Eldrin F. Lewis, MD, MPH

All Publications

• Measuring Health Status in Patients With Tricuspid Regurgitation. JAMA cardiology Lewis, E. F. 2024

  View details for DOI 10.1001/jamacardio.2024.4287

  View details for PubMedID 39476024

• Vericiguat Global Study in Participants with Chronic Heart Failure: Design of the VICTOR trial. European journal of heart failure Reddy, Y. N., Butler, J., Anstrom, K. J., Blaustein, R. O., Bonaca, M. P., Corda, S., Ezekowitz, J. A., Lam, C. S., Lewis, E. F., Lindenfeld, J., McMullan, C. J., Mentz, R. J., O'Connor, C., Patel, M., Ponikowski, P., Rosano, G. M., Saldarriaga, C. I., Senni, M., Udelson, J., Voors, A. A., Zannad, F. 2024

  Abstract

  In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy.The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo.VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

  View details for DOI 10.1002/ejhf.3501

  View details for PubMedID 39473305

• Home-Time, Mortality, and Readmissions Among Patients Hospitalized With Heart Failure: A Baseline Prior to IMPLEMENT-HF. Circulation. Heart failure Tang, A. B., Solomon, N., Chiswell, K., Greene, S. J., Yancy, C. W., Jessup, M., Kittleson, M., Butler, J., Sweitzer, N. K., Goldberg, L. R., Lindenfeld, J. A., Lewis, E. F., Peterson, P. N., Paul, S., Serdynski, L. M., Rutan, C., Congdon, M., Cherkur, S., Fonarow, G. C. 2024: e011795

  Abstract

  Home-time is an emerging, patient-centered outcome that represents the amount of time a patient spends alive and outside of health care facility settings, comprising of hospitals, skilled nursing facilities, and acute rehabilitation centers. Studies evaluating home-time in the context of heart failure are limited, and the impact of quality improvement interventions on home-time has not been studied.Medicare beneficiaries aged 65 years or older who were hospitalized for heart failure in the Get With the Guidelines-Heart Failure registry between 2019 and 2021 were included. Postdischarge home-time, mortality, and readmission rates at 30 days and 1 year were calculated with the goal of establishing baseline metrics before the initiation of IMPLEMENT-HF, a multicenter quality improvement program aimed at improving heart failure management.Overall, 66 019 patients were included across 437 sites. Median 30-day and 1-year home-time were 30 (18-30) and 333 (139-362) days, respectively. Only 22.1% of patients experienced 100% home-time in the year after discharge. Older patients spent significantly less time at home, with a median 1-year home-time of 302 (86-359) compared with 345 (211-365) days in patients over 85 and those between 65 and 74 years old, respectively (P<0.001). Black patients also experienced the least amount of home-time with only 328 (151-360) days at 1-year follow-up. Rates of heart failure readmission and all-cause mortality 1-year post-discharge were high at 29.8% and 37.0%, respectively.In this contemporary multicenter cohort, patients hospitalized with heart failure spent a median of 91.2% of their time in the year after discharge alive and at home, largely driven by high mortality rates. These findings serve as a preimplementation baseline for IMPLEMENT-HF, which will evaluate the impact of targeted heart failure initiatives on home-time and other clinical outcomes.

  View details for DOI 10.1161/CIRCHEARTFAILURE.124.011795

  View details for PubMedID 39381871

• Expanding Opportunities by Adding Accessibility to Diversity, Equity, and Inclusion. Circulation Clair, W. K., Sumner, A. E., Lewis, E. F. 2024; 150 (12): 903-904

  View details for DOI 10.1161/CIRCULATIONAHA.124.071728

  View details for PubMedID 39283929

• Race in Heart Failure: A Pooled Participant-Level Analysis of the Global PARADIGM-HF and PARAGON-HF Trials. JACC. Heart failure Lu, H., Claggett, B. L., Packer, M., Pabon, M. A., Pfeffer, M. A., Lewis, E. F., Lam, C. S., Rouleau, J., Zile, M. R., Lefkowitz, M., Desai, A. S., Jhund, P. S., McMurray, J. J., Solomon, S. D., Vaduganathan, M. 2024

  Abstract

  Mechanisms of disease pathobiology, prognosis, and potentially treatment responses might vary by race in patients with heart failure (HF).The authors aimed to examine the safety and efficacy of sacubitril/valsartan among patients with HF by self-reported race.PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) were global, randomized clinical trials testing sacubitril/valsartan against a renin-angiotensin system inhibitor ([RASi], enalapril or valsartan, respectively) in patients with HF and left ventricular ejection fraction ≤40% (PARADIGM-HF) or left ventricular ejection fraction ≥45% (PARAGON-HF). Patients with self-reported race were categorized as White, Asian, or Black. We assessed the composite of first HF hospitalization or cardiovascular death, its components, and angioedema across races.Among 12,097 participants, 9,451 (78.1%) were White, 2,116 (17.5%) were Asian, and 530 (4.4%) were Black. Over a median follow-up of 2.5 years, Black (adjusted HR: 1.68; 95% CI: 1.42-1.98) and Asian patients (adjusted HR: 1.32; 95% CI: 1.18-1.47) experienced higher risks of the primary outcome compared with White patients. Treatment effects of sacubitril/valsartan vs RASi on the primary endpoint were consistent among White (HR: 0.84; 95% CI: 0.77-0.91), Asian (HR: 0.92; 95% CI: 0.78-1.10), and Black patients (HR: 0.79; 95% CI: 0.58-1.07; Pinteraction = 0.58). Rates of severe angioedema were higher with sacubitril/valsartan vs RASi (White: 0.2% vs 0.1%; Black: 1.5% vs 0.0%; Asian: 0.1% vs 0.1%).In a pooled experience of 2 global trials, Black and Asian patients exhibited a higher risk of cardiovascular events than White patients. The benefits of sacubitril/valsartan were consistent across races. Risks of severe angioedema were low but numerically higher with sacubitril/valsartan. (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure [PARADIGM-HF]; NCT01035255; Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

  View details for DOI 10.1016/j.jchf.2024.08.008

  View details for PubMedID 39387766

• Edetate Disodium-Based Chelation for Patients With a Previous Myocardial Infarction and Diabetes: TACT2 Randomized Clinical Trial. JAMA Lamas, G. A., Anstrom, K. J., Navas-Acien, A., Boineau, R., Nemeth, H., Huang, Z., Wen, J., Rosenberg, Y., Stylianou, M., Jones, T. L., Joubert, B. R., Yu, Q., Santella, R. M., Mon, A. C., Ujueta, F., Escolar, E., Nathan, D. M., Fonseca, V. A., Aude, Y. W., Ehrman, J. K., Elliott, T., Prashad, R., Lewis, E. F., Lopes, R. D., Farkouh, M. E., Elliott, A., Newman, J. D., Mark, D. B., TACT2 Investigators, Bear, P., Prouty, D., Baxter, J., Ehrman, J., Golden, H., Katoch, V., Krikorian, R., Paixao, A., Anazawa, F., Ramirez-Kelly, L., Nolen, A., Barney, V., Natzke, G., Pop-Busui, R., Plunkett, C., Meyer, L., Roberts, J., Rollins, S., Hollis, T., Vijay, N., Washam, M., Zidar, D., Semenec, T., Huntington, L., Klumpp, A., Doughty, M. S., Baker, J., Allen, J., Cortez, R., Purushottam, B., Stauffacher, K., Airey, K., Christofides, E., Conway, J., Hoffman, D., Schuler, P., Solbrig, R., Chacon, L., Levy, P., Gojcevic, L., Collins, R., McClure Ii, J. M., Mook, E., DeFilippi, C., Sheaffer, W., Bonaccorso, A., Donovan, D., Hartwell, J., Garner, A., Kalbfliesh, D., Hsi, D., Ducey, M., Trump, P., Leuenberger, U., Loffredo, K., Persico, B., Magaziner, A., Goodman, D., Garabedian, M., Coates, J., Wingo, J., Gottlieb, S., Schachter, M., Minniefield, S., Akinboboye, O., Ullah, K., Wolske, K., Friedman, D., Lorber, D., Tsovian, M., Druz, R., Hodnett, P., Meller, S., Bartolome, M., Cortez Vargas, G., Ergui, I., Ujueta, F., Valls, P., Lozada, M., Blanco, R., Arenas, I., Escolar, E., Pan, X., Seidel, I., Corado-Williams, M., Lamas, A., Viera-Navarro, M., Trevino, M., Mai, K., Eidelman, R., Reyes, G., Brown, K., Yaryura, R., Little, A., Varela, H., Bienes, M., Jeanfreau, R., Neff, P., Thompson, M., Lineberger-Moore, M., Miller, D., Prashad, R., Schmedtje, J. J., Shelton, M., Treasure Ii, C., Freel, A., Rojas, G., Bruceles, D., Uwaifo, G., Hixon-Calliet, V., Passini, A., Melton, S., Moreno, D., Blanco, A., Otero, A., Rodriguez, M., Sogade, F., Oludare, S., Fonseca, V., Moreau, C., Marquez, S., Duncan, P., Davis, U., Tang, S., DeMuth, B., Christie, D., Roberts, L., Martin, A., Luo, L., Waddle, S., Brown, S., Bianco, S., Steinberg, H., Bell, A., Patel, D., Bailey, A., Rice, M., Herrington, D., Blinson, K., Doomy, L., Smith, D., Norton, J., Gross, S., Mouhaffel, A., Guillory, C., Korn, S., Aude, Y. W., Esparza, Y., Leal, S., Abreu, L., Auerbach, E., Huff, C., Brooks, M., Johnson, M., Allen, T., Berkson, A., McAuliffe, K., Little, H., Little, R., Abbas, J., Collard, C., Foreman, J., Richardson, S., Desire, A., Shneker, A., Cordero, O., Kunik, P., Kiesz, R., Sasser, K., Golden, P., Garden, R., Green, A., Fung, G., Uyemura, K., Hamal, S., Budoff, M., Dinh, D., Nguyen, J., Erande, A., Brink, K., Malik, S., Chronos, N., Maslanka, N., O'Donnell, P., Bittorf, M. A., Garg, R., Matheson, D., Martinez, A., Hernandez, Y., Haught, W. H., Eskridge, L., Jaffrani, N., Trimble, M., Powell, J. J., Bryant, W., Bryant, N., Bergman, S., Libuit, R., Bringas, A., Visentin, D., Murphy, L., Junek, A., Nahas, S., Berlingieri, J., Urso, C., Moshiri, A., Elliott, T., Inducil, M., Parker, W., Stults, R., Kim, H., Acevedo, B. 2024

  Abstract

  Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)-based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI).Objective: To replicate the finding of TACT in individuals with diabetes and previous MI.Design, Setting, and Participants: A 2*2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons.Interventions: Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study.Main Outcomes and Measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion.Results: Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P=.53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 mug/L at baseline to 3.46 mug/L at infusion 40 (P<.001). Corresponding levels in the placebo group were 9.3 mug/L and 8.7 mug/L, respectively.Conclusions and Relevance: Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI.Trial Registration: ClinicalTrials.gov Identifier: NCT02733185.

  View details for DOI 10.1001/jama.2024.11463

  View details for PubMedID 39141382

• Rates of Sudden Death After Myocardial Infarction-Insights From the VALIANT and PARADISE-MI Trials. JAMA cardiology Curtain, J. P., Pfeffer, M. A., Braunwald, E., Claggett, B. L., Granger, C. B., Køber, L., Lewis, E. F., Maggioni, A. P., Mann, D. L., Rouleau, J. L., Solomon, S. D., Steg, P. G., Finn, P. V., Fernandez, A., Jering, K. S., McMurray, J. J. 2024

  Abstract

  Sudden death is a leading cause of death after acute myocardial infarction (AMI). The Prospective ARNi vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) and Valsartan in Acute Myocardial Infarction (VALIANT) trials enrolled patients with pulmonary congestion and/or left ventricular dysfunction after AMI. Whether the prognosis in such patients has changed over time has not been examined.To compare the rate of sudden death/resuscitated cardiac arrest (RCA) after AMI in the PARADISE-MI and VALIANT trials.This was a secondary analysis of multicenter randomized clinical trials enrolling patients after AMI. In the primary analysis, the VALIANT cohort was restricted to patients with "PARADISE-MI-like" characteristics (eg, at least 1 augmenting risk factor and no history of heart failure). The baseline characteristics of people in both trials were compared. The VALIANT trial enrolled from December 1998 to June 2001, and the PARADISE-MI trial enrolled between December 2016, and March 2020. The median follow-up in the VALIANT and PARADISE-MI trials was 24.7 and 22 months, respectively. People with AMI, complicated by pulmonary congestion and/or left ventricular dysfunction, were included in the analysis.Sudden death after AMI.A total of 5661 patients were included in the PARADISE-MI cohort (mean [SD] age, 63.7 [11.5] years; 4298 male [75.9%]), 9617 were included in the VALIANT (PARADISE-MI-like) cohort (mean [SD] age, 66.1 [11.5] years; 6504 male [67.6%]), and 14 703 patients were included in the VALIANT (total) cohort (mean [SD] age, 64.8 [11.8] years; 10 133 male [68.9%]). In the PARADISE-MI-like cohort of the VALIANT trial, 707 of 9617 participants (7.4%) experienced sudden death/RCA. A total of 148 of 5661 people (2.6%) in the PARADISE-MI trial experienced sudden death/RCA. Sudden death rates were highest in the first month after infarction in both trials: 19.3 (95% CI, 16.4-22.6) per 100 person-years in the VALIANT trial and 9.5 (95% CI, 7.0-12.7) per 100 person-years in the PARADISE-MI trial, and these rates declined steadily thereafter. Compared with the VALIANT cohort, people in the PARADISE-MI trial were more often treated with percutaneous coronary intervention for their qualifying AMI and received a β-blocker, statin, and mineralocorticoid receptor antagonist more frequently.After AMI, the risk of sudden death/RCA was highest in the first month, declining rapidly thereafter. Results revealed that compared with counterparts from 20 years ago, the rate of sudden death/RCA in patients with a reduced left ventricular ejection fraction and/or pulmonary congestion was 2- to 3-fold lower in people receiving contemporary management. Interventions to further protect people in the highest risk first month after infarction are needed.ClinicalTrials.gov Identifier: NCT02924727.

  View details for DOI 10.1001/jamacardio.2024.2356

  View details for PubMedID 39110471

  View details for PubMedCentralID PMC11307160

• Acute changes in kidney function and outcomes following an acute myocardial infarction: Insights from PARADISE-MI. European journal of heart failure Mc Causland, F. R., McGrath, M. M., Claggett, B. L., Barkoudah, E., East, C., Fernandez, A., Jering, K. S., Lewis, E. F., McMurray, J. J., Mody, F. V., Solomon, S. D., Tokmakova, M., van der Meer, P., Zhou, Y., Pfeffer, M. A. 2024

  Abstract

  AIMS: Pharmacologic blockade of neurohormonal pathways in patients with acute myocardial infarction (MI) can result in acute changes in biomarkers of kidney function. We evaluated the effect of sacubitril/valsartan versus ramipril on initial changes in serum creatinine and the association of these changes with longer-term outcomes among participants in PARADISE-MI.METHODS AND RESULTS: In this randomized, double-blind, active-controlled, event-driven trial, 5661 patients with an acute MI were assigned to receive sacubitril/valsartan or ramipril, with no run-in. The frequency of an initial pre-specified increase in serum creatinine (≥26.5 or ≥44mumol/L) from baseline to week 1 was compared between arms. Multivariable Cox regression models were fit to examine the association of acute changes in serum creatinine with the primary cardiovascular composite outcome (cardiovascular death, first heart failure hospitalization, or outpatient heart failure), all-cause mortality, and longer-term changes in estimated glomerular filtration rate (eGFR). An initial increase in serum creatinine ≥26.5mumol/L occurred in 155 of 2604 (6.0%) patients assigned to sacubitril/valsartan and 120 of 2603 (4.6%) patients assigned to ramipril (odds ratio [OR] 1.32; 95% confidence interval [CI] 1.03-1.68). The corresponding numbers for an increase ≥44mumol/L were 57 (2.2%) and 42 (1.6%), respectively (OR 1.37; 95% CI 0.92-2.05). A higher odds of increased serum creatinine ≥26.5 and ≥44mumol/L for sacubitril/valsartan versus ramipril appeared to be restricted to patients who had a greater decline in systolic blood pressure over the same period (p-interaction=0.05 and 0.001, respectively). In multivariable analyses, neither an acute increase in serum creatinine ≥26.5 or ≥44mumol/L was associated with a higher risk of cardiovascular outcomes, all-cause mortality, or differences in longer-term eGFR slope. Findings were similar across the randomized treatment arms (p-interaction >0.6 for all).CONCLUSIONS: Following acute MI, patients assigned to sacubitril/valsartan had a higher frequency of initial increases in serum creatinine at 1week, compared with ramipril. In adjusted models, initial increases in serum creatinine with either treatment were not associated with adverse cardiovascular outcomes or changes in longer-term kidney function.

