Cardiac Adverse Drug Reactions Research Articles

Safety Profiles Related to Dosing Errors of Rapid-Acting Insulin Analogs: A Comparative Analysis Using the EudraVigilance Database.

Diabetes is a widespread condition that can lead to multiple and severe complications. Rapid-acting insulin analogs (RAIAs) and long-acting insulin analogs are prescribed for the effective management of diabetes. RAIAs are expected to be associated with a higher number of dosing errors because of their rapid onset, short duration of action, and the need for frequent dosing, compared to other insulin analogs. There are three approved RAIAs on the market: insulin lispro (LIS), insulin aspart (ASP), and insulin glulisine (GLU). The aim of this study is to evaluate the real-world evidence on dosing errors reported for RAIAs in EudraVigilance (EV), an established pharmacovigilance database, in comparison to other insulin analogs and human insulins. A descriptive analysis and a disproportionality analysis were conducted. ASP and LIS were associated with high percentages of adverse drug reactions (ADRs) (22% and 17%, respectively), with over 70% of the reports involving serious ADRs. A higher frequency of cardiac and eye disorder ADRs was observed for LIS compared with ASP and GLU. GLU showed a higher frequency of ADRs in the skin and subcutaneous tissue disorders category. LIS dosing errors accounted for 5% of the total number of cases, while dosing errors for ASP and GLU were less than 3%. The most frequently reported dosing errors involved improper dosing (49%). Although there were fewer dosing errors of RAIAs in comparison to other insulins, the severity of the potential outcome highlights the importance of precise dosing and timing. Improved the monitoring and reporting of these dosing errors could enhance diabetes patient care. Additionally, smart medical devices could improve therapeutic outcomes.

Противодементные лекарственные средства и синдром удлиненного интервала QT

Aim. Analysis and systematization of the results of domestic and foreign studies of drug-induced QT prolongation and the risk of Torsade de Pointes (TdP) associated with the use of antidementia drugs to update the knowledge of practicing neurologists about the possibility of predicting and preventing life-threatening cardiac adverse drug reactions. Key points. Dementia is a syndrome that accompanies various neurodegenerative diseases, which causes significant maladjustment and disability in the patient. Anti-dementia drugs are used to slow down the progression of dementia which require long-term (lifelong) appointment. Therefore, the safety profile of these drugs is important in practice, in particular such conditions as the long QT syndrome and the development of ventricular tachycardia (TdP). The authors searched for full-text domestic and foreign publications (full-text versions of original articles, clinical cases, systematic reviews, meta-analyses, Cochrane reviews) in Russian and English, available in knowledge-intensive bibliographic databases (eLIBRARY, PubMed, Scopus, Springer, ClinicalKeys, OxfordPress, Google Scholar, MedCredit, DrugBank, PharmGKB), by keywords and their combinations. The study was conducted in accordance with the requirements for the PRISMA 2022 systematic review. The search depth is 10 years (2013–2023). Conclusion. The systematic review demonstrated the variable effect of antidementia drugs on the processes of repolarization and depolarization of the ventricular myocardium: shortening of the QT interval, no effect, borderline prolongation of the QT interval, prolongation of the QT interval. Donepezil has the lowest cardiac safety profile. Studies of galantamine have yielded conflicting results. The lowest risk of QT prolongation and TdP development was observed with rivastigmine and memantine. There is insufficient data on the cardiac safety of the new generation of antidementia drugs: aducanumab, lecanemab and donanemab. Keywords: antidementia drugs, adverse drug reactions, dementia, prolongation of the QT interval, cardiotoxicity, long QT syndrome, Torsade de Pointes, ventricular tachycardia, sudden cardiac death.

Abstract 16689: Stress Cardiomypoathy in the Patient on Immune Checkpoint Inhibitors; a Pharmacovigilance Study From 2013-2023 FAERS Database

