BACKGROUND:Cardiogenic shock (CS) can be complicated by severe valvular heart disease (VHD). We analyzed cardiac intensive care unit (CICU) admissions according to VHD status. METHODS AND RESULTS:The Critical Care Cardiology Trials Network is a multicenter network of tertiary CICUs. Centers contributed data from consecutive admissions during 2-month annual snapshots from 2017-2023. CS admissions were classified as having CS attributed to VHD, CS with noncausative VHD or CS without severe VHD. Demographics and therapies were compared. Unadjusted and adjusted odds ratios for in-hospital mortality were calculated. We analyzed 5242 admissions with CS (4.1% attributed to VHD, 18.8% with noncausative VHD, 77.1% without severe VHD). Mitral regurgitation (32.1%) and aortic stenosis (27.9%) were the most common pathologies in CS attributed to VHD. Admissions with CS attributed to VHD more commonly had LVEF ≥ 40% on admission (present in 62.8%, 22.6% and 15.1%, respectively; P < 0.001). Valve intervention was performed in 32.1% of those with CS attributed to VHD. Unadjusted in-hospital mortality in admissions with CS attributed to VHD was 40.0%, compared to 33.4% and 30.3% in the other groups. CONCLUSIONS:VHD is the underlying cause of CS in a minority of CICU admissions but is associated with high in-hospital mortality rates.

For the last forty years in the United States, there has been a progressively widening disparity in cardiovascular disease (CVD) morbidity and mortality between rural and urban areas known as the “rural mortality penalty.” Drivers of rural-urban disparities in CVD are multifactorial, including differences in demographics, education, economic opportunity, access to care, and healthcare quality. Because of the complex and heterogenous nature of rural areas in the United States, definitions of rural vary significantly, leading to challenges in quantifying disparities and targeting interventions. Potential solutions to increase access to cardiovascular care in rural areas include initiatives to expand the primary care and cardiology workforces, build partnerships between rural healthcare providers and academic medical centers (AMC), establish more outreach clinics in underserved or poorly resourced rural communities, develop rural provider training programs, expand and improve telemedicine offerings, develop community wide CVD prevention programs, expand health insurance coverage in rural areas, continue government support of rural hospitals and address social determinants of health as rural populations often face higher rates of poverty, food insecurity, unemployment, housing instability, and limited access to education, all of which exacerbate health disparities.

Clinical practice in the contemporary cardiac intensive care unit (CICU) has evolved significantly over the last several decades. With more frequent multisystem organ failure, increasing use of advanced respiratory support, and the advent of new mechanical circulatory support platforms, clinicians in the CICU are increasingly managing patients with complex comorbid disease in addition to their high-acuity cardiovascular illnesses. Here, the authors discuss challenges associated with traditional trial design in the CICU setting and review novel clinical trial designs that may facilitate better evidence generation in the CICU.

BACKGROUND:Emulation of the "target trial" (TT), a hypothetical pragmatic randomized controlled trial (RCT), using observational data can be used to mitigate issues commonly encountered in comparative effectiveness research (CER) when randomized trials are not logistically, ethically, or financially feasible. However, cardiovascular (CV) health research has been slow to adopt TT emulation. Here, we demonstrate the design and analysis of a TT emulation using electronic health records to study the comparative effectiveness of the addition of a disease-modifying anti-rheumatic drug (DMARD) to a regimen of methotrexate on CV events among rheumatoid arthritis (RA) patients.METHODS:We used data from an electronic medical records-based cohort of RA patients from Northwestern Medicine to emulate the TT. Follow-up began 3 months after initial prescription of MTX (2000-2020) and included all available follow-up through June 30, 2020. Weighted pooled logistic regression was used to estimate differences in CVD risk and survival. Cloning was used to handle immortal time bias and weights to improve baseline and time-varying covariate imbalance.RESULTS:We identified 659 eligible people with RA with average follow-up of 46 months and 31 MACE events. The month 24 adjusted risk difference for MACE comparing initiation vs non-initiation of a DMARD was -1.47% (95% confidence interval [CI]: -4.74, 1.95%), and the marginal hazard ratio (HR) was 0.72 (95% CI: 0.71, 1.23). In analyses subject to immortal time bias, the HR was 0.62 (95% CI: 0.29-1.44).CONCLUSION:In this sample, we did not observe evidence of differences in risk of MACE, a finding that is compatible with previously published meta-analyses of RCTs. Thoughtful application of the TT framework provides opportunities to conduct CER in observational data. Benchmarking results of observational analyses to previously published RCTs can lend credibility to interpretation.

BACKGROUND:U.S. nationwide estimates of the proportion of patients newly diagnosed with heart failure with reduced ejection fraction (HFrEF) eligible for quadruple medical therapy, and the associated benefits of rapid implementation, are not well characterized. OBJECTIVES:This study sought to characterize the degree to which patients newly diagnosed with HFrEF are eligible for quadruple medical therapy, and the projected benefits of in-hospital initiation. METHODS:Among patients hospitalized for newly diagnosed HFrEF in the Get With The Guidelines-Heart Failure registry from 2016 to 2023, eligibility criteria based on regulatory labeling, guidelines, and expert consensus documents were applied for angiotensin receptor-neprilysin inhibitor, beta-blocker, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter 2 inhibitor therapies. Of those eligible, the projected effect of quadruple therapy on 12-month mortality was modeled using treatment effects from pivotal clinical trials utilized by the AHA/ACC/HFSA Guideline for the Management of Heart Failure, and compared with observed outcomes among patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blockers. RESULTS:Of 33,036 patients newly diagnosed with HFrEF, 27,158 (82%) were eligible for quadruple therapy, and 30,613 (93%) were eligible for ≥3 components. From 2021 to 2023, of patients eligible for quadruple therapy, 15.3% were prescribed quadruple therapy and 41.5% were prescribed triple therapy. Among Medicare beneficiaries eligible for quadruple therapy, 12-month incidence of mortality was 24.7% and HF hospitalization was 22.2%. Applying the relative risk reductions in clinical trials, complete implementation of quadruple therapy by time of discharge was projected to yield absolute risk reductions in 12-month mortality of 10.4% (number needed to treat = 10) compared with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, and 24.8% (number needed to treat = 4) compared with no GDMT. CONCLUSIONS:In this nationwide U.S. cohort of patients hospitalized for newly diagnosed HFrEF, >4 of 5 patients were projected as eligible for quadruple therapy at discharge; yet, <1 in 6 were prescribed it. If clinical trial benefits can be fully realized, in-hospital initiation of quadruple medical therapy for newly diagnosed HFrEF would yield large absolute reductions in mortality.

