• Immune checkpoint inhibitors significantly heightened risk for major adverse cardiovascular events vs. first-line chemotherapy.
• Patients had a higher risk for heart failure, myocardial infarction and stroke.

Treatment with immune checkpoint inhibitors can significantly increase risk for major adverse cardiovascular events among patients with cancer, including heart failure, myocardial infarction and stroke.

A retrospective analysis of more than 30,000 patients showed individuals treated with immune checkpoint inhibitors had a 40% higher risk for hospitalization from these events than those who received guideline-concordant frontline chemotherapy.

“These drugs have taken cancers that used to be a death sentence and made them survivable. That is not in dispute,” Salim S. Hayek, MD, chair of internal medicine at The University of Texas Medical Branch, told Healio.

“What it means is that immunotherapy has a side effect that we’re underestimating. Addressing cardiovascular risk upfront is more important now than ever — because thanks to modern therapies such as [immune checkpoint inhibitors], many patients survive their cancer, only to experience the setbacks of a cardiac event.”

Researchers estimated approximately 56% of patients with cancer in the U.S. were eligible to receive at least one immune checkpoint inhibitor in 2023, according to data published in International Journal of Cancer.

Only 1.5% of patients had eligibility in 2011, highlighting the rapid uptake of immune checkpoint inhibitors for numerous malignancies.

“Immune checkpoint inhibitors have been a major milestone and have revolutionized the [treatment] landscape for many types of cancers,” Hayek said. “A wide and growing number of malignances are now being treated with these drugs, which have extended the lives of millions of people. It’s absolutely remarkable.”

Clinicians have been predominantly concerned about immunotherapy’s risk for myocarditis, with an incidence of less than 1%, according to study background.

However, prior research also showed about 10% of patients treated with immune checkpoint inhibitors may develop major adverse cardiovascular events (MACE).

“Inflammation is a strong contributor to heart disease, whether it’s atherosclerosis or heart failure,” Hayek said. “If you’re unleashing the immune system onto the cancer, does that increased inflammation predispose to more long-term cardiovascular events?”

Hayek and colleagues used the TriNetX global health research network, which includes more than 120 million patients, to investigate.

They matched 15,360 patients (median age 63 years; standard deviation, 13; 57.9% men; 52.5% white) who initiated immune checkpoint inhibitor therapy between March 25, 2011, and March 25, 2014, with a cohort of 15,360 individuals (median age, 63.2 years; standard deviation, 13.6; 57.8% men; 52.7% white) who received first-line chemotherapy between March 25, 1997, and March 24, 2011.

Both cohorts had similar rates of malignancies and cardiovascular risk factors.

Hospitalization for MACE, defined as one of acute ischemic stroke, acute myocardial infarction and heart failure, within 24 months of patients’ index date served as the primary endpoint.

Patients treated with immune checkpoint inhibitors had significantly higher rate of hospitalization for MACE (5.2% vs. 3.7%; RR = 1.4; 95% CI, 1.26-1.56).

They had significantly higher risk for all three MACE: heart failure (RR = 1.39; 95% CI, 1.18-1.64), myocardial infarction (RR = 1.33; 95% CI, 1.12-1.57) and stroke (RR = 1.4; 95% CI, 1.16-1.7).

Hayek and colleagues observed similar results after restricting the chemotherapy cohort to patients treated between 2005 and 2011.

Among patients who received immune checkpoint inhibitors, those who also received radiation had significantly increased risk for overall MACE hospitalization (RR = 1.13; 95% CI, 1.04-1.23), stroke (RR = 1.26; 95% CI, 1.08-1.46) and myocardial infarction (RR = 1.16; 95% CI, 1.01-1.33).

Patients who received nivolumab (Opdivo, Bristol Myers Squibb) had the greatest risk for MACE within 2 years (RR = 2.34; 95% CI, 2.04-2.69), followed by durvalumab (Imfinzi, AstraZeneca; RR = 2.16; 95% CI, 1.79-2.6), ipilimumab (Yervoy, Bristol Myers Squibb) plus nivolumab (RR = 2.08; 95% CI, 1.65-2.64), pembrolizumab (Keytruda, Merck; RR = 1.64; 95% CI, 1.43-1.88) and atezolizumab (Tecentriq, Genentech; RR = 1.4; 95% CI, 1.16-1.68).

Ipilimumab plus nivolumab had the greatest risk for MACE hospitalization within the first 6 months, and durvalumab had the highest risk at 24 months.

Hayek emphasized clinicians should take these individual drug results cautiously.

“The pattern we saw is almost certainly not about the drug itself,” Hayek said. “The drug with the highest rate, for example, is the one that we give for lung cancer right after high-dose radiation to the chest, which itself damages the heart and the blood vessels. Our best explanation is that radiation plus immunotherapy could confer a higher cardiovascular risk than either alone, and that is a question now that we need to study properly. Most importantly, this is not a randomized controlled trial. We cannot attribute the damage to a very specific drug.”

Researchers acknowledged study limitations, including its retrospective design.

Hayek noted future research should investigate mechanisms causing MACE, and if specific drugs are needed to address these adverse events.

“Do we need to address the cardiovascular state of patients who have survived cancer or who have cancer differently than others? That is the most important question,” Hayek said.

Less research is needed to take cardiovascular risk seriously, though.

“We need to acknowledge that in an exponentially growing survivorship population, cardiovascular risk is no longer a small problem,” Hayek said. “I know that oncologists have a lot of checklists. Cardiovascular health needs to be part of that, and not something to think about after the fact. We need to integrate that in our systems, our workflows and operations.”

Salim S. Hayek, MD, can be reached at sahayek@utmb.edu.