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Myocarditis in the Setting of Cancer Therapeutics

Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.118.034497Circulation. 2019;140:80–91

    Abstract

    Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.

    The evolution of cancer therapy over the last decade has brought rapid advancement and improved outcomes. At the same time, therapies targeting specific pathways or harnessing the immune system have been associated with cardiovascular toxicities.1–3 One emerging toxicity is myocarditis. Most recently, this clinical entity has been observed in the setting of immune checkpoint inhibitors (ICIs). However, myocarditis has the potential to be associated with any therapy that modulates the immune system.4,5 The association between ICIs and myocarditis has largely been appreciated in the clinical realm rather than in the pivotal trials that led to the approval of ICIs. Identifying myocarditis in clinical trials may be challenging because of both low event rates but also the reliance on site reporting without standardized end point definitions. In this article, we discuss the observed association between ICIs and myocarditis to construct a conceptual framework for the proposal of a case definition for myocarditis to be applied prospectively in clinical trials. This definition is proposed to facilitate systematic ascertainment and consistent reporting across trials. While it is framed around ICI therapy, this definition is introduced as an option for any drug-induced myocarditis. The proposed case definition is intended for the identification of myocarditis in clinical trials, and as such favors specificity over sensitivity to reduce noise and improve the ability to characterize differences according to treatment. This is not intended for clinical use in which a different balance of sensitivity and specificity may be favored. In addition, it should be noted that the definitions presented are based largely on expert opinion.

    Myocarditis Associated with ICI

    In 2018, the Nobel prize in physiology and medicine was awarded jointly to Drs James Allison and Tusuku Honjo for their discovery of cancer therapy by inhibition of negative immune regulation (immune checkpoints). Indeed, ICIs have dramatically improved cancer treatment outcomes. These therapies target the host negative immune regulators (checkpoints), thus leading to activation of the immune system against the patient’s cancer cells.6 In the last 7 years, a total of 7 different ICIs have been approved, including PD-1 (programmed cell death-protein 1) inhibitors (anti PD-1 antibodies: nivolumab, pembrolizumab, cemiplimab), PD-L1 (programmed cell death-ligand 1) inhibitors (anti PD-L1 antibodies: atezolizumab, avelumab, durvalumab), and CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4) inhibitors (anti CTLA-4 antibodies: ipilimumab) with several more such therapies pending approval. Increasingly, ICIs are being either combined (eg, use of ipilimumab plus nivolumab) or combined with other cancer therapies in upcoming clinical trials. Early data suggest further benefit and improved clinical outcomes when ICIs are used in combination.7–9 There is emerging appreciation of toxicities from ICIs that stem from activation of autoreactive T cells damaging host tissues and causing immune-related adverse events in several organs including colon, liver, lungs, pituitary, thyroid, skin, and other organs.10,11 These toxicities are more frequent when combination therapies involving ICIs are delivered.

    In 2016, Johnson et al4 reported 2 cases of fulminant myocarditis shortly after combination ICI treatment, described the incidence of myocarditis in a retrospective clinical trial population, and defined basic clinical and pathophysiological characteristics of the syndrome. Since this publication, several case series have added to the growing appreciation of this new clinical syndrome.12–14 An interrogation of individual case safety reports from publicly available databases indicate substantially increased reporting of ICI-associated myocarditis by health care providers in 2017.13 The current data suggest that only severe cases are being identified and reported in the literature.15 Early data also suggest that ICIs may be associated with other cardiovascular immune-related adverse events including pericarditis and vasculitis.16 Takotsubo syndrome, which may resemble myocarditis, has also been reported in association with ICIs.17 The concomitant presence of other immune-related adverse events (specifically myositis and myasthenia gravis) with ICI-associated myocarditis may further raise the suspicion of ICI-associated myocarditis.18 The possibility of other cardiovascular immune-related adverse events broaden the differential diagnosis for the treating clinician. With increasing recognition of this new clinical syndrome, it will be important to identify less severe cases to appropriately document the full spectrum of the condition and ascertain the true long-term outcomes.

