Prognostic Indicators and Cardiac Remodeling after CRT · LODO-CRT Trial - Preliminary Experience CRT response DSE test response R NR R 25 2 NR 0 15 Sensitivity: 100% Specificity:

Prognostic Indicators and Cardiac

Remodeling after CRT

Saverio Iacopino, MD, FACC, FESC

Prevalence and Prognosis of Ventricular Dysynchrony

Ventricular dysynchrony impairs diastolic and systolic function 4-6: Reduced LV filling time; Increased mitral regurgitation; Depressed dP/dt

4. Grines, et al. Circulation 1989;79:845-53 5. Xiao, et al. Br Heart J 1991;66:443-7 6. Xiao et al. Br Heart J 1992;68:403-7

Increased All-Cause Mortality with Wide QRS at 45 Months (3)

34%

49%

QRS < 120 ms

QRS > 120 ms

3. Iuliano et al. AHJ 2002;143:1085-91

P < 0.001

LBBB More Prevalent with Impaired LV Systolic Function

38%

24%

8%

Mod/Sev HF (2)

Impaired LVSF (1)

Preserved LVSF (1)

1. Masoudi, et al. JACC 2003;41:217-23 2. Aaronson, et al. Circ 1997;95:2660-7

The only reliable predictive criterion of positive response to CRT is the degree of QRS shortening

Limitations of ECG in the Evaluation of Asynchrony

ü  It does not have enough sensitivity to detect the presence of electromechanical delay in each region of the left ventricle ü  Some patients have mechanical asynchrony without delay electric (hypertrophy, fibrosis, collagen-ultrastructural changes of myocytes)

CRT: how many can benefit? Clinical response (NYHA, QoL) : 60%-75% of patients

Objective response (e.g., ventricular reverse remodeling): 50%-60% of patients

Birnie et al. Curr Opin Cardiol 2006

Responders: Why Not ? ü  DCM Etiology

ü  Variability of Dissinchrony

ü Available contractility reserve

How the Current Predictors Are Reliable?

QRS width remains the selectium criterium of dyssynchrony to identify patients suitable for CRT

Acute decrease in LV dyssynchrony

*

* ≥ 10% reduction in LVESV at 6 months

R=0.41 P<0.001

Extent of acute decrease in LV dyssynchrony and CRT response

Acute Mechanical Resynchronization (Biv Pacing) to Predict CRT Response

65 ms

10%

Bleeker GB et al - Circulation 2007;116:1440-8

Reduction of LVESV in Defining “Prognostic Responder” to CRT

Reduction in LVESV ≥10% at 3-6 months post-implantation predicts

all cause mortality (p = 0.0003)

Discriminatory ability was quite modest: sensitivity and specificity 70%

Yu CM et al. – Circulation 2005;112:1580-6

Sur

viva

l

All-cause mortality

ESV≥10%

ESV<10%

Reverse Remodeling After CRT Relates Linearly to Prognosis

Ypenburg C et al. – JACC 2009;53:483-90

More extensive reverse remodeling resulted in

lower mortality and hospitalization

37%

22%

12%

3%

Death, heart transplantation and hospitalization for HF

Necrotic tissue Healthy cells Interstitial fibrotic tissue

New Criteria for Patient Selection?

extent of scar area and quantity of the interstizial fibrotic tissue

presence and density of the myocardial beta-receptors

Is contractility assessment the key for success? A model of impulse conduction in impaired tissue ...

