The ABCs of Cardiac Screening and Electrocardiography

February 24, 2021
Margo C. Funk, MD, MA

,
Theodore A. Stern, MD

Dr Stern is the Ned H. Cassem Professor of Psychiatry in the field of Psychosomatic Medicine/Consultation at Harvard Medical School and Massachusetts General Hospital.

This comprehensive approach for assessing and addressing potential cardiac complications before prescribing psychotropics can enhance care.

SPECIAL REPORT: PSYCHOCARDIOLOGY

Psychiatrists prescribe many medications that are associated with cardiovascular risks, and they treat many individuals who have cardiovascular disease and take cardioactive agents. Unfortunately, adverse cardiac effects of psychotropics are wide ranging. They include electrical abnormalities (eg, conduction system abnormalities, tachyarrhythmias, and sudden cardiac death) and structural abnormalities (eg, ischemia, myocarditis, and heart failure).

The 12-lead electrocardiogram (ECG) is a common method for assessing functional and structural heart disease. Given the prevalence of cardiac disease and the frequency with which psychotropics can create cardiac adverse effects, psychiatrists should be proficient in the safe administration of medications that require ECG screening. Safe psychiatric practice dictates that a comprehensive personal and family history of cardiovascular disease is obtained before psychotropics are prescribed.

Psychiatrists should be able to recognize components of the ECG, measure specific intervals between waveforms (such as the QT interval), and decide whether (and for whom) medications are safe. Lastly, psychiatrists should understand the electrophysiologic effects of certain psychotropics so they can make informed decisions based upon the ECG findings, including dose adjustments, medication discontinuation, or referral for cardiology consultation.

When prescribing many common medications, clinicians should consider an ECG, along with the following questions: When should I order an ECG before starting a patient on a psychotropic medication? What categories of cardiac effects are associated with which medication classes? What electrophysiologic abnormalities should be identified on the ECG? Which ECG abnormalities make prescribing certain psychotropic medications problematic (Table)?

Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are sodium channel blockers with cardiac effects that closely resemble those of other class I antiarrhythmic medications. TCAs primarily delay cardiac conduction (through the His bundle), increase heart rate (via anticholinergic adverse effects), and cause orthostatic hypotension (via alpha blockade). Adverse cardiovascular events may also include hypertension, myocardial infarction (MI), and stroke. In healthy adults, TCAs typically lack significant cardiac effects when taken as prescribed. However, TCAs should be avoided in individuals with preexisting ventricular conduction delay ([VCD], most commonly a bundle branch block), Brugada syndrome, or ischemic heart disease (coronary artery disease including MI, history of percutaneous coronary intervention, or coronary artery bypass grafting), as TCAs confer an increased risk of symptomatic rhythm disturbances, mortality, and sudden cardiac death.1-3 Use of TCAs in the period following acute MI is contraindicated by the US Food and Drug Administration (FDA).1

Although no guidelines exist for using electrocardiographic screening and monitoring when prescribing TCAs, it is standard practice to obtain an ECG before prescribing a TCA to rule out unrecognized VCD or ischemic heart disease, especially in individuals aged 40 or older.4 Older adults who are prescribed a TCA should undergo cardiac and blood pressure monitoring on a regular basis.1

Stimulants

Stimulant medications are sympathomimetic amines that increase resting heart rate and systolic blood pressure. Cases of sudden death, MI, and stroke have been reported in both children and adults with concurrent use of stimulants.5 Package insert labeling on all stimulants warns of serious cardiovascular events in children, adolescents, and adults with structural cardiac abnormalities, cardiomyopathy, heart rhythm abnormalities, coronary artery disease, or other serious heart problems.6 All patients being considered for treatment with a stimulant should have a personal and family cardiac history collected and a physical exam performed. Screening positive for any cardiac issues requires further evaluation by cardiology, which may well include an ECG and echocardiogram.

