Publications by authors named "Renato D Lopes"

537 Publications

Three Times Weekly Dosing of Daprodustat versus Conventional Epoetin for Treatment of Anemia in Hemodialysis Patients: ASCEND-TD: A Phase 3 Randomized, Double-Blind, Noninferiority Trial.

Clin J Am Soc Nephrol 2022 Aug 2. Epub 2022 Aug 2.

Department of Medicine, Division of Nephrology, University of Wuerzburg, Wuerzburg, Germany.

Background And Objectives: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA).

Design, Setting, Participants, & Measurements: Patients on hemodialysis with a baseline hemoglobin of 8-11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly (=270) or conventional epoetin (=137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28-52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability.

Results: Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%).

Conclusions: Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated.

Clinical Trial Registry Name And Registration Number: Anemia Studies in Chronic Kidney Disease: Erythropoiesis a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033.
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http://dx.doi.org/10.2215/CJN.00550122DOI Listing
August 2022

Good practice statements for antithrombotic therapy in the management of COVID-19: Guidance from the SSC of the ISTH.

J Thromb Haemost 2022 Jul 7. Epub 2022 Jul 7.

Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Despite the emergence of high quality randomized trial data with the use of antithrombotic agents to reduce the risk of thromboembolism, end-organ failure, and possibly mortality in patients with coronavirus disease 2019 (COVID-19), questions still remain as to optimal patient selection for these strategies, the use of antithrombotics in outpatient settings and in-hospital settings (including critical care units), thromboprophylaxis in special patient populations, and the management of acute thrombosis in hospitalized COVID-19 patients. In October 2021, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary and international panel of content experts, two patient representatives, and a methodologist to develop recommendations on treatment with anticoagulants and antiplatelet agents for COVID-19 patients. The ISTH Guideline panel discussed additional topics to be well suited to a non-Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for Good Practice Statements (GPS) to support good clinical care in the antithrombotic management of COVID-19 patients in various clinical settings. The GPS panel agreed on 17 GPS: 3 in the outpatient (pre-hospital) setting, 12 in the hospital setting both in non-critical care (ward) as well as intensive care unit settings, and 2 in the immediate post-hospital discharge setting based on limited evidence or expert opinion that supports net clinical benefit in enacting the statements provided. The antithrombotic therapies discussed in these GPS should be available in low- and middle-income countries.
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http://dx.doi.org/10.1111/jth.15809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9349985PMC
July 2022

Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial.

JAMA 2022 07;328(3):259-269

Division of Cardiology, School of Medicine, Duke University Medical Center, Durham, North Carolina.

Importance: Exercise limitation is a cardinal manifestation of heart failure with reduced ejection fraction (HFrEF) but is not consistently improved by any of the current guideline-directed medical therapies.

Objective: To determine whether omecamtiv mecarbil, a novel direct myosin activator that improves cardiac performance and reduces the risk for cardiovascular death or first HF event in HFrEF, can improve peak exercise capacity in patients with chronic HFrEF.

Design, Setting, And Participants: Phase 3, double-blind, placebo-controlled randomized trial of patients with HFrEF (left ventricular ejection fraction ≤35%), New York Heart Association class II-III symptoms, N-terminal pro-B-type natriuretic peptide level of 200 pg/mL or greater, and baseline peak oxygen uptake (V̇o2) of 75% or less of predicted. Patients were randomized in a 2:1 ratio (omecamtiv mecarbil to placebo) between March 2019 and May 2021 at 63 sites in North America and Europe, with the last patient visit occurring on November 29, 2021.

Interventions: Omecamtiv mecarbil (n = 185) or matching placebo (n = 91), given orally twice daily at a dose of 25 mg, 37.5 mg, or 50 mg based on target plasma levels, for 20 weeks.

Main Outcomes And Measures: The primary end point was a change in exercise capacity (peak V̇o2) from baseline to week 20. Secondary end points included total workload, ventilatory efficiency, and daily physical activity as determined by accelerometry.

Results: Among 276 patients who were randomized (median age, 64 years; IQR, 55-70 years; 42 women [15%]), 249 (90%) completed the trial. The median left ventricular ejection fraction was 28% (IQR, 21-33) and the median baseline peak V̇o2 was 14.2 mL/kg/min (IQR, 11.6-17.4) in the omecamtiv mecarbil group and 15.0 mL/kg/min (IQR, 12.0-17.2) in the placebo group. Mean change in peak V̇o2 did not differ significantly between the omecamtiv mecarbil and placebo groups (mean, -0.24 mL/kg/min vs 0.21 mL/kg/min; least square mean difference, -0.45 mL/kg/min [95% CI, -1.02 to 0.13]; P = .13). Adverse events included dizziness (omecamtiv mecarbil: 4.9%, placebo: 5.5%), fatigue (omecamtiv mecarbil: 4.9%, placebo: 4.4%), heart failure events (omecamtiv mecarbil: 4.9%, placebo: 4.4%), death (omecamtiv mecarbil: 1.6%, placebo: 1.1%), stroke (omecamtiv mecarbil: 0.5%, placebo: 1.1%), and myocardial infarction (omecamtiv mecarbil: 0%, placebo: 1.1%).

Conclusions And Relevance: In patients with chronic HFrEF, omecamtiv mecarbil did not significantly improve exercise capacity over 20 weeks compared with placebo. These findings do not support the use of omecamtiv mecarbil for treatment of HFrEF for improvement of exercise capacity.

Trial Registration: ClinicalTrials.gov Identifier: NCT03759392.
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http://dx.doi.org/10.1001/jama.2022.11016DOI Listing
July 2022

The Intersection between Heart Failure and Critical Care Cardiology: An International Perspective on Structure, Staffing, and Design Considerations.

