Device therapy for heart failure monitoring and management

1. Device therapy for heart
failure management and
monitoring
Dipak Patade.

2. Burden
• Heart failure (HF) : a leading cause of high cardiovascular mortality and
morbidity.
• results in a significant financial burden on healthcare expenditure.
• particularly with hospital readmissions
• prevalence is increasing with a growing elderly population.
• Heart failure due to reduced left ventricular ejection fraction is treated
with medical therapy using a tiered approach. Despite advances in medical
therapy, heart failure (HF) is associated with high mortality.
• Despite GDMT , many patients remain symptomatic.

3. limitations
• Advanced HF is characterized by significantly impaired cardiac
function and symptomatic limitation, despite optimal medical
therapy.
• Advanced HF represents a stage of the disease where –
• patients’ symptoms are resistant to therapy
• and therapy remain very limited
• In patients with HFREF (particularly with a left ventricular ejection
fraction [LVEF] under 35%), there is a risk of lethal arrhythmia (mainly
ventricular arrhythmia) despite medical therapy.

4. Need of Device therapy
• Implantable cardioverter defibrillators(ICD) and cardiac resynchronisation therapy (CRT)
play an important role in the management of patients with advanced heart failure
• by treating life-threatening arrhythmias
• By improving morbidity and survival.
• Increasing quality of life
• An ICD can detect these arrhythmias and treat them with antitachycardia pacing (ATP)
and, if this is unsuccessful, defibrillation.
• In patients with HFREF who also have a QRS duration on their electrocardiogram (ECG) of
greater than 120 milliseconds, a CRT-P can improve symptoms and prognosis.
• A CRT-D offers both CRT-P and ICD capability.
• In this presentation, the evidence and indications for these devices will be discussed.

5. US FDA approval
• The U.S. Food and Drug Administration (FDA) approval of the first cardiac
resynchronization therapy (CRT) device in 2001 initiated a new era of implantable
device therapies for the management of heart failure (HF).
• ICDs became indicated for the primary prevention of all-cause mortality through
a reduction in the incidence of sudden cardiac death (SCD) in patients with heart
failure and reduced ejection fraction (HFrEF).
• Combined CRT-ICD devices were shown to reduce morbidity and mortality in HF
patients with ventricular dyssynchrony, with a suggestion of additive benefit over
a CRT device alone.
• Since then, implantable cardioverter-defibrillators (ICDs) and combined CRT-ICD
devices have also received FDA approval for the management of HF.
• the 2005 update to the American College of Cardiology/American Heart
Association
• (ACC/AHA) heart failure guideline included in 2005 and revised in 2013.

6. Monitoring
• implantable devices that monitor physiologic parameters such as
patient activity level, heart rate variability, intrathoracic impedance,
and hemodynamics have been developed.
• these data are already available in currently implantable CRT and ICD
devices.
• The utility of such device-based diagnostic or monitoring information
is unknown and currently under investigation.

7. Ventricular Dyssynchrony: the Target of Cardiac
Resynchronization Therapy
• abnormalities of ventricular conduction
• bundle branch blocks, that alter the timing and pattern of ventricular
contraction so as to place the already failing heart at a further
mechanical disadvantage.
• produce suboptimal ventricular filling,
• a reduction in left ventricular (LV) contractility,
• prolonged duration of mitral regurgitation,
• and paradoxical septal wall motion.
• Associated with increased mortality in HF patients.

8. Ventricular Dyssynchrony: the Target of Cardiac
Resynchronization Therapy
• Electrical dyssynchrony -has been defined by a prolonged QRS
duration, generally greater than 120 milliseconds, on the surface
electrocardiogram (ECG).
• Mechanical dyssynchrony -mechanical discoordination associated
with simultenous contraction and stretch in different regions of the lv
as well as delays in the time to peak contraction from one segment to
another.

9. Types of dyssynchrony
• 1.AV dyssynchrony
• 2.intraventicular dyssynchrony
• 3.Interventicular dyssynchrony

10. • AV dyssynchrony : delay between atrial and ventricular contraction, shortened
ventricular filling time & superimposition of atrial contraction on early passive
filling ---reduce LV filling. The ratio between diastolic filling time and duration of
a complete cardiac cycle (A LV filling time of < 40% cardiac cycle is indicative of A-
V dyssynchrony.
• Interventricular dyssynchrony :Delay between RV and LV activation. Occurs
mainly with left bundle branch block, in which RV contraction will precede LV
contraction, leading to abnormal (partially paradoxical) septal motion,
discoordinated LV contraction, and a decreased LV ejection fraction. The LV
septum shortens upto 10% prior to ejection, has minimal subsequent systolic
shortening and undergoes late systolic stretch
• Intraventricular dyssynchrony normal ventricular activation sequence is
disrupted, resulting in discoordinated contraction of the LV segments. The result
is that those LV wall segments, which contract early, do not contribute to the
ejection of blood from the left ventricle, and segments that contract late do so at
a higher wall stress, causing the early contracting segments to stretch.
Additionally, MR worsens in part because of LV remodeling, and presystolic
regurgitation that may occur with ventricular dyssynchrony and delayed
contraction of papillary muscle root attachments.

