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Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of Data From the PARADIGM-HF Trial.
Srivastava, PK, Claggett, BL, Solomon, SD, McMurray, JJV, Packer, M, Zile, MR, Desai, AS, Rouleau, JL, Swedberg, K, Fonarow, GC
JAMA cardiology. 2018;(12):1226-1231
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Abstract
IMPORTANCE The addition of receptor-neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described. OBJECTIVE To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin-Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort. DESIGN, SETTING, AND PARTICIPANTS Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, ≤40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018. INTERVENTIONS Random assignment to sacubitril-valsartan or enalapril. MAIN OUTCOMES AND MEASURES Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality. RESULTS The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8 (11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for β-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy. CONCLUSIONS AND RELEVANCE The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF.
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Effect of organic and inorganic nitrates on cerebrovascular pulsatile power transmission in patients with heart failure and preserved ejection fraction.
Londono-Hoyos, F, Zamani, P, Beraun, M, Vasim, I, Segers, P, Chirinos, JA
Physiological measurement. 2018;(4):044001
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Abstract
OBJECTIVE Increased penetration of pulsatile power to the brain has been implicated in the pathogenesis of age-related cognitive dysfunction and dementia, a common comorbidity in patients with heart failure and preserved ejection fraction (HFpEF). However, there is a lack of knowledge on the effects of organic and inorganic nitrates administration in this population on the power carried by pressure and flow waves traveling through the proximal aorta and penetrating the carotid artery into the brain microvasculature. APPROACH We assessed aortic and carotid hemodynamics non-invasively in two sub-studies: (1) at baseline and after administration of 0.4 mg of sublingual nitroglycerine (an organic nitrate; n = 26); and (2) in a randomized controlled trial of placebo (PB) versus inorganic nitrate administration (beetroot-juice (BR), 12.9 mmol NO3; n = 16). MAIN RESULTS Wave and hydraulic power analysis demonstrated that NTG increased total hydraulic power (from 5.68% at baseline to 8.62%, P = 0.001) and energy penetration (from 8.69% to 11.63%; P = 0.01) from the aorta to the carotid, while inorganic nitrate administration did not induce significant changes in aortic and carotid wave power (power: 5.49%PB versus 6.25%BR, P = 0.49; energy: 8.89%PB versus 10.65%BR, P = 0.27). SIGNIFICANCE Organic nitrates, but not inorganic nitrates, increase the amount of hydraulic energy transmitted into the carotid artery in subjects with HFpEF. These findings may have implications for the adverse effect profiles of these agents (such as the differential incidence of headaches) and for the pulsatile hemodynamic stress of the brain microvasculature in this patient population.
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Investigating a biomarker-driven approach to target collagen turnover in diabetic heart failure with preserved ejection fraction patients. Effect of torasemide versus furosemide on serum C-terminal propeptide of procollagen type I (DROP-PIP trial).
Trippel, TD, Van Linthout, S, Westermann, D, Lindhorst, R, Sandek, A, Ernst, S, Bobenko, A, Kasner, M, Spillmann, F, González, A, et al
European journal of heart failure. 2018;(3):460-470
Abstract
AIM: Heart failure with preserved ejection fraction (HFpEF) is associated with myocardial remodelling including severe pro-fibrotic changes contributing to an increase in left ventricular stiffness and diastolic dysfunction. Serum C-terminal propeptide of procollagen type I (PIP) strongly correlates with the turnover of extracellular cardiac matrix proteins and fibrosis. Torasemide, but not furosemide, was described to reduce collagen type I synthesis in clinically unstable patients with heart failure with reduced ejection fraction. We evaluated whether its effect translated to HFpEF patients with type 2 diabetes mellitus (T2DM) and abnormal basal PIP levels. METHODS AND RESULTS We performed a relatively small, single-centre, randomised, double-blind, two-arm parallel-group, active controlled clinical trial in 35 HFpEF patients with T2DM to determine the effects of a 9-month treatment with torasemide vs. furosemide on changes of serum PIP levels. Patients with increased PIP levels (≥110 ng/mL), or evidence of structural changes with a left atrial volume index (LAVI) >29 mL/m2 and abnormal PIP levels (≥70 ng/mL), were eligible to participate. Fifteen patients were female (42%), mean age was 69 years, body mass index was 34.7 kg/m2 , 83% were in New York Heart Association class II/III. Echocardiographic characteristics showed a mean left ventricular ejection fraction of >60%, a left ventricular mass index >120 g/m2 , an E/e' ratio of 14, and a LAVI of 40 mL/m2 with a NT-proBNP of 174 ng/L and a 6-minute walk distance of 421 m. Mean per cent change in PIP was 2.63 ± 5.68% (±SEM) in torasemide vs. 2.74 ± 6.49% in furosemide (P = 0.9898) treated patients. Torasemide was not superior to furosemide in improving functional capacity, diastolic function, quality of life, or neuroendocrine activation. CONCLUSION In this hypothesis-generating, mechanistic trial in stable HFpEF patients with T2DM, neither long-term administration of torasemide nor furosemide was associated with a significant effect on myocardial fibrosis, as assessed by serum PIP. Further studies are urgently needed in this field. More specific diuretic and anti-fibrotic treatment strategies in T2DM and/or HFpEF are warranted.
