More Heart Damage than Expected with Cancer Checkpoint Inhib
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Immune checkpoint inhibitor (ICI) therapy for cancer was more cardiotoxic than previously reported, according to a large cohort study from Denmark.

Within 1 year after first ICI administration, the absolute risk of cardiac events (i.e., arrhythmia, pericarditis or myocarditis, heart failure, or cardiovascular death) was:

- 9.7% for lung cancer patients treated with a programmed cell death-1 (PD1) inhibitor
- 6.6% for patients with malignant melanoma treated with a PD1 inhibitor
- 7.5% for malignant melanoma patients who received cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor therapy.

The 1.8% incidence of pericarditis or myocarditis among treated patients in the study was much higher than observed in previous pharmacovigilance studies, in which myocarditis was seen in only 0.06%-0.27% of people, according to the researchers.

Researchers performed a retrospective study based on the nationwide registries of Denmark. The study period was from 2011, when ICIs were first introduced, to 2017, the last year with available data for the investigators.

Patients included were 25,573 consecutive people with incident lung cancer (median age 71 years, 50.5% men) and another 13,568 with malignant melanoma (median age 60 years, 45.7% men). Prevalence of hypertension was 37.2% and 21.5%, respectively, whereas that of diabetes was 13.2% and 6.6%.

Of the people with lung cancer, 743 were treated with a PD1 inhibitor. As for malignant melanoma, 145 received PD1 inhibitor therapy and 212 CTLA-4 inhibitor treatment.

Comparing cancer patients who received PD1 inhibitor therapy against controls who did not, the team found relatively more cardiac events for the former across various time periods:

- Lung cancer patients within 6 months of first PD1 inhibitor administration: adjusted HR 2.14, 95% CI 1.50-3.05
- Lung cancer patients at 6-12 months: adjusted HR 2.26, 95% CI 1.27-4.02
- Malignant melanoma patients within 6 months: adjusted HR 4.30, 95% CI 1.38-13.42

Cardiac risk did not persist to 6-12 months for malignant melanoma patients on PD1 inhibitors. Both short-term and mid-term increases in cardiac risk were seen with CTLA-4 inhibitors:

- Malignant melanoma patients within 6 months: adjusted HR 4.93, 95% CI 2.45-9.94
- Malignant melanoma patients at 6-12 months: adjusted HR 3.48, 95% CI 1.91-6.35

"It has been suspected that most cardiac side effects [of ICIs] occur early after treatment within the 1st week to months. These results suggest that increased rates of cardiac events are also seen after the initial 6 months of the 1st administration," researchers noted.

"The mechanisms behind the immune-related side effects are not fully elucidated and several hypotheses of different mechanisms exist including increased T-cell activity against antigens present in myocytes, increasing levels of autoantibodies and inflammatory cytokines, and enhanced complement-mediated inflammation," according to the investigators.