Introduction

The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway is one of the major immune checkpoints for mitigating the immune response to prevent autoimmunity. The T-cell mediated pathway for cancer detection requires coinhibitory signal, in addition to the binding of T cell receptor on T cells. PD-1 and PD-L1, one of the best characterized co-inhibitory signaling pathway, control the magnitude and duration of response against autoimmunity [1]. However, cancer cells often devise strategies to hijack these mechanisms to evade anti-tumor immunity. In this regard, inhibitors of PD-1 (e.g., pembrolizumab, nivolumab, cemiplimab) and PD-L1 (e.g., atezolizumab, avelumab, durvalumab) have shown clinical efficacies against different types of solid tumors, including melanoma, non-small cell lung cancer (NSCLC), urothelial carcinoma and bladder cancer. Pembrolizumab is also the first agent to receive a “pan-cancer” approval by the United States Food and Drug Administration (FDA) for the treatment of unresectable or metastatic solid tumors that have high microsatellite instability or mismatch repair deficiency.

Despite their treatment efficacy in clinical oncology, immune-related adverse events associated with the use of immune checkpoint inhibitors (ICIs) are now increasingly recognized [2,3,4,5]. Adverse events include atherosclerosis, colitis, hepatitis, adrenocorticotropic hormone insufficiency, hypothyroidism, type 1 diabetes mellitus, and acute kidney injury [6,7,8]. To this end, cardiovascular complications are estimated to constitute approximately 2% of ICI-related adverse drug reactions [9]. The commonest is myocarditis, but other cardiovascular abnormalities reported are left ventricular dysfunction, acute myocardial infarction (AMI), cardiac arrhythmias and heart failure [10]. These cardiovascular complications typically present with clinical heterogeneity, and in turn account for the high morbidity and mortality rates observed in such patient cohorts. Whilst cardiotoxicity is being documented with an increasing frequency, their cumulative incidence rates remain largely unexplored. In this territory-wide study, we examined the incidence of cardiovascular events of incident heart failure, acute myocardial infarction, atrial fibrillation, or atrial flutter in cancer patients receiving PD-1 or PD-L1 inhibitors.

Methods

Study Population

This study was approved by The Joint Chinese University of Hong Kong - New Territories East Cluster Clinical Research Ethics Committee. Patients receiving PD-1 or PD-L1 inhibitors since their launch up to 31st December 2020 at publicly funded hospitals or their associated outpatient/ambulatory care facilities, without pre-existing cardiac complications (including heart failure, myocardial infarction, atrial fibrillation, and atrial flutter) were included. 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. The system has been previously used by both our team and other teams in Hong Kong [11,12,13].

Patient Data

The following clinical data were extracted: patient characteristics, including demographic details (baseline age and gender), specific pre-existing comorbidities before drug prescriptions, laboratory examinations (including complete blood counts, biochemical tests, lipid/glycemic profiles) were extracted. Past comorbidities from January 1st, 2013, to December 31st, 2020, were extracted, and categorized into hypertension, liver diseases, hip fractures/accident falls, renal diseases, diabetes mellitus, malignant dysrhythmia, chronic obstructive pulmonary disease, ischemic heart disease, peripheral vascular disease, endocrine diseases, gastrointestinal diseases, and stroke/transient ischemic attack. The International Classification of Disease, Ninth Edition (ICD-9) codes that were used to extract the specific comorbidities and outcomes are included in Supplementary Table 2. The overall dosage and the duration of exposure to PD-L1 and PD-1 inhibitors for patients with new-onset cardiac complications are reported.

Primary outcomes on follow-up

The primary outcome was a composite of incident heart failure, acute myocardial infarction, atrial fibrillation, and 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 August 31st, 2020, 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 χ2 test with Yates’ correction was used for 2 × 2 contingency data, and Pearson’s χ2 test was used for contingency data for variables with more than two categories. The patients with PD-L1 were matched with PD1 controls through propensity score matching of 1:2 ratio, based on patient demographics, Charlson’s standard comorbidity index, past comorbidities, and non-PD-1/PD-L1 medications. Negligible post-weighting intergroup standardized mean difference (SMD) was defined as SMD < 0.2. To identify the important predictors associated with new-onset cardiac complications of patients after PD-1/PD-L1 treatment, univariable Cox regression was used to calculate hazard ratios (HRs) and 95% CIs. In addition to propensity score matching, the following approaches based on the propensity scores were employed: propensity score stratification [14], inverse probability weighting [15], and high-dimensional propensity score adjustment [16]. Paired hospitalization characteristics of patients before and after treatment were compared both in the unmatched and matched cohorts. A two-sided α of < 0.05 was considered statistically significant. Statistical analyses were performed using RStudio software (Version: 1.1.456) and Python (Version: 3.6).