European Journal of Heart FailureEarly View Invited Editorial Implementation of sodium–glucose cotransporter 2 inhibitors for heart failure with reduced ejection fraction: Where we are versus where we need to be Jacob B. Pierce, Jacob B. Pierce Department of Medicine, Duke University School of Medicine, Durham, NC, USASearch for more papers by this authorJaved Butler, Javed Butler Baylor Scott and White Research Institute, Dallas, TX, USA Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USASearch for more papers by this authorStephen J. Greene, Corresponding Author Stephen J. Greene [email protected] Division of Cardiology, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Durham, NC, USA Corresponding author. Duke Clinical Research Institute, 300 West Morgan Street, Durham, NC 27701, USA. Tel: +1 919 684-8111, Fax: +1 919 668-7078, Email: [email protected]Search for more papers by this author Jacob B. Pierce, Jacob B. Pierce Department of Medicine, Duke University School of Medicine, Durham, NC, USASearch for more papers by this authorJaved Butler, Javed Butler Baylor Scott and White Research Institute, Dallas, TX, USA Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USASearch for more papers by this authorStephen J. Greene, Corresponding Author Stephen J. Greene [email protected] Division of Cardiology, Duke University School of Medicine, Durham, NC, USA Duke Clinical Research Institute, Durham, NC, USA Corresponding author. Duke Clinical Research Institute, 300 West Morgan Street, Durham, NC 27701, USA. Tel: +1 919 684-8111, Fax: +1 919 668-7078, Email: [email protected]Search for more papers by this author First published: 15 August 2023 https://doi.org/10.1002/ejhf.2999 The opinions expressed in this article are not necessarily those of the Editors of the European Journal of Heart Failure or of the European Society of Cardiology. doi: 10.1002/ejhf.2971. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat References 1McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al.; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2022; 24: 4–131. https://doi.org/10.1002/ejhf.2333 2Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022; 79: e263–e421. https://doi.org/10.1016/j.jacc.2021.12.012 3Hussain A, Ramsey D, Lee M, Mahtta D, Khan MS, Nambi V, et al. Utilization rates of SGLT2 inhibitors among patients with type 2 diabetes, heart failure, and atherosclerotic cardiovascular disease: Insights from the Department of Veterans Affairs. JACC Heart Fail 2023; 11: 933–942. https://doi.org/10.1016/j.jchf.2023.03.024 4Pierce JB, Vaduganathan M, Fonarow GC, Ikeaba U, Chiswell K, Butler J, et al. Contemporary use of sodium-glucose cotransporter-2 inhibitor therapy among patients hospitalized for heart failure with reduced ejection fraction in the US: The Get With The Guidelines-Heart Failure Registry. JAMA Cardiol 2023; 8: 652–661. https://doi.org/10.1001/jamacardio.2023.1266 5Greene SJ, Pierce JB. Overcoming barriers to use of SGLT2 inhibitor therapy: The battle against clinical inertia. JACC Heart Fail 2023; 11: 943–945. https://doi.org/10.1016/j.jchf.2023.05.006 6Stolfo D, Lund LH, Benson L, Lindberg F, Ferrannini G, Dahlström U, et al. Real-world use of sodium-glucose cotransporter 2 inhibitors in patients with heart failure and reduced ejection fraction: Data from the Swedish Heart Failure Registry. Eur J Heart Fail. https://doi.org/10.1002/ejhf.2971 Published online ahead of print 07/07/23. 7Lund LH, Carrero JJ, Farahmand B, Henriksson KM, Jonsson Å, Jernberg T, et al. Association between enrolment in a heart failure quality registry and subsequent mortality – A nationwide cohort study. Eur J Heart Fail 2017; 19: 1107–1116. https://doi.org/10.1002/ejhf.762 8Savarese G, Kishi T, Vardeny O, Adamsson Eryd S, Bodegård J, Lund LH, et al. Heart failure drug treatment – Inertia, titration, and discontinuation: A multinational observational study (EVOLUTION HF). JACC Heart Fail 2023; 11: 1–14. https://doi.org/10.1016/j.jchf.2022.08.009 9Harrington J, Fonarow GC, Khan MS, Hernandez A, Anker S, Böhm M, et al. Medication-attributable adverse events in heart failure trials. JACC Heart Fail 2023; 11: 425–436. https://doi.org/10.1016/j.jchf.2022.11.026 10McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al.; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381: 1995–2008. https://doi.org/10.1056/NEJMoa1911303 11Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383: 1413–1424. https://doi.org/10.1056/NEJMoa2022190 12Khan MS, Butler J, Greene SJ. The time is now for sodium glucose co-transporter 2 inhibitors for heart failure: A call to overcome clinical inertia. Circ Heart Fail 2020; 13:e008030. https://doi.org/10.1161/CIRCHEARTFAILURE.120.008030 13Greene SJ, Butler J, Fonarow GC. Contextualizing risk among patients with heart failure. JAMA 2021; 326: 2261–2262. https://doi.org/10.1001/jama.2021.20739 14Ferreira JP, Zannad F, Pocock SJ, Anker SD, Butler J, Filippatos G, et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Coll Cardiol 2021; 77: 1397–1407. https://doi.org/10.1016/j.jacc.2021.01.044 15Greene SJ, Khan MS. Quadruple medical therapy for heart failure: Medications working together to provide the best care. J Am Coll Cardiol 2021; 77: 1408–1411. https://doi.org/10.1016/j.jacc.2021.02.006 Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Importance:Prior studies have suggested patients with heart failure (HF) from rural areas have worse clinical outcomes. Contemporary differences between rural and urban hospitals in quality of care and clinical outcomes for patients hospitalized for HF remain poorly understood.Objective:To assess quality of care and clinical outcomes for US patients hospitalized for HF at rural vs urban hospitals.Design, Setting, and Participants:This retrospective cohort study analyzed 774 419 patients hospitalized for HF across 569 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between January 1, 2014, and September 30, 2021. Postdischarge outcomes were assessed in a subset of 161 996 patients linked to Medicare claims. Data were analyzed from August 2022 to January 2023.Main Outcomes and Measures:GWTG-HF quality measures, in-hospital mortality, length of stay, and 30-day mortality and readmission outcomes.Results:This study included 19 832 patients (2.6%) and 754 587 patients (97.4%) hospitalized at 49 rural hospitals (8.6%) and 520 urban hospitals (91.4%), respectively. Of 774 419 included patients, 366 161 (47.3%) were female, and the median (IQR) age was 73 (62-83) years. Compared with patients at urban hospitals, patients at rural hospitals were older (median [IQR] age, 74 [64-84] years vs 73 [61-83] years; standardized difference, 10.63) and more likely to be non-Hispanic White (14 572 [73.5%] vs 498 950 [66.1%]; standardized difference, 34.47). In adjusted models, patients at rural hospitals were less likely to be prescribed cardiac resynchronization therapy (adjusted risk difference [aRD], -13.5%; adjusted odds ratio [aOR], 0.44; 95% CI, 0.22-0.92), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (aRD, -3.7%; aOR, 0.71; 95% CI, 0.53-0.96), and an angiotensin receptor-neprilysin inhibitor (aRD, -5.0%; aOR, 0.68; 95% CI, 0.47-0.98) at discharge. In-hospital mortality was similar between rural and urban hospitals (460 of 19 832 [2.3%] vs 20 529 of 754 587 [2.7%]; aOR, 0.86; 95% CI, 0.70-1.07). Patients at rural hospitals were less likely to have a length of stay of 4 or more days (aOR, 0.75; 95% CI, 0.67-0.85). Among Medicare beneficiaries, there were no significant differences between rural and urban hospitals in 30-day HF readmission (adjusted hazard ratio [aHR], 1.03; 95% CI, 0.90-1.19), all-cause readmission (aHR, 0.97; 95% CI, 0.91-1.04), and all-cause mortality (aHR, 1.05; 95% CI, 0.91-1.21).Conclusions and Relevance:In this large contemporary cohort of US patients hospitalized for HF, care at rural hospitals was independently associated with lower use of some guideline-recommended therapies at discharge and shorter length of stay. In-hospital mortality and 30-day postdischarge outcomes were similar at rural and urban hospitals.

