ICI-associated myocarditis
Also called: checkpoint inhibitor myocarditis · immune-mediated myocarditis · ICI myocarditis · immune checkpoint inhibitor-associated myocarditis
Uncommon and early — 1.14% of an eight-site registry, median 34 days in — but the most lethal irAE by reported share, and the card where the drug stops earliest: ASCO discontinues from grade 2. An asymptomatic troponin rise inside 12 weeks of an ICI is a presentation, not an incidental result.
Part of a syndrome that spans more than this organ — see Spans more than this organ below.
Reported frequency
1.14% — Prevalence of myocarditis
of ICI-treated patients across the registry's 8 sites · Multicentre ICI myocarditis registry, November 2013 to July 2017
cohort · 29567210
Severity and class
50% — Deaths among reported ICI myocarditis cases
of 61 of 122 myocarditis reports · VigiBase spontaneous reports, 1967 to January 2018 — a share of REPORTS, not a case-fatality rate: severe and fatal events are preferentially reported, so this is an upper-bound signal rather than a risk a patient can be quoted
pharmacovigilance · 30442497
34% vs. 2% — Combination ICI exposure among myocarditis cases vs ICI-treated controls
of 35 myocarditis cases vs a random sample of 105 ICI-treated patients without myocarditis · Eight-site multicentre myocarditis registry, November 2013 to July 2017
cohort · 29567210
Onset
Median time of onset 34 days after starting ICI (interquartile range 21 to 75 days) in the eight-site registry. SITC frames the window differently and more usefully for triage: a diagnosis should be considered in any patient who has received an ICI in the past 12 weeks and develops new cardiac symptoms, arrhythmias, heart block, or an asymptomatic troponin elevation. Values are stored in days because that is how both sources state them.
Presentation
- · New cardiac symptoms in a patient who has had an ICI within 12 weeks — SITC's trigger, and the reason this card is entered on suspicion rather than on a grade
- · Asymptomatic troponin elevation — named by SITC as a presenting cardiac lab finding, not as an incidental result to be repeated later
- · New arrhythmia or new heart block
- · A normal ejection fraction does not exclude it: 38% of the registry's major adverse cardiac events occurred with normal ejection fraction
- · Concurrent myositis or myasthenic features — SITC evaluates suspected myositis, myocarditis and myasthenia gravis with a shared set of diagnostics because the presentations overlap
Differential
- · Acute coronary syndrome and other non-immune causes of troponin rise — the reason the work-up is an EKG plus troponin plus imaging rather than troponin alone
- · Myositis with cardiac muscle involvement, and myasthenia gravis: SITC treats the three as an overlapping triad sharing one diagnostic work-up, so finding one is a reason to look for the other two rather than to stop
- · Pericardial disease, which SITC discusses separately and which this atlas does not yet carry as a card — see the 'Deliberately not carried' notes below rather than reading its absence as absence of risk
- · Progression of the underlying malignancy, and cardiotoxicity of a concomitant anti-cancer agent
Work-up
Serum troponin · All patients
SITC's first-line test in suspected myocarditis, and part of what defines the presentation. It also gates the pulse-steroid duration — the pulse runs until troponin normalizes.
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EKG · All patients
Ordered with troponin on suspicion. New arrhythmia or new heart block is itself an entry criterion.
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Hospital admission with cardiology consultation · All patients
SITC attaches both to SUSPICION, not to a confirmed diagnosis and not to a grade. Management is to take place in a coronary care unit with temporary pacemaker support available for rapid access if indicated.
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Cardiac MRI, if available · All patients
SITC's imaging step after EKG and troponin, with or without right heart catheterization and myocardial biopsy.
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Endomyocardial biopsy, with or without right heart catheterization · If atypical
Named by SITC as the gold standard for myocarditis. Positioned after the non-invasive work-up rather than as a first step.
