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1.
Eur J Heart Fail ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32077220

RESUMO

AIMS: Women with heart failure (HF) are under-represented in individual randomized clinical trials (RCTs). Little is known about sex-specific treatment effects in HF medications. We evaluated sex differences in the response to mineralocorticoid receptor antagonists (MRAs) in major HF MRA trials, including a broad spectrum of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Individual patient data fixed-effect meta-analysis was performed using 6167 patients (31.4% were women) recruited in three placebo-controlled RCTs: Randomized Aldactone Evaluation Study (RALES), Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) and Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT)-Americas. Compared to men, women were older, had higher body mass index and lower glomerular filtration rate. They also had higher LVEF and poorer New York Heart Association functional class and were less likely to be taking angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. Placebo-arm event rates were lower for women compared with men (15.4 vs. 22.1 per 100 person-year; P = 0.002). MRAs reduced consistently, in men and women, the relative risk for cardiovascular death or HF hospitalization (P for interaction = 0.83), cardiovascular death (P for interaction = 0.44) and all-cause death (P for interaction = 0.19). These findings remained consistent after adjustment for potential confounders, regardless of LVEF. There was no sex-specific impact of MRA on the rate of hyperkalaemia and worsening renal function during the median 22 months of follow-up. CONCLUSION: In three large MRA RCTs, women were substantially different from men with regard to their clinical features and event rates. Nonetheless, this meta-analysis supports a consistent and beneficial MRA effect regardless of sex.

2.
ESC Heart Fail ; 2020 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-32077268

RESUMO

AIMS: Increased body mass index (BMI) is common in heart failure (HF) patients and is associated with lower levels of N-terminal pro-brain natriuretic peptide (NT-proBNP). We evaluated the influence of BMI on lung ultrasonography (LUS) findings indicative of pulmonary congestion (i.e. B-lines) in patients with chronic and acute HF (AHF). METHODS AND RESULTS: We analysed ambulatory chronic HF (n = 118) and hospitalized AHF (n = 177) patients (mean age 70 years, 64% men, mean BMI 29 kg/m2 , mean ejection fraction 42%) undergoing echocardiography and LUS in eight chest zones. B-lines and chest wall thickness (skin to pleura) on ultrasound were quantified offline and blinded to clinical findings. NT-proBNP was available in AHF patients (n = 167). In chronic HF, B-line number decreased by 18% per 5 unit increase in BMI [95% confidence interval (CI) -35% to +5%, P = 0.11]. In AHF, the number of B-lines decreased by 12% per 5 unit increase in BMI (95% CI -19% to -5%, P = 0.001), whereas NT-proBNP concentration decreased by 28% per 5 unit increase in BMI (95% CI -40% to -16%, P < 0.001). For AHF, B-line number declined to a lesser degree than NT-proBNP concentration with increasing BMI (P = 0.020), and >6 B-lines were observed in half of AHF patients with severe obesity. There was an inverse relationship between B-line number and chest wall thickness, and this association varied by chest region. CONCLUSIONS: Despite an inverse relationship between B-lines and BMI, B-lines declined to a lesser degree than NT-proBNP with increasing BMI. These data suggest that LUS may be useful in patients with HF despite obesity.

3.
JACC Heart Fail ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035892

RESUMO

A central factor in the pathogenesis of heart failure (HF) with reduced ejection fraction is the initial decrease in systolic function. Prior attempts at increasing cardiac contractility with oral drugs have uniformly resulted in signals of increased mortality at pharmacologically effective doses. Omecamtiv mecarbil is a novel, selective cardiac myosin activator that has been shown to improve cardiac function and to decrease ventricular volumes, heart rate, and N-terminal pro-B-type natriuretic peptide in patients with chronic HF. The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial tests the hypotheses that omecamtiv mecarbil can safely improve symptoms, prevent clinical HF events, and delay CV death in patients with chronic HF. The GALACTIC-HF trial is an international, multicenter, randomized, double-blind, placebo-controlled, event-driven cardiovascular outcomes trial. More than 8,000 patients with chronic symptomatic (New York Heart Association functional class II to IV) HF, left ventricular ejection fraction ≤35%, elevated natriuretic peptides, and either current hospitalization for HF or history of hospitalization or emergency department visit for HF within a year of screening will be randomized to either oral placebo or omecamtiv mecarbil employing a pharmacokinetic-guided dose titration strategy using doses of 25, 37.5, or 50 mg twice daily. The primary efficacy outcome is the time to cardiovascular death or first HF event. The study has 90% power to assess a final hazard ratio of approximately 0.80 in cardiovascular death, the first secondary outcome. The GALACTIC-HF trial is the first trial examining whether selectively increasing cardiac contractility in patients with HF with reduced ejection fraction will result in improved clinical outcomes. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).

