In patients with chronic postinfarction heart failure, bone marrow-derived mononuclear cell (BMC) therapy has demonstrated mixed results to date.  One possible reason for this is that cell retention by the heart is more difficult in the stable setting in comparison to therapies given following acute myocardial infarction, however a recent discovery found that extracorporeal application of focused low-energy shock waves can upregulate chemokine expression and improve homing and attachment of cell therapies.  The purpose of this study was to determine whether this new technique could improve left ventricular ejection fraction (LVEF) in patients with chronic heart failure.

CELLWAVE was a radomised, double-blind, placebo-controlled trial.  Patients were given single-blind low-dose (n=42), high-dose (n=40), or placebo (n=21) shock wave pretreatment targeted to the left ventricular anterior wall.    The following day, patients receiving shock wave pretreatment were randomised to then receive a double-blind intracoronary infusion of BMCs or placebo, while patients receiving placebo shock wave therapy received intracoronary infusion of BMCs.  The primary endpoint was a change in LVEF from baseline to four months, and secondary endpoints included regional left ventricular function assessed by MRI, and clinical events.

In patients who received shock wave treatment followed by BMCs, the primary endpoint was significantly improved (absolute change in LVEF, 3.2%), compared with the shock wave and placebo infusion group (1.0%; P=.02).  Regional wall thickening also improved significantly in the former group but not the latter.  Furthermore, the shock wave and BMC group had fewer major adverse clinical events compared to both treatment groups (P=.02).

Conclusions:

This study of patients with chronic heart failure found that shock wave therapy augmented treatment with intracoronary bone-marrow cells, leading to a small but significant improvement in left ventricular function.  Further work will investigate whether this translates into improved clinical outcomes.

• Assmus B, Walter DH, Seeger FH et al.  Effect of Shock Wave-Facilitated Intracoronary Cell Therapy on LVEF in Patients with Chronic Heart Failure.  The CELLWAVE Randomized Clinical Trial.  JAMA 2013;309:1622-1631.

Anaemia is common in patients with systolic heart failure and is associated with lower functional capacity, worse quality of life, and higher rates of hospitalization and death. The cause of anaemia in these patients is often unclear but may be related to an absolute or relative deficiency of, or resistance to, erythropoietin. In this study Swedberg et al. evaluated the effects of erythropoietin replacement with darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anaemia.

In a multi-centre international randomized, double-blind trial, 2278 patients with systolic heart failure and mild-to-moderate anaemia (haemoglobin level, 9.0 to 12.0 g/dL) and no evidence of iron deficiency were randomised to receive either darbepoetin alfa (to achieve a haemoglobin target of 13 g/dL) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure.

The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin group and 565 of 1142 patients (49.5%) in the placebo group (HR in the darbepoetin group, 1.01; 95% CI, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes which included death, hospitalisation and a quality of life index. The neutral effect of darbepoetin was also consistent across all prespecified subgroups. Looking at the safety end-points, there was no difference in fatal or nonfatal stroke which occurred in 42 patients (3.7%) in the darbepoetin group and 31 patients (2.7%) in the placebo group (P=0.23) but thromboembolic events were significantly increased in the darbepoetin group (153 patients (13.5%) vs. 114 patients (10.0%) (P=0.01)).

Conclusions:

In this large randomised trial, treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anaemia.

• Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O’Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ. Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. N Engl J Med. 2013;368:2010-2019.

Heart failure with preserved ejection fraction (HFPEF) is now felt to be the most common form of heart failure in the community, and is associated with significant morbidity and mortality. Currently, effective therapies are needed as trials of traditional renin-angiotensin antagonists have failed to show an improvement in outcomes or clinical status. Experimental work has suggested that phosphodiesterase-5 inhibitors may be able to enhance cardiovascular function and this exercise capacity in HFPEF.

The RELAX (Phoshphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial compared the effects of the PDE-5 inhibitor sildenafil with placebo in patients with HFPEF. 216 stable outpatients with heart failure, an ejection fraction of >50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity were recruited between 2008 and 2012. 113 patients were given Sildenafil, and 103 placebo, 20mg three times a day for 12 weeks, followed by 60mg, three times a day for 12 weeks. The primary endpoint was the change in peak oxygen consumption after 24 weeks of therapy.

At 24 weeks follow-up, the median changes in peak oxygen consumption were not significantly different (P=0.90) between the sildenafil and the placebo groups.  Similarly, the mean clinical status rank scores were not significantly different (P=.85), nor were changes in 6-minute walk distance (P=.92). Serious adverse events occurred in 16 placebo patients (16%), and 25 sildenafil (22%) patients.