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CPK, drawn with the troponin · All patients
ASCO pairs CPK with troponin to rule out concurrent myositis, especially on combination immunotherapy, and asks that alternative reasons for a troponin rise be ruled out. An elevated troponin is also its cue to think of the triple-M overlap — myositis, myasthenia, myocarditis — and refer to the subspecialties.
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BNP, echocardiogram and chest X-ray · All patients
ASCO's first-pass cardiac assessment alongside ECG and troponin. It sits before the cardiology-guided tests below, not after them.
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Stress test or cardiac catheterization, guided by cardiology · If atypical
ASCO leaves these to cardiology rather than listing them as routine. They are also what separates this card's main differential — ischemic heart disease — from myocarditis.
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Shared myositis / myocarditis / myasthenia gravis diagnostic set · All patients
SITC evaluates the three together because symptoms overlap, and ASCO names the same triple-M overlap off an elevated troponin. Confirming one does not close the other two.
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Scheduled surveillance troponin in an asymptomatic patient · If atypical
Listed to record what SITC actually says about it: baseline and scheduled troponins CAN be obtained, but in asymptomatic patients there has been no evidence that this improves outcome or even gives early warning. It is carried as a negative finding so the card cannot be read as endorsing routine surveillance.
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Sources differ here
Second-line therapy
- ASCO 2021 (Table 9, section 9.1) (society guideline) — Add either mycophenolate, infliximab, or antithymocyte globulin to cardiac transplant rejection doses of corticosteroids when there is no immediate response to high-dose corticosteroids. The same chapter's qualifying statement contraindicates infliximab at high doses in patients with moderate-severe heart failure.
- SITC 2021 (society guideline) — Caution is advised against the use of infliximab for steroid-refractory myocarditis. ATG, mycophenolate mofetil, abatacept or alemtuzumab are the agents named instead.
Grade ladder
Grade 1
Hold — consider permanent discontinuationAdmitGrade 1 — abnormal cardiac biomarker testing without symptoms and with no ECG abnormalities (ASCO Table 9), where the table's footnote takes CTCAE v5.0's definition of an elevated troponin: above the upper limit of normal and below the manufacturer's myocardial-infarction level. ASCO holds the ICPi, rechecks troponin at 6 hours, and lets resumption be considered once it normalizes or if the rise is believed unrelated to the ICPi. SITC does not grade at all: any patient with an ICI in the past 12 weeks who develops new cardiac symptoms, new arrhythmias, new heart blocks or an asymptomatic troponin elevation is a suspected case, and it asks that permanent discontinuation be seriously considered in one. The encoded action is the conservative reading of the two, and the divergence row below carries ASCO's narrower position rather than burying it.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — SITC runs the pulse until troponin normalizes and asks for it as soon as the diagnosis is considered likely — before confirmation, not after. The chapter's cited basis for the urgency is a 126-patient multicentre analysis in which corticosteroids within 24 hours of admission were followed by major adverse cardiac events in 7.0%, against 34.3% at 24 to 72 hours and 85.1% beyond 72 hours.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the chapter cited does not specify a taper cadence, and one is not invented here.
Second line
- Cardiac transplant rejection doses of corticosteroids — methylprednisolone 1 g every day — with either mycophenolate, infliximab, or antithymocyte globulin added — ASCO's escalation for a patient without an immediate response to high-dose corticosteroids, instituted EARLY rather than after a longer trial. Abatacept or alemtuzumab is its further step in life-threatening cases.Infliximab is on ASCO's list, and this is the one place the two chapters give opposite instructions. ASCO's own qualifying statement contraindicates it at high doses in patients with moderate-severe heart failure; SITC advises caution against it in steroid-refractory myocarditis outright. The other agents on the list carry no such caution — see the divergence row.
