Cardiac Resynchronization Therapy for Heart Failure

Patient Selection and Clinical Outcomes

Edited by A kharazi M.Dcardiac electrophysiologist

Heart Failure (HF) Definition

A complex clinical syndrome in which the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return.

Etiology of Heart Failure

What causes heart failure?• The loss of a critical quantity of functioning

myocardial cells after injury to the heart due to:– Ischemic Heart Disease – Hypertension – Idiopathic Cardiomyopathy– Infections (e.g., viral myocarditis, Chagas’ disease)– Toxins (e.g., alcohol or cytotoxic drugs) – Valvular Disease – Prolonged Arrhythmias

Prevalence of HF by Age and Gender

United States: 1988-94

0

2

4

6

8

10

Percent of Population

20-24 25-34 35-44 45-54 55-64 65-74 75+

Males

Females

Source: NHANES III (1988-94), CDC/NCHS and the American Heart AssociationSource: NHANES III (1988-94), CDC/NCHS and the American Heart Association

New York Heart Association Functional Classification

Class I: No symptoms with ordinary activity

Class II: Slight limitation of physical activity. Rest comfortable but ordinary physical activity results in fatigue,

palpitation, dyspnea, or angina

Class III: Marked limitation of physical activity. Comfortable at

rest, but less than ordinary physical activity results in

fatigue, palpitation, dyspnea, or anginal pain

Class IV: Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may

be present even at rest

Poor Quality of Life for HF patients

Overall perception of health

36

45

55

48

48

52

56

58

70

Heart Failure NYHA Class IV

Heart Failure NYHA Class III

Heart Failure NYHA Class II

Chronic Bronchitis

Valve disease symptomatic

AF symptomatic

Angina

Depression

General population

Adjusted SF 36 means

Hobbs FDR, et al. Eur Heart J 2002;23:1867-1876

Doug Smith:Doug Smith:

MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). intervention trial in congestive heart failure (MERIT-HF). LANCET. LANCET. 1999;353:2001-07.1999;353:2001-07.

Severity of Heart FailureModes of Death

12%12%

24%24%

64%64%

CHFCHF

OtherOther

SuddenSuddenDeathDeath

n = 103n = 103

NYHA IINYHA II

26%26%

15%15%

59%59%

CHFCHF

OtherOther

SuddenSuddenDeathDeath

n = 103n = 103

NYHA IIINYHA III

56%56%

11%11%

33%33%

CHFCHF

OtherOther

SuddenSuddenDeathDeath

n = 27n = 27

NYHA IVNYHA IV

Volume Volume OverloadOverload

Pressure Pressure OverloadOverload

Loss of Loss of MyocardiumMyocardium

Impaired Impaired ContractilityContractility

LV DysfunctionLV DysfunctionEF < 40%EF < 40%

Cardiac Cardiac OutputOutput

Hypoperfusion Hypoperfusion

End Systolic Volume End Systolic Volume

End Diastolic Volume End Diastolic Volume

Pulmonary Congestion Pulmonary Congestion

Left Ventricular Dysfunction

Treatment Approach for the Patient with Heart Failure

Stage AStage A

At high risk, no At high risk, no structural diseasestructural disease

Stage BStage B

Structural heart Structural heart disease, disease,

asymptomaticasymptomatic

Stage DStage D

Refractory HF Refractory HF requiring requiring

specialized specialized interventionsinterventions

TherapyTherapy

• Treat HypertensionTreat Hypertension

• Treat lipid Treat lipid disordersdisorders

• Encourage regular Encourage regular exerciseexercise

• Discourage alcohol Discourage alcohol intakeintake

• ACE inhibitionACE inhibition

TherapyTherapy

• All measures All measures under stage Aunder stage A

• ACE inhibitors in ACE inhibitors in appropriate appropriate patientspatients

• Beta-blockers in Beta-blockers in appropriate appropriate patientspatients

TherapyTherapy

• All measures All measures under stage Aunder stage A

Drugs:Drugs:

