BACKGROUND:Coronary artery bypass grafting (CABG) remains a cornerstone in the management of coronary artery disease (CAD). In nonurgent surgical revascularization cases, preoperative optimization of modifiable risk factors can improve outcomes. There is increasing interest in the relationship between lipoprotein(a) levels and the risk for ischemic cardiovascular disease, particularly how CABG outcomes are in turn affected. This review highlights the role of lipoprotein(a) in the pathogenesis of CAD and CABG outcomes and discusses future directions for its optimal management in the perioperative period. METHODS:The PubMed/MEDLINE database was reviewed until March 2024 to capture publications that evaluated and/or described the relationship between lipoprotein(a) and CABG surgery or CAD outcomes. RESULTS:The available literature supports lipoprotein(a) as a causal and independent risk factor for the pathogenesis of CAD. Elevated lipoprotein(a) levels are associated with an increased risk of adverse post-CABG outcomes, including graft occlusion incidence and major adverse cardiovascular events. Genetic variations influencing lipoprotein(a) levels play a role in disease progression and surgical outcomes. Several therapies aimed at reducing lipoprotein(a) levels, currently in phase III clinical trials, show promise for improving the prognosis after CABG. CONCLUSIONS:Among individuals undergoing surgical revascularization for CAD, lipoprotein(a) levels may help define risk and inform best practices for perioperative management. We advocate for the routine measurement of lipoprotein(a) in all patients undergoing CABG. Emerging lipoprotein(a)-lowering agents show promise for secondary prevention of cardiac events, although dedicated analyses in cardiac surgical subcohorts will be important to evaluate their role in improving CABG outcomes.

The natural history of cardiac tumors is dismal, with death ensuing rapidly. This is especially true with incomplete resection (called R-2 resection). We present a patient with metastatic sarcoma, also involving the heart, too unwell to undergo chemotherapy, who underwent a debulking operation, resulting in early rapid recurrence but response from chemotherapy. Debulking cardiac tumors may be selectively offered to enable chemotherapy initiation.

Purpose of review Cardiac tumours present significant clinical challenges due to their wide differential, complex anatomical and physiological implications, as well as the potential for widespread invasion in the case of malignancies. This review synthesizes recent findings surrounding the diagnosis and management of specifically right-sided cardiac tumours, with a particular focus on surgical resection and reconstructive techniques. Recent findings Management of cardiac tumours can be categorized into three key phases. First: early and accurate diagnosis is critical for improving outcomes, especially in malignancies. Advances in imaging modalities like MRI, CT, PET-CT, and biopsy techniques enhance diagnostic accuracy. Second: surgical resection is a cornerstone treatment for both benign and malignant right-sided cardiac tumours. Surgery is often curative for benign tumours, while for malignant tumours, R0 resection (complete microscopic removal) in appropriate candidates correlates with better survival. Third: managing cardiac malignancies necessitates a multidisciplinary approach, integrating additional therapies such as chemotherapy, radiation, and emerging immunotherapies tailored to patient and tumour characteristics. Summary Managing right-sided cardiac tumours demands interdisciplinary expertise. Standardized protocols are limited by the rarity of cases and insufficient high-quality data. International collaboration and sharing of experiences through prospective registries and clinical studies are essential to advancing knowledge and improving patient outcomes.

