Mental illness, antipsychotic medication and cardiac health

1. Mental illness, antipsychotic medication and cardiac health • RCGP’s 6th Health & Justice Summit: Safety through Continuity • Dr Jonathan Bickford. GP Manor Surgery, Oxford & Visiting GP Littlemore Hospital & Broadmoor Hospital. • Dr Simon Modi. Consultant Cardiologist and Cardiac Electrophysiologist, Liverpool Heart and Chest Hospital.

2. Cardiac Morbidity & Current Practice Cardiac Health & Patients • Cardiovascular disease principle cause of premature death in patients with SMI • Death rates in people in contact with mental health services from Cardiovascular Disease are 3.3 times greater than wider population (PHE 2018) • Early onset and raised prevalence of IHD, Stroke & Heart Failure (PHE 2018) • Modifiable risk factors: smoking, obesity & social determinants of health • Action to address cardiovascular disease has the potential for greatest impact on people on mortality rates in SMI (PHE 2018) One of the largest HEALTH INEQUALITIES in the UK. Cardiac Health & Clinical Practice • Dyslipidaemia, Hypertension & Diabetes in SMI receive less interventions than wider population (Cooper et al, 2016) • Primary care incentives promoting physical primary care incentives promoting physical health reviews in people with SMI have improved identification but not treatment of cardiovascular risk factors (Wilson et al, 2017) • ECG screening for Sudden Cardiac Death in patients taking antipsychotic medication • Side effects of antipsychotic medication (in particular clozapine induced tachycardia)

3. Antipsychotic Medication • Long term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use (Tiihonen et al 2009). Mortality rates highest without antipsychotic medication. • Published & established data linking the typical antipsychotic drugs to an increased risk of sudden cardiac death (SCD) • Historical case reports: thioridazine, pimozide & chlorpromazine (& haloperidol) • Atypical antipsychotics 1. Sertindole clinical trials stopped secondary to SCD, 2. Ray et al NEJM 2009. Observational controlled epidemiological study using Medicaid data, incident rate rati0 of SCD 2.26. Dose related association. 3. Case reports (Small numbers and associated with comorbidities) • APA review of the above (Leiberman et al 2010):  do not endorse policy of routine serial measurement of the QTc interval in all patients initiating treatment with antipsychotic medication

4. The QT Interval • With the exception of clozapine a ‘routine’ ECG is taken specifically and only to record the QT interval in patients taking antipsychotic medication • The QT interval represents the period from onset of depolarisation to completion of repolarisation of the ventricular myocardium • Wide normal physiological variation in QTc interval: QT varies with gender, time of day, food intake, alcohol intake, menstrual cycle, ECG lead • Lack of consensus on how to measure (QT ‘corrected’) and significant interindividual and ECG machine variation in figures (DTB 2016, Kligfield et al 2014).

5. Torsades de Pointes • Torsade de pointes is a ventricular tachyarrhythmia, usually self limiting but associated with sudden cardiac death • Prolonged QTc increases the risk of Torsade de Pointes • Antipsychotic medications associated with a (varying degree) of QTc Prolongation • The QTc generally has low specificity for predicting arrhythmias (APA 2010) • Although prolongation of the QTc is the best available clinical surrogate for the development of TdP, it is an imperfect biomarker (APA 2010) • There is no evidence that atypical antipsychotic medication is associated with TdP*. The pathophysiology of SCD is assumption. • There is no other means to screen for SCD with antipsychotic medication HENCE QT interval used as screening as a risk for the development of TdP because this in turn increases the risk of SCD

6. ‘Routine’ ECG guidance & policies • Maudsley Guidelines (2018): ECG monitoring is essential for all patients prescribed antipsychotics. ‘On admission’ and annually. • NHSE 2018: (commissioned) annual physical health assessment to include ‘ECG if indicated’ as part ‘medicines reconciliation and review’. • The Scottish Intercollegiate Guidelines Network, Management of Schizophrenia (2013), similarly states that physical health assessment should include ‘ECG as clinically indicated’ • NICE (2009 & 2014): Before starting antipsychotic medication, offer if: specified in the summary of product characteristics (SPC) a physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure) there is a personal history of cardiovascular disease or the service user is being admitted as an inpatientPsychosis and Schizophrenia • Clinical Knowledge Summary, NICE (2015) suggests a clinically indicated approach to ECG monitoring as part of the physical health assessment (if risk factors). • British Association for Psychopharmacology (2011) likewise recommend a clinically indicated approach with no reference to undertaking ECG screening on admission without the presence of risk factors • APA (2010): For thioridazine, mesoridazine, pimozide or, in the presence of cardiac risk factors, ziprasidone, and with the addition of other meds which can affect QTc. NB no policy endorsing the routine serial measurement of the QTc interval in all patients on treatment with antipsychotic medication • US product labelling for atypical antipsychotic medication does not state pre-treatment ECG is necessary (except clozapine).