    Explosion of Cancer Immunotherapies and Risk of Myocarditis

    The success of ICIs have propelled the introduction of other means of enhancing the immune response against tumor cells. In 2019, immuno-oncological therapies include a broad range of agents including antibodies, vaccines, adjuvant therapies, cytokines, modified antibodies, and cellular therapies.19 Genetically engineered T cells, whereby the specificity of T cells are augmented with the use of gene-transfer techniques, represent an important and effective new class of therapies. Chimeric antigen receptors redirecting the specificity, function, and metabolism of T cells, have been approved for several indications.20–22 However, like ICIs, other forms of immunotherapies can lead to cardiovascular toxicities. These may include less specific clinical syndromes of fevers, hypotension, and hypoxia (cytokine release syndrome). On the other hand, more specific cardiovascular toxicities may be observed. For example, the use of genetically modified T cell receptors against a cancer antigen (MAGE-A3, melanoma-associated antigen 3) led to fatal cardiogenic shock as a result of myocarditis. Subsequent work-up revealed cross-reactivity of the T cells with titin, a myocardial protein.23,24 The explosion of these immune-related therapies in oncology clinical trials underscores the need to better define myocardial toxicities including myocarditis.

    Proposed Definition of Myocarditis in Clinical Trials

    General Considerations

    Myocarditis should be diagnosed in the setting of acute cardiac conditions without an alternative primary diagnosis (eg, acute coronary syndrome, trauma, etc). Therefore, consideration of these other conditions should be assessed before myocarditis in a hierarchical fashion. On the other hand, evidence of myocardial dysfunction and myocardial injury should be ascertained and accounted for even if not meeting a formal definition for myocarditis because these outcomes may represent subacute forms of myocarditis. Therefore, a high level of awareness and vigilance should be present for myocarditis. In addition to adjudicating the outcome of myocarditis, adjudicators should consider characterization by clinicopathologic classification. Moreover, timing of presentation relative to exposure to investigational therapy should be considered when relatedness of myocarditis is considered. Myocarditis related to ICIs can develop soon after ICI administration.13,14 A general framework for consideration of myocarditis is presented in Figure 1.

    Figure 1.

    Figure 1. A proposed approach to diagnosis of myocarditis in the setting of immune checkpoint inhibitor use. AF indicates atrial fibrillation; AHF, acute heart failure; AV, atrioventricular; CMR, cardiac magnetic resonance imaging; CT, computed tomography; EMB, endo-myocardial biopsy; LVEF, left ventricular ejection fraction; TTE, transthoracic echocardiography; and WMA, wall motion abnormality.

    Clinical Presentation

    The presenting clinical syndrome is useful in the evaluation of a case of suspected myocarditis. The clinical syndrome associated with myocarditis is broad and can encompass a spectrum of symptoms including palpitations, chest pain, acute or chronic heart failure, as well as findings including pericarditis and pericardial effusion. In addition, myocarditis may present in an indolent fashion with mild degrees of ventricular dysfunction.25 Patients with symptoms that are entirely attributable to another nonmyocarditis diagnosis will not be counted as having a clinical syndrome.

    Biomarker Elevations

    Biomarkers that may be useful for the diagnosis of myocarditis include markers of myonecrosis including cardiac troponin, CK-MB (creatine kinase–muscle/brain) or total CK (creatine kinase). Natriuretic peptides may be useful in terms of characterizing stress on the ventricle; however, they must be interpreted with caution in the setting of ICI myocarditis because they can be elevated directly through inflammatory pathways even in the setting of normal filling pressures.26,27 Natriuretic peptides are not specific for myocarditis but may be elevated in patients with significant left ventricular dysfunction and heart failure, and are frequently elevated in ICI-associated myocarditis.28 In addition, interpretation of natriuretic peptide elevations may be particularly complex in the setting of ICI-mediated myocarditis as elevations may be mediated by other mechanisms such as via inflammation including interleukin-6 signaling.29

    For cardiac biomarkers, laboratories should report an upper reference limit (URL). Troponin is the preferred biomarker especially in settings where concomitant myositis may result in significant elevations of CK, CK isoforms, and even troponin T. In this scenario, troponin I would be the most specific option for myocardial injury. If the 99th percentile of the URL from the respective laboratory performing the assay is not available, then the URL for myocardial necrosis from the laboratory should be used. If the 99th percentile of the URL or the URL for myocardial necrosis is not available, the myocardial infarction decision limit for the laboratory should be used as the URL. Laboratories can also report both the 99th percentile of the URL and the myocardial infarction decision limit. Reference limits from the laboratory performing the assay are preferred over the manufacturer’s listed reference limits in an assay’s instructions for use. In general, cardiac troponins are preferred. CK-MB should be used if troponins are not available, and total CK may be used in the absence of CK-MB and troponin.