Introduction: The safety of chest compressions (CC) during cardiopulmonary resuscitation (CPR) among pts with a durable left ventricular assist device (LVAD) is an area of controversy. Concerns regarding device malfunction or dislodgment with CC may result in significant delays or the withholding of life-sustaining intervention entirely. Current societal guidelines, based on small case reports, suggest that manual CC are probably not harmful, but offer no additional guidance. Furthermore, they acknowledge that there are no data regarding the use of machine-assisted CC. Methods: We retrospectively reviewed medical records of consecutive pts who underwent durable LVAD implantation at Duke University from 2013-2022. Charts were searched for “code”, “arrest”, “compressions”, and “rapid response team” to identify all instances of cardiac arrest (CA). Baseline pt characteristics, details of the arrest (including CC details), in-hospital care processes, and pt outcomes were abstracted. Results: Of 750 pts reviewed, 58 (mean age 64 years, 76% male, median LVAD support duration 19 months) had documented CA. Fifteen (26%) pts presented with an out-of-hospital CA. Twenty-four (41%) pts did not receive CC. The most commonly reported reason for avoiding CC was “LVAD in place - contraindicated.” The CPR duration was longer among those who received CC (median 30mins, range: 1-120 mins) than those who did not (median 20 mins, range: 2-79 mins). Two pts had support from a Lund University Cardiac Assist System (LUCAS) device. Among those who survived either manual and machine-assisted CC, 27% had a post-arrest TTE and none showed evidence of LVAD malfunction/dislodgment. Conclusions: Among pts with a durable LVAD who underwent CPR for CA we found no evidence of device dislodgment or safety concerns associated with either manual or LUCAS-assisted CPR. Future multicenter and prospective evaluation is necessary to both confirm these findings and to inform the guidelines.

Introduction: Little is known about the characteristics & outcomes of patients (pts) with significant valvular heart disease (VHD) and cardiogenic shock (CS). In addition, differences between pts with CS due to VHD vs VHD as “bystander” to CS have not been described. Methods: The Critical Care Cardiology Trials Network is a multicenter network of CICUs in North America coordinated by the TIMI Study Group. Participating centers capture all CICU admissions for 2 months annually. Pts with CS and significant VHD were classified as having CS due to VHD or CS with concomitant VHD not felt to be the cause of CS. Admissions from 2017 - 2021 were analyzed. Results: Of 3,974 CICU admissions with CS, 165 (4.2%) had CS due to VHD and 769 (19.4%) had CS with concomitant VHD. Pts with CS due to VHD were older (71 vs 67 y), less commonly had a hx of HF (47.3% vs 73.1%), & more commonly had LVEF>50% on admission (51.5% vs 16.8%); p<0.001 for all. Resource use varied significantly (Fig). Nearly 1/3 of pts (30.3%) with CS due to VHD underwent surgical/transcatheter valve procedures during CICU admission, contrasting with those with CS and concomitant VHD (13.5%; p<0.001). In-hospital mortality was similar between the 2 VHD groups (39.4% vs 33.8%, p=0.17). In-hospital mortality for allcomers with CS and VHD (concomitant or causative) was higher than in those with CS and no VHD (34.8% vs 29.7%; p=0.003), including adjusted for age, sex, SOFA score, and pre-CICU cardiac arrest (aOR 1.23; 1.03-1.47). Mortality was numerically lower in pts undergoing a valve procedure (23.4% died; 16% with CS due to VHD, 26.9% with CS and concomitant VHD; p=0.13), compared to pts who did not (37.1% overall; 49.6% & 34.9%, respectively; p=0.003). Conclusions: Although VHD is the primary cause of CS in a minority of pts, the presence of significant VHD is associated with higher mortality. In contemporary CICUs, procedural intervention is undertaken in ~1/3 of cases and mortality was numerically lower in pts who underwent valve procedures.

