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

ABSTRACT: 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.

SUBMITTER: Hilmi M

PROVIDER: S-EPMC7594046 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Hilmi Marc M Ederhy Stéphane S Waintraub Xavier X Funck-Brentano Christian C Cohen Ariel A Vozy Aurore A Lebrun-Vignes Bénédicte B Moslehi Javid J Nguyen Lee S LS Salem Joe-Elie JE

Pharmaceuticals (Basel, Switzerland) 20201021 10

<h4>Background</h4>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).<h4>Methods</h4>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 reportin ...[more]

PMID: 33096756

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Project description:BackgroundDoxorubicin and other anthracycline derivatives inhibit topoisomerase II and is an important class of cytotoxic chemotherapy in cancer treatment. The use of anthracycline is limited by dose-dependent cardiotoxicity, which may manifest initially as asymptomatic cardiac dysfunction with subsequent progression to congestive heart failure. Despite baseline assessment and periodic monitoring of cardiac function for patients receiving anthracycline agents, there are unmet needs in prediction and prevention of anthracycline-induced cardiotoxicity (AIC).Case summaryA 35-year-old African American female was found to have a 9-cm high-grade osteosarcoma of right femur and normal baseline cardiac function with left ventricular ejection fraction of approximately 60%-70% determined by transthoracic and dobutamine stress echocardiogram. She underwent perioperative doxorubicin and cisplatin chemotherapy with 3 cycles before surgery and 3 cycles after surgery, and received a total of 450 mg/m2 doxorubicin at the end of her treatment course. She was evaluated regularly during chemotherapy without any cardiac or respiratory symptoms. Approximately two months after her last chemotherapy, the patient presented to the emergency department with dyspnea for one week and was intubated for acute hypoxic respiratory failure. Echocardiogram showed an ejection fraction of 5%-10% with severe biventricular failure. Despite attempts to optimize cardiac function, the patient's hemodynamic status continued to decline, and resuscitation was not successful on the seventh day of hospitalization. The autopsy showed no evidence of osteosarcoma, and the likely cause of death was cardiac failure with the evidence of pulmonary congestion, liver congestion, and multiple body cavity effusions.ConclusionWe present a case of 35-year-old African American female developing cardiogenic shock shortly after receiving a cumulative dose of 450 mg/m2 doxorubicin over 9 mo. Cardiac monitoring and management of patients receiving anthracycline chemotherapy have been an area of intense research since introduction of these agents in clinical practice. We have reviewed literature and recent advances in the prediction and prevention of AIC. Although risk factors currently identified can help stratify patients who need closer monitoring, there are limitations to our current understanding and further research is needed in this field.

Project description:ObjectivesPharmacovigilance education is essential since adverse drug reactions (ADRs) are a serious health problem and contribute to unnecessary patient burden and hospital admissions. Healthcare professionals have little awareness of pharmacovigilance and ADR reporting, and only few educational interventions had durable effects on this awareness. Our future healthcare providers should therefore acquire an adequate set of pharmacovigilance competencies to rationally prescribe, distribute, and monitor drugs. We investigated the pharmacovigilance and ADR-reporting competencies of healthcare students to identify educational interventions that are effective in promoting pharmacovigilance.MethodsThe PubMed, EMBASE, Cochrane, CINAHL, PsycINFO, and ERIC databases were searched using the terms "pharmacovigilance," "students," and "education.".ResultsTwenty-five cross-sectional and 14 intervention studies describing mostly medical and pharmacy students were included. Intentions and attitudes on ADR reporting were overall positive, although most students felt inadequately prepared, missed the training on this topic, and lacked basic knowledge. Although nearly all students observed ADRs during clinical rounds, only a few had actually been involved in reporting an ADR. Educational interventions were predominately lectures, sometimes accompanied by small interactive working groups. Most interventions resulted in a direct increase in knowledge with an unknown long-term effect. Real-life learning initiatives have shown that healthcare students are capable of contributing to patient care while increasing their ADR-reporting skills and knowledge.ConclusionsThere is an urgent need to improve and innovate current pharmacovigilance education for undergraduate healthcare students. By offering real-life pharmacovigilance training, students will increase their knowledge and awareness but can also assist current healthcare professionals to meet their pharmacovigilance obligations.