BACKGROUND The EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial established the efficacy of empagliflozin in reducing heart failure (HF) outcomes among patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES The authors examined the outcomes of EMPEROR-Reduced as a function of background diuretic therapy. METHODS The EMPEROR-Reduced trial was a double-blind, randomized controlled trial of placebo vs empagliflozin 10 mg among 3,730 HFrEF patients. Herein, the population was stratified into 4 groups: no diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. RESULTS A total of 3,656 patients from the EMPEROR-Reduced trial were available for analysis. Of those patients, 482 (13.2%) were receiving no diuretic therapy, and 731 (20.0%), 1,411 (38.6%), and 1,032 (28.2%) were receiving <40 mg, 40 mg, and >40 mg, respectively. The efficacy of empagliflozin on the primary outcome (time to first event of hospitalization for HF or cardiovascular [CV] death) was consistent regardless of background diuretic therapy (>40 mg: HR: 0.88 [95% CI: 0.71-1.10]; 40 mg: HR: 0.65 [95% CI: 0.51-0.82]; <40 mg: HR: 0.65 [95% CI: 0.46-0.92]); no diuretic agents: HR: 0.78 [95% CI: 0.47-1.29]; Ptrend test 1/4 0.192). Baseline diuretic doses did not influence the effect of empagliflozin on body weight, systolic blood pressure, NT-proBNP, or hematocrit at 52 weeks. The safety profile of empagliflozin vs placebo was unaffected by baseline diuretic dose; however, independently of treatment allocation, total rates of adverse events were higher among patients with higher baseline doses of diuretic agents. CONCLUSIONS Empagliflozin exhibits a consistent effect on time to CV death or HF hospitalization and an unaltered safety profile regardless of baseline diuretic therapy. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977) (J Am Coll Cardiol HF 2024;12:35-46) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PURPOSE OF REVIEW:Heart failure with preserved ejection fraction (HFpEF) is a leading and growing cause of morbidity and mortality globally. Of the various phenotypes identified, the obesity (or cardiometabolic) phenotype appears to be most common. The purpose of this review is to provide the clinician with an abridged understanding of recent developments that have elucidated obesity/visceral adiposity as a central mechanism linking inflammation/immune dysregulation to the development of the HFpEF syndrome. Recent clinical trials examining the efficacy of pharmacological treatments that target obesity in HFpEF will also be discussed.RECENT FINDINGS:Recent data indicate that visceral adiposity and insulin resistance in HFpEF serve as key mechanisms driving inflammation and immune dysregulation, which play a critical role in the development of cardiac stiffness, diastolic dysfunction and fibrosis in HFpEF. In obesity, alterations in macrophage polarization, changes in innate and adaptive immune systems and altered myocardial energetics promote metabolic inflammation in HFpEF. Finally, emerging data suggest that inflammatory biomarkers, specifically, IL-6, may provide useful information about HFpEF severity and symptom burden in obesity.SUMMARY:The obesity phenotype of HFpEF is seen in upward of 80% with HFpEF. Obesity is not just a bystander, but plays an essential role in the pathobiology and clinical course of HFpEF. Targeting overweight/obesity in HFpEF with GLP-1 receptor agonists holds promise in these patients.

Metastatic disease is a relative contraindication for resection of malignant cardiac tumors. However, certain situations may present themselves when primary cardiac resection may be warranted. We present a 21-year-old male diagnosed with metastatic epithelioid hemangioendothelioma with right ventricular outflow tract involvement for whom surgical resection was successfully performed and discuss strategies.

Objective: To investigate the impact of national income level and sex on mortality trends from aortic aneurysm and dissection in addition to all aortic disease as a whole. Methods: Using data from the World Health Organization mortality database, we conducted an analysis of mortality trends from aortic disease between 2000 and 2019, Countries were categorized into middle-income and high-income countries (MICs and HICs) on the basis of income level. Age-standardized and sex-specific age-standardized mortality rates per 100,000 persons, along with male-to-female mortality ratios, were calculated. Trends over the study period were analyzed using joinpoint regression. Results: Our analysis comprised 29 MICs and 46 HICs, with an average population of 595 million and 1042 million during the observation period. During the observation period, age-standardized mortality rates from aortic disease decreased to 2.21 (2.17-2.25) and 2.28 (2.26-2.30) in MICs and HICs, respectively (average annual percentage change of- 0.5 % in MICs and- 1.8 % in HICs, P < .05 for both). However, mortality rates from aortic dissection increased in HICs from 2000 to 2019 (average annual percentage change of 1.3%, P < .001). Mortality from aortic disease, aortic dissection, and aortic aneurysm were male dominant in MICs and HICs but decreasing trends during the observation periods except for aortic dissection in MICs. Conclusions: We present the contemporary and comprehensive analysis of global socioeconomic status and aortic diseases mortality. Although trends of mortality from aortic diseases are on the decline in both MICs and HICs, there is a striking increase in mortality for aortic dissection, specifically in HICs.

Left atrial masses are most commonly diagnosed as myxomas. When clinicians doubt the diagnosis, a biopsy is warranted. However, this can be very difficult with left-sided tumors. We present a 71-year-old woman with a presumed left atrial myxoma with features concerning for a malignant lesion. She underwent a computed tomography-fluoroscopy-guided percutaneous biopsy, revealing a diagnosis of malignant spindle cell neoplasm, thus avoiding surgery and allowing for early treatment.

