Publications by authors named "James L Januzzi"

604 Publications

NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories.

JACC Heart Fail 2021 Jun 29. Epub 2021 Jun 29.

Singapore General Hospital, Singapore.

Objectives: The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories.

Background: Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain.

Methods: Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m), normal weight (BMI 18.5-24.9 kg/m), overweight (BMI 25-29.9 kg/m), and mildly (BMI 30-34.9 kg/m), moderately (BMI 35-39.9 kg/m), or severely (BMI ≥40 kg/m) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death.

Results: The study population included 12,763 patients (mean age 66 ± 12 y; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (β = -0.174 for 1 kg/m; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-y all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men.

Conclusions: NT-proBNP maintains its independent prognostic value up to 40 kg/m BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.
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http://dx.doi.org/10.1016/j.jchf.2021.05.014DOI Listing
June 2021

Lipoprotein(a) and Cardiovascular Diseases.

JAMA 2021 07;326(4):352-353

Division of Cardiology, Massachusetts General Hospital, Boston.

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http://dx.doi.org/10.1001/jama.2021.3632DOI Listing
July 2021

Soluble Suppression of Tumorigenicity-2 Associates With Ventilator Dependence in Coronavirus Disease 2019 Respiratory Failure.

Crit Care Explor 2021 Jul 29;3(7):e0480. Epub 2021 Jun 29.

Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA.

Objectives: We hypothesize that elevated soluble suppression of tumorigenicity-2 concentrations, a marker of pulmonary epithelial injury, reflect ongoing lung injury in acute hypoxemic respiratory failure due to coronavirus disease 2019 and associate with continued ventilator dependence.

Design: We associated serial plasma soluble suppression of tumorigenicity-2 levels and markers of systemic inflammation including d-dimer, C-reactive protein, and erythrocyte sedimentation rate with 30-day mortality and ventilator dependence.

Setting: Adult medical ICUs and general medicine wards at an academic teaching hospital in Boston, MA.

Patients: Adult patients with severe acute respiratory syndrome coronavirus 2 infection and acute hypoxemic respiratory failure admitted to the ICU ( = 72) and non-ICU patients managed with supplemental oxygen ( = 77).

Interventions: Observational study from April 25 to June 25, 2020.

Measurements And Main Results: ICU patients had a higher baseline body mass index and median soluble suppression of tumorigenicity-2, d-dimer, and C-reactive protein concentrations compared with non-ICU patients. Among ICU patients, elevated baseline modified Sequential Organ Failure Assessment score and log (soluble suppression of tumorigenicity-2) were associated with 30-day mortality, whereas initial Pao/Fio and markers of systemic inflammation were similar between groups. Only log (soluble suppression of tumorigenicity-2) associated with ventilator dependence over time, with the last measured log (soluble suppression of tumorigenicity-2) concentration obtained on ICU day 11.5 (interquartile range [7-17]) higher in patients who required reintubation or tracheostomy placement compared with patients who were successfully extubated (2.10 [1.89-2.26] vs 1.87 ng/mL [1.72-2.13 ng/mL]; = 0.03). Last measured systemic inflammatory markers, modified Sequential Organ Failure Assessment score, and Pao/Fio were not different between patients who were successfully extubated compared with those with continued ventilator dependence.

Conclusions: Plasma soluble suppression of tumorigenicity-2 is a biomarker readily measured in blood that can provide dynamic information about the degree of a patient's lung injury and real-time assessment of the likelihood of extubation success. Measures of systemic inflammation, illness severity, and oxygenation did not associate with ventilator outcomes.
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http://dx.doi.org/10.1097/CCE.0000000000000480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245109PMC
July 2021

Pre-analytical considerations in biomarker research: focus on cardiovascular disease.

Clin Chem Lab Med 2021 Jul 6. Epub 2021 Jul 6.

CIBERCV, Instituto de Salud Carlos III, Madrid, Spain.

Clinical biomarker research is growing at a fast pace, particularly in the cardiovascular field, due to the demanding requirement to provide personalized precision medicine. The lack of a distinct molecular signature for each cardiovascular derangement results in a one-size-fits-all diagnostic and therapeutic approach, which may partially explain suboptimal outcomes in heterogeneous cardiovascular diseases (e.g., heart failure with preserved ejection fraction). A multidimensional approach using different biomarkers is quickly evolving, but it is necessary to consider pre-analytical variables, those to which a biological sample is subject before being analyzed, namely sample collection, handling, processing, and storage. Pre-analytical errors can induce systematic bias and imprecision, which may compromise research results, and are easy to avoid with an adequate study design. Academic clinicians and investigators must be aware of the basic considerations for biospecimen management and essential pre-analytical recommendations as lynchpin for biological material to provide efficient and valid data.
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http://dx.doi.org/10.1515/cclm-2021-0377DOI Listing
July 2021

Downstream Cascades of Care Following High-Sensitivity Troponin Test Implementation.