4.
Circ Heart Fail ; 13(2): e006541, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32065760

RESUMO

BACKGROUND: Both BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro B-type natriuretic peptide) are widely used to aid diagnosis, assess the effect of therapy, and predict outcomes in heart failure and reduced ejection fraction. However, little is known about how these 2 peptides compare in heart failure and reduced ejection fraction, especially with contemporary assays. Both peptides were measured at screening in the PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure). METHODS: Eligibility criteria in PARADIGM-HF included New York Heart Association functional class II to IV, left ventricular ejection fraction ≤40%, and elevated natriuretic peptides: BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL (for patients with HF hospitalization within 12 months, BNP ≥100 pg/mL or NT-proBNP ≥400 pg/mL). BNP and NT-proBNP were measured simultaneously at screening and only patients who fulfilled entry criteria for both natriuretic peptides were included in the present analysis. The BNP/NT-proBNP criteria were not different for patients in atrial fibrillation. Estimated glomerular filtration rate <30 mL/min per 1.73 m2 was a key exclusion criterion. RESULTS: The median baseline concentration of NT-proBNP was 2067 (Q1, Q3: 1217-4003) and BNP 318 (Q1, Q3: 207-559), and the ratio, calculated from the raw data, was ≈6.25:1. This ratio varied considerably according to rhythm (atrial fibrillation 8.03:1; no atrial fibrillation 5.75:1) and with age, renal function, and body mass index but not with left ventricular ejection fraction. Each peptide was similarly predictive of death (all-cause, cardiovascular, sudden and pump failure) and heart failure hospitalization, for example, cardiovascular death: BNP hazard ratio, 1.41 (95% CI, 1.33-1.49) per 1 SD increase, P<0.0001; NT-proBNP, 1.45 (1.36-1.54); P<0.0001. CONCLUSIONS: The ratio of NT-proBNP to BNP in heart failure and reduced ejection fraction appears to be greater than generally appreciated, differs between patients with and without atrial fibrillation, and increases substantially with increasing age and decreasing renal function. These findings are important for comparison of natriuretic peptide concentrations in heart failure and reduced ejection fraction.

8.
Circ Heart Fail ; 13(1): e006638, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31957468

RESUMO

BACKGROUND: Spironolactone has been demonstrated to reduce heart failure (HF) hospitalization in patients with HF with preserved ejection fraction in the Americas region of the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). We assessed effects of 12 months of treatment with spironolactone on biomarkers reflecting myocardial stress, myocardial injury, renal function, and systemic inflammation. METHODS: This TOPCAT biorepository substudy evaluated 247 patients (14% of the total 1767 patients in the Americas region) with symptomatic HF, ejection fraction ≥45%, and elevated natriuretic peptides or a prior HF hospitalization. Paired blood samples at baseline and after 12 months of treatment with spironolactone or placebo were available in 204 patients. RESULTS: At baseline, the median (interquartile range) concentration of BNP (B-type natriuretic peptide) was 124 (69-197) ng/L, NT-proBNP (N-terminal-pro-B-type natriuretic peptide) 624 (307-1312) ng/L, hs-cTnI (high sensitivity cardiac troponin I) 6.3 (3.4-13.0) ng/L, hs-CRP (high sensitivity C-reactive protein) 2.8 (1.3-6.1) mg/L, uric acid 7.2 (5.8-8.7) mg/dL, and urine protein-creatinine ratio 0.11 (0.08-0.20) mg/mg. Compared with placebo-assigned participants at 12 months, those randomized to spironolactone experienced greater reductions from baseline in levels of NT-proBNP (P=0.017) and BNP (P=0.002); these differences persisted after adjustment for demographics, comorbidities, estimated glomerular filtration rate, and enrollment strata. No between-group differences in changes in hs-cTnI, CRP, uric acid, or urine protein-creatinine ratio were observed. CONCLUSIONS: This TOPCAT biorepository substudy suggests potential effects on markers of cardiac wall stress or filling pressures during 12 months of treatment with spironolactone in patients with chronic HF with preserved ejection fraction. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00094302.

