Clozapine-induced myocarditis and baseline echocardiograms

We read with interest the proposed monitoring protocol for patients starting clozapine therapy recently published by Ronaldson et al. (2011a) in the June 2011 issue of this journal.

While broadly supporting the recommendations, the evidence base for the proposed baseline echocardiogram (‘to exclude pre-existing cardiac dysfunction’) is unclear. Clozapine is contraindicated (in the data sheet) in patients with severe cardiac disorders, which should be evident from clinical assessment. Further, a baseline echocardiogram is neither necessary nor helpful in diagnosing myocarditis should it develop.

According to Kilian et al. (1999), who first described it, clozapine-induced myocarditis is a rare and currently unpredictable hypersensitivity myocarditis. Risk factors are uncertain, although McCormack et al. (2011) notes the genetic basis of carbamazepine hypersensitivity, including myocarditis. It is unlikely to be related to prior cardiac problems. Among ten fatal cases reported by Ronaldson et al. (2011b), only one patient had significant cardiac disease (non-obstructing coronary atheroma, probably an incidental autopsy finding). In Kilian’s series, five patients who died of clozapine-induced myocarditis had autopsies, and none of these had obstructing coronary atheroma.

We agree that the diagnosis of clozapine-induced myocarditis requires a high index of suspicion and concur on the value of recording vital signs, troponin and C-reactive protein (CRP) at baseline and for 4 weeks to facilitate early diagnosis. Once suspicion of myocarditis is aroused, clinical examination and further imaging would be indicated. According to recent myocarditis diagnostic guidelines by Magnani and Dec (2006), the presumptive diagnosis (if made by non-invasive imaging) by echocardiogram, supported by clinical evidence (fever, tachycardia, hypotension, lung crackles, elevated jugular venous pressure), biochemical evidence (CRP, troponins), with or without echocardiogram changes, does not justify prior imaging, as the diagnosis requires only left ventricular dysfunction, not evidence of a change in function. It is rare indeed for patients with myocarditis to have a previous echocardiogram available for comparison purposes, but this doesn’t preclude the diagnosis.

Many drugs can cause a hypersensitivity myocarditis. Requiring a baseline echocardiogram would mean prescribing any one of them would be a significant burden on health service budgets. Until there is evidence that baseline echocardiogram can identify those at particular risk of myocarditis, or improve early detection of this condition, the use of this resource seems unjustified.

Clinical review is the lodestone of identification of myocarditis. Clozapine is often commenced during inpatient care, which offers more opportunity for close clinical monitoring than when mesalazine or phenytoin (also linked with hypersensitivity myocarditis) are initiated in the community.

We therefore suggest that expensive baseline echocardiograms be foregone in place of documentation of a patient’s previous medical (including cardiac) history and a thorough cardiac examination before prescribing clozapine.