1. Journal Review-CRT Dr Pradeep Sreekumar Senior Resident Cardiology

2. Rationale for CRT Presence of a bundle branch block or other intraventricular conduction delay can worsen HF due to systolic dysfunction by causing ventricular dyssynchrony Presence of a bundle branch block or other intraventricular conduction delay can worsen HF due to systolic dysfunction by causing ventricular dyssynchrony Ventricular dyssynchrony exacerbates left ventricular dysfunction Ventricular dyssynchrony exacerbates left ventricular dysfunction Hemodynamic benefits follow the correction of dyssynchrony with CRT Hemodynamic benefits follow the correction of dyssynchrony with CRT

3. CARE-HF trial Randomly assigned 813 patients (mean age 67) with NYHA class III or IV HF (94 percent class III, 62 percent nonischemic), an LVEF ≤35 percent (median 25 percent), and QRS prolongation (median QRS duration 160 msec) to CRT with biventricular pacing and medical therapy or medical therapy alone. Randomly assigned 813 patients (mean age 67) with NYHA class III or IV HF (94 percent class III, 62 percent nonischemic), an LVEF ≤35 percent (median 25 percent), and QRS prolongation (median QRS duration 160 msec) to CRT with biventricular pacing and medical therapy or medical therapy alone.

4. The primary end point The primary end point Major secondary end point was death from any cause. Major secondary end point was death from any cause. Time of death from any cause Unplanned hospitalization for a major cardiovascular event

5. Significant benefits were noted with CRT at a mean of 29 months: Significant benefits were noted with CRT at a mean of 29 months: A reduction in the primary end point (39 versus 55 percent, hazard ratio [HR] 0.63, 95% CI 0.51-0.77). A reduction in the primary end point (39 versus 55 percent, hazard ratio [HR] 0.63, 95% CI 0.51-0.77). The benefit increased over time and did not vary with age, sex, NYHA class, baseline systolic pressure, LVEF, QRS duration, or routine therapies for HF The benefit increased over time and did not vary with age, sex, NYHA class, baseline systolic pressure, LVEF, QRS duration, or routine therapies for HF

6. A reduction in mortality (20 versus 30 percent, HR 0.64, 95% CI 0.48-0.85). A reduction in mortality (20 versus 30 percent, HR 0.64, 95% CI 0.48-0.85). The mortality benefit increased over time and was largely due to a reduction in deaths due to worsening HF (8.1 versus 13.9 percent), with a lesser reduction in SCD (7.1 versus 9.4 percent). The mortality benefit increased over time and was largely due to a reduction in deaths due to worsening HF (8.1 versus 13.9 percent), with a lesser reduction in SCD (7.1 versus 9.4 percent).

7. The mortality benefit for both HF and SCD increased slightly at extended follow-up of 38 months. The mortality benefit for both HF and SCD increased slightly at extended follow-up of 38 months. An increase in LVEF relative to the control arm of 3.7 percent at 3 months and 6.9 percent at 18 months. An increase in LVEF relative to the control arm of 3.7 percent at 3 months and 6.9 percent at 18 months. This was associated with a rise in systolic pressure of about 6 mmHg compared to no CRT (median baseline 110 mmHg) and a reduction in plasma N-terminal-pro- brain natriuretic peptide This was associated with a rise in systolic pressure of about 6 mmHg compared to no CRT (median baseline 110 mmHg) and a reduction in plasma N-terminal-pro- brain natriuretic peptide

8. At 90 days, improvements in quality of life and NYHA class was noted. At 90 days, improvements in quality of life and NYHA class was noted.

12. COMPANION trial The COMPANION trial was a study of CRT with and without an ICD in 1520 patients (mean age 67) with The COMPANION trial was a study of CRT with and without an ICD in 1520 patients (mean age 67) with NYHA class III or IV HF NYHA class III or IV HF a QRS duration ≥120 msec a QRS duration ≥120 msec LVEF ≤35 percent (median 21 percent) who had had a hospitalization for HF within the year prior to enrollment. LVEF ≤35 percent (median 21 percent) who had had a hospitalization for HF within the year prior to enrollment. Bristow MR, Feldman AM, Saxon LA. Heart failure management using Bristow MR, Feldman AM, Saxon LA. Heart failure management using implantable devices for ventricular resynchronization: Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure (COMPANION) trial. COMPANION Steering Committee and COMPANION Clinical Investigators. J Card Fail. 2000;6:276– 285.

