Dr. Lewis is a board-certified, fellowship-trained specialist in cardiovascular medicine. He is the chief of the Division of Cardiovascular Medicine and a professor of cardiovascular medicine.
Dr. Lewis is an esteemed clinician-scientist who specializes in the care of patients with advanced heart failure. He is an internationally recognized expert on heart failure, heart transplant, and quality of life for heart failure patients. He cares deeply about his patients as well as his colleagues, the hospital, and the School of Medicine. Dr. Lewis is committed to diversity and inclusion, as well as expanding Stanford clinical research initiatives.
A fundamental principle of Dr. Lewis’ practice is his belief that “there is more to life than death,” that cardiovascular care should go beyond helping patients survive to also helping them enjoy the best possible quality of life.
Dr. Lewis has deep expertise in conducting clinical trials examining diagnostic and therapeutic approaches to heart failure. He has done innovative work to create systems for incorporating quality of life measures for cardiovascular patients into electronic health records. This research has received support from the National Heart, Lung and Blood Institute and the National Institutes of Health.
Much of his quality of life research has focused on patient-reported outcomes. Dr. Lewis emphasizes the importance of looking at how a disease, whether chronic or acute, impacts people’s ability to function and perform their activities of daily living. Strategies to improve patients’ well-being focus not only on their physical symptoms but also on depression, anxiety, exercise capacity, and ability to function in daily living.
Dr. Lewis’ commitment to expanding clinical research initiatives will give patients more opportunities to participate in the clinical trials and access the latest care strategies that can translate into better outcomes. The goal is early access to the most advanced technology, pharmacology, and device therapy that can change outcomes for the better. He also envisions forming closer partnerships with community cardiologists and capitalizing further on Stanford’s proximity to and unique relationships with the digital technology leaders of Silicon Valley to enhance the use of digital technology for monitoring patients, optimizing treatment, and tracking outcomes.
He has authored nearly 200 articles published in peer-reviewed journals including the New England Journal of Medicine, Journal of the American College of Cardiology, Circulation, JAMA Cardiology, JAMA Internal Medicine, and many more. He is also on multiple editorial boards for cardiovascular journals and was an associate editor for Circulation–Heart Failure. In addition, he is an author of professional society clinical practice guidelines and scientific statements from both the American Heart Association (AHA) and the Food and Drug Administration.
Dr. Lewis’ honors for clinical care, scholarship, and research include the Joel Gordon Miller Award for community service and leadership from the University of Pennsylvania School of Medicine. He also was one of the first recipients of the Minority Faculty Development Award, which recognizes the research potential of young physicians. Dr. Lewis has received a grant from the Robert Wood Johnson Foundation to study the role of quality of life assessment in clinical decision making in patients with heart failure.
He is a fellow of the American College of Cardiology and the National American Heart Association (AHA) Research Committee. In addition, Dr. Lewis was as a member of the AHA Founders Affiliate Board of Directors, chair of the Council on Clinical Cardiology, and research chair of the Association of Black Cardiologists. He also serves on scientific committees to review grants for the AHA and on the FDA Task Force for the Standardization of Definitions for Endpoint Events in Cardiovascular Trials.
- Cardiovascular Disease
Board Certification: American Board of Internal Medicine, Advanced Heart Failure and Transplant Cardiology (2014)
Board Certification: American Board of Internal Medicine, Cardiovascular Disease (2003)
Fellowship: Brigham and Women's Hospital Heart Transplant (2002) MA
Fellowship: Brigham and Women's Hospital Cardiovascular Disease Fellowship (2001) MA
Residency: Brigham and Women's Hospital Internal Medicine Residency (1998) MA
Medical Education: Perelman School of Medicine University of Pennsylvania (1995) PA
Association of Hyper-Polypharmacy With Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.
Circulation. Heart failure
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.
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 2021
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.
2021; 326 (4): 314-323
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
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
2021; 384 (17): 1589–1600
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
2021; 384 (17): 1601–12
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
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
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.
2021; 13 (2): e13381
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 Randomized Trial of Strategies Using Darbepoetin Alfa To Avoid Transfusions in CKD.
Journal of the American Society of Nephrology : JASN
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
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.
2020; 19 (1): 175
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
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 2020; 2 (3): 397–99
- 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 2020: CIRCHEARTFAILURE120007193
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
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
- IMPROVE-IT: A Final Closure to Carcinogenicity of Ezetimibe? JACC. CardioOncology 2020; 2 (3): 397-399
Conduct of Clinical Trials in the Era of COVID-19: JACC Scientific Expert Panel.
Journal of the American College of Cardiology
2020; 76 (20): 2368–78
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
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 2019; 73 (3): 309–15
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
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
2018; 71 (9): 1021–34
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
2018; 137 (9): 961–72
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