Electrical impulse

Slow conduction

Dobutamine Eco-Stress Test

Agricola et al. Cardiovascular Ultrasound 2004

A reverse remodelling was significantly related to Contractile Reserve (r=0.63; p<0.00001) At Multivariate logistic regression (including QRS duration): Contractile Reserve (OR: 11.2; CI: 6.2-19.8; p<0.001)

LODO-CRT Trial - Preliminary Experience

CRT response

DSE test response

R NR

R 25 2

NR 0 15

Sensitivity: 100% Specificity: 88%

Tuccillo B, Muto C et al., J Interv Card Electrophysiol. 2008 Nov;23(2):121-6

ü  The nonresponse rate to CRT, evaluated by means of a remodeling end point, ranges from 40% to 50% of patients. Thus, assumed responder rate is estimated at 60% in this patient population

ü  The DSE responder-nonresponder ratio is estimated to be 3:1 ü  It is estimated that demonstration of LVCR using DSE (DSE-positive) will

increase CRT responder rate by 20% compared to the absence of DSE-assessed LVCR

ü  15% lost-to-follow-up rate

LODO-CRT - Methods

270 patients followed-up for 12 months

DSE test cut-off A patient is considered responder to DSE test if the increase of LVEF at peak

stress is at least 5 points with respect to the value at rest

Sample size justification

Muto C. et al., Am H J. 2008

Low-dose Dobutamine Stress-echocardiography to Predict Cardiac Resynchronization Therapy Response (LODO-CRT)

Trial - Baseline Characteristics of the Study Population Saverio Iacopino, MD; Maurizio Gasparini, MD; Francesco Zanon, MD; Cosimo

Dicandia, MD; Giuseppe Distefano, MD; Antonio Curnis, MD; Roberto Donati, MD; Valeria Calvi, MD; Carlo Peraldo Neja, MD; Mario Davinelli, PhD; Vanessa Novelli, BA; Carmine Muto, MD

Iacopino S. et al., CHF 2010

297 patients enrolled

290 patients implanted

271 patients considered for the analysis

19 incomplete baseline measures - 8 LVESV not measured - 11 echo not completed - inadequate or missing data

CRT implant success rate: 96%

EF assessment at rest

EF assessment Cut-off reached?

No

Yes



No

No

Yes

Yes

Final EF assessment

End test

End test

End test

Cut-off: increase of at least 5% in EF value with respect to rest

conditions

LODO-CRT – DSE Test

10 μg/Kg/min Dobutamine infusion for 5 min





LVEF at rest (%) 26± 6 LVEF at peak-stress (%) 35±9 CR+ n (%) 198 (73)

Test was interrupted in 3 patients due to ventricular arrhythmias onset

The test was feasible in 99% of the patients w/out complications

About 3 out of 4 patients showed presence of CR This confirms preliminary experiences

LODO-CRT – Acute DSE Results


DSE Test CR - (62) CR + (206) p value

LVEF at rest (%) 26±5 26 ±6 0,184

LVEF at peak stress (%) 28 ±6 38 ±8 <0,001



ECHO measures CR - 62 (23%) CR + 206 (77%) p value

LVEDD (mm) 71±9 66±8 0,001

LVESD (mm) 59±10 55±9 0,005

LVEDV (ml) 237±91 197±72 0,001

LVESV (ml) 178±74 145±59 0,001

LVEF (%) 26±5 27±6 0,433

IVMD (ms) 30±49 28±51 0,586

Inter-Ventricular delay presence n (%) 36 (58) 89 (43) 0,040

Q - Lateral wall delay (ms) 358±135 377±147 0,399

Q - E wave delay (ms) 493±106 522±96 0,052

Delayed Lateral Contraction n (%) 8 (11) 24 (12) 0,878

E-A duration (ms) 405±159 381±133 0,336

E/A 1,6± 1,6 1,1±0,9 0,030

E wave deceleration time (ms) 126±56 174±83 0,002

Presence of restrictive pattern n (%) 31 (44) 45 (23) <0,001

Mitral regurgitation 23 (38) 44 (22) 0,012



DSE test Ischemic Nonischemic p value

LVEF at rest (%) 26±5 26±6 0,600 LVEF at peak stress (%) 36 ±9 35±9 0,394 CR + (%) 76% 70% 0,270