13. Half of patients enrolled had a nonischemic etiology of HF. Half of patients enrolled had a nonischemic etiology of HF. Patients were randomly assigned to optimal medical therapy, CRT alone, or CRT with an ICD. Patients were randomly assigned to optimal medical therapy, CRT alone, or CRT with an ICD. Medical therapy for HF included angiotensin converting enzyme inhibitors or angiotensin receptor blockers in 89 percent, beta blockers in 66 percent, and spironolactone in 55 percent. Medical therapy for HF included angiotensin converting enzyme inhibitors or angiotensin receptor blockers in 89 percent, beta blockers in 66 percent, and spironolactone in 55 percent.

14. During the course of the study, a significant number of patients in the medical therapy only arm of the trial withdrew to receive a device because of arrhythmia or HF During the course of the study, a significant number of patients in the medical therapy only arm of the trial withdrew to receive a device because of arrhythmia or HF

15. Mean follow-up of 12 months Mean follow-up of 12 months There was a significant reduction in the incidence of the primary composite end point of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared to the medical therapy only arm (HR 0.80, 95% CI 0.68-0.95). There was a significant reduction in the incidence of the primary composite end point of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared to the medical therapy only arm (HR 0.80, 95% CI 0.68-0.95).

16. On subgroup analysis according to baseline characteristics, the primary end point benefit for device versus medical therapy did not vary with age, sex, NYHA class, ischemic or nonischemic origin of the cardiomyopathy, LVEF, or other routine therapies for HF (eg, angiotensin converting enzyme inhibitors, beta blockers etc). On subgroup analysis according to baseline characteristics, the primary end point benefit for device versus medical therapy did not vary with age, sex, NYHA class, ischemic or nonischemic origin of the cardiomyopathy, LVEF, or other routine therapies for HF (eg, angiotensin converting enzyme inhibitors, beta blockers etc). Characteristics associated with an increased absolute rate of SCD included male gender, renal dysfunction, NYHA class IV HF, and an LVEF ≤20 percent. Characteristics associated with an increased absolute rate of SCD included male gender, renal dysfunction, NYHA class IV HF, and an LVEF ≤20 percent.

17. The CRT plus ICD arm and the CRT only arm experienced a significant and an almost significant improvement, in the secondary end point of all-cause mortality alone The CRT plus ICD arm and the CRT only arm experienced a significant and an almost significant improvement, in the secondary end point of all-cause mortality alone (12 and 15 versus 19 percent in the medical therapy only arm, HR for CRT plus ICD versus medical therapy 0.64, 95% CI 0.48-0.86, HR for CRT only versus medical therapy 0.76, 95% CI 0.58-1.01). (12 and 15 versus 19 percent in the medical therapy only arm, HR for CRT plus ICD versus medical therapy 0.64, 95% CI 0.48-0.86, HR for CRT only versus medical therapy 0.76, 95% CI 0.58-1.01).

18. All-cause mortality for CRT plus ICD compared to CRT alone was significantly lower (odds ratio 0.79, 95% CI 0.60-1.06 ) All-cause mortality for CRT plus ICD compared to CRT alone was significantly lower (odds ratio 0.79, 95% CI 0.60-1.06 ) On subgroup analysis,the mortality benefit of CRT plus ICD as compared to medical therapy was significant in nonischemic cardiomyopathy (HR 0.50) and not quite significant in ischemic cardiomyopathy (HR 0.73). On subgroup analysis,the mortality benefit of CRT plus ICD as compared to medical therapy was significant in nonischemic cardiomyopathy (HR 0.50) and not quite significant in ischemic cardiomyopathy (HR 0.73).