11. Interventricular dyssynchrony
• Inter-ventricular dyssynchrony (lack of synchronous contraction of left and right ventricles) is often due
to right or left bundle branch block.
• LBBB seems most deleterious to cardiac function. LBBB causes delay in left ventricular (LV) free wall
contraction. Therefore, septal and right ventricular (RV) systole occur first, with thickening of the
septum and contraction towards the RV free wall, away from the left ventricular free wall. This will
result in efficient RV contraction
• prolongation of the isovolumic contraction time of the left ventricle and a fall in diastolic filling time as
a proportion of the cardiac cycle.
• By the time the LV free wall starts to contract, the septum has also begun to relax and so will be
pushed into the relaxing RV cavity, thereby impairing RV filling.
• The combined effects of LBBB dyssynchrony are to prolong isovolumic contraction and relaxation times
of the LV and isovolumic relaxation of the RV.
• The delay between the onset of ejection of blood into the pulmonary artery versus the aorta is termed
the inter-ventricular mechanical delay.
• In healthy people, this is probably less than 10 ms. A delay of more than 40 ms is considered arbitrarily
to indicate dyssynchrony but it is not clear that this is the best value on which to base therapeutic
decisions.
• Patients with delays of20–30 ms still appear to benefit from CRT.

12. cardiac resynchronization therapy.
• Electrical dyssynchrony seen in 33 % patients with HFrEF( one third)
• Ventricular electrical dyssynchrony may now be addressed with pacing
therapy, through the implantation of pacing leads to both right and left
ventricles.
• This form of pacing therapy is now known as cardiac resynchronization
therapy.
• CRT-sustained improvement in exercise tolerance, quality of life, NYHA
functional class.
• RCTs confirmed the beneficial effects of CRT on functional status and
outcomes, leading to the initial indications for this therapy.
• More recent trials have both expanded and limited the indications for CRT

14. RCTs for CRT in NYHA Class III and IV
Patients
• MUSTIC studies
• MIRACLE
• MIRACLE –ICD trial
• CONTAK CD device approval study
• CARE-HF trial
• COMPANION trial

15. Multisite Stimulation in Cardiomyopathy
Trials(MUSTIC)
• to evaluate the safety and efficacy of CRT in patients with advanced
HF, ventricular dyssynchrony, and either normal sinus rhythm or atrial
fibrillation (AF)
• First MUSTIC group-58 randomized patients with NYHA Class III HF,
normal sinus rhythm, and a QRS duration of at least 150 milliseconds
• Randomization-active pacing or no pacing
• Crossover after 12 weeks
• Second MUSTIC group involved- 37 AF patients(biventricular VVIR
pacing versus single-site right ventricular VVIR pacing (rather than no
pacing as in sinus rhythm group) were compared in this group of
patients with AF)

16. Multisite Stimulation in Cardiomyopathy
Trials(MUSTIC)
• The normal sinus rhythm arm of MUSTIC provided strong evidence of
benefit.
• The mean 6MHWD was 23% greater with CRT than without CRT (P <
0.001).
• Significant improvement was also seen in -
i. quality of life and NYHA
ii. functional class ranking
iii. fewer hospitalizations during active resynchronization therapy.
iv. The AF cohort evaluated in MUSTIC demonstrated similar
improvements

17. Multicenter InSync Randomized Clinical
Evaluation(MIRACLE)
• conducted between 1998 and 2000. approval in 2001.
• the first prospective, randomized, double-blind, parallel-controlled clinical trial
designed to evaluate the benefits of CRT
• Primary endpoints : change in NYHA class, quality of life score and 6MHWD.
• Secondary endpoints : assessments of a composite clinical response,
cardiopulmonary exercise performance, cardiac structure and function, a variety
of measures of worsening HF, and combined morbidity and mortality.
• Inclusions:453 patients with moderate to severe symptoms of HF associated with
LVEF of 35% or less and a QRS duration of at least 130 milliseconds
• randomized to CRT (n = 228) or to a control group (n = 225) x 6 months
• conventional therapy for HF was maintained.

18. • an improvement in the distance walked in
six minutes (+39 vs. +10 m, P=0.005)
• functional class (P<0.001)
• quality of life (–18.0 vs. –9.0 points, P=
0.001)
• time on the treadmill during exercise testing
(+81 vs. +19 sec, P=0.001)
• ejection fraction (+4.6 percent vs. –0.2
percent, P<0.001)
• fewer patients CRT group than control
required hospitalization (8 percent vs. 15
percent)
• intravenous medications (7 percent vs. 15
percent) (P<0.05 for both comparisons).
As compared with the control group, patients assigned
to CRT felt-

20. compared with controls CRT for 6 months in
MIRACLE was associated with
• reduced end-diastolic and end-systolic volumes (both P < 0.001),
• reduced LV mass (P < 0.01), increased LVEF (P < 0.001),
• reduced mitral regurgitant blood flow (P < 0.001),
• and improved myocardial performance index (P <0.001)
• Effects were seen in patients already receiving beta-blocker therapy.

