Cardiovascular Adverse Drug Reactions Research Articles

Cardiovascular Adverse Drug Reactions of Anti-Calcitonin Gene-Related Peptide Monoclonal Antibodies for Migraine Prevention: An Analysis from the European Spontaneous Adverse Event Reporting System.

Anti-calcitonin gene-related peptide monoclonal antibodies (anti-CGRP-mAbs) have recently been approved for the prevention of migraine, and their safety profile is not fully characterized. The aim of this study was to evaluate the adverse drug reactions (ADRs) of anti-CGRP-mAbs through the analysis of individual case safety reports (ICSRs) collected in the EudraVigilance (EV) database, with a specific focus on cardiovascular (CV) ADRs. Data on ICSRs recorded between July 2018 and December 2022 in the EV database, involving one of the anti-CGRP-mAbs for migraine prevention-erenumab (ERE), galcanezumab (GMB), fremanezumab (FMB), and eptinezumab (EPT)-were included in the analysis. All ICSRs reporting at least one CV ADR, as identified within the MedDRA® System Organ Classes (SOCs) "cardiac disorders" or "vascular disorders," were selected for the analysis. The frequency of disproportionate reporting was expressed as the reporting odds ratio (ROR) with its 95% confidence interval (CI), to evaluate the frequency of reporting of CV ADRs for each anti-CGRP-mAb compared with all other monoclonal antibodies (mAbs). A case-by-case analysis was conducted paying particular attention to serious CV ADR reports, focusing on the type of seriousness, age group, sex, and concomitant drugs. A total of 9441 ICSRs were recorded in the EV database from 2018 to 2022, of which more than half were related to ERE (58.9%), followed by GMB (21.4%), FMB (19.0%), and EPT (0.7%). CV ICSRs accounted for 1205 cases (12.8%), with a total of 1599 CV ADRs. The CV ICSRs were mainly related to female patients (82.6%) aged 18-64 years (73.4%). Of the reported CV ADRs, 67.5% were considered serious. Among the total number of ICSRs related to each anti-CGRP-mAb, those associated with FMB had a higher percentage of CV ADRs (n = 253; 14.1%), followed by ERE (n = 707; 12.7%), EPT (n = 8; 12.7%), and GMB (n = 237; 11.7%). A higher frequency of reporting hypertension was shown for ERE (ROR = 1.45; 95% CI = 1.14-1.85). Pallor was mainly observed with FMB (5.00; 1.68-14.89), as well as deep vein thrombosis (3.86; 1.57-9.51), hot flush (2.16; 1.43-3.25), and palpitations (1.48; 1.05-2.08). Atrial fibrillation (2.36; 1.02-5.46) and myocardial infarction (2.21; 1.37-3.58) were mostly reported for GMB. The analysis of anti-CGRP-related CV ADRs was consistent with the information reported in the literature. However, hypertension with ERE, atrial fibrillation and myocardial infarction with GMB, as well as pallor, deep vein thrombosis, hot flush, and palpitations with FMB were not reported in the Summary of Product Characteristics (SmPCs). Considering this, more post-marketing analyses are needed to improve knowledge on the CV safety profiles of anti-CGRP-mAbs, especially for the last approved medication, EPT.

Antibiotic Use Awareness and Practices in the Indian Community During Later Stages of COVID-19 Pandemic: A Cross-Sectional Survey

BACKGROUND: Irrational prescription of, and self medication with antibiotics is a rampant problem in LMIC'S like India. The prescription of antibiotics for symptoms similar to Covid-19 infection has aggravated the problem of antibiotic overuse, further worsening antimicrobial resistance. This study aims at understanding not only the extent of overuse, but also the social patterns and causes of overprescription or self medication of antibiotics in India. METHODS: A cross-sectional survey of the knowledge, attitude and practices on antibiotic use was conducted from September to October, 2022, using a Google form questionnaire. A virtual snowball technique was used to recruit respondents. RESULTS: A total of 309 responses were received (56% female and 44% male). 59.5% of the respondents were between 15 to 30 years. Surprisingly, inspite of a majority of respondents (around 70%) having a health sciences background, 67.8% of respondents falsely believe that antibiotics speed up recovery from most coughs and colds. 94.8% of respondents had used antibiotics in the last one year.17.2% of respondents had taken antibiotics without the prescription of a doctor. The most common antibiotic used on prescription and self medication was Azithromycin. Only 20.7% of respondents took antibiotics on suspicion of having Covid-19, with the most common one being Azithromycin. CONCLUSION: The study brings to light trends in the awareness and usage of antibiotics with greater emphasis on the Indian medical community. The findings of this study can be used to formulate a more effective Antimicrobial Stewardship Programs to curb antibiotic overuse. The use of antibiotics for self-limiting indications like cough, cold and sore throat needs to be restricted through stricter regulations. The study highlights that a greater knowledge on antibiotic use does not necessitate better attitude towards their cautious and rational use, nor does it guarantee a supportive attitude towards regulations on antibiotic dispensing. In spite of it's significant cardiovascular adverse drug reactions, Azithromycin was found to be the most commonly used antibiotic in our study. Relatively lower rate of self-medication with antibiotics was seen in our study, which might be due to a greater percentage of respondents with a healthcare background, thus exhibiting positive behavior practices on antibiotic use.