• DiureticsDiuretics

• ACE inhibitorsACE inhibitors

• Beta-blockersBeta-blockers

• DigitalisDigitalis

• Dietary salt Dietary salt restrictionrestriction

TherapyTherapy

• All measures All measures under stages A,B, under stages A,B, and Cand C

• Mechanical assist Mechanical assist devicesdevices

• Heart Heart transplantationtransplantation

• Continuous (not Continuous (not intermittent) IV intermittent) IV inotropic infusions inotropic infusions for palliationfor palliation

• Hospice careHospice care

Stage CStage C

Structural heart Structural heart disease with disease with prior/current prior/current

symptoms of HFsymptoms of HF

Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001Chronic Heart Failure in the Adult, 2001

Diuretics, ACE Inhibitors

Reduce the number of sacks on the wagon

ß-Blockers

Limit the donkey’s speed, thus saving energy

Digitalis Compounds

Like the carrot placed in front of the donkey

Ventricular Dysynchrony

• Abnormal ventricular conduction resulting in a mechanical delay– Wide QRS (IVCD); typically LBBB morphology– Poor systolic function– Impaired diastolic function

ECG depicting interventricular conduction delayECG depicting interventricular conduction delay

Prevalence of Ventricular Dyssynchrony in Heart Failure

Left Bundle Branch Block More Prevalent with Impaired LV Systolic Function

38%

24%

8%

Moderate/SevereHF (2)

Impaired LVSF(1)

Preserved LVSF(1)

1. Masoudi, et al. JACC 2003;41:217-232. Aaronson, et al. Circ 1997;95:2660-7

Elements of Cardiac Dyssynchrony

Atrio-ventricular

Inter-ventricular

Intra-ventricular

Cazeau, et al. PACE 2003; 26[Pt. II]: 137–143

Intra-ventricular DyssynchronySeptal-Posterior Wall Motion Delay

• Difference in times from peak excursions of the septum and of the posterior wall at the papillary muscle level

• SPWMD 130 ms predicted response (LVEDVi) to CRT in study of 25 pts with QRS 140 ms1 From parasternal short-axis

view at papillary muscle level

1. Pitzalis M, et al. JACC 2002;40:1615-1622

septum

Posteriorwall

Parasternal Long-axis View Shown

Animation – Ventricular Dysynchrony

Click to Start/StopClick to Start/Stop

11 Tavazzi L. Eur Heart J 2000;21:1211-1214. Tavazzi L. Eur Heart J 2000;21:1211-1214.22 Shenkman et al. Shenkman et al. CirculationCirculation 2000; 102(18):Suppl II, abstract 2293. 2000; 102(18):Suppl II, abstract 2293.

Etiology of Ventricular Dysynchrony

• What Causes Ventricular Dysynchrony?1

– Inter- or intraventricular conduction delays usually manifested as left bundle branch block

– Regional wall motion abnormalities with increased workload and stress—compromising ventricular mechanics

– Disruption of myocardial collagen matrix impairing electrical conduction and mechanical efficiency

• Estimated that 15% of all HF patients have ventricular dysynchrony2

Clinical Consequences of Ventricular Dysynchrony

• Abnormal interventricular septal wall motion1

• Reduced dP/dt3

• Reduced diastolic filling time1,2

• Prolonged MR duration1,2

11 Grines CL, Bashore TM, Boudoulas H, et al. Grines CL, Bashore TM, Boudoulas H, et al. CirculationCirculation 1989;79:845-853. 1989;79:845-853. 2 2 Xiao, HB, Lee CH, Gibson DG. Xiao, HB, Lee CH, Gibson DG. Br Heart J Br Heart J 1991;66:443-447.1991;66:443-447. 33 Xiao HB, Brecker SJD, Gibson DG. Xiao HB, Brecker SJD, Gibson DG. Br Heart J Br Heart J 1992;68:403-407.1992;68:403-407.