24. Multicenter InSync–Implantable Cardioverter-Defibrillator
Randomized Clinical Evaluation(MIRACLE ICD)
• intended to assess the safety and efficacy of a combined CRT-ICD
system in patients with
• Published in JAMA 2003
• Not powered to detect mortality difference
• dilated cardiomyopathy (LVEF ≤35%; LVEDD ≥55 mm, NYHA Class III or
IV HF,QRS ≥130 msec, and class I indication for ICD(class II different
study)
• Same design like miracle for 369 patients
• Randomization:182 were controls (ICD activate, CRT inactive), and
187 were in the resynchronization group (ICD activate, CRT active) x 6
months

26. MIRACLE ICD
• a greater improvement in median quality of life
score (–17.5 [–21 to –14] vs –11.0 [–16 to –
7], P = .02)
• functional class (–1 [–1 to –1] vs 0 [–1 to 0], P =
.007)
• no different in the change in distance walked in 6
minutes (55 m [44-79] vs 53 m [43-75], P = .36).
• although treadmill exercise duration increased
by 56 seconds (30-79) in the CRT group and
decreased by 11 seconds (–55 to 12) in controls
(P<.001).
• No significant differences were observed in
changes in left ventricular size or function,
overall HF status, survival, and rates of
hospitalization.
• No proarrhythmia was observed and arrhythmia
termination capabilities were not impaired.

27. message
• The magnitude of improvement was comparable to that seen in the
MIRACLE trial, suggesting that HF patients with an ICD indication
benefit as much from CRT as those without an indication for an ICD
• The combined CRT-ICD device used in this study was approved by the
FDA in June 2002 for use in NYHA Class III and IV systolic HF patients
with ventricular dyssynchrony and an ICD indication.

28. • First study to demonstrate the
benefits of CRT combined with ICD
therapy, enabling a single device
to treat two clinical outcomes
common to patients with
advanced heart failure
• Patient Population:
i. NYHA Class III–IV
ii. LVEF ≤ 35%
iii. QRS ≥ 120ms
iv. 581 patients at 47 US centers.
CONTAK CD device approval study

29. • Combined endpoint of all-cause
mortality, HF hospitalization and
VT/VF requiring intervention
• Improvements of functional class
were not observed in this study.
• The CONTAK CD device was
approved by the FDA for use in
NYHA Class III and IV systolic HF
patients with ventricular
dyssynchrony and an ICD
indication in May 2002.
CONTAK CD device approval study
• improvement in peak VO2 (p =
0.003)
• 6 Minute Walk distance (p = 0.029)
• NYHA class (p = 0.006)
• Quality Of Life (p = 0.017)

30. Cardiac Resynchronization in Heart Failure Trial
(CARE –HF trial)
• Randomly assigned 813 patients (mean age~ 67)
• NYHA class III or IV HF (94 % class III, 62 % nonischemic)
• an LVEF ≤35 percent (median 25 percent),
• QRS prolongation (median QRS duration 160 msec)
• to CRT with biventricular pacing and medical therapy or medical
therapy alone.
• The primary end point:Time of death from any cause Unplanned
hospitalization for a major cardiovascular event
• Major secondary end point was death from any cause.

31. CARE –HF trial
• Significant benefits were noted with CRT at a mean of 29 months:
• A reduction in the primary end point (39 versus 55 percent, hazard
ratio [HR] 0.63, 95% CI 0.51-0.77).
• A reduction in the primary end point (39 versus 55 percent, hazard
ratio [HR] 0.63, 95% CI 0.51-0.77).
• The benefit increased over time
• At 90 days, improvements in quality of life and NYHA class was noted.
• did not vary with age, sex, NYHA class, baseline systolic pressure,
LVEF, QRS duration, or routine therapies for HF

32. • A reduction in mortality (20 versus 30
percent, HR 0.64, 95% CI 0.48-0.85).
• The mortality benefit increased over time
and was largely due to a reduction in deaths
due to worsening HF (8.1 versus 13.9
percent), with a lesser reduction in SCD (7.1
versus 9.4 percent).
• The mortality benefit for both HF and SCD
increased slightly at extended follow-up of
38 months.
• An increase in LVEF relative to the control
arm of 3.7 percent at 3 months and 6.9
percent at 18 months.
• This was associated with a rise in systolic
pressure of about 6 mmHg compared to no
CRT (median baseline 110 mmHg) and a
reduction in plasma N-terminal-pro- brain
natriuretic peptide
CARE –HF trial

34. Comparison of Medical Therapy, Pacing, and
Defibrillation in Heart Failure(COMPANION)
• multicenter, prospective RCT designed ,12 months follow up
• to compare drug therapy alone to drug therapy combined with CRT in patients with
dilated cardiomyopathy, QRSd >120 msec, NYHA Class III or IV HF, and no indication for a
device.
• Randomization: 1520 patients into one of three treatment groups in a 1 :2:2
• group I :308 patients received optimal medical care only
• group II:617 patients received optimal medical care and the Guidant CONTAK TR
(biventricular pulse generator), and
• group III :595 patients received optimal medical care and the CONTAK CD (combined
HF/bradycardia-tachycardia device).
• The primary endpoint : a composite of all-cause mortality and all-cause hospitalization,
measured as time to first event, beginning from time of randomization.
• Secondary endpoints included all cause mortality and a variety of measures of CV
morbidity.

35. COMPANION trial
• Half of patients enrolled had a nonischemic etiology of HF.
• Medical therapy for HF included angiotensin converting enzyme
inhibitors or angiotensin receptor blockers in 89 %, beta blockers in
66 %, and spironolactone in 55 %.
• During the course of the study, a significant number of patients in the
medical therapy only arm of the trial withdrew to receive a device
because of arrhythmia or HF
• There was a significant reduction in the incidence of the primary
composite end point of all-cause mortality and all-cause
hospitalization in the two arms receiving CRT compared to the
medical therapy only arm (HR 0.80, 95% CI 0.68-0.95).

