Presenter Disclosure Information

John F. Beshai, MDRethinQ Trial Results

Disclosures Information:The following relationships exist related to this presentation:Consultant - St. Jude Medical, AtricureResearch Grant - St. Jude Medical

R Grimm : Speaker - St. Jude, Medtronic, GE Research Grant - GES Nagueh: Speaker - Medtronic Consultant - St. JudeJ Baker : no disclosuresS Beau: no disclosuresS Greenberg: Consultant - Medtronic, St. Jude, Boston ScientificL Pires: Consultant - St. JudeP Tchou: no disclosures

The Resynchronization Therapy in Normal QRS (RethinQ) Study

John F. Beshai, MD, Richard A. Grimm, DO, Sherif F. Nagueh, MD, James H. Baker II, MD, Scott L. Beau, MD, Steven M. Greenberg, MD,

Luis A. Pires, MD, Patrick J. Tchou, MD for the RethinQ study investigators

Study Sponsored by St. Jude Medical

Background

• Currently, indications for cardiac resynchronization therapy (CRT) include QRS duration > 120ms, LVEF < 35% and NYHA

Class III-IV. • 20-30% of patients do not respond to CRT despite application of

established selection criteria.

• Patients with normal conduction or a slightly prolonged QRS duration also exhibit mechanical abnormalities due to intraventricular dyssynchrony.

• Myocardial Tissue Doppler Imaging (TDI) allows both the velocity and timing of regional longitudinal motion to be measured.

• LV dyssynchrony may also be useful in predicting the benefit of

CRT before implantation of the pulse generator.

Hypothesis

•We hypothesized that patients with NYHA class III, left ventricular ejection fraction less than or equal to 35%, narrow QRS duration < 130 ms, and evidence of mechanical dyssynchrony on echocardiography may benefit from cardiac resynchronization therapy.

Overall ObjectiveDetermine CRT safety and efficacy in patients who are candidates for an ICD with NYHA Class III, narrow QRS duration (<130 ms) and evidence of mechanical dyssynchrony as measured by echocardiography/Tissue Doppler Imaging

Primary Endpoint

Improvement in Peak VO2 during CPET of at least 1.0ml/kg/min at 6 months.

Secondary EndpointsImprovement in quality of life score at 6-monthsImprovement in NYHA classification at 6-months

Study Design

Inclusion and Exclusion Criteria

Inclusion Criteria

• NYHA class III HF

• LVEF ≤ 35%

• Evidence of mechanical dyssynchrony

• QRS duration < 130ms

Exclusion Criteria

• NYHA class I, II, or IV

• Permanent Atrial Fibrillation

• Recent MI, unstable angina or cardiac revascularization

• Prior cardiac resynchronization therapy

Mechanical dyssynchrony considered present if either

•M-Mode - Septal posterior wall mechanical delay (SPWMD) ≥ 130 ms

OR

•Tissue Doppler Imaging (TDI) of the basal ventricular segments in apical 4/2/3 chamber views - Septal to lateral delay ≥ 65ms OR - Antero-septal to posterior delay ≥ 65ms

Echo Criteria for LV Dyssynchrony

172 patients randomized in 34

centers

Stratified by QRS < 120 ms or ≥ 120 ms

AndIschemic or Non-ischemic CM

Randomized to CONTROL or CRT

CONTROLFollowed for 6-months

CRTFollowed for 6-months

Study Design

Results

Baseline Characteristics Control

(n = 85)

CRT

(n = 87)

Age (yr), Mean ± SD 58 ± 14 60 ± 12

Male sex, n(%) 49 (58%) 62 (71%)

NYHA III, n(%) 84 (99%) 87 (100%)

QRS Duration (ms), Mean ± SD 106 ± 13 107 ± 12

Ischemic Cardiomyopathy, n(%) 43 (51%) 47 (54%)

Left ventricular ejection fraction (%) 26 ± 6 25 ± 5

Medications, n(%)

ACE inhibitor or substitute§

Beta-Blocker

Diuretic

Antiarrhythmic

77 (91%)

79 (93%)

74 (87%)

10 (12%)

77 (89%)

84 (97%)

73 (84%)

7 (8%)§ Includes ARBs and other ACE substitutes, including Hydralazine

Baseline Mechanical Dyssynchrony

Mechanical Dyssynchrony Parameters

Control

ms

CRT

ms

SPWMD - M-Mode

Mean ± SD

n = 12

165 ± 27

n = 9

151 ± 22

Septal to lateral - TDI

Mean ± SD

n = 69

99 ± 29

n = 67

96 ± 28

Antero-septal to posterior - TDI

Mean ± SD

n = 55

106 ± 29

n = 59

94 ± 23

Baseline Echocardiographic Data0

20

40

60

80

Control

n = 85

CRT

n = 87

LV end diastolic diameter (mm)