    Electrocardiographic Changes

    Electrocardiographic (ECG) changes can be used to support or confirm a diagnosis of myocarditis. ECG changes should be dynamic (change from baseline) in a timeframe consistent with the onset of the myocarditis syndrome. Possible changes are broad including arrhythmia, ST-T wave abnormalities, PR segment changes, or new arrhythmias (eg, new heart block or ectopy). ECG findings diagnostic for an alternative diagnosis (eg, regional ST segment elevation in the context of known acute coronary syndrome) should not be counted as changes consistent with myocarditis without appropriate investigation. Patients may also present with a range of arrhythmias including atrial tachyarrhythmia, premature ventricular contractions, and ventricular tachycardia. Bradyarrhythmia and heart block have been also described with infectious (eg, Lyme disease) and immune-mediated myocarditis.4,30

    Imaging

    Echocardiography is generally the first line imaging study to assess cardiac function. Echocardiography is commonly performed for patients with acute or subacute symptoms. Findings may include diffuse left ventricular systolic function, segmental wall motion abnormalities, and change in sphericity of the ventricle.31 Patients presenting acutely generally have normal cardiac dimensions; adverse remodeling and dilatation generally represent a more chronic process.32 Increased wall thickness, a pericardial effusion, and strain abnormalities have also been described in the acute phase. Echocardiography is not specific for myocarditis and lacks sensitivity in cases in which systolic function is relatively preserved.33,34

    Cardiac magnetic resonance imaging (CMR) is the preferred imaging modality for the diagnosis of myocarditis, offering several distinct advantages over echocardiography. The major strength of CMR is with tissue characterization techniques which can be used as a surrogate for myocardial injury.35–37 A combination of findings on CMR has been termed the Lake Louise Criteria for the diagnosis of acute myocarditis.36 Since the publication of these criteria, there have been significant advances in the use of quantitative tissue characterization techniques such as T1 and T2 mapping and calculation of the extracellular volume fraction. Other imaging modalities may be useful in the consideration of whether a case represents myocarditis. In some cases, nuclear medicine modalities including radionuclide ventriculography, which may confirm left ventricular systolic dysfunction. Positron emission tomography using traditional18 fluorodeoxyglucose may be used in certain circumstances to provide data supportive of inflammation, particularly in patients not suitable for CMR or where CMR results are equivocal. It is critical to use appropriate fluorodeoxyglucose–positron emission tomography protocols for cardiac inflammation with an 18 hour carbohydrate-free fast to avoid false-positive results. Newer inflammation tracers are currently being evaluated.

    Role for Endomyocardial Biopsy and Autopsy

    Patients experiencing potential cardiovascular complications from ICI therapy who die should have a postmortem examination. Even an autopsy limited to biopsies of the heart, analyzed by a cardiac pathologist, would provide critical information to adjudicate a clinical event for, or against, myocarditis. In a broader sense, the oncology and cardiology clinical and scientific communities can benefit from postmortem evaluations on all patients receiving ICI therapies, symptomatic or not, to further study ICI-associated myocarditis. In our experience, asymptomatic patients who die of progressive metastatic disease or other complications can indeed have milder degrees of myocarditis. In addition, endomyocardial biopsy should be considered when there is suspicion of the condition, and facilities and expertise should be made available for both the biopsy procedure and pathological processing and interpretation of the biopsy samples.

