Calcium-sensitizing agents
Levosimendan, a novel calcium sensitizer, improves myocardial contractility without causing an increase in myocardial oxygen demand. Its role in acute, decompensated heart failure is more established than in chronic heart failure, but it may reduce overall mortality and length of hospitalization.[175]Landoni G, Biondi-Zoccai G, Greco M, et al. Effects of levosimendan on mortality and hospitalization. A meta-analysis of randomized controlled studies. Crit Care Med. 2012 Feb;40(2):634-46.
http://www.ncbi.nlm.nih.gov/pubmed/21963578?tool=bestpractice.com
In the LIDO study, levosimendan improved survival and hemodynamic performance more effectively than dobutamine, in patients with severe, low-output heart failure.[176]Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002 Jul 20;360(9328):196-202.
http://www.ncbi.nlm.nih.gov/pubmed/12133653?tool=bestpractice.com
The superiority of levosimendan over dobutamine in improving central hemodynamics and left ventricular performance seems in part to be related to its anti-inflammatory and anti-apoptotic effects.[177]Adamopoulos S, Parissis JT, Iliodromitis EK, et al. Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol. 2006 Jul 1;98(1):102-6.
http://www.ncbi.nlm.nih.gov/pubmed/16784930?tool=bestpractice.com
n-3 polyunsaturated fatty acids (n3-PUFA)
The GISSI-HF trial showed that the addition of n3-PUFA produced a small improvement in mortality and hospital admissions in patients with heart failure.[178]Tavazzi L, Maggioni AP, Marchioli R, et al; Gissi-HF Investigators. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Oct 4;372(9645):1223-30.
http://www.ncbi.nlm.nih.gov/pubmed/18757090?tool=bestpractice.com
However, a 2012 meta-analysis has shown insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease.[179]Kwak SM, Myung SK, Lee YJ, et al. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med. 2012 May 14;172(9):686-94.
http://www.ncbi.nlm.nih.gov/pubmed/22493407?tool=bestpractice.com
Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in patients with New York Heart Association class II to IV symptoms and heart failure, unless contraindicated, to reduce mortality and cardiovascular hospitalizations.
Statins
Statins are not beneficial as adjunctive therapy when prescribed solely for treatment of heart failure in the absence of other indications for their use.[2]Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239.
http://www.onlinejacc.org/content/62/16/e147
http://www.ncbi.nlm.nih.gov/pubmed/23747642?tool=bestpractice.com
Statin therapy has been broadly implicated in prevention of adverse cardiovascular events, including new-onset heart failure. Originally designed to lower cholesterol in patients with cardiovascular disease, statins are known to have beneficial effects on inflammation, oxidative stress, and vascular performance. To date, a sufficient body of evidence does not exist to support the primary prescribing of statins for the treatment of heart failure to improve clinical outcomes.[2]Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct 15;62(16):e147-239.
http://www.onlinejacc.org/content/62/16/e147
http://www.ncbi.nlm.nih.gov/pubmed/23747642?tool=bestpractice.com
Nonspecific immunomodulation therapy
Inflammatory mediators are proposed to play a role in heart failure development and progression. In the ACCLAIM trial, nonspecific immunomodulation therapy reduced the risk of hospitalization or death, suggesting that this therapy may be of benefit in heart failure patients.[180]Torre-Amione G, Anker SD, Bourge RC, et al. Results of a non-specific immunomodulation therapy in chronic heart failure (ACCLAIM trial): a placebo-controlled randomised trial. Lancet. 2008 Jan 19;371(9608):228-36.
http://www.ncbi.nlm.nih.gov/pubmed/18207018?tool=bestpractice.com
Recombinant human growth hormone
Preliminary studies suggest that recombinant human growth hormone may have beneficial effects in patients with left ventricular dysfunction, although it may produce an increased risk of arrhythmias.[181]Tritos NA, Danias PG. Growth hormone therapy in congestive heart failure due to left ventricular systolic dysfunction: a meta-analysis. Endocr Pract. 2008 Jan-Feb;14(1):40-9.
http://www.ncbi.nlm.nih.gov/pubmed/18238740?tool=bestpractice.com
[182]Le Corvoisier P, Hittinger L, Chanson P, et al. Cardiac effects of growth hormone treatment in chronic heart failure: a meta-analysis. J Clin Endocrinol Metab. 2007 Jan;92(1):180-5.
http://www.ncbi.nlm.nih.gov/pubmed/17062772?tool=bestpractice.com
Further studies are required to determine the safety and efficacy of this treatment.