J Am Coll Cardiol 2021 Jun 3;77(25):3171-3179. Epub 2021 May 3.

Harvard Medical School, Boston, Massachusetts, USA; Division of Cardiology, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Patients with chest pain are often evaluated for acute myocardial infarction through troponin testing, which may prompt downstream services (cascades) of uncertain value.

Objectives: This study sought to determine the association of high-sensitivity cardiac troponin (hs-cTn) assay implementation with cascade events.

Methods: Using electronic health record and billing data, this study examined patient-visits to 5 emergency departments from April 1, 2017, to April 1, 2019. Difference-in-differences analysis compared patient-visits for chest pain (n = 7,564) to patient-visits for other symptoms (n = 100,415) (irrespective of troponin testing) before and after hs-cTn assay implementation. Outcomes included presence of any cascade event potentially associated with an initial hs-cTn test (primary), individual cascade events, length of stay, and spending on cardiac services.

Results: Following hs-cTn implementation, patients with chest pain had a 2.8% (95% confidence interval [CI]: 0.72% to 4.9%) net increase in experiencing any cascade event. They were more likely to have multiple troponin tests (10.5%; 95% CI: 9.0% to 12.0%) and electrocardiograms (7.1 per 100 patient-visits; 95% CI: 1.8 to 12.4). However, they received net fewer computed tomography scans (-1.5 per 100 patient-visits; 95% CI: -1.8 to -1.1), stress tests (-5.9 per 100 patient-visits; 95% CI: -6.5 to -5.3), and percutaneous coronary intervention (PCI) (-0.65 per 100 patient-visits; 95% CI: -1.01 to -0.30) and were less likely to receive cardiac medications, undergo cardiology evaluation (-3.5%; 95% CI: -4.5% to 2.6%), or be hospitalized (-5.8%; 95% CI: -7.7% to -3.8%). Patients with chest pain had lower net mean length of stay (-0.24 days; 95% CI: -0.32 to -0.16) but no net change in spending.

Conclusions: Hs-cTn assay implementation was associated with more net upfront tests yet fewer net stress tests, PCI, cardiology evaluations, and hospital admissions in patients with chest pain relative to patients with other symptoms.
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http://dx.doi.org/10.1016/j.jacc.2021.04.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091384PMC
June 2021

The Impact of Depression on Outcomes in Patients With Heart Failure and Reduced Ejection Fraction Treated in the GUIDE-IT Trial.

J Card Fail 2021 Jun 22. Epub 2021 Jun 22.

Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut; Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Background: It remains unclear why depression is associated with adverse outcomes in patients with heart failure (HF). We examine the relationship between depression and clinical outcomes among patients with HF with reduced ejection fraction managed with guideline-directed medical therapy (GDMT).

Methods And Results: Using the GUIDE-IT trial, 894 patients with HF with reduced ejection fraction were stratified according to a history of depression, and Cox proportional hazards regression modeling was used to examine the association with outcomes. There were 140 patients (16%) in the overall cohort who had depression. They tended to be female (29% vs 46%, P < .001) and White (67% vs 53%, P = .002). There were no differences in GDMT rates at baseline or at 90 days; nor were there differences in target doses of these therapies achieved at 90 days (NS, all). amino-terminal pro-B-type natriuretic peptide levels at all time points were similar between the cohorts (P > .05, all). After adjustment, depression was associated with all-cause hospitalizations (hazard ratio, 1.42, 95% confidence interval 1.11-1.81, P < .01), cardiovascular death (hazard ratio, 1.69, 95% confidence interval 1.07-2.68, P = .025), and all-cause mortality (hazard ratio, 1.54, 95% confidence interval 1.03-2.32, P = .039).

Conclusions: Depression impacts clinical outcomes in HF regardless of GDMT intensity and amino-terminal pro-B-type natriuretic peptide levels. This finding underscores the need for a focus on mental health in parallel to achievement of optimal GDMT in these patients.

Trial Registration: NCT01685840, https://clinicaltrials.gov/ct2/show/NCT01685840.
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http://dx.doi.org/10.1016/j.cardfail.2021.06.008DOI Listing
June 2021

Probabilistic Readjudication of Heart Failure Hospitalization Events in the PARAGON-HF Study.

