A D O N I S S F E R A , M D

I N C I D E N C E O F C L O Z A P I N E I N D U C E D C A R D I O M Y O PA T H YT R E N D S I N C L O Z A P I N E P R E S C R I B I N G

C A R D I O VA S C U L A R A D V E R S E E F F E C T S O F C L O Z A P I N ET I P S F O R C L I N I C I A N S

Clozapine and its Cardiac Adverse Effects: Myocarditis

and Cardiomyopathy

Clozapine a Complex Drug

Who Gets Clozapine?

Patients who have had a suboptimal response to adequate trials with two first line antipsychotics (haloperidol, loxapine, perphenazine, quetiapine, risperidone).

An adequate trial to determine clozapine’s effectiveness is 3-6 months.

Recommendations for Antipsychotic Selection in Schizophrenia and Schizoaffective Disorders, June 2012, Medical Advisory Panel.

Cardiomyopathy and Myocarditis Associated With The Use of Clozapine in US

Between the US approval of clozapine in September of 1989 and December 2, 1999, the FDA received reports of 28 cases of myocarditis, including 18 deaths, and 41 cases of cardiomyopathy.

N Engl J Med 2001;345:224-225, July 19, 2001 DOI:10.1056/NEJM2001071934550317

Incidence of Myocarditis or Cardiomyopathy in Clozapine Treated Patients

Clozapine is associated with a low risk (0.015%-0.188%) of potentially fatal myocarditis or cardiomyopathy

Merrill DB, Dec GW, Goff DCJ Clin Psychopharmacol. 2005 Feb;25(1):32-41. Adverse cardiac effects associated with

clozapine.

Trends in Clozapine Prescribing

The percentage of schizophrenia patients receiving clozapine rose from 9.0% in 1996 to 10.1% in 2007 (p<0.001).

In the same period, the percentage of patients having clozapine treatment augmented with another antipsychotic increased from 43.1% to 64.2%, p<0.001.

Psychiatrists More Hesitant to Prescribe Clozapine

Although, the percentage of schizophrenia patients receiving clozapine increased from 1996 to 2007, the time from diagnosis of schizophrenia until first prescription of clozapine increased.

Etiology of Clozapine Induced Myocarditis

Inflammation: Noting that clozapine increases inflammatory cytokines, some authors believe TNF-alpha and other inflammatory cytokines contribute to myocarditis.

Allergy: The common presence of peripheral eosinophilia on autopsy—including diffuse eosinophilic infiltrates in myocardial and perivascular areas—might suggest a hypereosinophilic syndrome mediated by clozapine.

Toxicity: direct toxic effect on cardiac myocytes related to impaired clozapine metabolism in some patients

Histopathological Features of Clozapine Induced Myocarditis

Myocytolysis and necrosis with florid infiltrate, consisting of lymphocytes, neutrophils, and prominent eosinophils (red granular cytoplasm with bilobed nucleus).

Cardiovascular Adverse Effects of Clozapine

Tachycardia – caused by anticholinergic activity

Orthostatic Hypotension – alpha adrenergic blockade

Myocarditis Cardiomyopathy Pericarditis

TIPS FOR CLINICIANS

At present there is no proven method for either predicting or preventing the development of myocarditis (a new protocol might be introduced).

Patients who have persistent tachycardia at rest, especially during the first two months of treatment, should be closely observed for other signs or symptoms of myocarditis or cardiomyopathy. These include palpitations, arrhythmias, symptoms mimicking myocardial infarction, chest pain and other unexplained symptoms of heart failure.

Patients in whom myocarditis or cardiomyopathy is suspected should stop clozapine and undergo urgent diagnostic evaluation by a cardiologist.

Patients with clozapine-induced myocarditis or cardiomyopathy must not be re-exposed to clozapine.

More Tips

Flu-like symptoms: unexplained fever, fatigue, lethargy Chest discomfort (often vague, or angina pectoris), palpitations Respiratory symptoms: tachypnea, dyspnea, orthopnea, paroxysmal nocturnal

dyspnea Abnormal vital signs: hypotension, narrowed pulse pressure, persistent resting

tachycardia Cardiovascular signs: raised jugular venous pressure, presence of a third or fourth

heart sound, pericardial friction rub, muffled first heart sound, mitral or tricuspid regurgitation, peripheral edema

Respiratory signs: crackles on auscultation ECG changes: sinus tachycardia, atrial or ventricular arrhythmias, left ventricular

hypertrophy, diffuse nonspecific ST-segment and T-wave abnormalities, low voltage and intraventricular conduction defects

CXR changes: possible cardiac enlargement, pulmonary venous congestion, pulmonary edema

Blood work changes: hypereosinophilia Many of these signs and symptoms are nonspecific, but if any occur in a clozapine-

treated patient, especially if the onset is sudden or unexpected, suspicions should be raised followed by prompt cardiologic assessment.

A New Monitoring Protocol For Clozapine-Induced Myocarditis

A study published in Australia in 2011 showed the following: -in 90% of patients troponin was increased at least twice -5 cases had C-reactive protein more than 100 mg/l

Proposed Protocol:Baseline troponin I/TC reactive protein on days 7, 14, 21 and 28Echocardiography (baseline).

Mild elevation in troponin or C-reactive protein, persistent tachycardia or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein values until features resolve.

Cessation of clozapine is advised if troponin is more than twice the upper limit of normal or C-reactive protein is over 100 mg/l.

Combining these two parameters has an estimated sensitivity for symptomatic clozapine-induced myocarditis of 100%.

The sensitivity for asymptomatic disease is unknown.

Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, McNeil JJ; A new monitoring protocol for clozapine-induced myocarditis based on an analysis of 75 cases and 94 controls; Aust NZ J Psychiatry; 2011 Jun;45(6)458-65 Epub 2011 Apr 27.

Transthoracic echocardiograms demonstrating enlargement of the left ventricle

(A) Short axis parasternal view showing dilation of both the left ventricle and atrium. (B) Long axis parasternal view demonstrating enlargement of the cardiac chambers. Abbreviations: LA, left atrium; LV, left ventricle, RA, right atrium; RV, right ventricle.

Makhoul B et al. (2008) Dilated cardiomyopathy: an unusual complication of clozapine therapyNat Clin Pract Cardiovasc Med doi:10.1038/ncpcardio1292

Future Screening

The level of B-type natriuretic peptide, a hormone secreted in response to ventricular wall stress, may be useful for evaluating patients with clozapine-induced cardiac dysfunction and may in the future be useful for screening asymptomatic patients.