RECENT ADVANCES IN THE MANAGEMENT OF REFRACTORY HEART FAILURE

Review Article

MANAGEMENT OPTIONS IN REFRACTORYHEART FAILURE

• 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’sprocedure)

• Others

(a) Ultra filtration

(b) CPAP

DEVICE THERAPY

Cardiac resynchronization therapy

Significant dyssynchrony between various walls of theleft ventricle (intraventricular dyssynchrony) and betweenright and left ventricle (interventricular dyssynchrony) or

RECENT ADVANCES IN THE MANAGEMENT OF REFRACTORY HEART FAILURE

Rajeshwari NayakConsultant Cardiologist, Apollo Hospitals, Greams Lane, Chennai 600 006, India.

E-mail: drrajeshwari_n@apollohospitals.com

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

Key word: Refractory heart failure.

between atria and ventricle (atrio ventricular) is commonin patient with systolic dysfunction contributing toreduced cardiac output [1]. Most patients withintraventricular dyssynchrony have left bundle branchblock pattern on the surface ECG. Nearly 25% of patientswith heart failure have LBBB and its presence confers ahigher risk of worsening heart failure and sudden cardiacdeath [2]. In patients with LBBB and left ventriculardyssynchrony, the left ventricular lateral wall iselectrically activated after the septal contraction whichleads to contraction of the lateral wall during relaxation ofthe septum. This will result in mechanical dysfunctionleading to an increase in the ventricular volume, reductionof contractility and worsening mitral regurgitation.

The myocardial contraction can be resynchronized bypacing the right and left ventricle, biventricularpacemaker (cardiac resynchronization therapy- CRT).Several studies have shown the favorable effect of CRTon symptoms, quality of life and ventricular function [3].The Care HF study showed significant reduction of thecombined endpoint of mortality and cardiovascularhospitalization by 37% [4]. CRT reduces regional leftventricular delay, caused by prolonged ventricularconduction, reduces mitral regurgitation and LV reverseremodeling and normalizes neurohormonal factors. It hasbeen shown that these benefits persist or even improve onlonger follow-up. The risk of arrhythmia and suddencardiac death also showed significant reduction. The CareHF included patients with NYHA class III-IV symptoms,despite being on optimal pharmacotherapy, LVEF <35%and QRS duration ≥120 msec. The patients with QRSinterval 120-149msec were required to have, two of three

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echocardiographic criteria for dyssynchrony: aninterventricular mechanical delay of >40 msec, an aorticpreejection delay of more than 140 msec, or delayedactivation of the postero lateral LV wall >130 msec. Fewsmall studies have shown benefit of CRT in patients withnarrow QRS and echocardiographic evidence ofdyssynchrony [3]. However rethiQ study a randomizedcontrolled trial failed to show any benefit of CRT innarrow QRS patients (<120 msec) [5]. The recentguidelines advocate the use of CRT in patients with anejection fraction of 35% or less, NYHA class III-IV andQRS duration more than or equal to 120msec [6]. MADIT-CRT, COMPANION, CARE-HF and MIRACLE studygroups have shown significant improvement in NYHAfunctional class, quality of life and EF.

Implantable cardioverter defibrillator

The progressive pump failure is the most commoncause of death in patients with advanced heart failure andincidence of sudden cardiac death is less in this group.However sudden cardiac death is the main cause of deathin less severe heart failure and ICDs are more effective inthis group. It has been shown that heart patients withadvanced heart failure can die of electromechanicaldissociation following even an appropriate shock [7]. Inthe landmark SCD –HEFT trial [7], it has been shown thatin patients with NYHA class II heart failure; there was46% relative reduction in the risk of death with ICD ascompared to amiodarone. There was 11.9% absolutereduction in mortality in NYHA class II patients at 5 yrs.However there was no significant reduction in death inpatients 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) inadvanced heart failure, CRT may improve function status,making patients eligible for ICD therapy. In theCompanion trial, either CRT alone or CRT-D reduced therate of death from any cause or hospitalization for anycause by 20% when compared to the group who receivedoptimal pharmacotherapy alone. However CRT-D groupdid not score over CRT arm in the combined outcomes ofdeath or hospitalization for any cause. But there was 36%reduction in the mortality, so whether patients shouldreceive CRT or Combo device should be at the discretionof the cardiologist, guided by cost, likely survival andsymptom status.

SURGICAL INTERVENTION

Out of various surgical options available cardiactransplant remains proven, most effective therapy. Theother interventions aim to either repair or reshape the heartto improve the heart function.

