Incidence and clinical course of immune checkpoint inhibitor-related cardiac adverse events: A descriptive study from the Middle East

Table 1 Baseline characteristics of the study population, n (%)/mean ± SD

Characteristic	Overall (n = 672)
Age at visit, year	54.2 ± 13.3
Gender
Males	474 (70.5)
Females	198 (29.5)
Ethnicity
Western Asia	240 (35.7)
Southern Asia	197 (29.3)
Northern Africa	115 (17.1)
South-Eastern Asia	63 (9.4)
Eastern Africa	16 (2.4)
Northern America	12 (1.8)
Others	29 (4.3)
First BMI result, kg/m2	26.2 ± 11.4
Last BMI result, kg/m2	26.2 ± 11.6
ICI therapy
Atezolizumab	84 (12.5)
Avelumab	4 (0.6)
Durvalumab	8 (1.2)
Ipilimumab	1 (0.2)
Nivolumab	162 (24.1)
Pembrolizumab	413 (61.5)

BMI: Body mass index; ICI: Immune checkpoint inhibitor.

Table 2 Distribution of cancer types among patients in the study cohort (n = 672)

Type of cancer	Number of patients (%)
Lung cancer	162 (24.1)
GIT cancer	121 (18.0)
Renal cancer	64 (9.5)
Hepatobiliary cancer	62 (9.2)
Oral cavity cancer	47 (7.0)
Breast cancer	40 (6.0)
Skin cancer	36 (5.4)
Endometrial cancer	17 (2.5)
Lymphoma	14 (2.1)
Other	109 (16.2)

GIT: Gastrointestinal tract cancer.

Table 3 Baseline characteristics of the patients who developed post-immune checkpoint inhibitors cardiac complications (n = 14), n (%)

Characteristic	Value
Median age, years (IQR)	59.5 (54-64)
Gender
Male	11 (78.6)
Female	3 (21.4)
Nationality
Filipino	3 (21.4)
Jordanian	3 (21.4)
Syrian	2 (14.3)
Bahraini	1 (7.1)
Bangladeshi	1 (7.1)
Egyptian	1 (7.1)
Indian	1 (7.1)
Palestinian	1 (7.1)
Qatari	1 (7.1)
Comorbidities
Hypertension	9 (64.3)
Dyslipidemia	7 (50.0)
Chronic kidney disease	6 (42.9)
Type 2 diabetes	5 (35.7)
Smoking	4 (28.6)
Ischemic heart disease	3 (21.4)
Hypothyroidism	2 (14.3)
Type 1 diabetes	1 (7.1)
Stroke	1 (7.1)
Chronic heart failure	1 (7.1)
Peripheral vascular disease	1 (7.1)
Previous cardiomyopathy	1 (7.1)
Previous arrhythmia	1 (7.1)
Type of ICI administered
Pembrolizumab	11 (78.6)
Atezolizumab	2 (14.3)
Nivolumab	1 (7.1)

IQR: Interquartile range; ICI: Immune checkpoint inhibitors.

Table 4 Clinical spectrum and temporal characteristics of post-immune checkpoint inhibitors cardiac adverse events (n = 14), n (%)

Characteristic	Value
Median time from ICI start to cardiotoxicity, days (IQR)	122 (92-355)
Type of cardiac complication1
Myocarditis	2 (14.3)
Atrial fibrillation	1 (7.1)
Heart block (complete)	1 (7.1)
Heart failure	6 (42.9)
Cardiomyopathy (ischemic)	1 (7.1)
Pericardial effusion	3 (21.4)
Cardiac tamponade	1 (7.1)
Cardiogenic shock	1 (7.1)
ACS/CAD	4 (28.5)
Sudden cardiac death	1 (7.1)
NCI CTCAE grade
Grade 1	0
Grade 2	3 (21.4)
Grade 3	4 (28.6)
Grade 4	3 (21.4)
Grade 5 (death)	4 (28.6)

¹Percentages may exceed 100% as individual patients could experience more than one type of cardiac complication.