Click to Start/StopClick to Start/Stop

Deleterious Effects of VentricularDyssynchrony on Cardiac Function

Reduced diastolic filling time 1

+ Weakened contractility 2

+ Protracted mitral regurgitation 2

+ Post systolic regional contraction 3

= Diminished stroke volume

1. Grines CL, et al Circulation 1989;79: 845-853 2. Xiao HB, et al Br Heart J 1991;66: 443-447 3. Søgaard P, et al. J Am Coll Cardiol 2002;40:723–730

Courtesy of Ole-A. Breithardt, MD

Cardiac Resynchronization Therapy

• The therapeutic intent of atrial-synchronized, biventricular pacing is to restore ventricular synchrony

• Complements drug therapy

Cardiac Resynchronization Therapy

Goals

• Improve hemodynamics

• Improve Quality of Life

Cardiac Resynchronization Therapy

• Cardiac resynchronization, in association with an optimized AV delay, improves hemodynamic performance by forcing the left ventricle to complete contraction and begin relaxation earlier, allowing an increase in ventricular filling time.

• Coordinate activation of the ventricles and septum.

ECG depicting cardiac resynchronizationECG depicting cardiac resynchronization

ECG depicting IVCDECG depicting IVCD

Cardiac Resynchronization Therapy

Increase the donkey’s (heart) efficiency

Achieving Cardiac Resynchronization

Goal: Atrial synchronous biventricular pacing

Transvenous approach for left ventricular lead via coronary sinus

Back-up epicardial approach

Doug Smith:Doug Smith:

Right AtrialLead

Right VentricularLead

Left VentricularLead

• Transvenous Approach– Standard pacing leads in RA and RV– Specially designed left heart lead placed in a left ventricular

cardiac vein via the coronary sinus

Achieving Cardiac ResynchronizationMechanical Goal: Pace Right and Left Ventricles

Cardiac Resynchronization SystemCardiac Resynchronization System

Proposed Mechanisms of Cardiac Resynchronization

• Improved Contraction Pattern

• AV Interval Optimization

Click to Start/StopClick to Start/Stop

0.14

0.16

0.18

0.20

0.22

0.24

500 600 700 800 900 1000

dP/dtmax (mmHg/s)

MV

O2/

HR

(R

elat

ive

Uni

ts)

LV Pacing

Dobutamine

Nelson et al. Nelson et al. CirculationCirculation 2000;102:3053-3059. 2000;102:3053-3059.

CRT Improves Cardiac Function at Diminished Energy Cost

p< 0.05

CRT Improves Cardiac Function at 6 Months in Moderate to Severe Heart Failure

0

2

4

6

P<0.001

P=0.12

P=0.029

LVEFAvg. Change(Absolute %)

-3

-2

-1

0

MIRACLE MIRACLE ICD Contak CD

P<0.001

P=0.58

Data sources: MIRACLE: Circulation 2003;107:1985-1990MIRACLE ICD:JAMA 2003;289:2685-2694Contak CD: J Am Coll Cardiol 2003;2003;42:1454-1459

Control CRT

MR Jet AreaAvg. Change

(cm2) Not Reported

Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk10

15

20

25

30

35

40

*

* †

*

*

*

†

†

Mitr

al r

egur

gita

tion

(%)

MR area

Baseline 1wk 1mo 3mo off-immed off-1wk off-4wk

100

125

150

175

200

225

**

*

*

†

* *

*

†

Left

ven

tric

ular

vol

ume

(mL) *

LV End Systolic and Diastolic Volumes

LV Reverse Remodeling after CRT

Pacing No pacing

N = 25Yu CM, et al, Circulation 2002;105:438-445

Mortality/Morbidity Comparison

Risk reduction with CRT or CRT + ICD

Study (n random.)

Follow-up

Treat-ment

Mor-tality

& Hosp.

Mortal. & HF Hosp.

Mor-tality

HF Mort.

HF Hosp.

MIRACLE1

(n=453)6 M CRT 39% 27% 50%

JAMA meta-analysis2 (n=1634)*

3-6M CRT 23% 51% 29%

P < 0.05

* Includes MIRACLE

Date Sources: 1. Abraham WT, et al. N Engl J Med 2002;346:1845-53 2. Bradley DJ, et al. JAMA 2003;289:730-740

CRT Improves Submaximal Exercise

Distance Walked in 6 MinutesDistance Walked in 6 Minutes Change from Baseline*Change from Baseline*

00

1010

2020

3030

4040

5050

6060

00 33 66Follow-up Period (Month)Follow-up Period (Month)

Met

ers

Met

ers

11* Paired median changeError bars are 95% CI.