Introduction: Among patients hospitalized for HF, patients hospitalized with worsening chronic heart failure (WCHF) are at increased risk for morbidity and mortality compared with those who are recently diagnosed with HF. Whether there are differences in clinical course during hospitalization for HF is unclear. Methods: We pooled 735 participants hospitalized for HF in the DOSE, CARRESS, and ROSE trials. We grouped participants by whether HF was recently diagnosed (≤12 months) or WHCF (>12 months). We compared changes in congestion, kidney function, and symptoms during hospitalization, as well as early post-discharge kidney and mortality outcomes. Results: Overall, 132 (18%) had recently diagnosed HF and 603 (82%) had WCHF. Compared with WCHF, patients with recently diagnosed HF tended to have lower serum creatinine and higher systolic blood pressure, ejection fraction, and serum NT-proBNP (all p<0.05). In the first 72 hours, changes in body weight, global well-being visual analog scale, serum creatinine, and serum NT-proBNP, as well as net fluid loss were similar between patients with recently diagnosed versus WCHF (all p>0.15) ( Figure ). Recently diagnosed HF showed improved dyspnea at 72 hours (p=0.03). There was no difference in change in serum creatinine from baseline to 60 days (p=0.75). There was a trend toward significantly increased odds of mortality during study follow-up (adjusted odds ratio 1.96 [95% confidence interval 0.97-3.94], p=0.06). Conclusion: Patients hospitalized for recently diagnosed and WCHF have generally similar in-hospital clinical trajectories, and similar changes in kidney function early post-discharge. Despite these similarities and adjustment for other clinical factors, patients with WCHF remain at increased risk for post-discharge mortality as compared with patients who are more recently diagnosed.

Importance:Clinical guidelines for patients with heart failure with reduced ejection fraction (HFrEF) strongly recommend treatment with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) to reduce cardiovascular mortality or HF hospitalization. Nationwide adoption of SGLT2i for HFrEF in the US is unknown.Objective:To characterize patterns of SGLT2i use among eligible US patients hospitalized for HFrEF.Design, Setting, and Participants:This retrospective cohort study analyzed 49 399 patients hospitalized for HFrEF across 489 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry between July 1, 2021, and June 30, 2022. Patients with an estimated glomerular filtration rate less than 20 mL/min/1.73 m2, type 1 diabetes, and previous intolerance to SGLT2i were excluded.Main Outcomes and Measures:Patient-level and hospital-level prescription of SGLT2i at hospital discharge.Results:Of 49 399 included patients, 16 548 (33.5%) were female, and the median (IQR) age was 67 (56-78) years. Overall, 9988 patients (20.2%) were prescribed an SGLT2i. SGLT2i prescription was less likely among patients with chronic kidney disease (CKD; 4550 of 24 437 [18.6%] vs 5438 of 24 962 [21.8%]; P < .001) but more likely among patients with type 2 diabetes (T2D; 5721 of 21 830 [26.2%] vs 4262 of 27 545 [15.5%]; P < .001) and those with both T2D and CKD (2905 of 12 236 [23.7%] vs 7078 vs 37 139 [19.1%]; P < .001). Patients prescribed SGLT2i therapy were more likely to be prescribed background triple therapy with an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, β-blocker, and mineralocorticoid receptor antagonist (4624 of 9988 [46.3%] vs 10 880 of 39 411 [27.6%]; P < .001), and 4624 of 49 399 total study patients (9.4%) were discharged with prescriptions for quadruple medical therapy including SGLT2i. Among 461 hospitals with 10 or more eligible discharges, 19 hospitals (4.1%) discharged 50% or more of patients with prescriptions for SGLT2i, whereas 344 hospitals (74.6%) discharged less than 25% of patients with prescriptions for SGLT2i (including 29 [6.3%] that discharged zero patients with SGLT2i prescriptions). There was high between-hospital variance in the rate of SGLT2i prescription in unadjusted models (median odds ratio, 2.53; 95% CI, 2.36-2.74) and after adjustment for patient and hospital characteristics (median odds ratio, 2.51; 95% CI, 2.34-2.71).Conclusions and Relevance:In this study, prescription of SGLT2i at hospital discharge among eligible patients with HFrEF was low, including among patients with comorbid CKD and T2D who have multiple indications for therapy, with substantial variation among US hospitals. Further efforts are needed to overcome implementation barriers and improve use of SGLT2i among patients with HFrEF.