- Infliximab — Carried for the caution on it, not as a recommendation of this atlas.SITC advises caution against the use of infliximab for steroid-refractory myocarditis. ASCO lists it among the agents to add to transplant-rejection-dose corticosteroids, then contraindicates it at high doses (above 5 mg/kg) in patients with moderate-severe heart failure — the population most of this card describes. It is listed so that a reader who reaches for the TNF-α inhibitor that works in ICI colitis meets both positions on the card rather than missing them.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Manage in a coronary care unit, with temporary pacemaker support available for rapid access if indicated
- · Do not wait for confirmation to start steroids — SITC's instruction is as soon as the diagnosis is considered likely
- · Evaluate for concurrent myositis and myasthenia gravis with the shared diagnostic set
Sources differ here
ICI action
- ASCO 2021 (Table 9, section 9.1) (society guideline) — Hold the ICPi for a grade 1 elevated troponin and recheck troponin 6 hours later. Resumption may be considered once it has normalized, or if the rise is believed not to be related to the ICPi.
- SITC 2021 (society guideline) — An asymptomatic troponin elevation within 12 weeks of an ICI is a suspected myocarditis, and permanent discontinuation of ICI therapy should be seriously considered in a suspected case. No grade is attached, and no route back is described.
Escalate when: No response to corticosteroids within 24 hours; any arrhythmia, conduction block or hemodynamic change. A normal ejection fraction is not reassurance — 38% of the registry's major adverse cardiac events occurred with one.
Grade 2
Discontinue permanentlyAdmitGrade 2 — abnormal cardiac biomarker testing with mild symptoms or new ECG abnormalities without conduction delay (ASCO Table 9). This is where ASCO's cardiac chapter stops the drug in its own words: hold the ICPi and discontinue for grade 2 or above. That is two rungs earlier than ASCO's cross-organ ladder would suggest, and the organ chapter governs. It is also where its corticosteroid starts — 1-2 mg/kg/d of prednisone, oral or IV depending on symptoms, begun within 24 hours. SITC's plan does not change here (same admission, same work-up, same pulse steroid, same 24-hour second-line trigger) and it already asks that permanent discontinuation be seriously considered in any suspected case, so the two converge at this rung.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — Until troponin normalizes, started as soon as the diagnosis is considered likely.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the chapter cited does not specify a taper cadence, and one is not invented here.
Second line
- Cardiac transplant rejection doses of corticosteroids — methylprednisolone 1 g every day — with either mycophenolate, infliximab, or antithymocyte globulin added — ASCO's escalation for a patient without an immediate response to high-dose corticosteroids, instituted EARLY rather than after a longer trial. Abatacept or alemtuzumab is its further step in life-threatening cases.Infliximab is on ASCO's list, and this is the one place the two chapters give opposite instructions. ASCO's own qualifying statement contraindicates it at high doses in patients with moderate-severe heart failure; SITC advises caution against it in steroid-refractory myocarditis outright. The other agents on the list carry no such caution — see the divergence row.
- Infliximab — Carried for the caution on it, not as a recommendation of this atlas.SITC advises caution against the use of infliximab for steroid-refractory myocarditis; ASCO lists it, then contraindicates it above 5 mg/kg in moderate-severe heart failure. Both positions are on the divergence row.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Coronary care unit management with rapid access to temporary pacing
- · Serial troponin — it is the marker the pulse duration is indexed to
- · Keep the ICI held; SITC asks that permanent discontinuation be seriously considered
Escalate when: No response within 24 hours of starting corticosteroids, or any new conduction abnormality.
Grade 3
Discontinue permanentlyICUGrade 3 — abnormal cardiac biomarker testing with either moderate symptoms or new conduction delay (ASCO Table 9). ASCO states its discontinuation rule once, for grade 2 and above, so it carries here unchanged, as does the within-24-hours high-dose corticosteroid. What is new at this rung is the conduction delay: ASCO asks for a pacemaker to be considered for a new one, and for immediate transfer to a coronary care unit for elevated troponin or conduction abnormalities. SITC's plan already did all of this on suspicion; here the case is simply unambiguous.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — Until troponin normalizes. The 24-hour window is the one that matters — the analysis SITC cites separates 7.0% major adverse cardiac events from 34.3% on that threshold.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the chapter cited does not specify a taper cadence, and one is not invented here.
