Abstract
Background
Immune‐checkpoint inhibitors (ICI) are associated with adverse cardiac events. Although troponin elevation is a diagnostic criterion for ICI‐related myocarditis (ICIrM) and myocardial infarction, data on other causes of troponin elevation and their outcomes in ICI‐treated patients are limited.
Methods
All patients treated with ICI who had hs‐TnT (high‐sensitivity troponin T) measured at a multicenter institution from 2011 to 2022 were included. Clinical data, outcomes (cardiac death, heart failure (HF), major adverse cardiovascular events [myocardial infarction, stroke, heart failure]), and cause of hs‐TnT elevation were assessed. Risks of cardiac events were compared across hs‐TnT elevation causes.
Results
Of 5423 patients treated with ICI, 1669 had post‐ICI hs‐TnT measurement (mean age 68.7±11.3 years, 58.3% male), with 1‐year follow‐up. Hs‐TnT elevation in patients with ICIrM (n=59) was associated with the highest risk for cardiac death (hazard ratio [HR], 52.7 [95% CI, 11.7–238.0], P<0.001), followed by hs‐TnT elevation due to heart failure (HR, 15.9), myocardial infarction/type 2 ischemia (HR, 11.6), and infection/sepsis (HR, 5.7), compared with those with no hs‐TnT elevation. ICIrM also carried highest risk for major adverse cardiovascular events (HR, 8.2, [95% CI, 4.4–15.3], P<0.001), followed by myocardial infarction/type 2 ischemia (HR, 8.1), heart failure (HR, 7.6), pulmonary embolus (HR, 5.1), infection/sepsis (HR, 4.1), and indeterminate cause (HR, 2.4). Among ICIrM, HsTnT value >576 ng/L best predicted risk for cardiac death and >319 ng/L for major adverse cardiovascular events.
Conclusions
Hs‐TnT elevation after ICI therapy is associated with increased risk of cardiac events, particularly in ICIrM, and a graded prognostic association depending on the cause of hs‐TnT elevation. Identifying the underlying cause and troponin thresholds may guide risk stratification and management.
Keywords: immune‐checkpoint inhibitors, myocarditis, troponin
Subject Categories: Cardio-Oncology
Nonstandard Abbreviations and Acronyms
- ICI
immune checkpoint inhibitor
- ICIrM
immune checkpoint inhibitor–related myocarditis
- MACE
major adverse cardiovascular events
Clinical Perspective.
What Is New?
In a large, multicenter cohort of patients undergoing immune checkpoint inhibitor (ICI) therapy, we found that elevated hs‐TnT (high‐sensitivity troponin T) levels occurred in nearly 1 in 5 patients, with ICI–related myocarditis carrying the highest risk of cardiac death, heart failure, and major adverse cardiovascular events.
Stratifying hs‐TnT elevations by cause provides critical prognostic information, with ICI–related myocarditis, myocardial infarction/type 2 ischemia, and chronic heart failure associated with the worst cardiovascular outcomes.
We identified cause‐specific hs‐TnT thresholds predictive of cardiac death and major adverse cardiovascular events, and demonstrated that patients with fulminant ICI–related myocarditis and concomitant myositis had significantly higher hs‐TnT levels and worse prognosis.
What Are the Clinical Implications?
Hs‐TnT is a valuable biomarker not only for the diagnosis of ICI–related myocarditis but also for risk stratification of cardiovascular events in patients receiving ICI therapy, including those without myocarditis.
Cause‐specific troponin thresholds may enhance early detection and guide intensity of cardiac monitoring and therapeutic decisions.
Integrating serial hs‐TnT measurement into routine clinical surveillance protocols for ICI‐treated patients could improve outcomes by enabling earlier recognition of cardiovascular complications.
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for many types of cancers. 1 , 2 , 3 , 4 However, their use is associated with cardiovascular toxicities, such as ICI‐related myocarditis (ICIrM) and other associated adverse cardiovascular events that can significantly impact patient prognosis. 5 , 6 , 7 , 8 , 9 , 10 Although rare, affecting ≈1% of patients, ICIrM carries high morbidity and mortality rates, with fatal outcomes reported in 25% to 40% of cases. 11 , 12 ICI therapy has also been associated with accelerated coronary atherosclerosis and myocardial infarction (MI). 13
Elevated hs‐TnT (high sensitivity troponin T), a key biomarker for cardiac injury, is a potential diagnostic and prognostic tool in the context of ICI therapy. 11 , 14 Elevated hs‐TnT forms part of the diagnostic criteria both for ICIrM and MI. The timely detection and management of the different causes of hs‐TnT elevation, especially ICIrM, are crucial for improving patient survival and mitigating long‐term cardiovascular damage. 15 Moreover, the underlying causes of hs‐TnT elevation and its clinical implications, particularly with respect to the prediction of adverse cardiovascular outcomes during treatment with ICI is not well understood. This study aims to characterize the causes of hs‐TnT elevation and its prognostic value for prediction of cardiovascular outcomes in patients undergoing ICI therapy.