Baseline ECG screening by psychiatrists for patients without a history of cardiac disease is controversial, especially in children. In 2008 the American Heart Association (AHA) recommended obtaining an ECG for all children before initiating treatment with a stimulant or atomoxetine. Later that year, the American Academy of Pediatrics (AAP) recommended against obtaining a baseline ECG, citing concern that the requirement for ECG screening may be a prohibitive public health barrier.7,8 Following these divergent recommendations, a joint statement by the AHA and AAP later that year advised that ECG screening in the absence of known cardiac disease is optional and should be based on the physician’s judgment. The joint statement was later revised to read that it is reasonable to obtain a pretreatment ECG.9

In a large 2011 study of children and young to middle-aged adults on medications for attention-deficit/hyperactivity disorder, researchers did not find an association between current stimulant use and an increased risk for serious cardiovascular events.10,11 The data remained mixed across age groups; in adults 55 years or older, use of stimulants may worsen existing cardiac disorders. All patients treated with stimulants should have their heart rate (HR) and blood pressure (BP) monitored regularly. For children and young to middle-aged adults, it is reasonable to obtain a screening ECG (if available) before initiating treatment. For geriatric patients, a pretreatment ECG with twice-yearly HR and BP monitoring is recommended.12

Clozapine

Psychiatrists are typically trained to obtain an ECG before starting clozapine because of the risk of death associated with clozapine-associated myocarditis, clozapine-associated cardiomyopathy, and subclinical clozapine-associated cardiotoxicity.13 Clozapine- associated myocarditis is an inflammation of the myocardium; its etiology is unclear but may be due to a type 1, immunoglobulin E–mediated acute hypersensitivity reaction to clozapine.14 Clozapine-associated myocarditis is best diagnosed through detection of clinical signs and symptoms, ECG changes, abnormal cardiac biomarkers, and results of cardiac imaging (eg, echocardiography and cardiac magnetic resonance imaging).

An endomyocardial biopsy remains the gold standard for diagnosing myocarditis; since it is an invasive procedure, its use is limited due to the inherent risk of complications. Clozapine-associated cardiotoxicity is a disorder of dysfunctional myocardial contractility that results in a reduced left-ventricular ejection fraction (EF). The diagnosis of clozapine-associated cardiotoxicity is supported by a reduced EF (< 50%) and an increased B-type natriuretic peptide (BNP).15 Subclinical clozapine-associated cardiotoxicity is typically asymptomatic; however, it includes paroxysmal atrial fibrillation and mild left ventricular/biventricular functional impairment. Echocardiography and elevation of N-terminal pro-BNP are helpful in the diagnosis of subclinical clozapine-associated cardiotoxicity.13

Most cases of clozapine-associated myocarditis, clozapine-associated cardiotoxicity, and subclinical clozapine-associated cardiotoxicity occur in patients without cardiac disease or other medical risk factors. In these cases, the utility of obtaining a baseline electrocardiography is controversial. An ECG is not required before initiating clozapine. Ordering an ECG must be balanced against the availability of resources in treatment settings, which may not have ready access to electrocardiography.15,16 Clear protocols for monitoring myocarditis and cardiomyopathy in patients treated with clozapine patients are lacking.13

Several studies have demonstrated that most cases of myocarditis occur in the first 4 weeks of treatment. Consequently, some investigators have suggested that levels of troponins and C-reactive protein should be obtained, and ECGs should be monitored at baseline and weekly for the first 4 weeks (being mindful of > 1 mm ST segment depression or T-wave inversion in 2 or more contiguous leads, other than lead aVR).17,18 Other investigators have suggested that ECG monitoring should be completed only if symptoms arise that are concerning for myocarditis (eg, dyspnea, palpitations, tachycardia, mild or moderate fever, influenza-like symptoms, nausea, dizziness, and chest discomfort) or cardiomyopathy (eg, dyspnea, tachycardia, palpitations, chest pain, and fatigue) or if a patient presents to the hospital for a medical concern.13,15,16

When resources allow, clinicians should consider a conservative approach to clozapine and should obtain a baseline ECG and a weekly ECG in addition to laboratory monitoring during the first 4 weeks of treatment. However, this conservative approach should not preclude treatment when it is outweighed by the risk of psychiatric morbidity in a high-risk psychiatric population.

