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Heart failure is a pathophysiological state in which structural or functional cardiac disorder impairs the ability of the heart to function as a pump to support the physiological circulation. The medical therapy remains the
mainstay of treatment in these patients. The medical therapy can improve the quality of life and the longevity in
these patients, but this becomes insufficient in refractory heart failure. The heart failure is considered refractory when patients continued to be symptomatic despite optimal dose of medications, characterized by advanced structural heart disease. These patients will need frequent hospitalizations and the overall prognosis is very poor.

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  2. 2. Review Article RECENT ADVANCES IN THE MANAGEMENT OF REFRACTORY HEART FAILURE Rajeshwari Nayak Consultant Cardiologist, Apollo Hospitals, Greams Lane, Chennai 600 006, India. E-mail: Heart failure is a pathophysiological state in which structural or functional cardiac disorder impairs the ability of the heart to function as a pump to support the physiological circulation. The medical therapy remains the mainstay of treatment in these patients. The medical therapy can improve the quality of life and the longevity in these patients, but this becomes insufficient in refractory heart failure. The heart failure is considered refractory when patients continued to be symptomatic despite optimal dose of medications, characterized by advanced structural heart disease. These patients will need frequent hospitalizations and the overall prognosis is very poor. Key word: Refractory heart failure. MANAGEMENT OPTIONS HEART FAILURE • IN REFRACTORY Device therapy (a) CRT (b) ICD (c) CRT -D (Combo device) • Surgical (a) Revascularization (b) Mitral valve repair / replacement (c) LVADs (d) Cardiac transplant (e) TAH (f) Stem cell therapy (g) LV remodeling surgeries (Batista or Dor’s procedure) • Others (a) Ultra filtration (b) CPAP DEVICE THERAPY Cardiac resynchronization therapy Significant dyssynchrony between various walls of the left ventricle (intraventricular dyssynchrony) and between right and left ventricle (interventricular dyssynchrony) or 175 between atria and ventricle (atrio ventricular) is common in patient with systolic dysfunction contributing to reduced cardiac output [1]. Most patients with intraventricular dyssynchrony have left bundle branch block pattern on the surface ECG. Nearly 25% of patients with heart failure have LBBB and its presence confers a higher risk of worsening heart failure and sudden cardiac death [2]. In patients with LBBB and left ventricular dyssynchrony, the left ventricular lateral wall is electrically activated after the septal contraction which leads to contraction of the lateral wall during relaxation of the septum. This will result in mechanical dysfunction leading to an increase in the ventricular volume, reduction of contractility and worsening mitral regurgitation. The myocardial contraction can be resynchronized by pacing the right and left ventricle, biventricular pacemaker (cardiac resynchronization therapy- CRT). Several studies have shown the favorable effect of CRT on symptoms, quality of life and ventricular function [3]. The Care HF study showed significant reduction of the combined endpoint of mortality and cardiovascular hospitalization by 37% [4]. CRT reduces regional left ventricular delay, caused by prolonged ventricular conduction, reduces mitral regurgitation and LV reverse remodeling and normalizes neurohormonal factors. It has been shown that these benefits persist or even improve on longer follow-up. The risk of arrhythmia and sudden cardiac death also showed significant reduction. The Care HF included patients with NYHA class III-IV symptoms, despite being on optimal pharmacotherapy, LVEF <35% and QRS duration ≥120 msec. The patients with QRS interval 120-149msec were required to have, two of three Apollo Medicine, Vol. 8, No. 3, September 2011
  3. 3. Review Article echocardiographic criteria for dyssynchrony: an interventricular mechanical delay of >40 msec, an aortic preejection delay of more than 140 msec, or delayed activation of the postero lateral LV wall >130 msec. Few small studies have shown benefit of CRT in patients with narrow QRS and echocardiographic evidence of dyssynchrony [3]. However rethiQ study a randomized controlled trial failed to show any benefit of CRT in narrow QRS patients (<120 msec) [5]. The recent guidelines advocate the use of CRT in patients with an ejection fraction of 35% or less, NYHA class III-IV and QRS duration more than or equal to 120msec [6]. MADITCRT, COMPANION, CARE-HF and MIRACLE study groups have shown significant improvement in NYHA functional class, quality of life and EF. Implantable cardioverter defibrillator The progressive pump failure is the most common cause of death in patients with advanced heart failure and incidence of sudden