FINANCIAL DISCLOSURES:NIH/NHLBI: R01; T32 Training GrantDepartment of Surgery Startup GrantGuidant Pacemaker/ICD FellowshipStrategic Pacing Systems, LLC

Biventricular Pacing for Acute Heart Failure

Henry M. Spotnitz, M.D.

UCLA, July 19, 2011

UNLABELED/UNAPPROVED USES DISCLOSURES:Use of the INSYNC III for temporary pacing after heart surgery is investigational only (FDA/ IDE)

BiPACS Multisite

ContributorsPrimary Investigators• George Berberian, M.D.• Santos Cabreriza, M.B.A.• David Rabkin, M.D.• Marc Richmond, M.D.• T. Alex Quinn, Ph.D.• Daniel Wang, M.D.• Alex Rusanov, M.D.

Coordinators• Vinay Yalamanchi, B.A.• Ashley Whyte, B.A.• Lauren Maskin, M.D.• Brianne Blumenthal, M.D.• Lauren Bedrosian• Suzanne Karl• Alexandra Murata• Mira Gendy

Additional Investigators• Cara Garofalo, M.D.• Josh Kanter, M.D.• Alistair Phillips, M.D.• John Artrip, M.D.• Alex Reyentovich, M.D.• Rabin Gerrah, M.D.• Manoj Saxena, M.D. • Ajay Mirani, M.D. • Mathew Martinez, M.D.• Sean Mazer, M.D.• Michelle Spotnitz, M.D.• Alan Weinberg• Bin Chen

Surgical Fellows•Mona Flores, M.D.•Steve Xydas, M.D.•Ryan Davies, M.D.•Jeff Morgan, M.D.•Mark Russo, M.D.•Isaac George, M.D.•George Comas, M.D.

P&S Medical Students•Catherine Albright, B.S.•Matthew Spotnitz, M.S.•Erin George, B.S.•Barry Breaux•Jamal Shillingford•Ben Rubinstein

Other Students•Justin Booth, M.S.•Justin Broyles, B.S.•Jon Kenny, M.D. •Jason Prasso, M.D.•Lauren Kelly•Rana Sahar•Chris Johnson•Casey Wong, M.D.•Giselle Brown

Attending Surgeons•Craig Smith, M.D.•Michael Argenziano, M.D.•Jonathan Chen, M.D.•Ralph Mosca, M.D.•Yoshifumi Naka, M.D.•Mehmet Oz, M.D.•Jan Quaegebeur, M.D.•Allan Stewart, M.D.•Mathew Williams, M.D.

Attending Cardiologists•Allen Hordof, M.D.•Hasan Garan, M.D.•Jose Dizon, M.D.

Other Faculty•Jeffrey Holmes, M.D., Ph.D.•Alan Weinberg, M.S.•Eric Rose, M.D.

Administrators•May Deutsch•Isabel Leger•Erika Harris•Isabel Leger

Physician Assistants•Debra Savarese

Adult CasesEF ≤ 40% Combined AVR/MVR Qualifying ER, QRS, EKG

No data provided

Giselle Brown, 2009

BiPACS Expansion – since November, 2010

1. UCLA agrees, $100k2. FDA OKs IDE3. NIH agrees4. DCC established (Andrews)5. IRB progressing at UCLA6. Investigator selection at UCLA7. Training program defined8. UCLA to send trainees to CUMC9. CUMC to send team to UCLA

The goal of the Biventricular Pacing After Cardiac Surgery (BiPACS) trial is to define a strategies for postbypass temporary pacing that will optimize hemodynamics in patients with depressed left ventricular function.

Premise: Nuances of temporary pacing are being lost in the face of powerful tools for pharmacologic and mechanical support. This predetermines increased dependence on these tools, increased costs, and an increase in related complications.

Our primary hemodynamic index in these studies is cardiac index, the ultimate determinant of global systemic perfusion.

We are not first, but we will be best….

BiPACS Accomplishments

1. Developed and demonstrated protocol for reproducible optimization of BiVP.2. Multiple related findings to be described.3. Multiple trends that cannot be confirmed without increased enrollment.4. Other trends that need confirmation in setting with differing SOC.

Future Accomplishments

5. CI with BiVP 10-15% higher the with SOC.6. Possible benefits for urine output and inotrope score.

Critical Next Step after March 30, 2012

7. Renewal of NIH support8. Demonstration that UCLA is viable second BiPACS site.9. Alternate funding source(s) if NIH fails – U01, industry.

Important Next Steps

1. Governance Plan.2. Publication Committee.

Goals/Questions for Expansion to UCLA:

1. Increase enrollment, completed studies2. Identify clinical relevance of temporary CRT3. Will BiPACS protocol work at UCLA?4. Will BiPACS success at CUMC extend to UCLA?5. Should BiPACS be expanded to multiple centers?6. Should BiPACS grant be renewed?7. Should BiPACS by adopted by U01 CTSN?

BiPACS Multisite

BiPACS Enrollment

• Goal 212 subjects• Current enrollment: 102

(69% of target)• Studied patients: 55

– Off-pump CABG– Development of AF

prior to randomization in OR

– Multiple enrolled patients at once

– Surgeon withdrawal due to clinical considerations

14

Early Goals and Questions in BiPACS Trial

Relevance of BiPACS to Permanent CRT in Dilated CM

Patient Selection – Eliminate non-respondersMechanisms of ActionOptimization of Site, AVD, and VVD

Current Focus – PostCPB Dysfunction Unique vs. Dilated CM

Patient Selection – Does higher preop EF identify responders?Mechanisms of Action - Is valve surgery better substrate?