Remdesivir: A Review in COVID-19.

Remdesivir (Veklury®), a nucleotide analogue prodrug with broad-spectrum antiviral activity, is approved for the treatment of coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus2 infection. Unlike some antivirals, remdesivir has a low potential for drug-drug interactions. In the pivotal ACTT-1 trial in hospitalized patients with COVID-19, daily intravenous infusions of remdesivir significantly reduced time to recovery relative to placebo. Subsequent trials provided additional support for the efficacy of remdesivir in hospitalized patients with moderate or severe COVID-19, with a greater benefit seen in patients with minimal oxygen requirements at baseline. Clinical trials also demonstrated the efficacy of remdesivir in other patient populations, including outpatients at high risk for progression to severe COVID-19, as well as hospitalized paediatric patients. In terms of mortality, results were equivocal. However, remdesivir appeared to have a small mortality benefit in hospitalized patients who were not already being ventilated at baseline. Remdesivir was generally well tolerated in clinical trials, but pharmacovigilance data found an increased risk of hepatic, renal and cardiovascular adverse drug reactions in the real-world setting. In conclusion, remdesivir represents a useful treatment option for patients with COVID-19, particularly those who require supplemental oxygen.

The Neuropsychiatric Safety Profile of Lasmiditan: A Comparative Disproportionality Analysis with Triptans.

Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT1B/1D receptor agonists, remain the first-line treatment, despite discouraged use in individuals at high cardiovascular risk. Lasmiditan, a selective lipophilic 5-HT1F agonist without vasoconstrictive effects, is an emerging option. We aimed to investigate the safety profile of lasmiditan in the WHO pharmacovigilance database (VigiBase®) using a comparative disproportionality analysis with triptans. VigiBase® was queried for all reports involving lasmiditan and triptans. Disproportionality analyses relied on the calculation of the information component (IC), for which 95% confidence interval (CI) lower bound positivity was required for signal detection. We obtained 826 reports involving lasmiditan. Overall, 10 adverse drug reaction classes were disproportionately reported with triptans, while only neurological (IC 1.6; 95% CI 1.5-1.7) and psychiatric (IC 1.5; 95% CI 1.3-1.7) disorders were disproportionately reported with lasmiditan. Sedation, serotonin syndrome, euphoric mood, and autoscopy had the strongest signals. When compared with triptans, 19 out of 22 neuropsychiatric signals persisted. The results of our analysis provide a more precise semiology of the neuropsychiatric effects of lasmiditan, with symptoms such as autoscopy and panic attacks. The cardiovascular adverse drug reaction risk with triptans was confirmed. In contrast, caution is warranted with lasmiditan use in patients with neurological or psychiatric comorbidities or serotonin syndrome risk. Our study was hindered by pharmacovigilance flaws, and further studies should help in validating these results. Our findings suggest that lasmiditan is a safe alternative for migraine treatment, especially when the neuropsychiatric risk is outweighed by the cardiovascular burden.

