Heart Failure - csanz.edu.au · an LVAD or heart transplant as expected have extremely limited physical activity at the time of surgery. Despite significant improvements in physical

BMMC = bone marrow mononuclear cell; BP = blood pressure;CRT-D = cardiac resynchronisation therapy with defibrillation;EF = ejection fraction; GFR = glomerular filtration rate;HF = heart failure; HFp/rEF = HF with preserved/reduced EF;HR = hazard ratio; LV = left ventricular; LVAD = LV assist device;(NT-pro)BNP = (N-terminal prohormone of) brain natriuretic peptide;NYHA = New York Heart Association; QOL = quality of life

Making Education Easy Issue 16 – 2014

Research ReviewTM

Heart Failure

www.researchreview.com.au a RESEARCH REVIEW publication

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Welcome to the sixteenth issue of Heart Failure Research Review.This issue begins with research showing worse outcomes in patients with HF who also have iron deficiency, regardless of whether they also have anaemia. Research from the US reports that while postdischarge use of spironolactone in patients with HFrEF and advanced chronic kidney disease increases readmissions, all-cause mortality and HF readmission rates are not significantly affected. An analysis of data from three clinical trials has shown that elevated plasma galectin-3 levels can predict early rehospitalisation in patients with HF. This issue concludes with Danish research comparing clinical outcomes associated with the various ß-blockers, at differing dose levels, in patients with HF.

I hope you find the articles selected for this issue interesting, and I look forward to hearing from you with your comments and feedback.

Kind Regards,

Prof Peter [email protected]

Iron deficiency status irrespective of anemia: a predictor of unfavorable outcome in chronic heart failure patientsAuthors: Rangel I et al.

Summary: This prospective study of 127 patients with stable chronic HF and LVEF ≤45% found that iron deficiency, which was present in 46 patients, was significantly more likely in women, patients with plasma BNP levels >400 pg/mL and those with right ventricular systolic dysfunction (p<0.05 for all). The composite endpoint of overall mortality and nonfatal cardiovascular events had occurred significantly more often at 225 ±139 days follow-up in patients with iron deficiency than those without (24% vs. 5% [p=0.001]) and those with versus without anaemia (25% vs. 8% [p=0.014]). A multivariate analysis adjusted for clinical variables including anaemia revealed a significant association between iron deficiency and an increased likelihood of a composite endpoint event (adjusted HR 5.38 [95% CI 1.54–18.87; p=0.009]).

Comment: The findings of this prospective observational study are consistent with similar recently published observational studies and demonstrate that iron deficiency with or without anaemia is common in patients with chronic HF and is associated with increased morbidity and mortality. The definition of iron deficiency used in this and other chronic HF studies is more liberal than that applied in most laboratories, and this may in part explain the high prevalence reported in chronic HF. Other studies have reported improved QOL and exercise performance in chronic HF patients with iron deficiency who are treated with IV iron. These studies have lacked the power to demonstrate an impact of IV iron therapy on mortality; however, iron deficiency is emerging as an important comorbidity in chronic HF and one that should be looked for routinely.

Reference: Cardiology 2014;128(4):320–6http://www.karger.com/Article/FullText/358377

In this issue:Iron deficiency predicts unfavourable outcomes in chronic HF

Hyponatraemia, diuretic response and creatinine in acute decompensated HF

Spironolactone increases readmissions in HFrEF with chronic kidney disease

Effects of LVAD implantation/heart transplantation on physical activity/QOL

Fragility is a key determinant of HF survival

Elevated galectin-3 increases HF rehospitalisation risk

CRT-D sensors for predicting HF events long term

LCZ696 effects in HFpEF not dependent on BP lowering

BMMCs for ischaemic HF

Clinical outcomes of different ß-blockers in HF

Abbreviations used in this review:

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Disclaimer: This publication is not intended as a replacement for regular medical education but to assist in the process. The reviews are a summarised interpretation of the published study and reflect the opinion of the writer rather than those of the research group or scientific journal. It is suggested readers review the full trial data before forming a final conclusion on its merits.

Research Review publications are intended for Australian health professionals.

