Cardiac Complications of Clozapine Treatment – Assessment and Management
1. Around 9% of patients prescribed with clozapine will develop orthostatic hypotension mainly due to the anticholinergic and anti-alpha-1 blockade, and 6% will go on to cardiogenic syncope.
2. Clozapine causes tachycardia, and 25% of patients with schizophrenia can experience 10-15 beats per minute increase in heart rate, which is usually benign. In normal volunteers, clozapine can also cause bradycardia, of which clinicians should be aware. Clozapine also causes dose-related QT-prolongation.
3. Myocarditis is the most severe problem associated with clozapine. Idiosyncratic IgE hypersensitivity reaction resulting in inflammation in the myocardium is considered to be a likely mechanism.
4. An Australian study evaluated 500 patients with schizophrenia on clozapine to assess the potential for cardiotoxicity [Khan A et al., 2017]. Although myocarditis and sudden cardiac death were uncommon, these complications were clinically meaningful.
- The incidence of sudden death and myocarditis were 2% and 3% respectively.
- The mean time to myocarditis post clozapine commencement was 15±7 days
5. A systematic review of clozapine-induced myocarditis shows a wide variation in incidence (~0.1% up to 8.5% of patients treated) [Bellissima B et al., 2018], and most patients who develop myocarditis do so within the first three months of therapy. Of these, the mortality is quite high, at 21% overall. It is important to rule out alternate causes of myocarditis (viral respiratory infection, autoimmune diseases, giant cell myocarditis, etc.). The main findings were:
The median age of patients and dose of clozapine at presentation was 30years and 250mg/day respectively. Symptoms and signs of myocarditis developed in 87% of patients within the first month of treatment. Clinical presentation included: shortness of breath (67%), fever (67%) and tachycardia (58%). Cardiac markers were elevated in 87% of the 54 cases that reported these markers. Global ventricular dysfunction was the predominant echocardiogram finding (57%).
Another systematic review and meta-analysis of 28 studies (n=258,961) showed the event rate of myocarditis was 0.7%, the absolute death rate was 0.o4% and the case fatality rate was 12.7%. The cardiomyopathy event rate was 0.6%, the absolute death rate was 0.03% and the case fatality rate was 7.8%. [Siskind D et al., 2020]
6. Symptoms and signs of heart failure may not be specific enough for a diagnosis but may include breathlessness, fatigue, ankle swelling, and a raised JVP. Around 50% of patients with heart failure have a normal chest X-ray, normal cardiothoracic ratio, and no signs of pulmonary oedema. An ECG should be carried out, although there is nothing specific to observe other than the ECG is abnormal.
7. A recent ‘guide for psychiatrists written by cardiologists’ [Patel et al., 2019] concluded:
Cardiovascular side-effects of clozapine are rare but include life-threatening myocarditis and dilated cardiomyopathy, but there is no clear evidence that the dose of clozapine has a direct effect on the risk of cardio-toxicity.
Clozapine-induced cardiotoxicity is likely over-reported in the literature with few patients receiving appropriate cardiac investigations. It is possible that this condition is rarer than thought and further, that many patients have therapy discontinued unnecessarily.
Only one protocol for monitoring of clozapine-induced cardiotoxicity exists which recommend baseline troponin, C-reactive protein and transthoracic echocardiogram.
Recommendations varied widely. Some authors recommended baseline laboratory monitoring, with or without follow-up testing, for C-reactive protein, creatine kinase MB, and troponin. Electrocardiography was commonly recommended, and echocardiography was less commonly recommended.
For asymptomatic patients receiving clozapine, testing could include baseline electrocardiography, echocardiography as part of a cardiac consultation if patients have cardiac disease or risk factors, and monitoring of C-reactive protein and troponin as indicated.
9. The mainstay of clozapine-induced cardiotoxicity is consideration of cessation of treatment, specialist review and use of disease-modifying cardiac agents (e.g. ACEI, Beta-blockers etc.). In all cases of fulminant myocarditis or cases where there is new, at least moderate, LV dysfunction, clozapine should be withheld. [Patel et al., 2019]
10. Heart failure cardiologists (but not interventional cardiologists or electrophysiologists) have access to a multi-professional team of professionals. This team can help the patient with up-titration of new medications and provide lifestyle advice for treating heart failure and cardiovascular risk factors, resulting in faster treatment for patients who need the continued benefit of clozapine.
11. Clozapine rechallenge [Patel et al., 2019]: The significant majority of evidence for rechallenge derives from case reports. The success rate of clozapine “re-challenge” following myocarditis in one series was 50–70%. Factors that facilitate rechallenge are
- slower up-titration
- close monitoring
- longer period to re-challenge from discontinuation
- ACE inhibitors have been shown to have a cardio-protective effect in animal studies and may aid clozapine rechallenge and facilitate the continuation of clozapine.
12. Clozapine, Covid-19 and Myocarditis:
Patients with COVID-19 have a higher risk of ( approx 16 times) myocarditis compared with patients without COVID-19. [Boehmer et al., 2021]
The symptoms of myocarditis include fever, flu-like symptoms, fatigue and dyspnoea which have an overlap with symptoms of COVID-19 infection.
Severe Covid illness is also associated with higher levels of troponin-I. Increased levels of cardiac troponin have been correlated with higher rates of CVD complications and mortality (independent predictor of 30-day mortality) in COVID-19 patients. [García de Guadiana‐Romualdo et al., 2021]
It is not known whether clozapine increases the risk of developing viral myocarditis in COVID-19 infection. Patients with underlying cardiac disease, including clozapine-related cardiovascular disease, should be assumed to be at higher risk of adverse outcomes if they contract COVID-19. [Gee et al , 2020]
Recommendations: [Gee et al , 2020]
Promptly investigate all patients in the first 2 months of treatment with clozapine presenting with flu-like symptoms and chest pain to rule out a diagnosis of myocarditis [take C-reactive protein (CRP) and troponin levels; do an antigen test].
Consider the likelihood of myocarditis in all other patients presenting with ‘flu-like symptoms; ensure that the possibility of a diagnosis of COVID-19 does not prevent investigation for other diagnoses.
García de Guadiana‐Romualdo, L., Morell‐García, D., Rodríguez‐Fraga, O., Morales‐Indiano, C., María Lourdes Padilla Jiménez, A., Gutierrez Revilla, J. I., … & Consuegra‐Sánchez, L. (2021). Cardiac troponin and COVID‐19 severity: Results from BIOCOVID study. European Journal of Clinical Investigation, 51(6), e13532.