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1.
J Pharm Pract ; : 8971900211004840, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813934

RESUMO

BACKGROUND: Although strategies for optimization of pharmacologic therapy in patients with heart failure with reduced ejection fraction (HFrEF) are scripted by guidelines, data from HF registries suggests that guideline-directed medical therapies (GDMT) are underutilized among eligible patients. Whether this discrepancy reflects medication intolerance, contraindications, or a quality of care issue remains unclear. OBJECTIVE: The objective of this initiative was to identify reasons for underutilization and under-dosing of HFrEF therapy in patients at a large, academic medical center. METHODS: Among 500 patients with HFrEF enrolled in a quality improvement project at a tertiary center, we evaluated usage and dosing of 4 categories of GDMT: ACE inhibitors/Angiotensin Receptor Blockers (ACE-i/ARB), Angiotensin Receptor-Neprilysin Inhibitors (ARNi), beta blockers, and Mineralocorticoid Receptor Antagonists (MRA). Reasons for nonprescription and usage of suboptimal doses were abstracted from notes in the chart and from telephone review of previous medication trials with the patient. RESULTS: Of 500 patients identified, 472 subjects had complete data for analysis. Among eligible patients, ACE-i/ARB were prescribed in 81.4% (293 of 360) and beta blockers in 94.4% (442 of 468). Of these patients, 10.6% were prescribed target doses of ACE-i/ARB and 12.4% were prescribed target doses of beta blockers. Utilization of other categories of GDMT was lower, with 54% of eligible patients prescribed MRAs and 27% prescribed an ARNi. In most cases, the reasons for nonprescription or under-dosing of GDMT were not apparent on review of the health record or discussion with the patient. CONCLUSION: Clear rationale for nonprescription and under-dosing of GDMT often cannot be ascertained from detailed review and is only rarely related to documented medication intolerance or contraindications, suggesting an opportunity for quality improvement.

2.
Circulation ; 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832352

RESUMO

Background: Patients with heart failure and reduced ejection fraction (HFrEF) will experience multiple hospitalizations for heart failure during the course of their disease. We assessed the efficacy of dapagliflozin on reducing the rate of total (i.e. first and repeat) hospitalizations for heart failure in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). Methods: The total number of HF hospitalizations and cardiovascular deaths was examined using the proportional rates approach of Lei-Wei-Ying-Yang (LWYY) and a joint frailty model for each of recurrent HF hospitalizations and time to cardiovascular death. Variables associated with the risk of recurrent hospitalizations were explored in a multivariable LWYY model. Results: Of 2371 participants randomized to placebo, 318 experienced 469 hospitalizations for heart failure among; of 2373 assigned to dapagliflozin, 230 patients experienced 340 admissions. In a multivariable model factors associated with a higher risk of recurrent HF hospitalizations included higher heart rate, higher NT-proBNP and NYHA class. In the LWYY model the rate ratio for the effect of dapagliflozin on recurrent HF hospitalizations or CV death was 0.75 (95%CI 0.65-0.88), p=0.0002. In the joint frailty model, rate ratio for total HF hospitalizations was 0.71 (95% CI 0.61-0.82), p<0.0001 while for cardiovascular death the hazard ratio was 0.81(95%CI 0.67-0.98), p=00282. Conclusions: Dapagliflozin reduced the risk of total (first and repeat) HF hospitalizations and cardiovascular death. Time-to-first event analysis underestimated the benefit of dapagliflozin in HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT03036124.

4.
Circ Heart Fail ; 14(3): e007891, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33663237

RESUMO

BACKGROUND: Treatment with sacubitril-valsartan reduces mortality and heart failure (HF) events in HF with reduced ejection fraction and may reduce HF hospitalization in women with HF with preserved ejection fraction. METHODS: EVALUATE-HF randomized 464 participants (109 women) with HF with reduced ejection fraction to sacubitril-valsartan or enalapril for 12 weeks. Documented left ventricular ejection fraction (LVEF) ≤0.40 within the prior 12 months was required, although core laboratory LVEF>0.40 was permitted. Assessments of aortic stiffness (pulse pressure and characteristic impedance, Zc) were performed at baseline and at trough and 4 hours postdose at weeks 4 and 12. RESULTS: In models of change from baseline adjusted for baseline value, treatment with sacubitril-valsartan produced greater overall reductions in mean arterial pressure (treatment group difference, -3.0±0.8 mm Hg, P<0.001) and pulse pressure (-3.0±0.8 mm Hg, P<0.001). Postdose reductions in Zc were greater in the sacubitril-valsartan group (-16±6 dyne×second/cm5, P=0.012). Post hoc analyses found evidence of effect modification by LVEF (interaction P=0.036). With LVEF<0.40, postdose reductions in Zc were greater in the sacubitril-valsartan group (trough, -3±8 dyne×second/cm5 versus post-dose, -17±8 dyne×second/cm5; interaction P=0.024) with no sex difference (treatment×sex interaction, P=0.3). With LVEF≥0.40, treatment with sacubitril-valsartan was associated with greater overall reductions in Zc in women (women, -80±21 dyne×second/cm5 versus men, -20±13 dyne×second/cm5; interaction P=0.019). CONCLUSIONS: In prespecified analyses that include pre- and postdose assessments at 4 and 12 weeks, treatment with sacubitril-valsartan was associated with greater postdose reductions in aortic Zc. In a post hoc analysis, sacubitril-valsartan was associated with sustained reductions in Zc in women with LVEF≥0.40. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT02874794.

