Immune Checkpoint Inhibitor Therapy Increases Risk of Atherosclerotic Cardiovascular Events
Key findings
- Massachusetts General Hospital researchers performed a matched cohort study (2,842 patients in each group) to determine whether the use of immune checkpoint inhibitors (ICI) leads to an increase in atherosclerotic cardiovascular events
- Cancer patients who underwent ICI treatment had a three-fold higher risk of a composite outcome (myocardial infarction, coronary revascularization and ischemic stroke) than cancer patients who did not receive ICIs
- A case-control study of the same cohort showed a 4.8-fold increase in cardiovascular events from the two-year period before starting an ICI to the two-year period afterward
- In an imaging substudy of 40 patients with melanoma, there was a three-fold increase in the rate of atherosclerotic plaque progression after initiation of ICI therapy
- The association with increased atherosclerotic plaque in the imaging substudy was attenuated in patients who concomitantly used statins or corticosteroids, suggesting that the adverse effect of ICIs can be modified
The immune checkpoint inhibitors now used routinely in cancer therapy are known to inhibit key pathways in atherosclerosis. However, data conflict about whether they increase atherosclerotic plaque and atherosclerosis-related cardiovascular events.
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By studying a cohort 20 times larger than in any previous study, researchers in the Cardiovascular Imaging Research Center at Massachusetts General Hospital including Zsofia D. Drobni, MD, research fellow at the Cardiovascular Imaging Research Center and PhD student at Semmelweis University, Udo Hoffmann, MD, director of the Cardiovascular Imaging Research Center and chief of Cardiovascular Imaging at the Department of Radiology, and Tomas G. Neilan, MD, MPH, co-director of the Cardiovascular Imaging Research Center and director of the Cardio-Oncology Program in the Corrigan Minehan Heart Center, and colleagues have found compelling evidence that the use of ICIs does lead to an increase in cardiovascular events. They report their findings in Circulation.
Study Methods
To minimize confounding, the researchers chose two study designs.
A matched cohort study:
- 2,842 case patients who received an ICI at Mass General through March 2019
- 2,842 control patients treated for cancer at Mass General between January 2008 and January 2012 who did not receive an ICI, matched to the cases on age, history of cardiovascular events and cancer type
Case-crossover study:
- The number of patients who had an event and the cumulative number of cardiovascular events were determined among the 2,842 patients treated with an ICI
Matched Cohort Study
The primary outcome was the occurrence of a cardiovascular event, defined as the composite of myocardial infarction, coronary revascularization and ischemic stroke. On multivariable analysis, ICI use was associated with a three-fold increase in the risk of the composite outcome (HR, 3.3; 95% CI, 2.0–5.5; P<0.001).
Case-Crossover Study
In the two-year period before starting an ICI, 66 patients had a cardiovascular event. In the two-year period afterward, 119 had an event. This represented an increase from 1.37 to 6.55 per 100 person-years (adjusted HR, 4.8; 95% CI, 3.5–6.5; P<0.001)
There were increased rates of each individual component of the primary outcome.
78 events occurred among the 66 patients during the two-year period pre-ICI and 139 events among the 119 patients during the two-year period post-ICI (IRR, 1.8; 95% CI, 1.4–2.4; P<0.001).
Imaging Substudy
40 patients using an ICI for melanoma underwent computed tomography at three time points. The rate of progression of total atherosclerotic plaque increased three-fold, from 2.1% per year pre-ICI to 6.7% per year afterward (P=NS). Thus, the imaging results support the biological plausibility of the clinical observations.
Compared with non-statin users, patients on statins showed a lower relative change in total plaque volume per year (8.3% vs. 5.2%, P=0.04). For corticosteroids, the corresponding figures were 7.4% and 5.9% (P=0.04).
Opportunities to Improve Care
According to a report in JAMA Network Open, there are now more than 50 indications for prescribing ICIs, and 36% of cancer patients are eligible for them, including adjuvant therapy. Considering this expanding pool of candidates, clinicians need to stay abreast of findings about cardiovascular effects. For now, candidates for ICI therapy should undergo a comprehensive cardiovascular risk evaluation, and those who receive ICIs should receive optimal preventive medical therapy with close monitoring.
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