Clozapine and incidence of myocarditis and sudden death – Long term Australian experience

Khan, Akhtar A.; Ashraf, Asma; Baker, David W.; Al-Omary, M.; Savage, L.; Ekmejian, A.; Singh, R. Harjit; Brienesse, S.; Majeed, Tazeen; Gordon, T.; Drinkwater, Vincent; Collins, Nicholas

doi:10.1016/j.ijcard.2017.03.013

Cited by 42 publications

(54 citation statements)

References 18 publications

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“…Clozapine has potentially fatal adverse effects such as myocarditis, constipation, and agranulocytosis . Yet, no reports in this analysis were reported as severe or leading to death.…”

Section: Discussionmentioning

confidence: 67%

“…Clozapine has potentially fatal adverse effects such as myocarditis, constipation, and agranulocytosis. [38][39][40][41] Yet, no reports in this analysis were reported as severe or leading to death. Overall, only 0.8% of all incidents were reported as an adverse drug reaction (ADR), possibly because of most ADRs being reported directly to medication manufacturers, licence holders, and through the Yellow Card Scheme.…”

Section: Degree Of Harmmentioning

confidence: 81%

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A mixed methods analysis of clozapine errors reported to the National Reporting and Learning System

Dabba

Elswood

Ahmed³

et al. 2019

Pharmacoepidemiology and Drug

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Purpose To review and analyse medication errors related to clozapine, an atypical antipsychotic, that were reported to the National Reporting and Learning System (NRLS). Methods Following extraction of one year of clozapine related errors from the NRLS, a qualitative analysis (thematic analysis and re‐classification) and quantitative analysis was performed. An incident was considered a clozapine error if there was a failure in its medication process (i.e. an error in the prescribing, dispensing, preparing, administering, monitoring or advising of clozapine). Results “Issues with stock/supply/ordering” was the most common theme derived from the qualitative thematic analysis (n = 338), followed by wrong dose/strength/frequency (n = 221) and medication omissions (n = 202). Most errors occurred in the “administration/supply” medication stage. Over half of reported clozapine incidents involved people 26 to 55 years old (n = 830) and 82% of errors were reported by mental health services (n = 1270). Only 1.5% of reports were classed as moderate/severe harm. Conclusion Issues with availability, stock, and supply were found to be the most common causes. This usually entailed a lack of stock to fulfil a patient's dose/supply. Such incidents could potentially be reduced by improved management of the supply process, and liaison between pharmacy and clinical staff. The implementation of emergency drug cupboards at the discretion of an on‐call pharmacist may prove to be a preventative measure for such errors. Despite the potential adverse effects associated with clozapine, very few incidents led to moderate/severe harm. Encouragement of NRLS reporting is recommended for incidents of all degrees of harm.

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“…Clozapine has potentially fatal adverse effects such as myocarditis, constipation, and agranulocytosis . Yet, no reports in this analysis were reported as severe or leading to death.…”

Section: Discussionmentioning

confidence: 67%

Section: Degree Of Harmmentioning

confidence: 81%

A mixed methods analysis of clozapine errors reported to the National Reporting and Learning System

Dabba

Elswood

Ahmed³

et al. 2019

Pharmacoepidemiology and Drug

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“…Несмотря на потенциальное аритмогенное действие клозапина [7], по данным ЭКГ не выявили аритмий сердца (экстрасистолы, паузы, желудочковая тахикардия) во всех группах.…”

Section: результаты и обсуждениеunclassified

“…Возникновение жизнеугрожающих побочных эффектов отмечено также и при приеме терапевтических доз препарата. Среди них значимое место занимают неблагоприятные кардиальные эффекты, такие как миокардиты, кардиомиопатии, перикардиты, сердечная недостаточность, внезапная сердечная смерть [7][8][9][10][11]. A. Al-Wahab и соавт.…”

Section: Introductionunclassified

“…Occurrence of life-threatening side effects was also noted during intake of therapeutic doses of the drug. An important role among them belongs to adverse cardiac effects such as myocarditis, cardiomyopathy, pericarditis, heart failure, sudden cardiac death [7][8][9][10][11]. A. Al-Wahab et al revealed in an experimental study the increased levels of noradrenaline, adrenaline, troponins, creatine phosphokinase-MB, interleukins, tumor necrosis factor alpha, cytokines in the blood of mice that received Clozapine [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Morphological and Functional Alterations of the Cardiovascular System during Acute Clozapine Poisoning (Experimental Study)