Background: Patient reported outcomes (PROs) are important measures in acquired heart disease but have not been well defined in Adult Congenital Heart Disease (ACHD). Our aim was to explore the discriminatory capacity of PRO survey tools in Fontan circulatory failure (FCF). Methods: Consecutive adults were enrolled from our ambulatory clinics. Inclusion criteria were age ≥18 years, a Fontan circulation or a hemodynamically insignificant shunt lesion, and sufficient cognitive/language abilities to complete PROs. A comprehensive package of PRO measures, designed to assess perceived health-related quality of life (HRQOL) was administered (including the Kansas City Cardiomyopathy Questionnaire [KCCQ-12], EuroQol-5-dimension [EQ5D], Short Form Health Status Survey [SF-12], self-reported New York Heart Association [NYHA] Functional Class, and Specific Activity Scale [SAS]). Results: We compared 54 Fontan patients (35 ± 10 years) to 25 simple shunt lesion patients (34 ± 11 years). The KCCQ-12 score was lower in Fontan versus shunt lesion patients (87 [IQR 79, 95] versus 100 [IQR 97, 100], p-value < 0.001). The FCF subgroup was associated with lower KCCQ-12 scores as compared with the non-FCF subgroup (82 [IQR 56, 89] versus 93 [IQR 81, 98], p-value = 0.002). Although the KCCQ-12 had the best discriminatory capacity for determination of FCF of all PRO tools studied (c-statistic 0.75 [CI 0.62, 0.88]), superior FCF discrimination was achieved when the KCCQ-12 was combined with all PRO tools (c-statistic 0.82 [CI 0.71, 0.93]). Conclusions: The KCCQ-12 questionnaire demonstrated good discriminatory capacity for the identification of FCF, which was further improved through the addition of complementary PRO tools. Further research will establish the value of PRO tools to guide management strategies in ACHD.

The Standard Model (SM) is a theory of fundamental particles and their interactions. Despite being a successful theory, the SM is unable to offer explanation for the existence of Dark matter (DM), matter-antimatter asymmetry, hierarchy problem, neutrino masses etc. Many models beyond the SM have evolved over the time to explain these limitations. One such model is Supersymmetry (SUSY) which has been proposed to solve these SM problems, and could also provide the DM candidate. A search for supersymmetric electroweakinos ( χ_1^± , χ_2^0 ) produced in the vector boson fusion (VBF) topology in proton-proton collisions at √(s)=13 TeV using the full Run 2 data collected by the Compact Muon Solenoid (CMS) detector at the Large Hadron Collider (LHC) is presented. The experimental features of VBF processes provide an increased sensitivity for compressed SUSY search, compared to traditional searches. The benchmark model for this search is the R-parity conserving Minimal Supersymmetric Standard Model (MSSM), where the lightest neutralino is the canonical dark matter candidate. This paper presents the search strategy, methodology, and the results on the background estimation using various control regions along with their validation.

Sarcomas represent the most common primary cardiac malignancy. A poor prognosis can be improved with multimodal management including aggressive surgical reconstruction in combination with neoadjuvant or adjuvant therapy. We present the case of a primary cardiac sarcoma to describe our approach to a more radical right atrial and bicaval reconstruction.

Undifferentiated cardiac tumors represent a diagnostic dilemma that requires meticulous workup. We present the case of a 67-year-old woman with a right atrial mass that was investigated with multiple modalities before being diagnosed as a cardiac lymphoma. The role of transvenous and/or percutaneous biopsy for guiding diagnosis and management is emphasized.

Negative trials comparing invasive cardiac procedures are remarkably fragile. The reporting of reverse fragility indices may help inform trial interpretation and application.

