heart failure and device therapy

1. Device Therapy in Heart Failure
Presenter: Dr R P Singh
Moderator: Dr Sameer Mehrotra

2. Heart Failure Incidence
400,000 5.0 million 250,000
Annual
Incidence
Heart Failure
Prevalence
Annual
Mortality
U.S.
• Up to 30 % of CHF patients have an IVCD (80% with a LBBB) which has been linked to
increases in mortality and morbidity.
• 1-2% of the population and 6% of the population >65 Yrs age.
• Prevalence is on the rise.

3. Class I
Asymptomatic
heart failure
ejection fraction
(EF) <40%
Class II
Mild symptomatic
heart failure
with ordinary
exertion
Class IV
Symptomatic
heart failure
at rest
Class III
Moderate
symptomatic
heart failure
with less than
ordinary exertionn
NYHA Class-evaluates the disability
imposed on the patient
• The FDA and the ACC/AHA Guidelines have approved
biventricular pacing for class 3 and 4.

4. SCD Rates in CHF Patients with LV Dysfunction
17
8
20
15
9
19
7
6
4
42 41 39.7 44
11
0
10
20
30
CHF-STAT GESICA SOLVD V-HeFT I MERIT-HF CIBIS-II CARVEDILOL-US
Control
Group
Mortality
Total Mortality
Sudden Death
Total Mortality ~15-40%; SCD accounts for ~50% of the total deaths.
12 months 16 months
41.4 months 27 months
13 months
45 months 6 months

5. SCD in Heart Failure
• Degree of SCD risk by class
• Mortality in NYHA class II is 5 to 15%
• 50 to 80% of the deaths are Sudden
• Mortality in NYHA class III is 20 to 50%
• Up to 50% of the deaths are Sudden
• Mortality in NYHA class IV is 30 to 70%
• 5 to 30% of deaths are Sudden

6. • In most patients with an IVCD (QRS > 130 ms) , the presence of
atrial-biventricular (RV + LV) pacing will provide early stimulation
to an otherwise late segment of electrical activation in the LV.
• This should translate into an increase in the EF, decrease of the LV
dimension, improvement in the QOL and NYHA class.
• This may translate into an decrease in CHF exacerbations ,
hospitalizations and a decrease in mortality.

8. Primary ICD Prevention Trials
• Several randomized controlled trials have been classified in the literature as
primary prevention trials: MADIT I, MUSTT, CABG-Patch and MADIT II.
Two types:
• (1) trials on patients with inducible sustained ventricular tachyarrhythmias during EP
study (MADIT I and MUSTT), and
• (2) trials on high risk patients with coronary disease who were not specifically required
to have inducible sustained ventricular tachycardia during EP study (CABG-Patch and
MADIT II).

9. MADIT I and MUSTT
• Both trials were randomized controlled trials with relatively large sample sizes (196 patients
and 704 patients, respectively).
• Both demonstrated significant improvements in survival for patients with prior myocardial
infarction, left ventricular dysfunction and inducible, sustained ventricular arrhythmias
during EP study that were treated with implantable defibrillators (54% and 55% reduction in
mortality, respectively).
• The results of these two trials are consistent and provide sufficient evidence on effectiveness
for the population of patients with EP inducible ventricular tachyarrhythmias.

10. MUSTT
• The Multicenter Unsustained Tachycardia Trial enrolled patients with
• LVEF ≤40%, prior MI, which had occurred more than 4 days before enrollment,
asymptomatic nonsustained VT at least 4 days post-MI or postrevascularization but
within 6 months of enrollment, and reproducibly inducible sustained VT with
programmed electrical stimulation.
• The trial randomized patients to receive either drug therapy on the basis of repeat
inducibility testing during programmed electrical stimulation or an ICD.
• An important finding was that ICD recipients were at significantly lower risk of
cardiac arrest or death from arrhythmia during follow-up compared with patients
who did not receive ICDs with a relative risk reduction of 76%.