Babkina

Рыжков

Antonova

et al. 2019

Obŝaâ reanimatologiâ

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Purpose of the study. To evaluate the influence of sublethal dose of Clozapine on the functional and morphological parameters of the cardiovascular system in rats 4 hrs. after the drug administration.Materials and methods. The experiments were carried out on male Wistar rats weighing 200–250g (n=14). Group I received 0.9% NaCl solution administered via enteral feeding tubing under general anesthesia using Sevoflurane; group II — Clozapine dosed at 150 mg/kg in 0.9% NaCl solution; group III — Clozapine dosed at 150 mg/kg in 40% ethyl alcohol solution. 4 hrs. after drug administration, arterial blood pressure (ABP), heart rate (HR), microcirculation in the skin using laser Doppler flowmetry (LSF), fluorescence intensity of coenzymes NADH and FAD were evaluated. After euthanasia, autopsy including withdrawal of the internal organs of rats for morphological analysis was performed. Thereafter, paraffin sections of hearts were made and subsequently stained with hematoxylin and eosin, which were later examined with the help of light microscope Nikon Eclipse Ni-U.Results. In both Clozapine groups, ABP and blood flow in the skin were lower than in the control group: ABP — by 12% in group I and by 15% in group II; blood flow — by 48% and 37%, respectively. No significant difference between the groups was observed in respect of the microcirculation indices studied. Increased fluorescence intensity of coenzyme NADH in the skin was found in the Clozapine groups compared to the control group (2.3-fold in group I and 1.9-fold in group II). Histological analysis of the hearts of animals that received Clozapine established uneven blood filling, erythrocyte sludges, fine-focal hemorrhaging, endotheliocyte nuclei oriented perpendicular to the basal membrane, uneven staining of myocardium with hypereosinophilic segments, fragmentation and undulating deformity of muscle fibers.Conclusion. During acute Clozapine poisoning, morphological signs of disturbed circulation and myocardium damage are found in the heart, which are accompanied with development of myocardium dysfunction with arterial hypotension and decreased peripheral blood flow, also disturbed oxidative metabolism in peripheral tissues.

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Diagnosis and Treatment of Acute Myocarditis

Ammirati

Moslehi

2023

JAMA

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ImportanceAcute myocarditis, defined as a sudden inflammatory injury to the myocardium, affects approximately 4 to 14 people per 100 000 each year globally and is associated with a mortality rate of approximately 1% to 7%.ObservationsThe most common causes of myocarditis are viruses, such as influenza and coronavirus; systemic autoimmune disorders, such as systemic lupus erythematosus; drugs, such as immune checkpoint inhibitors; and vaccines, including smallpox and mRNA COVID-19 vaccines. Approximately 82% to 95% of adult patients with acute myocarditis present with chest pain, while 19% to 49% present with dyspnea, and 5% to 7% with syncope. The diagnosis of myocarditis can be suggested by presenting symptoms, elevated biomarkers such as troponins, electrocardiographic changes of ST segments, and echocardiographic wall motion abnormalities or wall thickening. Cardiac magnetic resonance imaging or endomyocardial biopsy are required for definitive diagnosis. Treatment depends on acuity, severity, clinical presentation, and etiology. Approximately 75% of patients admitted with myocarditis have an uncomplicated course, with a mortality rate of approximately 0%. In contrast, acute myocarditis that is complicated by acute heart failure or ventricular arrhythmias is associated with a 12% rate of either in-hospital mortality or need for heart transplant. Approximately 2% to 9% of patients have hemodynamic instability, characterized by inability to maintain adequate end-organ perfusion, and require inotropic agents, or mechanical circulatory devices, such as extracorporeal life support, to facilitate functional recovery. These patients have an approximately 28% rate of mortality or heart transplant at 60 days. Immunosuppression (eg, corticosteroids) is appropriate for patients who have myocarditis characterized by eosinophilic or giant cell myocardial infiltrations or due to systemic autoimmune disorders. However, the specific immune cells that should be targeted to improve outcomes in patients with myocarditis remain unclear.Conclusions and RelevanceAcute myocarditis affects approximately 4 to 14 per 100 000 people per year. First-line therapy depends on acuity, severity, clinical presentation, and etiology and includes supportive care. While corticosteroids are often used for specific forms of myocarditis (eg, eosinophilic or giant cell infiltrations), this practice is based on anecdotal evidence, and randomized clinical trials of optimal therapeutic interventions for acute myocarditis are needed.

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Clozapine and incidence of myocarditis and sudden death – Long term Australian experience

Cited by 42 publications

References 18 publications

A mixed methods analysis of clozapine errors reported to the National Reporting and Learning System

A mixed methods analysis of clozapine errors reported to the National Reporting and Learning System

Morphological and Functional Alterations of the Cardiovascular System during Acute Clozapine Poisoning (Experimental Study)

Diagnosis and Treatment of Acute Myocarditis

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