    Categories of Myocarditis

    Definite Myocarditis

    Any of the following:

    1. Tissue pathology diagnostic of myocarditis (eg, on biopsy or autopsy)

    2. CMR diagnostic of myocarditis, a clinical syndrome and one of following:

      • a. Elevated biomarker of cardiac myonecrosis

      • b. ECG evidence of myo-pericarditis

    3. New wall motion abnormality on echocardiogram not explained by another diagnosis (eg, acute coronary syndrome, stress induced cardiomyopathy, sepsis) and all of the following:

      • a. Clinical syndrome consistent with myocarditis

      • b. Elevated biomarker of cardiac myonecrosis

      • c. ECG evidence of myo-pericarditis

      • d. Negative angiography or other testing to exclude obstructive coronary disease

    Probable Myocarditis

    Any of the scenarios below that are not explained by another diagnosis (eg, acute coronary syndrome, trauma, stress induced cardiomyopathy):

    1. CMR with findings diagnostic of myocarditis without any of the following:

      • a. Clinical syndrome consistent with myocarditis

      • b. Elevated biomarker of cardiac myonecrosis

      • c. ECG evidence of myo-pericarditis

    2. Nonspecific CMR findings suggestive of myocarditis with any 1 or more of the following:

      • a. Clinical syndrome consistent with myocarditis

      • b. Elevated biomarker of cardiac myonecrosis

      • c. ECG evidence of myo-pericarditis

    3. New wall motion abnormality on echocardiogram with a clinical syndrome consistent with myocarditis and either:

      • a. Elevated biomarker of cardiac myonecrosis

      • b. ECG evidence of myo-pericarditis

    4. A scenario meeting criteria for Possible Myocarditis (see below) with18 fluorodeoxyglucose positron emission tomography imaging showing patchy cardiac fluorodeoxyglucose uptake without another explanation

    Possible Myocarditis

    Any of the scenarios below that are not explained by another diagnosis (eg, acute coronary syndrome, trauma, stress induced cardiomyopathy):

    1. Nonspecific CMR findings suggestive of myocarditis with none of the following:

      • a. Clinical syndrome consistent with myocarditis

      • b. Elevated biomarker of cardiac myonecrosis

      • c. ECG evidence of myo-pericarditis

    2. New wall motion abnormality on echocardiogram and 1 of the following:

      • a. Clinical syndrome consistent with myocarditis

      • b. ECG evidence of myo-pericarditis

    3. New elevated biomarker (beyond baseline) and 1 of the following:

      • a. Clinical syndrome consistent with myocarditis

      • b. ECG evidence of myo-pericarditis

    For every case, all additional diagnostic information (eg, cardiac positron emission tomography scan or serial imaging) should be reviewed and integrated into the overall adjudication and may result in upgrade or downgrade by not more than 1 level (Figure 2). This includes muscle biopsy showing myositis in cases where cardiac biopsy is not available.

    Figure 2.

    Figure 2. Scope of ascertainment for cardiovascular events in oncology trials. Cardiac events should be adjudicated in a hierarchical manner excluding ischemia before establishing myocarditis. Simultaneous adjudication of heart failure and arrhythmia is recommended as event types may not be mutually exclusive. CV indicates cardiovascular; HTN, hypertension; and VTE, venous thrombo-embolism.

    All positively adjudicated cases of myocarditis or new systolic dysfunction above will also be subcategorized as follows:

    • Fulminant—presentation with hemodynamic or electric instability

    • Clinically Significant Non-Fulminant— Evidence of clinically significant myocarditis including signs, symptoms and hemodynamic instability but not meeting criteria for fulminant. The need for therapeutic intervention is indicative of clinical significance but is not mandatory.

    • Subclinical—not recognized or treated and no other evidence of clinical significance.

    In addition, systematic collection of objective information (eg, peak cardiac troponin, left ventricular ejection fraction, pericardial effusion, right ventricle involvement, arrhythmias) should be considered to provide further characterization of events.

    Assessment of Relatedness

    During the course of the trial, while treatment allocation may be blinded, it is often necessary to assess the relatedness of an event to the intervention being studied. Ultimately, any relationship is determined at the end of a study based on the presence or absence of imbalance with unblinded randomized therapy. Assessing relatedness during the trial, before unblinding, may be useful in alerting investigators to potential unexpected adverse effects of an investigational therapy so they are aware and evaluate for this effect.

    As part of standard safety reporting, investigators are generally asked about the likelihood of relatedness and whether the investigational agent appears to have a causal relationship (causality). During central case review, it may also be helpful for adjudicators to assess the likelihood of causality. Potential advantages to central assessment in addition to investigator assessment include greater consistency, systematic application of factors indicating causality and assessment by specialists.

