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Originally Published 2 October 2020
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Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque

Zsofia D. Drobni, MD https://orcid.org/0000-0002-1355-5318, Raza M. Alvi, MD, Jana Taron, MD, Amna Zafar, MD, Sean P. Murphy, MD, Paula K. Rambarat, MD, Rayma C. Mosarla, MD, … Show All … , Charlotte Lee, MD, Daniel A. Zlotoff, MD, PhD, Vineet K. Raghu, PhD https://orcid.org/0000-0003-3524-3945, Sarah E. Hartmann, BS, Hannah K. Gilman, BS, Jingyi Gong, MD, Leyre Zubiri, MD, PhD, Ryan J. Sullivan, MD, Kerry L. Reynolds, MD, Thomas Mayrhofer, PhD https://orcid.org/0000-0001-6287-5185, Lili Zhang, MD, MS https://orcid.org/0000-0002-9341-5832, Udo Hoffmann, MD, MPH, and Tomas G Neilan, MD, MPH https://orcid.org/0000-0002-1513-8833 [email protected]Author Info & Affiliations
Circulation
Volume 142, Number 24
https://doi.org/10.1161/CIRCULATIONAHA.120.049981
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VIEW EDITORIAL:By Releasing the Brakes With Immunotherapy, Are We Accelerating Atherosclerosis?

Abstract

Background:

Immune checkpoint inhibitors (ICIs) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events.

Methods:

The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls matched by age, a history of cardiovascular events, and cancer type. In a second design, a case-crossover analysis was performed with an at-risk period defined as the 2-year period after and the control period as the 2-year period before treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. All study measures and outcomes were blindly adjudicated.

Results:

In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (hazard ratio, 3.3 [95% CI, 2.0–5.5]; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5–6.5]; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids.

Conclusions:

Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk before, during, and after treatment should be considered among patients on an ICI.

Clinical Perspective

What Is New?

•
Immune checkpoint inhibitors are associated with a 3-fold higher risk for atherosclerotic cardiovascular events, including myocardial infarction, coronary revascularization, and ischemic stroke.
•
Immune checkpoint inhibitors are associated with a >3-fold higher rate of aortic plaque progression.
•
The increase in aortic atherosclerotic plaque was modified by concomitant statin and corticosteroid use.

What Are the Clinical Implications?

•
Optimization of cardiovascular risk factors before, during, and after treatment with immune checkpoint inhibitors is warranted.
•
Increased awareness of atherosclerotic cardiovascular risk during and after treatment with immune checkpoint inhibitors is needed.

Introduction

Editorial, see p 2312; Article, see p 2396
Immune checkpoint inhibitors (ICIs) represent a paradigm shift in cancer care, leveraging the immune system to identify and target cancer cells.1 The use of ICIs is rapidly expanding. For example, in 2014, ICIs were approved for 3 cancer indications.2 By 2020, this number had increased to >50, and the percentage of patients with cancer eligible for an ICI has increased from 1.5% in 2011 to >43.6%.3 The benefit of ICIs has expanded to the adjuvant setting in some malignancies4,5 and will continue to expand to patients with a much longer anticipated survival.4
Consistent animal and cellular studies have demonstrated that these immune checkpoints, currently targeted in approved indications, are critical negative regulators of atherosclerosis: PD-1 (programmed cell death protein 1), programmed death ligand 1, and CTLA-4 (cytotoxic T-lymphocyte–associated protein 4).6–8 However, there are conflicting clinical and imaging data testing whether ICIs, by inhibiting these key pathways in atherosclerosis, lead to an increase in atherosclerotic plaque and atherosclerosis-related cardiovascular events.9–12 Given the potentially significant impact on public health, we performed both a matched cohort study and a case-crossover study to determine whether the use of ICIs leads to an increase in cardiovascular events. To provide further insights, we also tested whether ICIs were associated with accelerated atherosclerotic plaque in a subsample.

Methods

The data, analytical methods, and study materials will be made available from the corresponding author on reasonable request after institutional approval and following institutional process.

Study Design, Setting, and Population

We chose 2 study designs to examine the association between ICIs and cardiovascular events: a matched cohort study and a case-crossover study. All individuals treated with an ICI through the end of March 2019 at a single academic institution (Massachusetts General Hospital, Boston) were included. The use of an ICI was derived from a pharmacy database. The study entry date for the cases was defined as the first date an ICI was administered. For the matched cohort study, controls were selected from all patients treated for cancer at our center between January 1, 2008, and December 31, 2012. For the control group, the use of an ICI at any time point was an exclusion criterion. There were 9793 individual patients with cancer treated at our institution during that period. Of these, 1250 were excluded because they were treated with an ICI subsequently. This resulted in a cohort of 8543 patients. From these, we randomly selected controls in a 1:1 ratio to match cases for age, a history of cardiovascular events, and cancer type (Figure 1). The study entry for the controls was their first visit after January 1, 2008. For the case-crossover design, we defined the observation period as the interval from 2 years before to the start of the ICI. We defined the at-risk period as the 2-year interval after the start of the ICI (Figure I in the Data Supplement). Covariates were derived from the Research Patient Data Registry. The study was approved by the Partners Human Research Committee, and no informed consent was required. The authors vouch for the completeness and accuracy of the data and all analyses.
Figure 1. Flow diagram.