  View details for DOI 10.1002/ejhf.3386

  View details for PubMedID 39056455

• Who are we missing? Language exclusivity of patient-reported outcomes in atrial fibrillation clinical trials. Journal of cardiovascular electrophysiology Lan, R. H., Guerrero, E. P., Lewis, E. F., Wang, P. J. 2024

  Abstract

  Patient-reported outcomes (PROs) are increasingly used to evaluate quality of life (QoL) in Atrial Fibrillation (AF) patients, providing crucial insights in clinical trials. This study examines the frequency of PRO use in AF trials and the linguistic accessibility of AF-specific PROs.As the United States becomes more multilingual, ensuring PROs are available in various languages is vital. The number of people speaking a language other than English at home has tripled from 23.1 million in 1980 to 67.8 million in 2019. This diversity necessitates the availability of PROs in multiple languages for inclusive clinical assessments.We queried ClinicalTrials.gov for all US interventional AF trials up to November 28, 2023, reviewing each for PRO usage as primary or secondary outcomes. We identified the five most common AF-specific and generic PROs, extracting their available translations and original languages from published sources.Of 233 identified trials, 191 had associated publications, with 180 (94.2%) conducted solely in English. Only one trial (0.4%) used an AF-specific PRO as a primary outcome, compared to four (1.7%) with a generic PRO. Ten trials (4.3%) used AF-specific PROs as secondary endpoints, versus 22 (9.4%) using generic PROs. AF-specific PROs had significantly fewer translations than generic PROs (11.2 vs. 148.8; p < .001). The AF Effect on Quality-of-Life (AFEQT) was available in 24 languages, with limited translations in commonly spoken US languages like Arabic and Asian languages.The limited availability of AF-specific PRO translations highlights a barrier to inclusive AF clinical trials. Expanding translations for AF-specific PROs is crucial for equitable QoL assessments.

  View details for DOI 10.1111/jce.16360

  View details for PubMedID 38953220

• American Heart Association Cardiogenic Shock Registry: Design and Implementation. Circulation. Cardiovascular quality and outcomes Morrow, D. A., Jessup, M., Abraham, W. T., Acker, M., Aringo, A., Batchelor, W., Chikwe, J., Costello, S., Drakos, S. G., Farmer, S., Gelijns, A., Gillette, N., Hochman, J. S., Isler, M., Kapur, N. K., Kilic, A., Kormos, R., Lewis, E. F., Lindenfeld, J., Lombardi, P., Mancini, D., Rao, S. V., Rutan, C., Samsky, M., Krucoff, M. W. 2024: e010637

  Abstract

  Cardiogenic shock is a morbid complication of heart disease that claims the lives of more than 1 in 3 patients presenting with this syndrome. Supporting a unique collaboration across clinical specialties, federal regulators, payors, and industry, the American Heart Association volunteers and staff have launched a quality improvement registry to better understand the clinical manifestations of shock phenotypes, and to benchmark the management patterns, and outcomes of patients presenting with cardiogenic shock to hospitals across the United States.Participating hospitals will enroll consecutive hospitalized patients with cardiogenic shock, regardless of etiology or severity. Data are collected through individual reviews of medical records of sequential adult patients with cardiogenic shock. The electronic case record form was collaboratively designed with a core minimum data structure and aligned with Shock Academic Research Consortium definitions. This registry will allow participating health systems to evaluate patient-level data including diagnostic approaches, therapeutics, use of advanced monitoring and circulatory support, processes of care, complications, and in-hospital survival. Participating sites can leverage these data for onsite monitoring of outcomes and benchmarking versus other institutions. The registry was concomitantly designed to provide a high-quality longitudinal research infrastructure for pragmatic randomized trials as well as translational, clinical, and implementation research. An aggregate deidentified data set will be made available to the research community on the American Heart Association's Precision Medicine Platform. On March 31, 2022, the American Heart Association Cardiogenic Shock Registry received its first clinical records. At the time of this submission, 100 centers are participating.The American Heart Association Cardiogenic Shock Registry will serve as a resource using consistent data structure and definitions for the medical and research community to accelerate scientific advancement through shared learning and research resulting in improved quality of care and outcomes of shock patients.

  View details for DOI 10.1161/CIRCOUTCOMES.123.010637

  View details for PubMedID 38887950

• Diversity in Atrial Fibrillation Trials: Assessing the Role of Language Proficiency as a Recruitment Barrier. Heart rhythm Lan, R. H., Guerrero, E. P., Shen, S., Qin, F., Ritter, V., Brown-Johnson, C., Clark, K., Rose, E., Lewis, E. F., Wang, P. J. 2024

  View details for DOI 10.1016/j.hrthm.2024.05.034

  View details for PubMedID 38777255

• Predictors of heart failure readmission and all-cause mortality in patients with acute heart failure. International journal of cardiology Espersen, C., Campbell, R. T., Claggett, B. L., Lewis, E. F., Docherty, K. F., Lee, M. M., Lindner, M., Brainin, P., Biering-Sorensen, T., Solomon, S. D., McMurray, J. J., Platz, E. 2024: 132036

  Abstract

  BACKGROUND: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking.METHODS: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death.RESULTS: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72).CONCLUSIONS: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations.

  View details for DOI 10.1016/j.ijcard.2024.132036

  View details for PubMedID 38599465

• Is Equity Being Traded for Access to Heart Transplant? JAMA Heidenreich, P. A., Lewis, E. F., Khush, K. K. 2024

  View details for DOI 10.1001/jama.2024.0812

  View details for PubMedID 38526454

• Angiotensin Receptor-Neprilysin Inhibition in Patients With STEMI vs NSTEMI. Journal of the American College of Cardiology Mann, D. L., Nicolas, J., Claggett, B., Miao, Z. M., Granger, C. B., Kerkar, P., Køber, L., Lewis, E. F., McMurray, J. J., Maggioni, A. P., Núñez, J., Ntsekhe, M., Rouleau, J. L., Sim, D., Solomon, S. D., Steg, P. G., van der Meer, P., Braunwald, E., Pfeffer, M. A., Mehran, R. 2024; 83 (9): 904-914

  Abstract

  Patients who sustain an acute myocardial infarction (AMI), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), remain at high risk for heart failure (HF), coronary events, and death. Angiotensin-converting enzyme inhibitors have been shown to significantly decrease the risk for cardiovascular events in both STEMI and NSTEMI patients.The objectives were to determine whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan, compared with ramipril, has impact on reducing cardiovascular events according to the type of AMI.The PARADISE-MI (Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) trial enrolled patients with AMI complicated by left ventricular dysfunction and/or pulmonary congestion and at least 1 risk-enhancing factor. Patients were randomized to either sacubitril/valsartan or ramipril. The primary endpoint was death from cardiovascular causes or incident HF. In this prespecified analysis, we stratified patients according to AMI type.Of 5,661 enrolled patients, 4,291 (75.8%) had STEMI. These patients were younger and had fewer comorbidities and cardiovascular risk factors than NSTEMI patients. After adjustment for potential confounders, the risk for the primary outcome was marginally higher in NSTEMI vs STEMI patients (adjusted HR: 1.19; 95% CI: 1.00-1.41), with borderline statistical significance (P = 0.05). The primary composite outcome occurred at similar rates in patients randomized to sacubitril/valsartan vs ramipril in STEMI (10% vs 12%; HR: 0.87; 95% CI: 0.73-1.04; P = 0.13) and NSTEMI patients (17% vs 17%; HR: 0.97; 95% CI: 0.75-1.25; P = 0.80; P interaction = 0.53).Compared with ramipril, sacubitril/valsartan did not significantly decrease the risk for cardiovascular death and HF in patients with AMI complicated by left ventricular dysfunction, irrespective of the type of AMI. (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI; NCT02924727).

  View details for DOI 10.1016/j.jacc.2024.01.002

  View details for PubMedID 38418004

• Pulmonary Congestion and Left Ventricular Dysfunction After Myocardial Infarction: Insights From the PARADISE-MI Trial CIRCULATION Petrie, M. C., Rouleau, J. L., Claggett, B., Jering, K., van der Meer, P., Kober, L., Miao, Z., Lewis, E., Granger, C., De Pasqulae, C. G., Mann, D., Steg, P., Maggioni, A., Amir, O., Lefkowitz, M., Braunwald, E., Solomon, S. D., McMurray, J. V., Pfeffer, M. A. 2024; 149 (4): 335-338

  View details for DOI 10.1161/CIRCULATIONAHA.123.066163

  View details for Web of Science ID 001147155700005

  View details for PubMedID 38252738

• Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin. Diabetes, obesity & metabolism McMurray, J. J., Solomon, S. D., Lock, J. P., Massaro, J. M., Zhu, F., Zhou, W., Skali, H., Lewis, E. F., Freeman, M. W., Halvorsen, Y. C. 2023

  Abstract

  AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin.METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority.RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR=0.82; 95% CI 0.59, 1.13; P=0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown.CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.

  View details for DOI 10.1111/dom.15394

  View details for PubMedID 38151752

• Opportunities to Increase Science of Diversity and Inclusion in Clinical Trials: Equity and a Lack of a Control. Journal of the American Heart Association Igwe, J., Wangdak Yuthok, T. Y., Cruz, E., Mueller, A., Lan, R. H., Brown-Johnson, C., Idris, M., Rodriguez, F., Clark, K., Palaniappan, L., Echols, M., Wang, P., Onwuanyi, A., Pemu, P., Lewis, E. F. 2023: e030042

  Abstract

  The United States witnessed a nearly 4-fold increase in personal health care expenditures between 1980 and 2010. Despite innovations and obvious benefits to health, participants enrolled in clinical trials still do not accurately represent the racial and ethnic composition of patients nationally or globally. This lack of diversity in cohorts limits the generalizability and significance of results among all populations and has deep repercussions for patient equity. To advance diversity in clinical trials, robust evidence for the most effective strategies for recruitment of diverse participants is needed. A major limitation of previous literature on clinical trial diversity is the lack of control or comparator groups for different strategies. To date, interventions have focused primarily on (1) community-based interventions, (2) institutional practices, and (3) digital health systems. This review article outlines prior intervention strategies across these 3 categories and considers health policy and ethical incentives for substantiation before US Food and Drug Administration approval. There are no current studies that comprehensively compare these interventions against one another. The American Heart Association Strategically Focused Research Network on the Science of Diversity in Clinical Trials represents a multicenter, collaborative network between Stanford School of Medicine and Morehouse School of Medicine created to understand the barriers to diversity in clinical trials by contemporaneous head-to-head interventional strategies accessing digital, institutional, and community-based recruitment strategies to produce informed recruitment strategies targeted to improve underrepresented patient representation in clinical trials.

  View details for DOI 10.1161/JAHA.123.030042

  View details for PubMedID 38108253

• Who Are We Missing? Reporting of Transgender and Gender-Expansive Populations in Clinical Trials. Journal of the American Heart Association Rice, E. N., Lan, R. H., Nunes, J. C., Shah, R., Clark, K., Periyakoil, V. S., Chen, J. H., Lin, B., Echols, M., Awad, C., Idris, M. Y., Cruz, E. R., Poullos, P. D., Lewis, E. F., Brown-Johnson, C., Igwe, J., Shen, S., Palaniappan, L., Stefanick, M. L., Ritter, V., Pemu, P., Rodriguez, F., Deb, B., Pundi, K., Wang, P. J. 2023: e030209

  View details for DOI 10.1161/JAHA.123.030209

  View details for PubMedID 37947088

• Disabilities Reporting in Cardiac Clinical Trials: How Are We Doing? Journal of the American Heart Association Lan, R. H., Rice, E. N., Nunes, J. C., Shah, R., Igwe, J. K., Clark, K., Periyakoil, V. S., Chen, J. H., Lin, B., Awad, C., Idris, M., Cruz, E. R., Lewis, E. F., Johnson, C. B., Wang, P. J. 2023: e029726

  View details for DOI 10.1161/JAHA.123.029726

  View details for PubMedID 37949834

• Catheter Ablation for Atrial Fibrillation in Heart Failure - An Option to Defer Transplantation? The New England journal of medicine Lewis, E. F. 2023; 389 (15): 1429-1430

  View details for DOI 10.1056/NEJMe2309658

  View details for PubMedID 37819960

• Cardiovascular Disease Burden and Outcomes Among American Indian and Alaska Native Medicare Beneficiaries. JAMA network open Eberly, L. A., Shultz, K., Merino, M., Brueckner, M. Y., Benally, E., Tennison, A., Biggs, S., Hardie, L., Tian, Y., Nathan, A. S., Khatana, S. A., Shea, J. A., Lewis, E., Bukhman, G., Shin, S., Groeneveld, P. W. 2023; 6 (9): e2334923

  Abstract

  American Indian and Alaska Native persons face significant health disparities; however, data regarding the burden of cardiovascular disease in the current era is limited.To determine the incidence and prevalence of cardiovascular disease, the burden of comorbid conditions, including cardiovascular disease risk factors, and associated mortality among American Indian and Alaska Native patients with Medicare insurance.This was a population-based cohort study conducted from January 2015 to December 2019 using Medicare administrative data. Participants included American Indian and Alaska Native Medicare beneficiaries 65 years and older enrolled in both Medicare part A and B fee-for-service Medicare. Statistical analyses were performed from November 2022 to April 2023.The annual incidence, prevalence, and mortality associated with coronary artery disease (CAD), heart failure (HF), atrial fibrillation/flutter (AF), and cerebrovascular disease (stroke or transient ischemic attack [TIA]).Among 220 598 American Indian and Alaska Native Medicare beneficiaries, the median (IQR) age was 72.5 (68.5-79.0) years, 127 402 were female (57.8%), 78 438 (38.8%) came from communities in the most economically distressed quintile in the Distressed Communities Index. In the cohort, 44.8% of patients (98 833) were diagnosed with diabetes, 61.3% (135 124) were diagnosed with hyperlipidemia, and 72.2% (159 365) were diagnosed with hypertension during the study period. The prevalence of CAD was 38.6% (61 125 patients) in 2015 and 36.7% (68 130 patients) in 2019 (P < .001). The incidence of acute myocardial infarction increased from 6.9 per 1000 person-years in 2015 to 7.7 per 1000 patient-years in 2019 (percentage change, 4.79%; P < .001). The prevalence of HF was 22.9% (36 288 patients) in 2015 and 21.4% (39 857 patients) in 2019 (P < .001). The incidence of HF increased from 26.1 per 1000 person-years in 2015 to 27.0 per 1000 person-years in 2019 (percentage change, 4.08%; P < .001). AF had a stable prevalence of 9% during the study period (2015: 9.4% [14 899 patients] vs 2019: 9.3% [25 175 patients]). The incidence of stroke or TIA decreased slightly throughout the study period (12.7 per 1000 person-years in 2015 and 12.1 per 1000 person-years in 2019; percentage change, 5.08; P = .004). Fifty percent of patients (110 244) had at least 1 severe cardiovascular condition (CAD, HF, AF, or cerebrovascular disease), and the overall mortality rate for the cohort was 19.8% (43 589 patients).In this large cohort study of American Indian and Alaska Native patients with Medicare insurance in the US, results suggest a significant burden of cardiovascular disease and cardiometabolic risk factors. These results highlight the critical need for future efforts to prioritize the cardiovascular health of this population.

  View details for DOI 10.1001/jamanetworkopen.2023.34923

  View details for PubMedID 37738051

  View details for PubMedCentralID PMC10517375

• Sex Differences in Clinical Characteristics and Outcomes After Myocardial Infarction With Low Ejection Fraction: Insights From PARADISE-MI. Journal of the American Heart Association Wang, X., Jering, K. S., Cikes, M., Tokmakova, M. P., Mehran, R., Han, Y., East, C., Mody, F. V., Wang, Y., Lewis, E. F., Claggett, B., McMurray, J. J., Granger, C. B., Pfeffer, M. A., Solomon, S. D. 2023: e028942

  Abstract

  Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all-cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05-1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05-1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow-up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

  View details for DOI 10.1161/JAHA.122.028942

  View details for PubMedID 37609931

• Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Treated Patients. Kidney medicine Parfrey, P. S., Burke, S. K., Chertow, G. M., Eckardt, K., Jardine, A. G., Lewis, E. F., Luo, W., Matsushita, K., McCullough, P. A., Minga, T., Winkelmayer, W. C. 2023; 5 (7): 100667

  Abstract

  Rationale & Objective: In the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials.Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial.Setting & Participants: A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD.Intervention: 1:1 randomization to receive vadadustat or darbepoetin alfa.Outcomes: The primary safety end point was the time to first MACE.Results: At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of≥10g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P=0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups.Limitations: Several analyses are exploratory.Conclusions: In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group.Funding: Akebia Therapeutics, Inc.Trial Registration: ClinicalTrials.gov identifier: NCT02680574.

  View details for DOI 10.1016/j.xkme.2023.100667

  View details for PubMedID 37427292

• Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non-Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Naive Patients. Kidney medicine Winkelmayer, W. C., Arnold, S., Burke, S. K., Chertow, G. M., Eckardt, K., Jardine, A. G., Lewis, E. F., Luo, W., Matsushita, K., McCullough, P. A., Minga, T., Parfrey, P. S. 2023; 5 (7): 100666

  Abstract

  Rationale & Objective: Prespecified analyses of the PRO2TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO2TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents.Study Design: Phase 3, global, open-label, randomized, active-controlled clinical trial.Setting and Participants: Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD.Intervention: Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa.Outcomes: The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACEplus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis).Results: In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of≤10mL/min/1.73m2 in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of≤10mL/min/1.73m2 and who may not have had access to dialysis.Limitations: Different regional treatment patterns of patients with NDD-CKD.Conclusions: The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.

