Baseline Cardiac Risk Research Articles

Cardiac assessment in Australian patients receiving (neo)adjuvant trastuzumab for HER2-positive early breast cancer: a population-based study.

Cardiac function assessment is important for detecting and managing trastuzumab-associated cardiotoxicity. Our study estimates rates and predictors of cardiac assessment among patients receiving trastuzumab for HER2-positive early breast cancer (HER2+EBC) in Australia. We conducted a retrospective cohort study of Australians initiating (neo)adjuvant trastuzumab for HER2+EBC between 1 January 2015 and 15 April 2019. We used administrative claims to determine the number of patients receiving guideline-recommended assessment, i.e. evidence of baseline cardiac assessment (between 120days before and 30days after trastuzumab initiation) and regular on-treatment cardiac assessments (at least every 120days). We examined factors associated with baseline and regular on-treatment cardiac assessment. Our study includes 5621 patients (median age 56years), of whom 4984 (88.7%) had a baseline cardiac function test. Among 4280 patients with at least 12months of follow-up, 2702 (63.1%) had guideline-recommended cardiac assessment. Rates of guideline-recommended assessment increased with later year of diagnosis (60.9% in 2015 vs 68.3% in 2018, OR 1.34, 95% CI 1.06-1.69). Patients with higher baseline comorbidities and greater socioeconomic disadvantage were less likely to have guideline-recommended cardiac assessment. Cardiac assessment practices varied by State/Territory. There was no association between baseline cardiac risk or anthracycline use and the likelihood of receiving guideline-recommended cardiac assessment. The majority of patients receiving (neo)adjuvant trastuzumab had guideline-recommended baseline and on-treatment cardiac assessment. Variations in cardiac assessment predominantly related to system-level factors, such as year of diagnosis and geography, rather than individual patient factors.

Statin Use, Heart Radiation Dose, and Survival in Locally Advanced Lung Cancer

PurposePatients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy. Methods and MaterialsWe performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression. ResultsStatin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively. ConclusionsAmong patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials.

Systematic review and meta-analysis of the incidence of recurrence of spontaneous coronary artery dissection.

Recurrence is a well-established complication of spontaneous coronary artery dissection (SCAD). However, the exact incidence and correlates of recurrence are unknown. We, therefore, performed a systematic review and meta-analysis to determine and consolidate the evidence on the global incidence of SCAD recurrence. A comprehensive search of the four major databases (EMBASE, OVID Medline, PubMed and Google Scholar) was performed from their inception to 17 January 2019. We included original research studies, recruiting ≥10 participants, with ≥12 months follow-up that reported data on recurrence in patients with SCAD. Out of 556 studies searched, 19 cohorts (1538 SCAD patients) were included in the analysis. There were 153 cases of de novo recurrence over a mean follow-up period of 31.2 months (95% confidence interval, 25-41 months). Type 1, 2 and 3 SCAD was noted in 33.2, 73.2 and 5.3%, respectively. The involved coronary artery was LMCA, LAD, RCA, LCx and multi-vessel CAD respectively in 3.5%, 53.4%, 19.8%, 20.4% and 12.6% of cases. The overall SCAD de novo recurrence was 7% (ES 0.07, 95% confidence interval, 0.04-0.10, I2 = 65.3%). On meta-regression, we found discharge medications at index admission, including β-blockers, ACE inhibitors, statins, as well as baseline cardiac risk factors, did not correlate with recurrence. SCAD recurrence is common, occurring in 7% of patients over medium-term follow up. No specific medications at discharge were found to reduce recurrence. Further long-term and prospective data are required.

Abstract 15089: Specificity for Inflammatory Pathways and Myocardial Injury Associated With Coronary Microvascular Dysfunction in Rheumatoid Arthritis

Background: Coronary microvascular disease (CMD) is associated with increased mortality in rheumatoid arthritis (RA). Studies suggest that higher RA disease activity is associated with a higher degree of CMD. However, it is not known whether specific inflammatory pathways implicated in RA play a stronger role than others in the pathogenesis of CMD. The objective of this study was to identify the associations between inflammatory cytokines, CMD, and resultant myocardial injury. Methods: We used baseline data from the first 53 subjects enrolled in a study of RA and CV risk (LiiRA, NCT02714881). LiiRA enrolls RA patients, age&gt;35, prior to TNF inhibitor initiation. All subjects underwent a stress myocardial perfusion PET scan to quantify coronary flow reserve (CFR). CFR is the ratio of myocardial blood flow during maximal hyperemia over that at rest. A lower CFR in the absence of obstructive coronary artery disease (CAD) is indicative of CMD. We tested the association between markers of inflammation and myocardial injury with CFR using the Spearman correlation. Results: Clinical characteristics of LiiRA subjects are shown in Table 1. Baseline cardiac risk factors were uncommon. IL-6, sTNFR2, NT-proBNP were correlated with lower CFR. However, no significant associations were observed between IL-1β, hsCRP, or hs-cTnT (Table 2). Conclusions: Among RA patients with no history of overt CAD, the severity of CMD was correlated with IL-6 and sTNFR2 but not IL-1β or hsCRP. CMD was further associated with increased levels of NT-proBNP but not hs-cTnT. These findings provide potential insight into the mechanisms by which inflammation mediates CMD and resultant myocardial dysfunction.