Heart Failure Research ReviewTM

Independent commentary by Professor Peter MacDonald.Peter Macdonald is a Conjoint Professor of Medicine in the University of New South Wales, senior staff cardiologist in the Heart & Lung Transplant Unit at St Vincent’s Hospital, Sydney and co-head of the Transplantation Research Laboratory at the Victor Chang Cardiac Research Institute. He is a past President of the Transplantation Society of Australia & New Zealand (TSANZ). His major research interests over the last 20 years have been in the areas of heart failure, pulmonary hypertension, transplant allograft rejection, donor management and organ preservation. He has published six national guidelines, 15 book chapters and over 200 peer-reviewed scientific papers.

http://www.researchreview.com.au

mailto:peter.macdonald%40researchreview.com.au?subject=Heart%20Failure%20Research%20Review

http://www.karger.com/Article/FullText/358377


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Association of hyponatremia to diuretic response and incidence of increased serum creatinine levels in hospitalized patients with acute decompensated heart failureAuthors: Ng TMH et al.

Summary: The associations between hyponatraemia and diuretic response, renal function and clinical outcomes in acute HF were explored in this retrospective study of 499 hospitalised patients treated with IV loop diuretics for ≥48 hours and stratified according to nadir sodium levels of ≥135 mEq/L (normal), 130–134 mEq/L (mild hyponatraemia; 36%) and <130 mEq/L (moderate-to-severe hyponatraemia; 18%). Compared with patients with normal sodium levels, those with mild and moderate-to-severe hyponatraemia had: i) significantly higher maximum furosemide equivalent doses (114 and 249, respectively, vs. 84 mg/day [p<0.001]); ii) significantly greater incidences of diuretic regimen escalation (16% and 44% vs. 11% [p<0.001]); iii) significantly higher incidences of acute increases in serum creatinine level (45% and 63% vs. 27% [p<0.001]); iv) greater blood urea nitrogen level increases; v) longer hospital stays; and vi) higher mortality rates. These differences were seen irrespective of whether hyponatraemia was acute or present at admission.

Comment: Hyponatraemia is commonly observed in patients with advanced HF and is generally considered to be an indicator of marked neurohormonal activation. Earlier studies have shown that hyponatraemia is a marker of increased sensitivity to and reduced tolerability of ACE (angiotensin converting enzyme) inhibitors and ß-blockers. This retrospective review of patients hospitalised with acute decompensated HF demonstrates that hyponatraemia is associated with higher diuretic dosage requirements (and by implication diuretic resistance), renal impairment, prolonged hospitalisation and increased mortality. Similar observations in earlier studies provided the rationale for the development of selective vasopressin antagonists such as tolvaptan and conivaptan; however, clinical trials with these agents have so far proved somewhat disappointing with at best modest symptomatic benefits over conventional therapy and no impact on mortality.

Reference: Cardiology 2014;128(4):333–42http://www.karger.com/Article/FullText/360604

Spironolactone use and higher hospital readmission for Medicare beneficiaries with heart failure, left ventricular ejection fraction <45%, and estimated glomerular filtration rate <45 ml/min/1.73m2

Authors: Inampudi C et al.

Summary: The relationship between spironolactone use and hospital re-admission was explored in 1140 hospitalised patients with HF with EF <45% and an estimated GFR <45 mL/min/1.73m2, 207 of who were prescribed spironolactone at discharge. Propensity score analyses showed that spironolactone use significantly increased the likelihood of re-admission for any cause at 30 days and 1 year (respective HRs 1.41 [95% CI 1.04–1.90] and 1.36 [1.13–1.63]), and the 1-year risk was greater among participants with an estimated GFR <15 vs. 15–45 mL/min/1.73m2 (4.75 [1.84–12.28] vs. 1.34 [1.11–1.61]; p=0.003 for interaction). Spironolactone use did not impact significantly on re-admission for HF or all-cause mortality.