J Card Fail 2022 Jul 14. Epub 2022 Jul 14.

Division of Cardiology, Duke University School of Medicine, Durham, North Carolina, USA.

The overall patient population in contemporary Cardiac Intensive Care Units (CICUs) has only increased with respect to patient acuity, complexity, and illness severity. The current population has more cardiac and non-cardiac comorbidities, a higher prevalence of multi-organ injury, and consumes more critical care resources than previously. Heart failure (HF) patients now occupy a large portion of contemporary tertiary or quaternary care CICU beds around the world. In this review, we will discuss core issues that relate to care of critically ill HF patients, including global perspectives on the organization, designation, and collaboration of CICUs regionally and across institutions, as well as unique models for provisioning care for HF patients within a healthcare setting. The latter will include a discussion of traditional and emerging models, specialized heart failure units, the makeup and implementation of multidisciplinary team-based decision-making, and cardiac critical care admission and triage practices. This manuscript will illustrate the ways in which critically ill HF patients have helped to shape contemporary CICUs throughout the world and explore how these very patients will similarly help to inform the future maturation of these specialized critical care units. Finally, we will critically examine broad, contemporary international models of heart failure and cardiac critical care delivery in North America, Europe, South America, and Asia, and conclude with opportunities for further investigation and generation of evidence for care delivery.
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http://dx.doi.org/10.1016/j.cardfail.2022.06.007DOI Listing
July 2022

Outcomes After Acute Coronary Syndrome in Patients With Diabetes Mellitus and Peripheral Artery Disease (from the TRACER, TRILOGY-ACS, APPRAISE-2, and PLATO Clinical Trials).

Am J Cardiol 2022 Jul 11. Epub 2022 Jul 11.

Duke Clinical Research Institute, Durham, North Carolina.

Patients with acute coronary syndrome (ACS) are at risk for recurrent adverse events, and multiple reports suggest that this risk is increased in patients with concomitant diabetes mellitus (DM) and peripheral artery disease (PAD). The aim of this article was to investigate cardiovascular outcomes in patients with DM presenting with ACS, stratified by PAD status. Data were derived from 4 randomized post-ACS trials (PLATO [Platelet Inhibition and Patient Outcomes], APPRAISE-2 p Apixaban for Prevention of Acute Ischemic Events 2], TRILOGY [Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage], and TRACER [Thrombin Receptor Agonist for Clinical Event Reduction in Acute Coronary Syndrome]). Using Cox regression analysis, we investigated major adverse cardiovascular events (MACEs), a composite of cardiovascular mortality, myocardial infarction (MI), or stroke and the individual components of MACE and all-cause mortality in patients with DM, presenting with ACS, stratified by PAD status as the risk modifier. This study included 15,387 patients with a diagnosis of DM and ACS, of whom 1,751 had an additional diagnosis of PAD. PAD was associated with more than doubled rates of MACE (hazard ratio [HR] 2.03, 95% confidence interval [CI] 1.81 to 2.27), all-cause mortality (HR 2.48, 95% CI 2.14 to 2.87), cardiovascular mortality (HR 2.42, 95% CI 2.04 to 2.86), and MI (HR 2.07, 95% CI 1.79 to 2.38). Patients with both PAD and DM were also more optimally treated with antihypertensive, antidiabetic, and statin medication at baseline. In conclusion, this analysis of 4 major post-ACS trials showed that patients with DM and PAD had a substantially higher risk of MACE, cardiovascular mortality, all-cause mortality, and MI despite being optimally treated with guideline-based therapies.
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http://dx.doi.org/10.1016/j.amjcard.2022.04.062DOI Listing
July 2022

NKG2A Expression among CD8 Cells Is Associated with COVID-19 Progression in Hypertensive Patients: Insights from the BRACE CORONA Randomized Trial.

J Clin Med 2022 Jun 27;11(13). Epub 2022 Jun 27.

D'Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil.

Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.
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http://dx.doi.org/10.3390/jcm11133713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9267446PMC
June 2022

Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial.

Lancet Haematol 2022 Aug 30;9(8):e594-e604. Epub 2022 Jun 30.

Thrombosis Research Institute, London, UK. Electronic address:

Background: COVID-19 is associated with inflammation and an increased risk of thromboembolic complications. Prophylactic doses of low-molecular-weight heparin have been used in hospitalised and non-critically ill patients with COVID-19. We aimed to evaluate the efficacy and safety of prophylactic low-molecular-weight heparin (enoxaparin) versus standard of care (no enoxaparin) in at-risk outpatients with COVID-19.

Methods: This open-label, multicentre, randomised, controlled, phase 3b trial (ETHIC) was done at 15 centres in six countries (Belgium, Brazil, India, South Africa, Spain, and the UK). We consecutively enrolled participants aged at least 30 years who had not received a COVID-19 vaccine and had symptomatic, confirmed COVID-19 in the outpatient setting plus at least one risk factor for severe disease. Within 9 days of symptom onset and by use of a web-based random block design (block size either 2 or 4), eligible participants were randomly assigned (1:1) to receive either subcutaneous enoxaparin for 21 days (40 mg once daily if they weighed <100 kg and 40 mg twice daily if they weighed ≥100 kg) or standard of care (without enoxaparin). The primary efficacy endpoint was the composite of all-cause hospitalisation and all-cause mortality at 21 days after randomisation and, in our main analysis, was analysed in the intention-to-treat population, which comprised all patients who were randomly assigned. Safety was also analysed in the intention-to-treat population for our main analysis. This trial is registered with ClinicalTrials.gov, NCT04492254, and is complete.

