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1 Author's Accepted Manuscript MADIT-CRT and His Many Sons Paul A. Rogers MD, Ph.D., Daniel P. Morin MD, MPH PII: DOI: Reference: S (15) TCM To appear in: trends in cardiovascular medicine Cite this article as: Paul A. Rogers MD, Ph.D., Daniel P. Morin MD, MPH, MADIT-CRT and His Many Sons, trends in cardiovascular medicine, org/ /j.tcm This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 MADIT-CRT and His Many Sons Paul A. Rogers, MD, PhD 1 and Daniel P. Morin, MD, MPH 1,2 1 John Ochsner Heart and Vascular Institute, Ochsner Medical Center, New Orleans, LA 2 Ochsner Clinical School, University of Queensland School of Medicine, New Orleans, LA Correspondence to: Daniel P. Morin, Ochsner Medical Center, 1415 Jefferson Highway, New Orleans, LA Phone dmorin@ochsner.org Father Abraham had many sons, and many sons had father Abraham, declares the children s song about a patriarchal figure of Judeo-Christian and Islamic belief. This respectful ballad underscores the extensive impact of Abraham s lineage, as tradition holds. In this issue of Trends in Cardiovascular Medicine, Kutyifa and colleagues review the landmark Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial and a selection of its important offspring sub-studies 1. Sudden cardiac death (SCD) is among the leading causes of death in the United States, with an annual incidence estimated at 450,000 and ranking second only to all cancers combined in terms of lives lost 2. Implantable cardioverterdefibrillators (ICDs) are a mainstay of modern SCD prevention, but the work of identifying all populations that would benefit from ICDs remains far from complete. This unsettling fact is manifested in the estimation that fully 66% of SCDs occur in patients without prior recognized coronary heart disease, or in

3 those deemed low-risk 3. Professional societal guidelines list myriad indications for ICD implantation, including an interplay between the severity of left ventricular (LV) dysfunction, its etiology (ischemic versus nonischemic), heart failure (HF) symptoms, and temporal relationships between HF diagnosis, myocardial infarction, and/or coronary revascularization 4. While patients with ICDs are relatively protected from SCD, the Multicenter Automatic Defibrillator Trial II (MADIT-II) trial suggested that some of the anti-scd benefit derived from ICDs is mitigated by longer time at risk for HF, partially replacing SCD with HF events 5. However, device therapy offers help for this problem as well: patients with a wide QRS and a depressed LVEF may derive benefit from biventricular pacing through cardiac resynchronization therapy (CRT) 6,7. Several prior studies evaluated CRT in patients with severe heart failure 8,9. MADIT-CRT, though, evaluated whether the benefit of CRT might extend to those with low LVEF and ECG evidence of dyssynchrony but only mild heart failure symptoms 10. The trial found that the group receiving CRT-D suffered fewer deaths and HF events than the ICD-only group. This finding is extremely important in its own right. What helps to make MADIT-CRT an even more important study is that adjunctive data were meticulously gathered during the trial. These comprehensive data

4 allow for many post-hoc analyses, generating important hypotheses and resulting in the numerous MADIT-CRT sub-studies that have been published already (on our count, 70!). Here, the devil is in the details. As Kutyifa explains, when the study population was stratified based on QRS morphology, benefit was seen only in those with left bundle branch block (LBBB). In fact, there was a trend toward increased risk of death when CRT-D was implanted in patients with non-lbbb morphologies 11, whereas LBBB CRT-D recipients lived longer 12. This LBBBspecific benefit of CRT certainly seems physiologically plausible. In the absence of LBBB, left ventricular pacing may actually induce cardiac dyssynchrony, not improve it. Further post-hoc analysis suggested that there might be a subpopulation with non-lbbb wide QRS that may benefit from CRT. Curiously, CRT showed differential effects based on PR interval. CRT-treated patients with a PR interval 230 ms showed a significant mortality benefit, whereas those with PR <230 ms had a higher risk of death 13. At this point, it is unclear whether it is a true finding that CRT in mildly symptomatic heart failure patients with a long PR improves atrio-biventricular synchrony, leading to this mortality benefit. It is possible that this is an example of post-hoc type I error that arose by chance among many parallel comparisons. However, it is an intriguing finding. Interestingly, the Resynchronization Therapy in Narrow QRS (ReThinQ) trial made a similar observation 14. In another fringe category of patients, those with significant systolic HF and LV dyssynchrony on echocardiography but with a narrow QRS,