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Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, mid-range and preserved ejection fraction.
Martens, P, Nijst, P, Verbrugge, FH, Smeets, K, Dupont, M, Mullens, W
Acta cardiologica. 2018;(2):115-123
Abstract
BACKGROUND Little information is available about the prevalence and impact on exercise capacity and outcome of iron deficiency in heart failure with mid-range (HFmrEF) and preserved (HFpEF) ejection fraction in comparison to heart failure with reduced ejection-fraction (HFrEF). Furthermore, no data is available about the progression of ID in patients without baseline anaemia. METHODS We evaluated baseline iron and haemoglobin-status in a single-centre, prospective heart failure database. Baseline functional status, VO2max, echocardiography and clinical-outcome (all-cause mortality and heart failure admissions) were evaluated. ID, anaemia, HFrEF, HFmrEF and HFpEF were defined according to established criteria. RESULTS A total of 1197 patients (71% male) were evaluated (HFrEF, n = 897; HFmrEF, n = 229; HFpEF, n = 72). The overall prevalence of ID was 53% (50% in HFrEF; 61% in HFmrEF; 64% in HFpEF) and 36% for anaemia. ID was associated with a lower VO2max in patients with HFrEF, HFmrEF and HFpEF (p < .001 in all). Iron status more closely related to a poor VO2max than anaemia status (p < .001). Furthermore, poor clinical-outcome was more strongly associated with iron status than anaemia status. Exposing eight patients without anaemia to iron deficiency for 39 months resulted in one patient developing new-onset anaemia (defined as progression of ID). Patients with progression of ID exhibited a significant higher risk of heart failure hospitalisation and all-cause mortality (HR = 1.4; CI = 1.01-1.94; p = .046) than patients without progression. CONCLUSIONS Iron deficiency is common in patients with HFrEF, HFmrEF and HFpEF, and negatively affects VO2max and clinical-outcome. Progression of iron deficiency parallels an increased risk for worsening of heart failure.
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Impact of sacubitril-valsartan combination in patients with chronic heart failure and sleep apnoea syndrome: the ENTRESTO-SAS study design.