ICI: Immune checkpoint inhibitors; IQR: Interquartile range; ACS: Acute coronary syndrome; CAD: Coronary artery disease; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.

Table 5 Comparison of pre- and post-immune checkpoint inhibitors echocardiographic parameters in patients with adverse cardiac events (n = 14), median (interquartile range)/mean ± SD

Variable	Pre-ICI	Post-ICI
LVEDD (mm)	46.5 (42-50)	47 (37.5-52)
LVESD (mm)	32 (28-35)	32.5 (27-37.5)
Left atrial volume index (mL/m2)	26.3 (21.9-30.9)	24.5 (21.4-28.2)
TAPSE (mm)	19 (15-22)	16 (14-20)
PASP (mmHg)	24.35 (21.84-32.04)	28.84 (17.22-31.67)
Mitral E/A ratio	0.89 (0.58-1.43)	0.98 (0.47-1.07)
TDI E/e’ ratio	7.07 (5.29-10.61)	7.89 (7.8-8)
IVST (mm)	11 (9-11.5)	10 (8.5-11.5)
PWT (mm)	9.5 (7.5-11)	10 (8-11)
Global longitudinal strain (%)	-17 ± 1.7	-12.1 ± 3.2

ICI: Immune checkpoint inhibitors; LVEDD: Left ventricular end-diastolic diameter; LVESD: Left ventricular end-systolic diameter; TAPSE: Tricuspid annular plane systolic excursion; PASP: Pulmonary artery systolic pressure; E/A ratio: Early diastolic/atrial contraction velocity ratio; TDI/E/e’: Tissue Doppler imaging e’/E ratio; IVST: Interventricular septal thickness; PWT: Posterior wall thickness.

Table 6 Ejection fraction categories before and after immune checkpoint inhibitors therapy in patients with post-immune checkpoint inhibitors cardiac complications (n = 14), n (%)

Ejection fraction category (%)	Pre-ICI	Post-ICI
< 30 (severe dysfunction)	1 (7.1)	1 (7.1)
30-39 (moderate dysfunction)	0 (0.0)	3 (21.4)
40-49 (mild dysfunction)	1 (7.1)	3 (21.4)
50-55 (borderline normal)	5 (35.7)	2 (14.3)
> 55 (normal)	7 (50.0)	5 (35.7)

ICI: Immune checkpoint inhibitors.

Table 7 Diagnostic features, therapeutic interventions, and clinical outcomes in patients with post-immune checkpoint inhibitors cardiac complications (n = 14), n (%)/median (interquartile range)

Characteristic	Value
Median troponin-T level, ng/L	41 (20-534)
Median NT-proBNP, pg/mL	494 (373.5-3052)
Cardiac magnetic resonance imaging suggestive of myocarditis	1 (7.1)
Reduced LVEF	8 (57.1)
Medical management
Beta-blockers	8 (61.5)
ACEi/ARB/ARNI	6 (46.2)
Aspirin	5 (38.5)
Statin	4 (30.8)
Clopidogrel	3 (23.1)
SGLT2 inhibitors	3 (23.1)
Corticosteroids	2 (15.4)
Loop diuretics	2 (15.4)
Spironolactone	1 (7.7)
Anti-arrhythmias	1 (7.7)
Ivabradine	1 (7.7)
Hospitalized	7 (50)
ICU admission	2 (14.3)
ICI therapy discontinued	14 (100)
Mortality
In-hospital	4 (28.6)
Died after discharge	2 (14.3)
Permanent cardiac dysfunction	10 (71.4)
Resolution of cardiac toxicity	1 (7.1)

NT-proBNP: N-terminal pro-B-type natriuretic peptide; LVEF: Left ventricular ejection fraction; ACEi: Angiotensin converting enzyme inhibitors; ARB: Angiotensin II receptor blockers; ARNI: Angiotensin receptor neprilysin inhibitor; SGLT2: Sodium-glucose cotransporter 2; ICU: Intensive care unit; ICI: Immune checkpoint inhibitors.