Adverse cardiovascular complications following prescription of Programmed Cell Death 1 (PD-1) and Programmed Cell Death Ligand 1 (PD-L1) inhibitors

Background: Programmed death 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors, such as pembrolizumab, nivolumab and atezolizumab, are a major class of immune checkpoint inhibitors that are increasingly used for cancer treatment. However, their use is associated with adverse cardiovascular events. We examined the incidence of new-onset cardiac complications in patients receiving PD-1 or PD-L1 inhibitors. Methods: Patients receiving PD-1 or PD-L1 inhibitors since their launch up to 31st December 2019 at the Hospital Authority of Hong Kong, without pre-existing cardiac complications were included. The primary outcome was a composite of incident heart failure, acute myocardial infarction (AMI), atrial fibrillation (AF) or atrial flutter with the last follow-up date of 31st August 2020. Results: A total of 1959 patients were included. Over a median follow-up of 136 days (IQR: 42-279), 320 (16.3%) patients met the primary outcome (heart failure: n=244, AMI: n=38, AF: n=54, atrial flutter: n=6) after PD-1/PD-L1 treatment. Univariate Cox regression showed that age, respiratory diseases, gastrointestinal diseases, a shorter readmission interval and total number of hospitalizations before PD-1/PD-L1 inhibitor prescription, PD-L1 inhibitor use, hyponatraemia, and reduced triglyceride levels were significant predictors of the primary outcome. On multivariate adjustment, older age, a shorter average readmission interval, and a higher number of hospital admissions remained significant predictors. Patients who developed cardiovascular complications had a shorter average readmission interval and a higher number of hospitalizations after PD-1/PD-L1 treatment. Conclusions: Cardiovascular complications are found in 16% of patients receiving PD-1 or PD-L1 inhibitors and are associated with more healthcare utilization.


Introduction
incidence of cardiovascular events of incident heart failure, AMI, atrial fibrillation (AF) or atrial flutter in cancer patients receiving PD-1 or PD-L1 inhibitors.

Study Population
This study was approved by The Joint Chinese University of Hong Kong -New Territories East Cluster Clinical Research Ethics Committee and The Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Patient data were obtained using the electronic health record database, which is connected to the territory-wide Clinical Data Analysis and Reporting System (CDARS). The system is an integrative centralized platform that permits the extraction of clinical data for analysis and reporting. The system attributes each patient a unique reference identification number, allowing for the retrieval of comprehensive medical records, including disease diagnoses, clinical comorbidities, laboratory parameters and operative procedures. Patients or the public were not involved in any aspect of this study.

Patient Data
The following clinical data were extracted: patient characteristics, including demographic details of baseline age and gender, and specific pre-existing comorbidities before drug prescriptions, laboratory examinations (including complete blood counts, biochemical tests, diabetes mellitus tests) were extracted. Comorbidities from January 1 st , 2013 to December 31 st , International Classification of Disease, Ninth Edition (ICD-9) codes that were used to extract the specific comorbidities and outcomes are included in Supplementary Materials. The overall dosage and accumulative duration for patients with new-onset cardiac complications are reported.

Primary outcomes on follow-up
The primary outcome was a composite of incident heart failure, AMI, AF or atrial flutter.
The follow-up period was defined as the first PD-1/PD-L1 prescription date until the primary endpoint or death occurred, or until the end date of December 31 st , 2019, whichever was earlier.

Statistical analysis
Continuous variables were presented as median (95% confidence interval [CI] or interquartile range [IQR]) and categorical variables were presented as count (%). The Mann-Whitney U test was used to compare continuous variables. The χ 2 test with Yates' correction was used for 2×2 contingency data, and Pearson's χ 2 test was used for contingency data for variables with more than two categories. To identify the important predictors associated with new-onset cardiac complications of patients after PD-1/PD-L1 treatment, univariate Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. The identified significant univariate predictors were used as the input into the multivariate Cox regression model. A two-sided Initially, 2,426 cancer patients receiving PD-1/PD-L1 inhibitors were identified ( Figure   1). Subsequently, those with prior cardiac complications (n=467, all HF) before PD-1/PD-L1 inhibitor treatment were excluded. Their baseline characteristics are shown in Table 1. Over a median follow-up of 136 days (IQR: 42-279) from initial PD-1/PD-L1 treatment, 320 (16.3%) met the primary outcome of developing new-onset cardiac complications (244 with HF, 38 with AMI, 54 with atrial fibrillation, 6 with atrial flutter; Figure 2

Predictors of cardiac complications
Univariate Cox proportional hazard analysis identified the significant predictors of the primary outcome ( Table 2). These were older age at initial PD-1/PD-L1 treatment (HR: 1.02, 95% . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint  Table 3).

