Immune checkpoint inhibitor myocarditis is not just reported more often in older adults because they receive these drugs more often. This study finds that myocarditis takes up a larger share of reports within older adults’ own reporting background. Cardiovascular toxicity is the immune-related adverse event with the highest reported fatality proportion among immune checkpoint inhibitor complications, and myocarditis mortality reaches 50%.

At the same time, immune checkpoint inhibitor use has expanded into older populations underrepresented in pivotal trials, while cardiotoxicity reporting in these patients has not been quantified. Immune checkpoint inhibitors are monoclonal antibodies targeting CTLA-4, PD-1, or its ligand, PD-L1.

Since the 2011 approval of ipilimumab for advanced melanoma, immune checkpoint inhibitors have become standard of care for multiple solid tumors. The class has expanded to over 100 approved indications across more than a dozen tumor types, and approximately 44% of patients with cancer in the United States are now eligible for an immune checkpoint inhibitor-containing regimen.

Older adults face several structural disadvantages in this clinical landscape, including an aging cardiovascular system with reduced myocardial contractile reserve, increased fibrosis, and stiffening of the conduction system. This cardiovascular substrate lowers tolerance to any acute insult, including immune-mediated injury.

Aging also brings declining thymic output, expanded clonal CD8-positive T-cell populations, and loss of peripheral immune tolerance, changes that may modify the risk of T-cell-mediated cardiotoxicity itself. Multimorbidity, polypharmacy, and frailty further complicate the picture because cardiovascular symptoms attributed to chronic comorbidity may delay recognition.

No previous analysis had stratified immune checkpoint inhibitor-associated cardiotoxicity reporting by patient age in a way that informs geriatric clinical practice. The open question was whether older patients are overrepresented in myocarditis reports beyond what differential exposure would predict.

The analysis therefore aimed to map cardiac adverse event reporting in FAERS and characterize age structure and age-stratified disproportionality across all six commercial immune checkpoint inhibitor agents. Together, these analyses quantify the reporting burden of immune checkpoint inhibitor cardiotoxicity borne by older adults and its implications for geriatric oncology practice.

The capture window spanned 1 January 2011, corresponding to the first FDA approval of an immune checkpoint inhibitor, through 31 March 2026. Six agents were searched by generic name: pembrolizumab, nivolumab, ipilimumab, atezolizumab, durvalumab, and cemiplimab. Eighteen MedDRA Preferred Terms were grouped into six categories: myocarditis, pericardial disease, heart failure or cardiotoxicity, arrhythmia, cardiac arrest, and myocardial infarction.

Takotsubo cardiomyopathy was searched but excluded from primary analyses because of low case counts. Two retrieval strategies were used. For the descriptive overview, drug by Preferred Term records were retrieved separately, so a single report contributing two Preferred Terms within the same category may appear twice.

For myocarditis-specific analyses, the pooled unique-case total of 4,107 was obtained by combining the three myocarditis Preferred Terms and de-duplicating reports containing more than one of them. Reporting odds ratios were calculated with a standard two-by-two disproportionality table against the full FAERS background of approximately 19.4 million reports.

Age-stratified analyses used the corresponding age-restricted background totals, and the ratio expressed fold-amplification in the 65-and-older stratum relative to the under-65 stratum. All reporting odds ratio point estimates exceeded the conventional disproportionality signal threshold of two, with the lower 95% confidence interval bound above one.

For comparison, Reeves and colleagues reported a pooled reporting odds ratio of 30.1 without age stratification. Between January 2011 and March 2026, 18,261 immune checkpoint inhibitor-associated cardiac adverse event drug–reaction records were retrieved from FAERS.

For myocarditis specifically, the unique-case query identified 4,107 reports across the same period. Pembrolizumab accounted for the largest share of cardiac adverse event records, followed by nivolumab, ipilimumab, atezolizumab, durvalumab, and cemiplimab.

Myocarditis records, with all variants combined, contributed 36.7% of overall reporting volume, followed by heart failure or cardiotoxicity at 20.3%. Looking across the myocarditis column, pembrolizumab has 1,897 unique reports compared with 51 for cemiplimab, a difference of 1,846.

In the arrhythmia column, nivolumab’s 1,086 records exceed pembrolizumab’s 948 by 138, while the heart-failure or cardiotoxicity column shows 1,477 versus 1,123. Annual reporting rose substantially over the study period. Total immune checkpoint inhibitor cardiac adverse event records increased from 85 in 2014 to 2,670 in 2024, a 31-fold rise.

The increase was sharper for myocarditis: three reports in 2014 grew to 1,253 in 2024, a 418-fold rise. Across all six agents, the interval between the first reported case and the current peak ranged from nine to twelve years, and no agent showed a plateau through 2024.

In the left panel, pembrolizumab’s blue curve accelerates sharply after twenty twenty, reaching the highest endpoint, while nivolumab remains comparatively elevated but fluctuates. In the right panel, the same late surge is especially clear for pembrolizumab, whereas nivolumab peaks earlier and then declines; the other agents remain in lower bands throughout.

Across approximately 19.4 million FAERS reports, all six immune checkpoint inhibitor agents showed highly elevated disproportionality signals for myocarditis. The pooled reporting odds ratio was 34.21, with a 95% confidence interval from 32.95 to 35.51, and was in line with the magnitude reported by Reeves and colleagues.

Drug-specific reporting odds ratios included 33.34 for pembrolizumab and 29.36 for ipilimumab. Reporting odds ratios in the 65-and-older stratum exceeded those in the under-65 stratum for all six immune checkpoint inhibitor agents. Among the five agents with adequate numbers in both strata, amplification ranged from 1.6-fold for atezolizumab to 3.1-fold for nivolumab.