Mean +/- 1 SD

p = 0.29

LV end systolic diameter (mm)

Mean +/- 1 SD

02

04

06

08

0

p = 0.06

CRT

n = 87

Control

n = 85

Baseline Echocardiographic Data (Cont)

05

01

00

20

03

00

LV end diastolic volume (mL)

Mean +/- 1 SD

p = 0.61

CRT

n = 87

Control

n = 85

05

01

00

20

03

00

LV end systolic volume (mL)

Mean +/- 1 SD

p = 0.43

CRT

n = 87

Control

n = 85

Baseline Evaluations0

51

01

52

02

50

51

01

52

02

5

Peak VO2(ml/kg/min)

Mean +/- 1 SD

p = 0.85

Control

n = 85

CRT

n = 87

05

10

15

05

10

15

Exercise Duration (min) Mean +/- 1 SD

p = 0.85

Control

n = 85

CRT

n = 87

Baseline Evaluations (Cont)0

20

40

60

80

10

0

Quality of Life Score

Mean +/- 1 SD

p = 0.43

Control

n = 85

CRT

n = 87

01

00

20

03

00

40

00

10

02

00

30

04

00

Six-minute Hall Walk Distance (m)

Mean +/- 1 SD

p = 0.95

Control

n = 85

CRT

n = 87

Patient Flow Analysis

•172 patients randomized (87 CRT and 85 control)

•11 patients in CRT group and 5 patients in control group not included in endpoint analysis–< 6 months of follow up (7 patients)–Unable to complete CPET at 6 month visit for

reason other than worsening HF (3 patients)–Death not due to worsening HF (3 patients)–Withdrawal prior to 6 month visit (3 patients)

•156 patients (76 CRT and 80 control) were available for efficacy analysis

Results - Primary Endpoint8

1012

14

Baseline 6-months

Peak VO2 (ml/kg/min) Median & 95% CI

p = 0.75

Control (n = 80)CRT (n = 76)

CRTn = 76

020

4060

8010

0

p = 0.63

41% 46%

Controln = 80

% Improved in Peak VO2

Results - Secondary Endpoints

Improved No Change Worsened

02

04

06

08

01

00

29%

54%64%

41%

8%5%

NYHA Class

p = 0.006

30

40

50

60

70

Baseline 6-months

Quality of Life

Median & 95% CI

p = 0.91

Control (n = 80)CRT (n = 76)

Control (n = 80)CRT (n = 76)

Change in LVEDV/ LVESV

Median & 95% CI

-40

-20

010

p = 0.71

LVEDV

p = 0.81

LVESV

Change in LVEDD/ LVESD

Median & 95% CI

-4-2

02

4

p = 0.49

LVEDD

p = 0.34

LVESD

ControlCRT

LV Volumes and Dimensions

Peak VO2 by sub-group

Peak VO2

(% improved from baseline)

020

4060

8010

0

QRS ≥ 120 ms

p = 0.02

QRS < 120 ms

p = 0.45

Control

n = 25

CRT

n = 17

Control

n = 55CRT

n = 59

Peak VO2

(% improved from baseline)

020

4060

8010

0

Ischemic

p = 0.82

Non-ischemic

p = 0.25

Control

n = 41

Control

n = 39

CRT

n = 40

CRT

n = 36

Summary

•This prospective, multi-center, randomized trial was designed to evaluate the effectiveness of CRT therapy in a HF population with narrow QRS duration and evidence of mechanical dyssynchrony.

•There was no statistical significant difference in the change in Peak VO2 between the treatment and control group during cardiopulmonary exercise testing.

•No improvement in other objective parameters including 6-minute walk test, LV reverse remodeling, and secondary endpoint - quality of life score .

Summary

•NYHA class improved to a greater extent in the treatment group than in the control group.

•Although numbers were small in the sub-group analysis, there was no statistically significant difference in the primary endpoint between ischemic and non-ischemic patients.

•Patients with QRS duration 120 - 130 ms demonstrated an improvement in peak VO2.

Conclusion

• CRT did not improve Peak VO2 during exercise in patients with NYHA Class III heart failure, QRS duration <130ms, EF ≤ 35% and mechanical dyssynchrony as specified in this trial.

• While there was a statistically significant improvement of NYHA class, a secondary endpoint, there was no improvement in quality-of-life, 6-minute walking test, or echocardiographic measures of reverse LV remodeling

• A subgroup of patients with QRS duration between 120 ms and 130 ms demonstrated an improvement from CRT, however

patients with QRS duration < 120 ms did not demonstrate improvement

• The subgroup of patients stratified on the basis of cardiomyopathy etiology did not demonstrate an improvement in peak VO2.