Real-World Evidence for the Safety and Effectiveness of Tirabrutinib in 140 Japanese Patients with Recurrent or Refractory Primary Central Nervous System Lymphoma: Interim Report of Postmarketing Surveillance

Background: Primary central nervous system lymphoma (PCNSL) is a brain tumor with a very poor prognosis. Tirabrutinib is a second-generation inhibitor of Bruton's tyrosine kinase with higher kinase selectivity than ibrutinib (Banerji et al., 2020), suggesting potentially fewer off-target adverse events-including infections, bleeding, and cardiovascular adverse events-that have been reported with ibrutinib. On the basis of results of a phase I/II study (ONO-4059-02; trial registration number: JapicCTI-173646), tirabrutinib was approved in Japan in March 2020 for recurrent or refractory PCNSL at a dose of 480 mg under fasted conditions. We conducted a prospective, noninterventional, multicenter, observational study (trial registration number: jRCT2011210002) to evaluate adverse drug reactions (ADRs) and the overall response rate (ORR) of tirabrutinib against recurrent or refractory PCNSL in Japan. This postmarketing all-case surveillance study started on May 20, 2020. We report the interim safety and effectiveness data for patients who started tirabrutinib administration from the start date through October 31, 2020. Methods: All patients were monitored up to 52 weeks. Collected data included baseline characteristics, laboratory test results, ADRs, and the ORR. ADRs were coded according to MedDRA, version 24.1. The ORR was evaluated according to the criteria of the International PCNSL Collaborative Group (IPCG). The timing and method of imaging study was at discretion of physician. Results: Data from 140 patients who received tirabrutinib treatment were analyzed for safety, and data from 127 of those patients were analyzed for effectiveness. A total of 13 patients were excluded from the effectiveness analysis because 9 patients had a history of prior treatment with tirabrutinib and 4 patients received tirabrutinib as off-label use for the treatment of newly diagnosed disease. Of the 140 patients, 72 (51.4%) were male. Their median age was 70 years (range, 30-88 years), and 98 patients (70.0%) were 65 years of age or older. The Karnofsky Performance Status scores were 80-100 for 49 patients (35.0%), 50-70 for 60 patients (42.9%), and ≤40 for 31 patients (22.1%). Fifteen patients (10.7%) had intraocular lymphoma. The median number of previous lines of treatment was 1 (range, 0-6) and for 67 patients (47.9%), tirabrutinib was second-line therapy. The median duration of tirabrutinib treatment was 147.0 days (range, 3-365 days); 28 patients (20.0%) continued taking tirabrutinib until the end of the observation period (365 days) and thereafter. Of the 95 patients who discontinued tirabrutinib treatment, 60 (63.2%) did so because of disease progression, 15 (15.8%) because of adverse events, 13 (13.7%) because they transferred to another hospital, 4 (4.2%) because they responded to treatment, and 13 (13.7%) for other reasons. The most common systemic ADRs were skin and subcutaneous tissue disorders, including rash, pruritus, erythema multiforme, and rash maculo-papular; these affected 43 (30.7%) of all 140 patients, of whom 12 (8.6%) had grade 3 or worse ADRs (Table 1). Seven patients (5.0%) discontinued tirabrutinib treatment due to grade 3 or worse (n = 6) or grade 2 (n = 1) skin-related ADRs. Infections and infestations were observed in 5 patients (3.6%), of whom 2 (1.4%) had grade 3 or worse infections or infestations. Grade 1 or 2 bleeding was observed in 2 patients (1.4%). No patients in this cohort had cardiovascular ADRs or grade 5 ADRs. At the end of the 52 weeks, 73 patients (52.1%) were still alive, 46 (32.9%) had died, and the status of 21 (15.0%) was unknown. With regard to effectiveness (n = 127), the ORR was 63.0% (n = 80) and the rate of confirmed or unconfirmed complete response was 37.0% (n = 47; Table 2). Conclusion: In this interim period of the postmarketing all-case surveillance study, the most common ADRs were skin and subcutaneous tissue disorders, and no new safety concerns were identified in addition to those in the clinical trial. The ORR and the rate of complete or unconfirmed complete response were comparable to those at the approved dose in the phase I/II study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Approaches to Assessing the Safety of Medicines during the COVID-19 Pandemic Using the Example of Azithromycin