5-year outcomes in patients with acute coronary syndrome treated with biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents

Abstract Background Newest generation drug-eluting stents (DES) combining ultrathin cobalt chromium platforms with biodegradable polymers may reduce target lesion failure (TLF) as compared to second generation DES among patients with acute coronary syndrome (ACS). While previous studies indicated a potential benefit within the first two years after percutaneous coronary intervention (PCI), it remains uncertain whether the clinical benefit persists after complete degradation of the polymer coating. Purpose To compare the long-term effects of ultrathin-strut biodegradable polymer sirolimus-eluting stents (BP-SES) versus thin-strut durable polymer everolimus-eluting stents (DP-EES) for PCI in patients with ACS. Methods We performed a subgroup analysis of ACS patients included into the BIOSCIENCE trial (NCT01443104), a randomized trial comparing BP-SES with DP-EES. The primary endpoint of the present post-hoc analysis was TLF, a composite of cardiac death, target vessel myocardial infarction (MI) and clinically indicated target lesion revascularization (TLR), at 5 years. Results Among 2,119 patients enrolled between March 2012 and May 2013, 1,131 (53%) presented with ACS (ST-segment elevation myocardial infarction, 36%). Compared to patients with stable CAD, ACS patients were younger, had a lower baseline cardiac risk profile, including a lower prevalence of hypertension, hypercholesterolaemia, diabetes mellitus, and peripheral artery disease, and had a greater incidence of previous revascularization procedures. At 5 years, TLF occurred similarly in 89 patients (cumulative incidence, 16.9%) treated with BP-SES and 85 patients (16.0%) treated with DP-EES (RR 1.04; 95% CI 0.78–1.41; p=0.78) in patients with ACS, and in 109 patients (24.1%) treated with BP-SES and 104 patients (21.8%) treated with DP-EES (RR 1.11; 95% CI 0.85–1.45; p=0.46) in stable CAD patients (p for interaction=0.77) (Figure 1, Panel A). Cumulative incidences of cardiac death (8% vs. 7%; p=0.66), target vessel MI (5.2% vs. 5.8%; p=0.66), clinically indicated TLR (8.9% vs. 8.3%; p=0.63) (Figure 1, Panel B-D), and definite thrombosis (1.4% vs. 1.0%; p=0.57) at 5 years were similar among ACS patients treated with ultrathin-strut BP-SES or thin-strut DP-EES. Overall, there was no interaction between clinical presentation and treatment effect of BP-SES versus DP-EES. Conclusion In a subgroup analysis of the BIOSCIENCE trial, we found no difference in long-term clinical outcomes between ACS patients treated with ultrathin-strut BP-SES or thin-strut DP-EES at five years. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Unrestricted research grant to the institution from Biotronik AG, Switzerland

Immune Checkpoint Inhibitors–Related Cardiotoxicity

Immunotherapy is a significant breakthrough in cancer therapy in the last decade. Immunotherapy is better tolerated compared with chemotherapy. However, it does have side effects, and one of the rare and serious side effects of immunotherapy is cardiotoxicity. Cardiotoxicity has been described with other cancer-related treatments such as chemotherapy and targeted therapy. A high index of suspicion is required, and prompt management with immunosuppression needs to be instituted as soon as possible to prevent fatal outcomes. Research is still ongoing to identify biomarkers that will help us to choose the patients, who will respond well to immunotherapy. Tumor-infiltrating lymphocytes, tumor PD-L1 expression, and tumor mutational burden explored as potential biomarkers. There are no predictive biomarkers to identify patients who are at higher risk of severe cardiotoxicity. Both cardiologists and oncologists should be aware of cardiac toxicity from immune checkpoint inhibitors. All patients who are starting immune checkpoint inhibitors should undergo baseline cardiac risk factor assessment with referral to a cardiologist in a patient with multiple risk factors or previous history of cardiovascular disease. Cardiac immune-related adverse events are higher in patients taking combination therapy with anti-CTLA-4/anti-PD-1 agents compared with monotherapy. Patients with known cardiac comorbidities require a higher level of vigilance to monitor for cardiac toxicity because nonspecific symptoms can lead to rapid clinical deterioration and a higher rate of mortality when treated with checkpoint inhibitors.

Cardio-toxicity among patients with sarcoma: a cardio-oncology registry

BackgroundChemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracyclines (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutics related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (LVEF) reduction of > 10%, to a value below 53%. The aim of our study was to estimate the prevalence of CTRCD in patients diagnosed with sarcoma and to describe the baseline risk factors and echocardiography parameters among that population.MethodsData were collected as part of the Israel Cardio-Oncology Registry (ICOR), enrolling all patients evaluated in the cardio-oncology clinic at our institution. The registry was approved by the local ethics committee and is registered in clinicaltrials.gov (Identifier: NCT02818517). All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. non-CTRCD group.ResultsAmong 43 consecutive patients, 6 (14%) developed CTRCD. Baseline cardiac risk factors were more frequent among the non-CTRCD group. Elevated left ventricular end systolic diameter and reduced Global Longitudinal Strain were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the non-CTRCD group.ConclusionsCTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.

N-terminal pro-brain natriuretic peptide levels after receipt of anthracycline for breast cancer.