  View details for DOI 10.1016/j.xkme.2023.100666

  View details for PubMedID 37427293

• Prognostic Importance of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) Following High-Risk Myocardial Infarction in the PARADISE-MI Trial. Circulation. Heart failure Jering, K. S., Claggett, B. L., Pfeffer, M. A., Granger, C. B., Køber, L., Lewis, E. F., Maggioni, A. P., Mann, D. L., McMurray, J. J., Prescott, M. F., Rouleau, J. L., Solomon, S. D., Steg, P. G., von Lewinski, D., Braunwald, E. 2023: e010259

  Abstract

  NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a potent predictor of death and heart failure (HF) across multiple populations. We evaluated the prognostic importance of NT-proBNP in patients with acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors enrolled in the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction).Patients were randomized to sacubitril/valsartan 200 mg or ramipril 5 mg twice daily within 0.5 to 7 days of a MI. Patients with prior HF were excluded. NT-proBNP and hs-cTnT (high-sensitivity troponin T) were collected at randomization in a prespecified substudy of 1129 patients. The primary end point of PARADISE-MI was a composite of cardiovascular death or incident HF (hospitalization or outpatient symptomatic HF), analyzed as time-to-first event; additional end points included all-cause death and the composite of fatal or nonfatal MI or stroke.Median NT-proBNP was 1757 ng/L (25th-75th percentiles, 896-3462 ng/L) at randomization (4.0±1.8 days after the index MI). Patients in the highest quartile of NT-proBNP were older, more commonly women and had more hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion on presentation (all P<0.001). NT-proBNP was strongly associated with the primary end point (adjusted hazard ratio, 1.45 per doubling of NT-proBNP; [95% CI, 1.23-1.70]), adjusted for clinical variables and baseline hs-cTnT. NT-proBNP was also independently associated with all-cause death (adjusted hazard ratio, 1.74 [95% CI, 1.38-2.21]) and fatal or nonfatal MI or stroke (adjusted hazard ratio, 1.24 [95% CI, 1.05-1.45]). NT-proBNP did not significantly modify the neutral treatment effect of sacubitril/valsartan relative to ramipril (P interaction=0.46).Within the first week of a high-risk MI NT-proBNP is associated with incident HF, death and atherosclerotic events. This prognostic information is independent of hs-cTnT.URL: https://www.gov; Unique identifier: NCT02924727.

  View details for DOI 10.1161/CIRCHEARTFAILURE.122.010259

  View details for PubMedID 37125529

• Geographic Differences in Patients With Acute Myocardial Infarction in The PARADISE-MI Trial. European journal of heart failure Butt, J. H., Claggett, B. L., Miao, Z. M., Jering, K. S., Sim, D., van der Meer, P., Ntsekhe, M., Amir, O., Cho, M. C., Carrillo-Calvillo, J., Núñez, J. E., Cadena, A., Kerkar, P., Maggioni, A. P., Steg, P. G., Granger, C. B., Mann, D. L., Merkely, B., Lewis, E. F., Solomon, S. D., Zhou, Y., Køber, L., Braunwald, E., McMurray, J. J., Pfeffer, M. A. 2023

  Abstract

  The globalization of clinical trials has highlighted geographic differences in patient characteristics, treatments, and outcomes. We examined these differences in PARADISE-MI.23.0% were randomized in Eastern Europe/Russia, 17.5% in Western Europe, 12.2% in Southern Europe, 10.1% in Northern Europe, 12.0% in Latin America (LA), 9.3% in North America (NA), 10.0% in East/South-East Asia and 5.8% in South Asia (SA). Those from Asia, particularly SA, were different from patients enrolled in the other regions, being younger and thinner. They also differed in terms of comorbidities (high prevalence of diabetes and low prevalence of AF), type of MI (more often STEMI), and treatment (low rate of primary PCI). By contrast, patients from LA did not differ meaningfully from those randomized in Europe or NA. Use of ACE-inhibitor/ARB (34.8%) and beta-blockers (65.5%) was low in SA, whereas MRA use was lowest in NA (22%) and highest in Eastern Europe/Russia (53%). Rates of the primary composite outcome of cardiovascular death or incident HF varied two-fold among regions, with the lowest rate in SA (4.6/100person-years) and the highest in LA (9.2/100person-years). Rates of incident HF varied almost six-fold among regions, with the lowest rate in SA (1.0/100person-years) and the highest in Northern Europe (5.9/100person-years). The effect of sacubitril/valsartan was not modified by region.In PARADISE-MI, there were substantial regional differences in patient characteristics, treatments and outcomes. Although the generalizability of these findings to a "real-world" unselected population may be limited, these findings underscore the importance of considering both regional and within-region differences when designing global clinical trials.

  View details for DOI 10.1002/ejhf.2851

  View details for PubMedID 37042062

• WHO ARE WE MISSING? REPORTING OF TRANSGENDER AND GENDER EXPANSIVE POPULATIONS IN CLINICAL TRIALS Rice, E., Lan, R., Nunes, J., Shah, R., Echols, M. R., Lunn, M., Bryant, L., Lewis, E. F., Awad, C., Idris, M. Y., Clark, K., Periyakoil, V., Cruz, E., Chen, J., Brown-Johnson, C., Palaniappan, L. P., Wang, P. J. ELSEVIER SCIENCE INC. 2023: 119

  View details for Web of Science ID 000990866100120

• DISABILITIES REPORTING IN CLINICAL TRIALS. HOW ARE WE DOING? Lan, R., Rice, E., Nunes, J., Shah, R., Joseph, I. E., Echols, M. R., Echols, M. R., Lunn, M., Bryant, L., Lewis, E. F., Awad, C., Idris, M. Y., Clark, K., Periyakoil, V., Cruz, E., Chen, J., Brown-Johnson, C., Palaniappan, L. P., Wang, P. J. ELSEVIER SCIENCE INC. 2023: 172

  View details for Web of Science ID 000990866100173

• Improving representativeness in trials: a call to action from the Global Cardiovascular Clinical Trialists Forum. European heart journal Filbey, L., Zhu, J. W., D'Angelo, F., Thabane, L., Khan, M. S., Lewis, E., Patel, M. R., Powell-Wiley, T., Miranda, J. J., Zuhlke, L., Butler, J., Zannad, F., Van Spall, H. G. 2023

  Abstract

  Participants enrolled in cardiovascular disease (CVD) randomized controlled trials are not often representative of the population living with the disease. Older adults, children, women, Black, Indigenous and People of Color, and people living in low- and middle-income countries are typically under-enrolled in trials relative to disease distribution. Treatment effect estimates of CVD therapies have been largely derived from trial evidence generated in White men without complex comorbidities, limiting the generalizability of evidence. This review highlights barriers and facilitators of trial enrollment, temporal trends, and the rationale for representativeness. It proposes strategies to increase representativeness in CVD trials, including trial designs that minimize the research burden on participants, inclusive recruitment practices and eligibility criteria, diversification of clinical trial leadership, and research capacity-building in under-represented regions. Implementation of such strategies could generate better and more generalizable evidence to reduce knowledge gaps and position the cardiovascular trial enterprise as a vehicle to counter existing healthcare inequalities.

  View details for DOI 10.1093/eurheartj/ehac810

  View details for PubMedID 36702610

• Functional and Symptomatic Clinical Trial Endpoints: The HFC-ARC Scientific Expert Panel. JACC. Heart failure Psotka, M. A., Abraham, W. T., Fiuzat, M., Filippatos, G., Lindenfeld, J., Ahmad, T., Felker, G. M., Jacob, R., Kitzman, D. W., Leifer, E. S., Lewis, E. F., Mentz, R. J., Nkulikiyinka, R., Ni, W., Schaber, D. E., Sharma, A., Solomon, S. D., Stockbridge, N., Teerlink, J. R., Unger, E. F., Whellan, D. J., Wittes, J., Anker, S. D., O'Connor, C. M. 2022; 10 (12): 889-901

  Abstract

  The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations.

  View details for DOI 10.1016/j.jchf.2022.09.012

  View details for PubMedID 36456063

• Health-Related Quality of Life Outcomes in PARAGON-HF. European journal of heart failure Chandra, A., Polanczyk, C. A., Claggett, B. L., Vaduganathan, M., Packer, M., Lefkowitz, M. P., Rouleau, J. L., Liu, J., Shi, V. C., Schwende, H., Zile, M. R., Desai, A. S., Pfeffer, M. A., McMurray, J. J., Solomon, S. D., Lewis, E. F. 2022

  Abstract

  AIMS: Heart failure (HF) is associated with poor health-related quality of life (HRQL). Patients with HF with preserved ejection fraction (HFpEF) have similar HRQL impairment as those with reduced ejection fraction. This study describes the impact of sacubitril/valsartan on HRQL in patients with HFpEF enrolled in the PARAGON-HF trial.METHODS AND RESULTS: Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol (EQ) at randomization, 4 months, 8 months, and annually thereafter. Changes in HRQL scores were evaluated using repeated measures models adjusted for treatment, baseline values and region. The pre-specified principal efficacy assessment was at 8 months at which time patients randomized to sacubitril/valsartan had borderline higher KCCQ-Clinical Summary score (CSS) with LSM adjusted difference of 1.0 (95% CI 0.0, 2.1); p=0.051. Including all visits up to 36 months, the LSM difference in KCCQ-CSS favored sacubitril/valsartan with average adjusted difference of 1.1 (95% CI 0.1, 2.0); p=0.034. Patients treated with sacubitril/valsartan had greater odds of clinically meaningful improvement (≥5-point increase) in KCCQ-CSS (OR 1.31; 95% CI 1.06, 1.61) at 8 months. At 8 months, there was no significant difference in the EQ visual analogue scale between the treatment arms, but sacubitril/valsartan was associated with higher EQ-5D utility score (US-based) with LSM adjusted difference of 0.01 (95% CI 0.00, 0.02); p=0.019.CONCLUSION: Compared with valsartan, sacubitril/valsartan has a borderline benefit on KCCQ-CSS at 8 months in patients with HFpEF. This benefit became more significant when data from all visits up to 36 months were included. This modest overall benefit was also supported by greater odds of patients reporting a clinically meaningful improvement in HRQL with sacubitril/valsartan. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.2738

  View details for PubMedID 36394533

• The Effects of Angiotensin Receptor-Neprilysin Inhibition on Major Coronary Events in Patients With Acute Myocardial Infarction: Insights From the PARADISE-MI Trial. Circulation Mehran, R., Steg, P. G., Pfeffer, M. A., Jering, K., Claggett, B., Lewis, E. F., Granger, C., Kober, L., Maggioni, A., Mann, D. L., McMurray, J. J., Rouleau, J., Solomon, S. D., Ducrocq, G., Berwanger, O., De Pasquale, C. G., Landmesser, U., Petrie, M., Leng, D. S., van der Meer, P., Lefkowitz, M., Zhou, Y., Braunwald, E. 2022

  Abstract

  BACKGROUND: In patients who survive an acute myocardial infarction (AMI), angiotensin-converting enzyme inhibitors decrease the risk of subsequent major cardiovascular events. Whether angiotensin-receptor blockade and neprilysin inhibition with sacubitril/valsartan reduce major coronary events more effectively than angiotensin-converting enzyme inhibitors in high-risk patients with recent AMI remains unknown. We aimed to compare the effects of sacubitril/valsartan on coronary outcomes in patients with AMI.METHODS: We conducted a prespecified analysis of the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitors Trial to Determine Superiority in Reducing Heart Failure Events After MI), which compared sacubitril/valsartan (97/103 mg twice daily) with ramipril (5 mg twice daily) for reducing heart failure events after myocardial infarction in 5661 patients with AMI complicated by left ventricular systolic dysfunction, pulmonary congestion, or both. In the present analysis, the prespecified composite coronary outcome was the first occurrence of death from coronary heart disease, nonfatal myocardial infarction, hospitalization for angina, or postrandomization coronary revascularization.RESULTS: Patients were randomly assigned at a median of 4.4 [3.0-5.8] days after index AMI (ST-segment-elevation myocardial infarction 76%, non-ST-segment-elevation myocardial infarction 24%), by which time 89% of patients had undergone coronary reperfusion. Compared with ramipril, sacubitril/valsartan decreased the risk of coronary outcomes (hazard ratio, 0.86 [95% CI, 0.74-0.99], P=0.04) over a median follow-up of 22 months. Rates of the components of the composite outcomes were lower in patients on sacubitril/valsartan but were not individually significantly different.CONCLUSIONS: In survivors of an AMI with left ventricular systolic dysfunction and pulmonary congestion, sacubitril/valsartan-compared with ramipril-reduced the risk of a prespecified major coronary composite outcome. Dedicated studies are necessary to confirm this finding and elucidate its mechanism.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT02924727.

  View details for DOI 10.1161/CIRCULATIONAHA.122.060841

  View details for PubMedID 36321459

• Treatment Differences in Medical Therapy for Heart Failure With Reduced Ejection Fraction Between Sociodemographic Groups. JACC. Heart failure Witting, C., Zheng, J., Tisdale, R. L., Shannon, E., Kohsaka, S., Lewis, E. F., Heidenreich, P., Sandhu, A. 2022

  Abstract

  There are sociodemographic disparities in outcomes of heart failure with reduced ejection fraction (HFrEF), but disparities in guideline-directed medical therapy (GDMT) remain poorly characterized.This study aimed to analyze GDMT treatment rates in eligible patients with recently diagnosed HFrEF, and to determine how rates vary by sociodemographic characteristics.This retrospective cohort study included patients diagnosed with HFrEF at Veterans Affairs (VA) hospitals from 2013 to 2019. The authors analyzed GDMT treatment rates and doses, excluding patients with contraindications. Therapies of interest were evidence-based beta-blockers (BBs), renin-angiotensin system inhibitors (RASIs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid antagonists (MRAs). The authors compared adjusted treatment rates by race and ethnicity, neighborhood social vulnerability, rurality, distance to medical care, and sex.The cohort comprised 126,670 VA patients with recently diagnosed HFrEF. The study found that racial and ethnic minorities had similar or higher treatment rates than White patients. Patients residing in socially vulnerable neighborhoods had 3.4% lower ARNI (95% CI: 1.9%-5.0%) treatment rates. Patients residing farther from specialty care had similar rates of GDMT therapy overall, but were less likely to be taking at least 50% of the target doses of either BBs (4.0% less likely; 95% CI: 3.1%-5.0%) or RASIs (5.0% less likely; 95% CI: 4.1%-6.0%) compared with those closer to care.Among VA patients with recently diagnosed HFrEF, the authors did not find that racial and ethnic minority patients were less likely to receive GDMT. However, appropriate dose up-titration may occur less frequently in more remote patients.

  View details for DOI 10.1016/j.jchf.2022.08.023

  View details for PubMedID 36647925

• Prevalence of cardiovascular diseases in COVID-19 related mortality in the United States. Progress in cardiovascular diseases Vasudeva, R., Challa, A., Al Rifai, M., Polana, T., Duran, B., Vindhyal, M., Lewis, E. F. 2022

  Abstract

  Several cardiovascular disease (CVD) risk factors and sequelae have been associated with COVID-19. Little is known about the distribution of CVD conditions in COVID-19 related deaths in the US population.The public-use dataset by CDC, "Conditions Contributing to COVID-19 Deaths, by State and Age, Provisional 2020-2021", was abstracted as of August 1, 2021. A descriptive analysis was conducted to explore the overall and age-specific prevalence of various CVD and risk factors grouped by pre-specified ICD-10 codes amongst COVID-19 patient deaths. Respective trends over the duration of the pandemic were analyzed using the Mann-Kendall method, including time-periods before and after the introduction of vaccines in January 2021. All time-related analysis was conducted between March 2020 and June 2021.A total of 600,241 COVID-19 related deaths were reported between March 2020 and June 2021. Hypertensive diseases were the most prevalent (19.6%), followed by diabetes (15.9%), ischemic heart disease (IHD;10.9%), heart failure (7.7%), cardiac arrhythmias (7.5%), other diseases of the circulatory system (6.6%), cerebrovascular diseases (5%), and obesity (4.1%). While a significant downward trend was noted for hypertensive diseases over the course of the pandemic, cardiac arrhythmias, heart failure (HF), obesity, and other circulatory system diseases demonstrated a significant upward trend. Since the introduction of vaccines, the trends for heart failure and cardiac arrhythmias remained steady while having demonstrated a significant rise in the pre-vaccination time-period. While obesity and other diseases of the circulatory system predominated (>50%) amongst the CVD burden in the younger population (0-24 years and 25-34 years), the percentage occurrence of cardiac arrhythmias, hypertensive diseases, HF, and IHD increased with age.Hypertensive diseases, diabetes, and IHD were the most prevalent cardiovascular conditions amongst COVID-19 related deaths. These patterns varied by age. While the trend for hypertensive diseases declined over the course of the pandemic, cardiac arrhythmias, HF, obesity, and other diseases of the circulatory system demonstrated an upward trend. An important limitation is the source of the data being limited to death certificates.

