Journal review

Trials on cardiac resynchronization therapy

• Early trials• Randomised controlled trials• Specific issues

– NYHA I/II– AF– Narrow QRS– Upgradation of pacemaker– Echo assessment of dyssynchrony– Role of CMR

• Cazeau et al ,1994– 54yr,NYHA IV,LBBB,QRS dur200 ms– Temp. 4 chamber pacing-improved hemodynamics– Permanent 4 chamber pacing-6 wks-marked

clinical imprvt• Observational studies• Epicardial leads to transvenous leads• Various pacing sites

PATH-CHF

• First randomised controlled trial,2001• 42 pts,NYHA III/IV,ischemic or non ischemic,SR,QRS

120ms,PR 150ms• Univentricular Vs biventricular pacing• Primary endpoints-Oxygen consumption at peak exercise

and at anerobic threshold,6-minute walk distance • Secondary endpoints-changes in New York Heart

Association functional class, hospitalization frequency and quality of life

• Trend towards improvement in all primary &sec endpts with biventricular pacing

MUSTIC-SR

• Single blind,randomised,crossover study• NYHAIII,SR,EF<35%,LVEDD>60,QRS>150ms,6min

walk<450m• 47pts completed• Randomised to resynchronization or to no pacing for 3

mth,crossed over to alternative group for 3 mths,followed up for 12 mths

• Primary endpt-6-min walked distance• Sec-peak Vo2, quality of life, NYHA class,worsening HF,total

mortality• Significant improvement

MUSTIC-SR results

MUSTIC-AF

• Same study design,41 pts• Significant imprvt,magnitude less than SR grp

MUSTIC-AF results

MIRACLE

• first prospective, randomized,double blind,parallel-controlled clinical trial

• Idiopathic or ischemic dilated cardiomyopathy, NYHA class III/IV , LVEF<35 %,LVEDD> 55 mm,QRS>130 ms,6min.walk<450 m

• CRT(n=228) Vs control(n=225) for 6 mths

MIRACLE ICD

• Trial design similar to MIRACLE• CRT+ICD Vs CRT• Included NYHA II also,all pts had class I

indication for ICD

NYHA II subgroup(MIRACLE-ICD)

CONTAK-CD

• randomized controlled, double-blind study• 6-month parallel control study design• NYHA II–IV ,LVEF< 35%, QRS>120 ms,indication for an ICD.• 581 patients were randomized, 248 into 3 mth crossover

study and 333 into the 6-month parallel controlled trial.• Primary endpnt was a composite of mortality,

hospitalizations for HF &VT/VF-insignificant trend favoring CRT grp

• Sec endpts-peak Vo2, 6-min.walk distance, quality of life, and NYHA class-significant imprvnt in CRT grp

• Imprvmnt NYHA class III–IV subgroup

COMPANION

• 1520 patients,NYHA III or IV ,ischemic or nonischemic cardiomyopathy,LVEF<35%, QRS ≥120 msec,PR int>150 ms, sinus rhythm, no clinical indication for pacemaker or ICD

• Randomly assigned in a 1:2:2 ratio to receive OMT,OMT+CRT,OMT+CRT-D

• Primary composite endpt-death from or hospitalization for any cause

• Sec endpt-death from any cause• Death from or hospitalization for cardiovascular causes and

death from or hospitalization for heart failure also noted

• Implantation successful in 87% in CRT,91% in CRT-D

• Follow-up 11.9 months OMT,16.2 months in CRT,15.7 months in CRT-D

• CRT&CRT-D reduced the risk of the primary end point by 20 %

• Death from or hospitalization for heart failure– reduced by 34 percent in the pacemaker

group(P<0.002)– 40 percent in the pacemaker–defibrillator group

(P<0.001)• Death from any cause reduced by

– 24 percent (P=0.059) in CRT– 36 percent (P=0.003) in CRT-D

CARE-HF

• Mortality benefit with CRT alone not significant in COMPANION• NYHA class III or IV,LVEF<35%,LVEDD>30 mm (indexed to

height),QRS≥150 ms/>120 ms +echo evidence of dyssynchrony,SR,no indication for pacing

• Primary end point-composite of death from any cause or an unplanned hospitalization for a major cardiovascular event

• Secondary outcome-death from any cause,composite of death from any cause and hospitalization with heart failure,NYHA class and quality of life

• OMT-404 patients Vs OMT+CRT-409,mean follow-up 29.4 mths

• McAlister et al,2004-meta-analysis of several CRT trials- HF hospitalizations were reduced by 32% and all-cause mortality by 25%

AHAscience advisory-2005,guidelines 2008,update 2009

• Sinus rhythm• LVEF <35%• Ischemic or nonischemic cardiomyopathy• QRS complex duration 120 ms• NYHA functional class III or IV• Maximal pharmacological therapy for heart

failure

ESC guidelines

CRT in NYHA I/II

• MIRACLE ICD,CONTAK CD-earlier trials• MADIT CRT,REVERSE-reduced morbidity• MADIT CRT

– 1820 patients – Ischemic I/II or nonischemic cardiomyopathy II– EF 30% or less– QRS duration of ≥130msec– NYHA I/II

• 3:2 ratio,CRT+ICD(n=1089) Vs ICD alone (n=731) • Follow-up of 2.4 years

• Primary end point:death or heart failure– CRT–ICD group (17.2%)Vs ICD-only group (25.3%)