37. COMPANION trial
• Compared to optimal medical therapy alone-
i. the combined endpoint of mortality or HF hospitalization was reduced by 35%
for patients receiving CRT (P < 0.001).
ii. 40% for patients receiving CRT-ICD (P < 0.001).
• For the mortality endpoint alone:
i. CRT patients had a 24% risk reduction (P = 0.060)
ii. CRT-D patients experienced a risk reduction of 36% (P <0.003), compared to
optimal medical therapy.
• confirmed the results of earlier CRT trials in improving symptoms, exercise
tolerance, and quality of life for HF patients with ventricular dyssynchrony.
• showed for the first time the impact of CRT-ICD in reducing allcause mortality
and suggested incremental benefit from combined device therapies.

38. Whether CRT is useful for patients in NYHA
Class I and II ?
• the landmark studies of CRT in this population
the Resynchronization Reverses Remodeling in Systolic Left
Ventricular Dysfunction (REVERSE) trial
Multicenter Automatic Defibrillator Implantation Trial with Cardiac
Resynchronization Therapy (MADIT-CRT)
Resynchronization/defibrillation for Ambulatory Heart Failure Trial
(RAFT).

39. the Resynchronization Reverses Remodeling in Systolic
Left Ventricular Dysfunction (REVERSE) trial
• a double-blinded RCT design 1:2
• to address the benefit of CRT on heart failure morbidity in patients with
mild HF compared to optimal medical therapy alone
• 610 patients with NYHA Class I and II HF (QRS ≥120 msec, LVEF ≤40%,
LVEDD ≥55 mm) were randomized.
• All patients received a CRT device with or without an ICD
i. 191 were assigned to the control of optimal medical therapy alone (CRT
off)
ii. 419 to the CRT group combined with optimal medical therapy.
• The primary endpoint : a clinical composite HF score.
• The study goal was to determine the effect on preventing disease
progression

40. REVERSE trial Results
Mean LVESVI, LVEDVI, and LVEF at Baseline and 12 Months in the CRT-
OFF and CRT-ON Groups Error bars represent 95% confidence intervals. .
the Heart Failure Clinical Composite Response The primary end point,
comparing the proportion of worsened subjects at 12 months (p = 0.10).
CRT-OFF = control patients; CRT-ON = patients receiving cardiac
resynchronization therapy.

41. • 16% worsened in CRT-ON compared with 21% in CRT-
OFF (p = 0.10).
• Patients assigned to CRT-ON experienced a greater
improvement in LV end-systolic volume index (−18.4 ±
29.5 ml/m2 vs. −1.3 ± 23.4 ml/m2, p < 0.0001) and
other measures of LV remodeling.
• Time-to-first HF hospitalization was significantly
delayed in CRT-ON (hazard ratio: 0.47, p = 0.03).
• CRT, in combination with optimal medical
therapy (±defibrillator), reduces the risk for
heart failure hospitalization and improves
ventricular structure and function in NYHA
functional class II and NYHA functional class I
(American College of Cardiology/American
Heart Association stage C) patients with
previous HF symptoms.
REVERSE trial

42. Multicenter Automatic Defibrillator Implantation Trial
with Cardiac Resynchronization Therapy(MADIT-CRT)
• multicenter RCT to address the potential survival and morbidity benefit of CRT in
NYHA Class I and II HF patients by assessing the reduction in risk of death and
nonfatal HF events in this population
• 1820 patients , follow-up of 2.4 years
• Optimal pharmacologic therapy
• LVEF ≤30%, QRS ≥130 msec ,sinus ,with either an ischemic (Class I patients) or any
(Class II patients) cause.
• Exclusions: Currently implanted pacemaker, ICD, or CRT device ,Current indication
for CRT ,Atrial fibrillation within one month of entry ,NYHA Class III/IV within
three months of entry ,CABG, PCI, or MI within three months of entry.
• 1.Prophylactic CRT combined with an ICD was compared(CRT-D) to
• 2.ICD only

43. MADIT-CRT
• Although ICD therapy is effective for the prevention of sudden cardiac arrest, it does not slow the
progression of heart failure
• However, progression of heart failure in these patients is associated with
increased mortality and diminished quality of life
• Designed to detect a 25% reduction in the risk of the primary end point
• Wang-Tsiatis group-sequential design
• 95% power at a two-sided significance level of 5%
• Sample size requirement of 1820 patients
• Randomized controlled trial
• Randomization on a 3:2 basis to CRT-D/ICD
• Stratified by ischemic status and clinical center
• Data analyzed on an intention-to-treat basis

46. MADIT-CRT
• the primary endpoint of death from any cause or nonfatal HF event occurred in
17.2% of the CRT-ICD group versus 25.2% of the ICD-only group, with RRR of 34%
(HR, 0.66; 95% CI 0.52 to 0.84; P = 0.001).
• This significant benefit was driven by a 41% reduction in HF events (13.9% vs.
22.8%; HR, 0.59; 95% CI 0.47 to 0.74; P < 0.001).
• both ischemic and nonischemic groups showed benefit
• a greater benefit : for women >> men
• a greater benefit was noted in patients with QRS of 150 milliseconds or longer.
• patients benefiting most had left bundle branch block (LBBB).
• The MADIT-CRT trial led the FDA to expand the indication for CRT to NYHA Class
II or ischemic Class I patients, with LVEF less than 30%, QRS duration longer
than 130 milliseconds, and LBBB, for the devices evaluated in this study.