19. At three and six months, both CRT arms showed significant improvements in NYHA class, six minute walk distance, and systolic pressure compared to medical therapy alone. At three and six months, both CRT arms showed significant improvements in NYHA class, six minute walk distance, and systolic pressure compared to medical therapy alone. All-cause, cardiac, and HF hospitalization rates were significantly reduced in both CRT arms compared to medical therapy alone - observed within days or weeks of CRT initiation and was sustained throughout the trial All-cause, cardiac, and HF hospitalization rates were significantly reduced in both CRT arms compared to medical therapy alone - observed within days or weeks of CRT initiation and was sustained throughout the trial

20. The mortality benefit in COMPANION began immediately in the CRT plus ICD group compared to eight months with CRT alone. The mortality benefit in COMPANION began immediately in the CRT plus ICD group compared to eight months with CRT alone. Delayed benefit was seen with CRT alone in CARE-HF also. Delayed benefit was seen with CRT alone in CARE-HF also. Suggest that the ICD prevents sudden death from the beginning, while the mortality benefit of CRT requires time for reverse ventricular remodeling. Suggest that the ICD prevents sudden death from the beginning, while the mortality benefit of CRT requires time for reverse ventricular remodeling.

23. Death from or hospitalization for heart failure Death from or hospitalization for heart failure reduced by 34 percent in the pacemaker group(P<0.002) reduced by 34 percent in the pacemaker group(P<0.002) 40 percent in the pacemaker–defibrillator group (P<0.001) 40 percent in the pacemaker–defibrillator group (P<0.001) Death from any cause reduced by Death from any cause reduced by 24 percent (P=0.059) in CRT 24 percent (P=0.059) in CRT 36 percent (P=0.003) in CRT-D 36 percent (P=0.003) in CRT-D

24. PATH-CHF First randomised controlled trial,2001 First randomised controlled trial,2001 42 patients,NYHA III/IV,SinusRhythm,QRS >120ms,PR 150ms 42 patients,NYHA III/IV,SinusRhythm,QRS >120ms,PR 150ms Univentricular Vs biventricular pacing Univentricular Vs biventricular pacing Primary endpoints-Oxygen consumption at peak exercise and at anerobic threshold,6-minute walk distance 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 Secondary endpoints-changes in New York Heart Association functional class, hospitalization frequency and quality of life Trend towards improvement in all primary &secondary endpoints with biventricular pacing Trend towards improvement in all primary &secondary endpoints with biventricular pacing

25. MUSTIC-SR Single blind,randomised,crossover study Single blind,randomised,crossover study NYHAIII,SR,EF 60,QRS>150ms,6min walk 60,QRS>150ms,6min walk<450m 47pts completed 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 Randomised to resynchronization or to no pacing for 3 mth,crossed over to alternative group for 3 mths,followed up for 12 mths Primary endpoint-6-min walked distance Primary endpoint-6-min walked distance Secondary end point-peak Vo2, quality of life, NYHA class,worsening HF,total mortality Secondary end point-peak Vo2, quality of life, NYHA class,worsening HF,total mortality Significant improvement in primary and secondary end points Significant improvement in primary and secondary end points

27. MIRACLE First prospective, randomized,double blind,parallel-controlled clinical trial 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 55 mm,QRS>130 ms,6min.walk<450 m CRT(n=228) Vs control(n=225) for 6 mths CRT(n=228) Vs control(n=225) for 6 mths

30. MIRACLE ICD Trial design similar to MIRACLE Trial design similar to MIRACLE CRT+ICD Vs CRT CRT+ICD Vs CRT Included NYHA II also(all pts had class I indication for ICD) Included NYHA II also(all pts had class I indication for ICD)

32. NYHA II subgroup(MIRACLE- ICD)

33. CONTAK-CD Randomized controlled, double-blind study Randomized controlled, double-blind study 6-month parallel control study design 6-month parallel control study design NYHA II–IV,LVEF 120 ms NYHA II–IV,LVEF 120 ms 581 patients were randomized, 248 into 3 mth crossover study and 333 into the 6-month parallel controlled trial. 581 patients were randomized, 248 into 3 mth crossover study and 333 into the 6-month parallel controlled trial. Primary endpoint was a composite of mortality, hospitalizations for HF &VT/VF Primary endpoint was a composite of mortality, hospitalizations for HF &VT/VF Secondary endpoints-peak Vo2, 6-min.walk distance, quality of life, and NYHA class-significant improvement in CRT grp Secondary endpoints-peak Vo2, 6-min.walk distance, quality of life, and NYHA class-significant improvement in CRT grp Improvement in NYHA class III–IV subgroup Improvement in NYHA class III–IV subgroup