Circulation 2021 Jun 7;143(23):2316-2318. Epub 2021 Jun 7.

Brigham and Women's Hospital, Boston, MA (A.S.D., S.D.S.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054496DOI Listing
June 2021

Concentration-dependent clinical and prognostic importance of high-sensitivity cardiac troponin T in heart failure and a reduced ejection fraction and the influence of empagliflozin: the EMPEROR-Reduced trial.

Eur J Heart Fail 2021 May 30. Epub 2021 May 30.

Université de Lorraine, Inserm INI-CRCT, CHRU, Nancy, France.

Aims: Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials.

Methods And Results: In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (>97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation. With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend < 0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and showed the least improvement in health status (as measured by the Kansas City Cardiomyopathy Questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analysed as hazard ratios or absolute risk reductions.

Conclusions: Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favourable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT.
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http://dx.doi.org/10.1002/ejhf.2256DOI Listing
May 2021

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

N Engl J Med 2021 05;384(21):2014-2027

From the Vascular Pathophysiology Area (R.B.-D., R.S.-D., A.M.-M., M. Relaño, R.J.-A., B.L.-P., K.T., D.A.P.-F., V.F., F.S.-M., P.M.) and the Myocardial Pathophysiology Area (L.A.-H., M. Ricote, H.B., L.F.-F., B.I.), Centro Nacional de Investigaciones Cardiovasculares (CNIC), the Department of Immunology (H.F., F.S.-M.), the Department of Cardiology (L.J.J.-B., M.M.G.-G., F.A.), the Department of Dermatology (E.D.), and the Department of Rheumatology (I.G.-A.), Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Fundación Jiménez Díaz (M.L.M.-M., B.I.), the Cardiology Department, Hospital Universitario 12 de Octubre, and Instituto de Investigación Sanitaria Hospital 12 de Octubre (G.M., R.M.-A., H.B.), the Department of Immunology, Hospital Ramón y Cajal (L.M.V.-G.), HM Hospitales-Centro Integral de Enfermedades Cardiovasculares (L.F.-F.), and CIBER de Enfermedades Cardiovasculares (R.S.-D., H.F., L.J.J.-B., F.A., D.A.P.-F., B.I., F.S.-M., P.M.), Madrid, Hospital Universitario Central de Asturias, Oviedo (A.M.-L.), and the Cardiology Department, Hospital Universitario Virgen de la Arrixaca, Murcia (D.A.P.-F.) - all in Spain; the Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL (K.A.B., D.F.); the Cardiovascular Division and Corrigan Minehan Heart Center, Massachusetts General Hospital, and Harvard Medical School, Boston (A.M.S.-G., S.A.M., N.E.I., J.L.J., S.D.); Kanntonsspital St. Gallen Klinik für Anesthesiologie und Intensivmedizin, St. Gallen, Switzerland (J.K.); Cardiology (S.I., A.B., A.L.P.C.) and the Cardiovascular Pathology Unit (C.B.), the Department of Cardiac, Thoracic, Vascular Sciences and Public Health, the Department of Laboratory Medicine (M.P., M.S.), and the Department of Medicine, Hematology and Clinical Immunology (R.M.), University of Padua, Padua, Italy; Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin (B.H.); Imperial College and Royal Brompton and Harefield Hospital, London (T.F.L.); and the Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York (V.F.).

Background: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis.

Methods: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls.

Results: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level.

Conclusions: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).
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http://dx.doi.org/10.1056/NEJMoa2003608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258773PMC
May 2021

Association Between Angiotensin Receptor-Neprilysin Inhibition, Cardiovascular Biomarkers, and Cardiac Remodeling in Heart Failure With Reduced Ejection Fraction.

Circ Heart Fail 2021 Jun 15;14(6):e008410. Epub 2021 May 15.

Massachusetts General Hospital, Boston (S.P.M., A.C., R.R.K., J.L.J.).

Background: Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T), and soluble suppressor of tumorigenicity 2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction treated with S/V is uncertain.

Methods: In a prospective study of S/V in patients with heart failure with reduced ejection fraction, this prespecified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate latent growth curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction and left atrial volume index.