Most of the medicines used to treat the novel coronavirus infection (COVID-19) are either approved under an accelerated procedure or not approved for the indication. Consequently, their safety requires special attention.The aim of the studywas to review methodological approaches to collecting data on the safety of medicines, using COVID-19 treatment regimens involving azithromycin as a case study.Materials and methods:PubMed® (MEDLINE), Scopus, eLIBRARY, and Cyberleninka databases were searched for publications on azithromycin as part of combination therapy for COVID-19 in 2020–2021. Search queries included names of the medicinal product or its pharmacotherapeutic group and words describing adverse drug reactions (ADRs) during treatment.Results:the analysis included 7 publications presenting the results of studies covering the use of azithromycin as part of COVID-19 combination therapy in more than 4000 patients. Most commonly, the patients receiving COVID-19 therapy including azithromycin developed cardiovascular ADRs (up to 30% of azithromycin prescription cases). In 3 of the analysed publications, safety information was collected through spontaneous reporting and active identification based on the findings of laboratory and instrumental investigations performed during the clinical studies; in other 3, only spontaneous reports were used; and in the last one, ADR database information was studied.Conclusion:currently, information on ADRs associated with the use of medicines is mainly gathered via spontaneous reporting. Direct sourcing of information on personal experiences with a certain product from patients, among other means through social media analysis, opens a promising direction towards the improvement of existing approaches to collecting safety data.

The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis.

Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). We searched the literature regarding withdrawn drugs due to safety-related issues (n =391) to compare them with all available small-molecule drugs (n =1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC-1 (Anatomical Therapeutic Chemical) level and ADR. We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6-2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9-3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4±0.8years), followed by achiral drugs (55.4±0.9years, P< .01) and chiral mixtures (52.4±1.4years, P< .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P= .02), in 1961-1980 (P< .001) or 1981-2000 (P< .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P= .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P< .01) and cardiovascular ADRs (P< .01). Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.

Adverse effects of gender-affirming hormonal therapy in transgender persons: Assessing reports in the French pharmacovigilance database.

Limited data are available on adverse drug reactions (ADRs) of gender-affirming hormone therapy (HT), mainly due to the lack of population-based studies with adequate controls, thus making spontaneous reporting systems a valuable tool to detect potential side reactions. In this nationwide retrospective study, we aimed to analyze ADRs related to gender-affirming HT reported in the French pharmacovigilance database (FPVD). We requested all the individual case safety reports related to gender-affirming HT recorded in the FPVD before May 27, 2020. We excluded previously published cases and those where gender-affirming HT was not the suspected drug. A total of 28 reports of ADRs were identified. Six concerned transgender men (21-40 years) and 22 transgender women (22-68 years). In transgender men taking testosterone enanthate, all reported ADRs were cardiovascular events, with pulmonary embolism in 50% of cases. Median time to onset (TTO) was 34 months. In transgender women, antiandrogens, mainly cyproterone acetate, were involved in 68% of cases, and estrogens in 77% of cases, mostly in association with progestin or cyproterone acetate. Meningiomas were the principal ADRs, followed by cardiovascular events, with a median TTO of 5.3months. Our data show a previously unreported, non-negligible proportion of cases indicating cardiovascular ADRs in transgender men younger than 40 years. In transgender women, cardiovascular events were the second most frequent ADR. Further research is necessary to identify risk factors that might help to the individualization of treatment strategies. There is a necessity to increase awareness, implement preventive and education measures.

Monoclonal-induced cardiotoxicity in patients with non-Hodgkin's lymphoma and breast cancer: A retrospective study in an oncology clinic.

Monoclonal antibodies, such as trastuzumab and rituximab, significantly contribute to the oncological therapeutic arsenal. However, they may be associated with the development of cardiotoxicity. This study collected data from clinical records of patients in the use of rituximab and trastuzumab in a private oncology clinic from 2017 to 2019. It also investigated cardiovascular adverse drug reactions and associated risk factors. Cardiotoxicity was defined as symptomatic in the presence of signs and symptoms suggestive of heart failure (HF) such as dyspnea, nocturnal cough, and fatigue, among others. Asymptomatic HF was confirmed by the decline in the left ventricular ejection fraction (LVEF) ≥10% of baseline or LVEF ≤50%. Among the 57 patients undergoing trastuzumab, 12 patients (21%) had cardiotoxicity and 8 patients (67%) had extreme or high-risk scores in the cardiotoxicity risk assessment algorithm. Among the 37 patients treated with rituximab, 3 patients (8%) had cardiotoxicity. The presence of previous diabetes mellitus significantly increased the risk of trastuzumab-induced cardiotoxicity (p = 0.02). However, none of the other risk factors influenced the incidence of trastuzumab- and rituximab-induced cardiotoxicity, which the sample size may explain. More studies are needed to investigate the association of risk factors with cardiotoxicity induced by trastuzumab and rituximab, aiming to establish strategies to prevent and manage this effect early.