Results

Baseline characteristics

Initially, 2426 cancer patients receiving PD-1/PD-L1 inhibitors were identified (Fig. 1). In total 1959 patients remained in the study cohort after excluding 433 patients with prior cardiac complications and 34 patients who received both PD1 and PDL1 treatments. Propensity score matching with 1:2 ratio between PD-1 and PD-L1 inhibitor use based on demographics, Charlson’s standard comorbidity index, prior comorbidities, and non-PD-1/PD-L1 medications was performed. This yielded a matched cohort of 663 patients (Table 1).

Fig. 1
figure 1

Study flow diagram describing derivation of the study cohort

Full size image
Table 1 Clinical characteristics of patients with PD-1 use and PD-L1 use before and after 1:2 propensity score matching
Full size table

Propensity score matching in 1:2 ratio between PD-1 users and PD-L1 users using the nearest neighbor search strategy (caliper as 0.1) was used. The results of logistics regression for potential confounders used in propensity score calculations, balance between groups, and estimations of bootstrapped standard error are shown in Supplementary Tables 3, 4 and 5, respectively. Distributions of propensity scores before and after matching are shown in Supplementary Fig. 1. These results indicate that the covariables between the groups are balanced after matching.

Adverse cardiovascular outcomes on follow-up and their significant predictors

In the matched cohort, 425 (IR: 64.10%) patients died and 91 (IR: 13.72%) developed new onset cardiac composite outcome. Amongst the latter, 75 (IR: 11.31%) developed heart failure, 8 (IR: 1.20%) developed acute myocardial infarction, 8 (IR: 1.20%) developed atrial fibrillation and 2 (IR: 0.30%) developed atrial flutter. The incidence rate of the composite outcome was lower in the PD-L1 cohort than in the PD-1 cohort (7.0% vs. 20.7%; P < 0.001).

In the 221 PD-L1 users, there were 11 patients (IR: 4.97%) who developed the composite outcome, in which 10 (IR: 4.52%) with heart failure, 1 (0.45%) with atrial fibrillation, but none with acute myocardial infarction or atrial flutter. In the 442 patients PD-1 users, 80 patients (IR: 18.09%) developed the composite outcome. Of the latter group, 65 (IR: 14.70%) developed heart failure, 8 (IR: 1.80%) developed acute myocardial infarction, 7 (IR: 1.58%) developed atrial fibrillation, and 2 (IR: 0.45%) developed atrial flutter.

The breakdown on the individual adverse events is shown in Fig. 1 and the patient characteristics stratified by adverse cardiovascular outcomes are shown in Tables 2 and 3. The cumulative incidence curves of new onset cardiac complications and all-cause mortality in cancer patients stratified by PD-1 or PD-L1 inhibitor use before and after 1:2 propensity score matching were presented in Figs. 2 and 3, respectively. The baseline characteristics of the cohort stratified by mortality status are shown in Supplementary Table 6.

Table 2 Clinical characteristics of patients who developed the composite outcome before and after 1:2 propensity score matching
Full size table
Table 3 Significant univariable predictors of new onset cardiac complication outcome and all-cause mortality before and after 1:2 propensity score matching
Full size table
Fig. 2
figure 2

Cumulative incidence curves of new onset cardiac complications and all-cause mortality in cancer patients stratified by PD-1 or PD-L1 inhibitor use before 1:2 propensity score matching

Full size image
Fig. 3
figure 3

Cumulative incidence curves of new onset cardiac complications and all-cause mortality in cancer patients stratified by PD-1 or PD-L1 inhibitor use after 1:2 propensity score matching

Full size image

Univariable Cox regression identified significant predictors of the primary composite outcome and all-cause mortality before and after propensity score matching (Table 3). Compared with PD-1 inhibitor treatment, PD-L1 inhibitor treatment was significantly associated with a lower risk of composite outcome both before (hazard ratio [HR]: 0.32, 95% CI: [0.18-0.59], P value=0.0002***) and after matching (HR: 0.34, 95% CI: [0.18-0.65], P value=0.001**), and lower all-cause mortality risk before matching (HR: 0.77, 95% CI: [0.64-0.93], P value=0.0078**) and after matching (HR: 0.80, 95% CI: [0.65-1.00], P value=0.0463).