5.
Circ Heart Fail ; 14(3): e008052, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33706551

RESUMO

BACKGROUND: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction. METHODS: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality. RESULTS: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes). CONCLUSIONS: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

6.
J Am Coll Cardiol ; 77(9): 1211-1221, 2021 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-33663739

RESUMO

BACKGROUND: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood. OBJECTIVES: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF. METHODS: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term. RESULTS: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF. CONCLUSIONS: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.

7.
Eur J Heart Fail ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33565237

RESUMO

AIMS: Prognostic models of sudden cardiac death (SCD) typically incorporate data at only a single time-point. We investigated independent predictors of SCD addressing the impact of integrating time-varying covariates to improve prediction assessment. METHODS AND RESULTS: We studied 8399 patients enrolled in the PARADIGM-HF trial and identified independent predictors of SCD (n = 561, 36% of total deaths) using time-updated multivariable-adjusted Cox models, classification and regression tree (CART), and logistic regression analysis. Compared with patients who were alive or died from non-sudden cardiovascular deaths, patients who suffered a SCD displayed a distinct temporal profile of New York Heart Association (NYHA) class, heart rate and levels of three biomarkers (albumin, uric acid and total bilirubin), with significant differences observed more than 1 year prior to the event (Pinteraction < 0.001). In multivariable models adjusted for baseline covariates, seven time-updated variables independently contributed to SCD risk (incremental likelihood chi-square = 46.2). CART analysis identified that baseline variables (implantable cardioverter-defibrillator use and N-terminal prohormone of B-type natriuretic peptide levels) and time-updated covariates (NYHA class, total bilirubin, and total cholesterol) improved risk stratification. CART-defined subgroup of highest risk had nearly an eightfold increment in SCD hazard (hazard ratio 7.7, 95% confidence interval 3.6-16.5; P < 0.001). Finally, changes over time in heart rate, NYHA class, blood urea nitrogen and albumin levels were associated with differential risk of sudden vs. non-sudden cardiovascular deaths (P < 0.05). CONCLUSIONS: Beyond single time-point assessments, distinct changes in multiple cardiac-specific and systemic variables improved SCD risk prediction and were helpful in differentiating mode of death in chronic heart failure.

8.
Eur J Heart Fail ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33609066

RESUMO

AIMS: The relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan. METHODS AND RESULTS: The relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up. CONCLUSIONS: Both hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.

9.
Am Heart J ; 2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33621540

RESUMO

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NTproBNP) plasma concentrations are independent prognostic markers in patients with heart failure with reduced ejection fraction (HFrEF). Whether a differential risk association between NTproBNP plasma concentrations and risk of cardiovascular (CV) versus non-CV adverse events exists is not well known. OBJECTIVE: To assess if there is a differential proportional risk of CV versus non CV adverse events by NTproBNP plasma concentrations. METHODS: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV versus non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/ml) at baseline using Cox regression adjusting for traditional risk factors. RESULTS: 14,737 patients with mean age of 62±8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/ml group to 142.3 in the ≥3000 pg/ml group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to presence of AF at baseline and prior HF hospitalization within last 12 months. CONCLUSION: The absolute CV event rates per patient years of follow up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

10.
J Am Heart Assoc ; 10(4): e019238, 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33522249

RESUMO

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.