Findings: Following the advice of the Data and Safety Monitoring Board, this study was terminated early due to slow enrolment and a lower-than-expected event rate. Between Oct 27, 2020, and Nov 8, 2021, 230 patients with COVID-19 were assessed for eligibility, of whom 219 were enrolled and randomly assigned to receive standard of care (n=114) or enoxaparin (n=105). 96 (44%) patients were women, 122 (56%) were men, and one patient had missing sex data. 141 (65%) of 218 participants with data on race and ethnicity were White, 60 (28%) were Asian, and 16 (7%) were Black, mixed race, or Arab or Middle Eastern. Median follow-up in both groups was 21 days (IQR 21-21). There was no difference in the composite of all-cause mortality and hospitalisation at 21 days between the enoxaparin group (12 [11%] of 105 patients) and the standard-of-care group (12 [11%] of 114 patients; unadjusted hazard ratio 1·09 [95% CI 0·49-2·43]; log-rank p=0·83). At 21 days, two (2%) of 105 patients in the enoxaparin group (one minor bleed and one bleed of unknown severity) and one (1%) of 114 patients in the standard-of-care group (major abnormal uterine bleeding) had a bleeding event. 22 (21%) patients in the enoxaparin group and 13 (11%) patients in the standard-of-care group had adverse events. The most common adverse event in both groups was COVID-19-related pneumonia (six [6%] patients in the enoxaparin group and five [4%] patients in the standard-of-care group). One patient in the enoxaparin group died and their cause of death was unknown.

Interpretation: The ETHIC trial results suggest that prophylaxis with low-molecular-weight heparin had no benefit for at-risk outpatients with COVID-19. Although the trial was terminated early, our data, combined with data from similar studies, provide further insights to inform international guidelines and influence clinical practice.

Funding: The Thrombosis Research Institute and Sanofi UK.
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http://dx.doi.org/10.1016/S2352-3026(22)00173-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243570PMC
August 2022

Factors associated with uncontrolled blood pressure in hypertensive Brazilians.

J Clin Hypertens (Greenwich) 2022 Jul 30;24(7):814-824. Epub 2022 Jun 30.

Pontifical Catholic University of Goiás, Goiânia, GO, Brazil.

Uncontrolled hypertension has a high prevalence and is related to numerous negative health outcomes. This study aimed to investigate the factors associated with the lack of blood pressure control in hypertensive Brazilians treated in public and private services. This is an analytical, multicentric, and national cross-sectional study, carried out with adult hypertensive patients, monitored in 45 outpatient clinics (September 2013 to October 2015) in a prospective record interview, clinical, and anthropometric assessment. Outcome variables included uncontrolled pressure (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg). Simple and multiple logistic regression analyses were performed. Two thousand six hundred forty-three participants were assessed with a mean age of 61.6 ± 11.9 years, 55.7% of women, and 46.4% with uncontrolled blood pressure (BP). The following were associated with uncontrolled BP: age over 60 years (OR: 1.31 [1.11-1.55]); practice of irregular physical activity (OR: 1.28 [1.06-1.55]); attending the emergency room for hypertensive crises in the last six months (OR: 1.80 [1.46-2.22]); increased body mass index (OR: 1.02 [1.01-1.04]); low adherence to drug treatment (OR: 1.22 [1.04-1.44]) and menopause (OR: 1.36 [1.07-1.72]). The following were negatively associated: fruit consumption (OR: 0.90 [0.85-0.94]); presence of dyslipidemia (OR: 0.75 [0.64-0.89]), acute myocardial infarction (OR: 0.59 [0.46-0.76]), and peripheral arterial disease (OR: 0.52 [0.34-0.78]). Factors associated with difficult-to-control blood pressure are the same that increase the risk for hypertension, while the presence of atherosclerotic disease and its outcomes were associated with better control.
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http://dx.doi.org/10.1111/jch.14501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9278566PMC
July 2022

Challenges of Conducting Clinical Trials during the SARS-CoV-2 Pandemic: The ASCEND Global Program Experience.

Kidney360 2022 04 10;3(4):728-733. Epub 2022 Feb 10.

Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

The coronavirus disease 2019 pandemic has had an unprecedented effect on health and health care and posed challenges to the conduct of clinical trials.Targeted mitigating strategies, on the basis of early and continued data collection from site surveys, limited disruption to the ASCEND trials.Flexibly allowing hemoglobin assessment at local laboratories to inform randomized treatment dosing was key to limiting the discontinuation of treatment.
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http://dx.doi.org/10.34067/KID.0006212021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9136902PMC
April 2022

Chest Pain Network with Support of Telemedicine: Impact on Reperfusion Therapy and Clinical Outcomes After 8 Years of Experience.

Telemed Rep 2021 22;2(1):284-292. Epub 2021 Dec 22.

Hospital Samaritano Paulista, São Paulo, Brazil.

Different approaches of evaluation by cardiologists using telemedicine have the potential of improving care of patients with ST elevation myocardial infarction (STEMI). To compare the use of pharmacoinvasive strategy and associated clinical outcomes (heart failure [HF] and mortality) among patients with STEMI before and after a program of telemedicine and also according to the level of support by telemedicine. A chest pain network with the support of a cardiologist through telemedicine was implemented in 2012 in 22 emergency departments without a local cardiac catheterization laboratory. Initially (phase 1 of telemedicine), the decision to discuss the case with the cardiologist was based on the judgment of the emergency physician. At the end of 2018, the use of telemedicine was modified and a dedicated cardiologist was available continuously to discuss systematically all suspected cases (phase 2 of telemedicine). The use of fibrinolytics and the rates of HF and in-hospital mortality were compared among three different periods: pretelemedicine (2011), and phase 1 and phase 2 of the telemedicine program. We evaluated 1034 STEMI patients and after comparing the three phases, we did not find significant differences regarding age, gender, and comorbidities. The use of fibrinolytics before transferring STEMI patients to a percutaneous coronary intervention center (pharmacoinvasive strategy) increased after telemedicine implementation (38% vs. 65.2%;  < 0.01), which was associated with a lower rate of HF (23.9% vs. 14.4%;  = 0.01) and death (7.9% vs. 4.0%;  = 0.05). The in-hospital mortality was lower in phase 2 with systematic evaluation by telemedicine compared with pretelemedicine (7.9% vs. 3.3%;  = 0.04). The implementation of a systematic and organized chest pain protocol, including telemedicine support, was associated with a significant increase in the use of pharmacoinvasive strategy and better clinical patient outcomes in patients with STEMI. Our findings provide important insights on how to improve the management of this high-risk population, reducing the gap between evidence and clinical practice.
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http://dx.doi.org/10.1089/tmr.2021.0033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8812289PMC
December 2021