Second line
- Cardiac transplant rejection doses of corticosteroids — methylprednisolone 1 g every day — with either mycophenolate, infliximab, or antithymocyte globulin added — ASCO's escalation for a patient without an immediate response to high-dose corticosteroids, instituted EARLY rather than after a longer trial. Abatacept or alemtuzumab is its further step in life-threatening cases.Infliximab is on ASCO's list, and this is the one place the two chapters give opposite instructions. ASCO's own qualifying statement contraindicates it at high doses in patients with moderate-severe heart failure; SITC advises caution against it in steroid-refractory myocarditis outright. The other agents on the list carry no such caution — see the divergence row.
- Infliximab — Carried for the caution on it, not as a recommendation of this atlas.SITC advises caution against the use of infliximab for steroid-refractory myocarditis; ASCO lists it, then contraindicates it above 5 mg/kg in moderate-severe heart failure. Both positions are on the divergence row.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Coronary care unit, with temporary pacemaker support available for rapid access
- · Cardiology leads; the diagnosis is established alongside treatment, not before it
- · Look for the myositis and myasthenia gravis that travel with it
Escalate when: Cardiogenic shock, cardiac arrest, ventricular arrhythmia or haemodynamically significant complete heart block — the components of the registry's major-adverse-cardiac-event endpoint.
Grade 4
Discontinue permanentlyICUGrade 4 — moderate to severe decompensation, IV medication or intervention required, life-threatening conditions (ASCO Table 9). Discontinuation was reached two rungs below and is not in question here; ASCO's cross-organ grade 4 rule says the same thing again. What belongs to this rung is the escalation ASCO reserves for life-threatening cases — abatacept or alemtuzumab added to the transplant-rejection steroid dose. SITC states its discontinuation position once, ungraded, as seriously considering permanent discontinuation.
Corticosteroid 1–2 mg/kg/day (oral)
Pulse: Methylprednisolone 1000 mg IV or equivalent, daily for 3–5 days — Until troponin normalizes, as soon as the diagnosis is considered likely.
Taper over 4–6 weeks, starting once: Troponin normalizes on pulse-dose methylprednisolone.
No step size or interval is carried: the chapter cited does not specify a taper cadence, and one is not invented here.
Second line
- Cardiac transplant rejection doses of corticosteroids — methylprednisolone 1 g every day — with either mycophenolate, infliximab, or antithymocyte globulin added — ASCO's escalation for a patient without an immediate response to high-dose corticosteroids, instituted EARLY rather than after a longer trial. Abatacept or alemtuzumab is its further step in life-threatening cases.Infliximab is on ASCO's list, and this is the one place the two chapters give opposite instructions. ASCO's own qualifying statement contraindicates it at high doses in patients with moderate-severe heart failure; SITC advises caution against it in steroid-refractory myocarditis outright. The other agents on the list carry no such caution — see the divergence row.
- Infliximab — Carried for the caution on it, not as a recommendation of this atlas.SITC advises caution against the use of infliximab for steroid-refractory myocarditis; ASCO lists it, then contraindicates it above 5 mg/kg in moderate-severe heart failure. Both positions are on the divergence row.
- ATG, mycophenolate mofetil, abatacept, or alemtuzumab — Signs or symptoms not responding to corticosteroid therapy within 24 hours.
- · Critical care with temporary pacing available; mechanical circulatory support is beyond what any chapter held here states
- · Permanent discontinuation of the ICI
- · Second-line immunosuppression on the 24-hour non-response rule, not after a longer trial
Escalate when: Already the top rung. Management of established fulminant ICI myocarditis is beyond what the chapters held here state, and this atlas stops rather than extrapolating.