Project description:This study was to scientifically and systematically explore the association between cardiotoxicity and immune checkpoint inhibitors (ICIs) and also to characterize the spectrum of ICI-related cardiac complications. From the first quarter of 2014 to the fourth quarter of 2019, data from the FDA Adverse Event Reporting System database were selected to conduct the disproportionality analysis. Reporting odds ratios and information components were used to evaluate the signal after statistical shrinkage transformation. In total, 7,443,137 cases and 36,326,611 drug-adverse event pairs were collected, among which 9,271 cases were identified to be related to ICI-induced cardiotoxicities. The number of male patients was much higher than that of females (5,579 vs. 3,031) and males presented a slightly higher reporting frequency than females in general, which was statistically significant (ROR = 1.04, 95%CI: 0.99-1.09, p < 0.001). Simultaneously, the proportion of serious or life-threatening outcomes in males was significantly higher than in females (ROR = 1.05, 95%CI: 0.96-1.15, p < 0.001). Importantly, ICIs were associated with over-reporting frequencies of cardiotoxicities in general (ROR025 = 1.06, IC025 = 0.08). PD-1 and PD-L1 were found to be related to cardiac adverse events, corresponding to ROR025 = 1.06, IC025 = 0.08, and ROR025 = 1.06, IC025 = 0.08, respectively, while anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) was significantly associated with some specific adverse events rather than common adverse events. The spectrum of cardiotoxicities induced by ICIs mostly differed among individual agents, but also demonstrated some common features. Dyspnea (N = 2,527, 21.25%), myocarditis (N = 614, 5.16%), atrial fibrillation (N = 576, 4.84%), cardiac failure (N = 476, 4.00%), and pericardial effusion (N = 423, 3.56%) were the top five cardiac adverse events reported in the database. Among them, myocarditis was the only one caused by all ICIs with strong signal value and high risk, warranting further attention. Overall, this investigation mainly showed the profile of cardiotoxicities caused by ICIs, which varied between different ICI therapies, but also shared some similarities in specific symptoms such as myocarditis. Therefore, it is vital and urgent to recognize and manage ICI-related cardiotoxicities, known to frequently occur in clinical practice, at the earliest point.

Project description:BackgroundImmune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized.MethodsWe performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant.ResultsAmong the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14.5-18.9]; IC025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC025 3.15), peripheral neuropathy (1.16% vs. 0.67%, IC025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~ 20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping.ConclusionsICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

Project description:BACKGROUND:Signals of adverse drug reactions (ADRs) form the basis of some regulatory risk-minimization actions in pharmacovigilance. Reviews of limited scope have highlighted that such signals are mostly supported by reports of ADRs or multiple types of evidence. The time that elapses between a report of a suspected ADR and the communication of a signal has not been systematically characterized. Neither has the features of reports of suspected ADRs that authors used to support putative causal relationships, although difficulties with establishing causal relationships between medicinal products and adverse events have been highlighted. The objectives of this study will be to describe the evidence underpinning signals in pharmacovigilance, the features of reports of ADRs supporting signals, and the time that it takes to communicate a signal. METHODS:We shall retrieve records from PubMed, EMBASE, Web of Science, and PsycINFO (from inception onwards), without language/design restrictions, and apply backward citation screening. We shall hand-search the websites of 35 regulatory agencies/authorities, restricted publications from the Uppsala Monitoring Centre, and drug bulletins. Signals will be requested from the competent stakeholder, if absent from websites. We shall use VigiBase, the World Health Organization's Global Individual Case Safety Report database, to determine the dates on which ADRs were reported. We shall manage records using EndNote (v. 8.2); one reviewer will screen titles/abstracts and full texts, a second will cross-validate the findings, and a third will arbitrate disagreements. Data will be charted via the Systematic Reviews Data Repository, following the same procedures as for data retrieval. Evidence will be categorized according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Features of reports of ADRs will be coded. Tables will display frequencies of types of evidence and features of reports of ADRs. We shall use plots or pictograms (if appropriate) to represent the time from the first report of a suspected ADR to a signal. DISCUSSION:We expect the findings from this review will allow a better understanding of global patterns of similarities or differences in terms of supporting evidence and timing of communications and identify relevant research questions for future systematic reviews. SYSTEMATIC REVIEW REGISTRATION: osf.io/a4xns.

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Dataset Information

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

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

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