9.
JAMA Cardiol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31995119

RESUMO

Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8011), and 70.6% were New York Heart Association class II (n = 5919 of 8011). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, ß-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by χ2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual's risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

10.
Eur Heart J Acute Cardiovasc Care ; : 2048872620901835, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31976745

RESUMO

BACKGROUND: Although pleural effusions are common among patients with acute heart failure, the relevance of pleural effusion size assessed on thoracic ultrasound has not been investigated systematically. METHODS: In this prospective observational study, we included patients hospitalised for acute heart failure and performed a thoracic ultrasound early after admission (thoracic ultrasound 1) and at discharge (thoracic ultrasound 2) independently of routine clinical management. A semiquantitative score was applied offline blinded to clinical findings to categorise and monitor pleural effusion size. RESULTS: Among 188 patients (median age 72 years, 62% men, 78% white, median left ventricular ejection fraction 38%), pleural effusions on thoracic ultrasound 1 were present in 66% of patients and decreased in size during the hospitalisation in 75% based on the pleural effusion score (P<0.0001). Higher values of the pleural effusion score were associated with higher pleural effusion volumes on computed tomography (P<0.001), higher NT-pro brain natriuretic peptide values (P=0.001) and a greater number of B-lines on lung ultrasound (P=0.004). Nevertheless, 47% of patients were discharged with persistent pleural effusions, 19% with large effusions. However, higher values of the pleural effusion score on thoracic ultrasound 2 did not identify patients at increased risk of 90-day heart failure rehospitalisations or death (adjusted hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.92-1.19; P=0.46) whereas seven or more B-lines on lung ultrasound at discharge were independently associated with adverse events (adjusted HR 2.43, 95% CI 1.11-5.37; P=0.027). CONCLUSION: Among patients with acute heart failure, pleural effusions are associated with other clinical, imaging and laboratory markers of congestion and improve with heart failure therapy. The prognostic relevance of persistent pleural effusions at discharge should be investigated in larger studies.

11.
Contemp Clin Trials ; 90: 105937, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31982649

RESUMO

BACKGROUND: The per-protocol effect provides important information in randomized trials with incomplete adherence. Yet, because valid estimation typically requires adjustment for prognostic factors that predict adherence, per-protocol effect estimates are often met with skepticism. In placebo-controlled trials, however, the validity of adjustment can be indirectly verified by demonstrating no association between adherence and the outcome among the placebo arm. Here, we describe a two-stage procedure in which we first adjust for time-varying adherence in the placebo arm and then use a similar procedure to estimate the per-protocol effect. METHODS: We use the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) randomized trial. First, we compare adherers versus non-adherers in the placebo arm, adjusting for pre- and post-randomization variables. Second, we use models validated in the placebo arm to estimate the per-protocol effect of adherence to candesartan versus placebo in the full trial. FINDINGS: We successfully estimated no association between adherence and mortality in the placebo arm; hazard ratio: 0.91 (95% CI: 0.51, 2.52). We then estimated the per-protocol effect under two sets of protocol-defined stopping criteria after adjustment for post-randomization confounders. The mortality hazard ratio estimates ranged from 0.91 to 0.93 for the per-protocol effect estimates, similar to the intention-to-treat effect estimates. INTERPRETATION: Adherence adjustment in the CHARM trial is feasible when appropriate assumptions about missing data and confounding are made. These assumptions cannot be verified but can be supported through the use of placebo-arm adherence assessment.

12.
Circulation ; 141(1): 21-33, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31779467

RESUMO

BACKGROUND: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. METHODS: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. RESULTS: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. CONCLUSIONS: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