47. Resynchronization/Defibrillation for Ambulatory Heart
Failure Trial(RAFT trial)
• the RAFT trial was the first to show a mortality benefit of combined CRT-
ICD over an ICD alone, and a mortality reduction with the addition of CRT
in patients in NYHA Class II HF.
• The primary outcome of all-cause mortality or hospitalization for HF
occurred in 40% and 33% of the ICD and CRT-D groups, respectively,
• with a significant delay to time of occurrence of the primary outcome in
the CRT-D group.
• Overall, 23.5% of the patients died.
• The 5-year death rate was lower (28.6% vs. 34.6%)
• these results, 14 patients would need to be treated with a CRT-ICD
for 5 years to prevent one death

48. CRT in narrow complex QRS patients
• The EchoCRT trial evaluated the effect of CRT in patients with NYHA Class III or IV
HF, LVEF of 35% or less, QRS duration less than 130 milliseconds, and
echocardiographic evidence of LV dyssynchrony.
• CRT turned on or off.
• The primary efficacy outcome was the composite of death from any cause or first
hospitalization for worsening HF.
• The study was stopped for futility on the recommendation of the Data and Safety
Monitoring Board.
• Of the 809 randomized patients followed for a mean of 19.4 months, the primary
outcome occurred in 116 of 404 patients in the CRT group, versus 102 of 405 in
the control group (28.7% vs. 25.2%; HR, 1.20; 95% CI 0.92 to 1.57; P = 0.15)
• There were 45 deaths in the CRT group and 26 in the control group (11.1% vs.
6.4%; HR, 1.81; 95% CI 1.11 to 2.93; P = 0.02),
• demonstrating the potential for harm in using CRT in narrow-QRS patients.
Thus, CRT is considered contraindicated in these patients.

50. The success rate
• some patients undergoing an implant procedure will not receive a
functioning system using this approach.
• Implant-related complications are similar to those seen with standard
pacemakers and defibrillators, with the additional risk of dissection or
perforation of the coronary sinus.
• Despite the results of randomized controlled CRT trials, some patients do
not respond to this therapy.
• The nonresponder rate for cardiac resynchronization therapy appears to be
about 25%, a rate that is similar to the nonresponder rate for HF drug
therapies.
• Factors proposed as contributing to the nonresponder rate associated with
CRT include- suboptimal LV lead placement, suboptimal AV and VV
• timing, ventricular scar, and HF disease progression.

51. Sudden Cardiac Death in Heart Failure trials
ICD used as prophylactic therapy would reduce total mortality by
reducing the incidence of SCD.
1. AVID trial
2. Multicenter Automatic Defibrillator Implantation II (MADIT II)
3. Defibrillator Implantation in Patients with Nonischemic Dilated
Cardiomyopathy (DEFINITE)
4. National Institutes of Health (NIH)–sponsored Sudden Cardiac
Death–Heart Failure Trial (SCD-HeFT)
5. DANISH study

52. • Pioneered by the work of Dr. Michael Mirowski and his
colleagues at Sinai Hospital in Baltimore (Hopkins affiliate).
• Began thinking of the idea after his mentor died suddenly after
having ventricular tachycardia just a few weeks earlier.
• Worked on his Defibrillator from 1968 to 1980.
• Because of Dr. Mirowski: In 1980, the first patient received an
ICD at Johns Hopkins Hospital.
• 1985: FDA approves sale and use of ICD’s
• First ICD’s required a thoracotomy and used epicardial
leads.The device was so large, that it needed to placed in the
abdomen.
• Invention of transvenous defibrillator in 1969 allowed for a
great reduction in ICD size, and made Mirowski’s idea practicle.
• Point out that the time span from the first concept of the
device (1966) to FDA approval (1985) was nearly 20 years!
ICDs

53. From the AVID and
other secondary
prevention trials,
those with a low EF
actually did much
better w/ ICD’s than
patients with
preserved EF.
AVID trial

54. Multicenter Automatic Defibrillator Implantation II
(MADIT II)
• powered to assess the survival benefit of ICDs in a population of post–myocardial infarction (MI) patients
with reduced EF (<30%). Importantly, this trial included no arrhythmic markers, such as nonsustained or
inducible ventricular tachycardia, for inclusion.
• The 1232 patients were randomly assigned in a 3 : 2 ratio to receive an ICD (742 patients) or conventional
medical therapy (490 patients).
• an average follow-up of 20 months,
• the all-cause mortality rates were 19.8% in the conventional therapy arm and 14.2% in the ICD group (31%
RRR; P = 0.016).
• The effect of ICD therapy on survival was similar in subgroup analyses stratified according to age, gender, EF,
NYHA class, and QRS duration.
• beta-blocker use was 72% in these patients and was well balanced between the ICD and conventional
therapy groups.
• majority of patients enrolled in MADIT II were NYHA Class II or III. Class IV patients were excluded, and the
Class I cohort was relatively small. The average LVEF was 23%.
• HF patients with mild to moderate symptoms and moderate to severe reductions in LVEF may benefit the
most from a prophylactic ICD.
• Moreover, the survival benefit observed in MADIT II began approximately 9 months after the device was
implanted.
• This observation may be important when considering the timing of device placement in eligible patients.