METHODS
Study Population
This retrospective cohort study was approved by the institutional review board. The data that support the findings of this study are available from the corresponding author upon reasonable request. All patients included had provided consent at time of treatment for research review, and consent was waived for this specific retrospective review of the data by the institutional review board. Adult patients (age>18 years) who were treated with an ICI between January 2011 and June 2022 at the 3 main Mayo Clinic sites (Rochester, MN, Phoenix, AZ, and Jacksonville, FL) and had a hs‐TnT value measured after initiation of therapy were identified from the Mayo Clinic institutional patients' records. Highest hs‐TnT value during ICI therapy was considered and elevated hs‐TnT level was defined as >14 ng/L. Roche Elecsys hs‐TnT assay was used in our institution, with a limit of blank of 2.5 mg/L, limit of detection of 3 ng/L, 99th percentile cutoff of 14 ng/L, and a coefficient of variation of 9% at 6 ng/L. Charts were reviewed for a clinical diagnosis including ICIrM, 16 , 17 MI/type 2 ischemia, 18 chronic heart failure (CHF), 19 pulmonary embolism (PE), 20 infection/sepsis, 21 or indeterminate cause per current guidelines to further subclassify the study population based on potential cause of hs‐TnT elevation. Infection/sepsis were categorized separately to type 2 MI when there was clear documentation of active infection at the time of hs‐TnT elevation to provide further granularity to the data. In contrast, cases adjudicated as type 2 MI were classified based on clinical judgment without evidence of concurrent sepsis. For ICIrM, the diagnosis was guided by current recommendations and incorporated clinical signs and symptoms, echocardiographic findings, cardiac magnetic resonance imaging or endomyocardial biopsy when available, and the presence of other concomitant immune‐related adverse events. 22
Clinical Data
Baseline demographics, cardiovascular risk factors and comorbidities, laboratory values, and echocardiographic parameters including left ventricular ejection fraction were manually extracted from electronic medical records. Oncological characteristics including type of cancer, previous treatment with potentially cardiotoxic agents, and type of ICI administered were recorded.
Clinical outcomes of interest included all‐cause and cardiac mortality, HF defined as a drop in left ventricular ejection fraction <50% accompanied by signs and symptoms or HF exacerbations/hospitalizations, ischemic stroke/transient ischemic attack, and MI. These events were adjudicated by specialist teams involved in clinical care and documented in the patients' notes, with use of respective current guideline definitions. 23 , 24 , 25 , 26 Major adverse cardiovascular events (MACE) was defined as HF, MI, and ischemic stroke/transient ischemic attack. To mitigate the potential confounding effect of cancer‐related mortality, we stratified outcomes into all‐cause and cardiovascular mortality.
Clinical Data for Patients With ICIrM
Patients identified as having ICIrM additionally underwent a detailed chart review to capture all hs‐TnT measurements during the ICIrM episode and all subsequent hs‐TnT measurements available. Data regarding the severity for the ICIrM episode were also assessed and are detailed in previous publication 22 ; fulminant ICIrM was defined by hemodynamic instability, HF requiring noninvasive or invasive ventilation, complete heart block, or significant ventricular arrhythmia. Nonfulminant ICIrM included symptomatic but hemodynamically and electrically stable patients and incidental cases diagnosed at the same time as other immune‐related adverse events.
Statistical Analysis
None of the variables in our data set had more than 5% missing values. For these instances, we assumed the data were missing completely at random and proceeded with a complete case analysis without performing imputation. Continuous variables were summarized as mean±SD or median and interquartile range (IQR) according to their distribution, and categorical variables were expressed as frequencies with percentages. Independent samples t test or nonparametric tests were employed to compare continuous variables and chi‐square to compare categorical variables. The association between hs‐TnT elevation and clinical outcomes at 1‐year follow‐up were summarized using hazard ratios (HR) and 95% CI, estimated with Cox regression models. Kaplan–Meier curves were applied to assess survival in patients' subgroups. P values of <0.05 were considered statistically significant for all analyses. Receiver operator curve analysis was conducted to assess the accuracy of hs‐TnT to detect cardiac death and MACE in patients with ICIrM. Statistical analyses were conducted using IBM SPSS Statistics software, version 28.0 (IBM SPSS Inc., Armonk, NY, USA).
RESULTS
Of 5423 patients treated with ICI, 1669 had post‐ICI hs‐TnT measurement. In patients with post‐ICI hs‐TnT, mean age was 68.7±11.3 years, and 58.4% were male, with follow‐up at 1 year after ICI initiation. Normal hs‐TnT was recorded in 533 (9.8%) patients. Of those with abnormal hs‐TnT, in 59 (5.2%) patients hs‐TnT elevation was attributed to a diagnosis of ICIrM, and 1077 (94.8%) patients were considered to have increased hs‐TnT due to other causes. Among patients with increased hs‐TnT due to other causes, 216 (20.0%) were due to infection/sepsis, 171 (15.9%) due to MI/type 2 ischemia, 70 (6.5%) due to CHF independent of ICIrM, 51 (4.8%) due to PE, and 569 (52.8%) were related to indeterminant cause, Figure 1. Baseline characteristics, coefficient of variation risk factors and history, and baseline cancer‐ and ICI‐related characteristics are reported in Table 1.