13.
Circulation ; 141(2): 100-111, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736328

RESUMO

BACKGROUND: The DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) showed that dapagliflozin added to other guideline-recommended therapies reduced the risk of mortality and heart failure hospitalization and improved symptoms in patients with heart failure and reduced ejection fraction. We examined the effects of dapagliflozin according to age, given potential concerns about the efficacy and safety of therapies in the elderly. METHODS: Patients in New York Heart Association functional class II or greater with a left ventricular ejection fraction ≤40% and a modest elevation of NT-proBNP (N-terminal pro-B-type natriuretic peptide) were eligible. Key exclusion criteria included systolic blood pressure <95 mm Hg and estimated glomerular filtration rate <30 mL·min-1·1.73 m-2. The primary outcome was the composite of an episode of worsening heart failure (heart failure hospitalization or urgent heart failure visit) or cardiovascular death, whichever occurred first. RESULTS: A total of 4744 patients 22 to 94 years of age (mean age, 66.3 [SD 10.9] years) were randomized: 636 patients (13.4%) were <55 years of age, 1242 (26.2%) were 55 to 64 years of age, 1717 (36.2%) were 65 to 74 years of age, and 1149 (24.2%) were ≥75 years of age. The rate of the primary outcome (per 100 person-years, placebo arm) in each age group was 13.6 (95% CI, 10.4-17.9), 15.7 (95% CI, 13.2-18.7), 15.1 (95% CI, 13.1-17.5), and 18.0 (95% CI, 15.2-21.4) with corresponding dapagliflozin/placebo hazard ratios of 0.87 (95% CI, 0.60-1.28), 0.71 (95% CI, 0.55-0.93), 0.76 (95% CI, 0.61-0.95), and 0.68 (95% CI, 0.53-0.88; P for interaction=0.76). Consistent benefits were observed for the components of the primary outcome, all-cause mortality, and symptoms. Although adverse events and study drug discontinuation increased with age, neither was significantly more common with dapagliflozin in any age group. CONCLUSIONS: Dapagliflozin reduced the risk of death and worsening heart failure and improved symptoms across the broad spectrum of age studied in DAPA-HF. There was no significant imbalance in tolerability or safety events between dapagliflozin and placebo, even in elderly individuals. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

14.
Circulation ; 141(2): 90-99, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31736335

RESUMO

BACKGROUND: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium-glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). METHODS: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. RESULTS: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3-91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57-0.86]; hazard ratio, 0.77 [95% CI, 0.61-0.98]; hazard ratio, 0.62 [95% CI, 0.46-0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P<0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78-0.90]; P<0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08-1.23]; odds ratio, 1.15 [95% CI, 1.08-1.22]; odds ratio, 1.14 [95% CI, 1.07-1.22]; number needed to treat=14, 15, and 18, respectively; P<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score). CONCLUSIONS: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03036124.

15.
J Am Coll Cardiol ; 75(3): 245-254, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31726194

RESUMO

BACKGROUND: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. OBJECTIVES: This study sought to determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to hospitalization for HF among patients with HF with preserved ejection fraction (HFpEF). METHODS: In this post hoc analysis of PARAGON-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ARB [Angiotensin Receptor Blocker] Global Outcomes in HFpEF), we assessed the risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (≥45%). The primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed by using a semiparametric proportional rates method, stratified by geographic region. RESULTS: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31 to 90 days, 435 (9%) within 91 to 180 days, and 694 (14%) after 180 days; 2,490 (52%) were never previously hospitalized. Over a median follow-up of 35 months, risk of total HF hospitalizations and cardiovascular death was inversely and nonlinearly associated with timing from prior HF hospitalization (p < 0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio: 0.73; 95% confidence interval: 0.53 to 0.99) to patients never hospitalized (rate ratio: 1.00; 95% confidence interval: 0.80 to 1.24; trend in relative risk reduction: pinteraction = 0.15). With valsartan alone, the rate of total primary events was 26.7 (≤30 days), 24.2 (31 to 90 days), 20.7 (91 to 180 days), 15.7 (>180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (≤30 days), 4.6% (31 to 90 days), and 3.4% (91 to 180 days), whereas no risk reduction was observed in patients screened >180 days or who were never hospitalized (trend in absolute risk reduction: pinteraction = 0.050). CONCLUSIONS: Recent hospitalization for HFpEF identifies patients at high risk for near-term clinical progression. In the PARAGON-HF trial, the relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrant prospective validation. (PARAGON-HF; NCT01920711).