  View details for DOI 10.1016/j.pcad.2022.09.002

  View details for PubMedID 36279944

• Soluble Guanylate Cyclase Stimulators in Patients with Heart Failure with Reduced Ejection Fraction Across the Risk Spectrum. European journal of heart failure Butler, J., Usman, M. S., Anstrom, K. J., Blaustein, R. O., Bonaca, M. P., Ezekowitz, J. A., Freitas, C., Lam, C. S., Lewis, E. F., Lindenfeld, J., McMullan, C. J., Mentz, R. J., O'Connor, C., Rosano, G. M., Saldarriaga, C. I., Senni, M., Udelson, J., Voors, A. A., Zannad, F. 2022

  Abstract

  Patients with heart failure with reduced ejection fraction (HFrEF) have a high residual risk of adverse outcomes, even when treated with optimal guideline-directed medical therapy and in a clinically stable state. Sodium guanylate cyclase (sGC) stimulators have the potential to lower this risk by modifying the nitric oxide-sGC-cyclic guanosine monophosphate cascade - a pathophysiological pathway that has been targeted with limited success in HFrEF previously. Vericiguat, an sGC stimulator, was shown to improve outcomes in patients with HFrEF in the VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial. However, this trial included patients with recently worsening disease. In this brief review, we discuss the rationale of evaluating sGC stimulators in lower-risk HFrEF patients. First, all key HFrEF medications have been evaluated in both higher and lower-risk populations, and the treatment effect is not always consistent across the risk spectrum. Second, preclinical studies and post-hoc studies of the VICTORIA trial have suggested that sGC stimulators may have cardioprotective effects - these effects may be more apparent when the medication is initiated earlier in the disease process. Third, the effect of vericiguat on cardiovascular mortality remains uncertain and a trial with a longer follow-up in a lower-risk population may allow better assessment of its effect on cardiovascular mortality. Therefore, there is a pertinent need to investigate the effects of vericiguat in optimally-treated, low-risk HFrEF patients (i.e., those without recent worsening heart failure). This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.2720

  View details for PubMedID 36250238

• Left atrial inflow propagation velocity derived by color M-mode Doppler in acute heart failure. The international journal of cardiovascular imaging Johannessen, Ø., Myhre, P. L., Claggett, B., Lindner, M., Lewis, E. F., Rivero, J., Cheng, S., Platz, E. 2022; 38 (10): 2155-2165

  Abstract

  Left atrial (LA) inflow propagation velocity from the pulmonary vein (LAIF-PV) has been proposed as a novel measure of LA reservoir function and is associated with pulmonary capillary wedge pressure in critically ill patients. However, data on LAIF-PV in acute heart failure (AHF) are lacking. We sought to examine the feasibility of measuring LAIF-PV and evaluate clinical and echocardiographic correlates of LAIF-PV in AHF. In a prospective cohort study of adults hospitalized for AHF, we used color M-mode Doppler of the pulmonary veins to obtain LAIF-PV in systole. Among 142 patients with appropriate images and no more than moderate mitral regurgitation, LAIF-PV measures were feasible in 76 patients (54%) aged 71 ± 14 years, including 68% men with left ventricular ejection fraction (LVEF) 38% ± 13. Mean LAIF-PV was 24.2 ± 5.9 cm/s. In multivariable regression analysis adjusted for age, sex, systolic blood pressure, heart rate, body mass index, New York Heart Association class, LA volume and LVEF, the only independent echocardiographic predictors of LAIF-PV were right ventricular (RV) S' [ß 0.46 cm/s per cm/s (95% CI 0.01-0.91), p = 0.045] and tricuspid annular plane systolic excursion (TAPSE) [ß 0.28 cm/s per mm (95% CI 0.02-0.54), p = 0.039]. Notably, LAIF-PV was not significantly correlated with measures of LV function, LA function or E/e'. In conclusion, LAIF-PV was measurable in 54% of patients with AHF, and lower values were associated with measures of impaired RV systolic function but not LV or LA function.

  View details for DOI 10.1007/s10554-022-02614-y

  View details for PubMedID 37726456

  View details for PubMedCentralID PMC10247843

• Health-related quality of life in acute heart failure: Association between patient-reported symptoms and markers of congestion. European journal of heart failure Lee, M. M., Campbell, R. T., Claggett, B. L., Lewis, E. F., Docherty, K. F., Lindner, M., Liu, J., Solomon, S. D., McMurray, J. J., Platz, E. 2022

  Abstract

  AIMS: The aim of this study was to examine the association between patient-reported symptoms and the extent of pulmonary congestion in acute heart failure (AHF).METHODS AND RESULTS: In this prospective, observational study, patient-reported symptoms were assessed at baseline using the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) (range 0-100; 0 worst) in patients hospitalized for AHF. In a subset, patient-reported dyspnea at rest and on exertion was examined (range 0-10; 10 worst) at baseline. In addition, 4-zone lung ultrasound (LUS) was performed at baseline at the time of echocardiography. B-lines were quantified offline, blinded to clinical findings, in a core laboratory. Chest x-ray (CXR) and physical examination findings were collected from the medical records. Among 322 patients (mean age 72, 60% men, mean LVEF 39%) with AHF, the median KCCQ-TSS score was 33 [interquartile range 18-48]. Worse KCCQ-TSS was associated with worse NYHA class, dyspnea at rest and on exertion, and peripheral edema (p trend <0.001 for all). However, KCCQ-TSS was not associated with the extent of pulmonary congestion, as assessed by the number of B-lines on LUS, or findings on CXR or physical examination (p trend >0.30 for all). Similarly, KCCQ-TSS was not significantly associated with echocardiographic markers of left ventricular filling pressure, pulmonary pressure or with NT-proBNP.CONCLUSIONS: Among patients hospitalized for AHF, at baseline, KCCQ-TSS was not associated with pulmonary congestion assessed by LUS, CXR or physical examination. These findings suggest that the profound reduction in KCCQ-TSS in patients with AHF may not be solely explained by pulmonary congestion. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.2699

  View details for PubMedID 36161429

• SACUBITRIL/VALSARTAN VERSUS RAMIPRIL FOR PATIENTS WITH ACUTE MYOCARDIAL INFARCTION: WIN-RATIO ANALYSIS OF THE PARADISE-MI TRIAL. European journal of heart failure Berwanger, O., Pfeffer, M., Claggett, B., Jering, K. S., Maggioni, A. P., Steg, P. G., Mehran, R., Lewis, E. F., Zhou, Y., van der Meer, P., De Pasquale, C., Merkely, B., Filippatos, G., McMurray, J. J., Granger, C. B., Solomon, S. D., Braunwald, E. 2022

  Abstract

  BACKGROUND: The win ratio can incorporate different types of outcomes and enhance statistical power, making it a useful method for analyzing composite outcomes in cardiovascular trials. The application of this approach to the PARADISE-MI trial provides an additional perspective into understanding the effects of sacubitril/valsartan in patients with acute myocardial infarction.METHODS: We conducted a post-hoc analysis of the PARADISE-MI trial, which randomly assigned patients with acute myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril/valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to guideline-recommended therapy. The principal composite outcome was analyzed in the hierarchical order of death due to cardiovascular causes, first hospitalization for heart failure, and first outpatient episode of symptomatic heart failure. We included events confirmed by the clinical event classification (CEC) committee as well as events identified by investigators that did not meet study definitions. Results were analyzed by the unmatched win ratio method. A win ratio that exceeds 1.00 reflects a better outcome.RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. The hierarchical analysis of the principal composite outcome demonstrated a larger number of wins [1,265,767 (15.7%)] than losses [1,079,502 (13.4%)] in the sacubitril/valsartan group (win ratio of 1.17, 95% confidence interval [CI],1.03 to 1.33; P=0.015). Sensitivity analyses using alternative definitions of the composite outcome showed results similar to those of the principal analysis, except for analysis restricted to events that met CEC definitions (win ratio of 1.11, 95% CI, 0.96 to 1.30; P=0.16).CONCLUSION: In this post-hoc analysis of the PARADISE-MI trial using the win ratio and including investigator-identified events not having CEC confirmation, sacubitril/valsartan was superior to ramipril among high-risk survivors of acute myocardial infarction. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/ejhf.2663

  View details for PubMedID 36054480

• Elucidating the Clinical Implications and Pathophysiology of Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Call to Action: A Science Advisory From the American Heart Association CIRCULATION Brittain, E. L., Thenappan, T., Huston, J. H., Agrawal, V., Lai, Y., Dixon, D., Ryan, J. J., Lewis, E. F., Redfield, M. M., Shah, S. J., Maron, B. A., Amer Heart Assoc Council Cardiopul, Council Arteriosclerosis Thrombosi, Council Lifestyle Cardiometab Hlth, Stroke Council 2022; 146 (7): e73-e88

  Abstract

  This science advisory focuses on the need to better understand the epidemiology, pathophysiology, and treatment of pulmonary hypertension in patients with heart failure with preserved ejection fraction. This clinical phenotype is important because it is common, is strongly associated with adverse outcomes, and lacks evidence-based therapies. Our goal is to clarify key knowledge gaps in pulmonary hypertension attributable to heart failure with preserved ejection fraction and to suggest specific, actionable scientific directions for addressing such gaps. Areas in need of additional investigation include refined disease definitions and interpretation of hemodynamics, as well as greater insights into noncardiac contributors to pulmonary hypertension risk, optimized animal models, and further molecular studies in patients with combined precapillary and postcapillary pulmonary hypertension. We highlight translational approaches that may provide important biological insight into pathophysiology and reveal new therapeutic targets. Last, we discuss the current and future landscape of potential therapies for patients with heart failure with preserved ejection fraction and pulmonary vascular dysfunction, including considerations of precision medicine, novel trial design, and device-based therapies, among other considerations. This science advisory provides a synthesis of important knowledge gaps, culminating in a collection of specific research priorities that we argue warrant investment from the scientific community.

  View details for DOI 10.1161/CIR.0000000000001079

  View details for Web of Science ID 000843014700003

  View details for PubMedID 35862198

• 2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Bozkurt, B., Das, S. R., Addison, D., Gupta, A., Jneid, H., Khan, S. S., Koromia, G., Kulkarni, P. A., LaPoint, K., Lewis, E. F., Michos, E. D., Peterson, P. N., Turagam, M. K., Wang, T. Y., Yancy, C. W., Amer Coll Cardiology, Amer Heart Assoc Task Force Clinic 2022; 80 (4): 388-465

  View details for DOI 10.1016/j.jacc.2022.03.355

  View details for Web of Science ID 000861828600003

• Creation of the American Heart Association Journals' Equity, Diversity, and Inclusion Editorial Board: The Next Step to Achieving the 2024 Impact Goal. Circulation Lewis, E. F., Beaty, C., Boltze, J., Breathett, K., Clair, W. K., de Las Fuentes, L., Essien, U. R., Goodell, H., Hinson, H. E., Kershaw, K. N., Knowles, J. W., Mazimba, S., Mujahid, M., Okafor, H. E., Woo Park, K., Schultz, J. 2022: 101161CIRCULATIONAHA122061450

  View details for DOI 10.1161/CIRCULATIONAHA.122.061450

  View details for PubMedID 35862071

• Machine Learning and Social Determinants of Health-An Opportunity to Move Beyond Race for Inpatient Risk Prediction in Patients With Heart Failure. JAMA cardiology Lewis, E. F. 2022

  View details for DOI 10.1001/jamacardio.2022.1924

  View details for PubMedID 35793074

• 2022 AHA/ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Bozkurt, B., Das, S. R., Addison, D., Gupta, A., Jneid, H., Khan, S. S., Koromia, G., Kulkarni, P. A., LaPoint, K., Lewis, E. F., Michos, E. D., Peterson, P. N., Turagam, M. K., Wang, T. Y., Yancy, C. W. 2022; 15 (7): e000111

  View details for DOI 10.1161/HCQ.0000000000000111

  View details for Web of Science ID 000827535900006

  View details for PubMedID 35737748

• Prognostic Impact of Cardiovascular versus Noncardiovascular Hospitalizations in Heart Failure with Preserved Ejection Fraction: Insights from TOPCAT. Journal of cardiac failure Barkoudah, E., Claggett, B. L., Lewis, E. F., O'Meara, E., Clausell, N., Diaz, R., Fleg, J. L., Pitt, B., Rouleau, J. L., Solomon, S. D., Pfeffer, M. A., Desai, A. S. 2022

  Abstract

  BACKGROUND: Patients with heart failure (HF) with preserved ejection fraction (HFpEF) are commonly admitted to the hospital for both cardiovascular (CV) and noncardiovascular (non-CV) reasons. The prognostic implications of non-CV hospitalizations in this population are not well understood. In this study, we aimed to examine the prognostic implications of hospitalizations due to CV and non-CV reasons in a HFpEF population.METHODS AND RESULTS: The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial (TOPCAT) randomized 3,445 stable outpatients with chronic HF with left ventricular ejection fraction >=45% and either prior hospitalization for HF or elevated natriuretic peptides to treatment with spironolactone or placebo. Hospitalizations for any cause were reported by investigators during study follow-up and characterized according to prespecified category causes. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (N=1,767), in which 2,973 hospitalizations were observed in 1,062 subjects (60%) over a mean follow-up of 3.3 years of study follow-up, of which 1,474 (49%) were ascribed to CV causes. Among 1,056 first hospitalizations, 478 (45%) were for CV reasons and 578 (55%) for non-CV reasons. Mortality rates were lowest for participants not hospitalized during the trial (3.2 per 100 patient-years (PY)), but similarly elevated following first hospitalization for CV and non-CV reasons (11.0 per 100 PY vs. 12.6 per 100 PY, respectively, p=0.24). Among those hospitalized for CV reasons, mortality rates were similar following hospitalization for HF and non-CV related reasons (15.2 per 100 PY vs. 12.6 per 100 PY, p=0.23). Recurrent hospitalization, whether due to CV or non-CV causes, was associated with heightened risk for subsequent mortality, with similar death rates following hospitalization twice for CV reasons (18.5 per 100 PY), twice for non-CV reasons (21.6 per 100 PY), or once each for CV and non-CV reasons (18.4 per 100 PY).CONCLUSION: Among patients with HFpEF, hospitalization for any cause is associated with heightened risk for post-discharge mortality, with even higher risk associated with recurrent hospitalization. Given the high burden of non-CV hospitalizations in this population, targeted management of comorbid medical illness may be critical to reducing morbidity and mortality.

  View details for DOI 10.1016/j.cardfail.2022.05.004

  View details for PubMedID 35636727

• The Trial to Assess Chelation Therapy 2 (TACT2): Rationale and Design. American heart journal Lamas, G. A., Anstrom, K. J., Navas-Acien, A., Boineau, R., Kim, H., Rosenberg, Y., Stylianou, M., Jones, T. L., Joubert, B. R., Santella, R. M., Escolar, E., Aude, Y. W., Fonseca, V., Elliott, T., Lewis, E. F., Farkouh, M. E., Nathan, D. M., Mon, A. C., Gosnell, L., Newman, J. D., Mark, D. B., TACT2 Investigators 2022

  Abstract

  The Trial to Assess Chelation Therapy 2 (TACT2) is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are being followed for 2.5 to 5 years. The primary endpoint is a composite of the time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial is designed to have >85% power to detect a 30% relative reduction in the primary endpoint for each active treatment versus placebo comparison. TACT2 also includes a Trace Metals and Biorepository Core Lab, which will test the novel hypothesis that the prognostic benefits of chelation, if present, are due to removal of lead and cadmium from patients. Most of the design features of TACT2 were chosen to replicate selected features of the first TACT trial, which demonstrated a statistically significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. Results from TACT2, if concordant with TACT, will provide definitive evidence of the benefit of edetate disodium-based chelation on cardiovascular outcomes, as well as the possible clinical importance of longitudinal changes in toxic metal levels of participants.

  View details for DOI 10.1016/j.ahj.2022.05.013

  View details for PubMedID 35598636

• Effect of continuous positive airway pressure treatment on ambulatory blood pressures in high-risk sleep apnea patients: a randomized controlled trial. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine Zhao, Y. Y., Wang, R., Gleason, K. J., Lewis, E. F., Quan, S. F., Toth, C. M., Song, Y., Morrical, M., Rueschman, M., Mittleman, M. A., Redline, S. 2022

  Abstract

  STUDY OBJECTIVES: The long-term effect of continuous positive airway pressure (CPAP) on 24-hour blood pressure (BP) in high-risk patients with obstructive sleep apnea (OSA) is uncertain. We aimed to determine the effect of CPAP treatment on ambulatory BP in individuals with moderate or severe OSA and cardiovascular disease (CVD) or multiple CVD risk factors without severe sleepiness.METHODS: In this randomized, controlled, parallel group study, 169 participants were randomly assigned to CPAP treatment or the control group. The primary outcome was the change in mean 24-hour systolic BP between groups from baseline to the average of 6 and 12 month measurements using mixed effect linear regression models.RESULTS: The 24-hour systolic BP did not significantly differ by group, although there was a trend of decrease in the CPAP group (treatment effect -2.7 mm Hg [95% confidence interval -5.9 to 0.6]; P=0.105) compared with control. CPAP had the greatest effect on nighttime systolic BP (treatment effect -5.9 mm Hg [95% confidence interval -9.9 to -1.9]; P=0.004). Similar improvements in other nocturnal BP indices were observed.CONCLUSIONS: In high risk patients with moderate-severe OSA without severe sleepiness, CPAP resulted in modest BP improvements over 6 to 12 months of follow-up, with possibly larger effects for nocturnal BP. Use of office blood pressure may under-estimate the effect of CPAP on BP profile in patients with OSA.CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Sleep Apnea Intervention for Cardiovascular Disease Reduction; Identifier: NCT01261390; URL: https://clinicaltrials.gov/ct2/show/NCT01261390.

  View details for DOI 10.5664/jcsm.10012

  View details for PubMedID 35459446

• Left atrial inflow propagation velocity derived by color M-mode Doppler in acute heart failure INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Johannessen, O., Myhre, P. L., Claggett, B., Lindner, M., Lewis, E. F., Rivero, J., Cheng, S., Platz, E. 2022

  View details for DOI 10.1007/s10554-022-02614-y

  View details for Web of Science ID 000785915500003

• Health System-Level Performance in Prescribing Guideline-Directed Medical Therapy for Patients with HFrEF: Results from the CONNECT-HF Trial. Journal of cardiac failure Granger, B. B., Kaltenbach, L. A., Fonarow, G. C., Allen, L. A., Lanfear, D. E., Albert, N. M., Al-Khalidi, H. R., Butler, J., Cooper, L. B., DeWald, T., Felker, G. M., Heidenreich, P., Kottam, A., Lewis, E. F., Pina, I. L., Yancy, C. W., Granger, C. B., Hernandez, A. F., DeVore, A. D. 2022

  Abstract

  BACKGROUND: Health system-level interventions to improve use of guideline-directed medical therapy (GDMT) often fail in the acute care setting. We sought to identify factors associated with high performance in adoption of GDMT among health systems in CONNECT-HF.METHODS AND RESULTS: Site-level composite quality scores were calculated at discharge and last follow-up. Site performance was defined as the average change in score from baseline to last follow-up and analyzed by performance tertile using a mixed-effects model with baseline performance as a fixed effect and site as a random effect. Among 150 randomized sites, mean 12-month improvement in GDMT was 1.8% (-26.4% to 60.0%). Achievement of ≥50% target dose for angiotensin-converting enzymes/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors and beta blockers at 12 months was modest, even at the highest performing sites (median 29.6% [23%, 41%] and 41.2% [29%, 50%]). Sites achieving higher GDMT scores had care teams that included social workers and pharmacists and patients able to afford medications and access medication lists in the electronic health record.CONCLUSIONS: Substantial gaps in site-level use of GDMT were found even among highest performing sites. Failure of hospital-level interventions to improve quality metrics suggests that a team-based approach to care and improved patient access to medications are needed for post-discharge success.