Long noncoding RNAs (lncRNAs) have emerged as critical regulators of cellular functions including maintenance of cellular homeostasis as well as the onset and progression of disease. LncRNAs often exhibit cell-, tissue-, and disease-specific expression patterns, making them desirable therapeutic targets. LncRNAs are commonly targeted using oligonucleotide therapeutics, and advances in oligonucleotide chemistry including C2 ribose sugar modifications such as 2'-fluoro, 2'-O-methyl, and 2-O-methoxyethyl modifications; 2'4'-constrained nucleotides such as locked nucleic acids and constrained 2'-O-ethyl (cEt) nucleotides; and phosphorothioate bonds have dramatically improved efficacy of oligonucleotide therapies. Novel delivery platforms such as viral vectors and nanoparticles have also improved pharmacokinetic properties of oligonucleotides targeting lncRNAs. Accumulating pre-clinical studies have utilized these strategies to therapeutically target lncRNAs and alter progression of many different disease states including Snhg12 and Chast in cardiovascular disease, Mirt2 and HOTTIP in sepsis and autoimmune disease, and Malat1 and HOXB-AS3 in cancer. Emerging oligonucleotide conjugation methods including the use of peptide nucleic acids hold promise to facilitate targeting to specific tissue types. Here, we review recent advances in lncRNA therapeutics and provide examples of how lncRNAs have been successfully targeted in pre-clinical models of disease. Finally, we detail remaining challenges facing the lncRNA field and how advances in delivery platforms and oligonucleotide chemistry might help overcome these barriers to catalyze the translation of pre-clinical studies to successful pharmaceutical development.