Comment: This ‘real world’ study of patients with chronic HF highlights the potential hazard of mineralocorticoid use in patients with the combination of HF and advanced renal disease. It is noteworthy that almost half the patients included in this analysis were diabetic, a known risk factor for worsening renal function with the use of mineralocorticoid antagonists. Patients discharged on spironolactone had higher rates of all-cause re-admission although not HF re-admission or mortality. The authors speculated that hyperkalaemia and worsening renal function were the most likely mechanisms resulting in increased rates of re-admission. The study highlights the importance of close clinical observation and monitoring of electrolyte levels and renal function in chronic HF patients receiving mineralocorticoid antagonists.

Reference: Am J Cardiol 2014;114(1):79–82http://www.ajconline.org/article/S0002-9149(14)00964-3/abstract

Effect of left ventricular assist device implantation and heart transplantation on habitual physical activity and quality of lifeAuthors: Jakovljevic DG et al.

Summary: This research involved 14 patients with LVADs implanted, 12 heart transplant recipients, 14 patients with HF and 14 matched healthy controls assessed for physical activity, energy expenditure and QOL. Baseline physical activity levels were 15%, 28% and 51% of that of healthy subjects for the LVAD, heart transplant and HF groups, respectively (p<0.01), and were associated with lower energy expenditure and increased sedentary time (p<0.01). No difference was seen for baseline QOL scores among the LVAD, heart transplant and HF groups (p=0.44). At 3 months, daily physical activity levels had increased by 60% and 52% in the LVAD implantation and heart transplantation groups, respectively, but the activity levels at 6 and 12 months remained unchanged. Similarly, LVAD implantation and heart transplantation were associated with significant improvements in QOL at 3 months (p<0.01) but no further change thereafter. Heart transplantation was associated with significantly higher activity levels than LVAD implantation at the 3-, 6- and 12-month timepoints (p<0.05) and better associated QOL, while patients with HF experienced significant decreases in physical activity and QOL at 12 months (p<0.05).

Comment: This small study demonstrates that patients with advanced HF who receive an LVAD or heart transplant as expected have extremely limited physical activity at the time of surgery. Despite significant improvements in physical activity over the first 3 months postoperatively, their exercise capacity remains very low compared with healthy controls. An important part of the preoperative evaluation of LVAD and heart transplant patients includes the assessment of frailty and comorbidities that may prevent or limit postoperative recovery and rehabilitation.

Reference: Am J Cardiol 2014;114(1):88–93http://www.ajconline.org/article/S0002-9149%2814%2900962-X/fulltext

Fragility is a key determinant of survival in heart failure patientsAuthors: Gastelurrutia P et al.

Summary: These researchers assessed the effect of fragility on long-term prognosis in 1314 outpatients with HF. Fragility, defined as ≥1 abnormal evaluation among four standardised geriatric scales (Barthel Index score <90; OARS scale <10 and <6 in women and men, respectively; Pfeiffer Test score >3 [±1 depending on educational grade]; and ≥1 positive response for depression on the abbreviated Geriatric Depression Scale), was present in 581 patients. There were 626 deaths during median follow-up of 3.6 years; the median follow-up for surviving patients was 4.9 years. Univariate and multivariable Cox regression analyses both showed that fragility was associated with decreased survival in all patients and in age and LVEF subgroups.

Comment: There is an increasing recognition that there are other determinants of survival in patients with HF beyond the severity of HF and the presence of comorbidities. Some patients with HF lose weight and muscle strength, or become depressed or cognitively impaired. A number of terms are being used by clinicians and researchers to try and characterise this population – cardiac cachexia, frailty or, as in this study, fragility. Similarly, a wide range of diagnostic tools are also being used to identify and quantify this entity. The bottom line is that ‘fragility’ is common, independent of age and associated with a poor prognosis. An important question for future research is the extent to which it is reversible with effective chronic HF therapy.

Reference: Int J Cardiol 2014;175(1):62–6http://tinyurl.com/qaxa7xl

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http://www.karger.com/Article/FullText/360604

http://www.ajconline.org/article/S0002-9149(14)00964-3/abstract

http://www.ajconline.org/article/S0002-9149%2814%2900962-X/fulltext

http://www.researchreview.com/RR/media/Public-Documents-AU/Reviews/Clinical-Life-25JUNE14-RW-D4.pdf


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Elevated plasma galectin-3 is associated with near-term rehospitalization in heart failureAuthors: Meijers WC et al.