34. CRT plus ICD versus CRT alone Most patients who are eligible for CRT also meet criteria for ICD implantation. COMPANION trial - CRT plus ICD showed an significant trend toward lower all-cause mortality compared to CRT alone in patients with NYHA class III or IV HF

35. REVERSE and MADIT-CRT trial results support the use of CRT plus ICD (CRT-D) in preference to ICD alone to reduce rehospitalization heart failure events remodeling in patients in NYHA class I or II HF, QRS ≥120 (particularly ≥150), and LVEF ≤30-40 percent

36. In NYHA class I or II HF The largest trial of CRT in patients with mild HF -MADIT-CRT trial Demonstrated a beneficial impact of cardiac resynchronization therapy on heart failure events and remodeling in patients with mild or no HF symptoms.

37. The study population consisted of 1820 patients with an LVEF ≤30 percent, QRS ≥130 msec, and NYHA class I (15 percent) or II (85 percent) HF who were randomly assigned to CRT-D or ICD alone. The study included patients with ischemic (55 percent; NYHA class I or II) or nonischemic (45 percent; NYHA class II ) cardiomyopathy. The primary endpoint was death from any cause or a nonfatal HF event (whichever came first). At average follow-up of 29 months, CRT-D produced a decrease in the primary endpoint as compared to ICD alone (17 versus 25 percent)

38. At 40 months mean follow-up, CRT-D decreased the primary outcome compared to ICD alone (33 versus 40 percent). The CRT-D group had significantly fewer deaths (21 versus 26 percent) and hospitalizations for HF (20 versus 26 percent). Adverse events (hemothorax or pneumothorax and device pocket hematoma or infection, or lead dislodgement requiring intervention, and coronary sinus dissection) were more frequent in the CRT-D than in the ICD group (13 versus 7 percent) in the 30 days after device implantation. The benefit was observed primarily in patients with a QRS duration ≥150 msec.

41. Predictive value of QRS duration A meta-analysis that included the COMPANION, CARE-HF, REVERSE, MADIT-CRT, and RAFT trials found that CRT reduced adverse clinical events in patients with HF and a baseline QRS interval of ≥150 msec but not in those with HF and a baseline QRS interval of <150 msec. This difference in response between those with QRS ≥150 msec and those with QRS interval of <150 was seen in patients with NYHA functional class I and II HF (P<0.001 and P=0.72, respectively) as well as those in those with NYHA class III and IV HF (P<0.001 and P=0.38).

42. Sex In the MADIT-CRT trial, CRT plus a defibrillator (CRT-D) versus ICD alone was associated with significantly greater benefit in women than in men. In women as compared to men, there were significantly greater reductions with CRT-D in the primary endpoint of heart failure or death, in heart failure alone, and in death alone. Significantly reduced mortality with CRT-D was seen in women but not men. Improvements in echocardiographic volumes and left ventricular ejection fraction with CRT-D were also greater in women than in men.

43. The overall adverse events rate was higher in women as compared to men (10.5 versus 7.9 percent) Women more likely to have pneumothorax (3 versus 0.73 percent) Men more likely to have lead dislodgement (1.7 versus 3.2 percent).

44. Age Randomized trials have not specifically addressed the benefit of CRT in elderly patients. In two major CRT trials (CARE-HF and COMPANION), the mean age was about 65 years and the benefit from CRT was similar in patients above and below the mean age. Equivalent benefits were also noted in an observational studies of patients ≥70 years of age (mean age 76) compared to patients <70 years of age (mean age 59)

45. Right bundle branch block The efficacy of CRT in patients with right bundle branch block (RBBB) is not established. Most patients in the controlled CRT trials had LBBB; RBBB was present in 5 to 13 percent of patients. The guidelines note that there is not yet sufficient evidence to provide specific recommendations for patients with right bundle branch block. In the MADIT-CRT trial, benefit was observed in only in the subgroup with LBBB.