Trimetazidine
In a meta-analysis, trimetazidine, which shifts energy production from fatty acid oxidation to glucose oxidation, was shown to have no effect on mortality, but it improves left ventricular ejection fraction (LVEF) and functional class.[183]Zhang L, Lu Y, Jiang H, et al. Additional use of trimetazidine in patients with chronic heart failure: a meta-analysis. J Am Coll Cardiol. 2012 Mar 6;59(10):913-22.
http://www.onlinejacc.org/content/59/10/913
http://www.ncbi.nlm.nih.gov/pubmed/22381427?tool=bestpractice.com
Stem-cell therapy
Some trials of stem-cell therapy in both ischemic and nonischemic heart failure have shown some potential benefit.[184]Sánchez LA, Guerrero-Beltrán CE, Cordero-Reyes AM, et al. Use of stem cells in heart failure treatment: where we stand and where we are going. Methodist Debakey Cardiovasc J. 2013 Oct-Dec;9(4):195-200.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846072/
http://www.ncbi.nlm.nih.gov/pubmed/24298309?tool=bestpractice.com
A systematic review on the use of stem-cell therapy for chronic ischemic heart disease and congestive heart failure suggests that at both short- and long-term follow-up (≥12 months) the use of autologous bone marrow stem-cell treatment reduces all-cause mortality, although the quality of evidence is low.[185]Fisher SA, Doree C, Mathur A, et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2016 Dec 24;(12):CD007888.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007888.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/28012165?tool=bestpractice.com
Gene therapy
An attractive strategy for treatment of heart failure is by gene therapy.[186]Tilemann L, Ishikawa K, Weber T, et al. Gene therapy for heart failure. Circ Res. 2012 Mar 2;110(5):777-93.
https://www.ahajournals.org/doi/full/10.1161/CIRCRESAHA.111.252981
http://www.ncbi.nlm.nih.gov/pubmed/22383712?tool=bestpractice.com
In a small randomized study of patients (n=56) with heart failure and LVEF <40%, intracoronary delivery of adenovirus 5 encoding adenylyl cyclase 6 (Ad5.hAC6) increased the LVEF at 4 weeks, with no increase in exercise duration.[187]Hammond HK, Penny WF, Traverse JH, et al. Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: a randomized clinical trial. JAMA Cardiol. 2016 May 1;1(2):163-71.
https://jamanetwork.com/journals/jamacardiology/fullarticle/2506673
http://www.ncbi.nlm.nih.gov/pubmed/27437887?tool=bestpractice.com
In a larger double-blind placebo-controlled study (n=250), intracoronary infusion of 1 × 1013 DNase-resistant particle of adeno-associated virus 1 (AAV1)/sarcoplasmic endoplasmic reticulum Ca2 - ATPase (SERCA2a) did not improve the clinical course of patients with heart failure and reduced ejection fraction (ejection fraction ≤35%).[188]Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016 Mar 19;387(10024):1178-86.
http://www.ncbi.nlm.nih.gov/pubmed/26803443?tool=bestpractice.com
Supportive mechanical assist devices
The use of mechanical circulatory assist devices in end-stage heart failure is an area of intense investigation. In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Extracorporeal devices can be used for short-term circulatory support in patients who are expected to recover from a major cardiac insult (e.g., myocardial ischemia, postcardiotomy shock, or fulminant myocarditis). Left ventricular assist devices provide similar degrees of hemodynamic support; many are implantable and thus allow for long-term support, patient ambulation, and hospital discharge.[189]Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist devices. N Engl J Med. 1998 Nov 19;339(21):1522-33.
http://www.ncbi.nlm.nih.gov/pubmed/9819452?tool=bestpractice.com
Most clinical experience with these devices has been derived from their use as a "bridge-to-transplantation therapy."[189]Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist devices. N Engl J Med. 1998 Nov 19;339(21):1522-33.
http://www.ncbi.nlm.nih.gov/pubmed/9819452?tool=bestpractice.com
[190]DeRose JJ, Argenziano M, Sun BC, et al. Implantable left ventricular assist devices: an evolving long-term cardiac replacement therapy. Ann Surg. 1997 Oct;226(4):461-70.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1191061/pdf/annsurg00020-0079.pdf
http://www.ncbi.nlm.nih.gov/pubmed/9351714?tool=bestpractice.com
[191]DeRose JJ Jr, Umana JP, Argenziano M, et al. Implantable left ventricular assist devices provide an excellent outpatient bridge to transplantation and recovery. J Am Coll Cardiol. 1997 Dec;30(7):1773-7.