Figure 1. Causes of increased hs‐TnT values.
CHF indicates chronic heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor related myocarditis; MI, myocardial infarction; and PE, pulmonary embolism. *The percentages in this figure are based on all 1136 patients with hs‐TnT elevation, which includes 59 patients with ICIrM and 1077 patients with other causes of hs‐TnT elevation. In the Results section, the percentages related to other causes of hs‐TnT elevation are calculated using only the 1077 patients with those causes.
Table 1.
Baseline Characteristics
| No hs‐TnT elevation (n=533) | ICIrM (n=59) | MI/type 2 ischemia (n=171) | CHF (n=70) | PE (n=51) | Infection/sepsis (n=216) | Indeterminate (n=569) | |
|---|---|---|---|---|---|---|---|
| Age, y | 64.2±11.6 | 70.3±11.3 | 71.4±9.9 | 72.7±12.3 | 69.8±9.4 | 71.9±10.7 | 70.1±10.4 |
| Sex, n (%) | |||||||
| Male | 254 (47.7%) | 39 (66.1%) | 104 (60.8%) | 45 (64.3%) | 32 (62.7%) | 147 (68.1%) | 353 (62.0%) |
| Female | 279 (52.3%) | 20 (33.9%) | 67 (39.2%) | 25 (35.7%) | 19 (37.3%) | 69 (31.9%) | 216 (38.0%) |
| Cardiovascular risk factors, n (%) | |||||||
| Hypertension | 308 (57.8%) | 48 (81.3%) | 139 (81.3%) | 62 (88.6%) | 41 (80.4%) | 175 (81.0%) | 448 (78.7%) |
| Dyslipidemia | 305 (57.2%) | 43 (72.9%) | 132 (77.2%) | 58 (82.9%) | 33 (64.7%) | 150 (69.4%) | 415 (72.9%) |
| Diabetes | 95 (17.8%) | 12 (20.3%) | 53 (31.0%) | 35 (50.0%) | 15 (29.4%) | 63 (29.2%) | 183 (32.2%) |
| Smoking | 301 (56.5%) | 31 (52.5%) | 112 (65.5%) | 40 (57.1%) | 31 (60.8%) | 144 (66.7%) | 332 (58.3%) |
| Family history of coronary artery disease | 171 (32.1%) | 22 (37.2%) | 58 (33.9%) | 28 (40.0%) | 18 (35.3%) | 75 (34.7%) | 197 (34.6%) |
| Cardiovascular diagnoses, n (%) | |||||||
| History of stroke/transient ischemic attack | 72 (13.5%) | 13 (22.0%) | 28 (16.4%) | 15 (21.4%) | 6 (11.8%) | 35 (16.2%) | 104 (18.3%) |
| History of MI | 40 (7.5%) | 5 (8.5%) | 44 (25.7%) | 16 (22.9%) | 4 (7.8%) | 41 (19.0%) | 96 (16.9%) |
| CHF | 35 (6.6%) | 9 (15.2%) | 32 (18.7%) | 34 (48.6%) | 7 (13.7%) | 59 (27.3%) | 112 (19.7%) |
| History of atrial fibrillation | 53 (9.9%) | 17 (28.8%) | 46 (26.9%) | 29 (41.4%) | 14 (27.4%) | 63 (29.2%) | 131 (23.0%) |
| History of ventricular tachycardia | 22 (4.1%) | 2 (3.4%) | 11 (6.4%) | 10 (14.3%) | 2 (3.9%) | 20 (9.2%) | 44 (7.7%) |
| Prior percutaneous coronary intervention | 32 (6.0%) | 6 (10.1%) | 30 (17.5%) | 12 (17.1%) | 2 (3.9%) | 24 (11.1%) | 74 (13.0%) |
| Prior coronary artery bypass grafting | 18 (3.4%) | 4 (6.8%) | 12 (7.0%) | 12 (17.1%) | 3 (5.9%) | 20 (9.2%) | 40 (7.0%) |
| Other medical comorbidities, n (%) | |||||||
| Chronic obstructive pulmonary disease | 123 (23.1%) | 10 (16.9%) | 53 (31.0%) | 27 (38.6%) | 11 (21.6%) | 81 (37.5%) | 159 (27.9%) |
| Obstructive sleep apnea | 92 (17.3%) | 13 (22.0%) | 43 (25.1%) | 22 (31.4%) | 12 (23.5%) | 60 (27.8%) | 143 (25.1%) |
| Transthoracic echocardiogram | |||||||
| Ejection fraction, % | 59.7±7.2 | 59.2±7.9 | 56.7±9.8 | 49.6±13.9 | 58.6±9.0 | 57.3±10.3 | 57.9±9.8 |
| Laboratory values | |||||||
| Hemoglobin, g/dL | 12.2±1.9 | 12.3±1.9 | 12.1±2.0 | 11.6±1.9 | 12.0±2.6 | 11.6±2.2 | 11.9±2.1 |
| Creatinine, mg/dL | 0.9±0.3 | 1.2±0.9 | 1.1±0.6 | 1.5±1.2 | 1.0±0.3 | 1.2±0.7 | 1.1±0.7 |