55. Defibrillator Implantation in Patients with Nonischemic Dilated
Cardiomyopathy Trial
(DEFINITE trial)
• the first RCT of primary prevention therapy with an ICD in nonischemic
cardiomyopathy patients.
• a prospective evaluation of 458 patients, Followed for 29.0 ±14.4 months,
• EF of 35% or less, history of symptomatic HF, and presence of ambient
arrhythmias, defined as an episode of non-sustained ventricular
tachycardia (VT) or at least 10 premature ventricular complexes (PVCs) per
24-hour period on continuous ambulatory electrocardiographic
monitoring.
• patients were randomized to study arm to receive either
i. an ICD and standard medical therapy (n=229 )
ii. standard medical therapy alone. (n=229 )

56. DEFINITE trial

57. DEFINITE trial
• There were 68 deaths reported in DEFINITE, 28 in the ICD group and
40 in the standard therapy group.
• The implantation of an ICD yielded a nonsignificant 35% reduction in
death from any cause (HR, 0.65; 95% CI 0.40 to 1.06; P = 0.08) and
significantly reduced the risk of SCD by a remarkable 80% (HR, 0.20;
95% CI 0.06 to 0.71; P = 0.006).
• the results demonstrated a strong trend toward a survival advantage
for patients receiving an ICD.

58. Sudden Cardiac Death–Heart Failure Trial
(SCD-HeFT trial)(2005)
• This landmark RCT enrolled 2521 patients between 1997 and 2001
• Patients with NYHA Class II (70%) or III (30%) HF ,reduced LVEF (≤35%; mean ≈ 25%) of either
ischemic (52%) or with nonischemic cardiomyopathy (48%)
• a three-arm trial
• comparing treatment with an ICD to amiodarone and placebo.
• angiotensin receptor blocker (ARB) in 85%, beta blocker in 69%, and aldosterone antagonists in
19%
• SCD-HeFT addressed at least two
• important issues in HF management:
• (1) whether or not empiric amiodarone therapy saved lives in well treated NYHA Class II and III HF
patients with no arrhythmic indication for the drug
• (2) whether or not a prophylactic ICD saved lives in such patients with HF from either an ischemic
or a nonischemic cause.

59. SCD-HeFT trial
• Mortality rates in the ICD,
amiodarone, and placebo
groups were, respectively
• 17.1%, 24%, and 22.3% at 3
years and
• 28.9%, 34.1%, and 35.9% at
5 years.

60. SCD-HeFT trial
• The ICD was associated with 23% reduction in all-cause mortality
compared to placebo (HR, 0.77; 97.5% CI 0.62 to 0.96; P = 0.007).
• Mortality in the amiodarone arm was not significantly different from
placebo across all subgroups (HR, 1.06; 97.5% CI 0.86 to 1.30).
• Similar degrees of benefit with the ICD were noted in patients with
ischemic (21% mortality reduction) and nonischemic (27% mortality
reduction) HF
• confirmed the findings of MADIT II and DEFINITE results.

61. Danish Study to Assess the Efficacy of ICDs in Patients
with Non-Ischemic
Systolic Heart Failure on Mortality (DANISH)
• Negative trial
• 1116 patients with systolic HF with nonischemic cardiomyopathy for 5.6
years
• an ICD (556 patients) versus usual care (560patients)
• primary outcome of death from any cause occurred in 120 patients in the
ICD group compared to 131 patients in the usual-care group (HR, 0.87; 95%
CI 0.68 to 1.12; P = 0.28)
• The secondary endpoint of SCD occurred in 24 patients in the ICD group
versus 46 patients in the usual-care group (P = 0.005).
• prophylactic ICD implantation in patients with symptomatic systolic heart
failure not caused by coronary artery disease was not associated with a
significantly lower long-term rate of death from any cause than was usual
clinical care.

63. DANISH trial CONCLUSIONS
• Implantation of an ICD in patients who had heart failure that was not
caused by ischemic heart disease did not provide an overall survival
benefit, although the risk of sudden cardiac death was halved with an
ICD.
• There was an important interaction with age that suggested that
younger patients may have a survival benefit in association with ICD
implantation.
• The results were independent of whether a patient received a CRT
device.

64. CRT indications

65. Indications for CRT

68. Indications for ICD

71. Monitoring devices
for heart failure

72. Stages of Heart Failure
A
High-risk patients
Hypertension, diabetes, coronary disease, family history, cardiotoxic drugs
B
Structural heart disease
LVH, MI, low LVEF, dilatation, valvular disease
C
Prior, current symptoms
D
Refractory
Heart Failure

73. • The AHA estimates that the total medical costs for HF are projected to
increase to $70B by 2030  a 2-fold increase from 2013.1
• 50% of the costs are attributed to hospitalization.2
Economic Burden of HF Will Continue to Rise Through 2030*
Graph: Heidenreich PA, et al. Circulation Heart Failure 2013.
*Study projections assumes HF prevalence remains constant and continuation of current hospitalization practices
1. Heidenreich PA, et al. Circulation Heart Failure 2013.
2. Yancy CW, et al. Circulation 2013.