7. Current practice • Only (routine) ECGs if taking antipsychotic medication (!) • ECGs within 72 hrs of admission (audit forensic services 2017: 44%) and at CPAs (ECG at least annually). Waiting list for ECGs > 100. • 6 month period 31 referrals to Cardiology 258 patients (West London NHS Trust) . Mainly incidental findings, none related to QTc • High number of Echo referrals secondary to incidental findings. NAD • Literature: Occurrence of QT prolongation is low. 1 (QTc 490)case in 452 patients taking APDs. None > 500. (Novotony et al)

8. Audit of ECG monitoring

9. Summary • Maudsley 2018: In the absence of conclusive data, assume all antipsychotics are linked to sudden cardiac death • QTc prolongation is associated with atypical antipsychotic medication • QTc prolongation is associated with TdP, but to what degree is unclear. • There is no evidence that atypical antipsychotic medication is associated with TdP • ?ECG monitoring reduces rate of SCD: there are no prospective studies. There is no figure for Number Needed to Screen to prevent a SCD. False +ve & False -ve • ?ECG monitoring is cost effective • There is no evidence to demonstrate that other such potential mechanisms of sudden death are identified by ECG screening • SCD is not predictable (in patients taking antipsychotics or otherwise) • Real risk but current practice not evidenced based, inefficient and in some cases not necessary. • Associated cardiovascular risk factors in SMI are the principle cause of the raised risk of SCD (Polcwiartek et al 2016)

10. Personalised risk assessment • Genetic : Congenital Long QT Syndromes. Is there a FH of sudden death < 40 years old? Is there a history of syncope? 16,000 screening ECGs are needed to identify a single asymptomatic case (DTB 2016). • Medication Related. Medicines reconciliation. Does the proposed APD have an established risk of TdP and / or SCD? • Individual factors & concurrent morbidity. ConsiderIschaemic Heart Disease, hypertension, arrhythmias, electrolyte abnormalities. Consider safe practice to start APD without pre-treatment and annual ECGs if the above do not apply? (Shah et al 2014)

11. When to stop antipsychotic medication? When to refer to Cardiology?APA, FDA & American College of Cardiology: An absolute QTc interval of >500 msec or an increase of 60 msec from baseline may be associated with an increased risk of TdP (Haddad and Anderson, 2002) and should prompt reduction or discontinuation of the offending agent.Maudsley Guidelines 2018:

12. QTc recording without a 12 lead ECG

13. Individual antipsychotic drugs and QTc

14. Drugs associated with prolonged QTc

15. Individual risk factors associated with QT prolongation

16. Antipsychotic induced tachycardia?association with cardiomyopathy and coronary artery disease

17. Tachycardia-induced Cardiomyopathy Cardiomyopathies are heart muscle disorders in the absence of underlying structural heart disease Probably under diagnosed phenomenon Predisposed if occurs in presence of underlying structural heart disease Untreated it is associated with LV dilitation, loss of myocardial contractility, heart failure and sudden cardiac death (probably through abnormalities in repolarisation re prolonged QT and in turn VT) Rate dependent, higher the rate the earlier the presentation Treatment is heart rate normalisation, ideally termination of the arrhythmia or otherwise rate control Most are reversible hence recognition critically important, can take up to 1 year for normalisation SinusTachycardia-induced cardiomyopathy? Case studies only Resting Sinus Tachycardia is a risk factor for Coronary Artery Disease

18. Antipsychotic–Induced Sinus Tachycardia Clozapine: only drug with established efficacy in treatment-resistant schizophrenia Associated with reduction in mortality rates compared with other antipsychotics. Despite safety concerns and side effects. 25% prevalence of tachycardia, sometimes symptomatic Causes discontinuation in 4% of clozapine users (Davis 2014) Sinus Tachycardia should not be a cause for discontinuation (Nielson 2013) Cochrane review 2016: insufficient data to inform clinical practice There are no trials that compare interventions for treatment NHSE standard for annual physical health assessments 2018: ‘must include’ a blood pressure and pulse check (though to ‘promote rapport’!) Complicates interpretation of QTc (probably overestimates QTc, using Bazett’s formula) Literature references to cardiomyopathies associated with clozapine use.

19. For discussion • Should we control heart rate? • Risk of coronary artery disease, cardiomyopathy and HF? • At what rate? • Which medication? Current practice is cardio-selective beta blocker. Ivabradine? • Significance of pre-treatment ECG findings, eg, AF, ST changes, Q waves • Exercise and tachycardia • Orthostatic hypotension & Myocarditis

20. Conclusions • Antipsychotics reduce mortality and other wide benefits • Consider carefully before stopping or reducing dose in light of routine ECG findings or other cardiovascular side effects. • Cardiovascular disease is principle cause of morbidity and mortality • Efforts to address prevention and treatment should focus upon evidence based practice • Evidence that routine ECGs are effective screening is lacking. • Investigations and surveillance should be targeted to those with raised risk.