Safety of Non-Steroidal Anti-Inflammatory Drugs in the Elderly: An Analysis of Published Literature and Reports Sent to the Portuguese Pharmacovigilance System.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently used agents to treat musculoskeletal disorders (principally by the elderly), thus raising the risk of adverse drug reactions (ADRs). This work aims to monitor NSAIDs safety profile in older people by using literature and pharmacovigilance data. Published clinical studies reporting the NSAIDs safety in elderly patients (age ≥ 65) were identified by a literature search and were then deeply analyzed. In addition, suspected ADRs reports submitted to the Portuguese Pharmacovigilance System (PPS) involving patients aged ≥65 with at least one NSAID as suspected drug were explored in detail. Most studies concluded that the risk of gastrointestinal, cardiovascular, and renal ADRs was significantly lower with cyclooxygenase-2 (COX-2)-selective NSAIDs use than with nonselective NSAIDs. The PPS data analysis showed that serious gastrointestinal ADRs occurred mostly in patients taking more than one NSAID and/or another concomitant drug that increases the incidence of these events, in the absence of gastroprotection. The results suggest that while NSAID toxicity is well understood, their safe use needs to be monitored in clinical practice. Furthermore, the pharmacovigilance data analyzed also showed that monitoring NSAIDs use in elderly remains essential to mitigate the associated risks, especially in those with comorbidities and under polytherapy.

Abstract 10520: Emerging Cardiovascular Side Effects of Selective and Non-Selective Immunotherapies in Cancer Patients: 2021 Results from the Global WHO Database

Introduction: Immune checkpoint inhibitors (ICIs), and adoptive cell transfer (ACT) - which involves collecting and using patient’s own immune cells to treat their cancer, are two rapidly emerging therapeutic modalities for various advanced stage cancers. Emerging cardiovascular side effects of ICIs and ACTs are currently being recognized. Objective: We analyzed the newly reported side-effect profiles of FDA-approved ICIs (anti-CTLA-4, anti-PD-1 and anti-PD-L1) and ACTs (also known as CAR-T therapy). Methods: We utilized the global data available in VigiBase®, World Health Organization’s global database for adverse drug reactions (ADRs), maintained by the Uppsala Monitoring Centre. We extracted information on reports of suspected ADRs, also called Individual Case Safety Reports (ICSRs). ICSRs of ICI and ACT therapy on cardiovascular system were extracted, and the side effect profile of the two groups of immunotherapies were systematically analyzed. Results: Based on the records obtained to-date, a total of 6,000 cardiovascular ADRs caused by ICIs (Ipilimumab, Nivolumab, Pembrolizumab, Cemiplimab, Atezolizumab, Avelumab and Durvalumab), and 500 ADRs by ACTs (Kymriah, Yescarta, Tecartus, Brevanzi and Abecma) have been reported. ICI therapies were predominantly associated with myocarditis (1098), cardiac failure (614), acute coronary syndrome (548) and pericarditis/pericardial effusion (516). ACT therapies were associated with tachyarrhythmia (263), cardiac arrest (44) and cardiorenal events (25). A propensity analysis demonstrated ICIs to be associated with autoimmunity-related ADRs, whereas ACTs were associated with acute cytokine release-related ADRs. Conclusions: Using a large-scale global WHO data platform, we have identified unique tendencies for cardiovascular ADRs resulting from non-selective (ICIs) and highly-selective (ACTs) immunotherapies for cancer: the former is associated with serious autoimmune effects, and the latter is associated with acute cytokine-release-related ADRs.

Adverse Drug Reactions and Atrioventricular Conduction Disorders - A Female Gender Related Aproach

Abstract Introduction. Although cardiovascular disease remains the leading cause of mortality regardless of gender, the female gender has remained an underrepresented population in studies in this field. Sustained initiatives by the European Society of Cardiology have brought to the fore the importance of studying gender differences regarding the safety profile of cardiovascular drugs in women. Common cardiovascular adverse drug reactions include atrioventricular conduction disorders. Materials and methods. The present study followed the clinical and paraclinical features of female patients with a primary diagnosis of bradycardia in relation to bradycardic medication. We included a group of 359 female patients, divided according to the presence or absence of bradycardia medication into a study group (n=206) and a control group (n=153). Results. Patients with associated bradycardic medication frequently required emergency admission (P &lt; 0.001), with prolonged hospitalization (P &lt; 0.001). The main atrioventricular conduction disorders identified were atrial fibrillation with slow ventricular response (P = 0.028), sinus bradycardia (P = 0.009) and sinus pauses (P = 0.009). Among comorbidities, heart failure (P&lt;0.001) and chronic kidney disease (P&lt;0.001), were common in the study group. Echocardiographic parameters of left ventricular (P=0.002) and biatrial (P&lt;0.001) dilatation, as well as severe left ventricular systolic dysfunction (P=0.009), showed statistical significance in this group. The most used drugs were beta-blockers, amiodarone, and digoxin. Conclusions. Our results indicate, as factors associated with medication-related bradyarrhythmias in female gender: heart failure with severe systolic dysfunction, renal dysfunction, atrial fibrillation, and left ventricular dilatation.