Coronary revascularization procedure

Many studies have shown a coronary artery diseaseprevalence of 50-70% in patients with advanced heartfailure [8].

Coronary artery bypass surgery or angioplasty shouldbe considered in appropriate patients with heart failureand suitable coronary artery anatomy. The patient whoshows evidence of viable myocardium or inducibleischemia should also be considered for revascularizationprocedure. The STICH trial prospectively evaluated thebenefit of coronary revascularization in patients withCAD and heart failure [9]. STICH included 1212 patientswith an ejection fraction of 35% or less and CAD patientsamenable to CABG surgery. Patients were randomized toeither CABG or medical therapy and followed up for amedian of 56 months. This study found no significantdifference between medical therapy alone and medicaltherapy plus CABG surgery with respect to death from anycause. Except for 30 day mortality, however, secondarystudy results favored CABG. Compared to the medicaltherapy group, CABG group had lower rates of death fromcardiovascular causes and of death from any cause orhospitalization for cardiovascular causes [9].

Stem cell therapy

The myocardial regeneration therapy with eitherpercutaneously or surgically delivered stem cell isundergoing extensive research. The initial result appearsto be promising. Improvement in ventricular function andsymptoms are shown with autologous bone marrow stemcell injection. Mesenchymal cell injection also has beentried [10].

Mitral valve surgeries

The mitral regurgitation is very common in patientswith heart failure occurring as a result of mitral annulardilation causing improper coaptation of leaflets or apicaldisplacement of papillary muscles causing restrictedleaflet motion [11]. The mitral valve annuloplasty indilated and ischemic cardiomyopathy is shown to be safewith low mortality (2%) and morbidity [11]. Severalstudies have shown significant improvement in symptoms,ejection fraction, quality of life and reduction inhospitalizations. However recurrence of mitralregurgitation is high after valve repair hence many centresrecommend mitral valve replacement rather than repair incardiomyopathy. Various percutaneous valve repairtechniques are used in different centres.

Cardiac remodeling surgeries

The Batista procedure or left ventriculectomy was

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popular few years ago; however its long term results arenot good. In patients with ischemic cardiomyopathy anddyskinetic segments reshaping surgeries may be ofbenefit. LV aneurysmectomy and endoventricular patchplasty (Dor’s procedure) is found to be promising [12].Various cardiac restraint devices are in use for patientswith LV dysfunction. They have been shown to improveventricular remodeling but showed no mortality benefit[13]. In ischemic cardiomyopathy, the left ventricleremodels from its normal elliptical shape to a sphericalshape. This geometrical change is partly responsible forthe symptom of heart failure. Ventricular restorationsurgery aim to correct the above mentioned pathologicalteration in geometry. In the RESTORE study, patientswith ischemic cardiomyopathy underwent Dor’sprocedure and the investigators reported among thepatients studied, EF increased from 29.6% to 39.5%, endsystolic volume index decreased and NYHA classimproved from 67% class III – IV before surgery to 85% I /II after surgery [14]

Again Yamaguchi, et al reported significantlyimproved 5 year survival in patients with ischemiccardiomyopathy who underwent ventricular restorationand CABG surgery versus patient who underwent CABGsurgery alone.

Left ventricular assist devices

In 1963, Dr Michael DeBakey made first clinical useof VAD in a patient who had cardiac arrest after AVRsurgery. However unfortunately that patient died. Nearly 3years later, Dr DeBakey successfully implanted a newerdevice in a patient who could not be weaned fromcardiopulmonary bypass, who received mechanicalsupport for 10 days which allowed the myocardium torecover and was successful.

Various LVADs are used both as bridge to transplant/recovery and destination therapy. Most recent LVADs areused as destination therapy, for patients who are ineligiblefor cardiac transplant. In a multicentre, prospective trial,129 patients with end stage heart failure who are ineligiblefor cardiac transplant were randomized to receive eitheran LVAD or optimal medical therapy. At one year follow-up there was 48% reduction in death and improved qualityof life in the LVAD group as compared to medical therapygroup [15]. Currently LVADs are indicated in patients whoare awaiting cardiac transplant who have becomerefractory to medical treatment as a bridge to transplant.Various percutaneous implantable devices are used forshort term stabilization of patients with refractory heartfailure. The intra aortic balloon counter pulsation is usedfor last several years but it is of only short term benefit.

