LV Dssynchrony and Cardiac Resynchronization Therapy

in Heart Failure

Nisha I. Parikh MD MPH

August 13th 2008

Summary of Talk Background CRT Rational and Evidence for Benefit LV Dssynchrony by Echocardiography Evidence for Ability of Echo to Predict CRT

Response

Hospital discharges for HF from 1979-2004

0

100

200

300

400

500

600

700

79 80 85 90 95 00 04

Years

Dis

ch

arg

es i

n T

ho

usa

nd

s

Male Female

399,000

1,099,000

American Heart Association. Heart Disease and Stroke Statistics — 2007 Update

1,099,000

HF Total Expenditures: $27.9 Billion

American Heart Association. Heart Disease and Stroke Statistics — 2007 Update

Percent Change in United States Crude Death Rates

from 1972 to 2000 by cause

NHLBI Morbidity and Mortality Chart Book. 2004

HF Therapy

Jessup M, Brozena S. Medical Progress--Heart Failure. N Eng J Med 2003; 348: 2007-2018. Copyright 2002 Massachusetts Medical Society. All rights reserved.

Electrical dyssynchrony Abnormal ventricular depolarization,

causing increased QRSd generates early and delayed ventricular contraction

QRSd directly associated with EF BBB present in 20% of HF patients and

35% of patients with severely impaired EF BBB is an independent predictor of

mortality especially QRSd > 120 ms

Mechanical dyssynchrony Intraventricular- refers to delayed activation

of one LV region to another Interventricular- refers to delayed activation

of LV relative to RV CRT aims to correct both

Achieving Cardiac ResynchronizationGoal: Atrial synchronous biventricular pacing

Transvenous approach for left ventricular lead via coronary sinus

Back-up epicardial approach

Right AtrialLead

Right VentricularLead

Left VentricularLead

From Dr. A. Goldman’s CRT Talk 2007

Cumulative Enrollment in Cardiac Resynchronization Randomized Trials

0

1000

2000

3000

4000

1999 2000 2001 2002 2003 2004 2005

Results Presented

Cum

ulat

ive

Pat

ient

s

PATH CHF

MUSTIC SR

MUSTIC AF

MIRACLE

CONTAK CD

MIRACLE ICD

PATH CHF II

COMPANION

MIRACLE ICD II

CARE HF

CRT benefits Reduced mitral regurgitation Increased 6-minute hall walk distance Improved NYHA functional class ranking Increased peak VO2 and treadmill exercise time Reduced QRS duration Reversal of maladaptive remodeling Fewer days in hospital over 6 months Improved clinical composite response Reduced morbidity and mortality

Improvement with CRT - MR

Regional Wall Motion With CRT: Improved LVEF

Septum

Lateral

Pacing OffPacing On

Reg

ion

al F

ract

ion

al A

rea

Ch

ang

e

Seconds 0.40

Seconds 0.40

Adapted from Kass DA. Rev Cardiovasc Med. 2003;4(suppl 2):S3-S13.

Adapted from Kawaguchi M, et al. J Am Coll Cardiol. 2002;39:2052-2058.

CRT Promotes Reverse Remodeling in Class II CHF

Left Ventricular End Diastolic Diameter

200

250

300

350

400cm3

Base 6 Mo

Left Ventricular End Systolic Diameter

200

250

300

350

400cm3

Base 6 Mo

Left Ventricular Ejection Fraction

20

22

24

26

28

30%

Base 6 Mo

Control (n=85) CRT (n=69)

Abraham et al., Circulation 2004; 110:2864-2868

P=0.04 P=0.01 P=0.02

CRT Improves Quality of Life and NYHA Functional Class

Average Change in Score

-20

-15

-10

-5

0

MIR

ACLE

MUS

TIC

SRCO

NTAK

CD

MIR

ACLE

ICD

Control CRT

* * * *

* P < 0.05

NYHA: Proportion Improving 1 or More Class

0%

20%

40%

60%

80%

MIRACLE CONTAKCD

MIRACLEICD

Control CRT

**

*

Abraham et al., 2003

CRT Improves Exercise Capacity

Average Change in 6 Minute Walk Distance

-40

-20

0

20

40

60

MIR

ACLE

MUS

TIC

SRCO

NTAK

CD

MIR

ACLE

ICD

m

Control CRT

**

*

* P < 0.05

Average Change in Peak VO2

00

1

2

3

mL/

kg/m

in

Control CRT

*

*

*

*

Abraham et al., 2003

Progressive Heart Failure Mortality51% Relative Reduction with CRT

0.1 1.0 10.0Odds Ratio (95% CI)0.5

Favors CRT Favors No CRT

CONTAK CD (n=490)