106 (39%) patients have HF of ischemic origin

LODO-CRT – Etiology


LODO-CRT Multivariable Logistic Regression


Presence of Left Ventricular Contractile Reserve Predicts Mid-term Response to Cardiac Resynchronization Therapy

Results from the LODO-CRT trial

Carmine Muto, Maurizio Gasparini, Carlo Peraldo Neja, Saverio Iacopino, Mario Davinelli, Francesco Zanon, Cosimo Dicandia, Giuseppe Distefano, Roberto Donati, Valeria Calvi,

Alessandra Denaro, Bernardino Tuccillo

Muto C. et al., Heart Rhythm 2010

Baseline Characteristics


CRT responders in patients with LVCR: 145/185 (78%)

Distribution of CRT Response in the Groups with and without LVCR


LVEF increase under DSE is significantly associated with CRT response (OR:1.35, c.i. 1.08-1.68, p=0.008 for each 5-point increase of LVEF) (Univariable Logistic Regression)

LVCR presence at baseline is an independent predictor of response to CRT (OR=5.59; c.i. 2.25-13.90; p<0.001) (Multivariable Logistic Regression)

LVESV Modifications After CRT (68%)


Prospect Study – CRT Responders (Change in LVESV > 15% of Reduction)

(56%)

Predictors of response to CRT Univariable analysis Multivariable analysis OR p-value 95%CI OR p-value 95%CI

QRS duration 1.02 0.041 1.00 1.05 No previous MI 2.53 0.017 1.18 5.42 Inter-V dyssynchrony presence 3.19 0.007 1.37 7.44 3.38 0.005 1.43 7.98 LVCR presence 2.35 0.040 1.04 5.31 2.57 0.028 1.11 5.98

Logistic Regression Analysis for Identification of Independent Predictors to Response to CRT

Predictors of response to CRT Univariable analysis Multivariable analysis OR p-value 95%CI OR p-value 95%CI

Hypertension 2.33 0.020 1.14 4.76 No previous revascularization 2.84 0.002 1.47 5.48 Left Ventricular End Systolic Diameter 0.96 0.014 0.93 0.99 Inter-V dyssynchrony presence 6.09 <0.001 2.66 13.93 10.81 0.001 2.69 43.47 LVCR presence 9.00 <0.001 4.10 19.73 39.36 <0.001 9.73 159.21

Clinical Response

ECHO Response

Gasparini M. et al., JAMA submitted

Assessment of Survival Over Time to MCE in Patients with and without LVCR


Positive Predictive Value of LVCR and inter-V Dyssynchrony Tests Combined


Study Limitations

ü The LODO-CRT is an observational trial

ü Results of this experience should in any case be confirmed by a randomized study, before considering the inclusion of the DSE test in the guidelines for CRT patient selection

ü The cut-off used for the definition of response to CRT is obviously arbitrary, although an association between this cut-off value and the long-term prognosis of these patients has been shown

The interaction between AF and HF means that neither can be treated optimally

without treating both

HF AF

promotes

aggravates

Implantable CRT Device Diagnostics Identify Patients

with Increased Risk for Heart Failure Hospitalization.

ICD Diagnostics quantify HF Hospitalization Risk

Giovanni B. Perego, MD; Maurizio Landolina, MD; Giuseppe Vergara, MD; Maurizio

Lunati, MD; Gabriele Zanotto, MD; Alessia Pappone, MD; Gabriele Lonardi, MD;

Giancarlo Speca, MD; Saverio Iacopino, MD; Annamaria Varbaro, MS; Shantanu Sarkar,

PhD; Doug A. Hettrick, PhD; Alessandra Denaro, MS;

on behalf of the physicians of the Optivol-CRT Clinical Service Observational Group.

To determine the association between device-determined diagnostic indices, including intrathoracic impedance, and

heart failure (HF) hospitalization

Journal of Interventional Cardiac Electrophysiology 2008

558 HF patients indicated for CRT-D were prospectively collected from 34 centers.

Device-recorded intrathoracic impedance fluid index threshold crossing event (TCE), mean activity counts, tachyarrhythmia events, night heart rate (NHR) and heart rate variability (HRV) were compared within patients with vs. without documented HF hospitalization.