Jaffuel, D, Molinari, N, Berdague, P, Pathak, A, Galinier, M, Dupuis, M, Ricci, JE, Mallet, JP, Bourdin, A, Roubille, F
ESC heart failure. 2018;(3):222-230
Abstract
AIMS: Sleep-disordered breathing (SDB) is a highly prevalent co-morbidity in patients with chronic heart failure (CHF) and can play a detrimental role in the pathophysiology course of CHF. However, the best way to manage SDB in CHF remains a matter of debate. Sacubitril-valsartan has been included in the 2016 European Society of Cardiology guidelines as an alternative to angiotensin-converting enzyme inhibitors to further reduce the risk of progression of CHF, CHF hospitalization, and death in ambulatory patients. Sacubitril and valsartan are good candidates for correcting SDB of CHF patients because their known mechanisms of action are likely to counteract the pathophysiology of SDB in CHF. METHODS AND RESULTS The ENTRESTO-SAS trial is a 3-month, multicentric, prospective, open-label real-life cohort study. Patients eligible for sacubitril-valsartan treatment (i.e. adults with left ventricular ejection fraction ≤35%, who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme inhibitor, a beta-blocker, and a mineralocorticoid receptor antagonist) will be evaluated before and after 3 months of treatment (nocturnal ventilatory polygraphy, echocardiography, laboratory testing, and quality-of-life and SDB questionnaires). The primary outcome is the change in the Apnoea-Hypopnoea Index, before and after 3 months of treatment. One hundred twenty patients are required to detect a significant 20% improvement of the Apnoea-Hypopnoea Index with a power of 90% at an alpha risk of 5%. CONCLUSIONS In the context of the SERVE-HF study, physicians are waiting for new trials and alternative therapies. We sought to assess in the ENTRESTO-SAS trial whether sacubitril-valsartan could improve the outcome of SDB in CHF patients.
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Therapeutic Approach to Patients with Heart Failure with Reduced Ejection Fraction and End-stage Renal Disease.
Inampudi, C, Alvarez, P, Asleh, R, Briasoulis, A
Current cardiology reviews. 2018;(1):60-66
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Abstract
BACKGROUND Several risk factors including Ischemic heart disease, uncontrolled hypertension, high output Heart Failure (HF) from shunting through vascular hemodialysis access, and anemia, contribute to development of HF in patients with End-Stage Renal Disease (ESRD). Guidelinedirected medical and device therapy for Heart Failure with Reduced Ejection Fraction (HFrEF) has not been extensively studied and may have limited safety and efficacy in patients with ESRD. RESULTS Maintenance of interdialytic and intradialytic euvolemia is a key component of HF management in these patients but often difficult to achieve. Beta-blockers, especially carvedilol which is poorly dialyzed is associated with cardiovascular benefit in this population. Despite paucity of data, Angiotensin-converting Enzyme Inhibitors (ACEI) or Angiotensin II Receptor Blockers (ARBs) when appropriately adjusted by dose and with close monitoring of serum potassium can also be administered to these patients who tolerate beta-blockers. Mineralocorticoid receptors in patients with HFrEF and ESRD have been shown to reduce mortality in a large randomized controlled trial without any significantly increased risk of hyperkalemia. Implantable Cardiac-defibrillators (ICDs) should be considered for primary prevention of sudden cardiac death in patients with HFrEF and ESRD who meet the implant indications. Furthermore in anemic iron-deficient patients, intravenous iron infusion may improve functional status. Finally, mechanical circulatory support with leftventricular assist devices may be related to increased mortality risk and the presence of ESRD poses a relative contraindication to further evaluation of these devices.
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Derangements in adrenergic-adipokine signalling establish a neurohormonal basis for obesity-related heart failure with a preserved ejection fraction.
Packer, M
European journal of heart failure. 2018;(5):873-878
Abstract
Among patients with heart failure and a preserved ejection (HFpEF), obesity is associated with a distinct phenotype that is characterized by adiposity-driven plasma volume expansion and cardiac overfilling, which is coupled with an impairment of ventricular distensibility. These pathophysiological abnormalities may be related to the increased actions of specific adipocyte-derived signalling molecules (aldosterone, neprilysin and leptin) that work in concert with increased renal sympathetic nerve traffic and activated beta2 -adrenergic receptors to promote sodium retention, microvascular rarefaction, cardiac fibrosis and systemic inflammation. This interplay leads to striking activation of the mineralocorticoid receptor, possibly explaining why obese patients with heart failure are most likely to benefit from spironolactone and eplerenone in large-scale clinical trials. Additionally, adipocytes express and release neprilysin, which (by degrading endogenous natriuretic peptides) can further promote plasma volume expansion and cardiac fibrosis. Heightened neprilysin activity may explain the low circulating levels of natriuretic peptides in obesity, the accelerated breakdown of natriuretic peptides in HFpEF, and the cardiac decompression following neprilysin inhibition in HFpEF patients who are obese. Furthermore, as adipose tissue accumulates and becomes dysfunctional, its secretion of leptin promotes renal sodium retention, microvascular changes and fibrotic processes in the heart, and systemic inflammation; these effects may be mediated or potentiated by the activation of beta2 -adrenergic receptors. These adrenergic-adipokine interactions provide a mechanistic framework for novel therapeutic strategies to alleviate the pathophysiological abnormalities of obesity-related HFpEF. Ongoing trials are well-positioned to test this hypothesis.