Procedures

Covariates of interest obtained included patient demographics, medications, and standard cardiovascular risk factors (eg, diabetes, hypertension, smoking). Data relevant to cancer included the cancer type, previous potentially cardiotoxic cancer therapies (radiation therapy, 5-fluorouracil, anthracyclines, and tyrosine kinase inhibitors), and the specific ICI treatments, including the use of combined immune checkpoint therapy. Data specific to the ICI cohort also included the number of ICI cycles, the occurrence of any immune-related adverse event, and the use of corticosteroids.

Clinical Outcomes

The primary outcome was the occurrence of a cardiovascular event, defined as a composite of myocardial infarction, coronary revascularization, and ischemic stroke. The individual components of these were prespecified as key separate secondary outcomes. Events were initially identified from individual chart review of all records with a broad key word search, and then all potential clinical events were independently adjudicated by a study team blinded to all other data and using standard definitions (Document I in the Data Supplement, Key Words and Definitions Used for Each of the Adjudicated Clinical Events).13–15

Imaging Study

We performed an imaging substudy in which we measured the thoracic atherosclerotic plaque burden over time among patients with melanoma who were treated with an ICI. Melanoma was chosen as the population for the substudy as it was one of the most common cancer seen in our study, ICIs are frequently used,16 and these therapies have had a marked impact on cancer outcomes.4,16 Studies were performed as part of their routine clinical care for cancer staging. Thoracic aortic plaque volume was measured from these studies in a standardized fashion in a core laboratory by investigators blinded to all other study variables, including treatment status and sequence of imaging studies. The plaque volume was assessed on a limited field of view that excluded the surrounding nonvascular structures. The full analysis protocol, accuracy, and reproducibility of these methods have been reported by our group previously (Figure II and III and Document II in the Data Supplement).13,14,17 This volumetric plaque assessment technique has demonstrated excellent intraobserver and interobserver, as well as interscan, reproducibilities.18–20 In brief, total and noncalcified thoracic aortic plaque volumes were measured on all 3 contrast computed tomography scans with dedicated software (QAngioCT, version 3.1.4.2, Medis Medical Imaging Systems, Leiden, the Netherlands).21 Relative plaque volume measures were assessed as percent of total segment volume. Plaque change was calculated as the difference in plaque volume measured on 2 consecutive scans (ie, scan 2−scan 1 and scan 1−scan 0). Annualized plaque progression rate was computed as plaque change per year given in absolute and relative rates (cubic millimeters and percent).

Statistical Analysis

Descriptive statistics were used to assess the distribution of variables; continuous variables were summarized as mean with SD or medians with interquartile ranges, and categorical variables were summarized as counts and percentages. In the matched cohort study, controls were matched 1:1 on the basis of age, a history of cardiovascular events, and cancer type. In the matched cohort and case-crossover designs, Cox proportional hazard regression analysis was performed to calculate hazard ratios (HRs) with 95% CIs, counting only the first cardiovascular event. Two approaches were applied. In the first, a parsimonious multivariable Cox proportional hazard model was performed, including known cardiovascular risk factors (model 1). In a second approach, a forward stepwise selection was used; clinically relevant unique predictor variables with a value of P<0.10 in univariable analysis were entered into the final multivariable model (model 2). The incremental value between steps was measured by the likelihood-ratio test. The proportional hazard assumption was tested with the use of log-log plots and examination of Schoenfeld residuals. We performed subgroup analyses of HRs by sex, age (<65 years versus ≥65 years), body mass index (<30 kg/m2 versus ≥30 kg/m2), a history of cardiovascular events, hypertension, diabetes, statin use, melanoma, and lung cancer. We evaluated the presence of interactions in these subgroups, and HRs stratified by these subgroups were compared with the χ2 test. In the case-crossover analysis,22,23 Cox proportional hazard regression analyses were performed with calculation of 100 person-years and an HR adjusted for age. We compared atherosclerotic cardiovascular events in the 2-year period before and the 2-year period after the start of the ICI. We used Poisson regression during the 2-year periods before and after ICI and calculated incidence rate ratio with the outcome variable as a count variable including all events (first event and the events that occurred subsequently after the first event during the follow-up period). In addition, we tested a narrower risk period (1 year before and 1 year after) and performed sensitivity analyses excluding patients who died within 60 days of the cardiovascular event. In the imaging substudy, the primary outcome of interest was the change in total plaque volume over time in patients from before to after ICI. The secondary imaging outcome was the change in noncalcified plaque volume. The annualized rate of change in plaque volume was compared from before to after ICI using the Wilcoxon signed-rank test. We performed analyses of plaque progression in prespecified subgroups defined by statin use and the use of corticosteroids during ICI therapy. All statistical tests were 2 tailed, and values of P<0.05 were considered to indicate statistical significance. Analyses were performed with SAS software, version 9.4 (SAS Institute, Cary, NC) and STATA software, version 15.1 (StataCorp, College Station, Texas).

