Identifying super responders to cardiac resynchronization therapy

Identifying Super-Responders to Cardiac Resynchronization Therapy

Jonathan C. Hsu, MD, MAS

Assistant Clinical Professor

Section of Cardiac Electrophysiology, Division of Cardiology

University of California, San Diego

March 16, 2015

• Evaluate background to Cardiac Resynchronization Therapy (CRT) response mechanisms by examining super-responders

• Clinical predictors of CRT response / super-response

• Ultimate clinical goal of improving the response rate to CRT

Objectives

CRT to Save the Day?

Cardiac Resynchronization Therapy The response factor

• Ventricular dyssynchrony can further impair pump function of a failing ventricle

• Resynchronization may improve pump performance and reverse the deleterious process of ventricular remodeling

Rationale of CRT

• Presence of a bundle branch block / intraventricular conduction delay • May worsen systolic dysfunction by:

• Inducing regional loading disparities

• Reducing the efficiency of contraction

• Dyssynchrony by imaging not enough • ASE consensus statement advises

dyssynchrony reports should NOT include a recommendation as to whether a patient should undergo CRT1

Rationale of CRT

1 Echocardiography for cardiac resynchronization therapy: recommendations for performance

and reporting--a report from the American Society of Echocardiography Dyssynchrony Writing

Group endorsed by the Heart Rhythm Society. Gorcsan J 3rd, et al. J Am Soc Echocardiogr.

2008;21(3):191.

Problem #1 Incompletely understood molecular mechanism of CRT response

• Clinical mechanisms of benefit: • Improved contractile function

• Reverse ventricular remodeling

• The basic molecular basis for mechanical changes affording improvement in LVEF improvement has not been completely elucidated • May generate more homogeneous activation of

stress kinases and reduce apoptosis1

Mechanisms of Benefit

1Reversal of global apoptosis and regional stress kinase activation by cardiac

resynchronization. Chakir K, Daya, et al. Circulation. 2008;117(11):1369.

• Improved contractile function • Improved coordination of global contraction

• In the CARE-HF trial1 (Median LVEF 25%):

• LVEF in the CRT compared to no CRT group increased by 3.7 percent at three months and 6.9 percent at 18 months

• CRT associated with a rise in systolic pressure of about 6 mmHg compared to no CRT (median baseline 110 mmHg) and a reduction in NT-pro BNP of 225 pg/mL at three months and 1122 pg/mL at 18 months

• MIRACLE trial2

• At six months, significantly greater increase in LVEF with CRT than without (3.6 versus 0.4 percent).


1The effect of cardiac resynchronization on morbidity and mortality in heart failure. Cleland

JG, et al. N Engl J Med. 2005;352(15):1539. 2Effect of cardiac resynchronization therapy on left ventricular size and function in chronic

heart failure. St John Sutton MG, et al. Circulation. 2003;107(15):1985.

• Reverse ventricular remodeling • Significant reductions in LV end-systolic and

end-diastolic dimensions, mitral regurgitant jet area

• CARE-HF trial1

• MIRACLE trial2

• Significant reductions in LV mass

• MIRACLE trial2

• All signs of beneficial remodeling


1The effect of cardiac resynchronization on morbidity and mortality in heart failure. Cleland

JG, et al. N Engl J Med. 2005;352(15):1539. 2Effect of cardiac resynchronization therapy on left ventricular size and function in chronic

heart failure. St John Sutton MG, et al. Circulation. 2003;107(15):1985.

Problem #2 Non-standard criteria for assessing CRT response

• Difficult comparing response to CRT across trials due to disparity of response criteria • A review identified 17 different primary

response criteria (clinical and imaging) in the 26 most cited CRT publications1

• Agreement among 15 of these criteria was assessed in 426 patients from the PROSPECT study

• 75 percent of comparisons showed poor agreement and only 4 percent showed strong agreement

Criteria for CRT Response

1Agreement is Poor Amongst Current Criteria Used to Define Response to Cardiac

Resynchronization Therapy. Fornwalt BK, et al. Circulation. 2010; 121(18):1985-9.

Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.

Ellenbogen KA, et al. J Am Coll Cardiol. 2012 Jun 19;59(25):2374-7.

Results of the Predictors of Response to CRT (PROSPECT)

Trial. Circulation.2008; 117: 2608-2616

Evaluating Response: Symptoms and Echo

How the Nerdy EP Thinks:

A Solution? Identify predictors of super-response in order to elucidate mechanisms of response and improve CRT response rates and subsequent hard clinical endpoints

Hsu, et al. J Am Coll Cardiol. 2012 Jun 19;59(25):2366-73.

Background

• Wide variability in the extent of LV remodeling and improvement in LVEF with CRT

• “Super-responders” may derive dramatic improvements, including near normalization of LVEF


Methods

• Included only patients randomized to CRT-D with paired echocardiograms at baseline and at 12 months (n=752).

• Super-response defined by the top quartile of LVEF change

• Best-subset regression analysis identified predictors of LVEF super-response

• Kaplan-Meier survival analysis and Cox proportional hazards regression • Investigate associations of response category with

development of nonfatal HF event or all-cause death.


Results

• All 191 super-responders experienced an LVEF increase of at least 14.5% (mean LVEF increase 17.5 ±2.7%)


Results

• In multivariable analysis, six predictors were associated with LVEF super-response to CRT-D therapy


Implications

• Clinical predictors may help the clinician to characterize who may have a dramatic response to CRT

• Importance of followup (12 month echo in this study) • Prognosis

• Counseling


Conclusions

• Six baseline factors predicted LVEF super-response in CRT-D–treated patients with mild HF: • Female sex • No prior myocardial infarction • QRS duration > 150 msec • LBBB • Body mass index <30 kg/m2 • Smaller baseline left atrial volume index

• Super-response was associated with reduced risk of subsequent cardiac events


Foreseeing super-response to cardiac resynchronization therapy: a perspective for clinicians.

Ellenbogen KA, et al. J Am Coll Cardiol. 2012 Jun 19;59(25):2374-7.

• Mechanisms of CRT response and formalized criteria for response require further efforts for clarification

• Established clinical predictors of CRT super-response may help guide strategies aimed at further improving CRT response rates

Summary

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Identifying super responders to cardiac resynchronization therapy

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