| C‐reactive protein, mg/L | 9.2 (29.4) | 5.1 (19.5) | 5.8 (25.9) | 8.1 (32.5) | 15.7 (29.2) | 10.9 (38.7) | 9.9 (37.3) |
| White blood cell count, ×109/L | 7.7±3.4 | 7.6±2.7 | 9.2±5.2 | 7.5±4.2 | 8.5±3.2 | 7.6±2.3 | 7.7±3.2 |
| Type of cancer, n (%) | |||||||
| Melanoma | 91 (17.1%) | 14 (23.7%) | 24 (14.0%) | 10 (14.3%) | 6 (11.8%) | 30 (13.9%) | 67 (11.8%) |
| Lung cancer | 268 (50.3%) | 19 (32.2%) | 90 (53.8%) | 31 (44.3%) | 29 (56.9%) | 112 (51.8%) | 274 (48.1%) |
| Gastrointestinal | 44 (8.2%) | 2 (3.4%) | 13 (7.6%) | 5 (7.1%) | … | 12 (5.6%) | 39 (6.8%) |
| Renal cell carcinoma | 86 (16.1%) | 14 (23.7%) | 34 (19.9%) | 19 (27.1%) | 11 (21.6%) | 53 (24.5%) | 142 (24.9%) |
| Hepatobiliary | 38 (7.1%) | 6 (10.1%) | 7 (4.1%) | 5 (7.1%) | 2 (3.9%) | 9 (4.2%) | 40 (7.0%) |
| Head and neck | … | … | 3 (1.7%) | … | 1 (2.0%) | … | 3 (0.5%) |
| Gynecological | 6 (1.1%) | 2 (3.4%) | … | … | 2 (3.9%) | … | 4 (0.7%) |
| Immune‐checkpoint inhibitors, n (%) | |||||||
| Pembrolizumab | 223 (41.3%) | 25 (42.4%) | 88 (51.4%) | 33 (47.1%) | 31 (60.8%) | 110 (50.9%) | 278 (48.9%) |
| Nivolumab | 106 (19.9%) | 9 (15.2%) | 18 (10.5%) | 14 (20.0%) | 5 (9.8%) | 23 (10.6%) | 83 (14.6%) |
| Ipilimumab | 9 (1.7%) | … | 2 (1.2%) | 1 (1.4%) | … | 1 (0.4%) | 2 (0.3%) |
| Atezolizumab | 73 (13.7%) | 6 (10.1%) | 21 (12.3%) | 12 (17.1%) | 3 (5.9%) | 30 (13.9%) | 70 (12.3%) |
| Durvalumab | 29 (5.4%) | 4 (6.8%) | 16 (9.3%) | 4 (5.7%) | 2 (3.9%) | 16 (7.4%) | 33 (5.8%) |
| Cemiplimab | 1 (0.2%) | … | 2 (1.2%) | … | 1 (2.0%) | 2 (0.9%) | 6 (1.0%) |
| Avelumab | 6 (1.1%) | … | … | … | … | 2 (0.9%) | 2 (0.3%) |
| Combined | 86 (16.1%) | 14 (23.7%) | 24 (14.0%) | 6 (8.6%) | 9 (17.6%) | 32 (14.8%) | 95 (16.7%) |
CHF indicates congestive heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor related myocarditis; MI, myocardial infarction; PE, pulmonary embolism.
Median hs‐TnT values at time of diagnosis are shown in Figure 2, with ICIrM patients exhibiting the highest median hs‐TnT value of 364 ng/L (IQR, 1096), followed by a median of 98 ng/L (IQR, 209) for MI/type 2 ischemia, 61 ng/L (IQR, 37) for infection/sepsis, 51 ng/L (IQR, 55) for PE, 50 ng/L (IQR, 70) for CHF, and 27 ng/L (IQR, 32) for indeterminate causes. Additionally, median time and median number of doses from first ICI dose to hs‐TnT elevation according to each of the diagnoses are depicted in Figure 3A and 3B, with ICIrM showing a median time of 44 days (IQR, 74) with a median of 2 doses (IQR, 3), the shortest median time and number of doses when compared with the other groups. Among patients with other causes of hs‐TnT elevation, the median time from ICI initiation to hs‐TnT elevation was 138 days (IQR, 326) for MI/type 2 ischemia, 149 days (IQR, 342) for CHF, 152 days (IQR, 258) for indeterminate cause, 158 days (IQR, 319) for infection/sepsis, and 159 days (IQR, 283) for PE. The median number of ICI doses received before hs‐TnT elevation was 6 for MI/type 2 ischemia and indeterminate cause and 5 for CHF, infection/sepsis, and PE.
Figure 2. Median hs‐TnT and IQR values (in brackets) for each diagnosis.
CHF indicates chronic heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor‐related myocarditis; IQR, interquartile range; MI, myocardial infarction; and PE, pulmonary embolism.
Figure 3. Time to each diagnosis after the initiation of ICI.