Results: Seven hundred fifteen out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline left ventricular ejection fraction and left atrial volume index were 29% and 40 mL/m, respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/mL, hs-cTnT of 15.9 ng/L, and sST2 of 24.7 ng/mL. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT, and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged -27.9% (95% CI, -35.1% to -20.7%; <0.001) for NT-proBNP; -6.7% (95% CI, -8.8% to -4.7%; <0.001) for hs-cTnT; and -1.6% (95% CI, -2.9% to -0.4%; <0.001) for sST2. NT-proBNP concentrations were predictive of later changes in hs-cTnT. The magnitude of reductions in NT-proBNP and hs-cTnT concentrations associated with improvements in left ventricular ejection fraction and left atrial volume index. There was no association between changes in sST2 and changes in other measures.

Conclusions: Following initiation of S/V, NT-proBNP, hs-cTnT, and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with left atrial and left ventricular reverse remodeling. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.008410DOI Listing
June 2021

Effects of Atrial Fibrillation on Heart Failure Outcomes and NT-proBNP Levels in the GUIDE-IT Trial.

Mayo Clin Proc Innov Qual Outcomes 2021 Apr 8;5(2):447-455. Epub 2021 Apr 8.

Section of Cardiovascular Medicine, Yale University, New Haven, CT.

Objective: To evaluate effects of atrial fibrillation (AF) on cardiac biomarkers and outcomes in a trial population of patients with heart failure (HF) with reduced ejection fraction treated with optimal guideline-directed medical therapy.

Methods: We performed a secondary analysis of 894 patients in the Guiding Evidence-Based Therapy Using Biomarker-Intensified Treatment in Heart Failure (GUIDE-IT) trial (January 2013-July 2016). Patients were stratified by AF status and compared with regard to guideline-directed medical therapy use, longitudinal levels of N-terminal pro-B type natriuretic peptide (NT-proBNP), and outcomes including HF hospitalization and mortality.

Results: After adjustment, AF was associated with a significant increase in the risk of HF hospitalization or cardiovascular death (hazard ratio, 1.28; 95% CI, 1.02 to 1.61; =0.04) and HF hospitalization (hazard ratio, 1.31; 95% CI, 1.02 to 1.68; =.03) but with no difference in mortality during a median 15 months of follow-up. There were no significant differences in medication treatment between those with and those without AF. At 90 days, a higher proportion of patients with AF (89.4% vs 81.5%; =.002) had an NT-proBNP level above 1000 pg/mL (to convert NT-proBNP values to pmol/L, multiply by 0.1182), and AF patients had higher NT-proBNP levels at all time points through 2 years of follow-up.

Conclusion: Among patients with HF with reduced ejection fraction, prevalent AF was associated with higher NT-proBNP concentrations through 2 years of follow-up and higher risk for HF hospitalization despite no substantial differences in medical therapy.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105522PMC
April 2021

Intercountry Differences in Guideline-Directed Medical Therapy and Outcomes Among Patients With Heart Failure.

JACC Heart Fail 2021 Jul 12;9(7):497-505. Epub 2021 May 12.

Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA; Center for Outcomes Research & Evaluation, Yale University and Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Objectives: The aim of this study was to examine patterns of care and clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) in the United States and Canada.

Background: In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial, the use of N-terminal pro-B-type natriuretic peptide-guided titration of guideline-directed medical therapy (GDMT) was compared with usual care alone for patients with HFrEF in the United States and Canada. It remains unknown whether the country of enrollment had an impact on outcomes or GDMT use.

Methods: A total of 894 patients at 45 sites across the United States and Canada with HFrEF (ejection fraction ≤40%) were enrolled in the trial. Kaplan-Meier survival estimates stratified by country of enrollment were developed for the trial outcomes, and log-rank testing was compared between the groups. GDMT use and titration were also compared.

Results: U.S. patients were more likely to be younger, to be Black, to have higher body mass index, and to have histories of defibrillator placement or sleep apnea. Use of β-blockers was significantly higher in Canada at baseline (99.3% vs. 94.0%; p = 0.01) and 6 months (99.0% vs. 94.1%; p = 0.04), and use of mineralocorticoid receptor antagonists was higher in Canada at 6 months (68.3% vs. 55.1%; p = 0.01). Canadian patients were less likely to experience the primary study endpoint (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.45 to 0.93; p = 0.01) due to decreased rates of HF hospitalization (HR: 0.57; 95% CI: 0.38 to 0.86; p = 0.003). The differences in outcomes were driven by increased heart failure hospitalization among U.S. Black patients.