FREQUENCY AND IMPACT OF ADVERSE DRUG REACTIONS INDUCED BY CARDIOVASCULAR DRUGS AND AFFECTING CARDIOVASCULAR SYSTEM: A NATIONAL 10 YEARs OF SURVEILLANCE

Abstract Objective: Cardiovascular (CV) disorders are a leading cause of death. Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Drugs for treatment of CV disorders and antithrombotic drugs (AT) are commonly prescribed and a cause of serious ADR (SAR). CV system is also a target for non-CV prescribed drugs. In a national survey we identified the most reported ADR associated with CV and AT drugs and the non-CV drugs more prone to affect CV system. Design and method: From January 2006 to December 2015 in a observational retrospective study we analyzed all reports of ADRs (and their determinants) submitted to the National Medicines Regulatory Agency (NMRA). Results: In the study period, 10% (n = 2724) of all ADR reports submitted to the NMRA (N = 28061) were related to CV or Antithrombotic drugs, 73.9% of them were SARs and fatal, 55.6% (n = 1479) in women. Mean age was 62 years and 51% of the episodes occurred in subjects &gt; 65 years. AT drugs were the class most frequently associated with SARS (mainly hemorrhages), 31.1% (n = 956, NOACs 251), followed by modulators of Renin-Angiotensin System (cough and dizziness), 19.97% (n = 544), and by lipid modifying agents (musculoskeletal disorders), 19.6% (n = 534). Reports/year to AT increased 7.7 from 2006 to2013 and 88.5 from 2013 to 2015. CV drugs also produced disorders at gastrointestinal (24,63%), skin (22,39%)and nervous system (20,74%). The most common CV ADR associated with non-CV drugs were hypotension (24.4%) and hypertension (16.5%) most commonly induced by antineoplastic, antibiotics and NSAIDs. Conclusions: Drugs used for treatment of CV disorders &amp; antithrombotic are a common cause of serious ADRs. ADRS involving the CV system by non-CV drugs are also frequent. All can be detected and identified by current pharmacovigilance tools providing valuable information about the safety of post-marked drugs.

Reports of cardiovascular adverse drug reactions with loperamide

Reports of cardiovascular adverse drug reactions with loperamide

Cardiotoxicity Associated with Gemcitabine: Literature Review and a Pharmacovigilance Study.

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization’s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 1 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) ≥ 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design.

INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists.