QTc-Prolonging Psychotropics

Psychiatrists routinely prescribe psychotropic medications that prolong cardiac repolarization, thereby increasing the risk for torsades de pointes (TdP), a potentially fatal cardiac arrhythmia. The corrected QT (QTc) interval on the ECG is the most widely accepted indicator of TdP risk and a major drug-safety benchmark.

In 2020, the American Psychiatric Association (APA) Council on Consultation-Liaison Psychiatry and the American College of Cardiology (ACC) published an official action paper, “QTc Prolongation and Psychotropic Medications.”19 This expert work group developed clinical guidelines for practicing psychiatrists. The guidelines addressed cardiovascular risk and monitoring for psychotropics that could increase the risk of TdP. One of the most important considerations was that there was no absolute maximum QTc levelat which a QTc-prolonging medication should not be prescribed.

Most cases of TdP occur when the QTc is greater than 500 milliseconds. This is routinely used as a cutoff point, above which the risk of cardiac complications substantially increases, even in the absence of other risk factors. Physicians must perform a comprehensive risk-benefit analysis, weighing the cardiac risk of prescribing a drug against the risk of psychiatric destabilization if the drug is not prescribed. Physicians must also consider other risk-mitigation strategies and request consultation from other specialties as applicable. When prescribing a medication that may prolong the QTc interval, recommendations for obtaining a baseline ECG as a screening test are highly variable and dependent on use of other drugs. (For a detailed assessment of QTc prolongation and risk of TdP, please see “Understanding the QTc: Issues for Psychiatrists” online.)

ECG Interpretation

It is critical for psychiatrists to establish adequate knowledge of and comfort with electrocardiographic abnormalities, such as QTc prolongation. Psychiatrists must learn to recognize when other abnormalities, like VCD or remote ischemia, should preclude prescription of a psychotropic medication. Psychiatrists should, and will, be looked on as complex psychopharmacology experts and must be comfortable understanding associated levels of cardiac risk.

Regarding the role of psychiatrists in ECG interpretation, 2 additional themes emerged from the 2020 APA action paper on QTc prolongation. First, there was an expectation that basic ECG interpretation is within the scope of a psychiatrist. A 2001 clinical competence statement on electrocardiography by the ACC and AHA recognized that physicians who are not formally trained in ECG interpretation may provide preliminary interpretations, especially in time-sensitive clinical scenarios or in the absence of a formally trained ECG interpreter.20

The second theme suggested that we should support, educate, and empower psychiatrists to develop competence in ECG interpretation. The ACC/AHA competence statement advised that physicians of any specialty whose interpretations contribute to clinical decision-making should be able to “define, recognize, and understand the basic pathophysiology of certain electrocardiographic abnormalities.”20 Unfortunately, psychiatrist competency and comfort with ECGs vary significantly, especially beyond the practice of consultation-liaison psychiatry and tertiary hospital settings. The training of psychiatrists in ECG interpretation represents a unique and much-needed opportunity for future program and curricular development.

Concluding Thoughts

It is essential for psychiatrists to be knowledgeable about the cardiac effects of psychotropic medications and to know when to consider pretreatment ECG screening. When prescribing TCAs, stimulants, clozapine, and high-risk QTc-prolonging medications, psychiatrists must perform a thorough personal and family history of cardiac disease and obtain an ECG or cardiology consultation when indicated. Premorbid cardiac conditions, specifically VCD, ischemic heart disease, and risk factors for TdP including concurrent QT-prolonging medications, electrolyte disturbance and bradycardia should prompt increased vigilance.