http://www.onlinejacc.org/content/30/7/1773
http://www.ncbi.nlm.nih.gov/pubmed/9385906?tool=bestpractice.com
[192]Oz MC, Argenziano M, Catanese KA, et al. Bridge experience with long-term implantable left ventricular assist devices. Are they an alternative to transplantation? Circulation. 1997 Apr 1;95(7):1844-52.
http://www.ncbi.nlm.nih.gov/pubmed/9107172?tool=bestpractice.com
[193]Mann DL, Willerson JT. Left ventricular assist devices and the failing heart: a bridge to recovery, a permanent assist device, or a bridge too far? Circulation. 1998 Dec 1;98(22):2367-9.
http://www.ncbi.nlm.nih.gov/pubmed/9832479?tool=bestpractice.com
[194]Helman DN, Addonizio LJ, Morales DL, et al. Implantable left ventricular assist devices can successfully bridge adolescent patients to transplant. J Heart Lung Transplant. 2000 Feb;19(2):121-6.
http://www.ncbi.nlm.nih.gov/pubmed/10703686?tool=bestpractice.com
[195]Yacoub MH. A novel strategy to maximize the efficacy of left ventricular assist devices as a bridge to recovery. Eur Heart J. 2001 Apr;22(7):534-40.
https://academic.oup.com/eurheartj/article/22/7/534/469250
http://www.ncbi.nlm.nih.gov/pubmed/11259141?tool=bestpractice.com
[196]Stevenson LW, Rose EA. Left ventricular assist devices: bridges to transplantation, recovery, and destination for whom? Circulation. 2003 Dec 23;108(25):3059-63.
http://www.ncbi.nlm.nih.gov/pubmed/14691019?tool=bestpractice.com
[197]Vitali E, Lanfranconi M, Bruschi G, et al. Left ventricular assist devices as bridge to heart transplantation: the Niguarda Experience. J Card Surg. 2003 Mar-Apr;18(2):107-13.
http://www.ncbi.nlm.nih.gov/pubmed/12757336?tool=bestpractice.com
[198]Topkara VK, Dang NC, Martens TP, et al. Bridging to transplantation with left ventricular assist devices: outcomes in patients aged 60 years and older. J Thorac Cardiovasc Surg. 2005 Sep;130(3):881-2.
https://www.jtcvs.org/article/S0022-5223(05)00451-4/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/16153945?tool=bestpractice.com
[199]Zimpfer D, Zrunek P, Roethy W, et al. Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates. J Thorac Cardiovasc Surg. 2007 Mar;133(3):689-95.
https://www.jtcvs.org/article/S0022-5223(06)02098-8/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/17320566?tool=bestpractice.com
The REMATCH trial established the efficacy of device therapy as permanent or "destination" therapy in selected nontransplant-eligible patients.[200]Rose EA, Moskowitz AJ, Packer M, et al. The REMATCH trial: rationale, design, and end points. Ann Thorac Surg. 1999 Mar;67(3):723-30.
http://www.ncbi.nlm.nih.gov/pubmed/10215217?tool=bestpractice.com
However, device-related adverse events are numerous including bleeding, infection, thromboembolic events, and device failure.[201]Goldstein DJ, Beauford RB. Left ventricular assist devices and bleeding: adding insult to injury. Ann Thorac Surg. 2003 Jun;75(6 Suppl):S42-7.
http://www.ncbi.nlm.nih.gov/pubmed/12820734?tool=bestpractice.com
[202]Gordon SM, Schmitt SK, Jacobs M, et al. Nosocomial bloodstream infections in patients with implantable left ventricular assist devices. Ann Thorac Surg. 2001 Sep;72(3):725-30.
http://www.ncbi.nlm.nih.gov/pubmed/11565648?tool=bestpractice.com
[203]Rothenburger M, Schmid C, Huelksen G, et al. Thrombolytic therapy due to thrombus formation associated with left ventricular assist devices. J Heart Lung Transplant. 2005 Dec;24(12):2305.