e24103 Background: Many of the 200,000 patients diagnosed with breast cancer (BC) annually in the United States receive anthracycline-based therapy, increasing their risk of future congestive heart failure. N-terminal brain natriuretic peptide (NT-proBNP) has been used as a biomarker of asymptomatic cardiac dysfunction in the general population and is of interest to identify patients who might benefit from echocardiography during survivorship. This study aimed to assess how age, baseline comorbidities, and time since BC diagnosis impact NT-proBNP levels after anthracycline-based chemotherapy. Methods: This retrospective study, using samples collected in our ongoing prospective Mayo Clinic Breast Disease Registry, included 20 survivors of non-metastatic BC patients per year for each of the first 5 years after anthracycline-based chemotherapy (n=100 total). NT-pro-BNP levels were assessed using a Roche immunoassay. Cardiac risk factors were obtained by chart review. Multivariable linear regression models assessed associations between NT-proBNP values and these independent variables: baseline cardiac risk factors (including hypertension, hyperlipidemia, obesity, diabetes mellitus, and smoking), tumor ER status (surrogate for possible endocrine therapy), time between diagnosis and serum collection, T and N status, use of trastuzumab, and age. Results: The mean age at the time of BC diagnosis was 52.2 (SD 9.8). 13% of tumors were human epidermal growth factor receptor (HER2)-positive and 71% were estrogen receptor (ER) positive. NT-proBNP was elevated in 34%. Mean NT-BNP level was higher (p=0.047) for those in years 4-5 (158 pg/mL) compared to those in years 1-3 (106 pg/mL) (See Table.) Models revealed years from diagnosis to serum draw (p=0.026), older age (p=0.006), more cardiac risk factors (p=0.064), and N2-3 (p=0.001) were associated with elevated NT-pro-BNP level. Use of trastuzumab, ER status, and tumor size were not associated with NT-proBNP. Conclusions: NT-proBNP is elevated in 1/3 of survivors who received anthracycline therapy for BC. As expected, cardiac risk factors and advancing age are associated with higher NT-proBNP. NT-proBNP values &gt;300 were only found in patients who were 4-5 years after diagnosis. Additional research will be needed to further define the diagnostic and prognostic merit of NT-proBNP in survivors after receipt of anthracycline therapy. [Table: see text]

Cardiac toxicity of lung cancer radiotherapy.

Radical radiotherapy of lung cancer with dose escalation has been associated with increased tumor control. However, these attempts to continually improve local control through dose escalation, have met mixed results culminating in the findings of the RTOG trial 0617, where the heart dose was associated with a worse overall survival, indicating a significant contribution to radiation-induced cardiac morbidity. It is, therefore, very likely that poorly understood cardiac toxicity may have offset any potential improvement in overall survival derived from dose escalation and may be an obstacle that limits disease control and survival of patients. The manifestations of cardiac toxicity are relatively common after high dose radiotherapy of advanced lung cancers and are independently associated with both heart dose and baseline cardiac risk. Toxicity following the treatment may occur earlier than previously thought and, therefore, heart doses should be minimized. In patients with lung cancer, who not only receive substantial heart dose, but are also older with more comorbidities, all cardiac events have the potential to be clinically significant and life-threatening. Sophisticated radiation treatment planning techniques, charged particle therapy, and modern imaging methods in radiotherapy planning, may lead to reduction of the heart dose, which could potentially improve the clinical outcomes in patients with lung cancer. Efforts should be made to minimize heart radiation exposure whenever possible even at doses lower than those generally recommended. Heart doses should be limited as much as possible. A heart dosimetry as a whole is important for patient outcomes, rather than emphasizing just one parameter.

P1968Five-year outcomes in patients with diabetes mellitus treated with biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents

Abstract Background Patients with diabetes mellitus (DM) remain at higher risk for adverse events after percutaneous coronary intervention (PCI) compared with non-diabetic individuals. Among available drug-eluting stents (DES), thin-strut durable polymer everolimus-eluting stents (DP-EES) were shown to provide the best safety and efficacy profile in diabetics. Whether biodegradable polymer DES provide additional long-term clinical benefit compared with DP-EES among diabetic patients remains uncertain. Purpose To compare the long-term performance of ultrathin-strut biodegradable polymer sirolimus-eluting stents (BP-SES) versus DP-EES for PCI in patients with insulin-requiring and non-insulin-requiring DM. Methods We performed a prespecified subgroup analysis of the randomized, multicenter, non-inferiority BIOSCIENCE trial (NCT01443104). Patients with stable coronary artery disease or acute coronary syndrome were randomly assigned to treatment with ultrathin-strut BP-SES or thin-strut DP-EES. Patients were further divided according to diabetic status. The primary endpoint was target lesion failure (TLF), a composite of cardiac death, target-vessel myocardial infarction (MI) and clinically-indicated target lesion revascularization (TLR), within 12 months. Results Among 2'119 patients enrolled between March 2012 and May 2013, 486 (22.9%) presented with DM (insulin-requiring, 33.1%). Compared with non-diabetics, patients with DM were older and had a greater baseline cardiac risk profile, including higher prevalence of hypertension, hypercholesterolaemia, peripheral artery disease, chronic renal failure and prior PCI, coronary artery bypass graft surgery, or stroke. At 5 years, TLF occurred similarly in 74 patients (cumulative incidence, 31.0%) treated with BP-SES and 57 patients (25.8%) treated with DP-EES (RR 1.23; 95% CI 0.87–1.73; p=0.24) in diabetics, and in 124 patients (16.8%) treated with BP-SES and 132 patients (16.8%) treated with DP-EES (RR 0.98; 95% CI 0.77–1.26; p=0.90) in non-diabetics (p for interaction=0.31). Cumulative incidences of cardiac death (14.9% vs. 9.5%; p=0.10), target-vessel MI (11.4% vs. 11.0%; p=0.81), clinically-indicated TLR (16.9% vs. 15.8%; p=0.68), and definite thrombosis (3.0% vs. 2.5%; p=0.63) at 5 years were similar among diabetic patients treated with ultrathin-strut BP-SES or thin-strut DP-EES. Overall, there was no interaction between diabetic status and treatment effect of BP-SES versus DP-EES. Conclusion In a prespecified subgroup analysis of the BIOSCIENCE trial, we found no difference in clinical outcomes throughout five years between diabetic patients treated with ultrathin-strut BP-SES or thin-strut DP-EES. Acknowledgement/Funding BIOSCIENCE was an investigator-initiated trial supported by a dedicated research grant from Biotronik, Bülach, Switzerland

Characterization of Cardiovascular Adverse Events and B-Type Natriuretic Peptide Levels in Patients with Multiple Myeloma Who Are Treated with Carfilzomib