    Several factors should be considered in the assessment of causality. These include: time course of the event relative to exposure with the investigational therapy, consistency or plausibility based on the mechanism of action of the investigational therapy, the absence of an alternative explanation (eg, exposure to another intervention known to cause the adverse event), response to removal of the therapy and rechallenge, and the results of relevant diagnostic testing. Based on these and other factors, the adjudicators may determine if there is a reasonable possibility that the event was related to drug exposure. In the absence of evidence of a causal relationship, events are generally assessed as unrelated to treatment exposure. Specific guidance for causality assessment should be determined for each study program and in accordance with regulatory guidance.

    Other Myocardial Injury not Meeting the Definition of Myocarditis

    It may be useful to categorize events not meeting the formal definition of myocarditis above but where there is evidence of a change in cardiac function or of myocardial injury. We suggest the following categories.

    New Ventricular Systolic Dysfunction Without Evidence of Ischemia or Myocarditis

    New imaging evidence (eg, ECG, CMR, ventriculogram, multigated acquisition radionuclide angiogram) of left or right ventricular systolic dysfunction not meeting definitions above for cardiac ischemic event or myocarditis. Dysfunction should be defined, for example, as an ejection fraction <50% and a change of ≥10% from baseline. Whenever possible, cases will be subcategorized as below and will also include a categorization of chronicity (acute transient, acute persistent, chronic, unknown):

    1. Suspected stress-induced cardiomyopathy (includes Takotsubo cardiomyopathy syndrome)

    2. Suspected sepsis-related cardiac dysfunction, or other catechol-mediated syndromes

    3. Suspected direct cardiac toxicity (eg, chemotherapy, alcohol)

    4. Suspected genetic cardiomyopathy (eg, arrhythmogenic right ventricular cardiomyopathy, familial cardiomyopathy)

    5. Suspected tachyarrhythmia induced cardiomyopathy

    6. Suspected hypertensive cardiomyopathy

    7. Other/Idiopathic cardiomyopathy

    Unspecified Biochemical Evidence of Myocardial Injury

    Elevated biomarker indicating myocardial injury without evidence of myocarditis (any category), ischemia or trauma and with normal left and right ventricular systolic function.

    Ascertaining Potential Myocarditis in Clinical Trials

    Myocarditis in oncology trials may occur in a population at heightened risk of cardiovascular events and in the context of previous and current oncology therapies that are associated with a range of cardiovascular complications, including uncontrolled hypertension, cardiomyopathy, arrhythmias, vascular complications,1 venous thromboembolism, and increased thrombotic risk.3,38 The potential diverse complications are particularly relevant to the concept of ascertainment and adjudication of myocarditis as the clinical presentations (chest pain, dyspnea, elevated cardiac troponin) may overlap with myocarditis and therefore broad adjudication of cardiovascular toxicities is necessary to differentiate true cases (Figures 1 and 3). Sensitive cardiac biomarkers may also be elevated in many contexts or be falsely elevated in the setting of inflammatory insults.27,29 In such a context myocarditis, or subacute forms of myocardial toxicity, may be a diagnosis of exclusion. We therefore propose a hierarchical approach for adjudication to first exclude other causes (eg, myocardial ischemia) and then categorize the event in terms of the level of certainty with which myocarditis can be defined.

    The most specific tests to confirm myocarditis are myocardial biopsy and CMR. Both tests, however, are challenging to obtain and resource intensive, particularly in the setting of acute illness. Patients with more fulminant forms of myocarditis may have complications including unstable arrhythmia and/or cardiogenic shock. Furthermore, patients diagnosed with these complications have high rates of a progressive course and rapid onset mortality. This often results in an absence of definitive diagnostic data for a significant number of cases where myocarditis is suspected. One approach may be to mandate certain testing (eg, biopsy or CMR) in patients with myocarditis both to confirm diagnosis using a gold standard as well as to provide opportunity for discovery. Another approach with regards to events of suspected myocarditis without biopsy or CMR would be to adjudicate them as not myocarditis. An advantage to this approach would be greater specificity; however, this would come at a cost of excluding a significant number of cases that likely represent milder cases of myocarditis, reducing rates and power to detect an imbalance with therapy. As an alternative, counting all cases as myocarditis would sacrifice specificity. Therefore, an optimal solution would be to be broadly inclusive of cases where definitive testing was not possible, but also endeavor to maintain specificity.

