Kailash, Vidur

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events in diabetics. This study aimed to investigate the cardiac, cancer, and overall mortality effects of GLP-1 RAs in diabetics treated with anthracyclines. Methods and results We retrospectively identified 1384 diabetics treated with anthracyclines from 2013 to 2023; 56 received GLP-1 RAs between their first and last dose of anthracycline. These patients were propensity score matched 4:1 to 224 controls without concurrent GLP-1 RA use. Because stage was not available for 10 of the 56 patients, a repeat analysis was conducted with additional matching for cancer stage in 46 cases and 92 controls. Major endpoints were rate of all-cause and cancer-related and cardiovascular disease (CVD)–related mortality, no evidence of disease (NED), and hospitalization for CVD including heart failure (HF), over 5 years. Survival analyses were conducted using cause-specific hazards Cox regression. Patients on GLP-1 RAs had a significantly lower 5 year overall mortality (HR 0.46, CI 0.24–0.87, P = 0.007) and cancer-related mortality (HR 0.42, CI 0.19–0.91, P = 0.03). This mortality risk reduction remained significant even when accounting for covariates (HR 0.39, CI 0.20–0.75, P = 0.002). The percentage of patients with NED was higher in the GLP-1 RA than control group (60.9% vs. 38.0%, P = 0.007). A decline in left ventricular ejection fraction was seen in controls but not in patients on GLP-1 RAs. There was no significant difference in CVD hospitalization; the rate of HF-related hospitalization was very low overall. Conclusion GLP-1 RAs may offer survival benefits and better cancer- and cardiac function-related outcomes in diabetics undergoing anthracycline chemotherapy.

Abstract Purpose To assess incidence and risk factors for anthracycline-induced left ventricular dysfunction, and associated mortality in order to inform patients and providers of the risk, as well as for clinical trial endeavours. Background Anthracyclines (ACs) are very effective cancer therapeutics, but their use is confronted by the risk of cardiotoxicity. Estimates of AC-induced cardiotoxicity based on systematic analyses are limited and have not recently been defined. We present here a systematic review and meta-analysis of the incidence of anthracycline induced subclinical (AC-LVD) and clinical LV dysfunction (AC-CHF) and AC-CHF related mortality in non-liposomal AC recipients over the last 3 decades. Methods We searched Ovid MEDLINE(R), Embase, Cochrane Database and other major databases from their inception until June 22, 2023 for studies examining the rate of AC induced cardiomyopathy in patients receiving ACs and anthraquinones for haematologic, breast (BC) and sarcomatous malignancies. Covidence was used to aid with the management of our systematic review. Screening of abstracts and data extraction was independently performed by 2 reviewers. Results 6,365 abstracts were reviewed, of which 74 were included in the final analysis. 72 studies (n=41,138) reported data on AC-LVD, and 47 studies (n=27,012) reported data on AC-CHF. The average age was 53 years and 50% of the patients were female. Data on cardiac function at baseline was available in only 70% of the studies. Overall, AC-LVD occurred in 8.2% (95% CI 6.8%-10.2% I2 97%) (Fig 1). AC-CHF was noted in 2.2% (95% CI 1.6% to 2.9%, I2 91%) (Fig 2A), mortality related to decompensated AC-CHF was 0.5% (95% CI 0.3%-0.9%, I2 88%) (Fig 2B) while total mortality rate among AC recipients was 24.9% (95% CI 14.8-38.7%, I2 99%). Incidence of AC-LVD was higher in doxorubicin recipients (vs other ACs 10.5% vs 5-5.6%), studies from North America & Asia (vs other regions; 9.3-9.6% vs 6.7%), and prospective studies (vs retrospective studies; 8.7% vs 7.5%). AC-LVD was more common in BC patients (vs other cancers; 8.7% vs 3.5-7.2%) while AC-CHF was more common in lymphoma patients (8.5% vs 1.6-4.1%). AC-LVD was 4.6 times (95% CI 1.2-17.1, p=0.02) more likely in patients with a mean age >70 (vs <70). 21 definitions for AC-LVD were used across the studies. The most common definition (15 studies; n=7904) was "any decline in LVEF from baseline" resulting in a 5.8% rate of AC-LVD. Conclusions AC-LVD and AC-CHF has been reported in up to 10% and 3% of AC recipients, respectively. AC-CHF related mortality occurs in <1% of anthracycline recipients and has a 2-3% share in overall mortality among these patients. The type of malignancy and anthracycline can influence the rate of AC-LVD, AC-CHF and AC-CHF related mortality. Global region, age of the patient population and study design also seem to influence incidence rates. There is noteworthy heterogeneity in definitions for cardiotoxicity across studies.