Conclusions: In GUIDE-IT, patients with HFrEF in Canada were significantly less likely to be hospitalized for heart failure. Differences in GDMT use, along with differences in sociodemographics and care delivery structures, may contribute to these differences, highlighting the importance of increasing diversity in clinical trials. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).
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http://dx.doi.org/10.1016/j.jchf.2021.02.011DOI Listing
July 2021

Obesity-Mediated Disruption of Natriuretic Peptide-Blood Pressure Rhythms.

J Am Coll Cardiol 2021 May;77(18):2304-2306

Mount Sinai Medical Center, New York, New York, USA; Clinical Trial Center, Cardiovascular Research Foundation, New York, New York, USA. Electronic address: https://twitter.com/RezaMohebiMD.

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http://dx.doi.org/10.1016/j.jacc.2021.03.317DOI Listing
May 2021

Differences in NT-proBNP Response and Prognosis in Men and Women With Heart Failure With Reduced Ejection Fraction.

J Am Heart Assoc 2021 May 6;10(10):e019712. Epub 2021 May 6.

Duke University Medical Center Durham NC.

Background NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a prognostic biomarker in heart failure (HF) with reduced ejection fraction. However, it is unclear whether there is a sex difference in NT-proBNP response and whether the therapeutic goal of NT-proBNP ≤1000 pg/mL has equivalent prognostic value in men and women with HF with reduced ejection fraction. Methods and Results In a secondary analysis of the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial we analyzed trends in NT-proBNP and goal attainment by sex. Differences in clinical characteristics, HF treatment, and time to all-cause death or HF hospitalization were compared. Landmark analysis at 3 months determined the prognostic value of early NT-proBNP goal achievement in men and women. Of the 286 (32%) women and 608 (68%) men in the GUIDE-IT trial, women were more likely to have a nonischemic cause and shorter duration of HF. Guideline-directed medical therapy was less intense over time in women. The absolute NT-proBNP values were consistently lower in women; however, the change in NT-proBNP and clinical outcomes were similar. After adjustment, women achieving the NT-proBNP goal had an 82% reduction in death or HF hospitalization compared with a 59% reduction in men. Conclusions Men and women with HF with reduced ejection fraction had a similar NT-proBNP response despite less intensive HF treatment among women. However, compared with men, the early NT-proBNP goal of ≤1000 pg/mL had greater prognostic value in women. Future efforts should be aimed at intensifying guideline-directed medical therapy in women, which may result in greater NT-proBNP reductions and improved outcomes in women with HF with reduced ejection fraction. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01685840.
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http://dx.doi.org/10.1161/JAHA.120.019712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200692PMC
May 2021

Clinical phenogroups are more effective than left ventricular ejection fraction categories in stratifying heart failure outcomes.

ESC Heart Fail 2021 Aug 2;8(4):2741-2754. Epub 2021 May 2.

ICES, McMaster University, Hamilton, Ontario, Canada.

Aims: Heart failure (HF) guidelines place patients into 3 discrete groups according to left ventricular ejection fraction (LVEF): reduced (<40%), mid-range (40-49%), and preserved LVEF (≥50%). We assessed whether clinical phenogroups offer better prognostication than LVEF.

Methods And Results: This was a sub-study of the Patient-Centered Care Transitions in HF trial. We analysed baseline characteristics of hospitalized patients in whom LVEF was recorded. We used unsupervised machine learning to identify clinical phenogroups and, thereafter, determined associations between phenogroups and outcomes. Primary outcome was the composite of all-cause death or rehospitalization at 6 and 12 months. Secondary outcome was the composite cardiovascular death or HF rehospitalization at 6 and 12 months. Cluster analysis of 1693 patients revealed six discrete phenogroups, each characterized by a predominant comorbidity: coronary heart disease, valvular heart disease, atrial fibrillation (AF), sleep apnoea, chronic obstructive pulmonary disease (COPD), or few comorbidities. Phenogroups were LVEF independent, with each phenogroup encompassing a wide range of LVEFs. For the primary composite outcome at 6 months, the hazard ratios (HRs) for phenogroups ranged from 1.25 [95% confidence interval (CI) 1.00-1.58 for AF] to 2.04 (95% CI 1.62-2.57 for COPD) (log-rank P < 0.001); and at 12 months, the HRs for phenogroups ranged from 1.15 (95% CI 0.94-1.41 for AF) to 1.87 (95% 1.52-3.20 for COPD) (P < 0.002). LVEF-based classifications did not separate patients into different risk categories for the primary outcomes at 6 months (P = 0.69) and 12 months (P = 0.30). Phenogroups also stratified risk of the secondary composite outcome at 6 and 12 months more effectively than LVEF.