MIRACLE ICD (n=554)

MIRACLE (n=532)

MUSTIC (n=58)

Overall (n=1634)

Bradley DJ, et al. JAMA 2003;289:730-740

Overall odds ratio (95% CI) of 0.49 (0.25 - 0.93)

Summary of Major Trials Significant clinical benefit of CRT in patients with class III-IV

HF, low EF, and QRS > 120 Improvement in symptoms Improvement in objective standards of HF

Meta-analysis 29% decrease in HF hospitalization (13% vs. 17.4%) 51% decrease in deaths from HF (1.7% vs. 3.5%) Trend toward decrease in overall mortality (4.9% vs 6.3%)

BUT: >30% non-responders consistent through most trials

Bradley et al. JAMA 2003;289:730

How to best predict who will respond to CRT?

?Use of Echo/ imaging parameters

Intraventricular Dyssynchrony M-Mode Echo Tissue Velocity Strain Imaging Three Dimensional Echo

M-Mode Septal to posterior wall delay Measures time between maximal

displacement of septum and posterior wall (SPWMD)

≥ 130 ms considered significant Easy to perform No specific equipment needed

Copyright ©2008 American Heart Association Anderson, L. J. et al. Circulation 2008;117:2009-2023

M-mode echocardiography with color-coded tissue velocity. a, Timing of ventricular septal (VS) wall motion is difficult to define because of

its severe hypokinesis and the lack of distinct peaks. b, Color coding of tissue velocity helps to identify the exact wall motion timing as

transition point of blue to red color for septal wall (arrows) and red to blue color for posterior wall (arrowheads) (right)

M-Mode- SPWMD Disadvantages Can only be quantified in regions

perpendicular to U/S beam Only feasible in half of patients studied In several reports, septal-posterior wall

delay didn’t predict outcome after CRT Only assesses motion of septal and

posterior walls

Tissue Velocity Measurement of either longitudinal tissue velocity

or deformation (strain)- Opposing wall peak delay of > 60-65 ms1-2

- Yu index: global 12 segment Asynchrony Index ≥ 33 ms3

High temporal resolution Color-coded TDI- allows simultaneous processing

of multiple samples from the same image Susceptible to translational motion or tethering

effect

Bax et al, Am J Card 2003Bax et al, Am J Card 2004

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023

Tissue velocity waveforms in a normal subject from 4-chamber (left), apical long-axis (middle), and 2-chamber views (right)

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023

Color-coded tissue velocity recordings from 12 LV segments before (a) and after (b) CRT in 65-year-old patient with

nonischemic cardiomyopathy whose LVEF improved by 17% at 6 months after CRT

Before CRT

After CRT

Apical 4 Ch Long axis 2 Chamber

Tissue Velocity- Disadvantages Susceptible to translational motion or

tethering effect Color coding can vary with time window

setting Requires specific equipment

Strain Imaging TDI-derived and Speckle tracking Abnormal strain pattern- premature early

systolic shortening of septum accompanied by lateral prestretch and followed by postsystolic lateral wall shortening

Less affected by tethering / translational motion

Copyright ©2008 American Heart Association

Anderson, L. J. et al. Circulation 2008;117:2009-2023

Radial strain curves from short-axis view of speckle tracking Echocardiography: Significant timing difference was found among

time to peak radial strain before CRT (a), and it was reduced after CRT (b).

Strain imaging Dependent on image quality; not feasible in

all patients Mixed results with respects to predicting

success after CRT

3-D Echo Only one image allows entire assessment Short-term improvements in 3-D

dyssynchrony index noted after CRT

Three Dimensional Echocardiography

3-D Echo No study to date shows 3D Echo predicts

response to CRT Highly dependent on image quality Incomplete inclusion of the apex Can’t perform in a-fib or rhythm with several

ectopic beats

Interventricular Dyssynchrony Difference in preejection period between PW

doppler in Ao and PA- Correlates with QRSd- Exceeds 40s in patients with QRDs>150 ms- Shown to be predictive of response post-CRT in

SCART and CARE-HF trials TV delay between RV and LV free wall not

predictive of effect of CRT

Evidence for echo in predicting CRT outcomes

Limited echo-CRT studies with hard endpoints

Thus far, trials have enrolled 4000 patients based on ECG versus ~500 by echocardiogram