P=0.004P=0.004

P=0.003P=0.003P=0.005P=0.005

Baseline (meters)Baseline (meters)

291 ± 101

305 ± 85

Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853

CRTCRT

ControlControl

CRT Improves Patients’ Quality of Life

Minnesota Living with Heart Failure QuestionnaireMinnesota Living with Heart Failure Questionnaire

Baseline (score)Baseline (score)

59 ± 21

59 ± 20

Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853

* Paired median changeError bars are 95% CI.

Change from Baseline*Change from Baseline*

00

55

1010

1515

2020

2525

00 33 66Follow-up Period (Month)Follow-up Period (Month)

Sco

re I

mp

rove

men

t (p

oin

ts)

Sco

re I

mp

rove

men

t (p

oin

ts)

11

P=0.001P=0.001P<0.001P<0.001P<0.001P<0.001

CRTCRT

ControlControl

CRT Improves NYHA Functional Class

00

2020

4040

6060

8080

100100

120120

Nu

mb

er o

f P

atie

nts

Nu

mb

er o

f P

atie

nts

Improved 2 orImproved 2 ormore classesmore classes

Improved 1Improved 1classclass

No ChangeNo Change WorsenedWorsened

ControlControl CRTCRT

6%6%

32%32%

59%59%

4%4%

16%16%

52%52%

30%30%

2%2%

P<0.001P<0.001

Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853

CRT Improves Exercise Capacity in Moderate to Severe Heart Failure

-20

0

20

40

60 P<0.001 P=0.36 P=0.029

P<0.0016 Min WalkAvg. Change

(m)

000

1

2

3

MIRACLE MUSTIC SR MIRACLE ICD Contak CD

P<0.001

P=0.029

P=0.04P=0.003

Data sources:MIRACLE: Circulation 2003;107:1985-90MUSTIC SR: NEJM 2001;344:873-80MIRACLE ICD:JAMA 2003;289:2685-94Contak CD: J Am Coll Cardiol 2003;2003;42:1454-59

Control CRT

Peak VO2

Avg. Change (mL/kg/min)

Optimizing VV Delay Based on Aortic VTI

• Obtain Pulsed Wave Doppler of LVOT with several different sequential ventricular paced intervals

• Select the setting yielding the largest VTI as the optimal paced interval

• CSA is assumed constant, therefore optimal delay is based on VTI alone

LV first by 4 ms

LV first by 20 ms

RV first by 40 ms

Relative Cost of CRT

Cost per patient

$0$20$40$60

CRT+ICD

CRT

Hip/ knee replace

PTCA

CABG

Dialysis

$ thousands

Total Annual Expenditures

$0 $5 $10 $15 $20

$ Billions

Doug Smith:Doug Smith:

CRT: Moderate to severe systolic heart failure with wide QRS

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

Patient Indications

CRT device:

– Moderate to severe HF (NYHA Class III/IV) patients

– Symptomatic despite optimal, medical therapy

– QRS 130 msec

– LVEF 35%

CRT plus ICD:

– Same as above with ICD indication

Cardiac Resynchronization Therapy

– is safe and well tolerated

– improves quality of life, functional class, and exercise capacity

– Improves cardiac function and structure

– improves heart failure composite response

– may have a favorable effect on combined measures of morbidity and mortality

In NYHA Class III and IV systolic heart failure In NYHA Class III and IV systolic heart failure patients with intraventricular conduction delays, patients with intraventricular conduction delays, cardiac resynchronization therapy:cardiac resynchronization therapy:

Abraham WT, Fisher WG, Smith AL, et al. Abraham WT, Fisher WG, Smith AL, et al. N Engl J MedN Engl J Med 2002;346:1845-1853 2002;346:1845-1853

Conclusions

Summary

• Large number of patients studied in RCTs• Concordant proof that CRT improves

quality of life, exercise capacity, functional capacity– Improvements persist through 1 year

• CRT reduces the risk of mortality and heart failure due to worsening HF

• CRT + ICD reduces risk of mortality• CRT improves cardiac function and

structure