Cardiac Resynchronization Therapy and ICD

CRT

Terminology

• CRT = Cardiac Resynchronization Therapy.
  
• Biventricular pacing = Simultaneous pacing from the standard right ventricular pacing site and the lateral or posterolateral left ventricle wall site.
  

General information

• A new promising non pharmacological treatment for chronic heart failure. A compliment to but not substitute for optimal medical therapy.
• Benefit for further improvement of quality of life and less hospitalization from those patients who were considered to have maximal benefit from optimal medical therapy has been established from few recent randomized trials. CARE-HF is the first randomized trial that demonstrated the all cause mortality benefit ( N Engl J Med. 2005 Apr 14;352(15):1539-49).
• These trials tested patients in NYHA III and IV (mostly III).

Theory and technical aspect

• 25% of the advanced LV systolic dysfunction patients have inter and intraventricular conduction abnormality (BBB and/or IVCD), usually assessed by surface electrocardiogram QRS width of > 120 ms It usually associates with higher morbidity and mortality.
• This conduction abnormality creates discoordination of left ventricular contraction and has been demonstrated to reduce systolic ejection indices, stroke volume, cardiac output, ejection fraction. The end systolic volume increases, elevating wall stress and stimulating further growth and remodeling. The energy consumption increases. There is a higher incidence of arrhythmia due to late stretch-activated secondary calcium release. Mitral regurgitation is exacerbated.
• How CRT works to benefit heart failure patients is not well understood. CRT is an attempt to improve the left ventricular contraction coordination by early stimulation of the late activation part (usually the LV lateral wall). The current left ventricular lead is in the left lateral or posterolateral ventricular branch of the coronary vein.

  Video of LV wall strain 1. Normal, 2. Dilated cardiomyopathy (Click at the arrow head at the left lower corner of the picture to start each cardiac cycle). From Curry CW, Nelson GS, Wyman BT, Declerck J, Talbot M, Berger RD, McVeigh ER, Kass DA. Circulation. 2000 Jan 4;101(1):E2.

Current CRT recommendation

• On optimal medical therapy.
• Not during acute decompensation. No primary valvular disease. No hypertrophic cardiomyopathy.
• LVEF < 35%, LVEDD (Left ventricular end diastolic dimension of > 55-60 mm by echocardiogram is also included in some trials.)
• NYHA class III (and IV).
• QRS duration > 120 - 150 (mostly > 130) ms
  - Newer techniques for identifying LV asynchrony are being investigated, i.e. MRI; PET scan; Tissue Doppler Imaging (TDI). These procedures may improve patient selection. The latter technique is likely to be readily available sooner.
  - Note that shortening of QRS duration by CRT does not consistently correlate with clinical improvement, and QRS duration may not be a good criteria for patient selection.
• Contraindication or non suitable cases:
  • CRT should be delayed until acute or unstable cardiac conditions and concomitant illness have resolved or become more stable.
  • Bacteremia.
  • Severe bleeding disorders.
  • Terminal disease with short life expectancy (1 year).
  • Poor quality of life from co morbidity illness.

Expected result

• For patients with characteristics similar to those in the trials.
• 1/2 - 2/3 attained significant quality of life improvement (The responder patients). The end points of most trials include NYHA class, 6 minute walk or exercise capacity and duration, peak VO2, quality of life questionnaires, and decrease hospitalization. It should be noted that there was fair amount of placebo effect as expected in medical device treatment.
• CARE-HF demonstrated all cause mortality reduction.
• Successful LV lead implantation is up to 80 - 90% in experienced operators. Further improvement of lead technology and implantation technique are expected, including more epicardial lead insertion techniques.
• Implantation complications exist but are considered acceptable with experienced operators.

Potential future patient candidate

• Atrial fibrillation. Likely will need AV nodal ablation to ensure complete pacing control.
• Patients who already have standard pacing for bradycardia, an update to CRT, since RV pacing may be detrimental to heart failure patients.
• Utilizing other criteria for diagnosis LV dyssynchrony rather QRS duration.
• Patients who will receive ICD. (See ICD below)

Unanswered issues

• How does CRT work to benefit heart failure patients?
• How to better select the "responder" patients.
• Do patients with RBBB receive the same result as LBBB?
• Where is the best LV stimulation site and is LV pacing alone as effective as biventricular pacing?
• Is RV pacing detrimental to heart failure patients? (MOST, DAVID, MADIT II and PAVE trials).
• Benefit in patients in NYHA I and II, since CRT appears to improve remoldering.

ICD

• Primacy prevention of arrhythmic death in patients with poor LV systolic function.
• Does not improve quality of life.
• There are 3 recent trials that showed significant mortality benefit from ICD.
  1. MADIT II
     Mortality benefit in post MI patients (ICD was implanted in between 1-3 months post MI) with EF < 30%. Patients did not have to have CHF, did not have to have arrhythmic indication for ICD. Patients were in NYHA class I - III. There was no QRS duration criteria (Medicare however added another criteria of QRS duration > 120 ms based on subset group analysis). It should be noted that patients were hospitalized with heart failure more often in ICD group.
  2. COMPANION
     Hospitalization reduction and mortality benefit of ICD plus CRT. Patients had EF < 30%, and in NYHA class III and IV. They were in both ischemic and non ischemic type. They had QRS duration of > 120 ms and LVEDD of > 60 mm. Note that CRT alone had all cause mortality (not combine with hospitalization) benefit trend but not statistically significant when the trial was terminated prematurely by the safety monitoring board.
  3. SCD-HeFT
     Comparing medical therapy, amiodarone therapy and ICD in patient with low LVEF (<35%) from both ischemic and non ischemic origin. Patients were in NYHA class II (70%) - III. There was no QRS duration criteria, which is similar to MADIT II. The back up pacemaker was programmed to VVI at low rate of 50 along with hysteresis down to 34.
• Current ICD recommendation for primary prevention of arrhythmic death in low LV systolic function patients. CMS has added new ICD indications for heart failure patients.