Healthcare utilization before and after treatment with PD-1/PD-L1 inhibitors
Further, we compared the hospitalization characteristics before and after PD-1/PD-L1 treatment in patients with cardiovascular complications (  . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ;

Discussion
The main findings are that: i) the incidence of cardiovascular complications after PD-1 or PD-L1 inhibitor use was 16% in this territory-wide cohort of Chinese patients from Hong Kong, ii) multivariate Cox regression showed older age, a shorter average readmission interval and a higher number of hospital admissions were significant predictors of cardiovascular complications and iii) patients who developed cardiovascular complications had shorter average readmission interval and higher number of hospitalizations after treatment with PD-1/PD-L1 inhibitors.
Cardiac involvement in PD1 or PD-L1 inhibitors is variable, and can potentially affect the conduction system, myocardium or pericardium 3 . Thus, heart block 4 , Takotsubo cardiomyopathy 5 , myocarditis 6, 7 and pericarditis 8 have been reported. A meta-analysis performed in 2018 found that "anti-PD-1/PD-L1-related fatalities were often from pneumonitis However, previous studies have largely been limited to case reports 4, 10 , case series 11 or single-center studies 12 or small registries 13,14 . In this territory-wide study from Hong Kong, we found that cardiovascular complications occurred in 16% of all patients receiving PD1 or PD-L1 inhibitors. Of these, the commonest is HF. Previously, acute HF has been described in the context of myocarditis 15 , but HF without myocarditis has also been reported 16 . Our study also identified cases of AMI following the initiation of PD-1/PD-L1 inhibitor therapy. Such findings would be in keeping with coronary toxicity that has been reported in the context of PD-1 inhibitor therapy 13 .
. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ; Interestingly, our study did not identify any patients with myocarditis after treatment with PD-1 or PD-L1 inhibitors. Moreover, within the excluded patients with prior cardiovascular complications, none developed subsequent myocarditis. In 964 patients attending Massachusetts General Hospital, the incidence of myocarditis was 1.1% (n = 35) 14 . In this cohort, myocarditis was more frequently observed in patients with pre-existing cardiovascular comorbidities.
Nevertheless, another study using the VigiBase database found 101 cases of severe myocarditis, of which 75% of the myocarditis cases did not have pre-existing cardiovascular disease 17 . A single-center study of 283 patients from China found only 3 cases (1.1%) of myocarditis, with variable presentations such as palpitations, dyspnea, and fatigue, or asymptomatic with incidental finding of grade 3 atrioventricular block and premature ventricular complexes on the electrocardiogram 12 . In a pooled, retrospective review of three trials including 448 patients with advanced melanoma receiving PD-1/PD-L1 inhibitor therapy, no cases of myocarditis were identified 18 . In association with myocarditis, different investigators have reported the presence of conduction abnormalities in the form of atrioventricular block 4,11,12,19 .

Conclusions
Cardiovascular complications are found in 16% of patients receiving PD-1 or PD-L1 inhibitors and are associated with more healthcare utilization.

Consent for publication
N/A. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ;

Availability of data and material
Data availability upon request to the corresponding author.

Competing interests
None.

Funding
None.

Authors' contributions
JZ, GT: data analysis, data interpretation, statistical analysis, manuscript drafting, critical revision of manuscript XW, IL, SL, LY, TL, YX: data interpretation, manuscript drafting EWC, ICKW: project planning, data acquisition, data interpretation, critical revision of manuscript WTW, QZ: study conception, study supervision, project planning, data interpretation, statistical analysis, manuscript drafting, critical revision of manuscript
. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ; https://doi.org/10.1101/2020.12.21.20248648 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review) preprint
The copyright holder for this this version posted December 22, 2020. ;    is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ; is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ; <0.0001* ** . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ; Figure 1. Study flow diagram describing derivation of the study cohort.
. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ; . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint The copyright holder for this this version posted December 22, 2020. ;