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Journal review Trials on cardiac resynchronization therapy.

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Presentation on theme: "Journal review Trials on cardiac resynchronization therapy."— Presentation transcript:

1 Journal review Trials on cardiac resynchronization therapy

2 Early trials Randomised controlled trials Specific issues – NYHA I/II – AF – Narrow QRS – Upgradation of pacemaker – Echo assessment of dyssynchrony – Role of CMR

3 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



6 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

7 MUSTIC-SR Single blind,randomised,crossover study NYHAIII,SR,EF 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

8 MUSTIC-SR results


10 MUSTIC-AF Same study design,41 pts Significant imprvt,magnitude less than SR grp

11 MUSTIC-AF results

12 MIRACLE first prospective, randomized,double blind,parallel-controlled clinical trial Idiopathic or ischemic dilated cardiomyopathy, NYHA class III/IV, LVEF 55 mm,QRS>130 ms,6min.walk<450 m CRT(n=228) Vs control(n=225) for 6 mths



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


17 NYHA II subgroup(MIRACLE-ICD)

18 CONTAK-CD randomized controlled, double-blind study 6-month parallel control study design NYHA II–IV,LVEF 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

19 COMPANION 1520 patients,NYHA III or IV,ischemic or nonischemic cardiomyopathy,LVEF 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

20 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 %



23 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


25 CARE-HF Mortality benefit with CRT alone not significant in COMPANION NYHA class III or IV,LVEF 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



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

29 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

30 ESC guidelines

31 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

32 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





37 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

38 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

39 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

40 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

41 ESC guidelines

42 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)


44 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


46 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

47 ESC guidelines

48 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)

49 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

50 ESC guidelines

51 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

52 Echocardiographic assessment of dyssynchrony





57 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




61 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


63 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 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)

64 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)





69 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

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