Kathlyn J. Ronaldson

A New Monitoring Protocol for Clozapine-Induced Myocarditis Based on an Analysis of 75 Cases and 94 Controls:

Objective: To develop an evidence-based monitoring protocol for clozapine-induced myocarditis. Methods: Potential cases of clozapine-related myocarditis occurring between January 1994 and January 2009 and a comparative group of patients taking clozapine for at least 45 days without cardiac disease were documented from the patients’ medical records. Results: A total of 75 cases and 94 controls were included. Nine cases died. The time to onset was 10–33 days with 83% of cases developing between days 14 and 21 inclusive. At least twice the upper limit of normal troponin was found in 90% of cases, but 5 cases had C-reactive protein more than 100 mg/L and left ventricular impairment by echocardiography without a clinically significant rise in troponin. The proposed monitoring protocol recommends obtaining baseline troponin I/T, C-reactive protein and echocardiography, and monitoring troponin and C-reactive protein on days 7, 14, 21 and 28. Mild elevation in troponin or C-reactive protein, persistent abnormally high heart rate or signs or symptoms consistent with infective illness should be followed by daily troponin and C-reactive protein investigation 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. Conclusion: This protocol recommends active monitoring for 4 weeks, relying predominantly on troponin and C-reactive protein results. It encourages continuation of clozapine in the presence of mild illness, but defines a threshold for cessation.

Risk factors for rhabdomyolysis with simvastatin and atorvastatin.

AbstractObjective: To assess the frequency of risk factors for rhabdomyolysis with simvastatin and atorvastatin in cases reported to the Australian Adverse Drug Reactions Advisory Committee (ADRAC). Design: Reports meeting the definition of rhabdomyolysis were reviewed for risk factors including age ≥70 years, dose ≥40mg, hepatic dysfunction, diabetes mellitus, hyperkalaemia, hypothyroidism and the use of concomitant interacting medications. Results: Only one report associated with simvastatin and five reports associated with atorvastatin did not list any risk factors for rhabdomyolysis. Interacting medicines featured in 77% of reports of rhabdomyolysis associated with simvastatin and 44% of reports associated with atorvastatin.A comparison of the age profile for reports of atorvastatin- and simvastatin-associated rhabdomyolysis with that for all adverse drug reaction reports received, and for all reports of muscle disorders, suggested a trend towards an increasing risk of rhabdomyolysis with increasing age with simvastatin but not with atorvastatin. Similarly, comparing prescribed tablet strengths from Pharmaceutical Benefits Scheme data with the HMG-CoA reductase inhibitor (‘statin’) doses in reports of rhabdomyolysis suggested a dose-related risk with simvastatin, but a less increased risk with high-dose atorvastatin. Conclusion: Risk factors for rhabdomyolysis featured in nearly all of the reports of statin-associated rhabdomyolysis and the majority of reports listed multiple risk factors, although dependence on risk factors appeared to be stronger with simvastatin than atorvastatin. The multiplication of risk factors in patients taking simvastatin and atorvastatin should be minimised.

Clozapine-induced myocarditis, a widely overlooked adverse reaction

We review the published cases of clozapine‐induced myocarditis and describe reasons for the higher incidence in Australia (>1%) than elsewhere (<0.1%).

Clinical course and analysis of ten fatal cases of clozapine-induced myocarditis and comparison with 66 surviving cases

BACKGROUND Fatal clozapine-induced myocarditis has not been investigated systematically. We describe the clinical course of 10 fatal cases of myocarditis with clozapine and identify factors associated with fatality. METHODS Cases of myocarditis were documented from the patients medical records and fatal cases also from autopsy reports. RESULTS The fatal cases of myocarditis occurred 1996-2009 and were diagnosed at autopsy. Before death, three had no symptoms of illness and only three had cardiac-specific diagnostic results. None was investigated by cardiac imaging techniques, and in none was myocarditis suspected before death. Duration of clozapine for the fatal cases was 14-33 days with an outlier at 4.5 months. Only 3 cases had significant coronary artery disease at autopsy. Comparison of these ten cases with 66 non-fatal cases indicated no significant difference in gender, age, smoking status, dose at onset or concomitant sodium valproate. However, obesity (BMI > 30 kg/m2) was significantly more frequent among fatal than non-fatal cases (60% vs. 26%; p < 0.03) and duration of clozapine was significantly longer for fatal cases (20.8 vs. 17.0 days; p < 0.006), after exclusion of one outlier. Creatine kinase (CK) > 1000 U/L was also associated with death (p = 0.0004). CONCLUSIONS Routine monitoring for myocarditis for the first 4 weeks of clozapine, and discontinuation of clozapine in the presence of evidence consistent with myocarditis may assist to prevent fatalities occurring from early-onset myocarditis. Investigation by cardiac imaging will give a measure of severity and need for intervention. Obesity may increase the risk of mortality and CK > 1000 U/L may indicate life-threatening illness.