More PD-L1 expenditure (HR:1.000; 95% CI: 1.000-1.000; P value=0.0528), shorter PD-L1 inhibitors duration (HR:0.99; 95% CI: 0.99-1.00; P value=0.0263*), more PD-1 expenditure, HKD (HR:1.000; 95% CI: 1.000-1.001; P value=0.0018**), and shorter PD-1 inhibitors duration (HR:0.998; 95% CI: 0.997-0.999; P value=0.0007***) were associated with new onset cardiac composite outcome in the matched cohort. Significant laboratory examinations significantly associated with new onset cardiac composite outcome include higher levels of mean corpuscular volume (HR:1.03; 95% CI: 1.00-1.07; P value=0.0470*), hematocrit (HR:566.25; 95% CI: 4.88-65751.46; P value=0.0090**), HbA1c (HR:1.19; 95% CI: 1.05-1.34; P value=0.0072**), total cholesterol (HR:1.42; 95% CI: 1.00-2.00; P value=0.0490*), and low-density lipoprotein (HR:1.67; 95% CI: 1.14-2.45; P value=0.0091**).

In addition, greater variability in laboratory tests, including the standard deviations (SD) of alkaline phosphatase (HR:1.002; 95% CI: 1.000-1.004; P value=0.0359*), HbA1c (HR:1.94; 95% CI: 1.36-2.76; P value=0.0003***), lactate dehydrogenase (HR:1.002; 95% CI: 1.000-1.003; P value=0.0056**), and low-density lipoprotein (HR:7.64; 95% CI: 1.84-31.77; P value=0.0051**) were significantly associated with the composite outcome. The boxplots of significant measures of variability stratified by PD-1/PD-L1 inhibitor treatment in the matched cohort are shown in Fig. 4.

Fig. 4
figure 4

Boxplots of significant laboratory examination variability stratified by PD-1/PD-L1 inhibitor use and development of the composite outcome in the matched cohort

Full size image

In addition, multivariable Cox regression models (Table 4) with multiple adjustments with significant demographics, past comorbidities, and non-PD-L1/PD-1 drugs confirmed the protection effects of PD-L1 than PD-1 for adverse study outcomes (HR<1, P < 0.05).

Table 4 Comparisons of hospitalization characteristics before and after PD1/PD-L1 treatment in patients with new onset heart failure, acute myocardial infarction, atrial fibrillation, and atrial flutter
Full size table

Healthcare utilization before and after treatment with PD-1/PD-L1 inhibitors

Longer overall cumulative hospital stay (HR:1.01; 95% CI: 1.00-1.01; P value=0.0040**) and longer hospital stay after PD-1/PD-L1 drug use (HR:1.01; 95% CI: 1.00-1.01; P value=0.0040**) were significantly associated with the composite outcome. Furthermore, hospitalization characteristics before and after PD-1/PD-L1 treatment were compared in the subset of patients who developed the adverse outcomes, in both the unmatched and matched cohorts (Table 4). Patients who developed cardiovascular complications had a shorter average readmission interval, a higher number of hospitalizations and a longer duration of hospital stay after PD-1/PD-L1 treatment (P < 0.0001).

Sensitivity analysis

Supplementary Table 7 presented the adjusted hazard ratios (and 95% CIs) of PD-L1 vs. PD-1 with cause-specific and subdistribution hazard competing risk analysis models for new onset cardiac composite and mortality outcomes after 1:2 propensity score matching. Supplementary Table 8 presented the hazard ratios for associations of PD-L1 vs. PD-1 using Cox proportional hazard model for adverse new onset cardiac composite and mortality outcome in the 1:2 matched cohort, with half-year lag time. Supplementary Table 9 presented the risk of incident new onset cardiac composite and mortality outcomes associated with treatment of PD-L1 vs. PD-1 with multiple matching adjustment approaches including propensity score stratification, high-dimensional propensity score matching, and propensity score matching with inverse probability of treatment weighting. The above analysis confirmed the protective effects of PD-L1 treatment over PD-1 treatment on new onset cardiac complications and mortality risks (HR<1, P value<0.05).