P1591Cardiovascular toxicity of ibrutinib: a pharmacovigilance study

Abstract Importance Ibrutinib, a first in class Bruton tyrosine kinase inhibitor, has revolutionized treatment for several B-cell malignancies. However, early data suggested that ibrutinib was associated with supra-ventricular arrhythmias (SVA) and bleeding. Other types of cardiovascular adverse drug reactions (CV-ADR) induced by ibrutinib have been sporadically reported. Objective To determine the full spectrum of CV-ADR associated with ibrutinib and provide data concerning their clinical characteristics. Design An observational, retrospective, pharmacovigilance study Setting VigiBase, the World Health Organization's pharmacovigilance database. Main outcomes and measures A disproportionality analysis using reporting odds-ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and ADR using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) &gt;0 is considered statistically significant. Exposures Exposure to ibrutinib versus entire database. Results Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVA; ROR: 23.1 [21.6–24.7]; IC025:3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7 [3.4–4.1]; IC025:1.63), heart failure (HF; ROR: 3.5 [3.1–3.8]; IC025:1.46), ventricular arrhythmias (VA; ROR: 4.7 [3.7–5.9]; IC025:0.96), conduction disorders (CD; ROR: 3.5 [2.7–4.6]; IC025:0.76), CNS ischemic events (ROR: 2.2 [2.0–2.5]; IC025:0.73) and hypertension (ROR: 1.7 [1.5–1.9]; IC025:0.4). CV-ADR occurred early after ibrutinib administration, as soon as after the first dose, with a shorter median time to onset of 27.5 days (IQR: 1–138.5 days) for CD (p&lt;0.01, Kruskal-Wallis), as compared to CNS ischemic events (51 days; IQR: 17.5–160 days, p: 0.05 vs. CD), CNS hemorrhagic events (53.5 days; IQR: 20.3–183.3 days, p: 0.03 vs. CD), HF (54 days; IQR: 20–142.8 days, p: 0.05 vs. CD), VA (70 days; IQR: 28.5–152.5 days, p: 0.03 vs. CD), SVA (74 days; (IQR: 29.5–196.5 days, p: 0.0004 vs. CD) and hypertension (164 days; IQR: 20–274 days, p: 0.04 vs. CD). CV-ADR were associated with fatalities, with rates ranging from ∼10% (SVA and VA) to ∼20% (CNS events, HF and CD). More deaths occurred when SVA cases were associated with CNS hemorrhagic and/or ischemic events compared to their absence (15/52, 28.8% vs. 88/907, 9.7%, p&lt;0.0001, respectively). Conclusions Severe and occasionally fatal cardiac events related to cardiac SVA, VA, CD, HF, hypertension, CNS hemorrhagic and ischemic events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs.

Cardiovascular Toxicities Associated With Ibrutinib

BackgroundIbrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study. ObjectivesThe purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib. MethodsThis study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant. ResultsThis study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC025: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC025: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC025: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC025: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC025: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC025: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC025: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases). ConclusionsSevere and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215)

Computational models for the prediction of adverse cardiovascular drug reactions

BackgroundPredicting adverse drug reactions (ADRs) has become very important owing to the huge global health burden and failure of drugs. This indicates a need for prior prediction of probable ADRs in preclinical stages which can improve drug failures and reduce the time and cost of development thus providing efficient and safer therapeutic options for patients. Though several approaches have been put forward for in silico ADR prediction, there is still room for improvement.MethodsIn the present work, we have used machine learning based approach for cardiovascular (CV) ADRs prediction by integrating different features of drugs, biological (drug transporters, targets and enzymes), chemical (substructure fingerprints) and phenotypic (therapeutic indications and other identified ADRs), and their two and three level combinations. To recognize quality and important features, we used minimum redundancy maximum relevance approach while synthetic minority over-sampling technique balancing method was used to introduce a balance in the training sets.ResultsThis is a rigorous and comprehensive study which involved the generation of a total of 504 computational models for 36 CV ADRs using two state-of-the-art machine-learning algorithms: random forest and sequential minimization optimization. All the models had an accuracy of around 90% and the biological and chemical features models were more informative as compared to the models generated using chemical features.ConclusionsThe results obtained demonstrated that the predictive models generated in the present study were highly accurate, and the phenotypic information of the drugs played the most important role in drug ADRs prediction. Furthermore, the results also showed that using the proposed method, different drugs properties can be combined to build computational predictive models which can effectively predict potential ADRs during early stages of drug development.

Is there such a thing as a 'lope' dope? Analysis of loperamide-related European Medicines Agency (EMA) pharmacovigilance database reports.

BackgroundAmong over-the-counter (OTC) drugs, loperamide has recently emerged for its potential of misuse and cardiotoxicity issues. Hence, we aimed here at assessing the loperamide-related cases being reported to the EMA's EudraVigilance (EV) database.MethodsAll spontaneous EV reports relating to loperamide misuse/abuse/dependence/withdrawal and cardiotoxicity issues were here retrieved, performing a descriptive analysis.FindingsDuring the years 2005–2017, EV collected a number of 1,983 (out of a total of 7,895; 25.11%) loperamide-related misuse/abuse/dependence/withdrawal adverse drug reaction (ADR) reports, with a progressively increasing trend since 2014. Most cases were classified as drug use disorder (37.4%) or intentional overdose (25.4%). Loperamide was used on its own in 41.9% of cases; remaining, polydrug, cases included antidepressants; benzodiazepines; and other OTCs. Some 1,085 (1,085/7,895 = 13.7%) cardiovascular ADRs were reported, being conduction abnormalities and EKG alterations the most frequently identified.ConclusionsEV data may support the levels of concern relating to loperamide potential of abuse and associated cardiotoxicity issues.