Results

Patient Demographics, Comorbidities, and Cancer Data

Baseline demographics and clinical characteristics are summarized in Table 1. Baseline laboratory values are summarized in Table I in the Data Supplement. Overall, cases and controls were not different with respect to age, type of cancer, and history of any cardiovascular event. Non–small cell lung cancer (28.8%) and melanoma (27.9%) were the most common types of cancer. Controls had higher rates of hypertension (53.5% versus 49.2%; P=0.001) and diabetes (18.2% versus 15.7%; P=0.014). Controls were more likely female (46.9% versus 42.6%; P=0.001). The use of statins was not different between cases and controls (26.0% versus 27.7%; P=0.17). Among the cases, PD-1 inhibitor therapy was the most commonly prescribed (75.3%), and cases had a median of 5 cycles of the ICI administered. Overall, 43.2% of the cases had an immune-related adverse event, and 26.9% were treated with corticosteroids, 62.2% of those with immune-related adverse events.
Table 1. Baseline Characteristics of Patients Treated With ICIs and Controls
 CasesControlsP value
Demographics
 Patients, n28422842 
 Sex, n (%)
  Male1631 (57.4)1509 (53.1)0.001
  Female1211 (42.6)1333 (46.9)0.001
 Age, mean (SD), y64 (13)64 (13)0.14
 Age, median. (IQR), y66 (57–74)65 (55–74)0.11
Race or ethnic group, n (%)<0.001
 White2479/2704 (91.7)2851/2748 (93.9) 
 Asian96/2704 (3.6)43/2748 (1.6) 
 Black or African American57/2704 (2.1)64/2748 (2.3) 
 Hispanic29/2704 (1.1)40/2748 (1.5) 
 Other43/2704 (1.6)20/2748 (0.7) 
Clinical variables, mean (SD)
 Body mass index, kg/m227.0 (6.4)27.6 (5.7)<0.001
 Systolic blood pressure, mm Hg127.6 (18.6)127.6 (16.9)0.93
Cardiovascular risk factors, n (%)
 Hypertension1356/2756 (49.2)1518/2837 (53.5)0.001
 Diabetes433/2756 (15.7)517/2837 (18.2)0.014
 Smoking, current or previous429/2756 (15.6)405/2837 (14.3)0.19
 Hyperlipidemia840/2756 (30.5)1048/2837 (36.9)<0.001
Cardiovascular diagnoses, n (%)
 History of any cardiovascular event322/2842 (11.3)357/2842 (12.6)0.16
 History of myocardial infarction136/2842 (4.8)167/2842 (5.9)0.077
 History of coronary revascularization195/2842 (6.9)230/2842 (8.1)0.078
 History of ischemic stroke82/2842 (2.9)101/2842 (3.6)0.18
Cardiovascular medications, n (%)
 Angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker612/2704 (22.6)647/2423 (26.7)<0.001
 β-Blockers628/2704 (23.2)798/2423 (32.9)<0.001
 Calcium channel blockers396/2704 (14.6)360/2423 (14.9)0.86
 Statins704/2704 (26.0)672/2423 (27.7)0.17
 Nonstatin dyslipidemia therapies65/2704 (2.4)122/2423 (5.0)<0.001
 Aspirin578/2704 (21.4)603/2423 (24.9)0.003
 Other antiplatelet therapies66/2704 (2.4)98/2423 (4.0)0.001
Other medical comorbidities, n (%)
 Chronic obstructive pulmonary disease285/2756 (10.3)169/2837 (6.0)<0.001
 Chronic kidney disease327/2756 (11.9)326/2837 (11.5)0.69
Cancer types, n (%)
 Non–small cell lung819/2842 (28.8)819/2842 (28.8) 
 Melanoma794/2842 (27.9)794/2842 (27.9) 
 Head and neck344/2842 (12.1)344/2842 (12.1) 
 Renal and genitourinary182/2842 (6.4)182/2842 (6.4) 
 Breast119/2842 (4.2)119/2842 (4.2) 
 Gastrointestinal116/2842 (4.1)116/2842 (4.1) 
 Gynecological110/2842 (3.9)110/2842 (3.9) 
 Lymphoma82/2842 (2.9)82/2842 (2.9) 
 Hepatobiliary101/2842 (3.6)101/2842 (3.6) 
 Pancreatic37/2842 (1.3)37/2842 (1.3) 
 Other138/2842 (4.9)138/2842 (4.9) 
Previous potentially cardiotoxic cancer therapies, n (%)
 Radiation therapy572/2756 (20.8)287/2837 (10.1)<0.001
 5-Fluorouracil284/2723 (10.4)151/2710 (5.6)<0.001
 Anthracyclines151/2723 (5.5)153/2710 (5.6)0.92
 Tyrosine kinase inhibitors61/2723 (2.2)59/2710 (2.2)0.95
ICI type, n (%)
 Monotherapy
  Programmed death ligand-1283/2842 (10.0)  
  CTLA-4221/2842 (7.8)  
  PD-12141/2842 (75.3)  
  CTLA-4 or PD-12/2842 (0.1)  
 Combination therapy
  CTLA-4/PD-1195/2842 (6.9)  
  Cycles of ICI, n (IQR)5 (2–11)  
Immune-mediated adverse events after ICI start
 Gastrointestinal500/2748 (18.2)  
 Skin429/2748 (15.6)  
 Pulmonary189/2748 (6.9)  
 Hepatic179/2748 (6.5)  
 Endocrine175/2748 (6.4)  
 Renal120/2748 (4.4)  
 Neuromuscular98/2748 (3.6)  
 Pancreas61/2748 (2.2)  
 Any of the above adverse events1186/2748 (43.2)  
Immune-mediated adverse events treated with steroids, n (%)
 Among the entire cohort738/2748 (26.9)  
 Among those with immune-mediated adverse events738/1186 (62.2)  
CTLA-4 indicates cytotoxic-T-lymphocyte–associated protein 4; ICI, immune checkpoint inhibitor; IQR, interquartile range; and PD-1, programmed cell death protein 1.