BackgroundCarfilzomib (K), a second generation proteasome inhibitor that is approved for patients (pts) with relapsed refractory multiple myeloma (RRMM) is associated with increased cardiovascular (CV) adverse effects (AE), in particular hypertension (HTN), dyspnea and cardiac failure (CCF), based on the ENDEAVOR (Dimopoulos, MA. et al. Lancet 2016) and ASPIRE studies (Stewart, K.et al. NEJM 2015). The clinical characteristic and underlying mechanism of K induced CVAE have been poorly elucidated, and the limited published data on the utility of cardiac enzymes as biomarkers have not been revealing. We conducted a retrospective single centre review of K-treated pts who have undergone systemic serial cardiovascular and cardiac enzyme assessment, to profile the nature of CVAE and patterns in cardiac enzymes that might have predictive utility in K-induced CVAE.Method:Between January 2016 to June 2018, all pts who were treated with K (D1,2,8,9,15,16 in a 28 day cycle)-based regimen for RRMM at St.Vincent's Hospital Melbourne underwent systematic cardiovascular assessment including documentation of baseline cardiac risk factors (RF) and transthoracic echo (TTE). Serial troponin, creatinine kinase (CK) and B-type Natriuretic Peptide (BNP) were performed at baseline (C1D1 or 2), mid cycle (D8 or 9) and end of treatment (D16) of every cycle. Repeat TTE was done at physicians' discretion. Systematic documentations of CVAEs (graded according to CTCAEv5) were retrieved from medical records. The incidence and severity of CVAE was collated and correlated with serial cardiac enzyme levels, the association of which was tested using Student's t-test.Results76 pts (67% male; median age 66(46-86) years) with RRMM who received a median of 6 cycles (1-26) of K-based treatment were included in this analysis. At baseline, 16 pts (21%) had at least 1 CVRF including HTN, history of ischaemic heart disease, hyperlipidaemia, diabetes or smoking. The incidence of HTN prior to treatment was 39%. On treatment, the incidence of HTN was 85% (28% grade≥3). 17% of pts required the addition of antihypertensive medications and 11% had K dose reduction due to HTN. K-related dyspnea occurred in 53% of pts (28% grade≥3), 52% of who required K dose reduction/interruption. CCF occurred in 14.5% (grade≥3, 13%) that all necessitated K interruption/dose reduction. 69 pts had baseline TTE that showed a median RVSP (right ventricular systolic pressure) of 32mmHg (range 20-48). On treatment, 38 pts had repeat TTE, mainly driven by dyspnea with a median RVSP of 41(20-93mmHg). Of the 18 pts with grade≥3 dyspnea who had repeat TTE, 83% had RSVP ≥39mmHg and 33% had RVSP≥50mmHg, compared to 70% with RSVP ≥39mmHg and 10% RVSP≥50mmHg in the group with grade 1-2 dyspnea. Troponin_I and CK level did not change significantly throughout K-treatment. However BNP level rose and fell within each cycle, typically with peaks at mid cycle (D9 and D16) and troughs at the beginning of a new cycle (D1 or 2). 87.1% of pts had at least one elevated BNP (>100ng/L) with a median maximal level of 300ng/L (range 114-2320ng/L). There was a significant difference in the incidence of grade ≥3 CVAEs (mainly HTN) in pts whose mid cycle BNPs (D9 or 16) were elevated in ≥50% of measurements during the first 4 cycles of K compared to the rest (65.5% vs. 25.0%, p=0.0084). In pts with dyspnea, persistent rise in mid cycle BNPs that does not normalise prior to next treatment cycle trended towards an increased incidence of raised RVSP of ≥39mmHg (21.7% vs. 7.9%, p=0.0543).Conclusion.The incidence of CVAEs in pts treated with K is higher in the real-world setting compared to that reported in the Endeavor and ASPIRE studies. Dyspnea is frequent, the degree of which correlates with the degree of raised RVSP, thus indicating pulmonary hypertension as a contributor to dyspnea in the setting of K treatment. BNP level typically peaks during mid cycle and troughs at the beginning of next cycle, indicating a temporal relationship to K infusions. In pts with dyspnea, the association of persistent rise in mid-cycle BNP (rather than troponin or CK) with raised RVSP and HTN perhaps indicate transient endothelial dysfunction as the mechanism for K-induced CVAE rather than myocyte injury. DisclosuresQuach:Amgen: Consultancy, Research Funding; Sanofi Genzyme: Research Funding; Janssen Cilag: Consultancy; Celgene: Consultancy, Research Funding. Tam:Roche: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Gilead: Honoraria; Roche: Honoraria.

Usefulness of Global Longitudinal Strain for Early Identification of Subclinical Left Ventricular Dysfunction in Patients With Active Cancer

Cardiotoxicity from cancer therapy has become a leading cause of morbidity and mortality in cancer survivors. The most commonly used definition is cancer therapeutic related cardiac dysfunction defined as a left ventricular ejection fraction (LVEF) reduction of >10%, to a value below 50%. However, according to the recent American and European Society of Echocardiography, global longitudinal strain (GLS) is the optimal parameter for early detection of subclinical left ventricular dysfunction. The objective of this study was to evaluate the frequency of GLS reduction in patients with active cancer and its correlation to other echocardiographic parameters. Data were collected as part of the International Cardio-Oncology Registry. All patients performed at least 2 echocardiograms including GLS. We evaluated the frequency of GLS reduction (≥10% relative reduction), its correlation to LVEF reduction and whether there are other predicting echocardiographic parameters. In 64 consecutive patients, 12 (19%) had ≥10% GLS relative reduction, of which 75% had no concomitant ejection fraction reduction. There were no significant differences in the baseline cardiac risk factors (hypertension, diabetes, hyperlipidemia, or smoking). Treatment with Doxorubicin, Pertuzumab, or Ifosfamide was significantly more frequent in patients GLS reduction. No other echocardiographic parameters, including diastolic function or systolic pulmonary artery pressure were significant predictors for GLS reduction. In conclusion, our study demonstrates that GLS reduction is frequent in active cancer patients, precedes LVEF reduction and cannot be anticipated by other echocardiographic parameters. Using GLS routinely during therapy may lead to an early diagnosis of cardiotoxicity.

