Cardiac adverse events of immune checkpoint inhibitors in oncology patients: A systematic review and meta-analysis

Abstract

BACKGROUND Immune checkpoint inhibitors (ICIs) are novel therapeutic agents used for various types of cancer. ICIs have revolutionized cancer treatment and improved clinical outcomes among cancer patients. However, immune-related adverse effects of ICI therapy are common. Cardiovascular immune-related adverse events (irAEs) are rare but potentially life-threatening complications. AIM To estimate the incidence of cardiovascular irAEs among patients undergoing ICI therapy for various malignancies. METHODS We conducted this systematic review and meta-analysis by searching PubMed, Cochrane CENTRAL, Web of Science, and SCOPUS databases for relevant interventional trials reporting cardiovascular irAEs. We performed a single-arm meta-analysis using OpenMeta [Analyst] software of the following outcomes: Myocarditis, pericardial effusion, heart failure, cardiomyopathy, atrial fibrillation, myocardial infarction, and cardiac arrest. We assessed the heterogeneity using the I 2 test and managed to solve it with Cochrane’s leave-one-out method. The risk of bias was performed with the Cochrane’s risk of bias tool. RESULTS A total of 26 studies were included. The incidence of irAEs follows: Myocarditis: 0.5% [95% confidence interval (CI): 0.1%-0.9%]; Pericardial effusion: 0.5% (95%CI: 0.1%-1.0%); Heart failure: 0.3% (95%CI: 0.0%-0.5%); Cardiomyopathy: 0.3% (95%CI: -0.1%-0.6%); atrial fibrillation: 4.6% (95%CI: 1.0%-14.1%); Myocardial infarction: 0.4% (95%CI: 0.0%-0.7%); and Cardiac arrest: 0.4% (95%CI: 0.1%-0.8%). CONCLUSION The most common cardiovascular irAEs were atrial fibrillation, myocarditis, and pericardial effusion. Although rare, data from post market surveillance will provide estimates of the long-term prevalence and prognosis in patients with ICI-associated cardiovascular complications.

Immune Checkpoint Inhibitors and the Heart

“…For example, a systematic review that included 99 patients has found a fatality rate of 35%. Other observational studies have concluded that there is a 50% risk of major cardiac adverse events in ICIs related myocarditis in comparison to non-ICIs related myocarditis ( 47 – 49 ).…”

“…It appears that the inflammation secondary to T lymphocytes patchy infiltration in the sinoatrial and atrioventricular nodes is also responsible for atrial fibrillation. In conclusion, the development of atrial fibrillation is directly connected to the treatment with ICIs ( 49 , 58 ).…”

Thrombotic Complications Associated with Immune Checkpoint Inhibitors

“…The references in the relevant articles were also manually searched for related studies. Overall, 18 retrospective studies reporting incidences and/or outcomes of venous and/or arterial thrombosis in patients on ICIs [ 1 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ] and 4 additional relevant systematic reviews and meta-analyses [ 24 , 25 , 26 , 27 ] were identified and included in this review.…”

“…As noted previously, pre-clinical studies have shown that blockage of PD-1 or CTLA-4 could enhance atherosclerotic inflammation and promote atherosclerosis plaques [ 29 , 30 ]. Four meta-analyses (mostly of clinical trials) have shown a rate of myocardial infraction of ≤ 1% and that of stroke of 1–2% ( Table 3 ), but as with VTE, the rates could be under-reported [ 24 , 25 , 26 , 27 ]. Fewer retrospective studies have reported variable rates of ATE, ranging from 1 to 5% at 12 months ( Table 2 ).…”

Immune Checkpoint Inhibitors and Atherosclerotic Vascular Events in Cancer Patients

“…In a meta-analysis evaluating the incidence of cardiovascular irAEs in cancer patients treated with ICIs, the incidence of MI was as low as 0.4% (95% CI 0.0-0.07%), although this result could be an under-estimation given that the 26 studies included were not specifically designed to evaluate the incidence of cardiovascular toxicity and only 6 out of 26 reported the incidence of MI as an irAE (27). Similarly, another meta-analysis reported a low rate also for arterial thromboembolic events (1.1%, 95% CI 0.5-2.1%) among over 20,000 cancer patients treated with ICIs in 68 studies (Table 4) (28).…”