A study of over a thousand cancer patients treated with immunotherapy drugs has found these patients are at greater risk of heart problems, including death from heart attack or stroke.
The patients had either lung cancer or malignant melanoma (a type of skin cancer), for which immune checkpoint inhibitors such as a programmed cell death-1 (PD1) inhibitors or cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitors are used. The study, which is published today (Wednesday) in the European Heart Journal , found that the risks of heart problems in patients were higher than shown by previous safety data for these drugs.
The study was led by Dr Maria D’Souza, a medical doctor and postdoctoral research fellow in the Department of Cardiology at Herlev og Gentofte Hospital, Hellerup, Denmark. She and her colleagues found that one year after starting treatment with immune checkpoint inhibitors, nearly 10% of 743 lung cancer patients on PD1 inhibitors (either pembrolizumab or nivolumab) experienced some sort of heart problem, ranging from heart failure, irregular heart beat (arrhythmia), inflammation of the heart (myocarditis or pericarditis) or heart-related death, such as a heart attack.
Among 13,568 patients with malignant melanoma, 145 were treated with PD1 inhibitors and 212 were treated with the CTLA-4 inhibitor ipilimumab. One year after starting treatment, 6.6% and 7.5% respectively experienced a heart problem.
The researchers found that patients treated with immune checkpoint inhibitors had a higher risk of heart problems compared to those who were not being treated in this way. Within six months of starting treatment, patients with lung cancer on PD1 inhibitors had double the risk of heart problems; malignant melanoma patients had a 4.3-fold increased risk if they were being treated with PD1 inhibitors and a nearly five-fold risk if they were receiving the CTLA-4 inhibitor.
After six months, the risk of heart problems increased slightly for lung cancer patients receiving PD1 inhibitors to a 2.3-fold risk. However, the risk was not statistically significant for melanoma patients on PD1, and decreased slightly to a 3.5-fold risk for those receiving the CTLA-4 inhibitor.
The study analysed nationwide information from Danish national registries on 25,573 consecutive patients diagnosed with lung cancer or malignant melanoma between 2011, when immune checkpoint inhibitor treatment was introduced, and 2017.
Dr D’Souza said: “We believe this is the first study of this size, based on nationwide data on hospital admissions and drug administrations, to investigate the risk of heart problems in lung and melanoma patients treated with immune checkpoint inhibitors. We have been able to quantify the one-year absolute risks of heart problems in patients with lung cancer treated with PD1 inhibitors and in patients with malignant melanoma treated with either PD1 or CTLA-4 inhibitors. We found that these risks were higher than previously estimated by drug safety studies, which have suggested that around 0.03-1% of people treated with immune checkpoint inhibitors develop myocarditis or pericarditis within one year; our results show that 1.8% will.
“We also found that in comparison to patients who were not receiving immune checkpoint inhibitors, those who were being treated with them were at greater risk of heart problems. Previous studies have shown that most adverse side effects that affect the heart occur early after treatment has started, within the first few weeks or months. However, our results suggest that an increased risk of heart problems continues beyond the initial six months.
“We hope that this information may be useful for making doctors aware that extra attention needs to be given to patients treated with immune checkpoint inhibitors.
“Although these drugs will have been tested rigorously in randomised controlled clinical trials before being approved for clinical use, they may still have an impact on organs, causing both common and very rare side effects. Large scale epidemiological studies like ours may contribute to our knowledge on this with more accurate estimates of how often these side effects occur when the drugs are used for clinical treatment.”
The researchers say they need to find out more about the side effects of immune checkpoint inhibitor treatment, and they have launched an observational clinical study of patients receiving these drugs in order to monitor heart function. They hope this may help them to understand and predict which patients will develop serious or, occasionally, life-threatening side effects.
As this was an observational study, based on data from registries, treatment with immune checkpoint inhibitors was not randomised. The researchers took account of factors that could affect their results, such as age, sex and time with cancer; however, they did not have information on whether or not the patients smoked, the cancer stage and other clinical factors that could affect the results. Another limitation was that the study was not able to analyse reliably the risk of blood vessel problems, such as stroke, because these can take longer to develop than the average follow-up time in the study (164-326 days). Nor was it possible to look at the association between heart problems and different intensities of treatment and different combinations of treatments.
In an accompanying editorial , Dr Tomas Neilan, director of the cardio-oncology program at Massachusetts General Hospital (Boston, USA), and colleagues write: “…perhaps it is time for a broader description of ICI [immune checkpoint inhibitors]-induced cardiovascular complications to include the term ‘ICI-related cardiovascular disease’ and this is supported by the important insights presented by D’Souza and colleagues. Immediate steps include increasing our awareness for a broader range of potential cardiac toxicities related to ICI treatment . . . Longer term steps include broadening collaborations with our oncology and pharmaceutical partners, and expanded clinical research efforts in parallel and based on innovative basic experimental insights. These and other steps are needed to move this forward so we can improve cardiovascular outcomes among our cancer patients treated with an ICI.”
 “A risk of cardiac events in patients receiving immune checkpoint inhibitors: a nationwide Danish study”, by Maria D’Souza et al. European Heart Journal. doi:10.1093/eurheartj/ehaa884
 “Are we underestimating the potential for cardiotoxicity related to immune checkpoint inhibitors?” by Matthias Totzeck, Esther Lutgens and Tomas G. Neilan. European Heart Journal. doi:10.1093/eurheartj/ehaa959
The European Heart Journal is the flagship journal of the European Society of Cardiology. It is published on behalf of the ESC by Oxford Journals, a division of Oxford University Press. Please acknowledge the journal as a source in any articles.