PROSPECT Study- largest study

Copyright ©2008 American Heart Association

Chung, E. S. et al. Circulation 2008;117:2608-2616

Enrollment and follow-up of patients in PROSPECT

PROSPECT patient population

Mean age 68 years

Male 71%

NYHA class III 96%

Mean LVEF 23%

Prior MI 48%

Beta-blockers 85%

Ace-I 92%

Endpoints- Composite clinical score Worsened (died, hospitalized, worsened heart failure,

demonstrated worsening in NYHA class at last observation carried forward, moderate or marked worsening of patient global assessment score at last observation carried forward, or permanently discontinued CRT because of or associated with worsening heart failure

Improved (not worsened as defined above and demonstrated improvement in NYHA class at last observation carried forward or had moderate or marked improvement in patient global assessment score at last observation carried forward)

Unchanged (the patient was neither improved nor worsened)

Copyright ©2008 American Heart Association

Chung, E. S. et al. Circulation 2008;117:2608-2616

PROSPECT RESULTS: CCS and LVESV response rates

Table 5. Sensitivity, Specificity, and Area Under the Curve for Primary End Points

CCS

LVESV

Echocardiography

Type

Dyssynchrony Measure

Evaluable Echocardiograms,

(yield) %

Sensitivity, %

Specificity, %

AUC

P for AUC

Sensitivity, %

Specificity, %

AUC

P for AUC

M mode SPWMD 71.7 55.4 (48.3–

62.3) 50.0 (39.1–

60.9) 0.54 0.27 63.6 (54.8–

71.8) 52.1 (41.6–

62.4) 0.62 0.003

IVMD 92.4 55.2 (48.9–61.4)

56.4 (46.9–65.6)

0.58 0.013 59.7 (51.5–67.6)

54.1 (44.8–63.2)

0.59 0.009

LVFT/RR 85.3 36.3 (30.2–42.7)

76.6 (67.5–84.3)

0.57 0.032 41.0 (32.9–49.5)

74.1 (65.0–81.9)

0.60 0.007

Pulsed Doppler

LPEI 94.6 66.3 (60.2–72.0)

47.1 (38.0–56.4)

0.60 0.001 72.0 (64.3–78.8)

42.4 (33.6–51.6)

0.59 0.014

M mode+ Doppler LLWC 60.7 6.3 (3.2–11.0)

91.7 (82.7–96.9)

0.52 0.63 9.5 (4.7–16.8)

92.9 (85.3–97.4)

0.50 0.98

Ts (Lat-Sep) 66.8 42.4 (34.4–50.7)

56.9 (44.7–68.6)

0.50 0.85 52.6 (42.1–63.0)

69.2 (57.8–79.2)

0.61 0.012

Ts-SD 50.0 74.1 (65.2–81.8)

35.3 (22.4–49.9)

0.60 0.034 77.5 (66.0–86.5)

30.6 (19.6–43.7)

0.55 0.35

TDI, published

PVD 81.4 67.6 (60.3–74.3)

37.8 (27.8–48.6)

0.51 0.89 67.8 (58.6–76.1)

34.4 (25.0–44.8)

0.55 0.30

TDI+SRI DLC 81.1 41.7 (34.4–49.2)

60.4 (49.6–70.5)

0.51 0.75 43.6 (34.4–53.1)

59.4 (48.9–69.3)

0.51 0.75

Ts-peak displacement

37.4 54.8 (43.5–65.7)

56.1 (39.7–71.5)

0.56 0.32 58.0 (43.2–71.8)

54.5 (38.8–69.6)

0.57 0.25 TDI, median value used as cutoff

Ts-peak basal 82.0 51.9 (44.4– 53.8 (43.1– 0.55 0.19 52.1 (42.8– 55.7 (45.2– 0.57 0.10

Area Under the Curve

Sen

sitiv

ity

1-Specificity

Sen

sitiv

ity

1-Specificity

Odds ratios fora binary markerOdds ratios fora binary marker

PROSPECT Conclusions Echocardiographic measures of dyssynchrony

aimed at improving patient selection criteria for CRT did not have a clinically relevant impact on improving response rates

Echocardiographic parameters assessing dyssynchrony do not have enough predictive value to be recommended as selection criteria for CRT beyond current indications

Current ACC/AHA/NASPE 2005 Guideline Update Patients with LVEF 35%, sinus rhythm,

and New York Heart Association functional class III or ambulatory class IV symptoms despite recommended optimal medical therapy and who have cardiac dyssynchrony, which is currently defined as a QRS duration >120 ms, should receive CRT unless contraindicated (Class: I, Level of Evidence: A).

Other roles for Echo in CRT Assess LVEF Assess pre- and post-valvular regurgitation Assess best location of lead placement

Future directions >30% non-responders consistent through most

trials Studies should aim to characterize the non-

responders