Re-adjudication of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) with study-level meta-analysis of hospitalization for heart failure from cardiovascular outcomes trials with dipeptidyl peptidase-4 (DPP-4) inhibitors.

Clin Cardiol 2022 Jul 17;45(7):794-801. Epub 2022 Jun 17.

TIMI Study Group, Cardiovascular Medicine Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events.

Methods: TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed.

Results: After re-adjudication of potential HHF events in the intent-to-treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person-years) and 239 patients in the placebo arm (1.13/100 person-years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78-1.13, p = .49). Concordance between the outcome of the original adjudication and the re-adjudication for HHF events was 82.7%. The meta-analysis of CV outcomes trials with DPP-4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83-1.39), with moderate heterogeneity (p = .45, I  = 62.07%).

Conclusion: The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity.
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http://dx.doi.org/10.1002/clc.23844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9286326PMC
July 2022

P2Y inhibitor monotherapy in patients undergoing percutaneous coronary intervention.

Nat Rev Cardiol 2022 Jun 13. Epub 2022 Jun 13.

University of Florida College of Medicine, Jacksonville, FL, USA.

For 20 years, dual antiplatelet therapy (DAPT), consisting of the combination of aspirin and a platelet P2Y receptor inhibitor, has been the gold standard of antithrombotic pharmacology after percutaneous coronary intervention (PCI). In the past 5 years, several investigations have challenged this paradigm by testing the efficacy and safety of P2Y inhibitor monotherapy (that is, without aspirin) following a short course of DAPT. Collectively, these studies suggested a reduction in the risk of major bleeding and no significant increase in thrombotic or ischaemic events compared with guideline-recommended DAPT. Current recommendations are evolving to inform clinical practice on the ideal candidates for P2Y inhibitor monotherapy after PCI. Generalizing the results of studies of P2Y inhibitor monotherapy requires a thorough understanding of their design, populations, interventions, comparators and results. In this Review, we provide an up-to-date overview on the use of P2Y inhibitor monotherapy after PCI, including supporting pharmacodynamic and clinical evidence, practical recommendations and future directions.
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http://dx.doi.org/10.1038/s41569-022-00725-6DOI Listing
June 2022

Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants: A Review.

JAMA Cardiol 2022 Jul;7(7):747-759

Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, University of Liverpool, Liverpool, United Kingdom.

Importance: Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.

Observations: Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.

Conclusions And Relevance: Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.
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http://dx.doi.org/10.1001/jamacardio.2022.1292DOI Listing
July 2022

Apixaban or Warfarin and Aspirin or Placebo After Acute Coronary Syndrome or Percutaneous Coronary Intervention in Patients With Atrial Fibrillation and Prior Stroke: A Post Hoc Analysis From the AUGUSTUS Trial.

JAMA Cardiol 2022 Jul;7(7):682-689

Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.

Importance: Data are limited regarding the risk of cerebrovascular ischemic events and major bleeding in patients with atrial fibrillation (AF) and recent acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI).

Objective: Determine the efficacy and safety of apixaban or vitamin K antagonists (VKA) and aspirin or placebo according to prior stroke, transient ischemic attack (TIA), or thromboembolism (TE).

Design, Setting, And Participants: In this prospective, multicenter, 2-by-2 factorial, randomized clinical trial, post hoc parallel analyses were performed to compare randomized treatment regimens according to presence or absence of prior stroke/TIA/TE using Cox proportional hazards models. Patients with AF, recent ACS or PCI, and planned use of P2Y12 inhibitors for 6 months or longer were included; 33 patients with missing data about prior stroke/TIA/TE were excluded.

Interventions: Apixaban (5 mg or 2.5 mg twice daily) or VKA and aspirin or placebo.

Main Outcomes And Measures: Major or clinically relevant nonmajor (CRNM) bleeding.

Results: Of 4581 patients included, 633 (13.8%) had prior stroke/TIA/TE. Patients with vs without prior stroke/TIA/TE were older; had higher CHA2DS2-VASC and HAS-BLED scores; and more frequently had prior bleeding, heart failure, diabetes, and prior oral anticoagulant use. Apixaban was associated with lower rates of major or CRNM bleeding and death or hospitalization than VKA in patients with (hazard ratio [HR], 0.69; 95% CI, 0.46-1.03) and without (HR, 0.68; 95% CI, 0.57-0.82) prior stroke/TIA/TE. Patients without prior stroke/TIA/TE receiving aspirin vs placebo had higher rates of bleeding; this difference appeared less substantial among patients with prior stroke/TIA/TE (P = .01 for interaction). Aspirin was associated with numerically lower rates of death or ischemic events than placebo in patients with (HR, 0.71; 95% CI, 0.42-1.20) and without (HR, 0.93; 95% CI, 0.72-1.21) prior stroke/TIA/TE (not statistically significant).

