Advances in Cardiac Resynchronization Therapy: Insights from Early Randomized Trials

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<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,worseningHF,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,doubleblind,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

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< 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

19. COMPANION • 1520 patients,NYHA III or IV ,ischemic or nonischemiccardiomyopathy,LVEF<35%, QRS ≥120 msec,PRint>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<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

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 nonischemiccardiomyopathy • QRS complexduration 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 nonischemiccardiomyopathy 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 clinele 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