Introduction: Immune checkpoint inhibitors (ICIs) are a form of immunotherapy widely used in the treatment of different cancers. These inhibitors function by blocking specific proteins, such as PD-1 (programmed cell death protein 1) or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), which regulate the immune response. While ICIs have demonstrated significant benefits, they can also lead to immune-related adverse drug reactions (ADRs). Although rare, cardiac immune-related ADRs are associated with high mortality rates. Hypothesis: The aim of this study to investigate the potential association between stress cardiomyopathy and the use of immune checkpoint inhibitors. Methods: We conducted an analysis using individual case safety reports obtained from the FDA Adverse Event Reporting System (FAERS) Database. These reports encompassed the period from the marketing authorization of each specific ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) up until March 2023. The synthesized data was further examined based on outcome severity, age, and gender. Results: Among 9,772 individual cardiac adverse events associated with immune checkpoint inhibitors, 121 cases (1.2%) of stress cardiomyopathy were reported from 2013 to 2023. The highest occurrence of stress cardiomyopathy adverse events (57.8%) was observed in the age group of 65-85 , compared to 26.4% in the age group of 14-64. Females were more frequently affected, accounting for 55.3% of the cases, while males constituted 41.3%. The three most commonly reported ICIs associated with stress cardiomyopathy were pembrolizumab (39.6%), nivolumab (33.8%), and ipilimumab (16.5%). Among the 121 cases, 19% resulted in mortality, while 26.5% had life-threatening outcomes. Additionally, 79.3% of cases required hospitalization, 5.7% experienced disability, and 57.8% had outcomes that were not characterized. Conclusions: Immune checkpoint inhibitor-induced cardiac ADRs, specifically stress cardiomyopathy, were found to be serious and associated with unfavorable outcomes. Physicians should remain vigilant regarding cardiac symptoms in patients receiving immune checkpoint inhibitors, as early detection can improve overall outcomes.

Anamorelin in Japanese patients with cancer cachexia: an update.

Anamorelin was approved for production and marketing in Japan on 22 January 2021 for cancer cachexia in non-small-cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer. The authors describe the updates of anamorelin for cancer cachexia in Japan. Recent evidence showed that anamorelin improved lean body mass, body weight, and appetite in patients with cancer cachexia in clinical practice. Anamorelin does not increase body weight in the severe-weight-loss group in cachectic patients with pancreatic cancer. Several case reports showed that anamorelin can cause cardiac adverse drug reactions. Among the cardiac adverse reactions, fatal arrhythmias should be monitored carefully even if it is the first dose. Anamorelin combined with nutrition, physical activity, and exercise may be more useful than anamorelin alone for treating cancer cachexia. An interim analysis from post-marketing all-case surveillance was performed; however, details have not yet been published. When anamorelin cannot be used for cancer cachexia, Kampo medicines can be considered as an option. Anamorelin has changed the clinical practice of cancer cachexia in Japan. The authors hope that anamorelin is available for other disease-related cachexia along with appropriate multidisciplinary interventions.

Unraveling Structural Alerts in Marketed Drugs for Improving Adverse Outcome Pathway Framework of Drug-Induced QT Prolongation.

In pharmaceutical treatment, many non-cardiac drugs carry the risk of prolonging the QT interval, which can lead to fatal cardiac complications such as torsades de points (TdP). Although the unexpected blockade of ion channels has been widely considered to be one of the main reasons for affecting the repolarization phase of the cardiac action potential and leading to QT interval prolongation, the lack of knowledge regarding chemical structures in drugs that may induce the prolongation of the QT interval remains a barrier to further understanding the underlying mechanism and developing an effective prediction strategy. In this study, we thoroughly investigated the differences in chemical structures between QT-prolonging drugs and drugs with no drug-induced QT prolongation (DIQT) concerns, based on the Drug-Induced QT Prolongation Atlas (DIQTA) dataset. Three categories of structural alerts (SAs), namely amines, ethers, and aromatic compounds, appeared in large quantities in QT-prolonging drugs, but rarely in drugs with no DIQT concerns, indicating a close association between SAs and the risk of DIQT. Moreover, using the molecular descriptors associated with these three categories of SAs as features, the structure-activity relationship (SAR) model for predicting the high risk of inducing QT interval prolongation of marketed drugs achieved recall rates of 72.5% and 80.0% for the DIQTA dataset and the FDA Adverse Event Reporting System (FAERS) dataset, respectively. Our findings may promote a better understanding of the mechanism of DIQT and facilitate research on cardiac adverse drug reactions in drug development.

The role of DNA-profiling in predicting anticonvulsant-induced QT prolongation diseases based on pharmacogenetic aspects

Anticonvulsants or antiepileptic drugs (AEDs) are widely used for various neurological and psychiatric diseases and are often prescribed for a long period. In this regard, the issue of their safety profile is acute, including risk assessment for the development of life-threatening conditions and adverse drug reactions (ADRs). From the point of view of personalized medicine, it is important to develop an interdisciplinary approach to the development of a new strategy for a personalized approach to predicting AED-induced prolongation of the QT interval as one of the most unfavorable prognostic cardiac ADRs (including sudden death syndrome — SDS). We searched the databases of full-text publications for the period from 2012 to 2022 for keywords and their combinations. We have discovered and systematized monogenic and multifactorial forms of long QT syndrome (LQTS) and candidate genes that slow down AEDs metabolism in the liver. Identification of risk alleles of single nucleotide variants (SNV) of candidate genes predisposing to the development of AED-induced LQTS and SDS will allow adjusting the choice and dosage of these drugs and preventing the development of the ADR, which will improve the quality of life and help prevent SDS in patients with mental and neurological disorders

Adverse reactions with levamisole vary according to its indications and misuse: A systematic pharmacovigilance study.

