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.

1. RECENT ADVANCES IN THE MANAGEMENT OF
REFRACTORY HEART FAILURE

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: drrajeshwari_n@apollohospitals.com
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. 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. 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. 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 S.london 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. 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. 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