PURPOSE OF REVIEW:A growing number of adult patients with congenital heart disease (ACHD) are entering the healthcare system as a result of advances in the diagnosis and management of congenital heart defects. Heart failure is a common final pathway for this diverse patient population, representing the leading cause of mortality in ACHD patients. Herein, we review present guideline-directed management of heart failure in ACHD patients.RECENT FINDINGS:There exists a dearth of data to guide management of ACHD-related heart failure. Given this gap, recent guidelines have been limited in the recommendations they can provide for this patient population, with practitioners being consequently forced to generalize findings from studies of acquired heart disease patients based on mechanistic plausibility. The small number of studies directly assessing ACHD patients have been largely limited in their clinical relevance through being negative, small, observational, limited to specific subsets of ACHD patients or assessing nonvalidated outcomes.SUMMARY:Despite the prevalence and impact of ACHD-related heart failure, there are limited evidence-based therapies for its management. Given the rising burden of this clinical problem, definitive trials assessing newer therapies are required to establish their potential role in heart failure amongst ACHD patients.

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 43, No. 7Presence of Peripheral Artery Disease Is Associated With Increased Risk of Heart Failure Events: Insights From EMPEROR-Pooled Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBPresence of Peripheral Artery Disease Is Associated With Increased Risk of Heart Failure Events: Insights From EMPEROR-Pooled Subodh Verma, Nitish K. Dhingra, Marc P. Bonaca, Javed Butler, Stefan D. Anker, João Pedro Ferreira, Gerasimos Filippatos, James L. Januzzi, Carolyn S.P. Lam, Naveed Sattar, Tomoko Iwata, Matias Nordaby, Martina Brueckmann, Stuart J. Pocock, Milton Packer and on behalf of the EMPEROR Trials Committees and Investigators Subodh VermaSubodh Verma Correspondence to: Subodh Verma, MD, PhD, St. Michael’s Hospital, University of Toronto, 30 Bond St, Toronto, Ontario M5B 1W8, Canada. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4018-8533 Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Canada (S.V., N.K.D.). , Nitish K. DhingraNitish K. Dhingra Division of Cardiac Surgery, St. Michael’s Hospital, University of Toronto, Canada (S.V., N.K.D.). , Marc P. BonacaMarc P. Bonaca https://orcid.org/0000-0002-9860-3584 Division of Cardiology, CPC Clinical Research, University of Colorado School of Medicine, Aurora (M.P.B.). , Javed ButlerJaved Butler https://orcid.org/0000-0001-7683-4720 Baylor Scott and White Research Institute, Dallas, TX (J.B.). University of Mississippi, Jackson (J.B.). , Stefan D. AnkerStefan D. Anker https://orcid.org/0000-0002-0805-8683 Department of Cardiology (CVK) of German Heart Center Charité, Institute of Health Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK), partner site Berlin, Charité Universitätsmedizin, Germany (S.D.A.). , João Pedro FerreiraJoão Pedro Ferreira Université de Lorraine, Inserm, Centre d’Investigations Cliniques, Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France (J.P.F.). Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, [email protected], Cardiovascular Research and Development Center, Portugal (J.P.F.). Internal Medicine Department, Heart Failure Clinic, Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal (J.P.F.). , Gerasimos FilippatosGerasimos Filippatos https://orcid.org/0000-0002-5640-0332 , James L. JanuzziJames L. Januzzi https://orcid.org/0000-0002-8338-1798 National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Greece (G.F.). Division of Cardiology, Harvard Medical School and Massachusetts General Hospital, Boston (J.L.J.). , Carolyn S.P. LamCarolyn S.P. Lam https://orcid.org/0000-0003-1903-0018 National Heart Centre Singapore, Duke-NUS Medical School (C.S.P.L.). , Naveed SattarNaveed Sattar https://orcid.org/0000-0002-1604-2593 School of Cardiovascular and Metabolic Health, University of Glasgow, Scotland, United Kingdom (N.S.). , Tomoko IwataTomoko Iwata Boehringer Ingelheim Pharma GmbH and Co. KG, Biberach, Germany (T.I.). , Matias NordabyMatias Nordaby Boehringer Ingelheim International GmbH, Germany (M.N., M.B.). , Martina BrueckmannMartina Brueckmann https://orcid.org/0000-0003-1215-0746 Boehringer Ingelheim International GmbH, Germany (M.N., M.B.). First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Germany (M.B.). , Stuart J. PocockStuart J. Pocock Department of Medical Statistics, London School of Hygiene and Tropical Medicine, United Kingdom (S.J.P.). , Milton PackerMilton Packer https://orcid.org/0000-0003-1828-2387 Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX (M.P.). Imperial College, London, United Kingdom (M.P.). and on behalf of the EMPEROR Trials Committees and Investigators Originally published18 May 2023https://doi.org/10.1161/ATVBAHA.123.319156Arteriosclerosis, Thrombosis, and Vascular Biology. 