  View details for DOI 10.1016/j.cardfail.2022.03.356

  View details for PubMedID 35462033

• Risk Estimates of Imminent Cardiovascular Death and Heart Failure Hospitalization Are Improved Using Serial Natriuretic Peptide Measurements in Patients With Coronary Artery Disease and Type 2 Diabetes. Journal of the American Heart Association Wolsk, E., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H. C., Kober, L., Lewis, E. F., Maggioni, A. P., McMurray, J. J., Probstfield, J. L., Riddle, M. C., Solomon, S. D., Tardif, J., Pfeffer, M. A. 2022: e021327

  Abstract

  Background Baseline and temporal changes in natriuretic peptide (NP) concentrations have strong prognostic value with regard to long-term cardiovascular risk stratification. To increase the clinical utility of NP sampling for patient management, we wanted to assess the incremental predictive value of 2 serial NP measurements compared with a single measurement and provide absolute risk estimates for cardiovascular death or heart failure hospitalization (HFH) within 6months based on 2 serial NP measurements. Methods and Results Consecutive NP samples obtained from 5393 patients with a recent coronary event and type 2 diabetes enrolled in the ELIXA (Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With Lixisenatide) trial were used to construct best logistic regression models with outcome of cardiovascular death or HFH (136 events). Absolute risk estimates of cardiovascular death or HFH within 6months using either BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal pro-BNP) serial measurements were depicted based on the concentrations of 2 serial NP measurements. During the 6-month follow-up periods, the incidence rate (±95% CIs) of cardiovascular death or HFH for patients was 14.0 (11.8‒16.6) per 1000 patient-years. Risk prediction depended on NP concentrations from both prior and current sampling. NP sampling 6months apart improved the predictive value and reclassification of patients compared with a single sample (AUROC [Area Under the Receiver Operating Characteristic curve]: BNP, P=0.003. NT-proBNP, P<0.0001), with a majority of moderate-risk patients (6-month risk between 1% and 10%) being reclassified on the basis of the second NP sample. Conclusions Serial NP measurements improved prediction of imminent cardiovascular death or HFH in patients with coronary artery disease and type 2 diabetes. The absolute risk estimates provided may aid clinicians in decision-making and help patients understand their short-term risk profile.

  View details for DOI 10.1161/JAHA.121.021327

  View details for PubMedID 35383463

• Performance On Guideline Directed Medical Therapy Remains Low In A Cluster-randomized Trial: Results From CONNECT-HF GRANGER, B. I., DEVORE, A. M., KALTENBACH, L. A., FONAROW, G. G., AL-KHALIDI, H. N., ALBERT, N. Y., LEWIS, E. N., BUTLER, J. D., PINA, I. A., HEIDENREICH, P. L., ALLEN, L. Y., YANCY, C. E., COOPER, L. N., FELKER, M. L., MCRAE, A. W., LANFEAR, D. D., HARRISON, R. T., DISCH, M. E., ARIELY, D. N., MILLER, J. E., GRANGER, C. R., HERNANDEZ, A. N. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2022: S43

  View details for Web of Science ID 000788638800109

• Cardiac structure and function and quality of life associations in HFpEF: An analysis from TOPCAT-Americas. International journal of cardiology Ferreira, J. P., Shah, A. M., Claggett, B. L., Pitt, B., Lewis, E. F., Solomon, S. D., Zannad, F. 1800

  Abstract

  BACKGROUND: Patients with heart failure with preserved ejection fraction (HFpEF) have poor health-related quality of life (HR-QoL). However, the relationship between HR-QoL measures and the alterations of cardiac structure and function that are present in patients with HFpEF remains unknown.AIMS: To study the associations between HR-QoL and echocardiographic parameters in HFpEF.METHODS: Regression modelling in patients from TOPCAT-Americas who had both HR-QoL questionnaires and a baseline echocardiogram.RESULTS: A total of 631 patients (36% of the TOPCAT-Americas population) had both echocardiographic and HR-QoL at baseline. KCCQ-23 Overall Summary Score (OSS; 0-100 points) was negatively (higher echocardiographic values-poorer/lower HR-QoL scores) associated with left ventricular end-diastolic diameter (LVEDD: beta=-3.56 [-7.00 to -0.13] points-per-1cm, P=0.042), interventricular septum thickness (beta=-1.31 [-2.19 to -0.42] points-per-1mm, P=0.004), posterior wall thickness (beta=-1.57 [-2.52 to -0.63] points-per-1mm, P=0.001 and left atrial width (beta=-3.27 [-6.39 to -0.15], P=0.040) points-per-1cm, and positively (higher echocardiographic values-better/higher HR-QoL scores) associated with left ventricular end-diastolic volume index (LVEDVi: beta=0.23 [0.09 to 0.37] points-per-1ml/m2, P=0.002) and left ventricular end-systolic volume index (LVESVi: beta=0.41 [0.18 to 0.63] points-per-1ml/m2, P<0.001). Body mass index (BMI: beta=-0.74 [-1.02 to -0.47] points-per-1Kg/m2, P<0.001), diabetes (beta=-6.01 [-10.05 to -1.97], P=0.004), and asthma (beta=-6.78 [-13.52 to -0.04], P=0.049) were negatively associated with OSS. A similar pattern of associations was observed for KCCQ-23 Clinical Summary Score, EQ5D-VAS and NYHA class.CONCLUSION: In patients with HFpEF, HR-QoL measures were associated with cardiac structure and function alterations. Extra-cardiac factors were also associated with HR-QoL, which may influence HR-QoL results when testing cardiovascular drugs.

  View details for DOI 10.1016/j.ijcard.2022.01.053

  View details for PubMedID 35101539

• Race and Ethnicity in HeartFailure: JACC Focus Seminar 8/9. Journal of the American College of Cardiology Pina, I. L., Jimenez, S., Lewis, E. F., Morris, A. A., Onwuanyi, A., Tam, E., Ventura, H. O. 2021

  Abstract

  Heart failure (HF) affects >6 million Americans, with variations in incidence, prevalence, and clinical outcomes by race/ethnicity. Black adults have the highest risk for HF, with earlier age of onset and the highest risk of death and hospitalizations. The risk of hospitalizations for Hispanic patients is higher than White patients. Data on HF in Asian individuals are more limited. However, the higher burden of traditional cardiovascular risk factors, particularly among South Asian adults, is associated with increased risk of HF. The role of environmental, socioeconomic, and other social determinants of health, more likely for Black and Hispanic patients, are increasingly recognized as independent risk factors for HF and worse outcomes. Structural racism and implicit bias are drivers of health care disparities in the United States. This paper will review the clinical, physiological, and social determinants of HF risk, unique for race/ethnic minorities, and offer solutions to address systems of inequality that need to be recognized and dismantled/eradicated.

  View details for DOI 10.1016/j.jacc.2021.06.058

  View details for PubMedID 34887145

• Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction. The New England journal of medicine Pfeffer, M. A., Claggett, B., Lewis, E. F., Granger, C. B., Kober, L., Maggioni, A. P., Mann, D. L., McMurray, J. J., Rouleau, J., Solomon, S. D., Steg, P. G., Berwanger, O., Cikes, M., De Pasquale, C. G., East, C., Fernandez, A., Jering, K., Landmesser, U., Mehran, R., Merkely, B., Vaghaiwalla Mody, F., Petrie, M. C., Petrov, I., Schou, M., Senni, M., Sim, D., van der Meer, P., Lefkowitz, M., Zhou, Y., Gong, J., Braunwald, E., PARADISE-MI Investigators and Committees, Pfeffer, M., Braunwald, E., Granger, C. B., Kober, L., Mann, D. L., Maggioni, A. P., McMurray, J. J., Rouleau, J. L., Solomon, S. D., Steg, P. G., Dargie, H., Foley, R., Francis, G. S., Komajda, M., Pocock, S., Lewis, E., Barkoudah, E., Brahimi, A., Correa-Gaviria, S., Cunningham, J., Finn, P., Hartley, H., Jering, K., McCausland, F. R., McGrath, M. M., Vaduganathan, M., Duong, C., Mercier, R., Roach, A., Saunders-Correa, B., Wivagg, A., Charytan, D., Joseph, J., Kaplan, A. P., Busse, P., Zuraw, B., Claggett, B., Fernandez, A., Barrionuevo, M., Albisu, J., Avaca, H., Brasca, D., Cartasegna, L., Casas, M., Costabel, J., de la Fuente, R., Duronto, E., Ferre Pacora, F., Guetta, J., Hominal, M., Hrabar, A., Luquez, H., Macin, S., Muntaner, J., Nani, S., Pizarro, R., Poy, C., Prado, A., Schiavi, L., Wenetz, L., Zapata, G., Zivano, D., De Pasquale, C., Amerena, J., Atherton, J., Lam, K., McKenzie, S., Roberts-Thomson, P., von Lewinski, D., Auer, J., Ebner, C., Hoppe, U., Mortl, D., Schober, A., Zaruba, M., Claeys, M., Cools, F., Gabriel, L., Janssens, S., Mullens, W., Van der Stighelen, H., Vanduynhoven, P., Berwanger, O., Arantes, F., Kormann, A., Maia, L., Manenti, E., Neuenschwander, F., Nicolau, J., Pimentel Filho, P., Precoma, D., Rassi, S., Rossi, P., Saraiva, J., Silva, R., Petrov, I., Atanasov, A., Dimitrov, C., Dimov, B., Gatzov, P., Jorgova Makedonska, J., Konteva, M., Markov, D., Mazhdrakov, G., Milanova, M., Panayotov, P., Raev, D., Stavreva, E., Stoyanov, M., Tisheva Gospodinova, S., Tokmakova, M., Tzekova, M., Tanguay, J., Gosselin, G., Mielniczuk, L., Moe, G., Robinson, S., Rodes-Cabau, J., Sia, Y., Welsh, R., Han, Y., Bai, F., Chen, J., Chen, H., Dong, Y., Fu, L., Gao, W., Gong, H., Huang, W., Li, Y., Li, X., Liu, S., Liu, F., Peng, D., Shen, A., Su, G., Sun, Y., Sun, J., Xu, B., Kong, X., Yao, Z., Yu, Z., Yuan, Z., Yuan, J., Zhou, Y., Cadena Bonfanti, A. J., Arana, C., Botero, R., Chavarriaga, J., Garcia, R., Gomez, E., Cikes, M., Gabor, M., Milicic, D., Trbusic, M., Widimsky, P., Belohlavek, J., Coufal, Z., Hromadka, M., Kala, P., Kettner, J., Motovska, Z., Podpera, I., Polasek, R., Schou, M., Due Vestergaard, L., Egstrup, K., Hollingdal, M., Koeber, L., Taskiran, M., Vraa, S., Vikman, S., Jaaskelainen, P., Nyman, K., Steg, G., Angoulvant, D., Barone-Rochette, G., Coste, P., Dubreuil, O., Elbaz, M., Henry, P., Mewton, N., Puymirat, E., Rosamel, Y., Landmesser, U., Bott, M., Brachmann, J., Cuneo, A., Dahl, J., Felix, S., Gutersohn, A., Haude, M., Horacek, T., Huegl, B., Jung, W., Kadel, C., Leschke, M., Lutz, M., Menck, N., Minden, H., Mittag, M., Nordbeck, P., Pfister, R., Pulz, J., Rassaf, T., Schwefer, M., Schwimmbeck, P., von Scheidt, W., Wienbergen, H., Winzer, E., Wolf, D., Yueksel, D., Zeh, W., Zeiher, A., Zeymer, U., Filippatos, G., Giamouzis, G., Karavidas, A., Milkas, A., Paraskevaidis, I., Patsilinakos, S., Tsioufis, K., Tziakas, D., Merkely, B., Andreka, P., Edes, I., Forster, T., Horvath, I., Kiss, R., Lupkovics, G., Noori, E., Tomcsanyi, J., Kerkar, P., Abdullakutty, J., Agarwal, D., Bhalani, N., Bhatia, T., Chanana, B., Chopada, M., Deshmukh, P., Hiremath, S., Karna, S., Mehta, A., Mittal, S., Premchand, R., Rathnavel, S., Ravikanth, A., Shah, U., Amir, O., Arbel, Y., Eisen, A., Halabi, M., Katz, A., Kinany, W., Zukerman, R., Senni, M., Barilla, F., Calabro, P., Camporotondo, R., Cannarile, P., D'Aiello, I., Ferrante, G., Fucili, A., Indolfi, C., Marenzi, G., Metra, M., Oliva, F., Pedone, C., Piovaccari, G., Prati, F., Sinagra, G., Taddei, F., Carrillo-Calvillo, J., Baleon, F., Bazzoni, A., de Los Rios, M., Leon, S., Rodriguez, J., Virgen, L., van der Meer, P., Al-Windy, N., De Nooijer, C., En Hartog, F., Dirksen, M., Elvan, A., Hamer, B., Jansen, A., Keijzers, M., Linssen, G., Magro, M., Manintveld, O., Nierop, P., Roemer, T., Schaap, J., Swart, H., Symersky, T., Troquay, R., van de Wal, R., van Heerebeek, L., Westendorp, I., Zoet, S., Gullestad, L., Al-Ani, R., Manhenke, C., Lema, J., Nunez, P., Rodriguez, A., Roldan, Y., Sanabria, E., Anonuevo, J., Abola, M., Sison, J., Tirador, L., Opolski, G., Blaszczak, P., Gil, R., Sobkowicz, B., Suckiel, M., Morais, J., Almeida, F., Azevedo, P., Brito, D., Ferreira, J., Lourenco, C., Marques, N., Moreira, J., Oliveira, L., Pereira, H., Pernencar, S., Cho, M., Jeong, M., Shim, W., Yoo, B., Vinereanu, D., Babes, K., Benedek, I., Chioncel, O., Ciobotaru, G., Dorobantu, M., Giuca, A., Iancu, A., Ionac, A., Militaru, C., Popescu, A., Rusu, R., Serban, L., Sinescu, C., Spiridon, M., Stanciulescu, G., Teodorescu, I., Teodoru, M., Todea, B., Tomescu, M., Barbarash, O., Agafina, A., Baranov, E., Berns, S., Boldueva, S., Kashtalap, V., Khaisheva, L., Khirmanov, V., Klein, G., Kobalava, Z., Kosmacheva, E., Kostenko, V., Lipchenko, A., Lomakin, N., Nosov, V., Petrov, A., Pevzner, D., Reznik, E., Ryabov, V., Scheglova, L., Shogenov, Z., Shvarts, Y., Timofeev, A., Yakovlev, A., Zykov, M., Sim Kheng Leng, D., D, S., Liew, M., Studencan, M., Blasko, P., Hudec, M., Jankajova, M., Slanina, M., Stevlik, J., Tomasovic, B., Ntsekhe, M., Corbett, C., Dawood, S., Gould, T., van Zyl, L., Nunez Villota, J., Bayon, J., Bueno, H., Crespo, M., Garcia, C., Garcia, E., Garcia, J., Gomez, J., Miro, V., Pascual, D., Pena, G., Reyes, A., Sionis, A., Christersson, C., Aladellie, L., Frick, M., Lonnberg, I., Mokhtari, A., Skoglund, K., Toernerud, M., Utter, F., Moccetti, T., Hunziker, L., Suter, T., Kobza, R., Maeder, M., Kao, H., Su, C. H., Chiang, C. Y., Tsao, H. M., Wen, M. S., Lo, P. H., Sung, S. H., Wu, Y. W., Kiatchoosakun, S., Ariyachaipanich, A., Kuanprasert, S., Sriratanasathavorn, C., Birhan Yilmaz, M., Akin, M., Badak, O., Cavusoglu, Y., Celik, O., Celik, A., Gecmen, C., Keles, T., Kutlu, M., Sahin, T., Turgut, O., Yigit, Z., Petrie, M., Zaman, A., Austin, D., Dixon, L., Glover, J., Hall, A., Jhund, P., Lee, K., Moriarty, A., O'Kane, P., Ryding, A., Squire, I., Trevelyan, J., Venugopal, V., East, C., Mehran, R., Mody, F., Ahmad, H., Alviar, C., Amidon, T., Ariani, M., Arora, V., Barman, N., Baron, S., Barringhaus, K., Bass, K., Bernstein, M., Bhagwat, R., Birchem, J., Blair, G., Blick, D., Cavender, M., Cebe, J., Chen, M., Cohn, J., Colfer, H., Dib, N., Duffy, B., Erickson, B., Fischer, S., Fung, G., Ghazi, F., Go, J., Graham, B., Gudipati, C., Guynes, R., Haddad, T., Hage, F., Hamzeh, I., Harris, B., Harrison, R., Hawa, Z., Heilman, K., Hinchman, D., Horwitz, P., Huth, M., Iteld, B., Jaffrani, N., Jain, A., Kang, G., Khant, R., Kono, A., Kozak, M., Kumar, V., Landers, D., Laney, P., Lombardo, D., Maheshwari, A., McGinty, J., McMillan, E., Mikdadi, G., Miller, G., Moustakakis, E., Nader, S., Nelson, W., O'Brien, T., Olson, C., Ooi, H., Prasanna, V., Prashad, R., Rees, A., Rennyson, S., Rogers, C., Schultz, J., Shah, R., Sharma, S., Singh, N., Sizemore, B., Soverow, J., Steuter, J., Suh, D., Tolerico, P., Tran, H., Treasure, C., Wallace, E., Wang, J., Wang, L., Wiseman, A., Zughaib, M. 2021; 385 (20): 1845-1855