HomeCirculation: Heart FailureVol. 16, No. 1Adoption of Sacubitril/Valsartan Among Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The Get With The Guidelines-Heart Failure Registry Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBAdoption of Sacubitril/Valsartan Among Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: The Get With The Guidelines-Heart Failure Registry Jacob B. Pierce, Zhen Li, Melissa A. Greiner, Steven J. Lippmann, N. Chantelle Hardy, Xian Shen, Mark Stampehl, Robert J. Mentz, Larry A. Allen, Pamela N. Peterson, Gregg C. Fonarow, Emily C. O’Brien and Stephen J. Greene Jacob B. PierceJacob B. Pierce Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Zhen LiZhen Li Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Melissa A. GreinerMelissa A. Greiner https://orcid.org/0000-0002-3614-5602 Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Steven J. LippmannSteven J. Lippmann Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , N. Chantelle HardyN. Chantelle Hardy Department of Population Health Sciences (Z.L., M.A.G., S.J.L., N.C.H.), Duke University School of Medicine, Durham, NC. Search for more papers by this author , Xian ShenXian Shen Novartis Pharmaceuticals Corporation, East Hanover, NJ (X.S., M.S.). Search for more papers by this author , Mark StampehlMark Stampehl https://orcid.org/0000-0001-5001-9613 Novartis Pharmaceuticals Corporation, East Hanover, NJ (X.S., M.S.). Search for more papers by this author , Robert J. MentzRobert J. Mentz https://orcid.org/0000-0002-3222-1719 Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (R.J.M., E.C.O., S.J.G.). Search for more papers by this author , Larry A. AllenLarry A. Allen https://orcid.org/0000-0003-2540-3095 Palliative and Advanced Illness Research, Center and Department of Medicine, Pennsylvania Perelman School of Medicine, Philadelphia (L.A.A.). Search for more papers by this author , Pamela N. PetersonPamela N. Peterson https://orcid.org/0000-0001-6864-2016 Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora (P.N.P.). Division of Cardiology, Denver Health Hospital, CO (P.N.P.). Search for more papers by this author , Gregg C. FonarowGregg C. Fonarow https://orcid.org/0000-0002-3192-8093 Department of Medicine, University of California Los Angeles (G.C.F.). Search for more papers by this author , Emily C. O’BrienEmily C. O’Brien https://orcid.org/0000-0002-8257-7561 Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (R.J.M., E.C.O., S.J.G.). Search for more papers by this author and Stephen J. GreeneStephen J. Greene Correspondence to: Stephen J. Greene, MD, Duke Clinical Research Institute, 300 West Morgan St, Durham, NC 27701. Email E-mail Address: [email protected] https://orcid.org/0000-0001-6912-7374 Department of Medicine (J.B.P., R.J.M., E.C.O., S.J.G.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute, Durham, NC (R.J.M., E.C.O., S.J.G.). Search for more papers by this author Originally published31 Oct 2022https://doi.org/10.1161/CIRCHEARTFAILURE.122.010176Circulation: Heart Failure. 2023;16Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 31, 2022: Ahead of Print In February 2021, the US Food and Drug Administration (FDA) expanded the indication for the angiotensin receptor/neprilysin inhibitor sacubitril/valsartan beyond heart failure (HF) with reduced ejection fraction (EF) to newly include HF with mildly reduced (HFmrEF) or with preserved ejection fraction (HFpEF) based on results from the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor/Neprilysin Inhibitor [ARNI] With ARB Global Outcomes in HF With Preserved Ejection Fraction).1 The indication noted “benefits are most clearly evident among patients with left ventricular ejection fraction below normal,” phrasing that could be reasonably interpreted as EF ≤60%.2 However, nationwide trends in use of sacubitril/valsartan among patients with HFmrEF and HFpEF and the impact of FDA label expansion on adoption of sacubitril/valsartan remain unknown. In this study, we leveraged the American Heart Association’s Get With The Guidelines-Heart Failure registry to investigate temporal trends and patient characteristics associated with discharge prescription of sacubitril/valsartan among patients hospitalized for HF with EF 41% to 60% before and after FDA label expansion.We identified US patients hospitalized for HF in the Get With The Guidelines-Heart Failure registry with an EF 41% to 60% who were discharged alive between January 2016 and December 2021. EF was recorded quantitatively in the Get With The Guidelines-Heart Failure case report form, and represented the most recent value (ie, during index admission or prior). Patients were excluded if missing data on sacubitril/valsartan prescription at discharge, left against medical advice, transferred to an acute care facility, discharged to hospice, or had a history of heart transplantation, left ventricular assist device, or dialysis.We compared patient characteristics between those who were and were not prescribed sacubitril/valsartan at discharge using χ2 and Wilcoxon rank sum tests, as appropriate. We also calculated the percentage of patients prescribed sacubitril/valsartan for each quarter of the study period and tested for differences in the rate of sacubitril/valsartan prescription before and after FDA label expansion (landmark set as March 1, 2021 after FDA announcement February 2021). Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc). P<0.05 was considered statistically significant. The Duke University Health System Institutional Review Board approved this study.Among 148 762 hospitalizations for patients with EF 41% to 60% across 406 hospitals, 3001 (2.0%) included a prescription for sacubitril/valsartan at discharge. After FDA label expansion, discharge prescription of sacubitril/valsartan among patients with EF 41% to 60% more than doubled compared with earlier years (4.3% versus 1.6%; P<0.001), but absolute rates remained low (Figure [A]). Higher discharge prescription was concentrated at select hospitals, and 20.8% of hospitals had 0 prescriptions (Figure [B]).Download figureDownload PowerPointFigure. Discharge prescription of sacubitril/valsartan, among patients hospitalized for heart failure with ejection fraction 41% to 60% in the Get With The Guidelines-Heart Failure (GWTG-HF) registry (January 2016–December 2021). A, The quarterly rates of sacubitril/valsartan prescription among eligible HF patients. Publication of the PARAGON-HF trial is denoted by the red line (Quarter 4, 2019), and US Food and Drug Administration (FDA) label expansion is denoted by the blue line (Quarter 1, 2021). B, Details of the hospital-level variation in discharge prescription of sacubitril/valsartan among eligible hospital discharges. Data reflect only those hospitals contributing ≥10 eligible discharges, which was 371 (91.4%) of the 406 total hospitals in this analysis. C, Characteristics of eligible patients discharged with vs without prescriptions for sacubitril/valsartan. Data on discharge prescription of SGLT2i were missing for 68.9% and 86.2% of patients discharged with and without sacubitril/valsartan prescriptions, respectively. HFmrEF indicates heart failure with mildly reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; PARAGON-HF, Prospective Comparison of Angiotensin Receptor/Neprilysin Inhibitor (ARNI) With ARB Global Outcomes in HF With Preserved Ejection Fraction; and SGLT2i, sodium-glucose cotransporter-2 inhibitors.Patients prescribed sacubitril/valsartan were more likely to be younger (median 72 versus 76 years; P<0.001) and privately insured, and less likely to be female and of White race (Figure [C]). Median EF was lower among patients prescribed sacubitril/valsartan (48% versus 55%; P<0.001), and the proportion of patients with HFmrEF (EF 41–49%) was higher (53.0% versus 24.3%; P<0.001). Those prescribed sacubitril/valsartan had lower systolic blood pressure (median 123 versus 127 mm Hg; P<0.001), lower serum creatinine (median 1.2 versus 1.3 mg/dL; P<0.001), and higher rates of ischemic HF etiology (31.6% versus 27.2%; P<0.001) and diabetes (53.8% versus 49.4%; P<0.001). Concurrent prescription of mineralocorticoid receptor antagonist (31.8% versus 15.4%; P<0.001), and sodium/glucose cotransporter-2 inhibitor (19.7% versus 6.3%; P<0.001) therapies were also higher among patients prescribed sacubitril/valsartan. Among patients not prescribed sacubitril/valsartan, 40.3% were prescribed an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Patients prescribed sacubitril/valsartan before (n=2030) versus after FDA label expansion (n=971) were similar, with exception of patients prescribed after label expansion being younger (median 72 versus 73 years; P=0.04), less likely to be White (61.5% versus 69.6%; P<0.001), and more likely to have private insurance (88.2% versus 47.6%; P<0.001).Among US patients hospitalized for HF with EF 41% to 60%, patients prescribed sacubitril/valsartan had a distinct clinical profile and were more likely to have HFmrEF than HFpEF. Although the rate of sacubitril/valsartan prescription significantly increased following FDA label expansion, overall adoption of sacubitril/valsartan among patients with EF 41% to 60% remains low and concentrated at select hospitals.Limitations of this study should be noted. Admission medication data were limited, precluding assessment of in-hospital initiation versus in-hospital continuation of sacubitril/valsartan. Likewise, serial EF data were unavailable, and the degree to which these patterns of use include continuation of sacubitril/valsartan among patients with formerly reduced (and now recovered) EF is unknown.When considering EF ≤60% as below normal, a prior analysis estimated that expanded FDA labeling would increase the US population potentially eligible for sacubitril/valsartan by 1.8 million individuals.2 Likewise, compared with valsartan, complete implementation of sacubitril/valsartan among US patients with EF 41% to 60% would be projected to incrementally prevent or postpone >180 000 worsening HF events.2 Despite these potential benefits, our findings demonstrate slow early adoption of sacubitril/valsartan among patients with HFmrEF and HFpEF. Similar delays in implementation of sacubitril/valsartan were previously observed after initial FDA approval for patients with HFrEF.3 Given that patients with HFmrEF and HFpEF continue to face substantial risk of worsening HF and associated morbidity, continued efforts are needed to improve use and access to sacubitril/valsartan in this population.Article InformationSources of FundingThis study was funded by Novartis Pharmaceuticals Corporation (East Hanover, NJ). The Get With The Guidelines-Heart Failure program is provided by the American Heart Association and sponsored, in part, by Novartis, the Boehringer Ingelheim and Eli Lilly Diabetes Alliance, Novo Nordisk, Sanofi, AstraZeneca, and Bayer.Disclosures Drs Shen and Stempehl are employees of Novartis Pharmaceuticals Corporation (East Hanover, NJ). Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. Dr Allen has received grant funding from the National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Agency for Healthcare Research and Quality, and the American Heart Association; and consultant fees from ACI Clinical, Boston Scientific, Cytokinetics, and Novartis. Dr Peterson reports research support from the National Heart, Lung, and Blood Insititute. Dr Fonarow reports consulting for Abbott, Amgen, AstraZeneca, Bayer, Cytokinetics, Janssen, Medtronic, Merck, and Novartis. Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, the American Heart Association (929502), the National Heart, Lung, and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck & Co Inc, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim/Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, and Sanofi; serves as a consultant for Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim/Lilly, Corteria Pharmaceuticals, CSL Vifor, Merck, PharmaIN, Roche Diagnostics, Sanofi, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim and Cytokinetics. All other authors report no disclosures.FootnotesThis work was presented as an abstract at the American Heart Association Scientific Sessions, November 5–7, 2022, Chicago, IL.This article was sent to Prof John J.V. McMurray, MB, ChB, MD, Guest Editor, for review by expert referees, editorial decision, and final disposition.For Sources of Funding and Disclosures, see page 107.Correspondence to: Stephen J. Greene, MD, Duke Clinical Research Institute, 300 West Morgan St, Durham, NC 27701. Email stephen.[email protected].eduReferences1. Solomon SD, McMurray JJ, Anand IS, Ge J, Lam CS, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.N Engl J Med. 2019; 381:1609–1620. doi: 10.1056/NEJMoa1908655CrossrefMedlineGoogle Scholar2. Vaduganathan M, Claggett BL, Greene SJ, Aggarwal R, Bhatt AS, McMurray JJV, Fonarow GC, Solomon SD. Potential implications of expanded US Food and Drug Administration labeling for sacubitril/valsartan in the US.JAMA Cardiol. 2021; 6:1415–1423. doi: 10.1001/jamacardio.2021.3651CrossrefMedlineGoogle Scholar3. Luo N, Fonarow GC, Lippmann SJ, Mi X, Heidenreich PA, Yancy CW, Greiner MA, Hammill BG, Hardy NC, Turner SJ, et al. Early adoption of sacubitril/valsartan for patients with heart failure with reduced ejection fraction: insights from Get With the Guidelines–Heart Failure (GWTG-HF).J Am Coll Cardiol HF. 2017; 5:305–309. doi: 10.1016/j.jchf.2016.12.018CrossrefGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 2023Vol 16, Issue 1 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.122.010176PMID: 36314141 Originally publishedOctober 31, 2022 Keywordsheart failuresacubitril/valsartanejection fractionPDF download Advertisement SubjectsCardiomyopathyQuality and Outcomes