74. Data from the EFFECT study, n = 9138 patients1
Among 1 year survivors after index EFFECT-HF discharge, the
number of heart failure hospitalizations in the preceding year
stratified the risk of death in crude analysis.1
HF Hospitalizations are a Strong Predictor
of Mortality1,2
Data from Setoguchi et al., n = 14,374
patients2
KP cumulative mortality curve for all-cause
mortality
after each subsequent hospitalization for HF.2
Studies show each admission decreases a patient’s chance of survival.
1. Lee DS, et al. Am J of Med, 2009.
2. Setoguchi S, et al. Am Heart J, 2007.

75. With each subsequent HF-related admission, the patient leaves the hospital with a further decrease in cardiac
function.
Worsening Heart Failure Leading to HF Hospitalizations Contributes to Disease Progre
Graph adapted from: Gheorghiade MD, et al. Am J. Cardiol. 2005

76. • 90% of HF hospitalizations present with symptoms of pulmonary congestion.1,2
• Post-hoc analysis of 463 acute decompensated HF patients from DOSE-HF and CARRESS-HF
trials showed:
• 40% of patients are discharged with moderate to severe congestion.3
• Of patients decongested at discharge, 41% had severe or partial re-congestion by 60 days.3
59%24%
17%
Congestion state of patients discharged
without congestion at 60-day follow-up3
Maintained decongestion
Partial recongestion
Relapse to severe congestion
Current HF Management Is Inadequate For Identifying and
Managing Congestion Leading
to Decompensation
Identifying congestion early will lead to early treatment,
prevent hospitalizations and slow the progression of HF.
60%
40%
Congestion state at discharge
Absent or mild congestion
Moderate to severe congestion
1. Adams KF, et al. Am Heart J. 2005
2. Krum H and Abraham WT. Lancet 2009
3. Lala A, et al. JCF 2013

77. Increased pressure is the proximate cause of congestion
Mechanisms of Worsening Heart Failure
Pressures rise early and
have few confounders
Precipitating cause
Sympathetic activation Renal and dietary
Venous redistribution
(fast)
Fluid retention
(slow)
Increased L Heart Filling
LAP/PAP
Pulmonary capillary
transudation
Decompensation /
hospitalization

78. Pulmonary Artery Pressure
Left Heart Failure Right Heart Failure
Left Atrial Pressure Cardiac Output Right Atrial Pressure
Dyspnea
Orthopnea
Pulmonary Edema
Peripheral Edema
Fatigue
Confusion
Renal Insufficiency
Heptic Insufficiency
Renal Insufficiency
Peripheral Edema
Increases in Filling Pressure Start the Cycle of
Worsening Heart Failure Syndromes
 

Adapted from Jaski BE, “Basics of Heart Failure A Problem Solving Approach”

79. Physiologic Markers of Acute Decompensation
Time Course of Decompensation
Graph adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.

80. Physiologic Markers of Acute Decompensation
Graph adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.

81. Data from clinical evaluations has poor sensitivity and predictive value in determining hemodynamic profile
Clinical Examination has Limited Reliability in
Assessing Filling Pressures
Capomolla, 2005. N = 366
Variable
Estimate
of
Sensitivity (%) Specificity (%)
PPV
(%)
NPV
(%)
JVP
Edema
RAP 48
10
78
94
60
55
69
60
Pulse Press Cardiac Index 27 69 52 44
S3
Dyspnea
Rales
PCWP 36
50
13
81
73
90
69
67
60
54
57
48
Table adapted from Capomolla S, et al. Eur J Heart Failure, 2005.

83. Summary: Managing Pressures to Maintain Health
and Manage Acute Events
* Graph adapted from Adamson PB, et al. Curr Heart Fail Reports, 2009.
1. Steimle AE, et al. Circulation, 1997.
2. Abraham WT, et al. Lancet, 2011
3. Ritzema J, et al. Circulation, 2010.
4. Abraham WT, HFSA, 2009.
5. Conraads VM, et al. EHJ, 2011.
6. Whellan DJ, et al. JACC, 2010.
7. van Veldhuisen DJ, et al.
Circulation, 2011.
8. Chaudry SI, et al. NEJM 2010
9. Anker SD, et al. AHA 2010
Enables proactive and
personalized HF
management 1-3
May be used in
risk stratification,
but not actionable4-7
Unreliable, late, and
indirect markers8,9

84. CardioMEMS - The Champion Trial
• NYHA class III HF (all LVEF, all cause) with hospitalization within a year
• 550 implanted and randomized 1:1 to remote PA pressure monitoring vs. usual
care
• Analysis at 6 mo and end of study; mean f/u 15 month
Abraham WT, et. al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised
controlled trial, Lancet. 2011; 377: 658–66

85. CardioMEMS Remote Monitoring System
• First to show sensor
technology to improve
outcomes in a “randomized"
trial.
• Very reliable - NO sensor
failures
• Safe - No pulmonary embolism
or infarction related to the
device
• ASA 81 mg daily continuous
and clopidogrel 75 mg daily x
1 mo for thrombosis
prophylaxis
• Concerns regarding bias in the
study delayed approval for 3.5
yrs after initial application for
approval
• Likely to be post market
refinement of patient
populations who benefit