Conclusion: Among patients hospitalized for HF, clinical phenotypes generated by unsupervised machine learning provided greater prognostic information for a composite of clinical endpoints at 6 and 12 months compared with LVEF-based categories.

Trial Registration: ClinicalTrials.gov Identifier: NCT02112227.
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http://dx.doi.org/10.1002/ehf2.13344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8318507PMC
August 2021

Rationale for and Practical Use of Sacubitril/Valsartan in the Patient's Journey with Heart Failure and Reduced Ejection Fraction.

Card Fail Rev 2021 Mar 5;7:e06. Epub 2021 Apr 5.

Cardiovascular Department, Papa Giovanni XXIII Hospital Bergamo, Italy.

Sacubitril with valsartan (sacubitril/valsartan) is a relatively novel compound that has become a milestone in the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) in the last decade. Contemporary data suggest that sacubitril/valsartan is associated with improved outcomes compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and has a greater beneficial effect on myocardial reverse remodelling. Additionally, two recent trials have shown that sacubitril/valsartan is well-tolerated even in the acute HF setting, thus enabling a continuum of use in the patient's journey with HFrEF. This article summarises available data on the effectiveness and tolerability of sacubitril/valsartan in patients with HFrEF, and provides the clinician with practical insights to facilitate the use of this drug in every setting, with an emphasis on acute HF, hypotension, electrolyte imbalance and renal insufficiency.
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http://dx.doi.org/10.15420/cfr.2020.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054374PMC
March 2021

A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions.

Circulation 2021 Jul 20;144(2):159-169. Epub 2021 Apr 20.

Universite´ de Lorraine, INSERM CIC 1493, INI CRCT, CHRU, Nancy, France (F.Z.).

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
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http://dx.doi.org/10.1161/CIR.0000000000000981DOI Listing
July 2021

Cardiovascular Risk Factors are Associated with Future Cancer.

JACC CardioOncol 2021 Mar 16;3(1):48-58. Epub 2021 Mar 16.

Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.

Background: The extent to which co-occurrence of cardiovascular disease (CVD) and cancer is due to shared risk factors or other mechanisms is unknown.

Objectives: We investigated the association of standard CVD risk factors, CVD biomarkers, preexisting CVD, and ideal CV health metrics with the development of future cancer.

Methods: We prospectively followed Framingham Heart Study and PREVEND participants free of cancer at baseline, and ascertained histology-proven cancer. We studied the association of baseline CV risk factors, 10-year atherosclerotic CVD risk score, established CVD biomarkers, prevalent CVD, and AHA Life's Simple 7 CV health score with incident cancer using multivariable Cox models. Analyses of interim CVD events with incident cancer used time-dependent covariates.

Results: Among 20,305 participants (mean age 50 ± 14 years, 54% women), 2,548 incident cancer cases occurred over a median follow-up of 15.0 (13.3-15.0) surveillance years. Traditional CVD risk factors including age, sex, and smoking status were independently associated with cancer (P <0.001 for all). Estimated 10-year atherosclerotic CVD risk was also associated with future cancer (HR 1.16 per 5% increase in risk, 95% CI 1.14-1.17, P<0.001). We found that natriuretic peptides (NP) (tertile 3 vs 1: HR 1.40, 95% CI 1.03-1.91, p=0.035) was associated with incident cancer, but not high sensitivity troponin (hs-cTn) (p=0.47). Prevalent CVD and the development of interim CV events were not associated with higher risk of subsequent cancer. However, ideal CV health was associated with lower future cancer risk (HR 0.95 per 1-point increase in AHA health score, 95% CI 0.92-0.99, p=0.009).

Conclusions: CVD risk as captured by traditional CVD risk factors, 10-year atherosclerotic CVD risk score, and NP concentrations are associated with increased risk of future cancer. Conversely, a heart healthy lifestyle is associated with a reduced risk of future cancer. Our data suggest that the association between CVD and future cancer is attributable to shared risk factors.
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http://dx.doi.org/10.1016/j.jaccao.2020.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045786PMC
March 2021

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

J Am Coll Cardiol 2021 Apr;77(15):1922-1933

WCG Clinical and WCG-ACI Clinical, Bala Cynwood, Pennsylvania, USA.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.
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http://dx.doi.org/10.1016/j.jacc.2021.02.040DOI Listing
April 2021

A call to action for new global approaches to cardiovascular disease drug solutions.

Eur Heart J 2021 04;42(15):1464-1475

Université de Lorraine, INSERM CIC 1493, INI CRCT, CHRU Nancy, France.