Levamisole was initially prescribed for the treatment of intestinal worms. Because of immunomodulatory properties, levamisole has been used in inflammatory pathologies and in cancers in association with 5‐fluorouracil. Levamisole is misused as a cocaine adulterant. Post‐marketing reports have implicated levamisole in the occurrence of adverse drug reactions (ADRs) and its use is now limited in Europe and North America. In contrast, all other parts of the World continue to use single‐dose levamisole as an anthelmintic. The aim of this study was to identify ADRs reported after levamisole exposure in VigiBase, the World Health Organisation's pharmacovigilance database, and analyse their frequency compared to other drugs and according to levamisole type of use.MethodsAll levamisole‐related ADRs were extracted from VigiBase. Disproportionality analyses were conducted to investigate psychiatric, hepatobiliary, renal, vascular, nervous, blood, skin, cardiac, musculoskeletal and general ADRs associated with levamisole and other drugs exposure. In secondary analyses, we compared the frequency of ADRs between levamisole and mebendazole and between levamisole type of use.ResultsAmong the 1763 levamisole‐related ADRs identified, psychiatric disorders (reporting odds ratio with 95% confidence intervals: 1.4 [1.2–2.6]), hepatobiliary disorders (2.4 [1.9–4.3]), vasculitis (6.5 [4.1–10.6]), encephalopathy (22.5 [17.4–39.9]), neuropathy (4.3 [2.9–7.1]), haematological disorders, mild rashes and musculoskeletal disorders were more frequently reported with levamisole than with other drug. The majority of levamisole‐related ADRs occurred when the drug was administrated for a non–anti‐infectious indication.ConclusionThe great majority of the levamisole‐related ADRs concerned its immunomodulatory indication and multiple‐dose regimen. Our results suggest that single‐dose treatments for anthelmintic action have a good safety profile.

Immune Checkpoint Inhibitors and Cardiotoxicity: An Analysis of Spontaneous Reports in Eudravigilance.

IntroductionImmune checkpoint inhibitors (ICIs) are widely used in the treatment of many cancers as they improve clinical outcomes. However, ICIs have also been associated with the development of immune-related adverse drug reactions (ADRs). Among immune-related ADRs, cardiac immune-related ADRs are rare, but also associated with high mortality rates.ObjectiveThe objective of this study was to evaluate the occurrence of cardiac ADRs reported with ICIs in the European spontaneous reporting system.MethodsWe retrieved individual case safety reports on ICI-induced cardiac ADRs from the website of suspected ADR (www.adrreports.eu) of the European pharmacovigilance database (Eudravigilance). Data were retrieved from the date of marketing authorization of each ICI (ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, and cemiplimab) to 14 March, 2020. The reporting odds ratio and its 95% confidence interval were computed to assess the reporting frequency of cardiac ADRs for each ICI compared to all other ICIs.ResultsA total of 2478 individual case safety reports with at least one ICI as the suspected drug were retrieved from Eudravigilance, of which 249 (10%) reported more than one ICI. The three most reported ICIs were nivolumab (43.2%), pembrolizumab (32.5%), and the association of nivolumab/ipilimumab (9.4%). A total of 3388 cardiac ADRs were identified. Cardiac ADRs were serious (99.4%) and had a fatal outcome (30.1%). The most reported cardiac events were myocarditis, cardiac failure, atrial fibrillation, pericardial effusion, and myocardial infarction. Nivolumab was reported with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs (reporting odds ratio 1.09, 95% confidence interval 1.01–1.18).ConclusionsImmune checkpoint inhibitor-induced cardiac ADRs were serious and had unfavorable outcomes. In our study, nivolumab was the only ICI with a small increased reporting frequency of individual case safety reports with cardiac ADRs compared to all other ICIs. In this regard, further head-to-head studies are needed.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01086-8.

Cardiovascular toxicities associated with abiraterone compared to enzalutamide-A pharmacovigilance study.