Abstract P6-12-09: Association between cardiovascular risk factors and cardiac events among breast cancer patients enrolled in SWOG clinical trials

Abstract Background: Due to early detection and improved treatments, women with breast cancer are living longer. Breast cancer shares risk factors with cardiovascular disease (CVD), and its treatments have adverse cardiovascular effects. Less is known about the association between cardiac risk factors and long-term cardiac events among the patients enrolled in breast cancer trials, as most trials fail to collect this information. Methods: We examined the SWOG database to identify phase II/III breast cancer trials from 1999-2011. Among patients over 65 years, we linked the SWOG clinical records to Medicare claims data according to social security number and date of birth. This analysis included patients with 6+ months of Medicare coverage prior to baseline and 12+ months of Medicare coverage at any point after baseline. The comorbidities investigated at baseline were diabetes, hypertension, hypercholesterolemia, coronary artery/ischemic heart disease and obesity. A cardiac event was defined as an acute ischemic event or acute heart failure. Cox regression was used to calculate time-to-event, stratified by study ID and adjusted for baseline age, race, and prognostic risk score. Cox regression was performed separately for each CVD risk factor, and an additional analysis was performed to assess the impact of having multiple concurrent risk factors. Secondary analyses were performed separately by study type (Adjuvant, Advanced). Results: Among patients linked to Medicare included in this cohort (N=742), the median age was 70, and median follow-up was 6 years. The majority of patients were non-Hispanic white. The most prevalent conditions were hypercholesterolemia (58%) and hypertension (73%). Only 13% had no baseline risk CVD factors. In a Cox regression, all baseline risk factors except hypercholesterolemia and obesity were statistically significantly or borderline statistically significantly associated with an increased risk of eventual cardiac event, and for ischemic heart disease the increased risk was more than two-fold (HR=2.27, 95% CI=1.46-3.54, p=0.0003) and for baseline diabetes nearly two-fold (HR=1.75, 95% CI=1.13-2.71, p=0.01). In addition, there was evidence of a linear association of number of concurrent risk factors and cardiac events (HR per additional risk factor = 1.35 (1.09-1.66), p=0.005). In the stratified analysis, the associations were statistically significant only for participants on adjuvant studies. No association between baseline cardiac risk factors and cardiovascular outcomes were seen among patients with advanced cancer. Conclusions:In summary, we found that even among healthy breast cancer patients selected for clinical trials, baseline CVD risk factors are associated with an increased risk of cardiac events, however this association was not observed for patients with advanced disease, who are more likely to die from breast cancer before experiencing a cardiovascular event. Citation Format: Hershman DL, Till C, Wright JD, Ramsey SD, Barlow WE, Unger JM. Association between cardiovascular risk factors and cardiac events among breast cancer patients enrolled in SWOG clinical trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-09.

Effect of postoperative anemia and baseline cardiac risk on serious adverse outcomes after major vascular interventions

ObjectivePublished data suggest that permissive anemia strategies that allow nadir hemoglobin (nHb) values of 7 g/dL or lower are safe in a variety of clinical settings. The appropriateness of these strategies in patients at high risk for adverse postoperative cardiac events remains unclear. We sought to determine the combined effect of postoperative nHb and cardiac risk status on major complications after vascular surgical interventions. MethodsThis was a single-institution retrospective analysis of consecutive patients who underwent elective open procedures for occlusive vascular disease and aneurysm repair, either open or endovascular. The Revised Cardiac Risk Index (RCRI) was used to assess baseline cardiac risk. Primary outcome was a composite end point of mortality or major ischemic events (myocardial infarction, stroke, acute kidney injury, or coronary revascularization) within 90 days from the index operation. Secondary outcomes included intensive care unit (ICU) length of stay (LOS) and 90-day respiratory complications (pneumonia, ventilator dependence for >48 hours postoperatively, or reintubation). Hierarchical multivariable regression was used to model each outcome with adjustment for age, type of operation, baseline comorbidities, and intraoperative covariates. ResultsWe analyzed 2508 operations performed during 8 years in 2106 patients with a mean age of 67 years (range, 45-90 years). In the fully adjusted multivariable model, lower values of nHb increased the risk of the primary composite end point (odds ratio [OR], 1.24; P < .001, representing a 24% increase in the odds of the composite end point for each 1-g/dL increase in nHb). In the same model, RCRI class II (OR, 1.8; P < .001), class III (OR, 2.06; P < .0001), and class IV (OR, 2.35; P < .0001) were associated with progressively increasing odds of the composite end point compared with RCRI class I. An interaction term between transfusion and nHb was not significant statistically, indicating that the harmful effect of anemia was independent of blood transfusion. Lower values of nHb also increased the risk of respiratory complications (OR, 1.41; P = .002) and ICU LOS (average 2.6-day increase per 1-g/dL increase of nHb; P < .0001). ConclusionsPostoperative anemia increases the rate of early postoperative mortality and major ischemic events, particularly in patients at higher baseline cardiac risk. It also adversely affects respiratory complications and ICU LOS. Until a randomized trial definitively settles the issue, restrictive transfusion strategies should be practiced with caution in patients undergoing major vascular interventions.