11. CABG-Patch Trial and MADIT II
• For patients with prior myocardial infarction and left ventricular dysfunction
but without documented ventricular tachyarrhythmias, the study results have
been different.
• The CABG-Patch Trial and MADIT II focused on these types of patients at
high risk for sudden death without requiring inducible ventricular
arrhythmias or EP studies.

12. MADIT-II
• Patients had ischemic heart disease with prior myocardial infarction and an
LVEF less than 0.30.
• ICD therapy compared with investigator-selected standard medical therapy
resulted in a hazard ratio of 0.69.
• The MADIT II found a significant improvement in survival (14.2% mortality
rate in ICD group, 19.8% in conventional therapy group).

13. CABG-PATCH TRIAL
• The CABG-Patch Trial investigators found “no evidence of improved
survival among patients with coronary heart disease, a depressed left
ventricular ejection fraction, and an abnormal signal-averaged
electrocardiogram in whom a defibrillator was implanted prophylactically at
the time of elective coronary bypass surgery.”
• The investigators also suggested that “the occurrence of sustained
ventricular arrhythmias, either natural or induced, is a better marker than
abnormalities on the signal-averaged ECG.

14. DEFINITE Trial
• Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation
• 458 patients with nonischemic dilated cardiomyopathy (LVEF <36%) and premature
ventricular complexes or non-sustained VT, to either medical therapy or medical
therapy plus a single-chamber defibrillator.
• The degree of LV dysfunction was worse than previously published trials (mean LVEF
21%), and most patients were treated with ACE inhibitors and β-blockers.
• The trial found that ICD implantation significantly reduced the risk of sudden death
from arrhythmia but was associated with a nonsignificant reduction in all-cause
mortality.

15. SCD-HeFT
• Included patients with
• both ischemic and nonischemic cardiomyopathy,
• class II or class III heart failure symptoms, and
• LVEF less than 35%.
• Patients were randomized to an ICD, amiodarone, or placebo.
• Overall, ICD therapy resulted in a hazard ratio of 0.77, with the benefits
seen in the subgroup having class II heart failure.

16. SCD-Heft trial
• This resulted in FDA approval of the ICD (Jan 2005) in patients with CHF
and EF<35 % that included both ischemic and nonischemic cardiomyopathy
for primary prevention without a positive EP study or ventricular ectopy.
• No QRS cutoff was required.

17. DINAMIT and IRIS
• Both studies have looked at ICD therapy for primary prevention in high-risk
patients early after myocardial infarction.
• In both studies overall no mortality benefit seen.
• In these two studies, a decrease in arrhythmic deaths in the ICD group was
balanced by a corresponding increase in non-arrhythmic mortality.

18. DANISH- 2016
• To Assess the Efficacy of ICDs in Patients with Nonischemic Systolic Heart Failure on
Mortality provided a contemporary assessment of ICD implants for the primary prevention
of SCD in nonischemic cardiomyopathy.
• 1116 patients with symptomatic heart failure from nonischemic cardiomyopathy (LVEF
≤35%) to receive an ICD with standard clinical care or usual clinical care alone.
• Eligible patients for CRT received such treatment in both the ICD and usual clinical care,
resulting in about 58% of patients receiving CRT in both groups.
• The trial found no significant reduction of the primary end point of all-cause mortality with
ICD use, but there was a reduction of the risk of SCD by about 50% with defibrillator
therapy.

19. Secondary Prevention Trials

20. AVID Trial
• 1016 cardiac arrest and unstable VT survivors were randomly assigned to either
drug therapy (amiodarone or infrequently sotalol) or an ICD.
• Other indicated therapies were permitted, including β-adrenergic blockers, renin-
angiotensin system inhibitors, and revascularization.
• The primary endpoint, total mortality, was decreased by 39%, 27%, and 31% at 1-,
2-, and 3-year time points, respectively.
• The benefit of ICD implants was primarily in patients with left ventricular ejection
fraction (LVEF) <35%, and this set ground for design of subsequent trials for the
primary prevention of SCD.