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Rationale and design of the Study of Dietary Intervention Under 100 MMOL in Heart Failure (SODIUM-HF).
Colin-Ramirez, E, Ezekowitz, JA, ,
American heart journal. 2018;:87-96
Abstract
BACKGROUND Patients with heart failure (HF) remain at high risk for future events despite medical and device therapy. Dietary sodium reduction is often recommended based on limited evidence. However, it is not known whether dietary sodium reduction reduces the morbidity or mortality associated with HF. METHODS The SODIUM study is a pragmatic, randomized, open-label trial assessing the efficacy of dietary sodium reduction to <1500 mg daily counseling compared to usual care for patients with chronic HF. The intervention is provided by trained personnel at the site and uses 3-day food records for directing counseling. The primary outcome is an intention-to-treat analysis on the time to first cardiovascular event or death measured at 12 months. Secondary end points include the change in quality of life (using the Kansas City Cardiomyopathy Questionnaire), change in New York Heart Association class, and change in 6-minute walk test. The first patient was enrolled in March 2014, and subsequently, 27 sites in 6 countries enrolled patients. CONCLUSIONS The SODIUM-HF trial will provide a robust evaluation of the effects of dietary sodium reduction in patients with HF. Results are expected in 2020.
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Distinct Myocardial Targets for Diabetes Therapy in Heart Failure With Preserved or Reduced Ejection Fraction.
Paulus, WJ, Dal Canto, E
JACC. Heart failure. 2018;(1):1-7
Abstract
Noncardiac comorbidities such as diabetes mellitus (DM) have different outcomes in heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF). These different outcomes are the result of distinct myocardial effects of DM on HFpEF and HFrEF, which relate to different mechanisms driving myocardial remodeling in each heart failure phenotype. Myocardial remodeling is driven by microvascular endothelial inflammation in HFpEF and by cardiomyocyte cell death in HFrEF. Evidence consists of: different biomarker profiles, in which inflammatory markers are prominent in HFpEF and markers of myocardial injury or wall stress are prominent in HFrEF; reduced coronary flow reserve with microvascular rarefaction in HFpEF; and upregulation of free radical-producing enzymes in endothelial cells in HFpEF and in cardiomyocytes in HFrEF. As biopsies from patients with diabetic cardiomyopathy reveal, DM affects failing myocardium by phenotype-specific mechanisms. In HFpEF, DM mainly increases cardiomyocyte hypertrophy and stiffness, probably because of hyperinsulinemia and microvascular endothelial inflammation. In HFrEF, DM augments replacement fibrosis because of cardiomyocyte cell death induced by lipotoxicity or advanced glycation end products. Because DM exerts distinct effects on myocardial remodeling in HFpEF and HFrEF, the heart failure phenotype is important for DM therapy.
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Therapy for heart failure with preserved ejection fraction: current status, unique challenges, and future directions.
Upadhya, B, Haykowsky, MJ, Kitzman, DW
Heart failure reviews. 2018;(5):609-629
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Abstract
Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF. Among elderly women, HFpEF comprises more than 80% of incident HF cases. Adverse outcomes-exercise intolerance, poor quality of life, frequent hospitalizations, and reduced survival-approach those of classic HF with reduced EF (HFrEF). However, despite its importance, our understanding of the pathophysiology of HFpEF is incomplete, and despite intensive efforts, optimal therapy remains uncertain, as most trials to date have been negative. This is in stark contrast to management of HFrEF, where dozens of positive trials have established a broad array of effective, guidelines-based therapies that definitively improve a range of clinically meaningful outcomes. In addition to providing an overview of current management status, we examine evolving data that may help explain this paradox, overcome past challenges, provide a roadmap for future success, and that underpin a wave of new trials that will test novel approaches based on these insights.