Conclusions And Relevance: The safety and efficacy of apixaban compared with VKA was consistent with the AUGUSTUS findings, irrespective of prior stroke/TIA/TE. Aspirin increased major or CRNM bleeding, particularly in patients without prior stroke/TIA/TE. Although aspirin may have some benefit in patients with prior stroke, our findings support the use of apixaban and a P2Y12 inhibitor without aspirin for the majority of patients with AF and ACS and/or PCI, regardless of prior stroke/TIA/TE status.

Trial Registration: ClinicalTrials.gov Identifier: NCT02415400.
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http://dx.doi.org/10.1001/jamacardio.2022.1166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9134037PMC
July 2022

Biomarkers and heart failure events in patients with atrial fibrillation in the ARISTOTLE trial evaluated by a multi-state model.

Am Heart J 2022 Sep 13;251:13-24. Epub 2022 May 13.

Department of Medical Sciences, Cardiology, Uppsala University, Uppsala, Sweden; Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.

Background: Atrial fibrillation (AF) and heart failure (HF) often coexist. We investigated the prognostic impact of biomarkers on the development of HF and death in patients with AF and different left ventricular systolic function considering the influence of competing events.

Methods: The study included 11,818 patients with AF from the ARISTOTLE trial who at entry had information on history of HF, an estimate of left ventricular function and plasma samples for determination of biomarkers representing cardiorenal dysfunction (NT-proBNP, troponin T, cystatin C) and inflammation (GDF-15, IL-6, CRP). Patients were categorized into: (I) HF with reduced ejection fraction (HFrEF, n = 2,048), (II) HF with preserved ejection fraction (HFpEF, n = 2,520), and (III) No HF (n = 7,250). Biomarker associations with HF hospitalization and death were analyzed using a multi-state model accounting also for repeated events.

Results: Baseline levels of NT-proBNP, troponin T, cystatin C, GDF-15, IL-6, and CRP were highest in HFrEF and lowest in No HF. During median 1.9 years follow-up, 546 patients were hospitalized at least once for HF and 819 died. Higher levels of all investigated biomarkers were associated with both outcomes (all P< .0001), with highest event rates in HFrEF and lowest in No HF. The associations remained after adjustments and were more pronounced for first than for recurrent events.

Conclusions: In anticoagulated patients with AF, biomarkers indicating cardiorenal dysfunction and inflammation improve the identification of patients at risk of developing HF or worsening of already existing HF. These biomarkers might be useful for targeting novel HF therapies in patients with AF.
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http://dx.doi.org/10.1016/j.ahj.2022.03.009DOI Listing
September 2022

International Collaborations in Heart Failure: JCF in Latin America.

J Card Fail 2022 05;28(5):695-696

Duke Clinical Research Institute, Durham, NC, USA.

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http://dx.doi.org/10.1016/j.cardfail.2022.04.002DOI Listing
May 2022

Morphine and clinical outcomes in patients with ST segment elevation myocardial infarction treated with fibrinolytic and antiplatelet therapy: Insights from the TREAT trial.

Am Heart J 2022 Sep 6;251:1-12. Epub 2022 May 6.

Department of Medicine, Canadian Heart Research Centre (CHRC) and Division of Cardiology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

Background: Morphine is commonly used to relieve pain, anxiety and dyspnea in STEMI but it lowers blood pressure and delays the activity of oral antiplatelet agents. The impact of morphine on clinical outcomes remains unknown. This analysis was performed to determine if morphine use was associated with increased risk of adverse clinical events among STEMI patients treated with fibrinolytic therapy and clopidogrel or ticagrelor.

Methods: In the Ticagrelor in Patients with ST Elevation Myocardial Infarction Treated with Pharmacological Thrombolysis (TREAT) study, 3799 STEMI patients treated with fibrinolysis were randomized to receive clopidogrel or ticagrelor. Morphine use was left to the discretion of the treating physicians. In this pre-specified analysis, we evaluated clinical outcomes based on the use and timing of morphine administration. Outcomes were stratified by randomized treatment group. Multivariable analysis was performed using Inverse Probability Treatment Weighting (IPTW) weighting.

Results: Morphine was used in 53% of patients. After adjustment using IPTW weighting, morphine use was associated with higher hazard of reinfarction at 7 days (HR 4.9, P = .0006) and 30 days (HR 1.7, P = .04), and lower hazard of major bleeding (HR 0.37, P = .006). There was no significant difference in mortality at any time point.

Conclusions: Among patients with STEMI treated with fibrinolytic therapy, morphine use was associated with a higher risk of early reinfarction and a lower risk of major bleeding but no difference in mortality.

Clinical Trial Registration: clinicaltrials.gov Identifier: NCT02298088.
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http://dx.doi.org/10.1016/j.ahj.2022.05.005DOI Listing
September 2022

ReducinG stroke by screening for UndiAgnosed atRial fibrillation in elderly inDividuals (GUARD-AF): Rationale and design of the GUARD-AF randomized trial of screening for atrial fibrillation with a 14-day patch-based continuous ECG monitor.

Am Heart J 2022 07 25;249:76-85. Epub 2022 Apr 25.

Bristol Myers Squibb, Inc., NJ.

Background: Screening for atrial fibrillation (AF) is attractive because AF independently raises the risk of ischemic stroke, this risk is largely reversible by long-term oral anticoagulant therapy (OAC), and many patients with AF remain undiagnosed and untreated. Recent trials of one-time brief screening for AF have not produced a significant increase in the proportion of patients diagnosed with AF. Trials of longer-term screening have demonstrated an increase in AF diagnoses, primarily paroxysmal AF. To date, however, no trials have demonstrated that screening for AF results in lower rates of stroke. Clinical practice guidelines conflict in their level of support for screening for AF.