46. Lead position The position of the left ventricular and right ventricular pacing leads may affect the efficacy of CRT A retrospective study of 86 patients with QRS ≥120 ms and NYHA class III or IV HF found that the three-dimensional separation between the left ventricular and right ventricular lead tips was associated with reduction in NYHA class by one or more. A response rate of 88 percent was achieved in patients with QRS ≥160 ms and lead separation of ≥100 mm compared with 60 percent with QRS ≥160 ms with lead separation <100 mm

47. An analysis of MADIT-CRT data for patients with QRS ≥120 ms and NYHA class I or II HF found that an apical left ventricular lead position as compared with a basal or midventricular position was associated with a significantly increased risk for heart failure or death (HR=1.72, 95% CI, 1.09 to 2.71) and increased risk of death (HR=2.91, 95% CI, 1.42 to 5.97)

48. Major society guidelines CRT is recommended for patients with LVEF ≤35 percent, a QRS duration ≥120 msec, and NYHA functional class III or ambulatory class IV symptoms with optimal medical therapy. CRT is reasonable for patients with LVEF ≤35 percent with NYHA functional class III or ambulatory class IV symptoms who are receiving optimal recommended medical therapy and who have frequent dependence on ventricular pacing.

49. CRT may be considered for patients with LVEF ≤35 percent with NYHA functional class I or II symptoms who are receiving optimal recommended medical therapy and who are undergoing implantation of a permanent pacemaker and/or ICD with anticipated frequent ventricular pacing. CRT is not indicated for asymptomatic patients with reduced LVEF in the absence of other indications for pacing. CRT is not indicated for patients whose functional status and life expectancy are limited predominantly by chronic noncardiac conditions

50. Meta-analysis of CRT Meta-analysis of 14 randomized, controlled trials of 4420 patients Meta-analysis of 14 randomized, controlled trials of 4420 patients CARE-HF, COMPANION, MIRACLE and MIRACLE ICD, MUSTIC-SR and MUSTIC-AF, PATH-CHF, VENTAK CHF/CONTAK CD, and HOBIPACE CARE-HF, COMPANION, MIRACLE and MIRACLE ICD, MUSTIC-SR and MUSTIC-AF, PATH-CHF, VENTAK CHF/CONTAK CD, and HOBIPACE

51. Benefits of CRT were noted Benefits of CRT were noted A greater likelihood of improving at least one NYHA class (59 versus 37 percent, relative risk [RR] 1.6, 95% CI 1.3-1.9), with improvements in six minute walk distance (mean difference 24 meters) and quality of life. A greater likelihood of improving at least one NYHA class (59 versus 37 percent, relative risk [RR] 1.6, 95% CI 1.3-1.9), with improvements in six minute walk distance (mean difference 24 meters) and quality of life.

52. A reduced rate of hospitalizations for HF (RR 0.63, 95% CI 0.43-0.93). A reduced rate of hospitalizations for HF (RR 0.63, 95% CI 0.43-0.93). A reduced rate of all-cause mortality (RR 0.78, 95% CI 0.67-0.91), primarily due to fewer deaths from progressive HF (RR 0.64, 95% CI 0.49- 0.84). A reduced rate of all-cause mortality (RR 0.78, 95% CI 0.67-0.91), primarily due to fewer deaths from progressive HF (RR 0.64, 95% CI 0.49- 0.84).

55. Summary of CRT benefit Summary of CRT benefit The above randomized trial data support the use of CRT in patients with NYHA class III or IV HF, left ventricular ejection fraction (LVEF) ≤35 percent, and QRS duration ≥120 to 140 msec to reduce symptoms, reduce hospitalizations and improve survival. The above randomized trial data support the use of CRT in patients with NYHA class III or IV HF, left ventricular ejection fraction (LVEF) ≤35 percent, and QRS duration ≥120 to 140 msec to reduce symptoms, reduce hospitalizations and improve survival. The symptomatic benefit (improvement by about one NYHA class or increased six minute walk distance) occurs early. The symptomatic benefit (improvement by about one NYHA class or increased six minute walk distance) occurs early.

56. Conclusion CRT is an accepted modality of treatment with mortality benefit in NYHA III/IV HF CRT is an accepted modality of treatment with mortality benefit in NYHA III/IV HF Reduce morbidity in NYHA II Reduce morbidity in NYHA II No evidence of benefit in HF with narrow QRS No evidence of benefit in HF with narrow QRS

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