Rechallenge
Rechallenge is contraindicated
ASCO's cardiac chapter says it outright: the appropriateness of rechallenging remains unknown. Its ladder discontinues from grade 2, and SITC asks that permanent discontinuation be seriously considered in any suspected case. Neither chapter describes conditions under which an ICI would be resumed after myocarditis, and no source cited here reports what happens when it is. Against a reported fatality of 50% in the pharmacovigilance record, an unanswered question is not an open door — the stance is the conservative reading, and the empty recurrence field says the question has not been answered here rather than answered favorably. The one resumption either chapter permits is ASCO's at grade 1, where a held troponin normalizes or is judged unrelated; that is a decision not to attribute the rise to the drug, not a rechallenge after myocarditis.
- · None are stated by any source cited here. This is a stopping point, not a gated pathway — a prerequisite list would imply a route through it that no chapter held here describes
Deliberately not carried
- Quoted source text — how it was extracted — ASCO's chapter reaches this atlas through a PDF text layer, and two glyphs did not survive it: "$" is "≥" and a "." before a number is ">". Both were read off the printed page at 300 dpi before anything on this card was written, and both are stored unrepaired — hand-repairing a quote is what got the first ASCO wiring attempt rejected. Inline superscript reference numerals and the footnote marker on "troponin" are left as extracted for the same reason. The quote text is stored for provenance and is never rendered, so no corrupted glyph reaches a reader. The one elision drops the copyright watermark the extractor interleaves after the section heading; both sides of the marker are verbatim.
- Corticosteroid route — Encoded as oral, which is SITC's post-pulse prednisone. ASCO states "oral or IV depending on symptoms" for the same 1-2 mg/kg/d band and does not say where the boundary falls, so the encoded route is the narrower of the two rather than a rule either chapter states. The IV option is real; it is on this row rather than in a field that would render it as settled.
- Grade 3 or higher share — No source cited here reports a CTCAE grade ≥3 rate for ICI myocarditis. The registry's 46% major-adverse-cardiac-event figure is a composite study endpoint — cardiovascular death, cardiogenic shock, cardiac arrest, haemodynamically significant complete heart block — measured among patients who already have myocarditis. Filing it here would render a study endpoint as a severity rate in a field the UI treats as one; it is carried as prose and as escalation triggers instead.
- Median time to onset — Both sources state onset in days (median 34, IQR 21-75). Converting to weeks produces 4.857, a number no source printed, and this field's contract forbids an estimated median. The days figure is in onset.note verbatim.
- Taper step size and interval — SITC states a 4–6 week 1–2 mg/kg prednisone taper and a start trigger, and no step size or step interval; ASCO's cardiac chapter states no taper at all. All three cadence fields are left empty together rather than back-filled from the kidney taper planner's illustrative 25%-every-1-2-weeks, which is an example rather than a cardiac recommendation.
- Diagnostic test performance — SITC states that nearly all registry myocarditis cases had elevated troponin and an abnormal EKG and that ejection fraction was normal in about half, attributing the figures to Mahmood et al. Those numbers are not in Mahmood's abstract, so they are held here only as one document's summary of another's full text. No sensitivity or negative predictive value is stored, and the work-up rows say what to order and why without one.
- Second-line comparative outcomes — SITC cites a 60-patient retrospective in which patients needing second-line immunosuppression had higher all-cause mortality than those on steroids alone, and in which infliximab carried an odds ratio of 12.0 for cardiovascular death. That record was not resolved to a PMID in this pass. The infliximab CAUTION is carried because it is in SITC's own recommendation sentence; the numbers behind it are not.
- Other cardiac phenotypes — This organ has one card, and both chapters cover more than it. ASCO's section 9.1 heading also names pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis, but answers all of them in the single merged management cell quoted here — so it supplies no phenotype-specific ladder to build a second card from, and splitting one out would put myocarditis's instructions under another diagnosis's name. Pericardial disease has reporting data here (20 of 95 reports fatal) and still no ladder of its own. Venous thromboembolism does have a graded ASCO ladder (section 9.2) and a SITC chapter, but it is an anticoagulation pathway that explicitly continues the ICPi through grade 2 and gives no steroid — a different shape from an irAE card, and SITC's own text declines to separate ICI-induced from cancer-induced events. Accelerated atherosclerosis has no grade ladder at all. All of it is recorded as outstanding in the citation ledger rather than sketched here.