21. CIDS Trial
• Canadian Implantable Defibrillator Study- 696 patients with cardiac arrest,
sustained VT, or syncope with induced VT were randomized between an
ICD and amiodarone.
• 5 Yrs follow up data- Statistically nonsignificant reduction in mortality and
arrhythmic deaths with ICD use versus amiodarone.

22. CASH Trial
• Included only cardiac arrest survivors ( N = 346) and randomized them to
either an ICD or drug therapy (amiodarone, metoprolol, or propafenone).
• The propafenone arm was terminated early because of excess mortality.
• At the 2-year time point, the mortality rate was 37% lower in the ICD group
than in the combined amiodarone and metoprolol group.

23. Cardiac Resynchronization
Clinical Trials

26. MIRACLE trial
• Multicenter In-Sync Randomized Clinical Evaluation confirmed symptomatic
benefits of CRT in terms of 6-minute walk tests, NHYA functional class,
time on treadmill during exercise, as well as improvement in LVEF in
patients (n=453) with NYHA functional class III or IV, LVEF <35%, and
QRS width >130 ms.

27. COMPANION:2004
• OPT
1
• OPT
• CRT
+
2
• OPT
• CRT-D
+
2
Randomization
Comparison of Medical Therapy, Pacing and
Defibrillation in Heart Failure

28. COMPANION
• Enrolled 1520 patients class 3 and 4, QRS >120 ms
• Primary endpoint: death or hospitalization for any cause
• CRT met the primary endpoints and the CRT +/- ICD significantly reduces
mortality
• This was the first to show mortality benefit from CRT alone
• Showed that patients with CRT also benefit from ICD therapy
• OPT had SCD in 36%, 23% in CRT and 2.9% in CRT+ICD

29. • CRT arm had 20% reduction in mortality and hospitalization over OPT arm but it
was not statistically significant
• Both CRT-P and CRT-D were found to reduce the risk of the primary end point with
hazard ratios of 0.81 and 0.80, respectively.
• Importantly, CRT-P decreased the risk of death from any cause by 24% while CRT-D
reduced the same by 36%.
• In current clinical practice, patients with characteristics similar to COMPANION’s
inclusion criteria are typically treated with CRT-D devices in the absence of
contraindications and on a case by case basis accounting for patient’s age,
comorbidities, overall prognosis, or patient preference. Otherwise, CRT-P devices are
primarily used in patients with mild to moderate syst
COMPANION

30. MADIT-CRT

31. • MADIT-CRT is the largest randomized NYHA Class I / II CRT-D trial to
date
• Full Trial Population: 1820 patients
• LBBB Population: 1281 patients
Inclusion Criteria:
• Male and female
• Over 21 years of age
• NYHA functional Class II, non-ischemic or ischemic cardiomyopathy or
• NYHA functional Class I, ischemic cardiomyopathy and
• Left ventricular dysfunction (LVEF ≤ 0.30) and
• Prolonged intraventricular conduction (QRS duration ≥ 130 ms) and
• Optimal HF pharmacologic therapy (OPT)
• 110 centers in 14 countries

32. • Results
• MADIT-CRT provides clinical evidence that in high-risk NYHA Class I and
II patients with LBBB, early CRT intervention reduces the relative risk of all-
cause mortality or first heart failure event by 57% when compared to ICD
therapy (p < 0.001).
•

33. BLOCK-HF trial
• Standard RV pacing vs biventricular pacing.
• Atrioventricular block require high pacing burden.
• N-691
• The primary outcome was the time to death from any cause, an urgent care visit for
heart failure that required intravenous therapy, or a 15% or more increase in the left
ventricular end-systolic volume index.
• The use of CRT in this study was associated with significantly lower incidence of
the primary outcome in both recipients of pacemakers or defibrillators, based on
standard ICD indications.
• In current practice, patients with LVEF ≤50% and pacing burden (or expected
pacing burden) >40% are typically referred for CRT.

