Progress Report - October 2007

The clozapine study now has 98 patients in the database including:

The 23 confirmed cases are:

• 16 men and 7 women
• Aged 22-58 years, mean 37 years

For 20 cases, the time to onset of myocarditis was 14-21 days.  Two cases were outliers at 26 and 33 days, and for one case the time to onset is unknown.

Two individuals died of clozapine-related myocarditis in the acute phase.  The other 21 recovered.

Emerging pattern

In 20 of the cases, rises in C-reactive protein (CRP) were documented.  Where CRP was determined early in the course of the illness, it was elevated prior to rises in troponin I and commonly to values >100 mg/mL.

Rises in eosinophils to ≥  2 times the upper limit of normal (ULN) were documented in 9 cases.  These rises tended to occur 2-7 days after the peak in troponin I.

Two cases of missed myocarditis?

Two cases that did not meet the case definition because the time to onset was > 45 days, and who developed serious cardiac illness, are of interest. 

Both had rises in eosinophils to > ULN about 3 weeks after starting clozapine.  The cause was not investigated.  Four weeks later one was found to have pericardial effusion of up to 2.5 cm without evidence of left ventricular failure.  The other was admitted after 4 months of clozapine with an ejection fraction of < 20% and died 9 months later.

It may be that both of these cases had undiagnosed myocarditis coinciding with the rise in eosinophils.  Continuing clozapine may have exacerbated their condition.

Excluded cases

The 12 potential cases were excluded because of:

• duration of clozapine > 45 days (n = 3)
• confounding factors (n = 4)
• insufficient documentation (n = 3)
• evidence not fitting the case definition (n = 6)

The confounding factors were possible neuroleptic malignant syndrome in 3 cases and respiratory infection in one case.