BackgroundAndrogen deprivation therapy (ADT) is standard-of-care for advanced prostate cancer. Studies have generally found increased cardiovascular risks associated with ADT, but the comparative risk of newer agents is under-characterized. We defined the cardiac risks of abiraterone and enzalutamide, using gonadotropic releasing hormone (GnRH) agonists to establish baseline ADT risk.MethodsWe used VigiBase, the World Health Organization pharmacovigilance database, to identify cardiac adverse drug reactions (ADRs) in a cohort taking GnRH agonists, abiraterone, or enzalutamide therapy for prostate cancer, comparing them to all other patients. To examine the relationship, we used an empirical Bayes estimator to screen for significance, then calculated the reporting odds ratio (ROR), a surrogate measure of association. A lower bound of a 95% confidence interval (CI) of ROR > 1 reflects a disproportionality signal that more ADRs are observed than expected due to chance.FindingsWe identified 2,433 cardiac ADRs, with higher odds for abiraterone compared to all other VigiBase drugs for overall cardiac events (ROR 1•59, 95% CI 1•48—1•71), myocardial infarction (1•35, 1•16—1•58), arrythmia (2•04, 1•82—2•30), and heart failure (3•02, 2•60—3•51), but found no signal for enzalutamide. Patients on GnRH agonists also had increased risk of cardiac events (ROR 1•21, 95% CI 1•12—1•30), myocardial infarction (1•80, 1•61—2•03) and heart failure (2•06, 1•76—2•41).InterpretationWe found higher reported odds of cardiac events for abiraterone but not enzalutamide. Our data may suggest that patients with significant cardiac comorbidities may be better-suited for therapy with enzalutamide over abiraterone.FundingNone

Pharmacodynamic Drug-Drug interactions of QT-prolonging drugs in hospitalized psychiatric patients.

At least 170 approved drugs are linked to QT prolongation, which can lead to serious adverse drug reactions (ADRs), such as Torsade de Pointes (TdP). The aim of this study was to analyze the prevalence and type of pharmacodynamic drug-drug interactions (DDIs) between QT-prolonging drugs in psychiatry. The present retrospective analysis used data from a large pharmacovigilance study, conducted in 10 psychiatric hospitals in Germany. Patients medication lists were screened for QT-prolonging drugs, classified according to the Arizona Center for Education and Research on Therapeutics (AZCERT). In total, 27,396 patient cases (46% female) with a mean (± standard deviation) age of 47 ± 18years were included in the study. Altogether, 83% of the cases received at least one and up to eight QT-prolonging drugs at the same time. Combination of drugs with a known or possible risk for TdP (according to the AZCERT) was detected in 13,670 cases (50%). Most frequently prescribed psychotropic high-risk drugs (n = 48,995) were the antipsychotics pipamperone (n = 6202), quetiapine (n = 5718), prothipendyl (n = 4298), and risperidone (n = 4265). The replacement of high-risk drugs such as tricyclic antidepressants, levomepromazine, melperone, and promethazine with more tolerable drugs could avoid 11% of QT-prolonging drugs and increase the tolerability of psychopharmacological treatment. More than 80% of psychiatric patients receive at least one QT-prolonging drug during their hospital stay, and almost 50% of these drugs are combined in clinical practice. For the prevention of cardiac ADRs, the physician should evaluate the risk for QT prolongation for each drug and patient-specific risk factors before prescribing these drugs or drug combinations.

Insights on the Evidence of Cardiotoxicity of Hydroxychloroquine Prior and During COVID-19 Epidemic.

The recent empirical use of hydroxychloroquine (HCQ) in coronavirus disease 2019 (COVID‐19) revived the interest in its cardiac toxicity, increasingly sidelined over time. We aimed to assess and compare the profile of cardiac adverse drug reactions (CADRs) associated with HCQ before and during COVID‐19. We performed a retrospective comparative observational study using the French Pharmacovigilance network database between 1985 and May 2020 to assess all postmarketing CADRs associated with HCQ notified before COVID‐19 in its approved indications for lupus and rheumatoid arthritis (preCOV), and those concerning its empirical use in COVID‐19 (COV). Eighty‐five CADR in preCOV were compared with 141 CADRs in COV. The most common CADR of preCOV were cardiomyopathies (42.4%) and conduction disorders (28.2%), both statistically more frequent than in COV (P < 0.001). COV notifications significantly highlighted repolarization and ventricular rhythm disorders (78.0%, P < 0.001) as well as sinus bradycardias (14.9%, P = 0.01) as compared with preCOV. Estimated incidence of CADR was significantly higher among patients exposed to off‐label use of HCQ in COVID‐19 (2.9%) than before COVID‐19 in its approved indications (0.01%, P < 0.001). The use of HCQ in COVID‐19 sheds a new light on the spectrum of its cardiac toxicity. This fosters the value of a closer monitoring of all patients treated with HCQ, regardless of its indication, and the importance of an update of its summary of product characteristics.