- Linked society recommendations — Left empty although ASCO and SITC are both in this atlas's guideline library: the recommendation stored against each of them there is scoped to ICI-related kidney injury, and linking them would put kidney dosing on a cardiac card. Both cardiac chapters are carried under Sources with their own quotes instead.
Sources
- Herrmann J, et al. (2026) Immune Checkpoint Inhibitor-Associated Cardiovascular Toxic Effects: International Cardio-Oncology Society Position StatementCited for: That myocarditis remains the dominant cardiovascular concern while its fatality rate has fallen and its presenting spectrum has broadened down to troponin elevation of uncertain significance, the breadth of non-myocarditis cardiovascular effects, and that ischemic heart disease is the main differential.Supporting text: the PubMed abstract (checkable at the link above)
- Brahmer JR, et al. (2021) Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse eventsCited for: That cardiac irAEs are uncommon but carry a high mortality rate; the diagnostic sequence and the explicit finding that scheduled troponins in asymptomatic patients have not been shown to help; the MACE-by-steroid-timing figures from Zhang et al; and the whole management ladder — the suspicion trigger, hospital admission with cardiology, the imaging and biopsy pathway, the pulse-dose steroid with its taper, the 24-hour non-response threshold for second line, the caution AGAINST infliximab, and the coronary-care-unit setting with pacing available.Supporting text: the full text
- Schneider BJ, et al. (2021) Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline UpdateCited for: ASCO's Table 9 section 9.1 cardiovascular chapter: that all grades warrant workup and intervention; the grade 1 rule (hold the ICPi for elevated troponin, recheck at 6 hours, and resumption may be considered once normalized or if the rise is believed unrelated) with footnote a's CTCAE v5.0 definition of that grade; the discontinuation threshold at grade 2 and above; high-dose corticosteroids at 1-2 mg/kg/d of prednisone within 24 hours from grade 2; admission for cardiology consultation with coronary-care transfer for elevated troponin or conduction abnormalities and a pacemaker for new conduction delay; the transplant-rejection escalation (methylprednisolone 1 g daily plus mycophenolate, infliximab, or antithymocyte globulin, then abatacept or alemtuzumab in life-threatening cases); the work-up including CPK for concurrent myositis and the triple-M warning; and the qualifying statement's position that the appropriateness of rechallenging remains unknown and that infliximab is contraindicated at high doses in moderate-severe heart failure.Supporting text: the full text
- Mahmood SS, et al. (2018) Myocarditis in Patients Treated With Immune Checkpoint Inhibitors.Cited for: Prevalence, onset window, the combination-ICI exposure skew, the MACE rate and its composition, the proportion of MACE occurring at a normal ejection fraction, the troponin-T threshold associated with MACE, and the observation that lower steroid doses tracked with higher residual troponin and higher MACE.Supporting text: the PubMed abstract (checkable at the link above)
- Salem JE, et al. (2018) Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.Cited for: The disproportionate reporting of myocarditis with ICIs, and the fatal share among reported cardiovascular irAEs — 50% of myocarditis reports, against 21% for pericardial disease and 6% for vasculitis. A share of REPORTS in a spontaneous-reporting database, which is what the framings built on it say.Supporting text: the PubMed abstract (checkable at the link above)
- Zhang L, et al. (2020) Major Adverse Cardiovascular Events and the Timing and Dose of Corticosteroids in Immune Checkpoint Inhibitor-Associated Myocarditis.Cited for: That the timing and dose of corticosteroids in ICI-associated myocarditis has been studied against a major-adverse-cardiovascular-event endpoint. The figures themselves are carried on SITC's span, not this one.Supporting text: the title
- Salem JE, et al. (2019) Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis.Cited for: That abatacept has been reported in severe ICI-associated myocarditis — the published record behind one of the four agents SITC lists for corticosteroid non-response. A single case report; it establishes existence, not efficacy.Supporting text: the title