cardiac death is less in this group. However sudden cardiac death is the main cause of death in less severe heart failure and ICDs are more effective in this group. It has been shown that heart patients with advanced heart failure can die of electromechanical dissociation following even an appropriate shock [7]. In the landmark SCD –HEFT trial [7], it has been shown that in patients with NYHA class II heart failure; there was 46% relative reduction in the risk of death with ICD as compared to amiodarone. There was 11.9% absolute reduction in mortality in NYHA class II patients at 5 yrs. However there was no significant reduction in death in patients with advanced heart failure with ICD therapy [7]. It has been shown in Companion trial [8] that when ICD, are combined with CRT (CRT-D or Combo device) in advanced heart failure, CRT may improve function status, making patients eligible for ICD therapy. In the Companion trial, either CRT alone or CRT-D reduced the rate of death from any cause or hospitalization for any cause by 20% when compared to the group who received optimal pharmacotherapy alone. However CRT-D group did not score over CRT arm in the combined outcomes of death or hospitalization for any cause. But there was 36% reduction in the mortality, so whether patients should receive CRT or Combo device should be at the discretion of the cardiologist, guided by cost, likely survival and symptom status. SURGICAL INTERVENTION Out of various surgical options available cardiac transplant remains proven, most effective therapy. The other interventions aim to either repair or reshape the heart to improve the heart function. Apollo Medicine, Vol. 8, No. 3, September 2011 Coronary revascularization procedure Many studies have shown a coronary artery disease prevalence of 50-70% in patients with advanced heart failure [8]. Coronary artery bypass surgery or angioplasty should be considered in appropriate patients with heart failure and suitable coronary artery anatomy. The patient who shows evidence of viable myocardium or inducible ischemia should also be considered for revascularization procedure. The STICH trial prospectively evaluated the benefit of coronary revascularization in patients with CAD and heart failure [9]. STICH included 1212 patients with an ejection fraction of 35% or less and CAD patients amenable to CABG surgery. Patients were randomized to either CABG or medical therapy and followed up for a median of 56 months. This study found no significant difference between medical therapy alone and medical therapy plus CABG surgery with respect to death from any cause. Except for 30 day mortality, however, secondary study results favored CABG. Compared to the medical therapy group, CABG group had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes [9]. Stem cell therapy The myocardial regeneration therapy with either percutaneously or surgically delivered stem cell is undergoing extensive research. The initial result appears to be promising. Improvement in ventricular function and symptoms are shown with autologous bone marrow stem cell injection. Mesenchymal cell injection also has been tried [10]. Mitral valve surgeries The mitral regurgitation is very common in patients with heart failure occurring as a result of mitral annular dilation causing improper coaptation of leaflets or apical displacement of papillary muscles causing restricted leaflet motion [11]. The mitral valve annuloplasty in dilated and ischemic cardiomyopathy is shown to be safe with low mortality (2%) and morbidity [11]. Several studies have shown significant improvement in symptoms, ejection fraction, quality of life and reduction in hospitalizations. However recurrence of mitral regurgitation is high after valve repair hence many centres recommend mitral valve replacement rather than repair in cardiomyopathy. Various percutaneous valve repair techniques are used in different centres. Cardiac remodeling surgeries 176 The Batista procedure or left ventriculectomy was
  4. 4. Review Article popular few years ago; however its long term results are not good. In patients with ischemic cardiomyopathy and dyskinetic segments reshaping surgeries may be of benefit. LV aneurysmectomy and endoventricular patch plasty (Dor’s procedure) is found to be promising [12]. Various cardiac restraint devices are in use for patients with LV dysfunction. They have been shown to improve ventricular remodeling but showed no mortality benefit [13]. In ischemic cardiomyopathy, the left ventricle remodels from its normal elliptical shape to a spherical shape. This geometrical change is partly responsible for the symptom of heart failure. Ventricular restoration surgery aim to correct the above mentioned pathologic alteration in geometry. In the RESTORE study, patients with ischemic cardiomyopathy underwent Dor’s procedure and the investigators reported among the patients studied, EF increased from 29.6% to 39.5%, end systolic volume index decreased and NYHA class