A, Median time from the first ICI dose to elevation of hs‐TnT. B, Median number of doses. CHF indicates chronic heart failure; ICIrM, immune‐checkpoint inhibitor related myocarditis; IQR, interquartile range; MI, myocardial infarction; and PE, pulmonary embolism.
Patients with hs‐TnT elevation had worse prognosis than those with no hs‐TnT elevation in terms of all‐cause death (HR, 1.2 [95% CI, 1.1–1.4], P=0.005), cardiac mortality (HR, 8.7 [95% CI, 2.1–36.4], P=0.003), HF (HR, 4.1 [95% CI, 2.4–7.0], P<0.001), and MACE (HR, 4.1 [95% CI, 2.7–6.4], P<0.001). Specifically for all‐cause mortality, patients with hs‐TnT elevation due to PE (HR, 1.6 [95% CI, 1.0–2.3], P=0.016) or infection/sepsis (HR, 1.5 [95% CI, 1.2–1.9], P<0.001) had an increased risk of death compared with those with no hs‐TnT elevation, Table 2, Figure 4. With respect to cardiac death, patients with ICIrM had the worst prognosis of all (HR, 52.7 [95% CI, 11.7–238.0], P<0.001), followed by patients with hs‐TnT elevation due to CHF (HR, 15.9 [95% CI, 2.9–87.0], P=0.001), MI/type 2 ischemia (HR, 11.6 [95% CI, 2.4–56.1], P=0.002), and infection/sepsis (HR, 5.7 [95% CI, 1.0–31.0], P=0.045), when compared with those with no hs‐TnT elevation Table 2, Figure 5. Patients with ICIrM exhibited the worst prognosis for MACE and HF (HR, 8.2 [95% CI, 4.4–15.3], P<0.001, HR, 11.3 [95% CI, 5.5–23.1], P<0.001), followed by patients with increased in hs‐TnT due to MI/type 2 ischemia (HR, 8.1 [95% CI, 5.0–13.1], P<0.001, HR, 5.6 [95% CI, 2.9–10.7], P<0.001), CHF (HR, 7.6 [95% CI, 4.2–13.7], P<0.001, HR, 10.2 [95% CI, 5.1–20.5], P<0.001), PE (HR, 5.1 [95% CI, 2.5–10.8], P<0.001, HR, 4.8 [95% CI, 1.9–12.6], P=0.001), infection/sepsis (HR, 4.1 [95% CI, 2.4–7.0], P<0.001, HR, 4.7 [95% CI, 2.5–9.0], P<0.001), and indeterminate cause (HR, 2.4 [95% CI, 1.5–3.8], P<0.001, HR, 2.1 [95% CI, 1.1–3.9], P=0.018), Table 2, Figures 6 and 7.
Table 2.
Outcomes in Patients With No Hs‐TnT Elevation Versus Those With Hs‐TnT Elevation Due to Different Causes
| No hs‐TnT elevation (n=533, median hs‐TnT=10) | ICIrM (n=59, median hs‐TnT=364) | MI/type 2 ischemia (n=171, median hs‐TnT=98) | CHF (n=70, median hs‐TnT=50) | PE (n=51, median hs‐TnT=51) | Infection/sepsis (n=216, median hs‐TnT=61) | Indeterminate (n=569, median hs‐TnT=27) | |
|---|---|---|---|---|---|---|---|
| All‐cause mortality | 237 (44.4%) | 28 (47.4%) | 83 (48.5%) | 33 (47.1%) | 31 (60.8%) | 127 (58.8%) | 278 (48.8%) |
| HR (95% CI) | Reference | 1.1 (0.7–1.7) | 1.2 (0.9–1.5) | 1.1 (0.8–1.6) | 1.6 (1.1–2.3) | 1.5 (1.2–1.9) | 1.1 (0.9–1.3) |
| P value | 0.004 | 0.512 | 0.203 | 0.498 | 0.016 | <0.001* | 0.119 |
| Cardiac death | 2 (0.4%) | 11 (18.6%) | 7 (4.1%) | 4 (5.7%) | 1 (1.9%) | 4 (1.8%) | 8 (1.4%) |
| HR (95% CI) | Reference | 52.7 (11.7–238.0)* | 11.6 (2.4–56.1) | 15.9 (2.9–87.1) | 5.9 (0.5–64.9) | 5.7 (1.0–31.0)* | 3.8 (0.8–18.3) |
| P value | <0.001 | <0.001* | 0.002* | 0.001* | 0.148 | 0.045* | 0.086 |
| Major adverse cardiovascular events | 24 (4.5%) | 17 (28.8%) | 51 (29.8%) | 20 (28.6%) | 10 (16.6%) | 33 (15.3%) | 57 (10.0%) |
| HR (95% CI) | Reference | 8.2 (4.4–15.3)* | 8.1 (5.0–13.1)* | 7.6 (4.2–13.7)* | 5.1 (2.5–10.8)* | 4.1 (2.4–7.0) | 2.4 (1.5–3.8)* |
| P value | <0.001 | <0.001* | <0.001 | <0.001 | <0.001 | <0.001* | <0.001* |
| Heart failure | 15 (2.8%) | 15 (25.4%) | 24 (14.0%) | 17 (24.2%) | 6 (11.7%) | 24 (11.1%) | 32 (5.6%) |
| HR (95% CI) | Reference | 11.3 (5.5–23.1)* | 5.6 (2.9–10.7)* | 10.2 (5.1–20.5)* | 4.8 (1.9–12.6)* | 4.7 (2.5–9.0) | 2.1 (1.1–3.9) |
| P value | <0.001 | <0.001* | <0.001* | <0.001 | 0.001 | <0.001* | 0.018* |
CHF indicates congestive heart failure; HR, hazard ratio; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor related myocarditis; MI, myocardial infarction; and PE, pulmonary embolism.