    An analogous situation is that of coronary stent thrombosis in which the definitive diagnosis hinges on visualization of thrombotic occlusion either through pathology or angiography. Therefore, in approaching a practically useful definition of myocarditis, a construct similar to that established for stent thrombosis by the Academic Research Consortium was considered.39 By integrating several degrees of certainty rather that treating outcomes in a binary fashion, investigators may analyze outcomes using differing levels of specificity to evaluate for consistency of effect and understand rates within a range.

    Establishing a clear baseline at randomization or start of treatment is critical in assessing changes occurring during the trial or therapy (Table 1). Baseline evaluation should include a physical examination and ECG. Baseline measurement of cardiac biomarkers (CK, troponin, potentially natriuretic peptides) and assessment of left ventricular dysfunction using echocardiography are recommended to allow adjudicators to determine whether there is a change from baseline in the context of case review after the start of the trial. Collection of biosamples (plasma and peripheral blood mononuclear cells) for future use should be considered high priority whenever possible for exploratory evaluation.

    Table 1. Testing for Consideration at Baseline and During Follow-Up

    Tests at Baseline
    Physical examinationTo evaluate for signs or symptoms of heart failure or vascular disease. Assessment of functional status (eg, New York Heart Association Heart Failure classification) should be included. Formal assessment such as 6-min walk should be considered.
    Cardiac troponin (troponin I preferred especially if suspicion of concomitant myositis)To evaluate for subclinical myocardial injury and to establish a baseline for subsequent testing. Abnormal values should be investigated. Other biomarkers (eg, natriuretic peptides, C-reactive protein) may also be helpful in establishing a baseline value.
    ECGTo evaluate for arrhythmias and evidence of conduction system disease, to establish a baseline.
    EchocardiogramEchocardiography as first line noninvasive bedside evaluation to rule out valvular diseases or other cardiomyopathies (whether dilated, hypertrophic or restrictive). To monitor patients with pericardial effusion, hemodynamic compromise, and to improve prognostic stratification. In all cases, to evaluate structural heart disease and to establish baseline biventricular function and hemodynamics.
    Other measure of LV function (eg, nuclear, MRI, CT)Cardiac MRI is the preferred imaging modality.
    Ambulatory 24-h blood pressure monitorConsider in trials where investigational or background therapy is anticipated to cause hypertension.
    Interval tests to evaluate for subclinical myocardial injury in the absence of symptoms
     Physical examinationTo evaluate for changes indicative of heart failure or vascular disease. Assessment of functional status (eg, New York Heart Association Heart Failure classification) should be included. Formal assessment such as 6-min walking should be performed if done at baseline to assess for change (at each visit).
     Cardiac troponin (troponin I preferred especially if suspicion of concomitant myositisTo evaluate for new rise indicative of myocardial injury (at each study visit).
     ECGTo evaluate for arrhythmias and evidence of conduction system disease relative to baseline (at each study visit).
     EchocardiogramTo evaluate ventricular function (annual), whatever baseline systolic function.
    Speckle Tracking: better sensitivity for detection of
    regional LV dysfunction compared with conventional echocardiography.
    Abnormalities in longitudinal myocardial deformation
    correlate significantly with lymphocytic infiltrates.
     Other measure of LV function (eg, nuclear, MRI, CT)MRI >> other imaging modalities.
    Noninvasive tissue characterization and thus myocarditis diagnosis.
    To detect hyperemia, myocardial edema and fibrosis (TI, T2 techniques).
     Ambulatory 24-h blood pressure monitorIf blood pressure elevated on home or office measurements, consider to better characterize blood pressure (as indicated).

    CT indicates computed tomography; LV, left ventricular; and MRI, magnetic resonance imaging.

    For case identification, any event that an investigator or treating physician considers a possible cardiac event should be a selected for adjudication (Figure 3). In addition, systematic criteria such as serial biomarkers of myocardial necrosis and serial assessments of left ventricular function may capture subclinical cardiac adverse events (Table 1).

    Figure 3.

    Figure 3. A proposed definition of myocarditis to be applied in clinical trials.. ACS indicates acute coronary syndrome; CMR, cardiac magnetic resonance imaging; PET, positron emission tomography; and WMA, wall motion abnormality.