Observations From 8 Cases of Clozapine Rechallenge After Development of Myocarditis

To the Editor: Clozapine is an exceptionally effective drug for the treatment of schizophrenia,1 but it may occasionally cause myocarditis, typically within 3 weeks of clozapine initiation.2 The effectiveness of clozapine in the individual patient may be manifest before the onset of myocarditis despite its early occurrence, and clozapine withdrawal may lead to rapid deterioration in psychiatric state.3,4 Hence, clozapine rechallenge has considerable appeal. In the course of data collection for a case-control study of clozapineinduced myocarditis, we have documented 8 cases of rechallenge that occurred between 2002 and 2006 and describe them here in an attempt to explore what factors may enhance the likelihood of successful rechallenge.

Clozapine-induced myocarditis and baseline echocardiography.

Australian & New Zealand Journal of Psychiatry, 46(10) 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.

Reporting of adverse events following immunization in Australia

Abstract:  It is an important component of any immunization programme that vaccine safety is monitored by carrying out surveillance for adverse events following immunization (AEFI). Such surveillance can be active or passive. Active surveillance will detect more AEFI, but the vast majority will be minor events. Passive surveillance is probably more appropriate for routine AEFI surveillance, while active surveillance can be used to monitor a new vaccine or to test whether a specific severe event is significantly associated with immunization. Australia has a predominantly passive surveillance system. The system has recently been centralized, providing useful national data on vaccine safety.

The Value of Patient-Centred Registries in Phase IV Drug Surveillance

In the past, postmarketing surveillance of drugs relied mainly on the spontaneous reporting of adverse drug reactions. There are now several other approaches used, including databases with individual prescription data (or prescription event monitoring systems), electronic health records and record linkage between health databases. The recent drug withdrawals have continued to highlight the inadequacies of current postmarketing surveillance and the need for better strategies to monitor the safety of new drugs. One such strategy is the use of drug registries.Drug registries facilitate a special form of prospective observational cohort study of patients exposed to a particular drug. They are particularly useful in establishing the safety of orphan drugs and ascertaining the safety of drugs in specific populations. To minimize bias, patient eligibility is defined and data capture is standardized. All patients are followed up systematically over a pre-defined time period, either manually or using electronic record linkage to other health databases. To establish the incidence of any adverse events using a drug registry, there should be complete follow-up of all patients.Drug registries may play an important role in postmarketing surveillance of new drugs. Unlike spontaneous reporting systems they have the benefit of being able to determine the incidence of one or more outcomes in the patient population. Drug registries do, however, have some limitations, including a potential for bias and confounding, long periods of follow-up and high cost.

Evolution of troponin, C-reactive protein and eosinophil count with the onset of clozapine-induced myocarditis

To the EditorThe frequency of rises in various parameters with clozapine-induced myocarditis has been reported, as well as the observation that rises in C-reactive protein (CRP) anticipate rises in troponin and any rise in eosin-ophil count is typically delayed (Ronaldson et al., 2010, 2011).Data collected for a case–control study (Ronaldson et al., 2012) of myo-carditis developing in patients com-mencing clozapine included all recorded diagnostic data for 109 cases and 299 controls. While no patient had daily diagnostic data, aggregated data could provide a picture of the evolution of troponin, CRP and eosin-ophil counts, including the inter-patient variation in these parameters.Graphical presentation of the evo-lution of CRP, troponin I/T and eosin-ophil count for cases (Figure 1a–c) indicates the range of responses in terms of each of these parameters. In particular, some experience a very marked rise in eosinophil count (to >2.5 × 10

Continuation of clozapine following mild myocarditis

DOI: 10.1177/0004867411433970 In the course of a study of clozapine and myocarditis, we have documented five individuals who met our case definition of myocarditis but yet continued clozapine without long-term cardiac injury. The case definition required clinical evidence, together with cardiac specific diagnostic evidence of myocarditis (Ronaldson et al., 2010). Each of the five (four men and one woman, aged 28–52 years) met the criteria, having tachycardia together with troponin I or T more than twice the upper limit of normal (Table 1). Three also had clinical symptoms of illness. Three had echocardiography around the time of the raised troponin and the result was normal for all three, as was follow-up echocardiography in two individuals. Each of these cases had only mild disease, as measured by troponin concentrations which were between twice and four times the upper limit of normal. However, the degree of the rise in eosinophils for Case 4 and in CRP for Case 5 was suggestive of more severe illness. Two of the cases continued clozapine with no interruption; one had a reduction in dose from 300 to 200 mg/day and two missed 1 or 1.5 days of clozapine and then continued. Acute clozapine-induced myocarditis, including in cases for whom it is asymptomatic or whose laboratory parameters give no indication of severe illness, can be fatal (Ronaldson et al., 2011a). Nevertheless, in some cases it is clearly safe to continue clozapine. Not only is it safe, but continuation of clozapine might also be highly desirable for the long-term mental health of the individual. The data available do not permit a demarcation between truly mild cases