Primary and Secondary Outcomes

Demographic, clinical, and cancer-related variables were included in a univariable Cox proportional hazard model (Table II in the Data Supplement). The use of an ICI was associated with a >4-fold increase in the risk for a composite cardiovascular event (univariable HR, 4.7 [95% CI, 3.5–6.2]; P<0.001). For the individual outcomes, similar results were found (Figure 2) in which the use of an ICI was associated with a higher risk for myocardial infarction (univariable HR, 7.2 [95% CI, 4.5–11.5;] P<0.001), a 3-fold increase in the risk for coronary revascularization (univariable HR, 3.0 [95% CI, 1.9–4.8]; P<0.001), and a 4-fold increase in the risk for ischemic stroke (univariable HR, 4.6 [95% CI, 2.9–7.2]; P<0.001). Kaplan-Meier curves of the cumulative hazard in cases and controls of the composite and individual component outcomes and the event rates at 3 years are shown in Figure 2.
Figure 2. Kaplan-Meier curves of the cumulative hazard for atherosclerotic cardiovascular events. A, Cumulative hazard for the composite cardiovascular outcome. B–D, Individual components of the primary outcome. Cases (those treated with an immune checkpoint inhibitor [ICI]) are marked with red; controls (not treated with an ICI) are marked with blue. HR indicates hazard ratio.
In a parsimonious multivariable model, which included known cardiovascular risk factors (male sex, age, body mass index, hypertension, diabetes, chronic kidney disease, smoking, history of a cardiovascular event, statin use, aspirin use, hemoglobin, and low-density lipoprotein), the use of an ICI was associated with a 3-fold increase in the risk for a composite cardiovascular event (multivariable HR, 3.3 [95% CI 2.0–5.5]; P<0.001; Table 2, model 1). In a second approach, the variables, identified as P<0.1 in the univariable Cox model, were entered into a multivariable model. In this model, the use of an ICI was associated with a 4-fold increase in the risk for a composite cardiovascular event (multivariable HR, 4.5 [95% CI, 3.3–6.1]; P<0.001; Table 2, model 2).
Table 2. Multivariable Cox Proportional Hazard Model Results of the Composite Cardiovascular Outcome (Myocardial Infarction, Revascularization, Ischemic Stroke)
 HR95% CIWald test P value
Multivariable model 1
 ICIs3.311.995.51<0.001
 Male sex1.711.142.540.009
 Age1.041.021.06<0.001
 Body mass index1.031.001.060.076
 Hypertension0.890.531.510.67
 Diabetes1.410.962.070.082
 Chronic kidney disease0.930.601.440.75
 Smoking, current or previous1.270.831.950.27
 History of any cardiovascular event2.141.393.290.001
 Statins0.720.481.090.12
 Aspirin1.140.761.690.53
 Hemoglobin0.880.790.980.023
 Low-density lipoprotein1.000.991.000.68
Multivariable model 2
 ICIs4.503.306.13<0.001
 Age1.031.021.04<0.001
 History of any cardiovascular event2.191.632.94<0.001
 Diabetes1.421.071.870.01
 Systolic blood pressure1.011.001.020.01
 Non–small cell lung cancer1.541.192.01<0.001
 Previous radiation therapy1.541.132.090.01
 Male sex1.291.001.660.05
ICI indicates immune checkpoint inhibitor; and HR, hazard ratio.
In the case-crossover study, the number of patients who had an event and the cumulative number of cardiovascular events were compared only among the 2842 patients who were treated with an ICI. Overall, among the 2842 patients who were treated with an ICI, 119 patients had a cardiovascular event during the 2-year period after starting an ICI compared with 66 patients in the 2-year period before starting an ICI, a 4-fold increase from 1.37 to 6.55 per 100 person-years (adjusted HR, 4.8 [95% CI, 3.5–6.5]; P<0.001; Table 3). In the case-crossover study, there was also an increase in each of the individual components of the primary outcome (Figure 3 and Table 3). The total numbers of events in the risk and control periods in the case-crossover study were also compared. Among the 2842 patients treated with an ICI, there were 139 events among the 119 patients during the 2-year period after ICI. In comparison, in the same cohort of 2842 patients, who subsequently were treated with an ICI, there were 78 events among the 66 patients during the 2-year period before ICI (incidence rate ratio, 1.8 [95% CI, 1.4–2.4]; P<0.001). Similar findings were also noted when the risk period and control period were restricted to 1 year before and 1 year after ICI (Figure 3 and Table III in the Data Supplement), and findings of a higher risk for atherosclerotic cardiovascular event with an ICI persisted after the exclusion of individuals who died within 60 days of the event (Table IV in the Data Supplement).
Table 3. Number of Patients With an Event and Number of Events, Rate per 100 Person-Years From Our Cohort of 2842 Cases, and HR for Cardiovascular Events
Outcome, n (%)Before treatmentAfter treatment  
Events, n (%)Rate per 100 person-yEvents, n (%)Rate per 100 person-yHazard ratio* (95% CI)P value
Patients with cardiovascular events66 (2.32)1.37119 (4.2)6.554.78 (3.50–6.53)<0.001
Myocardial infarction27 (0.95)0.4858 (2.04)2.734.84 (2.76–8.09)<0.001
Coronary revascularization25 (0.87)0.4436 (1.26)1.703.18 (1.46–6.10)<0.001
Ischemic stroke26 (0.91)0.4645 (1.58)2.122.97 (1.41–5.53)<0.001
Cardiovascular events are compared for the 2-year period before immune checkpoint inhibitor and 2-year period after immune checkpoint inhibitor. ICI indicates immune checkpoint inhibitor; and HR, hazard ratio.
*
Cox proportional hazard model
Figure 3. Cardiovascular events in the case-crossover study. A, Composite cardiovascular outcomes in the 2-year periods before and after immune checkpoint inhibitor (ICI). Cardiovascular event rates per 100 person-years from the 2 years before the start of an ICI to 2 years after starting an ICI are included. Individual components of the primary outcome are also shown. B, Composite cardiovascular outcomes in the 1-year period before and after ICI.