  Abstract

  BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking.METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first.RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P=0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group.CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

  View details for DOI 10.1056/NEJMoa2104508

  View details for PubMedID 34758252

• Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction. Circulation. Heart failure Minamisawa, M., Claggett, B., Suzuki, K., Hegde, S. M., Shah, A. M., Desai, A. S., Lewis, E. F., Shah, S. J., Sweitzer, N. K., Fang, J. C., Anand, I. S., O'Meara, E., Rouleau, J., Pitt, B., Pfeffer, M. A., Solomon, S. D., Vardeny, O. 2021: CIRCHEARTFAILURE120008293

  Abstract

  BACKGROUND: Polypharmacy is associated with a poor prognosis in the elderly, however, information on the association of polypharmacy with cardiovascular outcomes in heart failure with preserved ejection fraction is sparse. This study sought to investigate the relationship between polypharmacy and adverse cardiovascular events in patients with heart failure with preserved ejection fraction.METHODS: Baseline total number of medications was determined in 1758 patients with heart failure with preserved ejection fraction enrolled in the Americas regions of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist), by 3 categories: nonpolypharmacy (<5 medications), polypharmacy (5-9), and hyper-polypharmacy (≥10). We examined the relationship of polypharmacy status with the primary outcome (cardiovascular death, HF hospitalization, or aborted cardiac arrest), hospitalizations for any reason, and serious adverse events.RESULTS: The proportion of patients taking 5 or more medications was 92.5% (inclusive of polypharmacy [38.7%] and hyper-polypharmacy [53.8%]). Over a 2.9-year median follow-up, compared with patients with polypharmacy, hyper-polypharmacy was associated with an increased risk for the primary outcome, hospitalization for any reason and any serious adverse events in the univariable analysis, but not significantly associated with mortality. After multivariable adjustment for demographic and comorbidities, hyper-polypharmacy remained significantly associated with an increased risk for hospitalization for any reason (hazard ratio, 1.22 [95% CI, 1.05-1.41]; P=0.009) and any serious adverse events (hazard ratio, 1.23 [95% CI, 1.07-1.42]; P=0.005), whereas the primary outcome was no longer statistically significant.CONCLUSIONS: Hyper-polypharmacy was common and associated with an elevated risk of hospitalization for any reason and any serious adverse events in patients with heart failure with preserved ejection fraction. There were no significant associations between polypharmacy status and mortality.

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.008293

  View details for PubMedID 34674539

• Association of Myocardial Blood Flow Reserve With Adverse Left Ventricular Remodeling in Patients With Aortic Stenosis: The Microvascular Disease in Aortic Stenosis (MIDAS) Study. JAMA cardiology Zhou, W., Sun, Y., Divakaran, S., Bajaj, N. S., Gupta, A., Chandra, A., Morgan, V., Barrett, L., Martell, L., Bibbo, C. F., Hainer, J., Lewis, E. F., Taqueti, V. R., Dorbala, S., Blankstein, R., Slomka, P., Shah, P. B., Kaneko, T., Adler, D. S., O'Gara, P., Di Carli, M. F. 2021

  Abstract

  Importance: Impaired myocardial flow reserve (MFR) and stress myocardial blood flow (MBF) on positron emission tomography (PET) myocardial perfusion imaging may identify adverse myocardial characteristics, including myocardial stress and injury in aortic stenosis (AS).Objective: To investigate whether MFR and stress MBF are associated with LV structure and function derangements, and whether these parameters improve after aortic valve replacement (AVR).Design, Setting, and Participants: In this single-center prospective observational study in Boston, Massachusetts, from 2018 to 2020, patients with predominantly moderate to severe AS underwent ammonia N13 PET myocardial perfusion imaging for myocardial blood flow (MBF) quantification, resting transthoracic echocardiography (TTE) for assessment of myocardial structure and function, and measurement of circulating biomarkers for myocardial injury and wall stress. Evaluation of health status and functional capacity was also performed. A subset of patients underwent repeated assessment 6 months after AVR. A control group included patients without AS matched for age, sex, and summed stress score who underwent symptom-prompted ammonia N13 PET and TTE within 90 days.Exposures: MBF and MFR quantified on ammonia N13 PET myocardial perfusion imaging.Main Outcomes and Measures: LV structure and function parameters, including echocardiographic global longitudinal strain (GLS), circulating high-sensitivity troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-pro BNP), health status, and functional capacity.Results: There were 34 patients with AS (1 mild, 9 moderate, and 24 severe) and 34 matched control individuals. MFR was independently associated with GLS and LV ejection fraction, (beta,-0.31; P=.03; beta, 0.41; P=.002, respectively). Stress MBF was associated with hs-cTnT (unadjusted beta, -0.48; P=.005) and log NT-pro BNP (unadjusted beta, -0.37; P=.045). The combination of low stress MBF and high hs-cTnT was associated with higher interventricular septal thickness in diastole, relative wall thickness, and worse GLS compared with high stress MBF and low hs-cTnT (12.4 mm vs 10.0 mm; P=.008; 0.62 vs 0.46; P=.02; and -13.47 vs -17.11; P=.006, respectively). In 9 patients studied 6 months after AVR, mean (SD) MFR improved from 1.73 (0.57) to 2.11 (0.50) (P=.008).Conclusions and Relevance: In this study, in AS, MFR and stress MBF were associated with adverse myocardial characteristics, including markers of myocardial injury and wall stress, suggesting that MFR may be an early sensitive marker for myocardial decompensation.

  View details for DOI 10.1001/jamacardio.2021.3396

  View details for PubMedID 34524397

• A fourth pillar for all in the treatment of heart failure. European heart journal Lewis, E. F. 2021

  View details for DOI 10.1093/eurheartj/ehab612

  View details for PubMedID 34516624

• Effect of a Hospital and Postdischarge Quality Improvement Intervention on Clinical Outcomes and Quality of Care for Patients With Heart Failure With Reduced Ejection Fraction: The CONNECT-HF Randomized Clinical Trial. JAMA DeVore, A. D., Granger, B. B., Fonarow, G. C., Al-Khalidi, H. R., Albert, N. M., Lewis, E. F., Butler, J., Pina, I. L., Allen, L. A., Yancy, C. W., Cooper, L. B., Felker, G. M., Kaltenbach, L. A., McRae, A. T., Lanfear, D. E., Harrison, R. W., Disch, M., Ariely, D., Miller, J. M., Granger, C. B., Hernandez, A. F. 2021; 326 (4): 314-323

  Abstract

  Importance: Adoption of guideline-directed medical therapy for patients with heart failure is variable. Interventions to improve guideline-directed medical therapy have failed to consistently achieve target metrics, and limited data exist to inform efforts to improve heart failure quality of care.Objective: To evaluate the effect of a hospital and postdischarge quality improvement intervention compared with usual care on heart failure outcomes and care.Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 161 US hospitals and included 5647 patients (2675 intervention vs 2972 usual care) followed up after a hospital discharge for acute heart failure with reduced ejection fraction (HFrEF). The trial was performed from 2017 to 2020, and the date of final follow-up was August 31, 2020.Interventions: Hospitals (n=82) randomized to a hospital and postdischarge quality improvement intervention received regular education of clinicians by a trained group of heart failure and quality improvement experts and audit and feedback on heart failure process measures (eg, use of guideline-directed medical therapy for HFrEF) and outcomes. Hospitals (n=79) randomized to usual care received access to a generalized heart failure education website.Main Outcomes and Measures: The coprimary outcomes were a composite of first heart failure rehospitalization or all-cause mortality and change in an opportunity-based composite score for heart failure quality (percentage of recommendations followed).Results: Among 5647 patients (mean age, 63 years; 33% women; 38% Black; 87% chronic heart failure; 49% recent heart failure hospitalization), vital status was known for 5636 (99.8%). Heart failure rehospitalization or all-cause mortality occurred in 38.6% in the intervention group vs 39.2% in usual care (adjusted hazard ratio, 0.92 [95% CI, 0.81 to 1.05). The baseline quality-of-care score was 42.1% vs 45.5%, respectively, and the change from baseline to follow-up was 2.3% vs -1.0% (difference, 3.3% [95% CI, -0.8% to 7.3%]), with no significant difference between the 2 groups in the odds of achieving a higher composite quality score at last follow-up (adjusted odds ratio, 1.06 [95% CI, 0.93 to 1.21]).Conclusions and Relevance: Among patients with HFrEF in hospitals randomized to a hospital and postdischarge quality improvement intervention vs usual care, there was no significant difference in time to first heart failure rehospitalization or death, or in change in a composite heart failure quality-of-care score.Trial Registration: ClinicalTrials.gov Identifier: NCT03035474.

  View details for DOI 10.1001/jama.2021.8844

  View details for PubMedID 34313687

• Disparity in the Setting of Incident Heart Failure Diagnosis. Circulation. Heart failure Sandhu, A. T., Tisdale, R. L., Rodriguez, F., Stafford, R. S., Maron, D. J., Hernandez-Boussard, T., Lewis, E., Heidenreich, P. A. 2021: CIRCHEARTFAILURE121008538

  Abstract

  BACKGROUND: Early heart failure (HF) recognition can reduce morbidity, yet HF is often initially diagnosed only after a patient clinically worsens. We sought to identify characteristics that predict diagnosis in the acute care setting versus the outpatient setting.METHODS: We estimated the proportion of incident HF diagnosed in the acute care setting (inpatient hospital or emergency department) versus outpatient setting based on diagnostic codes from a claims database covering commercial insurance and Medicare Advantage between 2003 and 2019. After excluding new-onset HF potentially caused by a concurrent acute cause (eg, acute myocardial infarction), we identified demographic, clinical, and socioeconomic predictors of diagnosis setting. Patients were linked to their primary care clinicians to evaluate diagnosis setting variation across clinicians.RESULTS: Of 959 438 patients with new HF, 38% were diagnosed in acute care. Of these, 46% had potential HF symptoms in the prior 6 months. Over time, the relative odds of acute care diagnosis increased by 3.2% annually after adjustment for patient characteristics (95% CI, 3.1%-3.3%). Acute care diagnosis setting was more likely for women compared with men (adjusted odds ratio, 1.11 [95% CI, 1.10-1.12]) and for Black patients compared with White patients (adjusted odds ratio, 1.18 [95% CI, 1.16-1.19]). The proportion of acute care diagnosis varied substantially (interquartile range: 24%-39%) among clinicians after adjusting for patient-level risk factors.CONCLUSIONS: A large proportion of first HF diagnoses occur in the acute care setting, particularly among women and Black patients, yet many had potential HF symptoms in the months before acute care visits. These results raise concerns that many HF diagnoses are missed in the outpatient setting. Earlier diagnosis could allow for timelier high-value interventions, addressing disparities and reducing the progression of HF.

  View details for DOI 10.1161/CIRCHEARTFAILURE.121.008538

  View details for PubMedID 34311559

• Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD. The New England journal of medicine Chertow, G. M., Pergola, P. E., Farag, Y. M., Agarwal, R., Arnold, S., Bako, G., Block, G. A., Burke, S., Castillo, F. P., Jardine, A. G., Khawaja, Z., Koury, M. J., Lewis, E. F., Lin, T., Luo, W., Maroni, B. J., Matsushita, K., McCullough, P. A., Parfrey, P. S., Roy-Chaudhury, P., Sarnak, M. J., Sharma, A., Spinowitz, B., Tseng, C., Tumlin, J., Vargo, D. L., Walters, K. A., Winkelmayer, W. C., Wittes, J., Eckardt, K., PRO2TECT Study Group, Porto, A., Glenny, J., Alvarisqueta, A., Vallejos, A., Cusumano, C., Chacon, C., Garcia, C., Goycoa, C., Stoppa, D., Otreras, F., Gorosito, G., Beresan, H., MacKinnon, I., Resk, J., Santos, J., Bittar, J., Schiavi, L., Rista, L., Maurich, M., Mansilla, M., Pelagagge, M., Garcia, N., Penalba, N., Ramallo, P., Calella, P., Leon de la Fuente, R., Visco, V., Irish, A., McMahon, L., Mathew, M., Suranyi, M., Boudville, N., Phoon, R., Ford, S., McDonald, S., Ludvik, B., Wiesholzer, M., Costa E Forti, A., Sousa, A., Goncalves, B., Teles Barretto, C., Fraga, C., Rinaldi Dos Santos, D., Miltersteiner, D., D'Avila, D., Contieri, F., Veronese, F., Neto, G., Sander, G., de Lourdes Noronha, I., Rodrigues Bacci, M., Gomes Bastos, M., Mara da Silva, M., Canziani, M., Paschoalin, N., Simoes Pires von Eye, O., Macedo de Souza, P., Silva, P., Armani, R., Barbieri, D., Paschoalin, R., Montenegro, R. J., Franco, R., Pecoits Filho, R., Yamada, S., Duro Garcia, V., Vasileva, A., Angelova, A., Kostadinova, A., Kundurdziev, A., Bogov, B., Kostadinova, D., Popov, I., Ashikova, K., Nikolova-Dimitrova, M., Petrova-Obretenova, P., Rangelov, R., Boyadzhieva, S., Vasilev, S., Bakardzhiev, T., Staykova, T., Atanasova, V., Hristov, V., Iliev, V., Simeonov, V., Todorova, V., Hristozov, V., Ting, R., Boltansky Brenner, A., Schneider Contreras, H., Garcia Lozada, H., Rueda Hernandez, J., Terront Lozano, M., Parikova, A., Dusilova Sulkova, S., Tesar, V., Mariat, C., Thervet, E., Fessi, H., Kazes, I., Lang, P., Rosenberger, C., Draganova, D., Toussaint, K., Krueger, T., Ladanyi, A., Palinkas, A., Csiky, B., Literati-Nagy, B., Pall, D., Magyar, K., Major, L., Zsom, M., Molnar, M., Keresztesi, S., Zolyomi, S., Szabo, T., Szelestei, T., Nemeth, Z., Szigeti, Z., Beberashvili, I., Hassan, K., Assady, S., Yagil, Y., Naticchia, A., Gambaro, G., Esposito, C., Aucella, F., Garibotto, G., Nicola, L. D., Vecchio, L. D., Zacchia, M., Ondei, P., David, S., Yang, C., Koh, E., Song, H., Chin, H., Joo, K., Han, S., Jo, S., Han, S., Yoo, S., An, W., Kim, Y., Kim, T., Kim, Y., Ching, C., Ong, L., Mohd, R., Lim, S., Leguizamo Dimas, A., Calvo Vargas, C., Tellez Chavez, E., Pelayo Orozco, E., Flores Lozano, F., Murguia Martin, F., Quintana Pina, F., Sanchez Mijangos, J., Tamayo Y Orozco, J., Herrara Jimenez, L., Nevarez Ruiz, L., Islas Guerrero, M., Vazquez Contreras, P., Austria Garcia, P., Banda Elizondo, R., Orozco Castellanos, R., Monreal Puente, R., Avila Pardo, S., Irizar Santana, S., Irigoyen Monroy, V., Limas Juarez, A., Pescador Martinez, Y., Achim, C., Bogeanu, C., David, C., Peride, I., Bako, G., Petrica, L., Vishnevsky, A., Smirnov, A., Pichkov, D., Reznik, E., Vaskina, E., Tsyba, L., Rossovskaya, M., Fomina, N., Barysheva, O., Kostitsina, O., Lesnyak, O., Sigitova, O., Ageeva, T., Marasaev, V., Tirmenstajn-Jankovic, B., Maksic, D., Maric, I., Velickovic-Radovanovic, R., Damjanovic, T., Dimkovic, N., Lazarevic, T., Lezaic, V., Krajnakova, A., Bobak, L., Vojtko, M., Muranda, A., Rayner, B., Malan, D., Engelbrecht, J., van Zyl, L., Van Jaarsveld, M., Mollentze, W., Sarvan, M., Nortje, M., Makanda, M. B., Ayoob, N., Chelin, N., Welkovics, N., Naiker, P., Moodley, R., Arnold, S., Govind, U., Naidoo, V., Galan Serrano, A., Garcia Carro, C., Hernandez Marrero, D., Gonzalez Martinez, F., Sanjuan, J., Ballarin Castan, J., Molas Coten, J., Torras Ambros, J., Hernandez-Jaras, J., Santos, J. P., Baro Salvador, M., Munar Vila, M., Slon Roblero, M., Yildiz, A., Kalender, B., Duranay, M., Tuglular, S., Ursol, G., Dudar, I., Rudyk, I., Vyshnyvetskyy, I., Kolesnyk, M., Tryshchuk, N., Pyvovarova, N., Sydor, N., Legun, O., Levchenko, O., Lyulko, O., Godlevska, O., Matushchak, O., Abrahamovych, O., Yatsyshyn, R., Kolupayev, S., Kostynenko, T., Vizir, V., Maslovskyi, V., Stus, V., Mostovoy, Y., Mikhail, A., Vilar, E., Yaqoob, M., Wilkie, M., El Kossi, M., Kalra, P., Shah, S., Nossuli, A. K., Jamal, A., Buridi, A., Murillo, A., Khan, A., Ijaz, A., Aswad, A., Awad, A., Sawhney, A., Esquenazi, A., Velar, A., Sprague, A., O'Shaughnessy, A., Agarwal, A., Parikh, S., Terrelonge, A., Dhandayuthapani, A., Chauhan, R., Silva, A., Mehta, A., Chaudhry, A., Bailey, A., Buerkert, J., Jones, A., Turk, T., Torres Consuegra, A., Sachdeva, B., Mehta, B., Thajudeen, B., Roy-Chaudhury, P., Spinowitz, B., Voinescu, C. G., Leon-Forero, C., Martinez, C., Ortiz-Butcher, C., Hernandez, C., Montoya, M., Arora, C., Sun, C., Argyropoulos, C., Galphin, C., Gadegbeku, C., Kovesdy, C., Christiano, C., Checketts, D., Arfaania, D., Goldfarb, D., Scott, D., Tietjen, D., Whittman, D., Price, D., Rizos, D., Dev, D., Belo, D., Brandon, D., Lanier, D., Hopkins, E., Linfert, D., Shemin, D., Gonzalez, E., Cosby, J., Rodriguez-Araya, E., Brown, E., Galindo-Ramos, E., Al-Saghir, F., Bangash, F., Castillo, F., Cid, J., Trespalacios, F., Finkelstein, F., Varghese, F., Vaz, G., Ramamurthy, G., Garcia Saez, G., Fadda, G., Hon, G., Nassar, G., Bueso, G., Diaz, G., Varallo, G., Pitone, J., Alvarez, G., Hernandez, G., Hadi, G., De La Calle, G., Krishna, G., Allen, G. J., Greenwood, G., Stewart, D., Toka, H., Boghara, H., Kumar, H., Niegos, F., Brar, H., Hubert, H., Szerlip, H., Farooq, H., Gonzalez, H., Martinez, L., Cosma, I., Drakakis, J., Shirazian, S., Reich, J., Tumlin, J., Colomar, J., Kumar, J., Moya, J., Rimmer, J., Navarro, J., Li, J., Meyer, J., Topf, J., Pullman, J., Alvarez-Moreno, J., Loredo, J., Posada, J., Fernandez, J., Gandhi, K., Servilla, K., Mootoo, K., Hendon, K., Choi, K., Bashir, K., Shah, K., Lalwani, T., Chaudhary, K., Thomas, K. V., Kooienga, L., Block, G., Forgosh, L., Spry, L., Adan, L., Glaser, L., Schneider, L., Seney, F., Lewy Alterbaum, L., Diaz-Secades, L., Perez, G., Garcia-Mayol, L., Bodell, M., Martinson, M., Sahani, M., Montero, M., Sanchez, M., Chang, M., Guillen, M., Henriquez, M., Lawrence, M., Vernace, M., Chan, M., Anger, M., Levey, S., Chang, I., Fredericks, M., Germain, M., Hassman, M., Levine, M., Patel, M., Issa, M., Dhillon, M., Moustafa, M., Siddiqui, N., Vo, N., Shahid, N., Atray, N., Khosla, N., Chronos, N., Stankus, N., Daboul, N., Frontela, O., Mendez, J., Ayodeji, O., Adler, O., Pergola, P., Kalirao, P., Peters, P., Santos, P., Van Buren, P., Lazowski, P., Ranjan, P., Krish, P., Suchinda, P., Gonzalez, R., Grillo, R., Abdullah, R., Zabaneh, R., Alappan, R., Yalavarthy, R., Patak, R., Berenji, R., Guadiz, R., Mendez, R., Sastre, R., Gaona, R., John, R., Sothinathan, R., Darwish, R., O'Donovan, R., Sandler, R., Szewc, R., Manllo-Karim, R., Gupta, R., Afsari, R., Raina, R., Benjamin, S., Kronfli, S., Sonbol, S., Butt, S., Sader, S., Kantor, S., Anand, S., Sharma, S., Dua, S., Kharait, S., Mandayam, S., Sitar, S., Zeig, S., Handelsman, S., Clarke, S., Joshi, S., Lalla-Reddy, S., Lee, S., Mustafa, E., Boone, T., Hart, T., Pillai, U., Subramanian, V., Prasad, V., Din, Z. 2021; 384 (17): 1589–1600

