Cardiac Complications Associated with Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area

Abstract Background Immune checkpoint inhibitors, including programmed cell death-1 (PD-1), programmed cell death ligand-1 (PDL-1) and cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitors, have emerged as important therapeutic alternatives for advanced malignancies. This drug class upregulates T-cell activity, leading to an immune response against cancer cells. However, the increased activity of T cells can lead to autoimmune reactions. Methods We conducted a systematic review of all published articles and grey literature in Pubmed, Medline, and Embase on cardiac complications associated with checkpoint inhibitor use from September 1, 1996 up to November 10, 2017. Results The search strategy yielded 908 unique abstracts. Of these, 835 were excluded based on abstract and full text review. A total of 73 studies met eligibility criteria and were included. We found a total of 99 cases of cardiotoxicity with the use of checkpoint inhibitors. Myocarditis (45%) was the most common cardiotoxicity. The overall case fatality rate was 35%. This was notably higher in patients with myocarditis, complete heart block or conduction abnormalities, and ventricular arrhythmias. There was no difference in outcomes for patients treated with or without steroids. Immunosuppressive therapies such as infliximab, mycophenolate, intravenous immunoglobulin, anti-thymocyte globulin, and/or plasmapheresis were used in twelve patients leading to survival in nine of these patients (75%). Conclusions Immune checkpoint inhibitors are associated with cardiotoxicity. Given the high case-fatality rate, close surveillance and prompt empiric therapy for cardiovascular complications of checkpoint inhibitors should be considered. Aggressive treatment with immunosuppressive agents and/or plasmapheresis may lead to clinical improvement and increased survival.