Additional CMS coverage (1/2005)

• Patients with ischemic cardiomyopathy who experienced an MI >40 days previously and who have NYHA class 2-3 HF and an LVEF <35%.
• Patients with nonischemic dilated cardiomyopathy (DCM) for at least 9 months* who have NYHA class 2-3 HF and an LVEF <35%.
• Patients who meet existing reimbursement eligibility for cardiac resynchronization therapy (CRT) and have NYHA class 4 HF.
  
  * "Since the data are less convincing for patients with nonischemic DCM of less than nine months, they will need to be entered into a data collection system that is more sophisticated, such as a clinical trial or registry containing longitudinal data," Dr Steve Phurrough, director of the CMS Coverage and Analysis Group,

• Contraindication or non suitable cases:
  • ICD should be delayed until acute or unstable cardiac conditions and acute concomitant illness have resolved or become more stable.
  • Bacteremia.
  • Severe bleeding disorders.
  • Terminal disease with short life expectancy.
  • Poor quality of life from co morbidity illness.
    
• The cost of this treatment is significant high initially but cost-effective analysis compares costs per life-year saved of ICD treatment on MADIT II criteria favorably with coronary stenting in patients with angina and single vessel coronary artery disease or hypertension therapy.

ICD with CRT

• ICD has been proven to improve mortality by preventing ventricular arrhythmic sudden death.
• CRT has been proven to improved quality of life, reverse LV remodeling, decrease heart failure hospitalization and trend to improve mortality.
• Combining the 2 treatments appear attractive and in fact FDA has approved such the devices.
• Current ICD + CRT recommendation
  • If the patient has criteria for CRT at the ICD implantation time or vice versa.
  • Adding CRT to ICD may be considered in patients with low LVEF in NYHA class II-III, particularly if the patient is expecting to have RV pacing most of the time. There has been several studies that suggest or concern about RV pacing has deleterious effect in patients with low LVEF (MOST, DAVID, MADIT II, PAVE and other trials).
• The cost of this treatment is significant high initially but cost-effective analysis compares costs per life-year saved of ICD treatment on MADIT II criteria favorably with coronary stenting in patients with angina and single vessel coronary artery disease or hypertension therapy.

Randomized control trials for ICD and CRT with mortality benefit in low LVEF patients. (1)

.	CARE-HF	MADIT II		SCD-HeFT (2)		COMPANION
CRT / ICD	CRT	ICD		ICD		ICD&CRT
No. of patients	813	1232		2521		1632
Ischemic CM		Yes		.		.
Both isch and non isch CM	Yes	.		Yes		Yes
.	.	MI >1 month		.		Hosp for HF >1 mo, < 12 month
NYHA	.	I (39%)		.		.
.	III	II - III (57%)		II (70%) III (30%)		III  (CRT 87%) (CRT+ICD 86%)
.	IV (6-7%)	IV (4%)		.		IV (CRT 13%) (CRT+ICD 14%)
LVEF	<35 %	< 30 %		< 35 %		< 30 %
LVED	>30 mm (Index)	.		.		> 60 mm
QRS duration	>120 ms	No		No		> 120 ms
PR	.	.		.		> 150 ms
Arrhythmic criteria	No	No		No		No
Backup pacing (3)	.	Not specified		VVI, 50		CRT pacing.
Optimal Medical Therapy (OMT)	Yes	Yes		Yes		Yes
Concern	.	More HF hosp in ICD group(3)		.		.
Result (Mortality reduction)	CRT	ICD		ICD		CRT		CRT + ICD
• All-cause mortality		31 %	p <0.016	23 %	p <0.007	23.9 %	p <0.12	43.4 %	p <0.002
• Combined all-cause mortality and all-cause hospitalization		.	.	.	.	18.6 %	p <0.015	19.3 %	p <0.005
• Combined all-cause mortality and HF hospitalization		.	.	.	.	35.8 %	p <0.001	39.5 %	p <0.001

(1) ICD therapy for primary prevention of arrhythmic death.
(2) Comparing mortality of OMT, OMT+Amiodarone and OMT + ICD therapy. Amiodarone + OMT was ineffective.
(3) Possible detrimental effect of RV pacing, among other etiologies.

Compare to mortality data from Beta blocker trials

Study	Drug	NYHA	No. of Pts	All-Cause Mortality Reduction		All-Cause Hospitalization Reduction
US Carvedilol	Carvedilol	II - III	1094	65 %	p <0.001	27 %	p <0.036
CIBIS II	Bisoprolol	II - III	2647	34 %	p <0.0001	20 %	p <0.0006
MERIT HF	Metoprolol_succinate (Metoprolol CR/XL)	II - III	3991	34 %	p <0.0062	18 %	p <0.004
COPERNICUS	Carvedilol	(III) - IV	2289	35%	p <0.0014	29 %	p <0.002

This table is an example of how much proper medical therapy can achieve. It emphasizes the important of the Optimal Medical Therapy before and during the devices therapy.

References

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