Dr Funk is the program director of the Harvard South Shore Psychiatry Residency Training Program in the US Department of Veterans Affairs. Dr Stern is the Ned H. Cassem Professor of Psychiatry in the field of Psychosomatic Medicine/Consultation at Harvard Medical School and Massachusetts General Hospital.

References

1. Pamelor. Prescribing information. Mallinckrodt Pharmaceuticals; 2019. Accessed December 23, 2020. https://www.mallinckrodt.com/products/brands/central-nervous-system-products/pamelor-nortriptyline-hcl-capsules-usp-50-mg/

2. Glassman AH, Roose SP, Bigger JT Jr. The safety of tricyclic antidepressants in cardiac patients: risk-benefit reconsidered. JAMA. 1993;269(20):2673-2675.

3. Glassman AH. Cardiovascular effects of antidepressant drugs: updated. J Clin Psychiatry. 1998;59(suppl 15):13-18.

4. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60(11):1524-1534.

5. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med. 2006;354(14):1445-1448.

6. Ritalin. Prescribing information. Novartis Pharmaceuticals Corporation; 2019. Accessed December 23, 2020. https://www.novartis.us/sites/www.novartis.us/files/ritalin_ritalin-sr.pdf

7. Hammerness PG, Perrin JM, Shelley-Abrahamson R, Wilens TE. Cardiovascular risk of stimulant treatment in pediatric attention-deficit/hyperactivity disorder: update and clinical recommendations. J Am Acad Child Adolesc Psychiatry. 2011;50(10):978-990.

8. Chen CY, Bussing R, Hartzema AG, et al. Stimulant use following the publicity of cardiovascular safety and the introduction of patient medication guides. Pharmacoepidemiol Drug Saf. 2016;25(6):678-686.

9. Vetter VA, Elia J, Erickson C, et al; American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee; American Heart Association Council on Cardiovascular Nursing. Cardiovascular monitoring of children and adolescents with heart disease receiving medications for attention deficit/hyperactivity disorder [corrected]: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young Congenital Cardiac Defects Committee and the Council on Cardiovascular Nursing. Circulation. 2008;117(18):2407-2423.

10. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896-904.

11. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683.

12. Michielsen M, Kleef D, Bijlenga D, et al. Response and side effects using stimulant medication in older adults with ADHD: an observational archive study. J Atten Disord. Published online June 8, 2020.

13. Kanniah G, Kumar S. Clozapine associated cardiotoxicity: issues, challenges and way forward. Asian J Psychiatry. 2020;50:101950.

14. Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyopathy associated with clozapine. Lancet. 1999;354(9193):1841-1845.

15. Curto M, Girardi N, Lionetto L et al. Systematic review of clozapine cardiotoxicity. Curr Psychiatry Rep. 2016;18(7):68.

16. Freudenreich O. Clozapine-induced myocarditis: prescribe safely but do prescribe. Acta Psychiatr Scand. 2015;132(4):240-241.

17. Ronaldson KJ, Taylor AJ, Fitzgerald PB, et al. Diagnostic characteristics of clozapine-induced myocarditis identified by an analysis of 38 cases and 47 controls. J Clin Psychiatry. 2010;71(8):976-981.

18. Munshi TA, Volochniouk D, Hassan T, Mazhar N. Clozapine-induced myocarditis: is mandatory monitoring warranted for its early recognition? Case Rep Psychiatry. 2014;2014:513108.

19. Funk MC, Beach SR, Bostwick JR, et al. QTc prolongation and psychotropic medications. Am J Psychiatry. 2020;177(3):273-274.

20. Kadish AH, Buxton AE, Kennedy HL, et al. ACC/AHA clinical competence statement on electrocardiography and ambulatory electrocardiography. a report of the ACC/AHA/ACP-ASIM Task Force on Clinical Competence (ACC/AHA Committee to Develop a Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography). J Am Coll Cardiol. 2001;38(7):2091-2100.❒