Nivolumab had a reporting odds ratio of 12.39 in patients under 65 and 38.32 in patients aged 65 or older; pembrolizumab had values of 19.46 and 42.07. Cemiplimab returned the numerically largest ratio, with a reported value of 5.3-fold, but the sentence does not provide the complete confidence interval.

The forest plot’s pink region makes the separation especially clear: the older-group points for pembrolizumab and cemiplimab lie at or beyond the ROR forty boundary, while their younger-group points remain to the left. In the right-hand column, the bold red ratios identify the largest amplifications, whereas cemiplimab’s exceptionally wide younger-group interval visually signals substantial uncertainty.

Among 3,996 unique myocarditis reports with recorded patient age, 36.6% occurred in patients under 65, 35.2% in those aged 65 to 74, and 28.3% in those aged 75 or older. Two-thirds, or 63.4%, of all immune checkpoint inhibitor myocarditis reports therefore occurred in patients aged 65 or older, and over a quarter occurred in patients aged 75 or older.

These proportions exceeded the participation rates of these age groups in pivotal trials by 10.4 to 25.7 percentage points. The age distribution differed across agents: pembrolizumab and atezolizumab were more balanced, while nivolumab, ipilimumab, and durvalumab showed greater concentration in older patients.

Look across the red segments: they expand from twenty percent for atezolizumab and twenty-seven percent for pembrolizumab to thirty-three percent for durvalumab, while cemiplimab reaches fifty-three percent. The far-right sample-size labels also show why that last proportion should be interpreted cautiously: cemiplimab is based on only thirty age-recorded reports.

The fatal-outcome proportions by agent were 31.4% for pembrolizumab, 35.5% for nivolumab, 33.4% for ipilimumab, 26.9% for atezolizumab, 33.9% for durvalumab, and 49.0% for cemiplimab. Cardiac arrest events demonstrated the highest case-fatality rates of any reaction category, ranging from 76.3% to 81.6% across five agents with adequate sample sizes, with a pooled fatality of 78.1%.

Ventricular fibrillation reports also showed high mortality, with pooled mortality of 50.6% across agents. Reaction categories with the highest fatality rates also showed higher proportions of records in patients aged 75 or older. In the upper region, the five cardiac-arrest bubbles sit tightly together despite differing age distributions, while the cemiplimab star is separated at the far right.

The myocarditis points spread across roughly the mid-thirties to upper-forties on the age-skew axis, with the cemiplimab myocarditis point furthest right among them. The key observation is not simply that older adults account for most immune checkpoint inhibitor myocarditis reports, because that partly follows from who receives these drugs.

The key observation is that older adults’ reporting odds for myocarditis are elevated relative to their own age-matched reporting background. Because each stratum is compared with the FAERS background for the same stratum, the amplification is not generated by older patients’ larger overall report volume or greater exposure to medication and reporting in general.

The 1.6- to 3.1-fold amplification describes a change in the composition of what is reported: within everything reported about older patients, myocarditis occupies a larger share than among younger patients. Among patients aged 75 or older, 17.0% had a co-prescribed QT-prolonging agent, beta-blocker, or diuretic, compared with 9.7% of patients under 65.

Beta-blocker co-prescription was 2.5-fold higher, and diuretic co-prescription was 3.2-fold higher, in the 75-and-older stratum. The interval from the earliest recorded immune checkpoint inhibitor start date to FAERS report receipt was shorter in older patients: a median of 97 days in those aged 75 or older versus 148 days in those under 65.

Nearly half of patients aged 75 or older had myocarditis reports received within 90 days of recorded treatment start, compared with 37.8% of younger patients; this is a temporal reporting pattern rather than true clinical onset. FAERS is a spontaneous reporting system with incomplete case ascertainment, unknown denominators, and reporting rates that vary with drug familiarity, indication expansion, regulatory attention, and clinician awareness.

Apparent rises in reporting cannot be cleanly attributed to rising true incidence rather than rising recognition or reporting fidelity. Although age-stratified reporting odds ratios compare each age group with its same-stratum background, residual confounding from indication mix, comorbidity, and reporting behavior remains possible.

Fatal-outcome proportions from FAERS may over-represent severe outcomes because mild events are less often reported. Across 4,107 unique immune checkpoint inhibitor-associated myocarditis reports filed over 15 years, myocarditis was disproportionately concentrated in older adults.

Two-thirds of cases occurred in patients aged 65 or older, and the disproportionality signal was amplified in this age group for every agent examined. Among the five agents with adequate numbers in both strata, amplification ranged from 1.6- to 3.1-fold, while cemiplimab had a larger but unstable ratio because its comparison stratum contained three reports.

Older adults therefore appear disadvantaged through both under-representation in pivotal trials and an age-amplified pharmacovigilance signal concentrated in the group those trials studied least. Figure five presents an illustrative, non-prescriptive three-stage framework for patients aged sixty-five and older receiving immune checkpoint inhibitors.

Stage one combines geriatric screening, cardiovascular assessment, polypharmacy review, and counselling; stage two places age-stratified myocarditis reporting odds ratios alongside cautions about surveillance and small numbers; and stage three emphasizes symptom recognition, escalation, and follow-up.

The visual matters because it connects existing geriatric and cardio-oncology guidance while clearly distinguishing reporting signals from incidence or causal risk. Across more than four thousand unique myocarditis reports, older adults made up most cases and showed higher reporting odds for every agent examined.

The signal supports closer cardiac surveillance in geriatric oncology, while remaining a disproportionality signal rather than proof of incidence or causation.