    Investigators should receive special training on the ascertainment and reporting of suspected cardiovascular events, particularly if those are outside of the investigator’s own specialty. In addition, investigators should be educated about myocarditis, when to suspect the diagnosis, and what testing to obtain to assess for the diagnosis. Current consensus statements outline a clinical approach to the diagnosis and treatment of patients with myocarditis and should be used as a reference.28 In general, myocarditis should be considered in patients who have a rise in cardiac troponin, ECG changes, arrhythmia, or abnormalities of left ventricular systolic function (eg, ejection fraction) particularly if unexplained by another diagnosis. Testing should be performed in accordance with guidelines and consensus statements. Tests to consider in selected clinical scenarios are presented in Table 2.

    Table 2. Tests to Be Obtained If Myocarditis Is Suspected

    PresentationTesting to Consider
    Nonspecific symptoms including palpitations, dyspnea, chest pain, syncope• Physical examination
    • ECG
    • Cardiac troponin (troponin I preferred)
    • Echocardiogram
    • Stress testing with imaging when appropriate
    • Additional testing (eg, cardiac MRI) based on results of initial evaluation
    • Positron emission tomography in selected patients with suspected myocardial inflammation particularly in patients presenting with ventricular arrhythmia or heart block
    New congestive heart failure• Physical examination
    • ECG
    • Cardiac troponin and natriuretic peptides
    • C-reactive protein if an inflammatory cause is suspected
    • Serum cardiac autoantibodies
    • Echocardiogram
    • Stress testing with imaging when appropriate
    • Coronary angiography (CT or traditional angiography)
    • Cardiac MRI with selected tissue characterization
    • Positron emission tomography in select patients with suspected myocardial inflammation (eg, suspected sarcoidosis)
    • Endomyocardial biopsy should be considered if myocarditis is suspected to establish the diagnosis
    Cardiogenic shock• Physical Examination
    • ECG
    • Cardiac troponin and natriuretic peptides
    • C-reactive protein if an inflammatory cause is suspected
    • Echocardiogram
    • Coronary angiography
    • Hemodynamic monitoring if needed
    • Endomyocardial biopsy should be considered to establish the diagnosis and assist in management
    In cases where ICI-myocarditis is suspected, a skeletal muscle biopsy may be helpful particularly if signs or symptoms of myositis and cardiac MRI and myocardial biopsy cannot be obtained. Signs or symptoms raising concern for myositis include:
    • Muscle weakness
    • Elevated total CK (MB fraction) beyond that expected for the degree of myocardial injury
    • Muscle FDG update on PET imaging
    • Electromyography suggestive of myopathy

    CK indicates creatine kinase; CT, computed tomography; FDG, fluorodeoxyglucose; MRI, magnetic resonance imaging; and PET, positron emission tomography.

    General considerations for source document submission for suspected cardiac events include collection of clinical records with redaction of identifying information. Clinical records and reports including imaging studies, laboratory results, ECGs, and procedure reports may be collected. In addition, collection of primary data for core laboratory review may be considered in selected cases including CMR images, ECGs, and biopsy tissue (Table 3).

    Table 3. Source Document Collection for Cardiac Event Adjudication

    TestPrimary data or ReportComment
    Clinical Assessments• Clinical evaluation
    • Emergency room documentation
    • Admission notes
    • Specialty consultation notes
    • Discharge summaries
    ECG• ECG tracings
    • Treating physician assessment
    Core laboratory review not mandatory provided adjudicators are trained in cardiovascular medicine. If other concern (eg, QT prolongation) then core laboratory review should be considered.
    Cardiac biomarkers• All laboratory reports including assay name and normal range
    Echocardiogram• ReportCore laboratory review likely of limited value
    Cardiac MRI• Report
    • Consider MRI data
    Core laboratory review may be of value in understanding specificity of findings for myocarditis
    Cardiac FDG PET• ReportCore laboratory review likely of limited value
    Coronary CT angiography• ReportCore laboratory review likely of limited value
    Coronary angiography• Cath laboratory and procedure reportsCore laboratory review likely of limited value
    Cardiac hemodynamics• ReportTracings likely of limited value
    Biopsy specimens• Report
    • Consider collection of tissue
    Centralized pathology may be of value for core histopathology review

    CT indicates computed tomography; FDG PET, fluorodeoxyglucose positron emission tomography; and MRI, magnetic resonance imaging.