Incidence of Myocardial Infarction After High-Risk Vascular Operations in Adults

Advances in perioperative cardiac management and an increase in the number of endovascular procedures have made significant contributions to patients and postoperative myocardial infarction (POMI) risk following high-risk vascular procedures. Whether these changes have translated into real-world improvements in POMI incidence remain unknown. To examine the temporal trends of myocardial infarction (MI) following high-risk vascular procedures. A retrospective cohort study was performed using data collected from January 1, 2005, to December 31, 2013, in the American College of Surgeons National Surgery Quality Improvement Program database, to which participating hospitals across the United States report their preoperative, operative, and 30-day outcome data. A total of 90 303 adults who underwent a high-risk vascular procedure-open aortic surgery or infrainguinal bypass-during the study period were identified. Patients were divided into cohorts based on their year of operation, and their baseline cardiac risk factors and incidence of POMI were compared. Cases from 2005 to 2014 in the database were eligible for inclusion if one of their Current Procedural Terminology codes matched any of the operations identified as a high-risk vascular procedure. Data analysis took place from August 1, 2016, to November 15, 2016. The main exposure was the year of the operation. Other variables of interest included demographics, comorbidities, and other risk factors for MI. Primary outcome of interest was the incidence of POMI. Of the 90 303 patients included in the study, 22 836 (25.3%) had undergone open aortic surgery and 67 467 (74.7%) had had infrainguinal bypass. The open aortic cohort comprised 16 391 men (71.9%), had a mean (SD) age of 69.1 (11.5) years, and was predominantly white (18 440 patients [80.8%] self-identified as white race/ethnicity). The infrainguinal bypass cohort included 41 845 men (62.1%), had a mean (SD) age of 66.7 (11.7) years, and had 51 043 patients (75.7%) who self-identified as white race/ethnicity. During the study period, patients who underwent open aortic procedures were more likely to be classified as American Society of Anesthesiologists class IV (7426 patients [32.6%] vs 15 683 [23.3%] for the infrainguinal bypass cohort) or class V (1131 [5.0%] vs 206 [0.3%]; P < .001) and to undergo emergency procedures (4852 [21.3%] vs 4954 [7.3%]; P < .001). The open aortic procedure cohort also experienced significantly higher actual incidence of POMI (464 [3.0%] vs 1270 [1.9%]; P < .001). From 2009 to 2014, the incidence of POMI demonstrated no substantial temporal change (2.7% in 2009 to 3.1% in 2014; P = .64 for trend). Postoperative MI was consistently associated with poor prognosis, with a 3.62-fold (95% CI, 2.25-5.82) to 11.77-fold (95% CI, 6.10-22.72) increased odds of cardiac arrest and a 3.01-fold (95% CI, 2.08-4.36) to 6.66-fold (95% CI, 4.66-9.52) increased odds of mortality. The incidence of MI did not significantly decrease in the past decade and has been consistently associated with worse clinical outcomes. Further inquiry into why advanced perioperative care did not reduce cardiac complications is important to quality improvement efforts.

Hypothyroidism in Infants With Congenital Heart Disease Exposed to Excess Iodine.

Thyroid hormone is critical for neonatal brain development, and even transient hypothyroidism can cause adverse neurocognitive outcomes. Infants exposed to excess iodine are at risk of developing hypothyroidism, especially those with congenital heart disease (CHD), because they are routinely exposed to excess iodine from intravenous iodinated contrast media and topical antiseptics. The aim of the present study was to identify the proportion of neonates with CHD exposed to iodine who developed hypothyroidism and to identify the associated risk factors. This was a retrospective study of neonates undergoing cardiac catheterization at Boston Children’s Hospital during a 3-year period, some of whom also underwent cardiac surgery. Hypothyroidism was defined as an elevated thyroid-stimulating hormone level (>20 mIU/L at 24 to 96 hours of age and >15 mIU/L at >96 hours of age by heel-stick sampling and >9.1 mIU/L at 1 to 20 weeks of age by serum testing). Multivariate logistic regression was performed to predict the odds of developing hypothyroidism. Hypothyroidism was diagnosed incidentally in 46 of 183 infants (25%) with CHD after iodine exposure. Controlling for baseline cardiac risk, postnatal age, and gestational age, we found a fourfold increase in odds of developing hypothyroidism in neonates with serum creatinine >0.9 mg/dL and a fourfold increase in those who underwent more than three procedures. Hypothyroidism in neonates with CHD exposed to excess iodine is associated with multiple procedures and impaired renal function. Routine serial monitoring of thyroid function in these neonates is warranted. Future studies should examine the association between hypothyroidism and neurocognitive function in this population.

OA24.03 Cardiac Toxicity after Radiation for Stage III NSCLC: Pooled Analysis of Dose-Escalation Trials Delivering 70-90 Gy