86. Patients with moderate NYHA class III HF for at least 3 months, irrespective of
LVEF and a HF hospitalization within the past 12 months were included in the
study.
CHAMPION Clinical Trial: The Effect of Pulmonary Artery Pressure-
Guided Therapy on HF Hospitalizations vs. Standard of Care
550 Pts with CardioMEMS™ HF System Implants
All Pts Take Daily readings
Treatment
270 Pts
Management Based on
PA Pressure +Traditional Info
Control
280 Pts
Management Based on
Traditional Info
26 (9.6%) Exited
< 6 Months
15 (5.6%) Death
11 (4.0%) Other
Primary Endpoint: Rate of HF Hospitalization
26 (9.6%) Exited
< 6 Months
20 (7.1%) Death
6 (2.2%) Other
Secondary Endpoints:
 Change in PA Pressure at 6 months
 No. of patients admitted to hospital for HF
 Days alive outside of hospital
 QOL
Abraham WT, et al. Lancet, 2011.

87. CHAMPION Clinical Trial: Managing to
Target PA Pressures
550 Pts with CardioMEMS™ HF System Implants
All Pts Take Daily readings
Treatment
270 Pts
Management Based on
PA Pressure +Traditional Info
Control
280 Pts
Management Based on
Traditional Info
26 (9.6%) Exited
< 6 Months
15 (5.6%) Death
11 (4.0%) Other
Primary Endpoint: rate of HF Hospitalization
26 (9.6%) Exited
< 6 Months
20 (7.1%) Death
6 (2.2%) Other
Secondary Endpoints included:
 Change in PA Pressure at 6 months
 No. of patients admitted to hospital for HF
 Days alive outside of hospital
 QOL
PA pressures were managed to target goal
pressures by physicians with appropriate
titration of HF medications.
Target Goal PA Pressures:
 PA Pressure Systolic 15 – 35 mmHg
 PA Pressure diastolic 8 – 20 mmHg
 PA Pressure mean 10 – 25 mmHg
Abraham WT, et al. Lancet, 2011.

89. Pulmonary Artery Pressure Database
seconds
Trend Data
Discrete data Reading
Systolic: 24
Mean: 19
Diastolic: 16
Heart Rate: 81

90. CHAMPION Clinical Trial: PA Pressure-guided
Therapy Reduces HF Hospitalizations
Patients managed with PA pressure data had significantly fewer
HF hospitalizations as compared to the control group.
Abraham WT, et al. Lancet, 2011.

91. Treatment
(n = 270)
Control
(n = 280)
P-value
Primary Safety
Endpoints
Device-related or system-related complications
3 (1%) 3 (1%)
Total 8 (1%)* < 0.0001
Pressure-sensor failures 0 0 < 0.0001
Secondary
Endpoints
Change from baseline in PA mean pressure
(mean AUC [mm Hg x days])
-156 33 0.008
Number and proportion of patients hospitalized
for HF (%)
55 (20%) 80 (29%) 0.03
Days alive and out of hospital for HF (mean ±
SD)
174.4 ±
31.1
172.1 ± 37.8 0.02
Quality of life (Minnesota Living with Heart
Failure Questionnaire, mean ± SD)
45 ± 26 51±25 0.02
CHAMPION CLINICAL Trial: Both Primary Safety Endpoints and All
Secondary Endpoints Were Met at 6 months
* Total of 8 DSRCs including 2 events in Consented not implanted patients (n = 25)
Abraham WT, et al. Lancet, 2011.

92. Intervention Trial
Mean Duration
of Randomized
Follow-Up
Annualized Reduction
in HF Hospitalization
Rates
NNT per year to
Prevent 1 HF
Hospitalization
Beta-blocker COPERNICUS 10 months 33% 7
Aldosterone antagonist RALES 24 months 36% 7
CRT CARE-HF 29 months 52% 7
Beta-blocker MERIT-HF 12 months 29% 15
ACE inhibitor SOLVD 41 months 30% 15
Aldosterone antagonist EMPHASIS-HF 21 months 38% 16
Digoxin DIG 37 months 24% 17
Angiotensin
receptor blocker
Val-HeFT 23 months 23% 18
Angiotensin
receptor blocker
CHARM 40 months 27% 19
PA pressure monitoring CHAMPION 17 months 33% 4
CHAMPION Clinical Trial: The Number Needed to Treat (NNT) to
Prevent One HF-related Hospitalization is Lower vs. Other Therapies

93. • Preserved Ejection Fraction
Heart Failure (HFpEF) or
diastolic HF patients
represent ~50% of all HF
patients
• Pulmonary artery pressure-
guided therapy significantly
reduced HF hospitalizations
in HFpEF patients in the
treatment group by 46% at 6
months (p<0.0001) and by
50% at 18 months (p<0.0001)
• The effect in HFpEF patients
is even more dramatic than
HFrEF or systolic patients
with an estimated NNT = 2
CHAMPION Clinical Trial: PA Pressure-Guided Therapy Improves
Outcomes in Patients with Preserved Ejection Fraction
Adamson PB,, et al.. Circ Heart Fail. 2014.
0%
10%
20%
30%
40%
50%
60%
HFrEF HFpEF
RelativeRiskReduction
HF Hospitalization Reduction
(18 mo follow-up)
P<0.0001 vs. control
preserved EF (≥ 40%)
p<0.0001 vs. control
reduced EF (< 40%)