In a study reported in JACC: CardioOncology, Lavanya Kondapalli, MD, of the University of Colorado School of Medicine, Aurora, and colleagues found that cardiovascular events common in the general population were observed both prior to and after the initiation of immune checkpoint inhibitor therapy for cancer; myocarditis was more common posttreatment but infrequent. Agreement between International Classification of Diseases (ICD) code and adjudication using established definitions was good for some cardiovascular events and poorer for others.¹

Lavanya Kondapalli, MD

Study Details

The study included all 1,813 patients aged 18 years and older who received immune checkpoint inhibitors within the University of Colorado Health System from January 2011 to April 2019. Electronic medical records were used to identify potential cardiovascular events; those of interest included myocardial infarction, hospitalization for unstable angina, hospitalization for heart failure or heart failure exacerbation requiring treatment, transient ischemic attack, stroke, hypertensive emergency, noncoronary (peripheral) vascular events, venous thromboembolism (including deep vein thrombosis and pulmonary embolism), and immune checkpoint inhibitor–related myocarditis. 

For potential cardiovascular events identified by ICD code, all electronic medical record data including encounter notes, specialist assessments, diagnostic testing, and medications were independently reviewed by two cardiologists and adjudicated using prespecified definitions; discrepancies were resolved by consensus. Agreement between ICD code and adjudicated diagnoses was assessed using the kappa statistic.

Patients received immune checkpoint inhibitor treatment for both solid tumors and hematologic malignancies, with the most common cancers consisting of melanoma (35.5%), lung cancer (25.8%), and kidney/urinary tract cancers (12.4%). Cardiovascular risk factors common at baseline (pretreatment) included hypertension (48.2%), coronary revascularization (17.0%), diabetes (16.1%), chronic kidney disease (11.4%), and current smoking (11.3%). The most commonly used immune checkpoint inhibitors were pembrolizumab (46.9%), nivolumab (42.4%), and ipilimumab (26.1%), irrespective of combination treatment.

Cardiovascular Events

Mean duration of care was 3.2 ± 3.2 years pre–immune checkpoint inhibitor treatment and 1.4 ± 1.4 years posttreatment. For adjudicated events, incidence rates pre- vs posttreatment were 11.4% (206 patients) vs 11.3% (205 patients) for venous thromboembolism, with pulmonary embolism in 4.9% (89 patients) vs 5.4% (97 patients) and deep vein thrombosis in 8.1% (146 patients) vs 8.2% (148 patients); myocardial infarction in 1.8% (33 patients) vs 3.0% (54 patients); heart failure in 2.2% (40 patients) vs 2.8% (50 patients); stroke in 1.8% (33 patients) vs 1.6% (29 patients); and myocarditis in 1 patient vs 6 patients (0.3%). Adjudicated hypertensive emergency occurred in one vs three patients and non-coronary vascular events in five vs two patients.

ICD-Coded vs Adjudicated Events

Apart from myocardial infarction, ICD coding overestimated the occurrence of cardiovascular events relative to adjudication for each event type. Overall, the numbers of ICD-coded vs adjudicated events follow: 476 vs 381 for venous thromboembolism; 74 vs 86 for myocardial infarction; 93 vs 59 for stroke; 10 vs 6 for myocarditis; 215 vs 86 for heart failure; 22 vs 4 for hypertensive emergency; 47 vs 3 for transient ischemic attack; and 25 vs 1 for unstable angina.

ICD codes correlated well with adjudicated diagnosis for venous thromboembolism (kappa = 0.82, 95% confidence interval [CI] = 0.79–0.85) and myocardial infarction (kappa = 0.74, 95% CI = 0.66–0.82), less well for heart failure (kappa = 0.47, 95% CI = 0.40–0.54) and myocarditis (kappa = 0.50, 95% CI = 0.20–0.80), and poorly for hypertensive emergency (kappa = 0.23, 95% CI = 0.01–0.44), transient ischemic attack (kappa = 0.12,  95% CI = –0.00 to 0.24), and unstable angina (kappa = 0.08, 95% CI = –0.06 to 0.22).

The investigators concluded: “ICD codes correlated well with adjudicated events for [venous thromboembolism] and [myocardial infarction], but correlation was worse for heart failure and myocarditis. Adjudication with standardized definitions can enhance understanding of the incidence of [cardiovascular] events related to [immune checkpoint inhibitor]-therapy.”

They stated: “Immune checkpoint inhibitor therapy is becoming a mainstay of contemporary cancer therapy with incompletely understood [cardiovascular] impact. In this analysis of real-world patients, common [cardiovascular] events such as venous thromboembolism, myocardial infarction, heart failure, and stroke were also those most frequently identified in patients post-[immune checkpoint inhibitor] therapy, whereas myocarditis was rare. This work shows that ICD codes can be used to determine incidence of [myocardial infarction] and [venous thromboembolism]; however, [they lack] the fidelity needed to accurately identify other [cardiovascular] events. Adjudication, which is typical of [cardiovascular] trials, is an effective approach to determine the rates of [cardiovascular] events in patients treated with [immune checkpoint inhibitors].” 

DISCLOSURE: Electronic medical record data extraction was supported by the Health Data Compass Data Warehouse project. Dr. Kondapalli reported no conflicts of interest.

REFERENCE

1. Kondapalli L, Hsia J, Miller R, et al: Burden of cardiovascular disease in immune checkpoint inhibitor–treated patients: Reconciling adjudicated and coded outcomes. JACC: CardioOncol 4:649-656, 2022.