Radiation (RT) associated cardiac injury in patients with lung cancer is of unclear significance. RTOG 0617 demonstrated reduced overall survival (OS) with dose-escalated RT for Stage III NSCLC, with higher heart doses predicting for worse OS. We assessed the impact of heart doses on toxicity and survival for patients enrolled on several prospective RT dose-escalation trials. From 1996-2009, 133 patients with Stage III NSCLC (ECOG PS 0-1) were treated on six prospective trials using induction/concurrent chemotherapy and dose-escalated conformal RT to 70-90 Gy. Broad clinical outcomes (e.g. OS) were prospectively assessed. RT plans were reviewed, cardiac structures were defined, and dose/volume metrics were computed. Patient records were retrospectively reviewed for post-RT symptomatic cardiac events (symptomatic pericardial effusion, acute coronary syndrome, and pericarditis). Baseline cardiac risk was calculated using the World Health Organization / International Society of Hypertension (WHO/ISH) score. A competing risks model accounting for the risk of death was used for statistical analysis. 112 patients were included in the final analysis. Median f/u was 19 mo. (75 mo. for the 39 patients without documented progression). Median OS and PFS were 22 and 12 mo. Median prescribed RT dose was 74 Gy. 15 patients (13%) had symptomatic cardiac events (6 pericardial effusion, 5 myocardial infarction, 2 unstable angina, 2 pericarditis) at median 26 mo. post-RT (range, 7-68). On univariate analysis, Heart mean dose (p=0.001), Heart V5Gy (p<0.001), and Heart V30Gy (p=0.002) were associated with symptomatic cardiac events, whereas baseline WHO/ISH score (p=0.204) and coronary artery disease (p=0.109) were not. Heart doses were higher in patients with vs without events (mean 22Gy vs 11Gy, V5Gy 60% vs 35%, V30Gy 35% vs 14%). On multivariate pair analysis accounting for baseline risk, heart doses remained significant predictors of cardiac events (e.g. Heart mean dose, p=0.001, HR 1.05 / 1Gy). 2-year competing risk-adjusted rate of symptomatic cardiac events was 11.1% vs 1.5% for Heart mean dose ≥15Gy vs <15Gy (p=0.003, HR 6.7). 34 patients (30%) had asymptomatic pericardial effusions. There was no association between heart doses and OS. Clinically significant symptomatic cardiac events following high-dose thoracic RT for Stage III NSCLC occurred in 13% of patients at a median 2 years post-RT, with the rate appearing to be heart dose dependent. RT-associated cardiac toxicity in the definitive treatment of Stage III NSCLC may occur earlier than historically understood, and heart doses should be minimized. Supported in part by NIH grant CA69579.

Comparison of two care schedules for monitoring of cardiotoxicity in patients receiving trastuzumab-based therapy for early-stage breast cancer: study protocol for a randomized controlled non-inferiority trial

Background: Cardiotoxicity is a toxic side effect of trastuzumab-based therapy. Current guidelines for cardiac monitoring (every 3 months) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving trastuzumab-based therapy have been dictated by the increased risk of cardiotoxicity observed in clinical trials. However, the majority of these patients are at a low risk of cardiac complications and may not require such frequent monitoring. Objective: This randomized controlled clinical trial will be performed to demonstrate that cardiac monitoring (echocardiography (ECHO)/multiple gated acquisition scan (MUGA) every 4 months is not inferior to every 3 months in the detection of cardiac dysfunction (decrease in left ventricular ejection fraction (LVEF)) in patients receiving trastuzumab-based therapy for early-stage HER2-positive breast cancer. Study period: From June 2016 to December 2018. Study location: The Ottawa Hospital Cancer Centre. Principal investigator: Dr. Olexiy Aseyev and Dr. Susan Dent at Department of Medicine, Division of Medical Oncology, The Ottawa Hospital, University of Ottawa, Canada. Study design: A prospective, single-center, randomized controlled non-inferiority clinical trial. Study population: A total of 200 patients with early-stage HER2-positive breast cancer (n = 100 in each group) receiving trastuzumab-based therapy will be enrolled. Inclusion criteria: Patients with histologically confirmed early-stage HER2-positive breast cancer receiving trastuzumab-based therapy, who are over 18 years of age, have a normal baseline LVEF (> 53%) and are able to provide verbal consent will be included in this study. Exclusion criteria: Patients will be excluded if they have any contraindication to transthoracic echocardiography or MUGA. Randomization: Eligible and consented patients will be randomized using a permuted block design to receive cardiac evaluation (by either transthoracic echocardiography or MUGA) every 3 months, or every 4 months while on treatment, 100 patients for each type of cardiac evaluation. Primary outcome measure: The rate of changes in LVEF diagnosed by ECHO or MUGA throughout trastuzumab-based therapy in both groups. Secondary outcome measures: Rates of trastuzumab delay/discontinuation, referral to cardiology, rate of cardiac events. Human specimen collection: Not involved. Ethical approval: This study was approved by the Ottawa Health Science Network Research Ethics Board. Trial registration: ClinicalTrials.gov identifier: NCT02696707 on February 18, 2016. Study status: This study is currently recruiting participants. Study enrolment is expected to be completed by July 2018 and analysis of primary outcome measure will be completed by October 2018 and the study will be completed by December 2018. Discussion: This study will present data on the cardiac safety of less frequent cardiac monitoring in patients with early-stage HER2-positive breast cancer. Future trials will explore cardiac monitoring strategies using composite data including baseline cardiac risk factors, baseline cardiac imaging and cardiac biomarkers. Health care economics will be explored.

SS06. Effect of Postoperative Anemia and Baseline Cardiac Risk on Adverse Outcomes After Vascular Surgery Interventions