Significantly increased risk in these causes of elevation of hs‐TnT.
Figure 4. All‐cause mortality in patients with hs‐TnT elevation due to different causes versus patients with no hs‐TnT elevation.
CHF indicates chronic heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor‐related myocarditis; MI, myocardial infarction; and PE, pulmonary embolism.
Figure 5. Cardiac death in patients with hs‐TnT elevation due to different causes versus patients with no hs‐TnT elevation.
CHF indicates chronic heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor‐related myocarditis; MI, myocardial infarction; and PE, pulmonary embolism.
Figure 6. HF in patients with hs‐TnT elevation due to different causes versus patients with no hs‐TnT elevation.
CHF indicates chronic heart failure; HF, heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor‐related myocarditis; MI, myocardial infarction; and PE, pulmonary embolism
Figure 7. MACE in patients with hs‐TnT elevation due to different causes versus patients with no hs‐TnT elevation.
CHF indicates chronic heart failure; hs‐TnT, high‐sensitivity troponin T; ICIrM, immune‐checkpoint inhibitor‐related myocarditis; MACE, major adverse cardiovascular events; MI, myocardial infarction; and PE, pulmonary embolism.
For ICIrM, an optimal hs‐TnT cutoff value of 576 ng/L was identified as predictive of cardiac death, with an area under the curve (AUC) of 0.701, a sensitivity of 72.0% and specificity of 61.0%. To predict MACE in ICIrM, a cutoff of 319 ng/L was determined, with AUC of 0.607, sensitivity of 70.0%, and specificity of 52.0%. Among patients with hs‐TnT elevation due to other causes, a cutoff of 48.5 ng/L was predictive of cardiac death, with AUC of 0.661, sensitivity of 66.7%, and specificity of 61.0%. Additionally, a cutoff value of 44.5 ng/L was associated with MACE prediction, with AUC of 0.683, sensitivity of 68.4%, and a specificity of 62.0%.
Among patients with ICIrM, 40 underwent cardiac MRI, and 3 underwent endomyocardial biopsy. 10 Additionally, other immune‐related toxic effects in ICIrM included myositis in 25 (42.4%) patients, myasthenia gravis in 12 (20.3%), pneumonitis in 14 (23.7%), hepatitis in 19 (32.2%), pericarditis in 7 (11.9%), and colitis in 4 (6.8%). Triple M syndrome, defined as concomitant ICIrM, myositis, and myasthenia gravis, was present in 12 (20.3%) patients. 22 Median hs‐TnT in patients who presented with ICIrM alone was 169 (IQR, 532), whereas median hs‐TnT in those patients who presented with ICIrM and myositis was 1124 (IQR, 1484).
All hs‐TnT measurements in the first 30 days in the cohort with ICIrM are depicted in Figure 8. There were 32 patients who had hs‐TnT measurements beyond the first 30 days of ICIrM diagnosis, with median hs‐TnT within the first 30 days of 316 ng/L (IQR, 661), and median hs‐TnT after 30 days was 54 ng/L (IQR, 139). Of these 32 patients, 26 had hs‐TnT normalized or returned to baseline, with a median hs‐TnT of 274 (IQR, 728) during the ICIrM event and 36 ng/L (IQR, 31) upon return to baseline, achieved over a median of 111 days (IQR, 98, range 35 to 797 days), and the remaining 6 patients had a slow decrease in hs‐TnT from their highest level, and hs‐TnT values remained >100 ng/L. Of the 6 patients who experienced persistent hs‐TnT elevations, only 1 was rechallenged with the ICI, whereas the other 5 had their ICI therapy discontinued. For the patient who was rechallenged, the peak hs‐TnT level during the ICIrM event was 1414 ng/L, which decreased to 360 ng/L 3 months after the event. Among the other 27 patients from 59 with ICIrM who did not have a hs‐TnT measurement after 30 days, 15 died within the first 30 days and 12 had stopped measurements due to being under palliative care.
Figure 8. All hs‐TnT measurements within the first 30 days of ICIrM diagnosis.
hs‐TnT indicates high‐sensitivity troponin T; and ICIrM, immune‐checkpoint inhibitor‐related myocarditis.
Median hs‐TnT in those with severe/fulminant and nonsevere/nonfulminant ICIrM was 672 (IQR, 1516) and 147 (IQR, 559) respectively. Of the 59 patients with ICIrM, 6 were rechallenged with ICI. These patients had a median hs‐TnT level of 478 ng/L (IQR, 666), and no cardiac events post rechallenge (4 successfully continued ICI treatment without complications, and 2 had to discontinue ICI for noncardiac reasons such as development of lichenoid dermatitis and acute interstitial nephritis respectively). During follow‐up, 8 out of our 59 (13.8%) patients with ICIrM continued to exhibit elevated hs‐TnT levels despite the normalization of troponin I.