    Using Consensus Criteria for Adjudication of Myocarditis in Trials of Investigational Cancer Therapies

    As the appreciation for potential cardiotoxicity grows with ICI and other cancer immunotherapies, understanding of the risk factors, incidence, and outcomes for myocarditis has become increasingly important. Defining the outcome of interest, in this case myocarditis, using systematic consensus criteria, as is currently done for ischemic cardiac events, may enable systematic reporting and consistency across datasets.39,40 In addition, defining a spectrum of disease using definitions that allow ascertainment of less severe forms of myocardial injury, may help to identify the full spectrum of cardiotoxicity. In oncology trials, CTCAE (Common Terminology Criteria for Adverse Events) provides a standard chart for reporting the severity of adverse events. However, the most recent CTCAE version does not provide specific guidance to the care provider about which events should be defined as myocarditis. A general definition is provided, in which myocarditis is described as a disorder characterized by inflammation of the muscle tissue of the heart. Therefore, CTCAE maintains investigator reporting according to their judgment.

    The proposed definitions in this document then provide a framework to evaluate these reports and characterize the events according to systematic criteria, increasing consistency and specificity. Application would enable better assessment of drug effect as well as facilitate pooling of datasets and cross trial comparisons. Therefore, the current definitions are not intended as a modification or replacement of CTCAE, but rather as a complimentary step to add systematic criteria and improve specificity. In addition, because there is no current consensus definition for adjudicating myocarditis in clinical trials, reporting is largely based on traditional mechanisms for safety which maybe subject to greater variability and less specificity. Systematic ascertainment using a consensus definition would allow broader understanding of the predictors, risks and outcomes, as well as evaluation across trials, even across different cancer diagnoses such as melanoma or lung cancer.

    Discussion

    The rapid development of novel therapies to treat cancer has led to increasing awareness of potential new cardiac toxicities.1 This includes a range of adverse outcomes including hypertension, arrhythmias, thrombotic complications, accelerated atherosclerosis, and immune-mediated myocarditis. Understanding the risks of these therapies is complex because the prevalence of comorbid cardiovascular disease is high, cardiac events during the course of a given trial may be rare, and traditionally captured through standard safety reporting which lacks specificity.

    Systematic characterization at randomization including physical examination, electrocardiography, biomarkers, assessments of ventricular dysfunction and other assessments can help establish a baseline against which changes can be evaluated during trial follow up. Serial evaluations and testing in all patients can help ascertain early or subclinical events. Extensive reporting through dedicated case report form pages and by trained site investigators may help to capture these rare but potentially serious events.

    Adjudication using standardized definitions allows characterization of events with greater specificity allowing clearer signals and less noise for rare events. In addition, specialist adjudication may allow further characterization including the certainty of the diagnosis, the severity, and associated findings such as fold elevation in biomarker and objective assessment of left ventricular function. In addition, the use of standard definitions will allow pooling of data across trials giving more power to understand which patients are truly at risk, how they present, and their prognosis after diagnosis.

    Although there are established definitions for a range of cardiovascular outcomes, a clear case definition for myocarditis for use in clinical trials has not been established. Any practical definition must acknowledge that testing may be variable across sites and that some degree of uncertainty is inevitable. Hierarchical adjudication first excluding alternative diagnoses (eg, coronary disease), and then allowing characterization of myocarditis by the degree of certainty, would allow analysis across categories. In addition, capture of cases of subclinical biomarker elevation as well as mild ventricular systolic dysfunction may help to increase ascertainment, identifying preexposure risk, and enable a broader description of the range of clinical outcomes. This article proposes a definition for myocarditis and a process for ascertaining and adjudicating this definition in clinical trials of therapies to treat malignancy.

    Acknowledgments

    The contributions of Laleh Amiri-Kordestani represent her opinions and not those of the US Food and Drug Administration.

    Footnotes

    Marc P. Bonaca, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. Email
    Javid Moslehi, MD, Cardio-Oncology Program, Vanderbilt University Medical, 2220 Pierce Avenue, Nashville, TN 37232. Email , or

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