Published data suggest that permissive anemia strategies allowing nadir hemoglobin (nHb) 7 g/dL or lower are safe in a variety of clinical settings. The appropriateness of these strategies in patients at high risk for adverse postoperative cardiac events remains unclear. We sought to determine the combined effect of postoperative nHb and cardiac risk status on major complications after vascular surgical interventions. This was a single-institution retrospective analysis of patients who underwent elective open procedures for occlusive vascular disease or aneurysm repair, either open or endovascular. The Revised Cardiac Risk Index (RCRI) was used to assess baseline cardiac risk. Primary outcome was a composite end point (CE) of mortality or major ischemic events (myocardial infarction, stroke, acute kidney injury, or coronary revascularization) within 90 days from the index operation. Secondary outcomes included ICU length of stay (ICU LOS), and 90-day respiratory complications (pneumonia, ventilator dependence for >48 hours postoperatively, or reintubation). Hierarchical multivariable regression was used to model each outcome with adjustment for age, type of operation, comorbidities, and intraoperative covariates. We analyzed 2509 operations performed over 8 years in 1872 patients with mean age 65 (range, 43 to 94) years. In the fully adjusted multivariable model, higher values of nHb were strongly protective from the primary CE (OR, 0.79; P < .0001), representing 21% reduction in the odds of the CE per g/dL increase in nHb). In the same model, RCRI class II (OR, 1.8; P < .0001), class III (OR, 2.07; P < 0.0001), and class IV (OR, 2.38; P < 00001) were associated with progressively increasing odds of the CE compared with RCRI class I (Table). The curvilinear association between the probability of the primary end point occurring over a range of nHb and cardiac risk strata is demonstrated in the Fig. An interaction term between transfusion and nHb was not significant statistically, indicating that the harmful effect of anemia was independent of blood transfusion. Higher values of nHb were favorably associated with respiratory complications (OR, 0.7; P < .0001) and ICU LOS (average 0.47 day reduction per g/dL increase of nHb; P < .0001). Postoperative anemia increases the rate of early postoperative mortality and major ischemic events, particularly in patients at higher baseline cardiac risk. It also adversely affects respiratory complications and ICU LOS. Until a randomized trial definitively settles the issue, restrictive transfusion strategies should be practiced with caution in patients undergoing major vascular interventions.TableThe final fully adjusted multivariate model with the composite end point of 90-day mortality or ischemic events as the dependent variablePredictorOR95% CIP valueNadir hemoglobin0.79(0.74-0.85)<.0001RCRI Class IReferenceReferenceReference II1.76(1.29-2.42)<.0001 III2.06(1.45-2.93)<.0001 IV2.35(1.58-3.48)<.0001Intraoperative blood lossa1.03(1.00-1.06).05ACE inhibitors0.78(0.61-0.99).04ACE, Angiotensin converting enzyme; CI, confidence interval; OR, odds ratio; RCRI, Revised Cardiac Risk Index.aIntraoperative blood loss is modeled in increments of 100 mL, so the demonstrated OR indicates odds of the composite end point per 100-mL increase in blood loss. Open table in a new tab

Abstract P1-15-01: Adjuvant trastuzumab +/- anthracycline and cardiotoxicity in a community cohort of 962 HER2+ breast cancers from 2005-2011: Comparison of incidence by risk factors and by diagnostic codes vs clinical chart review

Abstract Background: Prospective clinical trials using clinical criteria and observational studies using diagnostic codes from electronic health records have reported seemingly contradictory cardiotoxicity risk for adjuvant trastuzumab (T). Accurate estimates of individualized patient specific cardiotoxicity risk are essential for treatment decisions in early HER2+ breast cancer (BC). Methods: 1,109 consecutive non-metastatic HER2+ invasive BC's diagnosed 5/1/2005 to 12/31/2011 at Kaiser Permanente Northern California receiving adjuvant T were reviewed for symptomatic congestive heart failure (SxCHF), baseline and post-T cardiac ejection fraction (EF), anthracycline (A) use, and CHF risk factors (RF) including age, race, hypertension (HTN), diabetes (DM), obesity, smoking. Records of patients with CHF ICD9 codes or an EF drop to &amp;lt;50% were reviewed by a RN, a cardiologist, and an oncologist. Primary outcomes were SxCHF (NYHA Class II or higher), EF fall to &amp;lt;50%, and &amp;lt; 38 weeks of T (75% of prescribed). Results: Median age of 962 eligible patients was 54 years (range 24-95). 305 (31.7%) were &amp;gt; 60 years old. During a median follow-up of 4.1 years, 4.6% of patients had CHF ICD9 codes, but only 2.5% had SxCHF or cardiac death confirmed by clinical review. At 1 year, cumulative incidence of an EF fall to &amp;lt;50% was 5.7% with T alone and 17.7% with T+ A. A total of 15.3% finished &amp;lt;38 weeks of T, 9.4% with T alone and 20.6% with T+A. The overall 2- and 5-year cumulative incidence of SxCHF/cardiac death was low: 1.3% and 2.7% with T alone and 2.2% and 3.1% with T + A. These rates were lower than reports based solely on diagnostic or billing codes, and varied substantially by RF (see table). The rates were similar to those predicted by the NSABP B-31 Cardiac Risk Score. Clinical heart failure based on diagnostic codes was not confirmed at chart review 48% of the time. Results from multivariable analyses will be presented. Predictors of Trastuzumab Cardiotoxicity Cumulative Incidence (%)PredictorsNFall EF to&amp;lt;50%Symptomatic CHF 1-year2-year5-yearAll96212.01.82.8Anthracycline50517.72.23.1Non-anthracycline4575.71.32.7Age&amp;lt;6065711.71.11.1Age 60-6922212.61.43.8Age 70-797112.77.111.0Baseline EF 50-55%9230.78.88.8HTN dx39212.63.44.7BMI 30+31516.32.64.5DM Dx10315.55.06.9Smoking (ever)33314.23.76.1HTN and BMI 30+18215.53.96.0HTN, BMI 30+, DM5016.08.212.2Age&amp;lt;50, BMI&amp;lt;30, No HTN/DM2197.30.00.0Age&amp;gt;60, 2+ RF(HTN, DM, BMI 30+)10114.95.08.9 Conclusions: Risk of clinically confirmed CHF/cardiac death was substantially lower than risk based on ICD codes alone. Risk was consistent with prior clinical trials and differed substantially by age, baseline EF, use of A, and other CHF risk factors. Greatest risk was with age of 70+, borderline baseline EF, and comorbidities known to increase CHF risk. Quite low risk (1.1% at 5 years) was seen in patients under 60 years old. Citation Format: Fehrenbacher L, Capra A, Krishnaswami A, Quesenberry C, Habel L. Adjuvant trastuzumab +/- anthracycline and cardiotoxicity in a community cohort of 962 HER2+ breast cancers from 2005-2011: Comparison of incidence by risk factors and by diagnostic codes vs clinical chart review. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-15-01.