In a sex‐stratified analysis of patients with elevated hs‐TnT, men exhibited a higher frequency of troponin elevation compared with women (73.9% versus 59.8%, P<0.001), with ICIrM being the most common cause in both groups, Tables S1. ICIrM was the strongest predictor of cardiac death in both sexes, with a higher HR in women, and conferred higher HF and MACE risk in men. MI/type 2 ischemia was associated with increased risk for all outcomes in women, but only for HF and MACE in men. CHF increased the risk of all outcomes in men, whereas in women cardiac death was the only significant association. PE and infection/sepsis were more significantly associated with adverse outcomes in men.
DISCUSSION
In a multicenter cohort of patients treated with ICI, we demonstrate that stratifying patients based on the cause of hs‐TnT elevation provides prognostic value and enables identification of high‐risk subgroups. We report that hs‐TnT elevations above the upper reference value were seen in nearly 1 out of 5 patients receiving ICI therapy. Importantly, the cause of these elevations were significantly associated with clinical outcomes, highlighting the potential for targeting high risk groups for aggressive management. Although ICIrM accounted for only 1.1% of the total ICI cohort, it carried the worst prognosis, underscoring the critical need for early recognition and intervention. Patients with ICIrM exhibited the highest median hs‐TnT levels and the shortest median time to hs‐TnT elevation after ICI initiation, reinforcing the need for serial hs‐TnT measurements for early detection.
Hs‐TnT elevation due to other causes was also associated with worse clinical outcomes. For example, patients with hs‐TnT elevation due to infection/sepsis or PE had a significantly increased risk of all‐cause mortality, whereas those with CHF and MI/type 2 ischemia demonstrated higher rates of MACE and HF (hospitalizations in those patients with CHF). Our findings are consistent with what has been reported in the literature; however, it identifies specific subgroups of patients and demonstrates a gradation of risk.
Petricciuolo et al. investigated pre‐ICI hs‐TnT thresholds predictive of adverse outcomes. Their study differs from ours not only in its focus on pretreatment hs‐TnT thresholds but also in its creation of a composite outcome for cardiovascular death, stroke/transient ischemic attack, PE, and new‐onset HF. 14 In contrast, our study analyzed post‐ICI hs‐TnT levels and identified specific thresholds for distinct patient subgroups, as we demonstrated that a hs‐TnT cutoff of 576 ng/L predicted cardiac death in patients with ICIrM, whereas a lower cutoff of 319 ng/L was predictive of MACE in this population, which may guide clinical decision‐making by prompting closer monitoring and more aggressive management in patients with elevation of the hs‐TnT above these numbers. Additionally, our study identified predictive hs‐TnT thresholds for nonmyocarditis cases, with values around 40 ng/L for cardiac death and MACE, suggesting a higher cutoff compared with the one proposed in the previously mentioned study. 14
A recent prospective observational study by van den Berg et al reported significant elevations in hs‐TnT in 26 out of 164 patients undergoing ICI treatment. 27 Among these 26 patients, only 8 (5%) were diagnosed with ICIrM, with hs‐TnT levels consistently exceeding 160 ng/L, whereas levels in patients without ICIrM remained <156 ng/L. Additionally, they observed a 12.5% cardiac mortality rate among patients with ICIrM. Although our study similarly identifies a comparable percentage of ICIrM diagnosis (5.2%) among patients with elevated hs‐TnT (59 out of 1136 patients), our cardiac mortality rate is notably higher (18.6%). This discrepancy could be attributed to the retrospective nature of our study, in contrast to the prospective design of van den Berg et al.'s study, which allows for earlier diagnosis of ICIrM and timely interventions to prevent progression to more severe stages of the disease.
Other key differences between the previously mentioned study and this study lie in hsTnT levels. Our study reports a median hs‐TnT of 364 ng/L in patients who developed ICIrM, compared with a median hs‐TnT of <100 ng/L in patients with elevated hs‐TnT due to other causes. Moreover, their study established that consistent low hs‐TnT values of less than 100 ng/L could effectively rule out ICIrM. 27 However, in our study, 3 out of the 59 patients diagnosed with ICIrM had consistent values of less than 100 ng/L and were also categorized under definitive diagnosis according to Bonaca et al., with 2 of them meeting the criteria for a positive ICIrM diagnosis according to European Society of Cardiology guidelines. These findings suggest that patients with hs‐TnT levels <100 ng/L should not be dismissed outright, highlighting the need for a more nuanced and individualized diagnostic approach.