Conclusions:

The use of the phosphodiesterase-5 inhibitor sildenafil in patients with HFPEF did not result in significant improvement in exercise capacity or clinical status when compared to placebo.

• Redfield MM, Chen HH, Borlaug BA et al. Phodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction. A Randomized Clinical Trial. JAMA 2013;309:1268-1277.

Heart failure with preserved ejection fraction (HF-PEF) accounts for more than 50% of heart failure cases. To date, medical therapy has failed to show improvements in diastolic dysfunction, cardiac remodelling, or cardiovascular outcomes. As mineralocorticoid receptor activation by aldosterone contributes to the pathophysiology of HF through several different mechanisms, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial was designed to assess the effects of spironolactone on diastolic dysfunction and exercise capacity in patients with HF-PEF.

Aldo-DHF was a multicenter, prospective, randomised, double-blind, placebo-controlled trial conducted between March 2007 and April 2012. 422 ambulatory patients (mean age 67 years; 52% female) with chronic NYHA class II or III HF, a preserved ejection fraction of 50% or greater, and evidence of diastolic dysfunction, were random assigned to 25mg of spironolactone once daily or matching placebo. The co-primary endpoints were changes in diastolic function (E/e’) on echocardiography and maximal exercise capacity (peak VO2) on cardiopulmonary exercise testing, both measured at 12 months.

While diastolic dysfunction was found to improve in patients taking spironolactone, it worsened in the placebo group (P<.001). In addition, spironolactone induced reverse remodeling (decrease in left ventricular mass) and improved neuroendocrine activation, but did not improve VO2, heart failure symptoms or quality of life.

Conclusions:

Long-term aldosterone receptor blockade with spironolactone improved diastolic function but did not affect clinical symptoms or exercise capacity. Therefore, further investigation into the clinical significance of these echocardiographic findings will be required in larger studies.

• Edelmann F, Wachter R, Schmidt AG et al. Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction. The Aldo-DHF Randomized Controlled Trial.  JAMA 2013;309:781-91. doi: 10.1001/jama.2013.905.

The risk of cardiovascular death in patients with chronic kidney disease is increased by a factor of ten in comparison with the general population. While a host of factors including chronic inflammation, increased oxidative stress and endothelial dysfunction contribute to this risk, disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute by promoting extraskeletal (including vascular) calcification. Cinacalcet is a calcimimetic agent that reduces levels of parathormone, calcium and phosphorous and in this large randomised controlled trial was assessed to reduce the risk of death or nonfatal cardiovascular events in patients on haemodialysis.

A total of 3883 patients with moderate-to-severe secondary hyperparathyroidism who were undergoing haemodialysis were randomised to receive either cinacalcet or placebo along with conventional therapy, including phosphate binders, vitamin D sterols, or both. Patients were followed for up to 64 months with the primary end point a composite of time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. In an intention to treat analysis there was no benefit demonstrated with cinacalcet with the primary composite end point reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (HR 0.93; 95% CI, 0.85 to 1.02; P=0.11) with no differences demonstrable in any of the components of the composite end-point between the two groups either. The results of the study however were clouded by a lower than anticipated event rate, a high dropout rate in both groups and almost 20% of the placebo group using commercially available cinacalcet, with adjusted analyses suggesting a nominally significant benefit for cinacalcet in reducing cardiovascular events (p=0.02).

Conclusions:

In an intention-to-treat analysis of this large randomised trial, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients undergoing renal dialysis. However, problems with the trial protocol suggest further study is necessary.

• Chertow GM, Block GA, Correa-Rotter R, Drüeke TB, Floege J, Goodman WG, Herzog CA, Kubo Y, London GM, Mahaffey KW, Mix TC, Moe SM, Trotman ML, Wheeler DC, Parfrey PS. Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med. 2012 Dec 27;367(26):2482-94.

Deteriorating renal function in patients with heart failure is a common situation, affecting approximately a third of patients presenting with acute pulmonary oedema, and is associated with worse outcomes. Due to the potentially nephrotoxic nature of many heart failure therapies, renal failure leads to difficult treatment decisions regarding ongoing diuretic therapy.  Few options yet exist in this challenging clinical situation, however one potential option is mechanical ultrafiltration devices but currently there is a lack of evidence to support their use.

In this multicenter, randomized, open-label study a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion were allocated in a 1:1 fashion either to a strategy of stepped pharmacologic therapy or ultrafiltration. The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after group assignment with patients followed for a total of 60 days. The results did not support the use of ultrafiltration which was inferior to pharmacologic therapy with respect to the bivariate end point (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level in the pharmacologic-therapy group was -3.5±46.9 μmol/l, as compared with +20.3±61.9 μmol/l in the ultrafiltration group (P=0.003). There was no significant difference in weight loss seen between the two groups (P=0.58). Added to this, a higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03), mainly related to device and access issues.