improved from 67% class III – IV before surgery to 85% I / II after surgery [14] Again Yamaguchi, et al reported significantly improved 5 year survival in patients with ischemic cardiomyopathy who underwent ventricular restoration and CABG surgery versus patient who underwent CABG surgery alone. Left ventricular assist devices In 1963, Dr Michael DeBakey made first clinical use of VAD in a patient who had cardiac arrest after AVR surgery. However unfortunately that patient died. Nearly 3 years later, Dr DeBakey successfully implanted a newer device in a patient who could not be weaned from cardiopulmonary bypass, who received mechanical support for 10 days which allowed the myocardium to recover and was successful. Various LVADs are used both as bridge to transplant/ recovery and destination therapy. Most recent LVADs are used as destination therapy, for patients who are ineligible for cardiac transplant. In a multicentre, prospective trial, 129 patients with end stage heart failure who are ineligible for cardiac transplant were randomized to receive either an LVAD or optimal medical therapy. At one year followup there was 48% reduction in death and improved quality of life in the LVAD group as compared to medical therapy group [15]. Currently LVADs are indicated in patients who are awaiting cardiac transplant who have become refractory to medical treatment as a bridge to transplant. Various percutaneous implantable devices are used for short term stabilization of patients with refractory heart failure. The intra aortic balloon counter pulsation is used for last several years but it is of only short term benefit. Other percutaneous devices like the Tandem Heart and Impella system may provide rapid and better circulatory support [16]. At present these devices are used for patients undergoing PCI or surgery with heart failure. The FDA approved mechanical circulatory devices are: (i) Abiomed BVS 5000 for short term support, (ii) Abiomed AB 5000 circulatory support system; (iii) Centrimag system; (iv) Thoratec paracorporeal and intracorporeal LVAD and RVAD; (v) Heart mate/ LVAD. HEART TRANSPLANTATION The heart transplantation is the most effective treatment options for patients with refractory heart failure [17]. The indication for cardiac transplant includes patients with refractory heart failure, NYHA class III-IV symptoms, oxygen consumption less than 10 mL/kg/mt. Over the last decade there has been significant improvement in survival rates following cardiac transplant as a result of improvement in patients selection, organ selection and preservation and postoperative management and availability of newer immunosuppressants. However donor availability is the most important limitation. Total artificial heart In 1969, Dr Denton Cooley implanted the first TAH in a high risk patient after a failed cardiopulmonary bypass after LV aneurysm repair. At present, 2 TAH are receiving attention (a) Cardiowest TAH; (b) Abiocor TAH. ULTRAFILTRATION In patients with refractory heart failure and fluid overload regular peritoneal dialysis is found to be useful. Peritoneal dialysis is shown to reduce hospitalization rates and improve the functional capacity [18]. In the UNLOAD trial, 200 patients with heart failure and fluid overload were randomized to ultra filtration or diuretic therapy. Ultra filtration was shown to produce greater fluid and weight loss. It also reduced rehospitalisation rate. CPAP The obstructive sleep apnea is common in patients with advanced heart failure. Continuous positive airway pressure (CPAP) is an effective treatment for sleep apnea. Small prospective trials have shown that CPAP improves LVEF, reduce urinary nor-adrenaline levels and improve cardiac output. NEWER VASODILATORS/INOTROPES NESIRITIDE (human BNP analog) is a vasodilator that is shown to alleviate heart failure symptoms faster 177 Apollo Medicine, Vol. 8, No. 3, September 2011
  5. 5. Review Article when compared to diuretics alone or in combination with low dose nitroglycerin (VMAC TRIAL). Nesiritide can be started if systolic blood pressure is greater than 100mmHg at an infusion rate of 0.005 mcg/kg/mt with or without an IV bolus of 2 mcg/kg. research is needed to promote angiogenesis and myocytogenesis. However as practicising physicians and cardiologist we should continue to provide the best supportive therapy for all patients with refractory heart failure. LEVOSIMENDAN is a calcium sensitiser used in the management of acutely decompensated congestive heart failure. It is marketed under the trade name Simdax. Levosimendan is indicated for inotropic support in acutely-decompensated severe congestive heart failure. REFERENCES 1. Bader H, Garrigue S, Lafilte S, et al. Left ventricular electromechanical asynchrony. New independent predictors of cardiac events in heart failure patients. Am coll cardiology 2004;43:248-256. 