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
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http://dx.doi.org/10.1093/eurheartj/ehab068DOI Listing
April 2021

National and Local Politics of the Heart.

J Am Coll Cardiol 2021 Apr;77(14):1744-1746

Vanderbilt Heart and Vascular Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1016/j.jacc.2021.02.053DOI Listing
April 2021

Can biomarkers help find the 'sweet spot' for treating patients with diabetes?

Eur J Heart Fail 2021 Jun 13;23(6):1037-1039. Epub 2021 Apr 13.

Massachusetts General Hospital, Harvard Medical School, and Baim Institute for Clinical Research, Boston, MA, USA.

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http://dx.doi.org/10.1002/ejhf.2175DOI Listing
June 2021

Discordance of High-Sensitivity Troponin Assays in Patients With Suspected Acute Coronary Syndromes.

J Am Coll Cardiol 2021 Mar;77(12):1487-1499

Cardiovascular Imaging Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts, USA.

Background: High-sensitivity cardiac troponin (hs-cTn) assays have different analytic characteristics.

Objectives: The goal of this study was to quantify differences between assays for common analytical benchmarks and to determine whether they may result in differences in the management of patients with suspected acute coronary syndrome (ACS).

Methods: The authors included patients with suspected ACS enrolled in the ROMICAT (Rule Out Myocardial Infarction/Ischemia Using Computer Assisted Tomography) I and II trials, with blood samples taken at emergency department presentation (ROMICAT-I and -II) or at 2 and 4 h thereafter (ROMICAT-II). hs-cTn concentrations were measured using 3 assays (Roche Diagnostics, Elecsys 2010 platform; Abbott Diagnostics, ARCHITECT i2000SR; Siemens Diagnostics, HsVista). Per blood sample, we determined concordance across analytic benchmarks (99th percentile). Per-patient, the authors determined concordance of management recommendations (rule-out/observe/rule-in) per the 0/2-h algorithm, and their association with diagnostic test findings (coronary artery stenosis >50% on coronary computed tomography angiography or inducible ischemia on perfusion imaging) and ACS.

Results: Among 1,027 samples from 624 patients (52.8 ± 10.0 years; 39.4% women), samples were classified as 99th percentile (7.2% vs. 6.0% vs. 6.2%) by Roche, Abbott, and Siemens, respectively. A total of 37.4% (n = 384 of 1,027) of blood samples were classified into the same analytical benchmark category, with low concordance across benchmarks (99th percentile 43.6%). Serial samples were available in 242 patients (40.1% women; mean age: 52.8 ± 8.0 years). The concordance of management recommendations across assays was 74.8% (n = 181 of 242) considering serial hs-cTn measurements. Of patients who were recommended to discharge, 19.6% to 21.1% had positive diagnostic test findings and 2.8% to 4.3% had ACS at presentation.

Conclusions: Caregivers should be aware that there are significant differences between hs-cTn assays in stratifying individual samples and patients with intermediate likelihood of ACS according to analytical benchmarks that may result in different management recommendations. (Rule Out Myocardial Infarction by Computer Assisted Tomography [ROMICAT]; NCT00990262) (Multicenter Study to Rule Out Myocardial Infarction by Cardiac Computed Tomography [ROMICAT-II]; NCT01084239).
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http://dx.doi.org/10.1016/j.jacc.2021.01.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040768PMC
March 2021

Novel Trial Design: CHIEF-HF.

Circ Heart Fail 2021 03 16;14(3):e007767. Epub 2021 Mar 16.

Janssen Scientific Affairs, LLC Titusville, NJ (M.B.,J.W.).

Background: The expense of clinical trials mandates new strategies to efficiently generate evidence and test novel therapies. In this context, we designed a decentralized, patient-centered randomized clinical trial leveraging mobile technologies, rather than in-person site visits, to test the efficacy of 12 weeks of canagliflozin for the treatment of heart failure, regardless of ejection fraction or diabetes status, on the reduction of heart failure symptoms.

Methods: One thousand nine hundred patients will be enrolled with a medical record-confirmed diagnosis of heart failure, stratified by reduced (≤40%) or preserved (>40%) ejection fraction and randomized 1:1 to 100 mg daily of canagliflozin or matching placebo. The primary outcome will be the 12-week change in the total symptom score of the Kansas City Cardiomyopathy Questionnaire. Secondary outcomes will be daily step count and other scales of the Kansas City Cardiomyopathy Questionnaire.

Results: The trial is currently enrolling, even in the era of the coronavirus disease 2019 (COVID-19) pandemic.