Conclusions

In this randomized study involving patients with acute decompensated heart failure and poor renal function, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration.  Ultrafiltration was also associated with a higher adverse event rate.

• Bart BA, Goldsmith SR, Lee KL, Givertz MM, O’Connor CM, Bull DA, Redfield MM, Deswal A, Rouleau JL, Lewinter MM, Ofili EO, Stevenson LW, Semigran MJ, Felker GM, Chen HH, Hernandez AF, Anstrom KJ, McNulty SE, Velazquez EJ, Ibarra JC, Mascette AM, Braunwald E; the Heart Failure Clinical Research Network. Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome. N Engl J Med. 2012 Nov 6. [Epub ahead of print]

Two trials in the Journal of the American Medical Association (JAMA) address the impact of bone marrow-derived cell therapy on safety and surrogate endpoints in patients with ventricular dysfunction due to ischaemic heart disease.

In the Timing in Myocardial Infarction Evaluation (TIME) trial, autologous bone marrow mononuclear (BMC) cells were given as an intracoronary infusion at day 3 or day 7 post catheterisation for ST-elevation myocardial infarction. All patients had a left ventricular ejection fraction of <46%, and the primary end points were change in global left ventricular ejection fraction, and regional wall motion in infarct and border zones at 6 months as measured by cardiac MRI. At 6 months, there was no significant increase in left ventricular ejection fraction for the BMC group compared to the placebo group, nor were any significant regional wall differences noted in infarct or border zones. The timing of treatment also had no effect on global or regional ventricular recovery.

In the POSEIDON study, mesenchymal stem cells (MSCs) were delivered myocardially to patients with established ischaemic cardiomyopathy; the goal of the trial was to compare the safety and efficacy of donor (allogeneic) MSCs compared to self-derived (autologous) MSCs. Both allogeneic and autologous MSCs decreased infarct size, but neither increased ejection fraction overall. Only allogeneic MSCs reduced left ventricular end-diastolic volumes, while autologous MSCs were associated with an improved 6-minute walk test and Minnesota Questionnaire score. Both allogeneic and autologous cells were associated with low rates of treatment-emergent adverse effects.

Conclusions:

In these two trials examining the use of bone-marrow derived cells in patients suffering from ischaemic heart disease, the use of bone marrow derived mononuclear cells did not improve ventricular function after acute infarction, while mesenchymal stem cells led to some improvement in functional capacity and ventricular remodelling in established ischaemic cardiomyopathy.

• Marban E, Malliaras K et al. Mixed Results for Bone Marrow-Derived Cell Therapy for Ischemic Heart Disease. JAMA 2012;308:2405-2406.

• Traverse JH, Henry TD, Pepine CJ et al. Effect of the Use and Timing of Bone MarrowMononuclear Cell Delivery on Left VentricularFunction After Acute Myocardial Infarction. The TIME Randomized Trial. JAMA 2012;308:2380-2389.

• Hare JM, Fishman JE, Gerstenblith G et al. Comparison of Allogeneic vs Autologous Bone Marrow–Derived Mesenchymal Stem Cells Delivered by Transendocardial Injection in Patients With Ischemic Cardiomyopathy. The POSEIDON Randomized Trial. JAMA 2012;308:2369-2379

Inhibition of the renin-angiotensin system with ACE-inhibitors or ARBs has failed to convincingly show that these drugs can improve survival and lower the risk of hospitalisation in patients with heart failure with preserved ejection fraction (HF-PEF). LCZ696 is a novel investigational combination angiotensin-receptor/neprilysin inhibitor (ARNI) consisting of valsartan and AHU-377 in a 1:1 mixture. AHU-377 is a prodrug that, when activated, inhibits the enzyme neprilysin. Neprilysin is a metalloprotease enzyme that is responsible for the degradation of atrial and brain natriuretic peptide and has antiangiotensin effects.

The Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction (PARAMOUNT) Phase-2 trial randomised 149 patients with NYHA class 2-3 heart failure, LVEF of at least 45% and N-terminal-pro-BNP levels >400 pg/mL to LCZ696 (up to 200 mg twice daily) and 152 to valsartan (up to 160 mg twice daily). The primary outcome looking at levels of NT-proBNP, found a reduction in 23% (p=0.005) over 12 weeks in those receiving LCZ696 but only a 15% (p=0.20) drop over 36 weeks among those receiving valsartan. Further subgroup analysis broke patients down by age, with or without diabetes, normal or elevated systolic blood pressure, with or without atrial fibrillation or poor renal function, and with or without a prior HF admission; the LCZ696 group showed significant reductions in levels of NT-proBNP in all of these groups. Furthermore, NYHA class also improved significantly with LCZ696 (p<0.05) at 36 weeks, as did left atrial width (p=0.03), left atrial volume (p=0.003), and left atrial volume index (p=0.007).