Subgroup Analyses

In the subgroup analyses, a significant interaction was noted between baseline hypertension and ICI use (P=0.003; Figure IV in the Data Supplement) in which the relative risk for a cardiovascular event was higher among patients without hypertension compared with patients with hypertension (HR, 10.7 [95% CI, 6.1–18.8] versus HR, 3.4 [95% CI, 2.4–4.9]). There was no relative difference in the risk for a cardiovascular event between males and females, those <65 years versus ≥65 years of age, and those with a body mass index <30 versus ≥30 kg/m2, a history of cardiovascular events, baseline diabetes, statin use, or a diagnosis of melanoma or lung cancer.

Imaging Substudy

The imaging study cohort included 40 patients with melanoma with computed tomography performed at 3 time points (Figure III in the Data Supplement). The clinical characteristics of the patients in the imaging substudy, apart from cancer type, were not different from those of the main study cohort (Table V in the Data Supplement). The presence of cardiovascular risk factors except for age, clinical variables, and the use of cardiac medications remained relatively constant throughout the study period (Table VI in the Data Supplement). There was an increase in the total and noncalcified plaque volumes over the duration of the 3 scans (Table VII in the Data Supplement). The progression rate, adjusted for the study interval, was greater in the period after ICI compared with before ICI for both total (P=0.02) and noncalcified plaque (P=0.02; Table 4). Specifically, the rate of total plaque volume progression increased 3-fold from 2.1%/y before to 6.7%/y after ICI. The rate of noncalcified plaque also increased after ICIs (Table VII in the Data Supplement). In stratified analysis, compared with statin nonusers, those on statins (n=18) showed a 3.1% absolute lower rate of plaque progression each year of total aortic plaque volume (5.2% versus 8.3%, P=0.04) and a 3.9% absolute lower yearly rate of noncalcified plaque progression (3.1% versus 7.0%; P=0.04; Table 5). Similarly, among patients who were prescribed corticosteroids during checkpoint therapy, there was a lower rate of plaque progression among those on corticosteroids (Table 5); specifically, the rate of noncalcified plaque progression was 3.5%/y among those prescribed a corticosteroid compared with a rate of progression of 6.9%/y among those not prescribed a corticosteroid (total plaque volume, P=0.04).
Table 4. Absolute and Relative Change in Thoracic Atherosclerotic Plaque Volume From Before Starting an ICI (Scan 0-Scan 1) to After Starting an ICI (Scan 1 to Scan 2)
ChangeIndexed change per yearPlaque volumeScan 0−scan 1Scan 1−scan 2P value*
Absolute changeIndexed change per year, mm3/yTotal plaque volume13.8 (−240 to 122)103 (0 to 511)0.02
Noncalcified plaque volume−18.2 (−274 to 57)53 (0 to 382)0.02
Relative changeIndexed change per year, %/yTotal plaque volume2.1 (−13.0 to 18.6)6.7 (2.2 to 28.1)0.17
Noncalcified plaque volume−2.3 (−14.0 to 12.7)5.3 (1.4 to 40.1)0.14
Values are median (interquartile range).
ICI indicates immune checkpoint inhibitor.
*
Wilcoxon signed-rank test comparing annual rate of progression in plaque volume from scan 0 to scan 1 and from scan 1 to scan 2. Relative change is the change in plaque volume per year.
Table 5. Subgroup Analysis of the Change in Plaque Volume After Starting an ICI by Statin and Corticosteroid Use
Plaque measure, median (IQR)Drug, yesDrug, noP value
Statin
 Total aortic plaque volume
  Before ICI, mm31903 (1038 to 2661)1281 (358 to 2691)0.38
  After ICI, mm32214 (1730 to 4090)1644 (588 to 4211)0.32
  Absolute change in total plaque, mm3/y79.2 (0 to 524)115 (0 to 509)0.001
  Relative change in total plaque volume, %/y5.2 (0.6 to 23.7)8.3 (4.7 to 42.5)0.04
 Noncalcified aortic plaque volume
  Before ICI, mm31233 (956 to 1835)998 (353 to 2663)0.68
  After ICI, mm31781 (1180 to 3517)1631 (576 to 3652)0.62
  Absolute change in noncalcified plaque, mm3/y45.3 (−38 to 387)69.5 (0 to 377)0.002
  Relative change in noncalcified plaque volume, %/y3.1% (−2.3 to 30.4)7.0% (2.6 to 43.6)0.04
Corticosteroid
 Total aortic plaque volume
  Before ICI, mm31687 (751 to 2661)1281 (655, 2691)0.65
  After ICI, mm32161 (690 to 4090)2214 (1193, 6165)0.77
  Absolute change in plaque, mm3/y61.8 (−52.8 to 451)278 (38.0 to 524)0.02
  Relative change in total plaque volume, %/y5.9% (−2.2 to 30.2)7.4% (4.7 to 21.0)0.04
 Noncalcified aortic plaque volume
  Before ICI, mm3998 (530 to 1835)1278 (654 to 2663)0.71
  After ICI, mm31548 (576 to 2750)1968 (1180 to 5029)0.28
  Absolute change in noncalcified plaque volume, mm3/y42.9 (−84.0 to 290)80.3 (37.5 to 494)0.02
  Relative change in noncalcified plaque volume, %/y3.5 (−11.3 to 43.4)6.8 (3.1 to 22.3)0.04
ICI indicates immune checkpoint inhibitor; and IQR, interquartile range.

Discussion

The rate of atherosclerotic cardiovascular events was higher after an ICI was started. In a matched cohort study, ICI treatment was associated with a 3-fold higher risk for atherosclerotic cardiovascular events compared with cancer patients who did not have ICI. Similar findings of a higher risk for atherosclerotic cardiovascular events were noted in a case-crossover study. In an imaging substudy, there was a >3-fold increase in the rate of atherosclerotic plaque progression after the initiation of ICI therapy. The association with increased atherosclerotic plaque was attenuated in patients with concomitant use of statins or corticosteroids, who had an ≈50% reduction in plaque progression compared with those not on statins or corticosteroids. Overall, these data suggest that patients treated with an ICI are at a higher risk for atherosclerotic cardiovascular events and that this risk is potentially mediated through accelerated atherosclerosis progression but may be modifiable. Our findings are important both for patients for whom ICIs are currently indicated and perhaps more so for the expanding pool of patients who are candidates for adjuvant and neoadjuvant therapy.
Data on the cardiac toxicities of ICIs have related principally to the development of myocarditis24–26; small cohort studies have suggested that myocarditis is an uncommon but potentially fatal complication.27–31 A limited number of previous studies have tested the association between ICIs and atherosclerotic cardiovascular disease. In a single-center case-control studies with 135 subjects, a single cancer type (non–small cell lung cancer), and a 6-month follow-up period, there were no increases in cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure with ICIs (HR, 1.2 [95% CI 0.6–2.4]; P=0.66).12 Similarly, in a study of 92 patients with non–small cell lung cancer, there was no increase in venous and arterial vascular events (pulmonary emboli, deep vein thrombosis, cerebrovascular accident, transient ischemic attack, and acute coronary syndrome) compared with patients being treated with cytotoxic chemotherapy.10 In contrast, in a pooled analysis of 59 oncological trials submitted to the US Food and Drug Administration for approval (sample size, 21 664), compared with traditional cytotoxic chemotherapies, there was a 35% (95% CI, 0.76–2.4) increase in coronary ischemia (defined with Medical Dictionary for Regulatory Activities Terminology) over 6 months of follow-up among patients on an ICI.11 Similarly, in a large retrospective meta-analysis including >20 000 ICI-treated patients, 9.8% of treatment-related deaths were from cardiovascular events, including heart failure, myocardial infarction, and the development of a cardiomyopathy.32 Consistent with previous studies in patients with cancer,33 we also found that older age, diabetes, ICI use, higher blood pressure, male sex, previous radiation treatment, and a history of a cardiovascular event all increased the risk for a composite cardiovascular event. Combined with our data, these studies suggest a higher rate of atherosclerotic cardiovascular events with ICIs. For comparison, the event rate noted in this study (5%/y) is higher than the event rate noted in patients presenting with chest pain (≈0.7%/y),13 in patients at risk of cardiovascular events (≈0.3%/y),34 and in other at-risk populations in whom immune activation and inflammation play a key role (eg, individuals with HIV, ≈0.5%/y).35
Progression of atherosclerotic plaque is a robust predictor of atherosclerotic cardiovascular events and an established outcome measure for randomized clinical trials.36–38 Our imaging substudy supports the biological plausibility of our clinical observations by demonstrating an association between ICI use and accelerated progression of atherosclerosis. The rate of plaque progression in our study (annually 6.7%) is nearly 3 times higher than that reported in patients with subclinical (2.4%/y)39 and clinical (0.5–1.3%/y) cardiovascular disease.40 Thus, the acceleration in atherosclerosis is substantial after an ICI and may be one mechanism by which there is an increase in incident cardiovascular events. However, there are other potential mechanisms by which ICIs can accelerate atherosclerosis. These other mechanisms in particular include vasculitis and focal myocarditis misdiagnosed as acute myocardial infarction.41 All diagnosed myocarditis cases were not included in the analysis, but myocarditis remains a difficult diagnosis,42,43 and not all patients underwent a coronary angiogram, so vasculitis remains a possibility. However, the potential for ICI to accelerate atherosclerosis is strongly supported by animal and cellular models, in which the same immune checkpoints being targeted for cancer are established negative regulators of atherosclerosis.6,8,44,45 For example, the PD-1/programmed death ligand 1 pathway downregulates the proatherogenic T-cell response, and mice lacking programmed death ligand 1 had a 3-fold increase in atherosclerotic plaque with an associated increase in T cells and macrophages.8,44 In addition, PD-1–deficient myeloid progenitors upregulate genes involved in cholesterol synthesis and uptake and downregulate genes promoting cholesterol metabolism, cumulatively leading to markedly increased cellular cholesterol levels.7 This latter finding is of particular relevance because statin use in our study was associated with reduced progression of atherosclerotic plaque after ICIs (annual progression rate of total plaque volume, 5.2% on statin versus 8.3% not on statin; P=0.04). However, we did not find an association between statin use and cardiovascular events in our clinical study. This analysis testing the association with statin therapy on clinical outcomes may have been confounded by indication, with patients on a statin being at a higher baseline risk for events. We observed a similar trend for reduced atherosclerotic plaque in patients receiving corticosteroids. However, these latter findings should be interpreted with caution because the mechanisms involved are less clear; corticosteroids may increase blood sugar and blood pressure and lead to lipid abnormalities, and the association between corticosteroids and overall cancer outcomes is unclear.46 Moreover, although this observation may be related to the potential anti-inflammatory association with corticosteroids, it may also be cofounded by the indication for corticosteroids (immune mediated adverse events) for which an ICI may be held or stopped if the adverse event is severe.
The primary limitation of our study is the retrospective nature of the study at a single center and the presence of missing data. However, our cohort of patients on ICI is >20 times larger than in any previous publication, the number of events was substantial, and the directionality of our findings is supported by previous smaller studies, overall providing much improved statistical power and thus confidence in our findings. Advantages and limitations relate to the use of the matched cohort and case-crossover designs,47,48 and using these 2 designs together may remove the potential fixed and time-varying confounding effects of specific cardiovascular risk factors or age. In addition, the risk of a cardiovascular event would not be expected to change 3-fold over a period of 2 to 4 years, and our results were consistent regardless of the analytical strategy. This was a retrospective study, and it is possible that several unmeasured residual confounders remain that may have influenced the association between ICI use and vascular events. These include physical activity, family history, and other active inflammatory ICI-related diseases such as a thyroid disease. An important limitation is that it is difficult to control for other variables that may change over time in a patient with cancer and that may also affect cardiovascular risk; however, we did not find significant changes over the study period in clinical variables (eg, blood pressure) or cardiovascular medication use in either the clinical or the imaging cohort. A limitation of this study design is whether the exposure to an ICI was altered by a previous cardiovascular event. However, previous cardiovascular disease is not a contraindication to ICI use49 and is not an exclusion from most of clinical trials testing the efficacy of ICI,4,16,50,51 and until this publication, the potential for an association between cardiovascular events and ICIs was not established. In addition, it should be noted that the median number of cycles of ICIs was between 4 and 5, and cycles are administered every 2 to 3 weeks, whereas the risk period was longer at 2 years for the primary analysis and 1 year for the secondary analysis. Combination ICI therapy has been associated with a higher risk for myocarditis. In this study, there was no association between combination ICI use and atherosclerotic cardiovascular events; however, only 6.9% of the patients were treated with combination ICIs, thus limiting the interpretation of this negative finding. ICIs are associated with an increase in inflammation. However, routine measures of inflammation such as measures of cytokines and C-reactive protein were not performed and would be affected by the presence and trajectory of cancer; thus, we are unable to test the association between inflammation secondary to ICIs and atherosclerosis or atherosclerosis-related events. We did measure other related markers such as the white blood cell count, neutrophil count, and lymphocyte count and found no difference between those with and those without events and no change over time. We also considered whether the increase in the event rate may have reflected a change in the goals of treatment after a major vascular event among patients with predominately late-stage cancer, specifically whether late-stage cancer influenced the treatment decisions after a major vascular event and led to a shorter follow-up period and a higher rate of events. For example, there was a significantly higher rate of myocardial infarction compared with the modest increase in coronary revascularization. Whether the relative risk of an event would be as high in patients with early-stage cancer with a longer cancer-related survival is less clear and will need to be studied in future cohorts.

Conclusions

In this study, there was a higher rate of cardiovascular events after an ICI was started. The study provides additional biological plausibility of the clinical findings by finding greater atherosclerotic plaque progression after an ICI was started, and we provide initial data suggesting that this effect can be modified. Taken together, these data provide a rationale to consider an approach treating immune checkpoint therapy as a modifier of cardiovascular risk and suggest that candidates for ICI therapy should undergo a comprehensive cardiovascular risk evaluation and optimization of preventive medical therapy with close monitoring thereafter.

Acknowledgments

The authors gratefully acknowledge the Cardiovascular Imaging Research Center research team for providing feedback on the study design and interpretation. The Cardiovascular Imaging Research Center is a combined effort from the Division of Cardiology and the Department of Radiology at Massachusetts General Hospital. T.N. and U.H. had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Z.D., T.N., U.H., L.Z., R.A., R.S., K.R., and J.T. drafted the study protocol and analysis plan. Z.D., J.T., A.Z., S.M., P.R., R.M., C.L., D.Z., V.R., S.H., H.G., J.G., L.Z., T.M., U.H., and T.N. helped with the data acquisition, analysis and interpretation of the data. All authors contributed to the data collection and the design, analysis, interpretation drafting of the manuscript.

Supplemental Material

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Go to Circulation
Circulation
Volume 142 • Number 24 • 15 December 2020
Pages: 2299 - 2311
PubMed: 33003973

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© 2020 American Heart Association, Inc.

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History

Received: 7 July 2020
Accepted: 2 September 2020
Published online: 2 October 2020
Published in print: 15 December 2020

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Keywords

  1. atherosclerosis
  2. immunomodulation
  3. plaque, atherosclerotic

Subjects

  1. Clinical Studies
  2. Vascular Biology

Authors

Affiliations

Zsofia D. Drobni, MD https://orcid.org/0000-0002-1355-5318
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary (Z.D.D.).
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Raza M. Alvi, MD
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Jana Taron, MD
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Department of Radiology, University Hospital Freiburg, Freiburg, Germany (J.T.).
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Amna Zafar, MD
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Sean P. Murphy, MD
Division of Internal Medicine (S.P.M., P.K.R., R.C.M., C.L.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Paula K. Rambarat, MD
Division of Internal Medicine (S.P.M., P.K.R., R.C.M., C.L.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Rayma C. Mosarla, MD
Division of Internal Medicine (S.P.M., P.K.R., R.C.M., C.L.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Charlotte Lee, MD
Division of Internal Medicine (S.P.M., P.K.R., R.C.M., C.L.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Daniel A. Zlotoff, MD, PhD
Division of Cardiology (D.A.Z., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Vineet K. Raghu, PhD https://orcid.org/0000-0003-3524-3945
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Sarah E. Hartmann, BS
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Hannah K. Gilman, BS
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Jingyi Gong, MD
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Leyre Zubiri, MD, PhD
Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., K.L.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Ryan J. Sullivan, MD
Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., K.L.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Kerry L. Reynolds, MD
Division of Oncology and Hematology, Department of Medicine (L. Zubiri, R.J.S., K.L.R.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Thomas Mayrhofer, PhD https://orcid.org/0000-0001-6287-5185
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
School of Business Studies, Stralsund University of Applied Sciences, Stralsund, Germany (T.M.).
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Lili Zhang, MD, MS https://orcid.org/0000-0002-9341-5832
Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY (L. Zhang).
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Udo Hoffmann, MD, MPH*
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Tomas G Neilan, MD, MPH* https://orcid.org/0000-0002-1513-8833 [email protected]
Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Division of Cardiology (D.A.Z., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
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Notes

*
Drs Hoffmann and Neilan contributed equally.
Sources of Funding, see page 2310
The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/circulationaha.120.049981.
Tomas G. Neilan, MD, MPH, Cardio-Oncology Program and Cardiovascular Imaging Research Center, Massachusetts General Hospital, 165 Cambridge St, Suite 400, Boston, MA 02114. Email [email protected]

Disclosures

Dr Neilan has been a consultant to and received fees from Parexel Imaging, Intrinsic Imaging, H3-Biomedicine, AbbVie, and Syros Pharmaceuticals. Dr Neilan also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to ICIs. Dr Hoffmann reports consulting fees from Abbott, Duke University (National Institutes of Health), and Recor Medical. Dr Sullivan has been a consultant to Asana, Bristol Myers Squibb, Merck, and Replimune and received research funding from Amgen and Merck. Dr Taron reports consultant fees from the Speakaers bureau of Siemens Healthineers. Dr Zubiri has been a consultant to Merck. The other authors report no conflicts.

Sources of Funding

Dr Neilan is supported by a gift from A. Curt Greer and Pamela Kohlberg, grants from the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL130539, R01HL137562, K24HL150238), and National Institutes of Health/Harvard Center for AIDS Research grant P30 AI060354. Drs Alvi, Zafar, and Raghu are supported by US National Institutes of Health/National Heart, Lung, and Blood Institute grant T32HL076136. Dr Taron is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, TA 1438/1-2). Dr Hoffmann is receiving grants on behalf of Massachusetts General Hospital from KOWA, MedImmune, HeartFlow, Duke University (Abbott), Oregon Health & Science University (American Heart Association, 13FTF16450001), Columbia University (National Institutes of Health, R01HL109711), and National Institutes of Health/National Heart, Lung, and Blood Institute (K24HL113128, T32HL076136, and U01HL123339).

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Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque
Circulation
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