Conclusions: CHIEF-HF (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) is deploying a novel model of conducting a decentralized, patient-centered, randomized clinical trial for a new indication for canagliflozin to improve the symptoms of patients with heart failure. It can model a new method for more cost-effectively testing the efficacy of treatments using mobile technologies with patient-reported outcomes as the primary clinical end point of the trial. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04252287.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982129PMC
March 2021

A Test in Context: Interpretation of High-Sensitivity Cardiac Troponin Assays in Different Clinical Settings.

J Am Coll Cardiol 2021 Mar;77(10):1357-1367

Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Baim Institute for Clinical Research, Boston, Massachusetts, USA. Electronic address:

High-sensitivity cardiac troponin (hs-cTn) assays have the ability to detect minute troponin concentrations and resolve minor changes in biomarker concentrations. Clinically, this allows for the ability to rapidly identify or exclude acute myocardial injury in the setting of acute chest discomfort-thus providing more rapid evaluation for acute myocardial infarction-but the improvements in troponin assays also create avenues for other applications where troponin release from the cardiomyocyte might confer prognostic information. These situations include cardiovascular risk assessment across a wide range of clinical circumstances, including apparently-well individuals, those at risk for heart disease, and those with prevalent cardiovascular disorders. The optimal hs-cTn threshold for each circumstance varies by the assay used and by the population assessed. This review will provide context for how hs-cTn assays might be interpreted depending on the application sought, reviewing results from studies leveraging hs-cTn for applications beyond "acute myocardial infarction diagnostic evaluation."
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http://dx.doi.org/10.1016/j.jacc.2021.01.011DOI Listing
March 2021

Re-appraisal of the obesity paradox in heart failure: a meta-analysis of individual data.

Clin Res Cardiol 2021 Aug 11;110(8):1280-1291. Epub 2021 Mar 11.

Department of Cardiology, Maastricht University Medical Centre, PO Box 5800, 6202AZ, Maastricht, The Netherlands.

Background: Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population.

Methods: In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m, 18.5-25.0 kg/m; 25.0-30.0 kg/m; 30.0 kg/m). Primary endpoints included all-cause mortality and HF hospitalization-free survival.

Results: Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity.

Conclusions: The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged < 75 years without co-morbidities (top). The prognostic effect largely disappears in multivariable analyses even for the former group. These findings question the protective effect of obesity in chronic heart failure (HF).
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http://dx.doi.org/10.1007/s00392-021-01822-1DOI Listing
August 2021

Causes of Cardiovascular Hospitalization and Death in Patients With Transthyretin Amyloid Cardiomyopathy (from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]).

Am J Cardiol 2021 06 3;148:146-150. Epub 2021 Mar 3.

Hospital Universitario La Paz, IdiPaz, CIBER-CV, Madrid, Spain.

In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis significantly reduced mortality and cardiovascular (CV)-related hospitalizations compared with placebo in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This analysis aimed to assess the causes of CV-related death and hospitalization in ATTR-ACT to provide further insight into the progression of ATTR-CM and efficacy of tafamidis. ATTR-ACT was an international, double-blind, placebo-controlled, and randomized study. Patients with hereditary or wild-type ATTR-CM were randomized to tafamidis (n = 264) or placebo (n = 177) for 30 months. The independent Endpoint Adjudication Committee determined whether certain investigator-reported events met the definition of disease-related efficacy endpoints using predefined criteria. Cause-specific reasons for CV-related deaths (heart failure [HF], arrhythmia, myocardial infarction, sudden death, stroke, and other CV causes) and hospitalizations (HF, arrhythmia, myocardial infarction, transient ischemic attack/stroke, and other CV causes) were assessed. Total CV-related deaths was 53 (20.1%) with tafamidis and 50 (28.2%) with placebo, with HF (15.5% tafamidis, 22.6% placebo), followed by sudden death (2.7% tafamidis, 5.1% placebo), the most common causes. The number of patients with a CV-related hospitalization was 138 (52.3%) with tafamidis and 107 (60.5%) with placebo; with HF the most common cause (43.2% tafamidis, 50.3% placebo). All predefined causes of CV-related death or hospitalization were less frequent with tafamidis than placebo. In conclusion, these data provide further insight into CV disease progression in patients with ATTR-CM, with HF the most common adjudicated cause of CV-related hospitalization or death in ATTR-ACT. Clinical trial registration ClinicalTrials.gov: NCT01994889.
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http://dx.doi.org/10.1016/j.amjcard.2021.02.035DOI Listing
June 2021
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