Background Clinical guidelines recommend titration of angiotensin converting enzyme inhibitors (ACEi) and betablockers among patients with heart failure with reduced ejection fraction (HFrEF) to maximally tolerated doses. Patient characteristics associated with dose titration and clinical outcomes subsequent to dose titration remain poorly characterized. Methods Among 1999 ambulatory patients with chronic HFrEF in the HF-ACTION trial, use and dosing of ACEi and evidence-based beta-blockers were examined at baseline and 6-month follow-up. Multivariable logistic regression models were used to assess factors associated with dose escalation (medication initation or dosing increase) or dose de-escalation (medication discontinuation or dosing decrease). Cox proportional hazard regression models were used to examine associations between dose trajectory group (stable target, stable sub-target, dose escalation, and dose de-escalation) and subsequent mortality and hospitalization outcomes. Results For both ACEi and beta-blockers, hospitalization for heart failure in the 6 months prior to enrollment (odds ratio [OR] 2.32 [95% confidence interval 1.58-3.42]) for ACEi; 1.42 [1.05-1.9] for beta-blockers) and higher systolic blood pressure (OR 1.01 [1.00-1.03] per 1 mmHg increase for ACEi; 1.01 [1.00-1.02] for beta-blockers) were associated with dose escalation. Hospitalization 6 months prior to enrollment for any cause (including HF or non-HF causes) was associated with dose de-escalation (OR 1.60 [1.14-2.25] for ACEi; 1.67 [1.20-2.33] for beta-blockers). After adjustment for patient characteristics, compared with stable target dosing, dose de-escalation of either medication was associated with greater allcause mortality (adjusted hazard ratio [aHR] 1.64 [1.11-2.42] for ACEi; 1.62 [1.04-2.53] for beta-blockers). Compared with stable target dosing, both dose de-escalation (aHR 1.98 [1.36-2.87]) and stable sub-target dosing (aHR 1.49 [1.18-1.87]) of beta-blockers were associated with greater cardiovascular mortality or hospitalization for heart failure. Conclusions Among outpatients with chronic HFrEF, patient characteristics including recent hospitalization status and blood pressure were associated with odds of subsequent escalation and de-escalation of ACEi and beta-blocker therapy. Compared with patients receiving guildeline-recommended target doses, dose de-escalation of either medication and subtarget dosing of beta-blockers were associated with greater morbidity and mortality over long-term follow-up. (Am Heart J 2022;251:115-126.)

Introduction: In February 2021, the US FDA expanded the indication for sacubitril/valsartan (S/V) to include patients with heart failure (HF) with mildly reduced (HFmrEF) or preserved ejection fraction (HFpEF), with benefits most evident among patients with EF below normal. However, the adoption of S/V among patients with EF >40% in US clinical practice is unknown. Methods: We identified hospitalizations for HF in the AHA Get With The Guidelines®-Heart Failure registry between January 2016 and December 2021 among patients with EF >40% to 60%, and not receiving dialysis. We evaluated prescription of S/V at discharge, and compared patient characteristics among those prescribed and not prescribed S/V. We also assessed temporal trends in S/V discharge prescription before and after FDA label expansion. We considered prescriptions of S/V on or after March 1, 2021, to have occurred after FDA label expansion. Results: Among 151,763 hospitalizations for patients with EF >40-60%, 3,001 (2.0%) included a prescription for S/V at discharge. Patients prescribed S/V were more likely to be younger, male, Black race, and privately insured compared with those not prescribed S/V (Figure, Panel A). Those prescribed S/V had lower EF (median 48% [Q1 45%, Q3 55%] versus 55% [50%, 58%]), lower blood pressure, lower rates of kidney disease, and higher rates of ischemic HF and diabetes. Following FDA label expansion, discharge prescription of S/V in the study population more than doubled compared with earlier years (4.3% vs 1.6%; p<0.001), but absolute rates remained low. ( Figure, Panel B ). Conclusion: Although the rate of S/V prescription among HF patients with EF >40-60% has significantly increased following FDA label expansion, use of S/V among these patients remains low. Compared with patients not prescribed S/V, patients with EF>40-60% receiving S/V at discharge have a distinct demographic and clinical profile, including tendency for HFmrEF more than HFpEF.