35. Factors that influenced ICD benefit
1. NYHA function class III,
2. AF,
3. QRS duration >120 milliseconds,
4. Age >70 years, and
5. BUN greater than 26 mg/dL
No of Risk
factors
Benefit from
ICD therapy
NIL No benefit
1 or 2 Greatest
benefit
>3 Attenuated

36. Predictors of mortality after ICD implantation
1. Age >75,
2. Class III heart failure,
3. Chronic lung disease,
4. Chronic kidney disease,
5. AF,
6. EF <20%, and
7. Diabetes

37. Complications
• The most common in-hospital complications after ICD insertion are
• Lead dislodgment or perforation,
• Pocket hematoma,
• Pneumothorax,
• Arrhythmias, and
• Coronary sinus dissection (if a left ventricular lead is attempted)

38. Device-related adverse events
• The most frequent are
• Inappropriate shocks,
• Infections,
• Lead or device malfunction, and
• Pacing- or lead-related hemodynamic effects.

39. ICD-related heart failure worsening
• Lead-induced Tricuspid valve dysfunction And
• By Dyssynchrony caused by Inappropriate RV apical pacing.
• Loss of left ventricular lead capture during CRT.

40. RV pacing
• MADIT II (2002) had a survival benefit with the ICD but in a subgroup analysis,
there was an increase in heart failure morbidity (more hospitalizations) felt due to
forced RV pacing compared to controls in which no pacing was present.

41. Right Ventricular Pacing
• RV apex pacing is harmful in patients with LV dysfunction
• “Paced” LBBB
• Abnormal LV activation
• Reduced stroke volume

42. Wearable Cardioverter Defibrillators
• As a temporary alternative to ICDs, WCDs have been shown to have similar efficacy in
terminating VT or VF but are limited by lack of pacing and as such inability to provide anti-
tachycardia pacing.
• However, in the early post-MI period, in patients with LVEF ≤35%, WCDs did
significantly lower the rates of arrhythmic deaths than in control, as found by the VEST
(Vest Prevention of Early Sudden Death Trial)
• The trial randomly assigned in a 2:1 ratio, 2302 patients with LVEF ≤35% early post-MI to
receive a WCD plus guideline-directed therapy or guideline-directed therapy alone.
• Arrhythmic deaths occurred in 1.6% of patients in the WCD group and 2.4% of those in
the control group.

43. Subcutaneous Defibrillators
• The subcutaneous defibrillator system consists of a pulse generator, which gets
implanted in a left mid-axillary position and connected to a subcutaneous lead with
shocking coil, typically tunneled under the skin and positioned in a left parasternal
position.
• Preprocedural electrical screening is typically required to ensure the device’s ability
to properly and adequately sense and adjudicate ventricular arrhythmia.
• Such system was found to successfully detect ventricular arrhythmias and to
successfully defibrillate in >95% of subcutaneous defibrillator recipients.

44. Single-Component and Multi-
Component Leadless Systems
• The WiSE-CRT study (Wireless Stimulation Endocardially for CRT) assessed
the feasibility of leadless ultrasound-based endocardial left ventricular pacing
in patients who had an indication for CRT.
• The device system has a subcutaneous pulse generator and a small receiver
electrode that is implanted in the left ventricular endocardium.
• The preliminary efficacy data from WiSE-CRT appeared promising, but the
study was terminated prematurely for safety reasons.

45. • A redesigned delivery system was tested in the SELECT-LV study (Safety
and Performance of Electrodes Implanted in the Left Ventricle) and showed
both feasibility (successfully implanted in 34 of 35 patients) and possible
clinical improvement with CRT using this system. This system, however, is
not entirely leadless as it depends on the presence of RV leads.

56. Summary
• Large number of patients studied in multiple RCTs.
• CRT improves quality of life, exercise capacity, functional
capacity, EF, peak VO2.
• CRT reduces the risk of mortality, worsening HF, and
hospitalizations for CHF.
• CRT + ICD significantly reduces risk of mortality.

57. • Currently approved and novel therapies that are in pipeline generally allow
targeting of a structural or neurohormonal abnormality that is not directly
amenable to pharmacologic therapeutic interventions.
• Device based therapies are primarily developed and approved for patients
with persistent symptomatic or progressive disease despite optimal GDMT.
• Device based therapies for HF should be considered complementary to
pharmacologic therapy.