglycaemia but also other symptoms such as polyuria, polydipsia and renal glucose excretion. In fact, a distinction between drugs inducing only a rise in glucose concentrations and drugs associated with diabetes is not clearly indicated in the article. From a medical point of view, it is necessary to differentiate drugs inducing diabetes (a permanent disease) and those inducing hyperglycaemia (which can be temporary). The second point involves the methodology chosen for the bibliography. Fathallah et al.’s work [1] indicated they used a MEDLINE search from 1960 to 2015 with selected words such as ‘hyperglycaemia’, ‘diabetes’ and ‘reviews’. In fact, the selection’s mode of articles and general reviews was not clearly explained. How many papers were selected after the MEDLINE search? How many were chosen for the final analysis? It is not clear if the paper is a systematic review or not. Thus, it appears that some papers were not included in Fathallah et al.’s work [1], such as, for example, the work we published in 2010 on the same topic [2]. It was a large study performed in the French PharmacoVigilance Database between 1985 and 2008, including a description of 1219 reports of drug-induced hyperglycaemia. Thus, this paper is one of the largest series ever published on this topic. The drug classes most frequently found were antiretroviral (28.8 % of the 2169 suspected drugs) followed by steroidal anti-inflammatory drugs (17.6 %), second-generation antipsychotics (3.8 %), immunosuppressive drugs (3.2 %) and diuretics (2.9 %). In our study, hyperglycaemia occurred one in four in diabetic patients or as a part of human immunodeficiency virus infection [2]. Moreover, besides the sole description of hyperglycaemia as an ADR, we performed a case/non-case analysis, a validated method of disproportionality for the identification of ADRs in a pharmacovigilance database [3]. Thus, we found signals for 34 drugs, the first three being methylprednisolone, tacrolimus and olanzapine, followed by prednisone, pentamidine, saquinavir, tetracosactide, asparaginase, indinavir, prednisolone, stavudine, didanosine, peg interferon-a2B, nelfinavir, lamivudine, ritonavir, betamethasone, ribavirine, mucophenoloate mofetil, interferon-a2A, isotretinoin, clozapine, lopinavir, zidovudine, hydrocortisone, glibenclamide, efavirenz, abacavir, salbutamol, dexamethasone, nevirapine, interferon-a2B, risperidone and bisoprolol [2]. Among these observations, hyperglycaemia was an ‘unexpected’ (unlabelled) ADR (i.e. an effect not described in the Summary of Product Characteristics) [4] for glibenclamide, mainly in & Jean-Louis Montastruc jean-louis.montastruc@univ-tlse3.fr