Epidemiological studies have highlighted the disparate impact of coronavirus disease 2019 (COVID-19) on racial and ethnic minority and socioeconomically disadvantaged populations, but data at the neighborhood-level is sparse. The objective of this study was to investigate the disparate impact of COVID-19 on disadvantaged neighborhoods and racial/ethnic minorities in Chicago, Illinois. Using data from the Cook County Medical Examiner, we conducted a neighborhood-level analysis of COVID-19 decedents in Chicago and quantified age-standardized years of potential life lost (YPLL) due to COVID-19 among demographic subgroups and neighborhoods with geospatial clustering of high and low rates of COVID-19 mortality. We show that age-standardized YPLL was markedly higher among the non-Hispanic (NH) Black (559 years per 100,000 population) and the Hispanic (811) compared with NH white decedents (312). We demonstrate that geomapping using residential address data at the individual-level identifies hot-spots of COVID-19 mortality in neighborhoods on the Northeast, West, and South areas of Chicago that reflect a legacy of residential segregation and persistence of inequality in education, income, and access to healthcare. Our results may contribute to ongoing public health and community-engaged efforts to prevent the spread of infection and mitigate the disproportionate loss of life among these communities due to COVID-19 as well as highlight the urgent need to broadly target neighborhood disadvantage as a cause of pervasive racial inequalities in life and health.

Background Adults in rural counties in the United States (US) experience higher rates broadly of cardiovascular disease (CVD) compared with adults in urban counties. Mortality rates specifically due to heart failure (HF) have increased since 2011, but estimates of heterogeneity at the county-level in HF-related mortality have not been produced. The objectives of this study were 1) to quantify nationwide trends by rural-urban designation and 2) examine county-level factors associated with rural-urban differences in HF-related mortality rates. Methods and findings We queried CDC WONDER to identify HF deaths between 2011–2018 defined as CVD (I00-78) as the underlying cause of death and HF (I50) as a contributing cause of death. First, we calculated national age-adjusted mortality rates (AAMR) and examined trends stratified by rural-urban status (defined using 2013 NCHS Urban-Rural Classification Scheme), age (35–64 and 65–84 years), and race-sex subgroups per year. Second, we combined all deaths from 2011–2018 and estimated incidence rate ratios (IRR) in HF-related mortality for rural versus urban counties using multivariable negative binomial regression models with adjustment for demographic and socioeconomic characteristics, risk factor prevalence, and physician density. Between 2011–2018, 162,314 and 580,305 HF-related deaths occurred in rural and urban counties, respectively. AAMRs were consistently higher for residents in rural compared with urban counties (73.2 [95% CI: 72.2–74.2] vs. 57.2 [56.8–57.6] in 2018, respectively). The highest AAMR was observed in rural Black men (131.1 [123.3–138.9] in 2018) with greatest increases in HF-related mortality in those 35–64 years (+6.1%/year). The rural-urban IRR persisted among both younger (1.10 [1.04–1.16]) and older adults (1.04 [1.02–1.07]) after adjustment for county-level factors. Main limitations included lack of individual-level data and county dropout due to low event rates (<20). Conclusions Differences in county-level factors may account for a significant amount of the observed variation in HF-related mortality between rural and urban counties. Efforts to reduce the rural-urban disparity in HF-related mortality rates will likely require diverse public health and clinical interventions targeting the underlying causes of this disparity.

BackgroundAdults in rural counties in the United States (US) experience higher rates broadly of cardiovascular disease (CVD) compared with adults in urban counties. Mortality rates specifically due to heart failure (HF) have increased since 2011, but estimates of heterogeneity at the county-level in HF-related mortality have not been produced. The objectives of this study were 1) to quantify nationwide trends by rural-urban designation and 2) examine county-level factors associated with rural-urban differences in HF-related mortality rates.Methods and findingsWe queried CDC WONDER to identify HF deaths between 2011-2018 defined as CVD (I00-78) as the underlying cause of death and HF (I50) as a contributing cause of death. First, we calculated national age-adjusted mortality rates (AAMR) and examined trends stratified by rural-urban status (defined using 2013 NCHS Urban-Rural Classification Scheme), age (35-64 and 65-84 years), and race-sex subgroups per year. Second, we combined all deaths from 2011-2018 and estimated incidence rate ratios (IRR) in HF-related mortality for rural versus urban counties using multivariable negative binomial regression models with adjustment for demographic and socioeconomic characteristics, risk factor prevalence, and physician density. Between 2011-2018, 162,314 and 580,305 HF-related deaths occurred in rural and urban counties, respectively. AAMRs were consistently higher for residents in rural compared with urban counties (73.2 [95% CI: 72.2-74.2] vs. 57.2 [56.8-57.6] in 2018, respectively). The highest AAMR was observed in rural Black men (131.1 [123.3-138.9] in 2018) with greatest increases in HF-related mortality in those 35-64 years (+6.1%/year). The rural-urban IRR persisted among both younger (1.10 [1.04-1.16]) and older adults (1.04 [1.02-1.07]) after adjustment for county-level factors. Main limitations included lack of individual-level data and county dropout due to low event rates (<20).ConclusionsDifferences in county-level factors may account for a significant amount of the observed variation in HF-related mortality between rural and urban counties. Efforts to reduce the rural-urban disparity in HF-related mortality rates will likely require diverse public health and clinical interventions targeting the underlying causes of this disparity.