2023;43:1334–1337Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 18, 2023: Ahead of Print While it is well established that peripheral artery disease (PAD) is associated with worsening major adverse cardiovascular events and major adverse limb events,1 the relationship between PAD in the context of heart failure (HF) is less well defined.2 To this aim, we performed a post hoc analysis of the EMPEROR-Pooled data set to evaluate outcomes of patients with HF across the spectrum of left ventricular ejection fraction by the presence or absence of PAD. We also studied the efficacy and safety of empagliflozin in people with coexistent HF and PAD.In EMPEROR-Pooled (n=9718), a total of 821 (8.4%) patients had PAD (261 in EMPEROR-Reduced [Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction] and 560 in EMPEROR-Preserved [Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction]) and 8897 patients did not (3469 in EMPEROR-Reduced and 5428 in EMPEROR-Preserved). Patients with PAD were more likely to be men (70.5% versus 62.6%), White (83.9% versus 72.9%), and older (72.2±8.3 versus 69.7±10.5 years). Patients with PAD were more symptomatic (median Kansas City Cardiomyopathy Questionnaire clinical summary scores [PAD, 68.8 versus no PAD, 75.0]; New York Heart Association class ≥III [PAD, 27.4% versus no PAD, 20.3%]) and were more likely to have ischemic HF (60.5% versus 39.9%), be previous/current smokers (65.0% versus 48.8%), as well as have diabetes (65.2% versus 47.9%), hypertension (90.6% versus 82.9%), and hypercholesterolemia (84.8% versus 62.9%). Left ventricular ejection fraction was similar in patients with and without PAD (45.6±14.5% versus 43.9±15.3%). Patients with PAD had higher systolic blood pressure (131.1±17.1 versus 127.8±16.3 mm Hg), lower eGFR (estimated glomerular filtration rate; 55.6±19.4 versus 61.7±20.6 mL/min per 1.73 m2), and a higher proportion of albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g, 51.0% versus 41.6%). With respect to background therapies, patients in both groups had similar rates of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor/neprilysin inhibitor (82.1% versus 83.7%) and β-blocker (90.5% versus 89.4%) use; however, mineralocorticoid receptor antagonist use was lower in the PAD group (43.1% versus 51.2%). Use of other antihypertensives including calcium channel blockers and renin inhibitors (30.1% versus 20.9%), lipid-lowering medications (86.0% versus 69.1%), and antiplatelet therapies (64.7% versus 48.3%) were higher among patients with PAD.In the pooled analyses, patients randomized to placebo with a history of PAD had an elevated risk of HF outcomes and mortality compared with people without PAD. Specifically, the hazard ratios for total hospitalizations for HF (HHF), cardiovascular death, all-cause mortality, and the composite of cardiovascular death and time to first HHF were higher in people with PAD (total HHF: HR, 1.51 [95% CI, 1.12–2.03]; P=0.007; time to cardiovascular death: HR, 1.40 [95% CI, 1.05–1.87]; P=0.02; time to all-cause mortality: HR, 1.42 [95% CI, 1.14–1.78]; P=0.002; time to first HHF or cardiovascular death: HR, 1.21 [95% CI, 0.98–1.49]; P=0.08). Renal outcomes, including slope of eGFR and the composite renal end point, were similar in both PAD and no-PAD patients randomized to placebo in the EMPEROR-Pooled, EMPEROR-Reduced, and EMPEROR-Preserved populations (not shown).The efficacy of empagliflozin on cardiorenal outcomes in EMPEROR-Pooled was consistent regardless of PAD history (Figure) (PAD: HR for total HHF, 0.64 [95% CI, 0.42–0.98] versus no PAD: HR for total HHF, 0.73 [95% CI, 0.63–0.84]; Pinteraction, 0.56). Since patients with PAD were at higher absolute risk, the associated absolute risk reductions for total HHF events was 6.0% amongst patients with PAD and 3.2% amongst those without PAD. The efficacy of empagliflozin was consistent across all other cardiovascular outcomes and concordant in both the EMPEROR-Reduced and EMPEROR-Preserved populations individually. In terms of patient-reported outcomes, empagliflozin increased the Kansas City Cardiomyopathy Questionnaire clinical summary scores by a similar magnitude irrespective of PAD status (adjusted mean difference in EMPEROR-Pooled at week 52: PAD, 2.82 [95% CI, 0.38–5.26]; no PAD, 1.46 [95% CI, 0.73–2.20]; Pinteraction, 0.30).Download figureDownload PowerPointFigure. Summary of major findings. Panel A displays end point data in EMPEROR-Pooled according to peripheral artery disease (PAD) versus no PAD history, and panel B displays mean cumulative function of