Spontaneous reported cardiotoxicity induced by lopinavir/ritonavir in COVID-19. An alleged past-resolved problem

The antiretroviral drug lopinavir/ritonavir has been recently repurposed for the treatment of COVID-19. Its empirical use has been associated with multiple cardiac adverse reactions pertaining to its ancillary multi-channel blocking properties, vaguely characterized until now. We aimed to characterize qualitatively the cardiotoxicity associated with lopinavir/ritonavir in the setting of COVID-19.Spontaneous notifications of cardiac adverse drug reactions reported to the national Pharmacovigilance Network were collected for 8 weeks since March 1st 2020. The Nice Regional Center of Pharmacovigilance, whose scope of expertise is drug-induced long QT syndrome, analyzed the cases, including the reassessment of all available ECGs. QTc ≥ 500 ms and delta QTc > 60 ms from baseline were deemed serious.Twenty-two cases presented with 28 cardiac adverse reactions associated with the empirical use of lopinavir/ritonavir in a hospital setting. Most adverse reactions reflected lopinavir/ritonavir potency to block voltage-gated potassium channels with 5 ventricular arrhythmias and 17 QTc prolongations. An average QTc augmentation of 97 ± 69 ms was reported. Twelve QTc prolongations were deemed serious. Other cases were likely related to lopinavir/ritonavir potency to block sodium channels: 1 case of bundle branch block and 5 recurrent bradycardias. The incidence of cardiac adverse reactions of lopinavir/ritonavir was estimated between 0.3% and 0.4%.These cardiac adverse drug reactions offer a new insight in its ancillary multi-channel blocking functions. Lopinavir/ritonavir cardiotoxicity may be of concern for its empirical use during the COVID-19 pandemic. Caution should be exerted relative to this risk where lopinavir/ritonavir summary of product characteristics should be implemented accordingly.