Summary: These authors pooled data from 902 participants from three clinical trials to investigate the value of galectin-3 levels for identifying patients at risk of rehospitalisation for HF. Rehospitalisation for HF by postdischarge days 30, 60, 90 and 120 was significantly more likely for patients with galectin-3 levels >17.8 ng/mL versus lower levels (respective odds ratios 2.80 [95% CI 1.41–5.57], 2.61 [1.46–4.65], 3.01 [1.79–5.05] and 2.79 [1.75–4.45]); galectin-3 level remained an independent predictor of rehospitalisation for HF after adjustments. Furthermore, improvements were seen for risk models that predict postdischarge rehospitalisation and fatal events at each timepoint when galectin-3 level was added.

Comment: Galectins are a family of soluble ß-galactoside-binding lectins that have been found to play a key regulatory role in multiple biological processes including inflammation and fibrosis. Galectin-3 is a novel biomarker that has been shown in multiple studies to be elevated in patients with HF (and also in multiple other profibrotic conditions). In this combined analysis of three studies, elevated galectin-3 levels identified HF patients at increased risk of early readmission. At this stage it is unclear whether galectin-3 is simply an ‘innocent bystander’ or a mediator of disease progression and a potential target for novel therapies.

Reference: Am Heart J 2014;167(6):853–60http://tinyurl.com/oe2vu23

Long-term effectiveness of the combined minute ventilation and patient activity sensors as predictor of heart failure events in patients treated with cardiac resynchronization therapyAuthors: Auricchio A et al.

Summary: This paper reported the long-term results of the CLEPSYDRA (Clinical Evaluation of the Physiological Diagnosis Function in the PARADYM CRT Device) trial, which investigated the sensitivity and false-positive rate of the physiological diagnostic algorithm for predicting HF events within 1 month in 521 patients with HF (NYHA class III–IV) implanted with CRT-D devices. Around one-quarter of participants (25.6%) experienced an HF event over mean follow-up of 17.0 months. The physiological diagnostic algorithm predicted such events with sensitivity of 34% and a false-positive rate of 2.4 per patient-year.

Comment: A key goal of HF therapy is the prevention of acute decompensation and the need for rehospitalisation. Multidisciplinary care that includes simple measures such as daily weighing has proved highly effective in identifying early signs of deterioration and reducing rehospitalisation rates. There has been considerable interest in the use of implantable physiological sensors to develop an even more sensitive ‘early warning system’ of acute decompensation. This study reported the findings of one such system that is incorporated into a CRT-D pacemaker. The results were disappointing, with the sensor detecting only one in three episodes of acute decompensation and false alarming on average more than twice per year. Other devices are currently under investigation.

Reference: Eur J Heart Fail 2014;16(6):663–70http://onlinelibrary.wiley.com/doi/10.1002/ejhf.79/abstract

Independence of the blood pressure lowering effect and efficacy of the angiotensin receptor neprilysin inhibitor, LCZ696, in patients with heart failure with preserved ejection fractionAuthors: Jhund PS et al.

Summary: This analysis of the PARAMOUNT trial, which randomised 301 patients with HFpEF to receive LCZ696 or valsartan, explored whether the effects of LCZ696 were independent of systolic BP lowering. LCZ696 and valsartan were respectively associated with 9/5mm Hg and 3/2mm Hg reductions in BP at 12 weeks. Poor correlations were seen between change in NT-proBNP level and change in systolic BP in both the LCZ696 and valsartan arms (respective r values 0.17 [p=0.06] and 0.05 [p=0.58]). The ratio of change in NT-proBNP level at 12 weeks for LCZ696 versus valsartan was similar before and after adjusting for systolic BP (0.76 [95% CI 0.63–0.93; p=0.008] and 0.76 [0.63–0.92; p=0.006], respectively; p=0.38 for interaction). The effects of LCZ696 on left atrial volume index, NYHA class and estimated GFR also occurred independently of change in systolic BP.