Abstract Aims The objective of this study was to assess the effect of HER2-directed therapy (HER2-Tx) on peripheral vasoreactivity and its correlation with cardiac function changes and the additive effects of anthracycline/cyclophosphamide (AC) therapy and baseline cardiovascular risk. Methods and results Single-centre, prospective cohort study of women with newly diagnosed stage 1–3 HER2-positive breast cancer undergoing HER2-Tx +/− AC. All participants underwent baseline and 3-monthly evaluations with Endo-Peripheral Arterial Tonometry (Endo-PAT), vascular biomarkers [C-type natriuretic peptide (CNP) and neuregulin-1 beta (NRG-1β)], and echocardiography. Cardiotoxicity was defined as a decrease in the left ventricular ejection fraction (LVEF) of >10% to a value <53%. Of the 47 patients enrolled, 20 (43%) received AC in addition to HER2-Tx. Deterioration of reactive hyperaemia index (RHI) on Endo-PAT by ≥20% was more common in patients receiving HER-Tx plus AC than HER2-Tx alone (65% vs. 22%; P = 0.003). A decrease in CNP and log NRG-1β levels by 1 standard deviation did not differ significantly between the AC and non-AC groups (CNP: 20.0% vs. 7.4%; P = 0.20 and NRG-1β: 15% vs. 11%; P = 0.69) nor did GLS (35% vs. 37%; P = 0.89). Patients treated with AC had a significantly lower 3D LVEF than non-AC recipients as early as 3 months after exposure (mean 59.3% (SD 3) vs. 63.8% (SD 4); P = 0.02). Reactive hyperaemia index and GLS were the only parameters correlating with LVEF change. Conclusion Combination therapy with AC, but not HER2-Tx alone, leads to a decline in peripheral vascular and cardiac function. Larger studies will need to define more precisely the causal correlation between vascular and cardiac function changes in cancer patients.

e19517 Background: Anthracycline-induced cardiotoxicity (AIC) is a well-known phenomenon, but event rates and predictors may not be as robust as commonly perceived. We performed a systematic review and meta-analysis to elucidate AIC definitions, incidence rates and predictors. Methods: 5323 reports were identified via searching Medline, Embase, and Scopus. Inclusion criteria for full text review included minimum of 100 lymphoma patients receiving ACs; median/mean follow up of at least 12 months; and specified evaluation of left ventricular ejection fraction. We investigated the definition, reported incidence, and predictors of AIC including subclinical AIC as detected by decrease in left ventricular systolic dysfunction. Meta-analysis was performed with Meta-analyst software with random effects model. Results: A total of 19 studies were included in the analysis. The overall incidence of AIC in 13926 patients was 13.8% (95% CI 4.8-22.8, I2 99.6% p < 0.001) at a mean/median follow-up ranging from 1 to 8 years. Subclinical AIC was seen in 8.2% of 5464 patients (95% CI 6.4 to 10%, I2 78.9%, p < 0.001) at a mean/median follow-up ranging from 1 to 20 years. Subclinical AIC is defined in most studies as asymptomatic decrease in LVEF by 10-15% from baseline of 50-55%. Older age, increasing AC dose or number of cycles, GLS (global longitudinal strain), and prior comorbidities such as CAD, HTN, DM and dyslipidemia were found to predict AIC. However, Heterogeneity was seen in definition of AIC, risk factor assessment and follow-up protocol, which limited the extent of correlative analyses for cardiotoxicity predictors. Conclusions: The overall incidence of clinical HF and subclinical AIC among lymphoma patients was 13.8% and 8.2% respectively. Older age, increasing AC dose or number of cycles, GLS, and prior comorbidities such as CAD, HTN, DM and dyslipidemia were found to predict AIC.