Torsades de Pointes in Coronavirus Disease 2019 Infection

A 73-YEAR-OLD MAN (weight 69 kg, height 175 cm) was transferred to the authors’ critical care unit with respiratory and acute renal failure secondary to coronavirus disease 2019 (COVID-19) infection. His past medical history included hypertension, diabetes, and previous stroke, from which he had made a full recovery. The patient was treated with mechanical ventilation and peritoneal dialysis. He was recruited into the hydroxychloroquine arm of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial. Baseline electrocardiogram (ECG) and subsequent ECG monitoring were normal and did not demonstrate any QT prolongation. Three days later, the patient developed a ventricular tachycardia with a circulatory collapse. Immediate cardiopulmonary resuscitation was initiated and defibrillator pads attached; however, the arrhythmia self-terminated within 2 minutes (Fig 1). After resuscitation, another ECG showed a normal QT interval. Arterial blood gas analysis did not show any signs of respiratory insufficiency or an acid-base disturbance. There were no signs of myocardial ischemia. A full panel of blood tests was performed, which did not demonstrate any relevant abnormalities in full blood count, biochemical studies, or coagulation. Hypomagnesemia and hypokalemia were absent. Echocardiography was normal. What is the diagnosis? Diagnosis: Torsades de pointes ventricular tachycardia presumably resulting from hydroxychloroquine therapy. Review of the telemetry data demonstrated a polymorphic ventricular tachycardia in the pattern of torsades de pointes, with a spontaneous onset and termination. A cardiac electrophysiology review was requested and confirmed the diagnosis of torsades de pointes. Review of ECGs, blood test results, and medication history allowed the authors to conclude that the arrhythmia had most likely been caused by hydroxychloroquine. Recommendations were made for stringent monitoring of serum electrolytes (to prevent hypomagnesemia and hypokalemia) and daily ECGs. No further antiarrhythmic therapy was recommended at this stage. Hydroxychloroquine was discontinued, and the patient's participation in the RECOVERY trial was terminated. No further arrhythmias were reported during the patent's stay. An adverse drug reaction report was submitted to the UK Medicines and Healthcare products Regulatory Agency (UK MHRA) to register the hydroxychloroquine-related life-threatening arrhythmia. In early 2020 during the COVID-19 pandemic, a number of studies reported possible therapeutic effects of hydroxychloroquine, and it was therefore included as 1 of the drugs in the platform UK RECOVERY trial.1Randomised evalution of COVID-19 Therapy (RECOVERY) Availible at: https://www.recoverytrial.net/files/protocol-archive/recovery-protocol-v4-0-2020-04-14.pdfGoogle Scholar However, preliminary data showed no benefit in hospitalized patients with COVID-19, which led to the UK MHRA instruction to stop recruitment into trials using hydroxychloroquine to treat patients with COVID-19.2UK Medicines & Healthcare products Regulatory AgencyMHRA suspends recruitment to COVID-19 hydroxychloroquine trials.2020https://www.gov.uk/government/news/mhra-suspends-recruitment-to-covid-19-hydroxychloroquine-trialsGoogle Scholar Hydroxychloroquine was introduced in 1955 as an anti-malarial drug. It has immunomodulatory properties that include inhibition of chemotaxis and phagocytosis, reduction of cytokine synthesis, inhibition of phospholipase A2, and signaling in lymphocytes.3Ben-Zvi I Kivity S Langevitz P et al.Hydroxychloroquine: From malaria to autoimmunity.Clin Rev Allerg Immunol. 2012; 42: 145-153Crossref PubMed Scopus (398) Google Scholar,4Kalia S Dutz JP. New concepts in antimalarial use and mode of action in dermatology.Dermatol Ther. 2007; 20: 160-174Crossref PubMed Scopus (187) Google Scholar Hydroxychloroquine has a large spectrum of side effects including cardiomyopathy and arrhythmias associated with the prolongation of the QT interval.3Ben-Zvi I Kivity S Langevitz P et al.Hydroxychloroquine: From malaria to autoimmunity.Clin Rev Allerg Immunol. 2012; 42: 145-153Crossref PubMed Scopus (398) Google Scholar Between 1964 and 2020, the UK MHRA registered 916 patients with adverse drug reactions, of whom 679 were classified as serious and 15 as fatal. The most commonly reported adverse drug reactions involved skin (454 cases) and the nervous system, including eye (285) and gastrointestinal tract (165). Cardiac adverse drug reactions were reported in 48 patients and included myocardial and/or pericardial disorders, arrhythmias, and heart failure.5UK Medicines & Healthcare products Regulatory AgencyInteractive drug analysis profile for hydroxychloroquine.2020https://info.mhra.gov.uk/drug-analysis-profiles/dap.html?drug=./UK_EXTERNAL/NONCOMBINED/UK_NON_000544442035.zip&agency=MHRAGoogle Scholar Cardiac arrhythmias were reported in 18 patients. Anesthesiologists should continue to be aware of the importance of a comprehensive drug history and are reminded of potential life-threatening arrhythmias when hydroxychloroquine is used. We declare that we have no known competing interests or relationships that could have influenced the work reported in this paper.

“Off-label” use of hydroxychloroquine, azithromycin, lopinavir-ritonavir and chloroquine in COVID-19: A survey of cardiac adverse drug reactions by the French Network of Pharmacovigilance Centers

SummaryIntroductionCOVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences.MethodsSince March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with “off-label” use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019.ResultsIn one month, 120 reports of cardiac adverse drug reactions have been notified, 103 of which associated with hydroxychloroquine alone (86%), or associated with azithromycin (60%). Their estimated incidence is 0.77% to 1.54% of all patients, notwithstanding strong underreporting. Lopinavir-ritonavir came third with 17 reports (14%) and chloroquine fourth with 3 reports (2.5%). There were 8 sudden, unexplained or aborted deaths (7%), 8 ventricular arrhythmias (7%), 90 reports of prolonged QTc (75%) most of them “serious” (64%), 48 of which proved ≥ 500 ms, 20 reports of severe conduction disorders (17%) and 5 reports of other cardiac causes (4%). Six reports derived from automedication.Discussion and conclusion“Off-label” use of treatments in COVID-19 increases the risk of cardiac ADRs, some of them avoidable. Even if these drugs are perceived as familiar, they are used in patients with added risk factors caused by infection. Precautions should be taken to mitigate the risk, even if they will be proven efficacious.