12.
ESC Heart Fail ; 8(2): 1130-1138, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33438360

RESUMO

AIMS: Diabetes mellitus (DM) is common in heart failure with preserved ejection fraction (HFpEF). Patients with DM and heart failure with reduced ejection fraction have higher levels of cardiac, profibrotic, and proinflammatory biomarkers relative to non-diabetics. Limited data are available regarding the biomarker profiles of HFpEF patients with diabetes (DM) vs. no diabetes (non-DM) and the impact of spironolactone on these biomarkers. This study aims to address such gaps in the literature. METHODS AND RESULTS: Biomarkers were measured at randomization and at 12 months in 248 patients enrolled in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist's North American cohort. At baseline, DM patients had significantly lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein, pro-collagen type III amino-terminal peptide, tissue inhibitor of metalloproteinase 1 (TIMP-1), and galectin-3 levels than those without diabetes. There was a significantly larger 12 month increase in levels of high-sensitivity troponin T (hs-TnT), a marker of myocyte death, in DM patients. Elevated pro-collagen type III amino-terminal peptide and galectin-3 levels were associated with an increased risk of the primary outcome (cardiovascular mortality, aborted cardiac arrest, or heart failure hospitalization) in DM patients, but not in those without diabetes. A statistically significant interaction between spironolactone and diabetes status was observed for hs-TnT and for TIMP-1, with greater biomarker reductions among those with diabetes treated with spironolactone. CONCLUSIONS: The presence of diabetes is associated with higher levels of cardiac, profibrotic, and proinflammatory biomarkers in HFpEF. Spironolactone appears to alter the determinants of extracellular matrix remodelling in an anti-fibrotic fashion in patients with diabetes, reflected by changes in hs-TnT and TIMP-1 levels over time.

13.
Eur Heart J ; 42(6): 700-710, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33351892

RESUMO

AIMS: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). METHODS AND RESULTS: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. CONCLUSION: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

14.
Clin Res Cardiol ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33301080

RESUMO

BACKGROUND: Sudden death (SD) and pump failure death (PFD) are leading modes of death in heart failure and preserved ejection fraction (HFpEF). Risk stratification for mode-specific death may aid in patient enrichment for new device trials in HFpEF. METHODS: Models were derived in 4116 patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial (I-Preserve), using competing risks regression analysis. A series of models were built in a stepwise manner, and were validated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)-Preserved and Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trials. RESULTS: The clinical model for SD included older age, men, lower LVEF, higher heart rate, history of diabetes or myocardial infarction, and HF hospitalization within previous 6 months, all of which were associated with a higher SD risk. The clinical model predicting PFD included older age, men, lower LVEF or diastolic blood pressure, higher heart rate, and history of diabetes or atrial fibrillation, all for a higher PFD risk, and dyslipidaemia for a lower risk of PFD. In each model, the observed and predicted incidences were similar in each risk subgroup, suggesting good calibration. Model discrimination was good for SD and excellent for PFD with Harrell's C of 0.71 (95% CI 0.68-0.75) and 0.78 (95% CI 0.75-0.82), respectively. Both models were robust in external validation. Adding ECG and biochemical parameters, model performance improved little in the derivation cohort but decreased in validation. Including NT-proBNP substantially increased discrimination of the SD model, and simplified the PFD model with marginal increase in discrimination. CONCLUSIONS: The clinical models can predict risks for SD and PFD separately with good discrimination and calibration in HFpEF and are robust in external validation. Adding NT-proBNP further improved model performance. These models may help to identify high-risk individuals for device intervention in future trials. CLINICAL TRIAL REGISTRATION: I-Preserve: ClinicalTrials.gov NCT00095238; TOPCAT: ClinicalTrials.gov NCT00094302; CHARM-Preserved: ClinicalTrials.gov NCT00634712.

15.
JAMA ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33275134

RESUMO

Importance: Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. Objective: To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. Design, Setting, and Participants: Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible. Interventions: Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons. Main Outcomes and Measures: The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed. Results: Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants. Conclusions and Relevance: In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population. Trial Registration: ClinicalTrials.gov Identifier: NCT02787044.

16.
Am Heart J ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33306993

RESUMO

Our analysis from a national registry shows that compared to cancer, cardiovascular disease (CVD) patients referred to palliative care are a decade older, have worse functional status and clinician-estimated prognosis. Both groups have very high symptom burden, with CVD patients experiencing more dyspnea while pain, nausea, and fatigue are more common in cancer.