Other percutaneous devices like the Tandem Heart andImpella system may provide rapid and better circulatorysupport [16]. At present these devices are used for patientsundergoing PCI or surgery with heart failure. The FDAapproved mechanical circulatory devices are: (i) Abiomed BVS 5000 for short term support, (ii) AbiomedAB 5000 circulatory support system; (iii) Centrimagsystem; (iv) Thoratec paracorporeal and intracorporealLVAD and RVAD; (v) Heart mate/ LVAD.

HEART TRANSPLANTATION

The heart transplantation is the most effectivetreatment options for patients with refractory heart failure[17]. The indication for cardiac transplant includespatients with refractory heart failure, NYHA class III-IVsymptoms, oxygen consumption less than 10 mL/kg/mt.Over the last decade there has been significantimprovement in survival rates following cardiac transplantas a result of improvement in patients selection, organselection and preservation and postoperative managementand availability of newer immunosuppressants. Howeverdonor availability is the most important limitation.

Total artificial heart

In 1969, Dr Denton Cooley implanted the first TAH ina high risk patient after a failed cardiopulmonary bypassafter LV aneurysm repair. At present, 2 TAH are receivingattention (a) Cardiowest TAH; (b) Abiocor TAH.

ULTRAFILTRATION

In patients with refractory heart failure and fluidoverload regular peritoneal dialysis is found to be useful.Peritoneal dialysis is shown to reduce hospitalization ratesand improve the functional capacity [18]. In theUNLOAD trial, 200 patients with heart failure and fluidoverload were randomized to ultra filtration or diuretictherapy. Ultra filtration was shown to produce greaterfluid and weight loss. It also reduced rehospitalisationrate.

CPAP

The obstructive sleep apnea is common in patientswith advanced heart failure. Continuous positive airwaypressure (CPAP) is an effective treatment for sleep apnea.Small prospective trials have shown that CPAP improvesLVEF, reduce urinary nor-adrenaline levels and improvecardiac output.

NEWER VASODILATORS/INOTROPES

NESIRITIDE (human BNP analog) is a vasodilatorthat is shown to alleviate heart failure symptoms faster

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when compared to diuretics alone or in combination withlow dose nitroglycerin (VMAC TRIAL). Nesiritide can bestarted if systolic blood pressure is greater than 100mmHgat an infusion rate of 0.005 mcg/kg/mt with or without anIV bolus of 2 mcg/kg.

LEVOSIMENDAN is a calcium sensitiser used in themanagement of acutely decompensated congestive heartfailure. It is marketed under the trade name Simdax.Levosimendan is indicated for inotropic support inacutely-decompensated severe congestive heart failure.

Some of the Phase-III studies in the extensive clinicalprogram were the trials LIDO (200 patients), RUSSLAN(500), CASINO (250), REVIVE-I (100), REVIVE-II(600) and finally SURVIVE (1350), [1] a head-to-headtrial between levosimendan and dobutamine in acutedecompensated heart failure. In total, the clinical data baseincludes more than 3500 patients in Phase IIb and IIIdouble-blind studies, which is the highest number ever intesting a drug for acute decompensated heart failure.

Despite an initial reduction in plasma B-typenatriuretic peptide level in patients in the levosimendangroup compared with patients in the dobutamine group ina head to head comparison study, levosimendan did notsignificantly reduce all-cause mortality at 180 days [1].However, the drug was proven to be superior todobutamine for treating patients with a history of CHF orthose on beta-blocker therapy when they are hospitalizedwith acute decompensations [19].

ANEMIA IN HEART FAILURE

Anemia is being increasingly recognized as animportant comorbidity in patients with heart failure.Nearly one- fifth to one- third of patients with heart failuremay experience anemia at a given time. Different factorscontribute to the development of anemia, includingincreasing age, renal dysfunction, hemodilution, chronicinflammation. Iron deficiency plays an important role inthe development of anemia in this group. Heart failurepatients with anemia can experience worse symptoms andare less exercise tolerant. Various erythropoiesisstimulating agents and intravenous iron therapy has beenshown to improve functional capacity and quality of life inthis group [20].

CONCLUSION

Management of refractory heart failure continuous tomake significant improvement. Further research isrequired to discover alternative therapies for cardiactransplantation as number of donors will always be muchlower than the potential recipients. The technology and

research is needed to promote angiogenesis andmyocytogenesis. However as practicising physicians andcardiologist we should continue to provide the bestsupportive therapy for all patients with refractory heartfailure.

REFERENCES

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17. Taylor DO,Edwards LB, Boucek MM, et al. Registry of theinternational society for heart and lung transplantation2005. J Heart Lung Transplant 2005; 24: 945-955.

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