  Abstract

  BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).

  View details for DOI 10.1056/NEJMoa2035938

  View details for PubMedID 33913637

• Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis. The New England journal of medicine Eckardt, K., Agarwal, R., Aswad, A., Awad, A., Block, G. A., Bacci, M. R., Farag, Y. M., Fishbane, S., Hubert, H., Jardine, A., Khawaja, Z., Koury, M. J., Maroni, B. J., Matsushita, K., McCullough, P. A., Lewis, E. F., Luo, W., Parfrey, P. S., Pergola, P., Sarnak, M. J., Spinowitz, B., Tumlin, J., Vargo, D. L., Walters, K. A., Winkelmayer, W. C., Wittes, J., Zwiech, R., Chertow, G. M. 2021; 384 (17): 1601–12

  Abstract

  BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

  View details for DOI 10.1056/NEJMoa2025956

  View details for PubMedID 33913638

• Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI): Design and Baseline Characteristics. European journal of heart failure Jering, K. S., Claggett, B., Pfeffer, M. A., Granger, C., Kober, L., Lewis, E. F., Maggioni, A. P., Mann, D., McMurray, J. J., Rouleau, J., Solomon, S. D., Steg, P. G., van der Meer, P., Wernsing, M., Carter, K., Guo, W., Zhou, Y., Lefkowitz, M., Gong, J., Wang, Y., Merkely, B., Macin, S. M., Shah, U., Nicolau, J. C., Braunwald, E. 2021

  Abstract

  AIMS: Patients surviving an acute myocardial infarction (AMI) are at risk of developing symptomatic heart failure (HF) or premature death. We hypothesized that sacubitril/valsartan, effective in the treatment of chronic HF, prevents development of HF and reduces cardiovascular death following high-risk AMI compared to a proven ACE inhibitor. This paper describes the study design and baseline characteristics of patients enrolled in the Prospective ARNI versus ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction (PARADISE-MI) trial.METHODS AND RESULTS: PARADISE-MI, a multinational (41 countries), double-blind, active-controlled trial, randomized patients within 0.5-7days of presentation with index AMI to sacubitril/valsartan or ramipril. Transient pulmonary congestion and/or LVEF ≤40% and at least one additional factor augmenting risk of HF or death (age ≥70years, eGFR <60ml/min/1.73m2 , diabetes, prior MI, atrial fibrillation, LVEF <30%, Killip class ≥III, STEMI without reperfusion) were required for inclusion. PARADISE-MI was event-driven targeting 708 primary endpoints [cardiovascular (CV) death, HF hospitalization or outpatient development of HF]. Randomization of 5669 patients occurred 4.3 ±1.8days from presentation with index AMI. The mean age was 64 ±12years, 24% were women. The majority (76%) qualified with ST-segment elevation MI; acute percutaneous coronary intervention was performed in 88% and thrombolysis in 6%. LVEF was 37 ±9% and 58% were Killip class ≥2.CONCLUSIONS: Baseline therapies in PARADISE-MI reflect advances in contemporary evidence-based care. With enrollment complete PARADISE-MI is poised to determine whether sacubitril/valsartan is more effective than a proven ACE inhibitor in preventing development of HF and CV death following AMI.

  View details for DOI 10.1002/ejhf.2191

  View details for PubMedID 33847047

• Sex differences in congestive markers in patients hospitalized for acute heart failure. ESC heart failure Espersen, C., Campbell, R. T., Claggett, B., Lewis, E. F., Groarke, J. D., Docherty, K. F., Lee, M. M., Lindner, M., Biering-Sorensen, T., Solomon, S. D., McMurray, J. J., Platz, E. 2021

  Abstract

  AIMS: We sought to examine sex differences in congestion in patients hospitalized for acute heart failure (AHF). Understanding congestive patterns in women and men with AHF may provide insights into sex differences in the presentation and prognosis of AHF patients.METHODS AND RESULTS: In a prospective, two-site study in adults hospitalized for AHF, four-zone lung ultrasound (LUS) was performed at the time of echocardiography at baseline (LUS1) and, in a subset, pre-discharge (LUS2). B-lines on LUS and echocardiographic images were analysed offline, blinded to clinical information and outcomes. Among 349 patients with LUS1 data (median age 74, 59% male, and 87% White), women had higher left ventricular ejection fraction (mean 43% vs. 36%, P<0.001), higher tricuspid annular plane systolic excursion (mean 17 vs. 15mm, P=0.021), and higher measures of filling pressures (median E/e' 20 vs. 16, P<0.001). B-line number on LUS1 (median 6 vs. 6, P=0.69) and admission N-terminal pro-B-type natriuretic peptide levels (median 3932 vs. 3483pg/mL, P=0.77) were similar in women and men. In 121 patients with both LUS1 and LUS2 data, there was a similar and significant decrease in B-lines from baseline to discharge in both women and men. The risk of the composite 90day outcome increased with higher B-line number on four-zone LUS2: unadjusted hazard ratio for each B-line tertile was 1.86 (95% confidence interval 1.08-3.20, P=0.025) in women and 1.65 (95% confidence interval 1.03-2.64, P=0.037) in men (interaction P=0.72).CONCLUSIONS: Among patients with AHF, echocardiographic markers differed between women and men at baseline, whereas B-line number on LUS did not. The dynamic changes in B-lines during a hospitalization for AHF were similar in women and men.

  View details for DOI 10.1002/ehf2.13300

  View details for PubMedID 33709520

• Heart Failure Admission Service Triage (H-FAST) Study: Racialized Differences in Perceived Patient Self-Advocacy as a Driver of Admission Inequities. Cureus Cleveland Manchanda, E. C., Marsh, R. H., Osuagwu, C., Decopain Michel, J., Dugas, J. N., Wilson, M., Morse, M., Lewis, E., Wispelwey, B. P. 2021; 13 (2): e13381

  Abstract

  Background Racial inequities in mortality and readmission for heart failure (HF) are well documented. Inequitable access to specialized cardiology care during admissions may contribute to inequity, and the drivers of this inequity are poorly understood. Methodology This prospective observational study explored proposed drivers of racial inequities in cardiology admissions among Black, Latinx, and white adults presenting to the emergency department (ED) with symptoms of HF. Surveys of ED providers examined perceptions of patient self-advocacy, outreach to other clinicians (e.g., outpatient cardiologist), diagnostic uncertainty, and other active co-morbid conditions. Service census, bed availability, prior admission service, and other structural factors were explored through the electronic medical record. Results Complete data were available for 61/135 patients admitted with HF during the study period, which halted early due to coronavirus disease 2019. No significant differences emerged in admission to cardiology versus medicine based on age, sex, insurance status, education level, or perceived race/ethnicity. White patients were perceived as advocating for admission to cardiology more frequently (18.9 vs. 5.6%) and more strenuously than Black patients (p = 0.097). ED clinicians more often reported having spoken with the patient's outpatient cardiologist for whites than for Black or Latinx patients (24.3 vs. 16.7%, p = 0.069). Conclusions Theorized drivers of racial inequities in admission service did not reach statistical significance, possibly due to underpowering, the Hawthorne effect, or clinician behavior change based on knowledge of previously identified inequities. The observed trend towards racialdifferences in coordination of care between ED and outpatient providers, as well as in either actual or perceived self-advocacy by patients, may beas-yet undemonstrated components of structural racism driving HF care inequities.

  View details for DOI 10.7759/cureus.13381

  View details for PubMedID 33628703

• A-lines and B-lines in patients with acute heart failure. European heart journal. Acute cardiovascular care Johannessen, Ø., Claggett, B., Lewis, E. F., Groarke, J. D., Swamy, V., Lindner, M., Solomon, S. D., Platz, E. 2021; 10 (8): 909-917

  Abstract

  Lung ultrasound (LUS) relies on detecting artefacts, including A-lines and B-lines, when assessing dyspnoeic patients. A-lines are horizontal artefacts and characterize normal lung, whereas multiple vertical B-lines are associated with increased lung density. We sought to assess the prevalence of A-lines and B-lines in patients with acute heart failure (AHF) and examine their clinical correlates and their relationship with outcomes.In a prospective cohort study of adults with AHF, eight-zone LUS and echocardiography were performed early during the hospitalization and pre-discharge at an imaging depth of 18 cm. A- and B-lines were analysed separately off-line, blinded to clinical and outcome data. Of 164 patients [median age 71 years, 61% men, mean ejection fraction (EF) 40%], the sum of A-lines at baseline ranged from 0 to 19 and B-line number from 0 to 36. One hundred and fifty-six patients (95%) had co-existing A-lines and B-lines at baseline. Lower body mass index and lower chest wall thickness were associated with a higher number of A-lines (P trend < 0.001 for both). In contrast to B-lines, there was no significant change in the number of A-lines from baseline to discharge (median 6 vs. 5, P = 0.80). While B-lines were associated with 90-day HF readmission or death, A-lines were not [HR 1.67, 95% confidence interval (CI) 1.11-2.51 vs. HR 0.97, 95% CI 0.65-1.43].A-lines and B-lines on LUS co-exist in the vast majority of hospitalized patients with AHF. In contrast to B-lines, A-lines were not associated with adverse outcomes.

  View details for DOI 10.1093/ehjacc/zuab046

  View details for PubMedID 34160009

• Impact of Sacubitril/Valsartan Versus Ramipril on Total Heart Failure Events in the PARADISE-MI Trial. Circulation Pfeffer, M. A., Claggett, B., Lewis, E. F., Granger, C. B., Køber, L., Maggioni, A. P., Mann, D., McMurray, J. J., Rouleau, J. L., Solomon, S. D., Steg, P. G., Berwanger, O., Cikes, M., De Pasquale, C. G., Fernandez, A., Filippatos, G., Jering, K., Landmesser, U., Menon, V., Prof Merkely, B., Petrie, M. C., Petrov, I., Schou, M., Senni, M., Sim, D., van der Meer, P., Lefkowitz, M., Zhou, Y., Wang, Y., Braunwald, E. 2021

  View details for DOI 10.1161/CIRCULATIONAHA.121.057429

  View details for PubMedID 34797725

• Underrepresentation of Ethnic and Racial Minorities in Atrial Fibrillation Clinical Trials. Circulation. Arrhythmia and electrophysiology Nunes, J. C., Rice, E. N., Stafford, R. S., Lewis, E. F., Wang, P. J. 2021: CIRCEP121010452

  View details for DOI 10.1161/CIRCEP.121.010452

  View details for PubMedID 34789014

• Evaluation of Quality of Care for US Veterans With Recent-Onset Heart Failure With Reduced Ejection Fraction. JAMA cardiology Sandhu, A. T., Kohsaka, S., Turakhia, M. P., Lewis, E. F., Heidenreich, P. A. 2021

  Abstract

  Multiple guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF) are available and promoted by performance measures. However, contemporary data on the use of these therapies are limited.To evaluate trends in guideline-directed medical therapy, implantable cardioverter-defibrillator (ICD) use, and risk-adjusted mortality among patients with recent-onset HFrEF.This cohort study analyzed claims and electronic health record data of patients with recent-onset HFrEF diagnosed at US Department of Veterans Affairs (VA) health care system facilities from July 1, 2013, through June 30, 2019. Veterans who had a history of heart transplant or used a ventricular assist device were among the patients who were excluded.Guideline-directed medical therapy (any β-blocker, guideline-recommended β-blocker [bisoprolol, carvedilol, or metoprolol succinate], angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonist, and hydralazine plus nitrate) and ICD.Treatment rates for guideline-directed medical therapies and ICDs were calculated within 6 months of the index HFrEF date using medication fills, procedural codes for implantation and monitoring, and diagnosis codes. Risk-adjusted mortality was calculated after adjusting for baseline patient characteristics. For both treatment rates and risk-adjusted mortality, we evaluated the change over 3 periods (period 1: July 1, 2013, to June 30, 2015; period 2: July 1, 2015, to June 30, 2017; and period 3: July 1, 2017, to June 30, 2019) and variation across VA facilities.The final cohort comprised 144 074 eligible patients with incident HFrEF that was diagnosed between July 1, 2013, and June 30, 2019. The cohort had a mean (SD) age of 71.0 (11.4) years and was mostly composed of men (140 765 [97.7%]). Overall, changes in medical therapy rates were minimal over time, with the use of a guideline-recommended β-blocker increasing from 64.2% in 2013 to 72.0% in 2019. Rates for mineralocorticoid receptor antagonist therapy increased from 23.9% in 2013 to 26.9% in 2019, and rates for hydralazine plus nitrate therapy remained stable at 24.2% over the study period. Rates for angiotensin receptor-neprilysin inhibitor therapy increased since its introduction in 2015 but only to 22.6% in 2019. Among patients with an ICD indication, early use rates decreased over time. Substantial variation in medical therapy rates persisted across VA facilities. Risk-adjusted mortality decreased over the study period from 19.9% (95% CI, 19.6%-20.2%) in July 1, 2013, to June 30, 2015, to 18.4% (95% CI, 18.0%-18.7%) in July 1, 2017, to June 30, 2019 (OR, 0.96 per additional year; 95% CI, 0.96-0.97).This study found only marginal improvement between 2013 and 2019 in the guideline-recommended therapy and mortality rates among patients with recent-onset HFrEF. New approaches to increase the uptake of evidence-based HFrEF treatment are urgently needed and could lead to larger reductions in mortality.