17.
Eur J Heart Fail ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33368858

RESUMO

AIMS: Chronic obstructive pulmonary disease (COPD) is an important comorbidity in heart failure (HF) with reduced ejection fraction (HFrEF), associated with worse outcomes and often suboptimal treatment because of under-prescription of beta-blockers. Consequently, additional effective therapies are especially relevant in patients with COPD. The aim of this study was to examine outcomes related to COPD in a post hoc analysis of the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial. METHODS AND RESULTS: We examined whether the effects of dapagliflozin in DAPA-HF were modified by COPD status. The primary outcome was the composite of an episode of worsening HF or cardiovascular death. Overall, 585 (12.3%) of the 4744 patients randomized had a history of COPD. Patients with COPD were more likely to be older men with a history of smoking, worse renal function, and higher baseline N-terminal pro B-type natriuretic peptide, and less likely to be treated with a beta-blocker or mineralocorticoid receptor antagonist. The incidence of the primary outcome was higher in patients with COPD than in those without [18.9 (95% confidence interval 16.0-22.2) vs. 13.0 (12.1-14.0) per 100 person-years; hazard ratio (HR) for COPD vs. no COPD 1.44 (1.21-1.72); P < 0.001]. The effect of dapagliflozin, compared with placebo, on the primary outcome, was consistent in patients with [HR 0.67 (95% confidence interval 0.48-0.93)] and without COPD [0.76 (0.65-0.87); interaction P-value 0.47]. CONCLUSIONS: In DAPA-HF, one in eight patients with HFrEF had concomitant COPD. Participants with COPD had a higher risk of the primary outcome. The benefit of dapagliflozin on all pre-specified outcomes was consistent in patients with and without COPD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT03036124.

18.
JACC Heart Fail ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33189630

RESUMO

BACKGROUND: Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes. OBJECTIVES: The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations. METHODS: From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls. RESULTS: The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p < 0.001), nearly identical to this dataset (1.08 points; p < 0.001). CONCLUSIONS: Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

19.
Circulation ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33040613

RESUMO

Background: Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease (CKD) which complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on kidney function after randomization. Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease (CKD) which complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on kidney function after randomization. Methods: HFrEF patients with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (CV death or worsening HF) according to eGFR category at baseline (<60 and ≥60 ml/min/1.73m2) as well as using eGFR at baseline as a continuous measure. Secondary cardiovascular outcomes and a pre-specified composite renal outcome (≥ 50% sustained decline eGFR, end stage renal disease (ESRD) or renal death) were also examined, along with decline in eGFR over time. Results: Of 4742 with a baseline eGFR, 1926 (41%) had eGFR <60 ml/min/1.73m2. The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% confidence interval (CI)) for the primary endpoint in patients with CKD was 0.71 (0.59, 0.86) vs. 0.77 (0.64, 0.93) in those with an eGFR ≥60 ml/min/1.73m2 (interaction p=0.54). The composite renal outcome was not reduced by dapagliflozin (HR=0.71, 95% CI 0.44, 1.16; p=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.41, -0.78) vs. placebo -2.87 (-3.19, -2.55) ml/min/1.73m2 per year (p<0.001). This was observed in those with and without type 2 diabetes (p for interaction=0.92) Conclusions: Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Clinical Trial Registration: https://clinicaltrials.gov Unique Identifier: NCT03036124.

20.
ESC Heart Fail ; 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-33078584

RESUMO

AIMS: Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM-HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM-HF. METHODS AND RESULTS: HF duration was categorized as 0-1, >1-2, >2-5, and >5 years. Outcomes were adjusted for prognostic variables, including N-terminal pro-brain natriuretic peptide (NT-proBNP). The primary endpoint was the composite of HF hospitalization or cardiovascular death. The number of patients in each group was as follows: 0-1 year, 2523 (30%); >1-2 years, 1178 (14%); >2-5 years, 2054 (24.5%); and >5 years, 2644 (31.5%). Patients with longer-duration HF were older, more often male, and had worse New York Heart Association class and quality of life, more co-morbidity, and higher troponin-T but similar NT-proBNP levels. The primary outcome rate (per 100 person-years) increased with HF duration: 0-1 year, 8.4 [95% confidence interval (CI) 7.6-9.2]; >1-2 years, 11.2 (10.0-12.7); >2-5 years, 13.4 (12.4-14.6); and >5 years, 14.2 (13.2-15.2); P < 0.001. The hazard ratio was 1.26 (95% CI 1.07-1.48), 1.52 (1.33-1.74), and 1.53 (1.33-1.75), respectively, for >1-2, >2-5, and >5 years, compared with 0-1 year. The benefit of sacubitril/valsartan was consistent across HF duration for all outcomes, with the primary endpoint hazard ratio 0.80 (95% CI 0.67-0.97) for 0-1 year and 0.73 (0.63-0.84) in the >5 year group. For the primary outcome, the number needed to treat for >5 years was 18, compared with 29 for 0-1 year. CONCLUSIONS: Patients with longer-duration HF had more co-morbidity, worse quality of life, and higher rates of HF hospitalization and death. The benefit of a neprilysin inhibitor was consistent, irrespective of HF duration. Switching to sacubitril/valsartan had substantial benefits, even in patients with long-standing HF.

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