(hazard ratio=0.66; P = 0.001)• 34% reduction in the risk of death or heart

failure• Superiority of CRT was driven by a 41%

reduction in the risk of heart-failure events,primarily in subgroup with a QRS >150 ms

REVERSE

• NYHA Class II or I (previously symptomatic),QRS 120 ms; LVEF 40%; LVEDD 55 mm ,SR,Optimal medical therapy (OMT)

• 610 pts,12 mth follow up

• Primary Composite endpoint : all-cause mortality, HF hospitalizations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in double blind manner

• Secondary: Left Ventricular End Systolic Volume Index

• No significant difference primary end point• Significant degree of reverse LV remodelling was

observed in CRT, manifested by decreases in the LVESV&LVEDV and increase in LVEF

• LV end-systolic volume index was significantly smaller in CRT grp

• MADIT-CRT and REVERSE enrolled a small proportion of asymptomatic patients, only 15% and 18%, respectively

• NYHA class I, MADIT-CRT did not show significant reduction in the all-cause mortality or HF by CRT over ICD

• REVERSE-trend toward less clinical efficacy conferred by CRT among class I compared to class II

ESC guidelines

CRT in AF

• Prevalence of AF in patients with HF-5% in NYHA I as compared with 25–50% in NYHA III/IV

• Intrinsic AF rhythm reduces the percentage of effectively biventricular paced captured beats (BVP%).

• Effective ‘CRT-dose’ may be reduced compared to atrial-synchronous rhythm with a short AV interval (as in SR)

• MUSTIC AF first randomized trial demonstrating possible benefits of CRT in HF in pts with permanent AF

• Two trials comparing CRT in SR Vs AF-comparable but benefit more in SR-Leclercq et al (AJC 2000),Molhoek et al (AJC 2004)

• OPSITE trial- ‘rate control’ by AVJ ablation significantly improved symptoms &functional status

• PAVE trial-‘ablate and pace’ approach-greater benefit of the BVP mode in patients with depressed LVEF (45%) and/or in NYHA functional class III

• 5 studies followig a total of 1,164 patients• Mortality was not significantly different at 1

year• NYHA class improved similarly both groups• SR patients showed greater relative

improvement in 6-min walk&Minnesota score• AF patients-statistically significant greater

change in ejection fraction

ESC guidelines

Upgradation to biventricular pacing

• small prospective studies• Clinical benefit of upgrading to biventricular pacing

with long-standing right ventricular pacing, severe ventricular dysfunction, NYHA class III symptoms, regardless of QRS duration- Vatankulu MA et al(AJC 2009),Paparella G(Pacing clin ele 2010)

• Detrimental effects of RV pacing on symptoms and LV function in patients with HF of ischaemic origin and preserved LVEF (Kindermann M et al ,HOBIPACE-JACC 2006)

• In patients with a conventional indication for pacing, NYHA III/IV symptoms, an LVEF of ≤35%, and a QRS width of ≥120 ms,CRT-P/CRT-D is indicated.

• RV pacing will induce dyssynchrony• Chronic RV pacing in patients with LV

dysfunction should be avoided• CRT may permit adequate up-titration of B-

blocker

ESC guidelines

CRT in narrow QRS

• RethinQ study• Patients with a indication for ICD,LVEF<35%, NHYA class III

heart failure,QRS<130 ms,echo evidence of dyssynchrony• 172 patients,6 months follow up• Primary end point was the proportion of patients with an

increase in peak oxygen consumption• CRT group and the control group did not differ

significantly in proportion of patients with the primary end point (46% Vs 41%)

• No significant difference in HF events

Echocardiographic assessment of dyssynchrony

PROSPECT

• 498 patients with standard CRT indications• Twelve echocardiographic parameters of dyssynchrony• Positive CRT response were improved clinical composite

score and 15% reduction in LVESV at 6 months• Ability of the 12 echo parameters to predict clinical

composite score response-– sensitivity ranging from 6% to 74%– specificity ranging from 35% to 91%

• No single echocardiographic measure of dyssynchrony may be recommended to improve patient selection for CRT beyond current guidelines

Role of CMR in CRT

• Venous anatomy– assessed noninvasively to determine whether a

transvenous approach is feasible or surgical approach should be used for LV lead placement

• Assessment of dyssynchrony:– 77 patients undergoing CRT, those with a CMR-TSI

≥ 110 ms were more likely to meet the endpoints of death or adverse cardiac events

– Leyva F et al:JACC 2007

• Internal flow fraction fraction (IFF) is defined as the total internal flow as a percentage of stroke volume

• IFF of 10 ± 5% in typical CRT patients (NYHA class III or IV,LVEF < 35%, QRS > 150 ms) and of 1 ± 1% in the healthy controls (p < 0.001)

• IFF cut-off of 4% discriminated b/w patients and controls with 90% sensitivity and 100% specificity.

• Fornwalt et al (JMRI,2008)

• Assessment of scar – White et al-scar burden < 15% as the best cut-off

for predicting a clinical response to CRT• LV lead placement

– pacing outside the LV free wall scar is associated with a better response than pacing over thescar (86% vs 33%, p = 0.004)

Conclusion

• CRT is an accepted modality of treatment with mortality benefit in NYHA III/IV HF

• Reduce morbidity in NYHA II• No evidence of benefit in HF with narrow QRS• In AF with III/IV HF reduces morbidity&AV nodal

ablation may be necessary• Echo parameters of dyssynchrony not proven to be

useful• CMR may prove to be useful to assess dyssynchrony

and feasibility of CRT