Journal of Interventional Cardiac Electrophysiology 2008

Gasparini M. JACC 2006; 48, 734-43

Long-Term Effects of CRT

CRT response=reduction in LVESV >10%

Patient Characteristics (N=490) Variable Responders

(n = 263) Non-responders

(n = 227) p-value

Age (years) 65 ± 10 66 ± 11 0.392

Gender M/F 202/61 190/37 0.070 Ischemic etiology (n) 129 (49%) 164 (72%) <0.001 QRS duration (ms) 159 ± 33 154 ± 31 0.130 Serum creatinine (µmol/l) 104 ± 30 127 ± 51 <0.001 eGFR (ml/min/1.73m2) 74 ± 26 64 ± 28 <0.001

LVEDV (ml) Baseline 234 ± 86 219 ± 79 0.055 follow-up 179 ± 71* 223 ± 75 <0.001 LVESV (ml) Baseline 176 ± 77 167 ± 70 0.181 follow-up 116 ± 58‡ 167 ± 66 <0.001 LVEF (%) Baseline 26 ± 8 25 ± 8 0.293 follow-up 37 ± 9* 26 ± 8 <0.001

J Am Coll Cardiol 2011;57:549-555

eGFR subgroups Variable eGFR <60 ml/min/

1.73m2 N = 193

eGFR 60-90 ml/min/1.73m2 N = 204

eGFR ≥ 90 ml/min/1.73m2

N = 93

p-value

Age (years)

71 ± 8

65 ± 8

56 ± 11

<0.001

Gender M/F 152/41 165/39 75/18 0.856 Ischemic etiology (n) 123 (64%) 121 (59%) 49 (53%) 0.200 QRS duration (ms) 161 ± 30 159 ± 33 147 ± 35 0.001

NYHA class 3.1 ± 0.3 3.1 ± 0.3 3.0 ± 0.2 0.160 6 MWT (m) 266 ± 99 308 ± 105 352 ± 98 <0.001 QoL score 37 ± 16 38 ± 18 33 ± 18 0.091

LVEDV (ml) 218 ± 77 235 ± 92 229 ± 72 0.127 LVESV (ml) 168 ± 71 177 ± 80 170 ± 64 0.423 LVEF (%) 24 ± 8 26 ± 8 27 ± 8 0.022 MR grade 1.7 ± 1.1 1.5 ± 1.1 1.1 ± 0.8 <0.001

J Am Coll Cardiol 2011;57:549-555

Differences in Response to CRT Between the 3 eGFR sub-groups

<60 (n = 193) 60-90 (n = 204) ≥90 (n = 93)0%

20%

40%

60%

80%RespondersNon-responders

eGFR (ml/min)

* *

RJ Van Bommel et al. J Am Coll Cardiol 2011;57:549-555

All-cause Mortality in the 3 eGFR subgroups

0 12 24 36 48 600%

20%

40%

60%

80%

100%

Follow-up (months)

Eve

nt-

free

su

rviv

al

eGFR <60

eGFR ≥90

p<0.001

eGFR 60-90


Changes in eGFR from Baseline to 6 Months Follow-up, Responders vs. Non-responders

(N=133)

Responders Non-responders-8

-6

-4

-2

0

Cha

nge

in e

GFR

(ml/

min

)

p<0.05


Even though patient selection for CRT may not be altered by knowledge of some pre-implantation variables, it may help to place the individual patient in the appropriate part of the response spectrum and aid in setting of expectations

Conclusion

Documents

Prognostic Indicators and Cardiac Remodeling after CRT · LODO-CRT Trial - Preliminary Experience CRT response DSE test response R NR R 25 2 NR 0 15 Sensitivity: 100% Specificity: