Introduction and Context
Immune checkpoint inhibitors (ICIs) — drugs that unleash T-cell responses against tumors — have transformed outcomes across many cancers. Yet their immune-activating mechanism also produces immune-related adverse events (irAEs). Among those, cardiovascular (CV) toxic effects have emerged as a high-stakes problem because they can be sudden, severe, and sometimes fatal. The International Cardio-Oncology Society (ICOS) convened cardiologists, oncologists, hematologists, and allied specialists to issue a comprehensive position statement on ICI-associated cardiovascular toxic effects, published in JAMA Oncology (Herrmann et al., 2025). This statement synthesizes recent evidence and expert consensus to guide diagnosis, grading, treatment, monitoring, and decisions about continuing or rechallenging ICI therapy.
The ICOS document matters now because: 1) ICIs are used in more indications and in combination regimens, increasing exposure; 2) clinical recognition has broadened beyond fulminant myocarditis to a spectrum that includes subclinical troponin elevations, pericardial disease, arrhythmias, and accelerated atherosclerotic events; and 3) emerging immunomodulatory strategies (e.g., abatacept) offer new treatment options but lack randomized evidence.
Key prior guidance (ASCO 2018; ESC cardio-oncology guidance) focused primarily on immune-related myocarditis. The new ICOS position statement expands scope, offers practical algorithms, and highlights gaps for research.
New Guideline Highlights
Major themes and takeaways from the ICOS position statement:
– Myocarditis remains the dominant CV concern but exists on a wide clinical spectrum, from isolated troponin rise to fulminant, life-threatening disease. Fatality rates have declined but risks persist.
– CV toxic effects extend beyond myocarditis: pericarditis, vasculitis, ICI-associated acceleration of atherosclerosis (with myocardial infarction and stroke), noninflammatory cardiac dysfunction (stress cardiomyopathy), and arrhythmias.
– Early detection and rapid, multidisciplinary management are essential. A standardized approach using clinical assessment, ECG, cardiac troponin, natriuretic peptides, echocardiography, cardiac MRI (CMR), and selective endomyocardial biopsy (EMB) is recommended.
– Treatment is risk-stratified: corticosteroids are first-line for suspected myocarditis; high-dose intravenous steroids are indicated for moderate-to-severe disease. For steroid-refractory or life-threatening cases, additional immunosuppression (e.g., mycophenolate, antithymocyte globulin, abatacept, tocilizumab, IVIG, plasmapheresis) is considered based on clinical scenario and center experience.
– ICI rechallenge is possible in selected patients with mild or resolved toxicity after careful multidisciplinary review, but it is generally discouraged after severe or fulminant myocarditis.
Clinical contexts emphasized: baseline cardiac risk assessment prior to ICI, tailored surveillance for high-risk patients, urgent cardiology involvement for suspected myocarditis, and shared decision-making about therapy continuation.
Updated Recommendations and Key Changes from Prior Guidance
What’s new or different in the ICOS statement compared with earlier guidance (e.g., ASCO 2018, ESC cardio-oncology advisories):
– Broader taxonomy: The statement explicitly lists a wider spectrum of ICI cardiac effects beyond myocarditis, including noninflammatory cardiomyopathies and ICI-accelerated atherosclerosis.
– Diagnostic emphasis: ICOS places stronger emphasis on baseline and serial troponin and ECG monitoring for high-risk patients and provides a stepwise diagnostic algorithm integrating troponin, ECG, echo, CMR, and EMB.
– Graded management: The position statement clarifies management stratified by severity (asymptomatic troponin elevation → mild → moderate → severe/fulminant myocarditis) and links treatment intensity to grade.
– New therapeutic options: While corticosteroids remain first-line, the statement acknowledges growing clinical experience with agents such as abatacept and antithymocyte globulin for refractory cases and discusses risks/uncertainties.
– Rechallenge guidance: ICOS offers a more detailed, conditional approach to ICI rechallenge after cardiac toxicity, emphasizing individualized decision-making and risk tolerance.
Evidence driving updates includes larger multicenter registries and case series (Mahmood et al., 2018) demonstrating variable presentations, lower but persistent mortality in myocarditis, and small series reporting benefit from targeted immunomodulators.
Topic-by-Topic Recommendations
Note: The ICOS position statement is consensus-based; not all recommendations were graded with formal GRADE ratings. Below are the core, practical recommendations distilled by topic.
1) Baseline assessment and risk stratification
– Before initiating ICI, perform a baseline clinical CV assessment: history, focused exam, ECG. Obtain baseline cardiac troponin I or T and natriuretic peptide in patients with known CV disease or those planned for combination ICI regimens or with other high-risk features.
– For patients with active CV disease (recent MI, symptomatic heart failure, uncontrolled arrhythmia), optimize CV status and engage cardio-oncology input before starting ICI.
2) Surveillance during ICI therapy
– Routine universal serial troponin monitoring for all ICI recipients is not mandated by ICOS, but targeted surveillance is recommended for higher-risk groups (combination ICI, preexisting CV disease, prior cardiotoxic cancer therapy).
– Suggested surveillance schedule for high-risk patients: ECG and troponin before each cycle for the first 6–12 weeks (when myocarditis most often occurs), then as clinically indicated.
3) Diagnostic approach to suspected ICI-associated myocarditis or CV toxicity
– Initial evaluation for any new cardiac symptom (chest pain, dyspnea, syncope, palpitations) or new ECG/troponin abnormality should include ECG, cardiac troponin, BNP/NT-proBNP, and transthoracic echocardiography (TTE).
– If troponin is elevated or ECG is abnormal, hospitalize for telemetry and expedite cardiology consultation.
– Cardiac MRI (CMR) is recommended to assess myocarditis (edema and late gadolinium enhancement) when feasible and when the patient is hemodynamically stable.
– Endomyocardial biopsy (EMB) should be considered when results will change management — for example, discordant CMR findings, atypical presentation, or when confirming myocarditis before long-term ICI decisions; EMB is favored in fulminant cases or where diagnosis is uncertain.
4) Grading and treatment of myocarditis (practical stratification)
– Asymptomatic troponin elevation: Withhold ICI, repeat troponin and ECG within 24–48 hours, consider cardiology input. If troponin normalizes and no clinical or imaging evidence of myocarditis, some centers may resume therapy on a case-by-case basis after shared decision-making.
– Mild myocarditis (symptoms without hemodynamic compromise and preserved LVEF): Hold ICI; initiate corticosteroids (prednisone 0.5–1 mg/kg/day or IV equivalent), monitor closely in-hospital or with rapid outpatient follow-up, and perform CMR. Consider cardiology follow-up and taper steroids over at least 4–6 weeks guided by biomarkers and symptoms.
– Moderate myocarditis (symptoms with evidence of myocardial injury, reduced LVEF, or arrhythmia): Hospitalize, telemetry monitoring, initiate high-dose IV corticosteroids (methylprednisolone 1–2 mg/kg/day). Consider additional immunosuppression (mycophenolate mofetil) if inadequate response within 24–48 hours.
– Severe/fulminant myocarditis (hemodynamic instability, cardiogenic shock, malignant ventricular arrhythmias): Urgent ICU care, high-dose IV pulse steroids (methylprednisolone 500–1000 mg daily for 1–3 days then transition), consider mechanical circulatory support if needed. For steroid-refractory cases, consider escalated immunosuppression: antithymocyte globulin, abatacept, tocilizumab, IVIG, or plasmapheresis — decisions individualized and ideally made with multidisciplinary input.
Important therapeutic caveats:
– Avoid infliximab in patients with significant heart failure because of risk of worsening cardiac function; infliximab may still be considered for other irAEs but with caution in cardiac toxicity.
– Abatacept (a CTLA-4–Ig fusion) and antithymocyte globulin have shown promise in case series and are discussed as rescue options, but randomized evidence is lacking; their use should be centralized in experienced centers and ideally captured in registries.
5) Arrhythmias and conduction system disease
– Continuous telemetry is recommended for suspected myocarditis because atrial and ventricular arrhythmias, as well as high-degree AV block, may occur.
– Manage arrhythmias per standard cardiology practice (antiarrhythmics, pacing, defibrillator therapy when indicated) while addressing underlying inflammation.
6) Pericardial disease and vasculitis
– Pericarditis can occur alone or with myocarditis. Treatment includes NSAIDs, colchicine, and corticosteroids per standard practice for pericarditis while considering need to hold ICI.
– Vasculitis related to ICI may involve large or small vessels and should be managed with rheumatology/cardiology and immunosuppression per disease severity.
7) Ischemic events and atherosclerosis
– ICOS recognizes that ICI may exacerbate chronic inflammatory atherosclerosis leading to myocardial infarction or stroke. When ischemia is suspected, evaluate with standard ischemic workup and manage per cardiology/PCI protocols.
– Continue guideline-directed secondary prevention and consider aggressive risk-factor modification during and after ICI therapy.
8) Decisions about ICI continuation and rechallenge
– For severe or fulminant myocarditis: permanent discontinuation of ICI is generally recommended.
– For mild, isolated troponin elevation or resolved low-grade myocarditis: rechallenge may be considered in a multidisciplinary setting with informed patient consent and close monitoring.
– Shared decision-making is emphasized: weigh cancer control urgency, alternative therapies, severity of cardiac event, response to immunosuppression, and patient values.
9) Follow-up and long-term care
– After an ICI cardiac event, structured cardiology follow-up is recommended: clinical review, ECG, troponin, natriuretic peptide, and echocardiography at intervals guided by severity (e.g., at 2–6 weeks, 3 months, and beyond).
– For patients with persistent ventricular dysfunction, manage per heart failure guidelines (ACE inhibitors/ARBs/ARNI, beta-blockers, mineralocorticoid antagonists) as tolerated.
Expert Commentary and Insights
Committee perspectives and notable commentary from the ICOS statement and authors:
– Myocarditis is still the priority focus, but clinicians must maintain a broad differential diagnosis. ‘‘Think myocarditis, but don’t miss ischemia, pericarditis, or arrhythmia-driven deterioration,’’ the authors advise (Herrmann et al., 2025).
– The panel acknowledges heterogeneity in practice: some centers perform routine troponin monitoring for all ICI patients while others reserve it for higher-risk scenarios. ICOS advocates risk-adapted surveillance rather than a universal mandate.
– There is optimism about targeted immunomodulation (e.g., abatacept) for refractory myocarditis, but experts emphasize the urgent need for prospective trials and registries to define efficacy and safety.
– A recurring theme is the need for multidisciplinary care pathways including oncology, cardiology, critical care, and when relevant, rheumatology and neurology. Early involvement of cardiology shortens time to diagnosis and may improve outcomes.
– Key controversies include: the optimal surveillance strategy (who to screen and how often), thresholds for invasive testing (EMB), and precise algorithms for steroid tapering and second-line immunosuppression. The statement intentionally leaves room for center-specific implementation while noting these as research priorities.
Practical Implications for Clinicians
– Operationalizing the ICOS recommendations requires local protocols: establish pathways for rapid troponin/ECG assessment, expedited CMR access, and clear criteria for cardiology consultation.
– Education for oncology teams to recognize cardiac symptoms and act promptly is critical; many cases are identified first by oncologists or oncology nurses.
– Build multidisciplinary tumor boards that include cardio-oncology expertise for complex decisions about ICI continuation or rechallenge.
– Report cases to institutional registries and consider enrolling patients in prospective studies to accelerate knowledge about optimal management.
Fictional vignette (illustrative):
John, a 62-year-old man with metastatic melanoma, began combination ipilimumab and nivolumab. He developed fatigue and palpitations after his second cycle. ECG showed new conduction changes and troponin was elevated. Cardiology consulted: John was admitted to telemetry, treated with IV methylprednisolone 1 mg/kg, and underwent CMR showing myocardial inflammation. The team initiated a steroid taper, held further ICI therapy, and after multidisciplinary discussion and recovery with normalization of troponin and improved symptoms, they opted for alternative non-ICI therapy. This case illustrates rapid recognition, in-hospital monitoring, high-dose steroid therapy, and shared decision-making about oncologic strategy — all recommended by the ICOS statement.
Gaps in Knowledge and Research Priorities
ICOS identifies several priority research areas:
– Prospective studies to define the optimal surveillance strategy (who to screen and optimal intervals) and the prognostic significance of isolated troponin elevations during ICI therapy.
– Randomized or controlled studies to test second-line immunosuppressive agents (abatacept, antithymocyte globulin, tocilizumab) for steroid-refractory myocarditis.
– Better biomarkers and imaging markers to predict severity and guide therapy intensity.
– Long-term outcomes data to determine the cardiovascular sequelae of ICI events and to refine rechallenge safety.
References
– Herrmann J, Barac A, Carver J, et al. Immune Checkpoint Inhibitor–Associated Cardiovascular Toxic Effects: International Cardio-Oncology Society Position Statement. JAMA Oncol. 2025 Nov 13. doi:10.1001/jamaoncol.2025.4543
– Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755–1764. doi:10.1016/j.jacc.2018.02.037
– Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–1768. doi:10.1200/JCO.2017.77.6385
– Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology: developed by the European Society of Cardiology (ESC). Eur Heart J. 2022;43(41):4229–4361. (Guideline text and recommendations on monitoring and management of cancer therapy–related cardiovascular toxicity.)
– Additional contemporary reviews and registry data cited within the ICOS statement and growing literature on targeted immunomodulatory therapy for steroid-refractory cases.
Bottom Line
The International Cardio-Oncology Society position statement synthesizes current evidence and expert experience to provide pragmatic, multidisciplinary guidance for identifying and managing ICI-associated cardiovascular toxic effects. Clinicians should recognize the broad spectrum of cardiac presentations, adopt risk-adapted surveillance, initiate prompt cardiology involvement for suspected myocarditis, treat according to severity with high-dose corticosteroids as first-line therapy, and reserve advanced immunomodulation for refractory or life-threatening cases. Shared decision-making about ICI rechallenge is essential. Filling knowledge gaps will require prospective studies and registries to guide evidence-based refinements.