16.
Europace ; 22(1): 74-83, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31595294

RESUMO

AIMS: Catheter ablation for atrial fibrillation (CAF) improves symptoms, but whether CAF improves outcome is less clear. The purpose of this study was to investigate whether CAF is associated with improved outcome in atrial fibrillation (AF) patients with previous direct current (DC) cardioversion. METHODS AND RESULTS: We performed a nationwide cohort study including all patients who underwent their 1st direct current cardioversion for AF in the period 2003-15 (N = 25 439). End points were all-cause death, cardiovascular death, stroke/thromboembolism, and incident heart failure (HF). Catheter ablation for AF was treated as a time-varying covariate and the association with outcome was assessed using Cox regression. We also constructed a propensity-matched cohort and assessed the association between CAF and outcome. Median follow-up was 5.3 years (inter-quartile range 3.0-8.7 years). A total of 3509 patients (13.8%) underwent CAF during the study period. Following adjustment for age, gender, comorbidities, medications, educational level, household income, and CHA2DS2VASc score, CAF was associated with reduced risks of all-cause death, cardiovascular death, and incident HF [all-cause death: hazard ratio (HR) 0.69, P < 0.001; cardiovascular death: HR 0.68, P = 0.003; incident HF: HR 0.76, P = 0.011]. Catheter ablation for AF was not associated with a reduced risk of stroke/thromboembolism. These results were replicated in a propensity-matched cohort. CONCLUSION: In AF patients with a prior DC cardioversion, CAF was associated with a reduced risk of all-cause and cardiovascular death. This may be due to a reduced risk of HF.

17.
Circ Heart Fail ; 12(12): e006539, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813280

RESUMO

BACKGROUND: To describe characteristics and outcomes in women and men with heart failure with preserved ejection fraction. METHODS: Baseline characteristics (including biomarkers and quality of life) and outcomes (primary outcome: composite of first heart failure hospitalization or cardiovascular death) were compared in 4458 women and 4010 men enrolled in CHARM-Preserved (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) (EF≥45%), I-Preserve (Irbesartan in heart failure with Preserved ejection fraction), and TOPCAT-Americas (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial). RESULTS: Women were older and more often obese and hypertensive but less likely to have coronary artery disease or atrial fibrillation. Women had more symptoms and signs of congestion and worse quality of life. Despite this, the risk of the primary outcome was lower in women (hazard ratio, 0.80 [95% CI, 0.73-0.88]), as was the risk of cardiovascular death (hazard ratio, 0.70 [95% CI, 0.62-0.80]), but there was no difference in the rate for first hospitalization for heart failure (hazard ratio, 0.92 [95% CI, 0.82-1.02]). The lower risk of cardiovascular death in women, compared with men, was in part explained by a substantially lower risk of sudden death (hazard ratio, 0.53 [0.43-0.65]; P<0.001). E/A ratio was lower in women (1.1 versus 1.2). CONCLUSIONS: There are significant differences between women and men with heart failure with preserved ejection fraction. Despite worse symptoms, more congestion, and lower quality of life, women had similar rates of hospitalization and better survival than men. Their risk of sudden death was half that of men. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00853658, NCT01035255.

18.
Circ Heart Fail ; 12(12): e006231, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813281

RESUMO

BACKGROUND: The VANISH trial (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression. We describe the baseline characteristics of the VANISH cohort and compare to previous trials evaluating angiotensin receptor blockers. METHODS: Applying a randomized, double-blinded, placebo-controlled design, 178 participants with nonobstructive HCM (age, 23.3±10.1 years; 61% men) were randomized in the primary cohort and 34 (age, 16.5±4.9 years; 50% men) in the exploratory cohort of sarcomeric mutation carriers without left ventricular hypertrophy. RESULTS: In the primary cohort, maximal left ventricular wall thickness was 17±4 mm for adults and Z score 7.0±4.5 for children. Nineteen percent had late gadolinium enhancement on cardiac magnetic resonance. Mean peak oxygen consumption was 33 mL/kg per minute, and 92% of participants were New York Heart Association functional class I. New York Heart Association class II was associated with older age, MYH7 variants, and more prominent imaging abnormalities. Six previous trials of angiotensin receptor blockers in HCM enrolled a median of 24 patients (range, 19-133) with mean age of 51.2 years; 42% of patients were in New York Heart Association class ≥II, and sarcomeric mutations were not required. CONCLUSIONS: The VANISH cohort is much larger, younger, less heterogeneous, and has less advanced disease than prior angiotensin receptor blocker trials in HCM. Participants had relatively normal functional capacity and mild HCM features. New York Heart Association functional class II symptoms were associated with older age, more prominent imaging abnormalities, and MYH7 variants, suggesting both phenotype and genotype contribute to disease manifestations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01912534.

20.
J Am Coll Cardiol ; 74(23): 2858-2873, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31806129

RESUMO

BACKGROUND: The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity. OBJECTIVES: The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies. METHODS: Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors. RESULTS: Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m2; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm2; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e' ratio, pulmonary artery systolic pressure, and event rates. CONCLUSIONS: Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

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