Methods: The GUARD-AF individually randomized trial is designed to test whether screening for AF in individuals age 70 years or greater using a 2-week single-lead electrocardiographic patch monitor can identify patients with undiagnosed AF and lead to treatment with OAC, resulting in a reduced rate of stroke in the screened population. The trial's efficacy end point is hospitalization for stroke (either ischemic or hemorrhagic) and the trial's safety end point is hospitalization for a bleeding event. End points will be ascertained via Medicare claims or electronic health records at 2.5 years after study start. Enrollment is based in primary care practices and the OAC decision for screen-detected cases is left to the patient and their physician. The initial planned target sample size was 52,000, with 26,000 allocated to either screening or to usual care.

Results: Trial enrollment was severely hampered by the novel coronavirus disease 2019 (COVID-19) pandemic and stopped at a total enrollment of 11,931 participants. Of 5,965 randomized to the screening arm, 5,713 patients (96%) returned monitors with analyzable results. Incidence of screen-detected and clinically detected AF and associated stroke and bleeding outcomes will be ascertained.

Conclusions: GUARD-AF is the largest AF screening randomized trial using a longer-term patch-based continuous electrocardiographic monitor. The results will contribute important information on the yield of patch-based AF screening, the "burden" of AF detected (percent time in AF, longest episode), and physicians' OAC decisions as a function of AF burden. GUARD-AF's stroke and bleed results will contribute to pooled trial analyses of AF screening, thereby informing future studies and guidelines.
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http://dx.doi.org/10.1016/j.ahj.2022.04.005DOI Listing
July 2022

Association of Non-Alcoholic Fatty Liver Disease With in-Hospital Outcomes in Primary Heart Failure Hospitalizations With Reduced or Preserved Ejection Fraction.

Curr Probl Cardiol 2022 Apr 9:101199. Epub 2022 Apr 9.

Division of Cardiology, Department of Medicine, Duke University, Durham, NC; Department of Cardiology, Duke Clinical Research Institute, Durham, NC.

Recent studies focusing on the prevalence, characteristics, and outcomes of primary heart failure (HF) with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF) in non-alcoholic fatty liver disease (NAFLD) are sparse. We sought to assess these using a nationally-representative population. We used the 2016-2018 National Inpatient Sample database to study the prevalence, characteristics, clinical risk profiles, morbidity, mortality, cost, and resource utilization among primary HFpEF and HFrEF hospitalizations with and without NAFLD. In the period from January 1, 2016, to December 31, 2018, there were 3,522,459 admissions of patients aged ≥18 years with a diagnosis of primary HF. Of these, 82,585 (2.3%) hospitalizations had secondary diagnosis of NAFLD. Admissions with NAFLD and HFrEF were associated with higher rates of in-hospital mortality (aOR 1.84, CI 1.66-2.04, P < 0.001) compared to admissions of HFrEF without NAFLD. Similarly, hospitalizations with HFpEF-NAFLD were associated with higher rates of in hospital mortality (aOR 1.65 CI 1.43-1.9, P < 0.001) compared to HFpEF admissions without NAFLD. Pressors use, cardiogenic shock, AKI with or without dialysis use, cardiac arrest, LOS and hospitalization cost were higher in admissions of HFrEF and HFpEF with NAFLD compared to those without NAFLD. In-hospital mortality, was higher in primary HFrEF and HFpEF admissions with NAFLD compared to without NAFLD. Physicians must be aware of the worse clinical outcomes of HFrEF and HFpEF in patients with NAFLD. Further clinical research is needed to address the knowledge gap and treatment options available for the patients with HF and NAFLD.
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http://dx.doi.org/10.1016/j.cpcardiol.2022.101199DOI Listing
April 2022

Discontinuing vs continuing ACEIs and ARBs in hospitalized patients with COVID-19 according to disease severity: Insights from the BRACE CORONA trial.

Am Heart J 2022 07 8;249:86-97. Epub 2022 Apr 8.

D'Or Institute for Research and Education (IDOR), Rio de Janeiro, Brazil; Programa de Pós-Graduação em Medicina Translacional, Universidade Federal de São Paulo, São Paulo, Brazil; Brazilian Clinical Research Institute, São Paulo, Brazil; Rede D'Or São Luiz (RDSL), São Paulo, Brazil; Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. Electronic address:

Background: We explored the effect of discontinuing versus continuing angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on clinical outcomes in patients with COVID-19 according to baseline disease severity.

Methods: We randomized 659 patients with a confirmed diagnosis of COVID-19 and classified them as having mild or moderate COVID-19 disease severity at hospital presentation using blood oxygen saturation and lung imaging. The primary outcome was the mean ratio of number of days alive and out of the hospital at 30 days according to disease severity.

Results: At presentation, 376 patients (57.1%) had mild and 283 (42.9%) had moderate COVID-19. In patients with mild disease, there was no significant difference in the number of days alive and out of the hospital between ACEI/ARB discontinuation (mean 23.5 [SD 6.3] days) and continuation (mean 23.8 [SD 6.5] days), with a mean ratio of 0.98 (95% CI 0.92-1.04). However, in patients with moderate disease, there were fewer days alive and out of the hospital with ACEI/ARB discontinuation (mean 19.6 [SD 9.5] days) than continuation (mean 21.6 [SD 7.6] days), with a mean ratio of 0.90 (95% CI 0.81-1.00; P-interaction = .01). The impact of discontinuing versus continuing ACEIs/ARBs on days alive and out of hospital through 30 days differed according to baseline COVID-19 disease severity.

Conclusions: Unlike patients with mild disease, patients with moderate disease who continued ACEIs/ARBs had more days alive and out of hospital through 30 days than those who discontinued ACEIs/ARBs. This suggests that ACEIs/ARBs should be continued for patients with moderate COVID-19 disease severity.