5 ReThinQ showed no overall clinical benefit to CRT. However, CRT-treated patients with a PR interval 180 ms showed greater improvement in HF symptoms, increase in VO 2 max on cardiopulmonary stress testing, and improvement in LVEF as compared with those with a shorter PR. Kutyifa and colleagues further describe MADIT-CRT s insight into the anatomic and physiologic manifestations of CRT-D response, including reduced LV enddiastolic and end-systolic volumes, reduced left atrial volume, improved RV function, and improved LV dyssynchrony and LVEF. In addition, they discuss a MADIT-CRT sub-study showing that patients most likely to benefit from CRT-D had only mild to moderate (i.e., non-severe) echocardiographic dyssynchrony and higher myocardial strain on speckle tracking echocardiography 15. This finding suggests further segmentation of the MADIT-CRT-like population: perhaps those with only mild symptoms and a wide QRS but with myocardial burn-out, as evidenced by severe dyssynchrony and low LV strain, may be unable to benefit from CRT. Remarkably, in MADIT-CRT, resynchronization s ability to produce a clinical benefit did not seem to be dependent upon LVEF. The MADIT-CRT core echocardiography laboratory identified subjects with LVEF under-measured by the enrolling center that was in fact >30%. The resultant sub-study showed no interaction between EF and outcomes, suggesting that patients with a wide QRS but only mild HF symptoms and only mild systolic dysfunction may still benefit

6 from CRT-D 16. Across a wide array of CRT studies, it is strikingly consistent that 30-50% of patients remain nonresponders 17,18. Based on MADIT-CRT and its sub-studies, can we formulate a predictive model to better select patients for CRT, so as to improve the odds of response? Does QRS morphology matter? Should we measure the PR interval before considering CRT? Should myocardial strain be evaluated routinely? Do we need to rethink EF and HF class cutoffs when deciding whether to offer these devices? These incompletely answered questions demand dedicated studies to properly evaluate the suggestions of MADIT-CRT s post-hoc analyses, hopefully verifying truth rather than type I error. MADIT-CRT and his many sub-study sons have provided many answers, and have posed many more questions that need answering. As the tales of Abraham and his many sons have influenced countless people of various religious traditions, MADIT-CRT and its many sub-studies continue to enrich our understanding of cardiac resynchronization therapy. 1. Kutyifa V, Goldenberg I, Moss AJ. Lessons Learned from the Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy (MADIT-CRT). Trends in Cardiovascular Medicine. Article in Press. 2. Deo R, Albert CM. Epidemiology and genetics of sudden cardiac death. Circulation 2012;125:

7 3. Myerburg RJ, Junttila MJ. Sudden cardiac death caused by coronary heart disease. Circulation 2012;125: Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA, 3rd, Freedman RA, Gettes LS, et al ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2013;61:e Goldenberg I, Moss AJ, Hall WJ, McNitt S, Zareba W, Andrews ML, et al. Causes and consequences of heart failure after prophylactic implantation of a defibrillator in the multicenter automatic defibrillator implantation trial II. Circulation 2006;113: Nelson GS, Berger RD, Fetics BJ, Talbot M, Spinelli JC, Hare JM, et al. Left ventricular or biventricular pacing improves cardiac function at diminished energy cost in patients with dilated cardiomyopathy and left bundle-branch block. Circulation 2000;102: St John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:

8 8. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350: Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352: Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009;361: Zareba W, Klein H, Cygankiewicz I, Hall WJ, McNitt S, Brown M, et al. Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). Circulation 2011;123: Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW, Dan A, et al. Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 2014;370: Kutyifa V, Stockburger M, Daubert JP, Holmqvist F, Olshansky B, Schuger C, et al. PR interval identifies clinical response in patients with non-left bundle branch block: a Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy substudy. Circ Arrhythm Electrophysiol 2014;7:

9 14. Joshi NP, Stopper MM, Li J, Beshai JF, Pavri BB. Impact of baseline PR interval on cardiac resynchronization therapy outcomes in patients with narrow QRS complexes: an analysis of the ReThinQ Trial. J Interv Card Electrophysiol Knappe D, Pouleur AC, Shah AM, Cheng S, Uno H, Hall WJ, et al. Dyssynchrony, contractile function, and response to cardiac resynchronization therapy. Circ Heart Fail 2011;4: Kutyifa V, Kloppe A, Zareba W, Solomon SD, McNitt S, Polonsky S, et al. The influence of left ventricular ejection fraction on the effectiveness of cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). J Am Coll Cardiol 2013;61: Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346: Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, et al. Combined cardiac resynchronization and implantable cardioversion defibrillation in advanced chronic heart failure: the MIRACLE ICD Trial. JAMA 2003;289: