e23081 Background: Cardiovascular, kidney, and metabolic (CKM) diseases impact cancer treatment tolerance and outcomes. We sought to detail CKM comorbidity burden at the time of breast cancer and lung cancer diagnosis among a representative sample of older adults in the United States. Methods: Using the SEER–Medicare linked database, we identified adults ≥ 65 years diagnosed with breast or lung cancer between 2010 and 2019 with Medicare A and B coverage in the year prior to cancer diagnosis. CKM conditions were identified using the CMS Chronic Conditions Data Warehouse, defined from ICD-9 and ICD-10 diagnosis codes from Medicare claims. CKM comorbidity burden was compared by age, sex, race, and Medicaid dual eligibility. Results: Among 129,047 lung cancer patients (mean age 74.7, 50.2% women, 10.2% black, 5.1% Asian), individual CKM conditions were highly prevalent, including ischemic heart disease (39.1%), heart failure (21.5%), diabetes (29.6%), and chronic kidney disease (23.2%). Among 279,418 breast cancer patients (mean age 73.2, 99.1% women, 11.3% black, 4.6% Asian), ischemic heart disease (27.4%), heart failure (14.7%), diabetes (26.1%), and chronic kidney disease (12.5%) were also common. Overall, CKM burden was greater in lung versus breast cancer, with higher prevalence of ≥1 (68.3% vs 61.2%), ≥2 (52.6% vs 42.0%), and ≥3 CKM comorbidities (38.1% vs 26.1%), and higher mean Charlson comorbidity index (2.03±2.04 vs 0.95±1.44). In both cancer types, CKM burden increased with age, with notable racial and socioeconomic differences. Among breast cancer patients, multi-comorbidity (≥3 CKM conditions) varied by self-identified race (21% of Asian, 35% of black, and 25% of white patients), with similar findings in lung cancer. Medicaid dual-eligible patients had a higher prevalence of ≥3 CKM comorbidities than non-dual-eligible patients in breast (43.7% vs 22.3%) and lung cancer (48.6% vs 35.0%). Conclusions: CKM comorbidity burden is highly prevalent among older adults with breast and lung cancer, with disparities by race and Medicaid dual-eligibility. Early targeted strategies addressing cardiometabolic disease alongside cancer care at diagnosis may help improve patient outcomes.

Aims Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use often leads to cardiovascular adverse effects, including cardiac dysfunction. Here, we hypothesized that a prior cardiac ischaemic injury could exacerbate cardiac dysfunction due to anti-programmed death protein 1 (PD-1) treatment. Furthermore, we investigated whether abatacept, a T-cell costimulation blocker, could ameliorate the ICI-induced cardiotoxicity in a pre-clinical model.Methods and results In a pre-clinical study, mice were treated with isoprenaline or control to induce reversible cardiac ischaemia. After 16 weeks of follow-up, recovery of cardiac function was confirmed via echocardiography, and mice from both groups were randomly treated with isotype control, anti-PD-1, or anti-PD-1 combined with abatacept, for 2 further weeks. Mice with prior ischaemic injury and anti-PD-1 treatment showed cardiac dysfunction with increased infiltration of T cells and macrophages and elevated expression of pro-inflammatory cytokines. Conversely, cardiac dysfunction and inflammation were less pronounced after anti-PD-1 treatment in mice without prior ischaemic injury. Mice with concomitant abatacept treatment exhibited normal cardiac function and alleviated pro-inflammatory response. In a parallel single-centre retrospective clinical cohort study, 1671 cancer patients receiving PD-1 inhibitors were analysed. Cases were defined as patients who developed incident heart failure (HF) after ICI initiation with a primary aim to test whether pre-existing ischaemic heart disease was associated with an increased risk for HF development post-ICI therapy. Sensitivity analyses included propensity score matching and comparison with non-ICI-treated cancer patients. Among ICI-treated patients, 109 (6.5%) developed HF over a median follow-up of 332 days. Multivariable logistic regression of the matched population showed increased odds of incident HF in patients with prior ischaemic cardiac events (odds ratio 2.11, 95% confidence interval 1.05-4.2, P = 0.033).Conclusion In mice, induction of cardiac inflammation and dysfunction by anti-PD-1 therapy was potentiated by prior transient ischaemic cardiac injury, which was ameliorated by abatacept cotreatment. Cancer patients with pre-existing ischaemic heart disease may be at greater risk for developing ICI-induced new-onset HF. Based on our findings, cardiac surveillance should be considered in patients starting ICI therapy with a prior history of ischaemic heart disease.

Background: Transthoracic echocardiographic (TTE) surveillance for left ventricular dysfunction following cardiotoxic chemotherapy, particularly anthracyclines, is a key component of cardio-oncology care. The 2017 American Society of Clinical Oncology (ASCO) guidelines recommend routine TTE screening in older adults after anthracycline-based chemotherapy, but it remains uncertain if these guidelines had an effect on physician TTE ordering frequency. Methods: The Surveillance, Epidemiology, and End Results (SEER) Medicare dataset was used to identify older adults (>65 years) with HER2-negative breast cancer, lymphoma, or soft tissue sarcoma who received anthracyclines for a first cancer diagnosis from 2010-2020. Monthly TTE surveillance rates (TTEs per eligible patient-month) in the first year following chemotherapy initiation were compared before and after the ASCO guideline release in January 2017 using an interrupted time series approach. Results: Of 15,045 individuals included (mean age 74.1 ± 5.9 years, 64.9% female, 84.9% White), 9,611 (63.9%) had lymphoma, 5,106 (33.9%) breast cancer, and 328 (2.2%) sarcoma. An average of 43.6% ± 1.3% of individuals received a surveillance TTE during the first year after chemotherapy (mean 7.2 ± 0.9% per month). The monthly TTE surveillance frequency remained constant prior to 2017 (-0.003%/month, 95% CI -0.01% to +0.007%, p = 0.58) and after 2017 (+0.18%/month, 95% CI -0.57% to +0.92%, p = 0.65), with no significant change following the ASCO guideline release (+0.03%/month, 95% CI -0.005% to +0.06, p = 0.11) ( Figure ). Conclusion: TTE surveillance rates did not significantly change following the release of the 2017 ASCO guidelines among older Medicare beneficiaries receiving anthracycline chemotherapy for non-HER2+ malignancies. More than half of older anthracycline treated patients did not receive a post-anthracycline TTE in the year after their cancer treatment.

12127 Background: The two most common therapies for the treatment of cancer-associated venous thromboembolism (VTE) are low molecular weight heparin (LMWHs) and direct oral anticoagulants (DOACs). However, there is a paucity of data on the optimal anticoagulation strategy specifically among patients receiving immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the comparable safety and efficacy of DOACs versus LMWHs in the treatment of VTE among patients receiving ICIs. Methods: We conducted a retrospective, propensity score-matched cohort study using the TriNetX Analytics Network, which contains de-identified data from over 120 healthcare institutions and 250 million patients. We included adult cancer patients who have received ICI therapy including nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, ipilimumab, dostarlimab and who also received a diagnosis of VTE. Patients treated with DOACs were matched in a 1:1 ratio to patients treated with LMWHs based on the variables: age, sex, metastatic disease, cancer therapy, underlying comorbidities, Khorana score, and history of intracranial and gastrointestinal bleeding. The primary outcome was the occurrence of a new VTE, a composite of pulmonary embolism (PE) and deep venous thrombosis (DVT). The safety outcomes included all-cause mortality, intracranial hemorrhage, and gastrointestinal bleeding within 2 years following the start of anticoagulation therapy. Results: We matched 4608 ICI-treated patients on a DOAC to 4608 ICI-treated patients on a LMWH. In a Cox proportional hazard analysis, patients receiving DOACs or LMWH had a similar risk of a subsequent VTE event (Hazard ratio (HR), 1.13 [95% CI: 0.84-1.50]). When comparing different types of VTEs, the DOAC group was associated with a lower risk of PE (HR, 0.72 [95% CI: 0.54-0.96]) and a similar risk of DVT (HR, 0.87 [95% CI: 0.70-1.09]) compared to LMWHs. Furthermore, DOACs were associated with a lower risk of intracranial hemorrhage and all-cause mortality. There were no detectable differences in the risk of gastrointestinal bleeding between the two groups. Conclusions: DOACs were associated with a similar risk for subsequent VTE events but a lower risk of intracranial bleeding as well as an improvement in mortality compared to LMWHs among ICI-treated patients with a diagnosis of VTE. Prospective trials are needed to validate these findings. [Table: see text]

A 30-year-old male electrician presented with two days of fever and positional left shoulder pain and was found to have elevated inflammatory markers and a large pericardial effusion with echocardiographic evidence of tamponade for which he underwent pericardiocentesis. He was discharged on a course of anti-inflammatory therapy with presumed diagnosis of idiopathic pericarditis based on negative cytology. He returned 6 months later with several weeks of upper respiratory infection symptoms as well as new abdominal discomfort and emesis. On presentation, his vital signs were notable for tachycardia to 113 and cardiac exam was notable for tachycardia, regular rhythm, no rubs or murmurs, nondisplaced precordial impulse, normal jugular venous pressure with Kussmaul sign, and pulsus paradoxus of 6. An electrocardiogram showed sinus tachycardia with diffuse ST segment changes (Figure A). His cardiac biomarkers were unremarkable (troponin 21). His labs revealed normocytic anemia with hemoglobin of 11 and erythrocyte sediment rate above assay. Echocardiogram demonstrated a circumferential complex pericardial effusion with echocardiographic evidence of early tamponade (Figure B, C). A pericardiocentesis was attempted with inability to advance wire within pericardial space. A malignancy workup was initiated. CT demonstrated multi-station thoracic and lower cervical lymphadenopathy, moderate left pleural effusion, and an intrapericardial mass with associated pericardial effusion (Figure D). Cardiac magnetic resonance imaging demonstrated a circumferential intrapericardial non-mobile mass measuring up to 22 mm in thickness posteriorly and the mass was isointense to myocardium indicating low-fat content (Figure E). A supraclavicular lymph node biopsy was obtained with immunohistochemical staining positive for WT1 and calretinin, consistent with metastatic epithelioid mesothelioma of pericardial versus pleural etiology (Figure F). A PET-CT subsequently showed a FDG-avid circumferential anterior pericardial mass and multiple pleural-based lesions concerning for metastatic mesothelioma. He was initiated on pemetrexed/carboplatin systemic chemotherapy. With systemic therapy, his disease has been stable for 6 months. Pericardial mesothelioma is a rare malignancy. This case underscores the diagnostic challenges associated with pericardial mesothelioma and the importance of cancer workup as part of the pericardial effusion workup.

The broad application of immune checkpoint inhibitors (ICIs) has led to significant gains in cancer outcomes. By abrogating inhibitory signals, ICIs promote T cell targeting of cancer cells but can frequently trigger autoimmune manifestations, termed immune-related adverse events (irAEs), affecting essentially any organ system. Among cardiovascular irAEs, immune-related myocarditis (irMyocarditis) is the most described and carries the highest morbidity. The currently recommended treatment for irMyocarditis is potent immunosuppression with corticosteroids and other agents, but this has limited evidence basis. The cellular pathophysiology of irMyocarditis remains poorly understood, though mouse models and human data have both implicated effector CD8+ T cells, some of which are specific for the cardiomyocyte protein α-myosin. While the driving molecular signals and transcriptional programs are not well defined, the involvement of chemokine receptors such as CCR5 and CXCR3 has been proposed. Fundamental questions regarding why only approximately 1% of ICI recipients develop irMyocarditis and why irMyocarditis carries a much worse prognosis than other forms of lymphocytic myocarditis remain unanswered. Further work in both murine systems and with human samples are needed to identify better tools for diagnosis, risk-stratification, and treatment.

Repeat elements can be dysregulated at a genome-wide scale in human diseases. For example, in Ewing sarcoma, hundreds of inert GGAA repeats can be converted into active enhancers when bound by EWS-FLI1. Here we show that fusions between EWS and GGAA-repeat-targeted engineered zinc finger arrays (ZFAs) can function at least as efficiently as EWS-FLI1 for converting hundreds of GGAA repeats into active enhancers in a Ewing sarcoma precursor cell model. Furthermore, a fusion of a KRAB domain to a ZFA can silence GGAA microsatellite enhancers genome wide in Ewing sarcoma cells, thereby reducing expression of EWS-FLI1-activated genes. Remarkably, this KRAB-ZFA fusion showed selective toxicity against Ewing sarcoma cells compared with non-Ewing cancer cells, consistent with its Ewing sarcoma-specific impact on the transcriptome. These findings demonstrate the value of ZFAs for functional annotation of repeats and illustrate how aberrant microsatellite activities might be regulated for potential therapeutic applications.

BACKGROUND Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with estab-lished heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.OBJECTIVES This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.METHODS This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.RESULTS Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013). CONCLUSIONS SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the con-ducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines. (J Am Coll Cardiol HF 2022;10:559-567) (c) 2022 by the American College of Cardiology Foundation.

There is increasing use of sodium glucose co-transporter 2 (SGLT2) inhibitors to treat diabetes. Since trials apply specific entry and exclusion criteria to ensure internal validity, comparisons of trial populations with nationally representative samples can inform the applicability of study findings to practice. To compare individuals with diabetes from a nationally representative sample to patients who underwent randomization in the EMPA-REG trial. A secondary aim was to characterize what proportion of individuals prescribed an SGLT2 inhibitor in a nationally representative sample would have been included in the EMPA-REG trial. Retrospective cross-sectional study. Adults with diabetes who took part in the National Health and Nutrition Examination Survey (NHANES) between 2011–2014 (primary analysis corresponding to EMPA-REG enrollment) and 2015–2018 (secondary analysis corresponding to contemporary sample). The primary outcome was a comparison of demographic (age, sex, ethnicity, and pregnancy status), clinical (comorbidities and medication use), examination (weight, body mass index, and systolic and diastolic blood pressure), and laboratory (hgba1c, low- and high-density lipoprotein cholesterol, triglycerides, and estimated glomerular filtration rate) characteristics of NHANES respondents versus EMPA-REG trial participants. The secondary outcome was the proportion of NHANES respondents who had been prescribed an SGLT2 inhibitor that would have met inclusion criteria for the EMPA-REG trial. There were 655 and 48 respondents, representing a weighted sample of 21,849,775 and 1,062,573 individuals, included in the primary and secondary analyses, respectively. Overall, 7.6% (95% CI 4.8–10.6%) of 2011–2014 NHANES respondents would have met all EMPA-REG trial inclusion criteria. NHANES respondents and EMPA-REG participants differed across demographic, clinical, examination, and laboratory domains. Of NHANES respondents from 2015 to 2018 who were prescribed an SGLT2 inhibitor, 10.6% (95% CI <1–24.7%) would have met all inclusion criteria for the EMPA-REG trial. The EMPA-REG population differed from a nationally representative sample, which could affect generalizability.

Background Early reports from the COVID‐19 pandemic identified coronary thrombosis leading to ST‐segment–elevation myocardial infarction (STEMI) as a complication of COVID‐19 infection. However, the epidemiology of STEMI in patients with COVID‐19 is not well characterized. We sought to determine the incidence, diagnostic and therapeutic approaches, and outcomes in STEMI patients hospitalized for COVID‐19. Methods and Results Patients with data on presentation ECG and in‐hospital myocardial infarction were identified from January 14, 2020 to November 30, 2020, from 105 sites participating in the American Heart Association COVID‐19 Cardiovascular Disease Registry. Patient characteristics, resource use, and clinical outcomes were summarized and compared based on the presence or absence of STEMI. Among 15 621 COVID‐19 hospitalizations, 54 (0.35%) patients experienced in‐hospital STEMI. Among patients with STEMI, the majority (n=40, 74%) underwent transthoracic echocardiography, but only half (n=27, 50%) underwent coronary angiography. Half of all patients with COVID‐19 and STEMI (n=27, 50%) did not undergo any form of primary reperfusion therapy. Rates of all‐cause shock (47% versus 14%), cardiac arrest (22% versus 4.8%), new heart failure (17% versus 1.4%), and need for new renal replacement therapy (11% versus 4.3%) were multifold higher in patients with STEMI compared with those without STEMI (P<0.050 for all). Rates of in‐hospital death were 41% in patients with STEMI, compared with 16% in those without STEMI (P<0.001). Conclusions STEMI in hospitalized patients with COVID‐19 is rare but associated with poor in‐hospital outcomes. Rates of coronary angiography and primary reperfusion were low in this population of patients with STEMI and COVID‐19. Adaptations of systems of care to ensure timely contemporary treatment for this population are needed.

Objectives Skeletal myopathies are highly morbid, and in rare cases even fatal, immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI). Skeletal myopathies are also a recognized statin-associated side effect. It is unknown whether concurrent use of statins and ICIs increases the risk of skeletal myopathies. Methods This was a retrospective cohort study of all patients who were treated with an ICI at a single academic institution (Massachusetts General Hospital, Boston, MA, USA). The primary outcome of interest was the development of a skeletal myopathy. The secondary outcome of interest was an elevated creatine kinase level (above the upper limit of normal). Results Among 2757 patients, 861 (31.2%) were treated with a statin at the time of ICI start. Statin users were older, more likely to be male and had a higher prevalence of cardiovascular and non-cardiovascular co-morbidities. During a median follow-up of 194 days (inter quartile range 65-410), a skeletal myopathy occurred in 33 patients (1.2%) and was more common among statin users (2.7 vs. 0.9%, P < 0.001). Creatine kinase (CK) elevation was present in 16.3% (114/699) and was higher among statin users (20.0 vs. 14.3%, P = 0.067). In a multivariable Cox model, statin therapy was associated with a > 2-fold higher risk for skeletal myopathy (HR, 2.19; 95% confidence interval, 1.07-4.50; P = 0.033). Conclusion In this large cohort of ICI-treated patients, a higher risk was observed for skeletal myopathies and elevation in CK levels in patients undergoing concurrent statin therapy. Prospective observational studies are warranted to further elucidate the potential association between statin use and ICI-associated myopathies.

Background There are limited data on the occurrence, associations and outcomes of pericardial effusions and pericarditis on or after treatment with immune checkpoint inhibitors (ICIs). Methods This was a retrospective study at a single academic center that compared 2842 consecutive patients who received ICIs with 2699 age- and cancer-type matched patients with metastatic disease who did not receive ICI. A pericardial event was defined as a composite outcome of pericarditis and new or worsening moderate or large pericardial effusion. The endpoints were obtained through chart review and were blindly adjudicated. To identify risk factors associated with a pericardial event, we compared patients who developed an event on an ICI with patients treated with an ICI who did not develop a pericardial event. Cox proportional-hazard model and logistical regression analysis were performed to study the association between ICI use and pericardial disease as well as pericardial disease and mortality. An additional 6-week landmark analysis was performed to account for lead-time bias. Results There were 42 pericardial events in the patients treated with ICI (n=2842) over 193 days (IQR: 64–411), yielding an incidence rate of 1.57 events per 100 person-years. There was a more than fourfold increase in risk of pericarditis or a pericardial effusion among patients on an ICI compared with controls not treated with ICI after adjusting for potential confounders (HR 4.37, 95% CI 2.09 to 9.14, p<0.001). Patients who developed pericardial disease while on an ICI had a trend for increased all-cause mortality compared with patients who did not develop a pericardial event (HR 1.53, 95% CI 0.99 to 2.36, p=0.05). When comparing those who developed pericardial disease after ICI treatment with those who did not, a higher dose of corticosteroid pre-ICI (>0.7 mg/kg prednisone) was associated with increased risk of pericardial disease (HR 2.56, 95% CI 1.00 to 6.57, p=0.049). Conclusions ICI use was associated with an increased risk of development of pericardial disease among patients with cancer and a pericardial event on an ICI was associated with a trend towards increase in mortality.

Introduction: Immune checkpoint inhibitors (ICI) leverage the immune system against cancer. Myocarditis is an uncommon but serious complication of ICI use. There are limited data on the utility of serum troponin levels in this setting. We assessed whether troponin values measured at different time points during admission have prognostic significance. Hypothesis: Baseline (admission), peak and inter-value trajectory (slope) of high-sensitivity cardiac Troponin T (hs-cTnT) levels predict cardiovascular events in ICI-myocarditis. Methods: A retrospective cohort of all patients admitted with ICI-myocarditis in a single integrated academic network was performed. Troponin measures were included from the 24 hours preceding admission until time of event/censoring. Optimal threshold values for baseline, peak hs-cTnT, and slope changes were obtained through ROC curves (Youden index). Major adverse cardiac event (MACE) was defined as a composite of cardiogenic shock, cardiac arrest, complete heart block and cardiac death. Results: A total of 980 hs-cTnT measures from 63 patients were identified (figure 1). Over a median follow-up period of 16 days, 24 events occurred. A higher baseline (>1248 ng/l, HR: 3.75, 95% CI: 1.57–9.00, p= 0.003) (figure 2) and peak hs-cTnT (>1959 ng/l, HR: 3.66, 95% CI: 1.49–8.98, p= 0.01) were associated with MACE adjusted for age and left ventricular ejection fraction (LVEF). Additional optimal threshold hs-cTnT values based on LVEF were also identified. For those with an LVEF < 50%, a baseline value >265 ng/l (HR: 4.9, 95% CI: 1.5-15.8, p< 0.01) and for those with an LVEF >50%, a baseline value >780 ng/l (HR: 3.6, 95% CI: 1.03-12.4, p=0.04) were associated with MACE. The hs-cTnT trajectory slope changes (baseline-to-peak, slope in first 24 hours, slope in first 48 hours) were not associated with events. Conclusion: Baseline and peak hs-cTnT during admission for ICI-related myocarditis associated with MACE. Cutoff values may vary by LVEF strata.

Background: Recent guidelines have outlined echo markers of diastolic dysfunction (DD); evidence is limited for their prognostic value for hospitalization for heart failure (HHF) in overweight and obese pts. Methods: CAMELLIA-TIMI 61 was a randomized placebo-controlled trial of the weight loss agent lorcaserin in 12,000 pts with BMI ≥27 with or at risk for CV disease (median follow-up, 3.3 yrs). Echo with core lab interpretation was performed on a subset of pts. Established DD parameters were measured, including the ratio of the peak early transmitral diastolic flow velocity over the early diastolic mitral annulus velocity (average E/e’), left atrium volume index (LAVi), and tricuspid regurgitation jet velocity (TRV). These were analyzed continuously, using the standard cutpoints of >14, >34 mL/m 2 , and >2.8 m/s, respectively, and separately to determine the optimal cutpoints. The primary outcome for this analysis was HHF. Results: In 3,972 pts with baseline ejection fraction ≥50%, all 3 variables on a continuous scale predicted increased risk of HHF; using standard cutpoints, only E/e’>14 remained independently associated with HHF after adjustment for the other 2 echo parameters and clinical variables ( Panel A ). In an analysis of optimal cutpoints in these overweight and obese pts, >13 was optimal for E/e’, >2.5 m/s for TRV, and >58 mL/m 2 for LAVi. In a model with all 3 echo parameters, all remained significant predictors of HHF. After incorporation of clinical variables, E/e’ (HR 2.15, 95%CI 1.24-3.72) and LAVi (HR 2.41, 1.33-4.36) remained independent predictors of HHF ( Panel A ). Rates of HHF were 0.6, 3.3, and 10.1% (p-trend<0.0001) in pts with none, one, or both measures of DD ( Panel B ). Conclusions: Several echocardiographic markers of diastolic dysfunction used in current guidelines predict increased risk of HHF events in the understudied obese and overweight population. A higher LAVi (> 58 ml/m 2 ) cutpoint should be considered in these pts to prognosticate risk of HHF.

HomeCirculation: Heart FailureVol. 14, No. 12Epidemiology of Cardiogenic Shock in Hospitalized Adults With COVID-19: A Report From the American Heart Association COVID-19 Cardiovascular Disease Registry Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEpidemiology of Cardiogenic Shock in Hospitalized Adults With COVID-19: A Report From the American Heart Association COVID-19 Cardiovascular Disease Registry Anubodh S. Varshney, Wally A. Omar, Erica L. Goodrich, Ankeet S. Bhatt, Ann E. Wolley, Jingyi Gong, Balimkiz C. Senman, Danuzia Silva, Michael W. Levangie, David D. Berg, Robert W. Yeh, James A. de Lemos, David A. Morrow, Dhruv S. Kazi and Erin A. Bohula Anubodh S. VarshneyAnubodh S. Varshney https://orcid.org/0000-0002-9697-8948 Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Wally A. OmarWally A. Omar Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (W.A.O., R.W.Y., D.S.K.). , Erica L. GoodrichErica L. Goodrich https://orcid.org/0000-0002-8541-264X Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Ankeet S. BhattAnkeet S. Bhatt Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Ann E. WolleyAnn E. Wolley Division of Infectious Disease, Department of Medicine (A.E.W.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Jingyi GongJingyi Gong Department of Medicine (J.G., B.C.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Balimkiz C. SenmanBalimkiz C. Senman Department of Medicine (J.G., B.C.S.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Danuzia SilvaDanuzia Silva University of Minnesota Medical School, Minneapolis (D.S.). , Michael W. LevangieMichael W. Levangie Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , David D. BergDavid D. Berg https://orcid.org/0000-0002-0366-5492 Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Robert W. YehRobert W. Yeh https://orcid.org/0000-0002-0564-4468 Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (W.A.O., R.W.Y., D.S.K.). , James A. de LemosJames A. de Lemos https://orcid.org/0000-0003-2211-7261 Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas (J.A.d.L.). , David A. MorrowDavid A. Morrow https://orcid.org/0000-0002-9589-5382 Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. , Dhruv S. KaziDhruv S. Kazi https://orcid.org/0000-0002-9510-2979 Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA (W.A.O., R.W.Y., D.S.K.). and Erin A. BohulaErin A. Bohula Correspondence to: Erin A. Bohula, MD, DPhil, TIMI Study Group, 60 Fenwood Rd, Ste 7022, Boston, MA 02115. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5559-8172 Levine Cardiac Intensive Care Unit, Thrombolysis in Myocardial Infarction Study Group, Cardiovascular Division, Department of Medicine (A.S.V., E.L.G., A.S.B., M.W.L., D.D.B., D.A.M., E.A.B.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA. Originally published18 Nov 2021https://doi.org/10.1161/CIRCHEARTFAILURE.121.008477Circulation: Heart Failure. 2021;14:e008477Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 18, 2021: Ahead of Print Patients with coronavirus disease 2019 (COVID-19) may develop cardiac injury, ranging from low-level cardiac biomarker elevation to myocardial infarction to cardiogenic shock (CS).1 However, the incidence and outcomes of CS in adults hospitalized with COVID-19 are poorly defined.2 We investigated the epidemiology, clinical management, and outcomes of CS in the American Heart Association COVID-19 Cardiovascular Disease Registry.The design of the American Heart Association COVID-19 Cardiovascular Disease Registry has been described.3 This registry is available to US hospitals treating adults with acute COVID-19. All data and materials were accessed through the American Heart Association Precision Medicine Platform (https://precision.heart.org) and are available to qualified researchers through a formal research proposal. Standardized definitions were used to collect demographics, medical history, presentation details, laboratories, resource utilization, and in-hospital outcomes for consecutive COVID-19 admissions. As deidentified data are retrospectively abstracted, individual patient consent is not required. The protocol was approved by the Mass General Brigham Institutional Review Board. This analysis included COVID-19 admissions between January 14, 2020, to September 20, 2020, from 104 hospitals (58% with <500 beds, 96% urban, and 85% teaching). Shock was identified and categorized by the investigator according to the first in-hospital event as CS, distributive shock (DS), mixed shock (MS; ie, vasodilatory CS, defined as having components of cardiogenic and DS), and other/unknown using the best available clinical data. Admissions complicated by CS or MS were compared with those with DS or without shock.Among 15 208 COVID-19 admissions, 1882 (12%) developed shock, including 105 (0.7%) CS, 159 (1%) MS, 1409 (9%) DS, and 209 (1%) as other shock. In a sensitivity analysis excluding patients with preexisting heart failure(n=13 540), the prevalence of shock and shock subtypes was similar to the overall cohort. Patients with CS were predominantly male and non-White (Table). Compared with patients with DS or without shock, patients with CS had a higher prevalence of prior myocardial infarction, coronary revascularization, and heart failure (Table). Patients with CS had higher rates of abnormal chest imaging and troponin, d-dimer, C-reactive protein, and natriuretic peptide elevations at admission compared with patients without shock (Table). Compared with MS and DS, CS admissions had lower prevalence of pulmonary infectious signs and symptoms. Among admissions where echocardiography was obtained, 28% of CS admissions had left ventricular ejection fraction <30%, compared with 6% of admissions without shock.Table. Baseline Characteristics, Presenting Variables, Resource Utilization, and Outcomes of COVID-19 Patients According to Shock StatusCS (n=105)MS (n=159)DS (n=1409)No shock (n=13 326)Baseline characteristics Age, y; median (IQR)64 (54–73)67 (59–75)66 (56–74)62 (48–75) BMI, kg/m2; median (IQR)28.1 (23.1–31.6)30.0 (25.1–36.6)30.0 (25.7–35.7)29.0 (25.0–34.6) Female sex38 (36%)61 (38%)528 (37%)6185 (46%) Race White40 (38%)50 (31%)445 (32%)4645 (35%) Black/African American28 (27%)54 (34%)442 (31%)3381 (25%) Asian5 (5%)13 (8%)68 (5%)567 (4%) Diabetes48 (46%)72 (45%)641 (45%)4498 (34%) Established ASCVD32 (30%)49 (31%)294 (21%)2931 (22%) Prior MI11 (10%)19 (12%)75 (5%)658 (5%) Prior coronary revascularization16 (15%)21 (13%)103 (7%)844 (6%) Prior heart failure34 (32%)37 (23%)193 (14%)1380 (10%) Chronic kidney disease17 (16%)39 (25%)237 (17%)1605 (12%)Presenting variables Selected COVID-19 symptoms Fever or chills42 (40%)95 (60%)904 (64%)7433 (56%) Cough59 (56%)82 (52%)876 (62%)7542 (57%) Shortness of breath57 (54%)107 (67%)1022 (73%)7371 (56%) Symptom onset to admission, d; median (IQR)4 (1–7)5 (3–9)5 (3–9)5 (2–9) Infiltrates on chest imaging81/105 (77%)136/158 (86%)1242/1405 (88%)8514/13 024 (65%) Elevated NT-proBNP or BNP*42/58 (72%)65/105 (62%)364/723 (50%)1902/5286 (36%) Troponin >2× ULN7/66 (11%)6/115 (5%)64/749 (9%)255/6497 (4%) CRP ≥10 mg/L57/62 (92%)102/111 (92%)828/915 (90%)6021/7456 (81%) D-dimer ≥500 ng/mL34/45 (76%)45/59 (76%)424/625 (68%)3218/5571 (58%) LVEF during admission LVEF <30%18/65 (28%)17/86 (20%)15/491 (3%)68/1114 (6%) LVEF 30%–50%22/65 (34%)26/86 (30%)76/491 (15%)217/1114 (19%) LVEF >50%25/65 (38%)43/86 (50%)400/491 (81%)829/1114 (74%)Management and resource utilization Empirical COVID-19 therapies Glucocorticoids45/104 (43%)101/158 (64%)763/1404 (54%)3336/13 274 (25%) Hydroxychloroquine41/105 (39%)73/158 (46%)739/1404 (53%)4958/13 257 (37%) Remdesivir17/105 (16%)20/158 (13%)206/1404 (15%)1243/13 273 (9%) Tocilizumab14/104 (13%)36/158 (23%)281/1404 (20%)747/13 274 (6%) COVID-19 convalescent plasma9/105 (9%)29/158 (18%)186/1403 (13%)545/12 970 (4%) Inotropes or vasopressors95/101 (94%)155/155 (100%)1345/1356 (99%)0 (0%) Mechanical ventilation94/105 (90%)14/1586 (92%)1257/1406 (89%)1354/13 326 (10%) V-V ECMO8/105 (8%)5/158 (3%)46/1402 (3%)21/13 307 (0.2%) Acute renal replacement therapy20/105 (19%)50/158 (32%)345/1406 (25%)171/13 307 (1.3%) Mechanical circulatory support11/101 (11%)6/155 (4%)6/1356 (0.4%)0/13 326 (0%) IABP7/101 (7%)2/155 (1.3%)0 (0%)0 (0%) PVAD6/101 (6%)2/155 (1.3%)3/1356 (0.2%)0 (0%) V-A ECMO0 (0%)2/155 (1.3%)3/1356 (0.2%)0 (0%) Coronary angiography10/105 (10%)3/158 (2%)4/1406 (0.3%)48/13 309 (0.4%) ≥1 obstructive coronary lesion5/9 (56%)2/2 (100%)1/3 (33%)25/37 (68%) PCI8/105 (8%)1/158 (0.6%)1/1406 (0.1%)27/13 310 (0.2%)In-hospital events Composite of death, cardiac arrest, AMI, or stroke81 (77%)124 (78%)898/1408 (64%)1667 (13%) Death Overall66 (63%)110 (69%)802 (57%)1379 (10%) In patients with IHCA39/47 (83%)40/41 (98%)292/318 (92%)323/346 (93%) In patients without IHCA27/28 (47%)69/117 (59%)506/1087 (47%)1040/12 960 (8%) Cause of death Respiratory31 (48%)74 (68%)616 (78%)967 (73%) Cardiovascular†21 (32%)13 (12%)50 (6%)152 (11%) Other13 (20%)22 (20%)128 (16%)205 (16%)Values reflect count (n) and proportion (%) unless otherwise specified. Differences in categorical variables were assessed across the study groups using the χ2 test or Fisher exact test as appropriate. Differences in continuous variables were assessed using the Kruskal-Wallis test. P value <0.05 for all comparisons between CS and no shock with the exception of age, race, chronic kidney disease, cough, shortness of breath, hydroxychloroquine, remdesivir, and convalescent serum. P value <0.05 for all comparisons between MS and no shock with the exception of race, fever or chills, cough, remdesivir, PCI, and cause of death. ASCVD includes established cerebrovascular disease, peripheral artery disease, prior MI, or prior coronary revascularization. AMI indicates acute myocardial infarction; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; BNP, brain natriuretic peptide; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CS, cardiogenic shock; DS, distributive shock; IABP, intra-aortic balloon pump; IHCA, in-hospital cardiac arrest; IQR, interquartile range; LVEF, left ventricular ejection fraction; MI, myocardial infarction; MS, mixed shock; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PCI, percutaneous coronary intervention; PVAD, percutaneous ventricular assist device; ULN, upper limit of normal; V-A ECMO, veno-arterial extracorporeal membrane oxygenation; and V-V ECMO, veno-venous extracorporeal membrane oxygenation.* Defined as NT-proBNP ≥450 pg/mL or BNP ≥100 pg/mL.† Includes death due to acute MI, arrhythmia, heart failure, or stroke.Inotropes and vasopressors, mechanical ventilation, renal replacement therapy, and empirical COVID-19 therapies were frequently utilized in patients with CS. Temporary mechanical circulatory support was used in 11% of patients, and 10% underwent invasive or noninvasive coronary angiography.The mortality rate for the overall cohort was 16%; 63% of patients with CS died during hospitalization, compared with 57% with DS and 10.3% without shock (P<0.001). While respiratory failure remained the most common cause of death in all patients, cardiovascular causes of death were more common in patients with CS compared with those with DS or no shock. The composite of in-hospital mortality, cardiac arrest, myocardial infarction, or stroke occurred in 77% of admissions with CS, compared with 64% with DS and 13% without shock. In a secondary analysis, patients with MS had generally similar baseline characteristics, clinical presentation, and event rates as patients with classic CS but were less likely to undergo coronary angiography or receive mechanical circulatory support (Table).In this analysis of a large and diverse population of patients hospitalized for COVID-19 predominantly in US urban teaching hospitals, ≈1 in 10 patients developed any shock. While CS or MS was rare (<2%), these disease states were associated with exceedingly high morbidity and mortality. Despite a high prevalence of cardiovascular risk factors and cardiovascular disease in patients with CS or MS, only ≈20% had acute myocardial infarction during hospitalization (inclusive of demand-related events). This is consistent with growing evidence implicating mechanisms of cardiac involvement in COVID-19 beyond acute coronary syndromes, including stress-induced cardiomyopathy, inflammatory myocarditis, microvascular dysfunction and thrombosis, and decompensation of underlying heart failure.1 Notably, coronary angiography, percutaneous coronary intervention, and temporary mechanical circulatory support placement were utilized in <10% of cases of CS or MS, reflecting rates that are substantially lower than in contemporary non–COVID-19 CS populations.4 Additionally, veno-arterial extracorporeal membrane oxygenation was used in only 5 admissions in the entire cohort, none of which had CS. Less than half of CS patients received glucocorticoids during this period. While evidence of benefit of glucocorticoids in COVID-19 exists,5 their role in patients with CS, who may benefit from suppression of cytokine storm yet may be harmed by resultant fluid retention, is uncertain.This analysis relied on site-level characterization of events by the local investigator using the best available clinical data and lacked centralized adjudication. Event rates may have been affected by center-level variation in cardiac testing. Absence of hemodynamic data precluded classification of CS severity. Nevertheless, this large multicenter registry of COVID-19 hospitalizations during 2020 provides generalizable insights into classic or vasodilatory CS resulting from COVID-19. Although rare, development of either form of CS was a marker for high rates of cardiovascular complications, including cardiac arrest, and worse hospital outcomes than observed in non–COVID-19 CS populations.4Article InformationAcknowledgmentsThe Get With The Guidelines programs are provided by the American Heart Association (AHA). The AHA Precision Medicine Platform (https://precision.heart.org/) was used for data analysis. IQVIA (Parsippany, NJ) serves as the data collection and coordination center.Sources of FundingThe American Heart Association (AHA) suite of registries is funded by multiple industry sponsors. AHA's COVID-19 Cardiovascular Disease Registry is partially supported by the Gordon and Betty Moore Foundation.DisclosuresDr Varshney is on the Advisory Board for Broadview Ventures and is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL007604 and the Daniel Pierce Family Fellowship in Advanced Heart Disease. Dr Bhatt reports speaking fees from Sanofi Pasteur and is supported by the National Heart, Lung, and Blood Institute T32 postdoctoral training grant T32HL007604. Dr Berg is supported by Harvard Catalyst KL2/Catalyst Medical Research Investigator Training (National Institutes of Health/National Center for Advancing Translational Sciences UL 1TR002541) and has received consulting fees from AstraZeneca. Dr Yeh is a consultant for Abbott Vascular, AstraZeneca, Boston Scientific, Edwards Life Sciences, Medtronic, Shockwave Medical, and Zoll Medical and receives research funding from AstraZeneca, BD Bard, Boston Scientific, Cook Medical, Medtronic, and Philips. Dr de Lemos reports grant support from Roche Diagnostics and Abbott Diagnostics and consulting fees from Ortho Clinical Diagnostics, Siemen's Health Care Diagnostics, Quidel, Eli Lilly, and Novo Nordisk. Dr Morrow has received consulting fees from Bayer Pharma, InCarda, Merck, Novartis, and Roche Diagnostics. Dr Bohula has received consulting fees from Novo Nordisk, Amgen, Medscape, Servier, and Kowa. Drs Morrow, Bohula, and Berg, M.W. Levangie, and E.L. Goodrich are members of the TIMI study group, which has received institutional research grant support through the Brigham and Women's Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, Arca Biopharma, AstraZeneca, Bayer HealthCare Pharmaceuticals Inc, BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Regeneron, Roche, Siemens, Takeda, The Medicines Company, and Zora Biosciences. The other authors report no conflicts.Footnotes*A.S. Varshney and W.A. Omar contributed equally.†D.S. Kazi and E.A. Bohula contributed equally.For Sources of Funding and Disclosures, see page 1356.Correspondence to: Erin A. Bohula, MD, DPhil, TIMI Study Group, 60 Fenwood Rd, Ste 7022, Boston, MA 02115. Email ebohula@bwh.harvard.eduReferences1. Atri D, Siddiqi HK, Lang JP, Nauffal V, Morrow DA, Bohula EA. COVID-19 for the cardiologist: basic virology, epidemiology, cardiac manifestations, and potential therapeutic strategies.JACC Basic Transl Sci. 2020; 5:518–536. doi: 10.1016/j.jacbts.2020.04.002CrossrefMedlineGoogle Scholar2. Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, Oczkowski S, Levy MM, Derde L, Dzierba A, et al. Surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (COVID-19).Crit Care Med. 2020; 48:e440–e469. doi: 10.1097/CCM.0000000000004363CrossrefMedlineGoogle Scholar3. Alger HM, Rutan C, Williams JH, Walchok JG, Bolles M, Hall JL, Bradley SM, Elkind MSV, Rodriguez F, Wang TY, et al. American Heart Association COVID-19 CVD registry powered by get with the guidelines.Circ Cardiovasc Qual Outcomes. 2020; 13:e006967. doi: 10.1161/CIRCOUTCOMES.120.006967LinkGoogle Scholar4. Berg DD, Bohula EA, van Diepen S, Katz JN, Alviar CL, Baird-Zars VM, Barnett CF, Barsness GW, Burke JA, Cremer PC, et al. Epidemiology of shock in contemporary cardiac intensive care units.Circ Cardiovasc Qual Outcomes. 2019; 12:e005618. doi: 10.1161/CIRCOUTCOMES.119.005618LinkGoogle Scholar5. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, et al; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19.N Engl J Med. 2021; 384:693–704. doi: 10.1056/NEJMoa2021436CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Meyerowitz E, Scott J, Richterman A, Male V and Cevik M (2023) Clinical course and management of COVID-19 in the era of widespread population immunity, Nature Reviews Microbiology, 10.1038/s41579-023-01001-1, 22:2, (75-88), Online publication date: 1-Feb-2024. Sunnaa M, Kerolos M, Ruge M, Gill A, Du-Fay-de-Lavallaz J, Rabin P, Gomez J, Williams K, Rao A, Volgman A, Marinescu K and Suboc T (2023) Association between number of vasopressors and mortality in COVID-19 patients, American Heart Journal Plus: Cardiology Research and Practice, 10.1016/j.ahjo.2023.100324, 34, (100324), Online publication date: 1-Oct-2023. Agarwal S, Bansal A, Debnath C, Akhtar K and Krishan S (2023) The impact of COVID-19 infection on outcomes of patients hospitalized for non-acute myocardial infarction cardiogenic shock, The American Journal of Emergency Medicine, 10.1016/j.ajem.2023.03.051, 68, (207-209), Online publication date: 1-Jun-2023. Boulos P, Freeman S, Henry T, Mahmud E and Messenger J (2023) Interaction of COVID-19 With Common Cardiovascular Disorders, Circulation Research, 132:10, (1259-1271), Online publication date: 12-May-2023. 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December 2021Vol 14, Issue 12 Advertisement Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.121.008477PMID: 34789004 Originally publishedNovember 18, 2021 KeywordsCOVID-19data collectionintensive care unitsregistriesshock, cardiogenicPDF download Advertisement SubjectsEpidemiologyQuality and Outcomes