Comment: LCZ696 is the ‘first in class’ of a dual-action angiotensin-receptor neprilysin inhibitor. Neprilysin degrades and inactivates atrial and brain natriuretic peptides. LCZ696 has been developed as a potential novel treatment for hypertension and HF. A large phase 3 trial of LCZ696 in HFrEF was stopped prematurely earlier this year due to a marked benefit of the drug on the combined endpoint of mortality and HF hospitalisation. In this phase 2 study, LCZ696 was compared with valsartan in patients with HFpEF. The main trial was published 2 years ago in the Lancet. In this follow-up study, LCZ696 was found to produce greater lowering of BNP level compared with valsartan and sustained improvements in a number of clinical endpoints. This is an exciting new drug with potential indications for both HFrEF and HFpEF.


Autologous bone marrow mononuclear cell transplantation in ischemic heart failureAuthors: Pätilä T et al.

Summary: Patients with ischaemic HF (LVEF ≤45%) scheduled for CABG (coronary artery bypass graft) were randomised to receive intraoperative injections of BMMCs (median 8.4×108 cells) or vehicle into the myocardial infarction border after 4–12 weeks of pharmacotherapy optimisation. At 1 year, no significant difference was seen between the BMMC and control groups for improvement in LVEF (primary endpoint; 4.8% and 5.6%, respectively [p=0.59]), median wall thickening increases in injected segments (5.5% and 4.5% [p=0.68]) or changes in viability by PET (positron-emission tomography) or SPECT (single-photon emission computed tomography). Recipients of BMMC injections had a significant decrease in median myocardial scar size assessed with MRI (magnetic resonance imaging) compared with controls, in who there was an increase (–13.1% vs. +5.1% [p=0.0002]).

Comment: The initial enthusiasm for stem-cell therapies as a treatment or even a cure for HF has been tempered by the results of clinical trials, which to date have shown at best very modest improvements in heart function with little or no change in clinical outcomes. This well-designed and carefully conducted trial provides more data, but unfortunately no further clarity regarding the efficacy of stem cells in the treatment of chronic HF. Despite showing a reduction in myocardial scar size following injection of BMMCs at the time of elective CABG, the investigators observed no change in global or regional LV function relative to control patients.

Reference: J Heart Lung Transplant 2014;33(6):567–74http://www.jhltonline.org/article/S1053-2498%2814%2900971-1/fulltext

Comparison of the clinical outcome of different beta-blockers in heart failure patientsAuthors: Bølling R et al.

Summary: This was a retrospective study of 58,634 Danish patients aged ≥35 years hospitalised with a first admission for HF during 1995–2011 who had started ß-blocker therapy ≤60 days postdischarge; the respective mortality and rehospitalisation rates during mean follow-up of 4.1 years were 51.4% and 80.1%. Using metoprolol ≥200 mg/day as a reference, the risks of death and rehospitalisation, both for any cause, were significantly lower among recipients of carvedilol ≥50 mg/day (respective adjusted HR 0.873 [CI 0.789–0.966] and 0.842 [0.774–0.915]), while recipients of bisoprolol ≥10 mg/day had a significantly higher risk of death and a statistically nonsignificantly lower risk of rehospitalisation for any cause (1.125 [1.004–1.261] and 0.948 [0.850–1.057]).

Comment: The largest published prospective randomised comparison between ß-blockers in HF was the COMET trial published more than 10 years ago. In that study, carvedilol 25mg twice daily (a nonselective ß1- and ß2-blocker) resulted in a reduction in mortality compared with metoprolol tartrate 50mg twice daily (a short-acting ß1-selective agent). Although not directly comparable, the findings of this massive prospective registry analysis support the findings of the original COMET study and suggest that (high-dose) nonselective ß-blockers may provide superior mortality reduction compared with ß1-selective agents. It is also noteworthy that more than half the patients entered into this registry had died by 4 years of follow-up, emphasising the poor prognosis for patients with chronic HF including those receiving evidence-based therapies.




http://onlinelibrary.wiley.com/doi/10.1002/ejhf.79/abstract


http://www.jhltonline.org/article/S1053-2498%2814%2900971-1/fulltext