The characteristics and regularities of cardiac adverse drug reactions induced by Chinese materia medica: A bibliometric research and association rules analysis

Chinese materia medica (CMM) has been widely used as an approach of ethnomedicine worldwide. Recently, there are growing concerns related to the potential cardiotoxicity of herbal medicines but comprehensive studies are limited. Comprehensive literature retrieval via publicly available electronic databases was performed to identify the case reports that focused on cardiac adverse reactions (ADRs) triggered by oral CMMs. And a bibliometric survey was conducted to analyze the most commonly suspected risk factors in terms of responsible CMMs, susceptible patients and clinical administration of cardiac ADRs. Moreover, the techniques of data mining were utilized to investigate the regularities and association between the ADRs status and major contributory factors. The available evidence of current research indicated that many influential factors were strongly associated with cardiac ADRs caused by oral CMMs inevitably, including pediatric patients, poisonous CMMs (especially herbs of Aconitum species), overdose and self-medication. Specifically, the timely and effective resuscitation could attribute their favorable capacity to reduce mortality for cardiac ADRs. Notably, the cardiac ADRs cases had often concomitant the ADRs of the nervous system and digestive system. The comprehensive features and risk factors of cardiac ADRs induced by oral CMMs can be discovered and elucidated through the approaches of bibliometric research, association rules analysis, and data mining technology, which raise the profile and awareness of the rational applications of CMMs and pharmacovigilance within relevant heart side effects.

Systematic review and meta-analysis of rates of clozapine-associated myocarditis and cardiomyopathy.

Clozapine is the most effective medication for treatment refractory schizophrenia, but is associated with cardiac adverse drug reactions. Myocarditis and cardiomyopathy are the most serious cardiac adverse drug reactions although reported rates of these conditions vary in the literature. We systematically reviewed and meta-analysed the event rates, the absolute death rates and case fatality rates of myocarditis and cardiomyopathy associated with clozapine. PubMed, EMBASE and PsycINFO were searched for studies that reported on the incidence of cardiomyopathy or myocarditis in people exposed to clozapine. Data were meta-analysed using a random effects model, with subgroup analysis on study size, time frame, region, quality, retrospective vs prospective, and diagnostic criteria of myocarditis or cardiomyopathy. 28 studies of 258,961 people exposed to clozapine were included. The event rate of myocarditis was 0.007 (95% confidence interval [CI] = [0.003, 0.016]), absolute death rate was 0.0004 (95% CI = [0.0002, 0.0009]) and case fatality rate was 0.127 (95% CI = [0.034, 0.377]). The cardiomyopathy event rate was 0.006 (95% CI = [0.002, 0.023]), absolute death rate was 0.0003 (95% CI = [0.0001, 0.0012]) and case fatality rate was 0.078 (95% CI = [0.018, 0.285]). Few included studies provided information on criteria for diagnosis of myocarditis and cardiomyopathy. Event rates of cardiomyopathy and myocarditis were higher in Australia. Clarity of diagnostic criteria for myocarditis remains a challenge. Observation bias may, in part, influence higher reported rates in Australia. Monitoring for myocarditis is warranted in the first 4 weeks, and treatment of comorbid metabolic syndrome and diabetes may reduce the risk of cardiomyopathy. The risks of myocarditis and cardiomyopathy are low and should not present a barrier to people with treatment refractory schizophrenia being offered a monitored trial of clozapine.

P2597Heart failure and atrial tachyarrhythmia on abiraterone: a characterization using pharmacovigilance databases

Abstract Background Abiraterone and enzalutamide are recently approved androgen deprivation therapies (ADT) for metastatic prostate cancer. The cardiac safety profile for the two drugs is unknown. Methods Using French and World Health Organization (WHO) pharmacovigilance databases, we performed a disproportionality-analysis of suspected adverse-drug-reactions (ADR) to evaluate the reporting-odds-ratio (ROR) of cardiac ADR associated with abiraterone compared to enzalutamide, other ADT used in prostate cancer, and entire database. Clinical and demographic characterization of patients with ADT-induced cardiac ADR was performed. Results In the 5,759,781 ADR reports in men, 55,070 pertained to ADT. The ROR of AT for abiraterone was of 4.1 [3.1–5.3] vs. enzalutamide, 3.7 [3–4.5] vs. other ADT, and 3.2 [2.7–3.7] vs. entire database. The corresponding ROR for HF were of 2.5 [2–3], 1.5 [1.3–1.7], and 2 [1.7–2.3], respectively. Mean time to AT and HF onset was shorter on abiraterone (5.2±0.8 and 4.5±0.6 months, respectively) vs. other ADT (13.3±3.2 and 9.2±1.1 months; p&lt;0.05). Cases on abiraterone vs. other ADT were more frequently associated with ≥2 ADR-terms including AT, HF, hypokalemia, hypertension and edema (13.6% vs. 6%, p&lt;10–4). For abiraterone, age but not dose was associated to reporting of AT/HF vs. any other ADR. Table 1 Number (available data) AT HF Hypokalemia Edema Hypertension Age (y) 5989 r: 0.03, p: 0.02 r: 0.05, p≤0.0001 r: 0.06, p≤0.0001 r: 0.04, p≤0.01 ns Dose of hydrocortisone equivalent (mg/day) 3828 ns ns ns r: −0.07, p≤0.001 r: −0.12, p≤0.0001 Dose of abiraterone (mg/day) 6285 ns ns ns ns ns Details concerning correlation (r) between clinical covariates and reporting for AT, HF, hypokalemia, edema and hypertension within overall adverse drug reaction on abiraterone (n: 9203) extracted from VigiBase (through 08/2017). Time to onset Conclusion Compared to other ADT, abiraterone was associated with a higher reporting of AT and HF associated with hypokalemia, hypertension and edema. These findings are consistent with the hyper-mineralocorticism induced by abiraterone and not with other ADT.