BACKGROUND:Immune checkpoint inhibitors (ICIs) are widely used cancer treatments. There are limited data on the risk for developing venous thromboembolism (VTE) among patients on an ICI. METHODS:This was a retrospective study of 2854 patients who received ICIs at a single academic centre. VTE events, defined as a composite of deep vein thrombosis or pulmonary embolism, were identified by individual chart review and blindly adjudicated using standard imaging criteria. A self-controlled risk-interval design was applied with an 'at-risk period' defined as the two-year period after and the 'control period', defined as the two-year before treatment. The hazard ratio (HR) was calculated using a fixed-effect proportional hazards model. RESULTS:Of the 2854 patients, 1640 (57.5%) were men; the mean age was 64 ± 13 years. The risk for VTE was 7.4% at 6 months and 13.8% at 1 year after starting an ICI. The rate of VTE was > 4-fold higher after starting an ICI (HR 4.98, 95% CI 3.65-8.59, p < 0.001). There was a 5.7-fold higher risk for deep vein thrombosis (HR 5.70, 95% CI 3.79-8.59, p < 0.001) and a 4.75-fold higher risk for pulmonary embolism (HR 4.75, 95% CI 3.20-7.10, p < 0.001). Comparing patients with and without a VTE event, a history of melanoma and older age predicted lower risk of VTE, while a higher Khorana risk score, history of hypertension and history of VTE predicted higher risk. CONCLUSIONS:The rate of VTE among patients on an ICI is high and increases after starting an ICI.