Conclusions:

In this Phase-2 trial, LCZ696 showed potential benefit in the management of patients with heart failure with preserved ejection fraction.

• Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet 2012; DOI:10.1016/S0140-6736(12)61227-6.

Heart failure is uncommon in children but carries a poor prognosis with 46% of children with severe systolic dysfunction dying or undergoing transplantation within five years. Survival among children after heart transplantation is 83% at 3 years, but the limited availability of donor hearts prolongs the waiting period, resulting in a high rate of death whilst on waiting lists.  Options for mechanical circulatory support have been limited in children, with one choice being extracorporeal membrane oxygenation (ECMO); however, this is only capable of providing shot term support at best. More recently, the Excor Paediatric pulsatile-flow ventricular assist device (Berlin Heart) has become available in a wide range of sizes.

In this study Fraser et al. tested the efficacy of the Berlin Heart as a bridge to transplant.  In a prospective single-group trial, using data from a matched historical control group undergoing ECMO as a comparator, patients 16 years of age or younger were divided into two cohorts according to body-surface area (cohort 1, <0.7 meters squared; cohort 2, 0.7 to <1.5 metres squared).  The primary outcome was the time to death or weaning from the device with an unacceptable neurologic outcome; safety data were also gathered. The results in both cohorts strongly favoured the Excor device with cohort 1 not reaching the median survival time at 174 days, whereas in the matched ECMO group, the median survival was 13 days (P<0.001). For participants in cohort 2 and the matched ECMO group, the median survival was 144 days and 10 days, respectively (P<0.001). However, serious adverse events were common in both cohorts including major bleeding (in 42% and 50% of patients, respectively), infection (in 63% and 50%), and stroke (in 29% and 29%).

Conclusions:

In paediatric patients with severe heart failure, survival rates are significantly higher with the Excor ventricular assist device than with ECMO. However, serious adverse events, including infection, stroke, and bleeding, still occur in a majority of patients.

• Fraser CD Jr, Jaquiss RD, Rosenthal DN, Humpl T, Canter CE, Blackstone EH, Naftel DC, Ichord RN, Bomgaars L, Tweddell JS, Massicotte MP, Turrentine MW, Cohen GA, Devaney EJ, Pearce FB, Carberry KE, Kroslowitz R, Almond CS. Prospective trial of a pediatric ventricular assist device. N Engl J Med. 2012 Aug 9;367(6):532-41.

Autologous stem/progenitor cells have been investigated for several years as a novel therapy for patients with advanced ischaemic heart disease, particularly those with ongoing angina or heart failure.  In particular, for patients with ischaemic cardiomyopathy, autologous bone marrow mononuclear cells (BMCs) have been shown to be safe and possibly effective.  However, none of the trials performed to date have been sufficiently powered to investigate clinical outcome measures.

The FOCUS-CCTRN trial (First Mononuclear Cells injected in the United States conducted by the  Cardiovascular Cell Therapy Research Network) was a phase II randomised double-blind, placebo-controlled trial.  All patients were symptomatic with either NYHA class II-III heart failure or CCS class III-IV angina and a left ventricular ejection fraction of 45% or less, a perfusion defect detected by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization but receiving maximal medical therapy.  The study took place at five large US research sites between 2009 and 2011.  Patients were randomised to receive either 100 million isolated BMCs injected transendocardially, or placebo.  The main outcome measures, assessed at six months, were: change in left ventricular end systolic volume (as assessed by ECHO), maximal oxygen consumption, and reversibility on SPECT.  Phenotypic and functional analyses of the cell product were performed by a biorepository core laboratory.

92 patients were randomised, 61 to BMCs and 31 to placebo.  However, there were no statistically significant changes seen in left ventricular end-systolic volume (p=.73), maximal oxygen consumption (p=.17), nor perfusion defects (p=.84).  Several secondary outcome measures, including regional wall motion, the percent myocardial defect, and clinical improvement, also showed no improvement.

Conclusions:

In this study of patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs -compared with placebo – did not improve left ventricular function, maximal oxygen consumption, or reversibility of myocardial ischaemia.

• Perin C, Willerson JT, Pepine CJ et al.  Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear Cells on Functional Capacity, Left Ventricular Function,and Perfusion in Chronic Heart Failure.  The FOCUS-CCTRN Trial.  JAMA 2012;307:1717-1726.