Impact of hospital pharmacist interventions on the combination of citalopram or escitalopram with other QT-prolonging drugs

Background Citalopram and escitalopram can both induce dose-dependent QT prolongation. The risk of arrhythmia may be increased with concomitant use of other drugs that induce QT prolongation. Objective To evaluate the prevalence and impact of pharmacist interventions on the combination of citalopram or escitalopram with other drugs that induce QT prolongation. Setting A French hospital with 517 computerized beds. Method All cardiac adverse drug reactions (ADRs) related to citalopram or escitalopram reported to the French pharmacovigilance database (FPDB) were analyzed. Then, over a 6-month period, all computerized prescriptions including citalopram or escitalopram and drug-drug interactions (DDI) were analyzed by pharmacists using a computerized provider order entry system (DXCare®, Medasys). Results Only 27 cardiac ADRs related to citalopram or escitalopram were reported in the database. Among the 57,857 prescriptions and 2116 contraindicated DDIs (3.7%) that were analyzed. 444 DDIs (0.8%) were considered to be clinically relevant by pharmacists and physicians and 168 (i.e., approximately 30%) were related to a combination including citalopram or escitalopram. Most of the prescriptions related to DDIs including citalopram or escitalopram were discontinued in response to a pharmacist intervention when initiated during the hospital stay. Conclusion A high number of hospital prescriptions including citalopram or escitalopram with another QT-prolonging drug occurred, highlighting the importance of involvement of clinical pharmacists in prevention of potential ADRs related to such contraindications.

Bortezomib and heart failure: case‐report and review of the French Pharmacovigilance database

Bortezomib is a proteasome inhibitor commonly indicated for the treatment of multiple myeloma and non Hodgkin lymphoma. Cardiac adverse drug reactions of this drug are not clearly established. We report case where direct involvement of bortezomib in the occurrence of heart failure is strongly suspected and 22 other cases spontaneously reported to the French Pharmacovigilance System. This report should increase cardiologist awareness about the risk of heart failure related to this drug. Moreover, these cases underline the need for a systematic cardiac screening in patients exposed to bortezomib.

Update on the Cardiac Safety of Moxifloxacin

Cardiac safety was compared in patients receiving moxifloxacin and other antimicrobials in a large patient population from Phase II–IV randomized active-controlled clinical trials. Moxifloxacin 400 mg once-daily monotherapy was administered orally (PO) or sequentially (intravenous/oral, IV/PO). Across 64 trials, 21,298 patients received PO therapy (10,613 moxifloxacin, 10,685 comparators) while 6846 received sequential IV/PO therapy (3431 moxifloxacin, 3415 comparators). Treatment-emergent cardiac adverse event (AE) rates were similar for moxifloxacin and comparators in PO (6.6% vs 5.8%) and IV/PO (11.0% vs 12.0%) trials. Treatment-emergent cardiac adverse drug reactions were rare in PO (moxifloxacin 3.2% vs comparators 2.4%) and IV/PO (moxifloxacin 1.4% vs comparators 1.5%) patients. There were five (<0.02%) treatment-emergent drug-related deaths due to cardiac events out of 28,144 patients; one PO patient died treated with comparators, one patient died treated with IV/PO moxifloxacin, and three patients died after treatment with IV/PO comparators. Only one case of treatment-related non-fatal torsade de pointes occurred in the comparator arm. Incidence rates of cardiac AEs remained low in populations at elevated risk of cardiac events predisposed to QTc prolongation (i.e. community-acquired pneumonia patients admitted to the intensive care unit and/or mechanical ventilation, patients with documented prolongation of baseline QTc interval, women, and patients ≥ 65 years old). There was no evidence of unexpected cardiac events. After moxifloxacin treatment, an expected small prolongation in QTcB and QTcF was found. This analysis of numerous clinical trials shows the favorable cardiac safety profile of moxifloxacin, when used appropriately and according to its label, versus other antibiotics.