http://www.ncbi.nlm.nih.gov/pubmed/16364888?tool=bestpractice.com
The Food and Drug Administration issued an alert about serious adverse events associated with left ventricular assist devices. These adverse events include an increased rate of pump thrombosis (blood clots inside the pump) and a high rate of stroke. Improvements in newer generations of devices will hopefully permit even further prolongation of survival. Presently, destination device therapy is anticipated to benefit those patients predicted to have a 1-year survival of less than 50%, such as those not eligible for transplant, requiring continuous intravenous inotropic infusions. Some reports have suggested that prolonged mechanical decompression of the failing heart may occasionally be followed by sufficient recovery of myocardial function to allow explantation of the device.[204]Helman DN, Maybaum SW, Morales DL, et al. Recurrent remodeling after ventricular assistance: is long-term myocardial recovery attainable? Ann Thorac Surg. 2000 Oct;70(4):1255-8.
http://www.ncbi.nlm.nih.gov/pubmed/11081881?tool=bestpractice.com
[205]Birks EJ, Tansley PD, Hardy J, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006 Nov 2;355(18):1873-84.
https://www.nejm.org/doi/10.1056/NEJMoa053063
http://www.ncbi.nlm.nih.gov/pubmed/17079761?tool=bestpractice.com
The use of continuous hemodynamic monitoring to guide care has also been investigated, but requires further evaluation.[206]Bourge RC, Abraham WT, Adamson PB, et al. Randomized controlled trial of an implantable continuous hemodynamic monitor in patients with advanced heart failure: the COMPASS-HF study. J Am Coll Cardiol. 2008 Mar 18;51(11):1073-9.
http://www.onlinejacc.org/content/51/11/1073
http://www.ncbi.nlm.nih.gov/pubmed/18342224?tool=bestpractice.com
[207]Adamson PB, Gold MR, Bennett T, et al. Continuous hemodynamic monitoring in patients with mild to moderate heart failure: results of The Reducing Decompensation Events Utilizing Intracardiac Pressures in Patients With Chronic Heart Failure (REDUCEhf) trial. Congest Heart Fail. 2011 Sep-Oct;17(5):248-54.
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1751-7133.2011.00247.x
http://www.ncbi.nlm.nih.gov/pubmed/21906250?tool=bestpractice.com
Surgical strategies
There have been numerous reports of alternate surgical approaches for the treatment of end-stage heart failure.[208]Klein P, Bax JJ, Shaw LJ, et al. Early and late outcome of left ventricular reconstruction surgery in ischemic heart disease. Eur J Cardiothorac Surg. 2008 Dec;34(6):1149-57.
https://academic.oup.com/ejcts/article/34/6/1149/337090
http://www.ncbi.nlm.nih.gov/pubmed/18760619?tool=bestpractice.com
Mitral valve repair or replacement has been shown to improve clinical status in patients who have a clinically important degree of mitral regurgitation that is secondary to left ventricular dilation.[209]Bolling SF, Pagani FD, Deeb GM, et al. Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg. 1998 Feb;115(2):381-8.
https://www.jtcvs.org/article/S0022-5223(98)70282-X/fulltext
http://www.ncbi.nlm.nih.gov/pubmed/9475533?tool=bestpractice.com
However, no controlled studies have evaluated the effects of this procedure on ventricular function, rehospitalizations, or survival. One single-center study designed to assess the effects of mitral valve annuloplasty on mortality in patients with mitral regurgitation and left ventricular systolic dysfunction failed to demonstrate any clear survival benefit.[210]Wu AH, Aaronson KD, Bolling SF, et al. Impact of mitral valve annuloplasty on mortality risk in patients with mitral regurgitation and left ventricular systolic dysfunction. J Am Coll Cardiol. 2005 Feb 1;45(3):381-7.
http://www.onlinejacc.org/content/45/3/381
http://www.ncbi.nlm.nih.gov/pubmed/15680716?tool=bestpractice.com
A variant of the aneurysmectomy procedure is now being developed for the management of patients with ischemic cardiomyopathy, but its role in the management of heart failure remains to be defined.[211]Athanasuleas CL, Stanley AW, Jr., Buckberg GD, et al. Surgical anterior ventricular endocardial restoration (SAVER) in the dilated remodeled ventricle after anterior myocardial infarction: RESTORE group – Reconstructive Endoventricular Surgery, returning Torsion Original Radius Elliptical Shape to the LV. J Am Coll Cardiol. 2001 Apr;37(5):1199-209.
http://www.onlinejacc.org/content/37/5/1199
http://www.ncbi.nlm.nih.gov/pubmed/11300423?tool=bestpractice.com
None of the current surgical reconstruction techniques offer "rescue therapy" to patients with critical hemodynamic compromise.