2. Baldasseronis, Opasich C, Gorini M, et al. Left bundle branch block is associated with increased 1 year sudden and fatal mortality rate in patients with congestive heart failure. Am heart J 2002;143: 398-405. Some of the Phase-III studies in the extensive clinical program were the trials LIDO (200 patients), RUSSLAN (500), CASINO (250), REVIVE-I (100), REVIVE-II (600) and finally SURVIVE (1350), [1] a head-to-head trial between levosimendan and dobutamine in acute decompensated heart failure. In total, the clinical data base includes more than 3500 patients in Phase IIb and III double-blind studies, which is the highest number ever in testing a drug for acute decompensated heart failure. 3. McAlister FA, Ezekowitz J, Hooton N, et al. Cardiac resynchronization therapy for patients with LV dysfunction JAMA 2007; 297(22): 2502-2514. 4. Cleland JG, Daubert JC, Erdmann et al. Cardiac resynchronization heart failure (CARE–HF) study investigator. N engl J Med 2005; 352(15): 1539-1549. 5. Besnai JF, Grimm RA, Naguch, et al. the RethiQ study investigators. N Engl J Med 2007; 357: 2461-2471. Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group in a head to head comparison study, levosimendan did not significantly reduce all-cause mortality at 180 days [1]. However, the drug was proven to be superior to dobutamine for treating patients with a history of CHF or those on beta-blocker therapy when they are hospitalized with acute decompensations [19]. 6. National institute for clinical excellence. Management of chronic heart failure in adults in primary and secondary care. Clinical guidelines NICE 2003. 7. Bardy GH, Lee KL, Mark JB, et al. Sudden cardiac death in heart failure trial (SCD-HCFT) investigator. N Engl J med 2005; 352 (33): 225-237. 8. Nohria A, Lewis E, Stevenson LW. Medical management of advanced heart failure. JAMA 2002; 287: 628 -640. ANEMIA IN HEART FAILURE Anemia is being increasingly recognized as an important comorbidity in patients with heart failure. Nearly one- fifth to one- third of patients with heart failure may experience anemia at a given time. Different factors contribute to the development of anemia, including increasing age, renal dysfunction, hemodilution, chronic inflammation. Iron deficiency plays an important role in the development of anemia in this group. Heart failure patients with anemia can experience worse symptoms and are less exercise tolerant. Various erythropoiesis stimulating agents and intravenous iron therapy has been shown to improve functional capacity and quality of life in this group [20]. CONCLUSION Management of refractory heart failure continuous to make significant improvement. Further research is required to discover alternative therapies for cardiac transplantation as number of donors will always be much lower than the potential recipients. The technology and Apollo Medicine, Vol. 8, No. 3, September 2011 9. Jones RH, Velazquez EJ, Michler RE, et al. for the STICH Hypothesis 2 Investigators. Coronary bypass surgery with or without surgical ventricular reconstruction. N Eng J Med 2009;309. 10. Seth S, Nirang R, Bhergava B, et al. AIIMS cardiovascular stem cell study group. J Am Coll Cardiol 2006; 48 (11): 250-251. 11. Bolling SF, Pagani FD, Deeb GM, et al. Intermediate firm outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381-388. 12. Calafiore A, Gulline S, D mayrom, et al. Left ventricular aneurysmectomy: J card surg 2003; 18: 93-100. 13. Acker MA, Bolling S, Shemin R, et al. Acorn trial principal investigators and study coordination. J Thoracic cardiovasc surg 2006; 132 (3): 568 -577. 14. DJ Kereiakes, NS Kleiman, J Ambrose, RESTORE trial investigators, J Am Coll Cardio,1996;27: 536-542. 15. Stenvenlon LW, Miller LW, Desvigne, et al. REMATCH investigators. Circulation. 2004; 110 (8): 975981. 16. Thilelc H, Sick P, Boudriot E, et al. Randomized 178
  6. 6. Review Article comparison of intra aortic balloon support with percutaneous left ventricular assist device in cardiogenic shock. Eur Heart J 2005; 26 (13): 1276-1283. 17. Taylor DO,Edwards LB, Boucek MM, et al. Registry of the international society for heart and lung transplantation 2005. J Heart Lung Transplant 2005; 24: 945-955. 18. Guglin M, Polavaram L. Ultrafiltration in heart failure. Cardiol Rev 2007; 15(5): 226-230. 19. Mebazaa, et al. Levosimendan in acute heart failure, Eur J Heart Fail 2009 11:304-311. 20. Anil K Agarwal, Stuart D Katz, Heart failure clinic. 2010, 6(3). 179 Apollo Medicine, Vol. 8, No. 3, September 2011
  7. 7. A o oh s i l ht:w wa o o o p a . m/ p l o p a : t / w .p l h s i lc l ts p / l ts o T ie: t s / ie. m/o p a A o o wt rht :t t r o H s i l p l t p /w t c ts l Y uu e ht:w wy uu ec m/p l h s i ln i o tb : t / w . tb . a o o o p a i a p/ o o l ts d F c b o : t :w wfc b o . m/h A o o o p a a e o k ht / w . e o k o T e p l H s i l p/ a c l ts Si s ae ht:w wsd s aen t p l _ o p a l e h r: t / w .i h r.e/ o o H s i l d p/ le A l ts L k d : t :w wl k d . m/ mp n /p l -o p a i e i ht / w . e i c c a y o oh s i l n n p/ i n no o a l ts Bo : t :w wl s l e l . / l ht / w . t a h a hi g p/ e tk t n