Prior literature has suggested that TnT >27 ng/L is associated with adverse outcomes in acute PE without hemodynamic compromise in the general population. 28 Although our median hs‐TnT was higher (51 ng/L), comparing these values is challenging as there may be differences in PE severity and hemodynamics. In terms of troponin elevation observed in other cancer therapies, there is report of elevated hs‐TnT levels in up to 62.5% of those tested in patients with cancer treated with anthracyclines or trastuzumab, 29 which is similar to the data for ICI in this study; however, there is a lack of data specifying the overall proportion of patients undergoing troponin measurements among patients with cancer receiving antineoplastic therapy in general. In those diagnosed with ICIrM, data on serial hs‐TnT measurements was highly variable (in terms of frequency of measures); a detailed chart review revealed significant fluctuations in hs‐TnT levels over time in most patients, with some requiring more than a year for levels to decrease. Although median hs‐TnT within the first 30 days was 316 ng/L (IQR, 661) and decreased to a median hs‐TnT of 54 ng/L (IQR, 139) after the first 30 days, the median time to normalization/return to baseline in patients who had follow‐up measurements was 111 days (IQR, 98). Of the 6 patients who had persistent hs‐TnT elevations, only 1 was rechallenged with ICI, whereas the other 5 had their ICI therapy discontinued. For the patient who was rechallenged, the peak hs‐TnT level during the ICIrM event was 1414 ng/L, which decreased to 360 ng/L 3 months after the event.
A number of studies have explored troponin I in the context of ICI treatment and as a marker during and following the development of ICIrM. 30 , 31 , 32 , 33 Data from our study suggest (for the minority of patients who had both types of troponin concurrently measured) that hs‐TnT has slower recovery to normal/baseline levels on follow‐up, as evidenced by the 8 (13.8%) out of 59 patients with ICIrM continuing to exhibit elevated hs‐TnT levels despite the normalization of troponin I.
In summary, our study underscores the critical importance of hs‐TnT as a biomarker for both diagnosing and prognosticating cardiovascular outcomes in patients undergoing ICI therapy. We provide actionable high‐risk hs‐TnT thresholds tailored to distinct patient subgroups that can enhance clinical decision‐making in the form of closer monitoring and initiation of treatment for mitigating myocardial injury. The high mortality associated with ICIrM highlights the need for vigilant and individualized monitoring strategies. Incorporating serial long‐term hs‐TnT measurements into routine practice, along with a more individualized diagnostic approach for patients with low yet persistently elevated values, has the potential to improve early detection, guide timely interventions, and ultimately optimize patient outcomes. As immunotherapy continues to transform the landscape of oncology, integrating robust cardiac biomarkers surveillance protocols will be essential to ensuring the safety and efficacy of these life‐saving treatments.
Limitations
This study is limited by its retrospective nature, with potential for selection bias. In particular, hs‐TnT measurements were measured in a subset of patients undergoing ICI therapy and was more likely to be measured in those with symptoms or evaluation for acute illness. The diagnosis of ICIrM is challenging, and only few patients had an endomyocardial biopsy for histologic confirmation; however, society endorsed diagnostic criteria were applied for diagnosis. 16 , 17 Due to evolving changes in practice and monitoring of myocardial injury over the span of the past decade, not all patients included in our analysis had baseline hs‐TnT measurements for comparison with posttreatment troponin values. Additionally, the results were not adjusted and could potentially be influenced by unrecognized confounders. Cancer stage and prognosis affect all‐cause mortality; however, these variables are complex to standardize across diverse malignancies and were not available in our data set. Although a minor limitation, the multicenter data set was extracted from a single health system potentially limiting the generalizability of our results.
The fair to moderate AUC of the predictive cutoffs for cardiac death and MACE may be influenced by the small outcome sample size. Other biomarkers such as NT‐proBNP or creatinine kinase were not consistently available across our cohort, limiting ability for assessing outcomes by combining biomarkers. Lack of NT‐proBNP (N‐terminal pro‐b‐type natriuretic peptide) data may have led to underrecognition of HF, particularly mild cases with preserved ejection fraction. Future prospective studies are warranted to validate our findings and refine the proposed troponin thresholds in diverse patient populations.
CONCLUSIONS
Hs‐TnT measurements have prognostic value for cardiac events in patients with cancer receiving ICI therapy, including in those without ICIrM. Patients with ICIrM demonstrated the highest median hs‐TnT levels, the shortest time to elevation, and the poorest outcomes, with a graded response observed: the worst prognosis in patients with hs‐TnT elevation due to ICIrM, followed by other causes, and those without hs‐TnT elevation had the best prognosis. Patients with fulminant ICIrM and those with concomitant myositis had significantly higher hs‐TnT levels than other patients with ICIrM. In a sex‐stratified analysis, men exhibited a higher frequency of hs‐TnT elevation compared with women. Identifying the underlying cause and troponin thresholds may help guide risk stratification and management.
Sources of Funding
This publication was supported by Mayo Clinic Arizona Cardiovascular Clinical Research Center (MCA CV CRC). We are thankful for their support. Contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the MCA CV CRC. A/Prof Chadi Ayoub is supported by the Mayo Clinic Clinician Engaged in Research award.
Disclosures
None.
Supporting information
Tables S1–S3
This article was sent to Tochukwu M. Okwuosa, DO, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.125.041680
For Sources of Funding and Disclosures, see page 12.
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Associated Data
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Supplementary Materials
Tables S1–S3