Clinical Trial Registration: ClinicalTrials.gov (NCT04364893).
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http://dx.doi.org/10.1016/j.ahj.2022.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993458PMC
July 2022

Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE - Coalition V): A double-blind, multicentre, randomised, controlled trial.

Lancet Reg Health Am 2022 Jul 31;11:100243. Epub 2022 Mar 31.

Academic Research Organization - Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.

Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers.

Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540.

Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04]).

Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting.

Funding: COALITION COVID-19 Brazil and EMS.
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http://dx.doi.org/10.1016/j.lana.2022.100243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968238PMC
July 2022

Efficacy and Safety of Daprodustat for Treatment of Anemia of Chronic Kidney Disease in Incident Dialysis Patients: A Randomized Clinical Trial.

JAMA Intern Med 2022 06;182(6):592-602

Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated as an oral alternative to conventional erythropoiesis-stimulating agent (ESA) therapy. Few studies of anemia treatment in an incident dialysis (ID) population have been reported.

Objective: To evaluate the efficacy and safety of daprodustat vs darbepoetin alfa in treating anemia of chronic kidney disease in ID patients.

Design, Setting, And Participants: This prospective, randomized, open-label clinical trial was conducted from May 11, 2017, through September 24, 2020, in 90 centers across 14 countries. Patients with advanced CKD were eligible if they planned to start dialysis within 6 weeks from screening or had started and received hemodialysis (HD) or peritoneal dialysis (PD) within 90 days before randomization, had a screening hemoglobin (Hb) concentration of 8.0 to 10.5 g/dL (to convert to grams per liter, multiply by 10) and a randomization Hb of 8.0 to 11.0 g/dL, were ESA-naive or had received limited ESA treatment, and were iron-replete.

Interventions: Randomized 1:1 to daprodustat or darbepoetin alfa.

Main Outcomes And Measures: The primary analysis in the intent-to-treat population evaluated the mean change in Hb concentration from baseline to evaluation period (weeks 28-52) to assess noninferiority of daprodustat vs darbepoetin alfa (noninferiority margin, -0.75 g/dL). The mean monthly intravenous (IV) iron dose from baseline to week 52 was the principal secondary end point. Rates of treatment-emergent and serious adverse events (AEs) were also compared between treatment groups to assess safety and tolerability.

Results: A total of 312 patients (median [IQR] age, 55 [45-65] years; 194 [62%] male) were randomized to either daprodustat (157 patients; median [IQR] age, 52.0 [45-63] years; 96 [61%] male) or darbepoetin alfa (155 patients; median [IQR] age, 56.0 [45-67] years; 98 [63%] male); 306 patients (98%) completed the trial. The mean (SD) Hb concentration during the evaluation period was 10.5 (1.0) g/dL for the daprodustat and 10.6 (0.9) g/dL for the darbepoetin alfa group, with an adjusted mean treatment difference of -0.10 g/dL (95% CI, -0.34 to 0.14 g/dL), indicating noninferiority. There was a reduction in mean monthly IV iron use from baseline to week 52 in both treatment groups; however, daprodustat was not superior compared with darbepoetin alfa in reducing monthly IV iron use (adjusted mean treatment difference, 19.4 mg [95% CI, -11.0 to 49.9 mg]). Adverse event rates were 76% for daprodustat vs 72% for darbepoetin alfa.

Conclusions And Relevance: This randomized clinical trial found that daprodustat was noninferior to darbepoetin alfa in treating anemia of CKD and may represent a potential oral alternative to a conventional ESA in the ID population.

Trial Registration: ClinicalTrials.gov Identifier: NCT03029208.
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http://dx.doi.org/10.1001/jamainternmed.2022.0605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8981070PMC
June 2022

Independence of clinical events committees: A consensus statement from clinical research organizations.

Am Heart J 2022 06 13;248:120-129. Epub 2022 Mar 13.

Division of Cardiology, Duke University Medical Center, Duke Clinical Research Institute, Durham, NC.

Background: Randomized clinical trials are the gold standard to assess the causal relationship between an intervention and subsequent outcomes, also known as clinical endpoints. In order to limit bias, central clinical events committees (CEC) are established to ensure consistent event reporting across participating centers, as well as complete and accurate ascertainment of endpoints. However, defining independence is challenging.

Methods: This consensus statement was generated by teleconferences and electronic communications among clinical research organizations from the United States, Europe and Australia. This document does not constitute regulatory guidance.

Results: An independent CEC is defined when the adjudicators are not primarily involved in designing, funding, sponsoring, organizing, conducting, analyzing or regulating the clinical trial for which they serve as an adjudicator, beyond their role as CEC member. Moreover, independence requires absence of conflicts of interest with the steering committee, sponsor, grant giver, manufacturer, coordinating center, other independent committees, core laboratories, medical monitor, safety physician, participating clinical sites, statistician or data manager, regulatory agencies or authorities, which could influence (or be perceived to influence) a member's objectivity in evaluating trial data. Such conflicts of interest include financial benefits, directing or advisory role (paid or unpaid), decision-making position, as well as being a direct relative. An independent adjudicator has no other role within a clinical trial.

Conclusions: This consensus statement presents a standardized definition of an independent CEC to be considered by clinical research organizations, manufacturers, and investigators. In addition, it provides recommendations on best practices for implementation of an independent CEC.
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http://dx.doi.org/10.1016/j.ahj.2022.03.005DOI Listing
June 2022

Effect of Alirocumab on Incidence of Atrial Fibrillation After Acute Coronary Syndromes: Insights from the ODYSSEY OUTCOMES Trial.

Am J Med 2022 07 14;135(7):915-918. Epub 2022 Mar 14.

Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Paris, France; National Heart and Lung Institute, Royal Brompton Hospital, Imperial College, London, UK.