Prediction strength of subclinical inflammatory biomarkers

In the matched cohort, higher aspartate transaminase-to-alanine transaminase ratio (HR: 1.09, 95% CI: [1.04-1.14], P value=0.0004) and higher monocyte-to-lymphocyte ratio (HR: 1.2, 95% CI: [1.02-1.43], P value=0.0305) were significantly associated with all-cause mortality. A higher urea-to-creatinine ratio (HR: 1.01, 95% CI: [1.00-1.01], P value=0.0007) was significantly associated with new onset cardiac composite outcome (Table 5). The boxplots of inflammatory biomarkers stratified by PD-1/PD-L1 inhibitor use and development of adverse outcomes are shown in Fig. 5.

Table 5 Multivariable univariable Cox regression models for new onset cardiac complication outcome and all-cause mortality in the matched cohort
Full size table
Fig. 5
figure 5

Boxplots of subclinical inflammatory biomarkers stratified by PD-1/PD-L1 inhibitor use and development of the composite outcome in the matched cohort

Full size image

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) multivariable 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 [17]. Thus, heart block [18], Takotsubo cardiomyopathy [19], myocarditis [20, 21] and pericarditis [22] have been reported. A meta-analysis performed in 2018 found that anti-PD-1/PD-L1-related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/ cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]) [23]. In an analysis of the World Health Organization global database of adverse drug reactions in 2019, 2.1% of 106,025 patients receiving PD-1 or PD-L1 inhibitors had cardiovascular complications [9]. However, previous studies have largely been limited to case reports [18, 24], case series [25], single-center studies [26] or small registries [27, 28]. 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 heart failure. Previously, acute heart failure has been described in the context of myocarditis [29], but heart failure without myocarditis has also been reported [30]. Our study also identified cases of acute myocardial infarction 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 [27].

It is worth noting that the present study is the first to compare the cardiotoxicity between PD-1 and PD-L1 inhibitor treatment. The reason for the protective effect of PD-L1 inhibitor to be stronger than PD-1 inhibitor may be the stronger immune-mediated effects of PD-1 inhibitor. Contrary to PD-1 inhibitor, which blocks the interaction between PD-1 and both PD-L1 and PD-L2, PD-L1 inhibitor only blocks the interaction between PD-1 and PD-L1. [31]Although cancer may escape from immune-mediated detection via the PD-1/ PD-L2 axis under PD-L1 inhibitor treatment, it also implies that PD-L1 inhibitor may have weaker autoimmunity, thus resulting in less immune-mediated cardiotoxicity. [32] Furthermore, patients who developed cardiovascular complications had a shorter average readmission interval and more hospitalizations, which is due to the deterioration in patients’ general health and treatment needed for the complications. For example, acute exacerbation of heart failure is known to be common reasons for frequent admissions. The presence of adverse cardiovascular events is detrimental to the overall health of cancer patients who are already frail, which may lead to the decline in health and related frequent admissions, which demonstrates the critical effects of cardiovascular complications on patients’ physical health and quality of life.

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) [28]. 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 [33]. 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 [26]. 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 [34]. In association with myocarditis, different investigators have reported the presence of conduction abnormalities in the form of atrioventricular block [18, 25, 26, 35].

Limitations

There are some limitations of this study that should be acknowledged. Firstly, this was an administrative database study, and therefore cancer staging details could not be extracted. Secondly, under-coding or miscoding remains a possibility as with studies of a similar nature. Thirdly, although no cases of myocarditis were found. As our study relies on ICD-9 coding, this might be due to under-coding. Alternatively, missed cases by the clinicians and subclinical myocarditis leading to heart failure are possible. Therefore, further studies accounting for parameters that may uncover undiagnosed myocarditis, such as creatine kinase, is needed to ensure that the diagnosis of myocarditis is not missed.

Conclusions

Compared with PD-1 inhibitor use, PD-L1 inhibitor use was significantly associated with lower risks of cardiac complications and all-cause mortality both before and after propensity score matching. Patients who developed cardiovascular complications had shorter average readmission intervals and a higher number of hospitalizations after treatment with PD-1/PD-L1 inhibitors.