  View details for DOI 10.1001/jamacardio.2021.4585

  View details for PubMedID 34757380

• A Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD. Journal of the American Society of Nephrology : JASN Toto, R., Petersen, J., Berns, J. S., Lewis, E. F., Tran, Q., Weir, M. R. 2020

  Abstract

  BACKGROUND: Exposure to high doses or a high cumulative dose of erythropoiesis-stimulating agents (ESAs) may contribute to cardiovascular events in patients with CKD and anemia. Whether using a low fixed ESA dose versus dosing based on a hemoglobin-based, titration-dose algorithm in such patients might reduce risks associated with high ESA doses and decrease the cumulative exposure-while reducing the need for red blood cell transfusions-is unknown.METHODS: In this phase-3, randomized trial involving 756 adults with stage-3 to -5 CKD and anemia, we evaluated incidence of red blood cell transfusions for participants randomized to receive darbepoetin given as a fixed dose (0.45 g/kg every 4 weeks) versus administered according to a hemoglobin-based, titration-dose algorithm, for up to 2 years. Participants received transfusions as deemed necessary by the treating physician.RESULTS: There were 379 patients randomized to the fixed-dose group, and 377 to the titration-dose group. The percentage of participants transfused did not differ (24.1% and 24.4% for the fixed-dose and titration-dose group, respectively), with similar time to first transfusion. The titration-dose group achieved significantly higher median hemoglobin (9.9 g/dl) compared with the fixed-dose group (9.4 g/dl). The fixed-dose group had a significantly lower median cumulative dose of darbepoetin (median monthly dose of 30.9 g) compared with the titration-dose group (53.6 g median monthly dose). The FD and TD group received a median (Q1, Q3) cumulative dose per 4 weeks of darbepoetin of 30.9 (21.8, 40.0) g and 53.6 (31.1, 89.9) g, respectively; the median of the difference between treatment groups was -22.1 (95% CI, -26.1 to -18.1) g.CONCLUSIONS: These findings indicate no evidence of difference in incidence of red blood cell transfusion for a titration-dose strategy versus a fixed-dose strategy for darbepoetin. This suggests that a low fixed dose of darbepoetin may be used as an alternative to a dose-titration approach to minimize transfusions, with less cumulative dosing.

  View details for DOI 10.1681/ASN.2020050556

  View details for PubMedID 33288629

• Cardiovascular Safety and Efficacy of Vadadust for the Treatment of Anemia in Non-Dialysis Dependent CKD: Design and Baseline Characteristics. American heart journal Chertow, G. M., Pergola, P. E., Agarwal, R., Block, G. A., Farag, Y. M., Jardine, A. G., Koury, M. J., Luo, W., Khawaja, Z., Lewis, E. F., Matsushita, K., McCullough, P. A., Parfrey, P. S., Wittes, J., Walters, K. A., Tseng, C., Lin, T., Sarnak, M. J., Vargo, D. L., Winkelmayer, W. C., Eckardt, K. 2020

  Abstract

  Current clinical practice guidelines for anemia management in non-dialysis dependent chronic kidney disease (NDD-CKD) recommend the use of erythropoiesis-stimulating agents (ESAs) as standard of care. Vadadustat, an investigational oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates endogenous erythropoietin production. The PRO2TECT program comprises two global, Phase 3, randomized, open-label, active-controlled, sponsor-blind clinical trials to evaluate safety and efficacy of vadadustat vs darbepoetin alfa in adult patients with anemia associated with NDD-CKD. Patients recruited into the ESA-untreated NDD-CKD trial (N=1751) had hemoglobin <10 g/dL and had not received an ESA within 8 weeks prior to inclusion in the study. Patients recruited into the ESA-treated NDD-CKD trial (N=1725) had hemoglobin between 8-11 g/dL (US) or 9-12 g/dL (non-US) and were actively treated with an ESA for anemia associated with CKD. Trial periods in both trials include 1) correction/conversion (weeks 0-23); 2) maintenance (weeks 24-52); 3) long-term treatment (week 53 to end of treatment); and 4) safety follow-up (end-of-treatment to 4 weeks later). The primary safety endpoint is time to first adjudicated major adverse cardiovascular event, defined as all-cause mortality, nonfatal myocardial infarction, or nonfatal stroke, pooled across both trials. The primary efficacy endpoint in each trial is change in hemoglobin from baseline to primary evaluation period (weeks 24-36), comparing vadadustat vs darbepoetin alfa treatment groups. Demographics and baseline characteristics were similar among patients in both trials and broadly representative of the NDD-CKD population. These trials will help to evaluate the safety and efficacy of vadadustat for management of anemia associated with NDD-CKD.

  View details for DOI 10.1016/j.ahj.2020.10.068

  View details for PubMedID 33129989

• Blood pressure and mortality in patients with type 2 diabetes and a recent coronary event in the ELIXA trial. Cardiovascular diabetology Wijkman, M. O., Claggett, B., Diaz, R., Gerstein, H. C., Kober, L., Lewis, E., Maggioni, A. P., Wolsk, E., Aguilar, D., Bentley-Lewis, R., McMurray, J. J., Probstfield, J., Riddle, M., Tardif, J., Solomon, S. D., Pfeffer, M. A. 2020; 19 (1): 175

  Abstract

  BACKGROUND: The relationship between blood pressure and mortality in type 2 diabetes (T2DM) is controversial, with concern for increased risk associated with excessively lowered blood pressure.METHODS: We evaluated whether prior cardiovascular disease (CVD) altered the relationship between baseline blood pressure and all-cause mortality in 5852 patients with T2DM and a recent acute coronary syndrome (ACS) who participated in the ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome) trial. Risk of death was assessed in Cox models adjusted for age, sex, race, heart rate, BMI, smoking, diabetes duration, insulin use, HbA1c, eGFR, brain natriuretic peptide (BNP), urine albumin/creatinine ratio, treatment allocation and prior coronary revascularization.RESULTS: Although overall there was no significant association between systolic blood pressure (SBP) and mortality (hazard ratio per 10mmHg lower SBP 1.05 (95% CI 0.99-1.12) P=0.10), lower SBP was significantly associated with higher risk of death (hazard ratio per 10mmHg lower SBP 1.13 (95% CI 1.04-1.22) P=0.002) in 2325 patients with additional CVD (index ACS+at least one of the following prior to randomization: myocardial infarction other than the index ACS, stroke or heart failure). In 3527 patients with only the index ACS no significant association was observed (hazard ratio per 10mmHg lower SBP 0.95 (0.86-1.04) P=0.26; P for interaction 0.005).CONCLUSIONS: The association between blood pressure and mortality was modified by additional CVD history in patients with type 2 diabetes and a recent coronary event. When blood pressures measured after an acute coronary event are used to assess the risk of death in patients with type 2 diabetes, the cardiovascular history needs to be taken into consideration. Trial registration ClinicalTrials.gov number NCT01147250, first posted June 22, 2010.

  View details for DOI 10.1186/s12933-020-01150-0

  View details for PubMedID 33046070

• Associations Between Depressive Symptoms and HFpEF-Related Outcomes. JACC. Heart failure Chandra, A., Alcala, M. A., Claggett, B., Desai, A. S., Fang, J. C., Heitner, J. F., Liu, J., Pitt, B., Solomon, S. D., Pfeffer, M. A., Lewis, E. F. 2020

  Abstract

  OBJECTIVES: This study analyzed changes in depressive symptoms in patients with heart failure and preserved ejection fraction (HFpEF) who were enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With HeartFailure and Preserved Systolic Function) trial.BACKGROUND: There are limited longitudinal data for depressive symptoms in patients with HFpEF.METHODS: In patients enrolled in the United States and Canada (n=1,431), depressive symptoms were measured using Patient Health Questionnaire-9 (PHQ-9). Clinically meaningful changes in PHQ-9 scores were defined as worse (≥3-point increase) or better (≥3-point decrease). Multivariate models were used to identify predictors of change in depressive symptoms. Cox proportional hazard models were used to determine the impact of symptom changes from baseline on subsequent incident cardiovascular events.RESULTS: At 12months, 19% of patients experienced clinically worsening depressive symptoms, 31% better, and 49% unchanged. Independent predictors of clinically meaningful improvement in depressive symptoms included higher baseline PHQ-9 scores, male sex, lack of chronic obstructive pulmonary disease, and randomization to spironolactone. After data were adjusted for cardiovascular comorbidities, higher baseline PHQ-9 was associated with all-cause mortality (hazard ratio [HR]: 1.09; 95% confidence interval [CI]: 1.02 to 1.16; p=0.011), whereas worsening depressive symptoms at 12months were associated with cardiovascular death (HR: 2.47; 95%CI: 1.32 to 4.63; p=0.005) and all-cause mortality (HR: 1.82; 95%CI: 1.13 to 2.93; p=0.014). Randomization to spironolactone was associated with modest but statistically significant reduction in depressive symptoms over the course of the trial (p=0.014).CONCLUSIONS: Higher baseline depressive symptoms and worsening depressive symptoms were associated with all-cause mortality. Randomization to spironolactone was associated with modest reduction in depressive symptoms. (Aldosterone Antagonist Therapy for Adults With HeartFailure and Preserved Systolic Function [TOPCAT]; NCT00094302).

  View details for DOI 10.1016/j.jchf.2020.06.010

  View details for PubMedID 32919912

• IMPROVE-IT A Final Closure to Carcinogenicity of Ezetimibe? JACC: CARDIOONCOLOGY Lewis, E. F., Rhee, J. 2020; 2 (3): 397–99

  View details for DOI 10.1016/j.jaccao.2020.08.003

  View details for Web of Science ID 000613114400004

• IMPROVE-IT: A Final Closure to Carcinogenicity of Ezetimibe? JACC. CardioOncology Lewis, E. F., Rhee, J. W. 2020; 2 (3): 397-399

  View details for DOI 10.1016/j.jaccao.2020.08.003

  View details for PubMedID 34396247

  View details for PubMedCentralID PMC8352260

• Response by Eberly et al to Letter Regarding Article, "Identification of Racial Inequities in Access to Specialized Inpatient Heart Failure Care at an Academic Medical Center". Circulation. Heart failure Eberly, L. A., Wispelwey, B., Richterman, A., Beckett, A. G., Cleveland Manchanda, E. C., Marsh, R. H., Chang, C. Y., Glynn, R. J., Brooks, K. C., Boxer, R., Kakoza, R., Goldsmith, J., Loscalzo, J., Lewis, E. F., Morse, M. 2020: CIRCHEARTFAILURE120007193

  View details for DOI 10.1161/CIRCHEARTFAILURE.120.007193

  View details for PubMedID 32498624

• Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel from the Heart Failure Collaboratory and Academic Research Consortium (HF-ARC). European journal of heart failure Abraham, W. T., Psotka, M. A., Fiuzat, M. n., Filippatos, G. n., Lindenfeld, J. n., Mehran, R. n., Ambardekar, A. V., Carson, P. E., Jacob, R. n., Januzzi, J. L., Konstam, M. A., Krucoff, M. W., Lewis, E. F., Piccini, J. P., Solomon, S. D., Stockbridge, N. n., Teerlink, J. R., Unger, E. F., Zeitler, E. P., Anker, S. D., O'Connor, C. M. 2020

  Abstract

  The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation. CONDENSED ABSTRACT: The Heart Failure Collaboratory and Academic Research Consortium multi-stakeholder partnership convened to establish expert consensus definitions and key concepts for heart failure clinical trials including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. With uniform definitions, heart failure interventions can be better standardized, evaluated, and compared between trials and patient populations, and the quality of generated evidence may be strengthened.

  View details for DOI 10.1002/ejhf.2018

  View details for PubMedID 33017862

• Conduct of Clinical Trials in the Era of COVID-19: JACC Scientific Expert Panel. Journal of the American College of Cardiology Psotka, M. A., Abraham, W. T., Fiuzat, M. n., Filippatos, G. n., Lindenfeld, J. n., Ahmad, T. n., Bhatt, A. S., Carson, P. E., Cleland, J. G., Felker, G. M., Januzzi, J. L., Kitzman, D. W., Leifer, E. S., Lewis, E. F., McMurray, J. J., Mentz, R. J., Solomon, S. D., Stockbridge, N. n., Teerlink, J. R., Vaduganathan, M. n., Vardeny, O. n., Whellan, D. J., Wittes, J. n., Anker, S. D., O'Connor, C. M. 2020; 76 (20): 2368–78

  Abstract

  The coronavirus disease-2019 (COVID-19) pandemic has profoundly changed clinical care and research, including the conduct of clinical trials, and the clinical research ecosystem will need to adapt to this transformed environment. The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory and the Academic Research Consortium, composed of academic investigators from the United States and Europe, patients, the U.S. Food and Drug Administration, the National Institutes of Health, and industry members. A series of meetings were convened to address the challenges caused by the COVID-19 pandemic, review options for maintaining or altering best practices, and establish key recommendations for the conduct and analysis of clinical trials for cardiovascular disease and heart failure. This paper summarizes the discussions and expert consensus recommendations.

  View details for DOI 10.1016/j.jacc.2020.09.544

  View details for PubMedID 33183511

• Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel From the Heart Failure Collaboratory and Academic Research Consortium. JACC. Heart failure Abraham, W. T., Psotka, M. A., Fiuzat, M. n., Filippatos, G. n., Lindenfeld, J. n., Mehran, R. n., Ambardekar, A. V., Carson, P. E., Jacob, R. n., Januzzi, J. L., Konstam, M. A., Krucoff, M. W., Lewis, E. F., Piccini, J. P., Solomon, S. D., Stockbridge, N. n., Teerlink, J. R., Unger, E. F., Zeitler, E. P., Anker, S. D., O'Connor, C. M. 2020

  Abstract

  The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

  View details for DOI 10.1016/j.jchf.2020.10.002

  View details for PubMedID 33199251

• Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) AMERICAN JOURNAL OF KIDNEY DISEASES Mc Causland, F. R., Claggett, B., Burdmann, E. A., Chertow, G. M., Cooper, M. E., Eckardt, K., Ivanovich, P., Levey, A. S., Lewis, E. F., McGill, J. B., McMurray, J. V., Parfrey, P., Parving, H., Remuzzi, G., Singh, A. K., Solomon, S. D., Toto, R. D., Pfeffer, M. A. 2019; 73 (3): 309–15

  View details for DOI 10.1053/j.ajkd.2018.10.006

  View details for Web of Science ID 000459248200005

• Treatment of Anemia With Darbepoetin Prior to Dialysis Initiation and Clinical Outcomes: Analyses From the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). American journal of kidney diseases : the official journal of the National Kidney Foundation Mc Causland, F. R., Claggett, B., Burdmann, E. A., Chertow, G. M., Cooper, M. E., Eckardt, K., Ivanovich, P., Levey, A. S., Lewis, E. F., McGill, J. B., McMurray, J. J., Parfrey, P., Parving, H., Remuzzi, G., Singh, A. K., Solomon, S. D., Toto, R. D., Pfeffer, M. A. 2018

  Abstract

  RATIONALE & OBJECTIVE: Evidence from clinical trials to guide patient preparation for maintenance dialysis therapy is limited. Although anemia is associated with mortality and cardiovascular (CV) disease in individuals initiating maintenance dialysis therapy, it is not known if treatment of anemia before dialysis therapy initiation with erythropoiesis-stimulating agents alters outcomes.STUDY DESIGN: Post hoc analysis of a randomized controlled trial.SETTING & PARTICIPANTS: Participants with type 2 diabetes and chronic kidney disease who progressed to dialysis therapy (n=590) in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).EXPOSURE: Randomized treatment assignment (darbepoetin vs placebo).OUTCOMES: All-cause mortality, CV mortality, nonfatal myocardial infarction, heart failure, and stroke within the first 180 days of dialysis therapy initiation.ANALYTICAL APPROACH: Proportional hazards regression.RESULTS: Overall, 590 of 4,038 (14.6%) participants initiated dialysis therapy during the trial (n=298 and 292 in the darbepoetin and placebo groups, respectively). Corresponding hemoglobin levels were 11.3±1.6 and 9.5±1.5g/dL (P<0.001). Death from any cause occurred in 31 (10.4%) participants assigned to darbepoetin and 28 (9.6%) assigned to placebo (HR, 1.16; 95% CI, 0.69-1.93), while death from CV causes occurred in 15 (5.0%) and 13 (4.5%) participants, respectively (HR, 1.21; 95% CI, 0.58-1.93). There were no differences in risk for nonfatal myocardial infarction or heart failure. Stroke occurred in 8 (2.8%) participants assigned to darbepoetin and 1 (0.3%) assigned to placebo (HR, 8.6; 95% CI, 1.1-68.7).LIMITATIONS: Post hoc analyses of a subgroup of study participants.CONCLUSIONS: Despite initiating dialysis therapy with a higher hemoglobin level, prior treatment with darbepoetin was not associated with a reduction in mortality, myocardial infarction, or heart failure in the first 180 days, but a higher frequency of stroke was observed. In the absence of more definitive data, this may inform decisions regarding the use of erythropoiesis-stimulating agents to treat mild to moderate anemia in patients with type 2 diabetes and chronic kidney disease nearing dialysis therapy initiation.

  View details for PubMedID 30578152

• 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Marler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., Hai, M., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C., Landray, M. J., Lincoff, A., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., McMurray, J. V., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O'Connor, C. M., Pfeffer, M. A., Hung, H., Stockbridge, N. L., Chaitman, B. R., Temple, R. J., Standardized Data Collection 2018; 71 (9): 1021–34

  Abstract

  This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

  View details for PubMedID 29495982

• 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials CIRCULATION Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Mar-Ler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., Hai, M., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C., Landray, M. J., Lincoff, A., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., McMurray, J. V., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O'Connor, C. M., Pfeffer, M. A., Hung, H., Stockbridge, N. L., Chaitman, B. R., Temple, R. J., Standardized Data Collection 2018; 137 (9): 961–72

  Abstract

  This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

  View details for PubMedID 29483172