Background: Using data from the ODYSSEY OUTCOMES trial (NCT01663402), we sought to identify factors associated with the development of incident atrial fibrillation in patients with recent acute coronary syndrome without prior atrial fibrillation and to determine whether alirocumab treatment influenced risk of incident atrial fibrillation.

Methods: ODYSSEY OUTCOMES compared alirocumab treatment with placebo in 18,924 patients with recent acute coronary syndrome and dyslipidemia despite high-intensity or maximum-tolerated statin therapy. The primary outcome of major adverse cardiovascular events (MACE) comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Patients were classified as having previous atrial fibrillation (present prior to or at randomization) or no previous atrial fibrillation. A multivariable model was used to determine factors associated with incident atrial fibrillation.

Results: Among 18,262 participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (hazard ratio 0.91; 95% confidence interval, 0.77-1.09). Patients with vs without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs 3.7 events per 100 patient-years), without significant interaction between atrial fibrillation and randomized treatment on risk of MACE (P = .78).

Conclusions: While alirocumab did not modify risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history. History of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.
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http://dx.doi.org/10.1016/j.amjmed.2022.02.016DOI Listing
July 2022

Sodium-Glucose Cotransporter 2 Inhibitors and Cardiac Remodeling.

J Cardiovasc Transl Res 2022 Mar 15. Epub 2022 Mar 15.

Division of Cardiology, Department of Medicine, Duke University, 2301 Erwin Road, Durham, NC, USA.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have evident cardiovascular benefits in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (only empagliflozin and dapagliflozin have been investigated in this group so far), and chronic kidney disease. Prevention and reversal of adverse cardiac remodeling is one of the mechanisms by which SGLT2 inhibitors may exert cardiovascular benefits, especially heart failure-related outcomes. Cardiac remodeling encompasses molecular, cellular, and interstitial changes that result in favorable changes in the mass, geometry, size, and function of the heart. The pathophysiological mechanisms of adverse cardiac remodeling are related to increased apoptosis and necrosis, decreased autophagy, impairments of myocardial oxygen supply and demand, and altered energy metabolism. Herein, the accumulating evidence from animal and human studies is reviewed investigating the effects of SGLT2 inhibitors on these mechanisms of cardiac remodeling.
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http://dx.doi.org/10.1007/s12265-022-10220-5DOI Listing
March 2022

Associated factors and clinical outcomes in mechanical circulatory support use in patients undergoing high risk on-pump cardiac surgery: Insights from the LEVO-CTS trial.

Am Heart J 2022 06 7;248:35-41. Epub 2022 Mar 7.

Department of Critical Care Medicine, University of Alberta, Edmonton, Alberta, Canada; Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta, Canada; Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Background: We describe variables and outcomes associated with peri-operative mechanical circulatory support (MCS) utilization among patients enrolled in the Levosimendan in patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial.

Methods: In the LEVO-CTS trial, MCS utilization (defined as intra-aortic balloon pump, extracorporeal membrane oxygenation, or surgical ventricular assist device) within 5 days of surgery was examined. The association between MCS use and outcomes including 90-day mortality, 30-day renal-replacement therapy, and hospital and critical stay length of stay were determined.

Results: Among the 849 patients from 70 centers randomized to levosimendan or placebo, 85 (10.0%) patients were treated with MCS (71 intra-aortic balloon pump, 7 extracorporeal membrane oxygenation, 7 ventricular assist device); with 89.4% started on post-operative day 0. Inter-institutional use ranged from 0% to 100%. Variables independently associated with MCS utilization included combined coronary artery bypass grafting and valve surgery (adjusted odds ratio [OR] 2.73, 95% confidence interval [CI] 1.70-4.37, P < .001), history of lung disease (OR 1.70, 95% CI 1.06-2.70, P = .029), and history of heart failure (OR 2.44, 95% CI 1.10-5.45, P = .027). Adjusted 90-day mortality (22.4% vs 4.1%, hazard ratio 6.11, 95% CI 3.95-9.44, P < .001) was higher, and median critical care length of stay (8.0 vs 4.0 days, P < .001) was longer in patients managed with MCS.

Conclusions: In a randomized controlled trial of high-risk cardiac surgical patients in North America, we observed patient, and surgical variables associated with MCS utilization. MCS use was associated with a higher risk of post-operative mortality.
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http://dx.doi.org/10.1016/j.ahj.2022.02.013DOI Listing
June 2022

Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients.

Arq Bras Cardiol 2022 02;118(2):378-387

Centro Internacional de Pesquisa, Hospital Alemão Oswaldo Cruz,São Paulo, SP - Brasil.

Background: Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation.

Objective: To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo.

Methods: The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540.

Results: Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle.

Conclusion: This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.
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http://dx.doi.org/10.36660/abc.20210832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8856682PMC
February 2022

The Anti-Coronavirus Therapies (ACT) Trials: Design, Baseline Characteristics, and Challenges.

CJC Open 2022 Jun 1;4(6):568-576. Epub 2022 Mar 1.

Department of Pathology and Molecular Medicine, McMaster University. Hamilton, Ontario, Canada.

Background: Effective treatments for COVID-19 are urgently needed, but conducting randomized trials during the pandemic has been challenging.

Methods: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3500 outpatients and 2500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine vs usual care, and aspirin vs usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization, it is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine vs usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily vs usual care. The primary outcome for the colchicine randomization is need for high-flow oxygen, need for mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization, it is major thrombotic events, need for high-flow oxygen, need for mechanical ventilation, or death.

Results: At the completion of enrollment on February 10, 2022, the outpatient trial had enrolled 3917 patients, and the inpatient trial had enrolled 2611 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals, and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic.

Conclusions: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine, and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban, across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.
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http://dx.doi.org/10.1016/j.cjco.2022.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8887957PMC
June 2022
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