total hospitalizations for heart failure (HHF) in both the placebo and empagliflozin groups by PAD versus no PAD history in EMPEROR-Pooled. EMPEROR-Pooled—a prospectively designed collective analysis of the EMPEROR-Reduced trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and a Reduced Ejection Fraction)3 and EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction)4—included 9718 patients with heart failure across the spectrum of left ventricular ejection fraction (LVEF). Patients were randomized to empagliflozin 10 mg or matching placebo. Outcomes assessed included total HHF, time to first HHF or cardiovascular (CV) death, time to first HHF, time to CV death, and all-cause mortality (ACM). An extended composite outcome of time to first CV death, HHF equivalent event, or intensification of diuretic therapy along with renal end points including the slope of eGFR (estimated glomerular filtration rate) change and a composite renal end point consisting of time to first event of sustained eGFR reduction of ≥50% or end-stage kidney disease (chronic dialysis/renal transplant or sustained eGFR <15 mL/min per 1.73 m2 for patients with baseline eGFR ≥30 mL/min per 1.73 m2 or sustained eGFR <10 mL/min per 1.73 m2 for patients with baseline eGFR <30 mL/min per 1.73 m2) or renal death were also presently analyzed. The Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-CSS), along with adverse events (AEs), were also assessed. The eGFR values presented are derived from the conventional CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, which utilizes serum creatinine and corrects for age, sex, and race. Institutional review board approval was obtained by each trial center, and informed consent was received from every participant. Baseline characteristics were compared between PAD and no-PAD patients using t tests for continuous variables and χ2 tests for categorical variables. Time-to-first event analyses were performed with a Cox proportional-hazards model, adjusted for age, sex, region (North America, Latin America, Europe, Asia, and Other), diabetes status (diabetes, prediabetes, no diabetes), eGFR at baseline, LVEF at baseline, and study. These analyses were performed according to the intention-to-treat principle for all randomized patients and included data up to the end of the planned treatment period. Event rates per 100 patient-years and adjusted hazard ratios are reported. Total (first and recurrent) HHF was evaluated accordingly with a joint frailty model that accounted for CV death, adjusted for the same covariates as the Cox model. Continuous end points were analyzed with the same covariates as the Cox model, in addition to visit by treatment by PAD status interaction and baseline value by visit interaction, in a mixed model with repeated measures. To assess the consistency of the treatment effects across PAD and no-PAD subgroups, subgroup-by-treatment interaction terms were added to the models. AEs were analyzed descriptively based on patients with events occurring during the on-treatment period (including 7 days after the last drug consumption by the patient); however, for lower limb amputations, all events up to study completion are shown.Placebo rates of safety outcomes were higher in people with PAD versus those without PAD in EMPEROR-Pooled, but there was no increase in those treated with empagliflozin compared with placebo (adverse events; PAD: empagliflozin, 89.2%; placebo, 89.1%; no PAD: empagliflozin, 81.5%; placebo, 82.9% and serious adverse events; PAD: empagliflozin, 56.0%; placebo, 62.9%; no PAD: empagliflozin, 44.4%; placebo, 49.1%). Rates of lower limb amputations were higher in people with PAD; however, rates were comparable in empagliflozin- versus placebo-treated patients (PAD: empagliflozin, 2.9%; placebo, 3.5%; no PAD: empagliflozin, 0.4%; placebo, 0.4%).In this large, contemporary cohort of patients with HF (with either reduced or preserved ejection fraction), we report a significantly elevated risk of HF outcomes among patients with PAD compared with those without PAD, including a ≈50% increase in total HHF and ≈40% increase in cardiovascular and all-cause mortality. While empagliflozin was efficacious in both populations, people with PAD had a higher absolute risk reduction on total HHF events compared with those without PAD. There was no excess in adverse events with empagliflozin in people with PAD, and specifically rates of lower limb amputations, which have been a previous concern with canagliflozin,5 were similar. These data underscore an important and previously underappreciated association of PAD with HF events.Data SharingTo ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE (International Committee of Medical Journal Editors) criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major regulatory authorities. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.Article InformationAffiliationsAcknowledgmentsThe authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors.Sources of FundingThis study was supported by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.Disclosures S. Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and speaking honoraria from Amarin, Amgen, AstraZeneca (AZ), Bayer, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Eli Lilly, EOCI Pharmacomm, Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk (NN), Sanofi, Sun Pharmaceuticals, PhaseBio, and the Toronto Knowledge Translation Working Group. He is a member of the Scientific Excellence Committee of the EMPEROR-Reduced trial and served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials. The salary of M.P. Bonaca is partially supported through funds from CPC—a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AZ, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women’s Hospital, BMS, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, NN, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group. He also reports stock in Medtronic and Pfizer and consulting fees from Audentes. J. Butler reports research support from the National Institutes of Health, Patient Centered Outcomes Research, and the European Union. He serves on the speakers’ bureau for Novartis, Janssen, and NN. He serves as a consultant and serves on the Steering Committee, Clinical Events Committee, or data safety monitoring boards for Abbott, Adrenomed, Amgen, Array, AZ, Bayer, Berlin-Cures, BI, BMS, Cardiocell, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, LinaNova, Luitpold, Medscape, Medtronic, Merck, Novartis, NN, Relypsa, Roche, Sanofi, Stealth-Peptide, SC Pharma, V-Wave, Ltd, Vifor, and ZS Pharma. S.D. Anker reports grants and personal fees from Vifor International and Abbott Vascular and personal fees from AZ, Bayer, Brahms, BI, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International. J. Pedro Ferreira is a consultant for BI. G. Filippatos reports lecture fees and committee member contributions in trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and BI and research support from the European Union. J.L. Januzzi is a Trustee of the American College of Cardiology; a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. C.S.P. Lam reports research support from Bayer, NN, and Roche Diagnostics; fees as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AZ, Bayer, BI, Boston Scientific, Cytokinetics, Darma, Inc, EchoNous, Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, NN, Prosciento, Inc, Radcliffe Group, Ltd, Recardio, Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and position as cofounder and nonexecutive director at Us2.ai. N. Sattar reports personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, NN, Pfizer, and Sanofi and grants and personal fees from AZ, BI, Novartis, and Roche Diagnostics. T. Iwata, M. Nordaby, and M. Brueckmann are employees of BI. S.J. Pocock is a consultant for BI. M. Packer reports personal fees from Abbvie, Actavis, Amarin, Amgen, AZ, BI, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. The other authors report no conflicts.FootnotesFor Sources of Funding and Disclosures, see page 1337.Correspondence to: Subodh Verma, MD, PhD, St. Michael’s Hospital, University of Toronto, 30 Bond St, Toronto, Ontario M5B 1W8, Canada. Email subodh.[email protected]toReferences1. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease.N Engl J Med. 2017; 377:1319–1330. doi: 10.1056/NEJMoa1709118CrossrefMedlineGoogle Scholar2. Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, Kuder J, Murphy SA, Jukema JW, Lewis BS, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).Circulation. 2018; 137:338–350. doi: 10.1161/CIRCULATIONAHA.117.032235LinkGoogle Scholar3. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.N Engl J Med. 2020; 383:1413–1424. doi: 10.1056/NEJMoa2022190CrossrefMedlineGoogle Scholar4. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Bohm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction.N Engl J Med. 2021; 385:1451–1461. doi: 10.1056/NEJMoa2107038CrossrefMedlineGoogle Scholar5. Matthews DR, Li Q, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Desai M, Hiatt WR, Nehler M, Fabbrini E, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS program.Diabetologia. 2019; 62:926–938. doi: 10.1007/s00125-019-4839-8CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails July 2023Vol 43, Issue 7 Advertisement Article InformationMetrics © 2023 The Authors.Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/ATVBAHA.123.319156PMID: 37199158 Originally publishedMay 18, 2023 Keywordsheart failureperipheral arterial diseasesodium-glucose transporter 2 inhibitorscreatininePDF download Advertisement SubjectsClinical Studies