Is dyssynchrony measurable and relevant?Optimization of Site Need more studies to answer

AVD Longer than “nominal” (180 msec vs 120 msec)?Latency dependent?

VVD - Less important than AVD?Time Post Bypass CRT vs. Heart Rate?

Contractility vs. Conduction Velocity?Importance of updated protocol?

BiPACS Multisite

Rabkin DG, Cabreriza SE, Curtis LJ, Mazer SP, Kanter JP, Weinberg AD, Hordof AJ, Spotnitz HM. Load dependence of cardiac output in biventricular pacing: Right ventricular pressure overload in pigs. J Thorac Cardiovasc Surg 2004;127(6): 1713-1722.

Rabkin DG, Curtis LJ, Cabreriza SE, Weinberg AD, Spotnitz HM. Load dependence of cardiac output in biventricular pacing: Right ventricular volume overload in pigs. J Thorac Cardiovasc Surg, 2004;128(1): 98-102.

Coleman DB, DeBarr DM, Morales DL, Spotnitz HM. Pacemaker lead thrombosis treated with atrial thrombectomy and biventricular pacemaker -defibrillator insertion. Ann Th Surg 2004;78:e83-4

Rabkin DG, Cabreriza SE, Curtis LJ, Quinn TA, AD Weinberg, Weinberg AD, Hordof AJ, Spotnitz HM. Mechanisms of optimized biventricular pacing in pulmonary stenosis: Effects on left ventricular geometry in swine. PACE 2004;27:1060-71.

Spotnitz HM. Optimizing temporary perioperative cardiac pacing (Editorial). J Thorac Cardiovasc Surg 2005;129:5-8.

Prasso JE, Quinn TA, Berberian G, Rabkin DG, Cabreriza SE, LJ Curtis, Spotnitz HM. Validation of mean arterial pressure as an indicator of acute changes in cardiac output. ASAIO Journal 2005;51:22–25.

Berberian G, Quinn TA, Vigilance D, Park D, Cabreriza SE, Curtis LJ, Weinberg AD, Spotnitz HM. Validation study of PulseCO system for continuous cardiac output measurement. ASAIO Journal 2005;51:37–40.

Berberian G, Quinn TA, Kanter JP, Curtis LJ, Cabreriza SE, Phillips AB, Artrip JH, Weinberg AD, Spotnitz HM. Optimized biventricular pacing in atrioventricular block after cardiac surgery. Ann Thorac Surg 2005;80:870-5.

Berberian G, Kanter JP, Quinn TA, Curtis LJ, Cabreriza SE, Stewart AS, Oz MC, Spotnitz HM. Optimized perioperative biventricular pacing in setting of right heart failure: A case report. Europace 2005;7:385-7.

Kenny JE, Berberian G, Rabkin DG, Cabreriza SE, Quinn TA, Curtis LJ, Spotnitz HM. Ethanol induction of complete heart block in swine. 2006 May;132(1):142-6.

Quinn TA, Berberian G, Cabreriza SE, Maskin LJ, Weinberg AD, Holmes JW, Spotnitz HM. Effects of sequential biventricular pacing during acute right ventricular pressure overload. Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2380-7. Epub 2006 Jun 2.

Berberian G, Cabreriza SE, Quinn TA, Garofalo CA, Spotnitz HM. Left ventricular pacing site-timing optimization during biventricular pacing using a multielectrode patch. Ann. Th. Surg. 2006 Dec;82(6):2292-4.

Berberian G, Quinn TA, Cabreriza SE, Kenny JS, Garofalo CA, Weinberg AD, Spotnitz HM. Left ventricular pacing site and timing optimization during biventricular pacing using a muli-electrode patch in pigs. J Thorac Cardiovasc Surg 2007 Sep;134(3):574-8.

Biventricular Pacing for Acute Heart Failure – Publications

Cardiac Output vs. Time and Experimental Phase

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BiPACS Multisite

Intraoperative Studies of CRT after Cardiopulmonary BypassFoster AH, Gold MR, McLaughlin JS: Acute hemodynamic effects of atrio-biventricular pacing in humans. Ann Thorac Surg 59:294-300, 1995

Saxon LA, Kerwin WF, Cahalan MK, Kalman JM, Olgin JE, Foster E, et al. Acute effects of intraoperative multisite ventricular pacing on left ventricular function and activation/contraction sequence in patients with depressed ventricular function. J Cardiovasc Electrophysiol 1998;9:13-21.

Weisse U, Isgro F, Werling Ch, Lehmann A, Saggau W. Impact of atrio-biventricular pacing to poor left-ventricular function after CABG. Thorac Cardiovasc Surg 2002;50:131-5.

Bacha EA, Zimmerman FJ, Mor-Avi V, Weinert L, Starr JP, Sugeng L, Lang RM. Ventricular resynchronization by multisite pacing improves myocardial performance in the postoperative single-ventricle patient. Ann Thorac Surg. 2004 Nov;78(5):1678-83

Tanaka H, Okishige K, Mizuno T, et al: Temporary and permanent biventricular pacing via left ventricular epicardial leads implanted during primary cardiac surgery. Jpn J Thorac Cardiovasc Surg 50: 284-289, 2002.

Zimmerman FJ, Starr JP, Koenig PR, et al: Acute hemodynamic benefit of multisite ventricular pacing after congenital heart surgery. Ann Thorac Surg 75:1775-1780, 2003

Berberian G, Quinn TA, Kanter JP, Curtis LJ, Cabreriza SE, Weinberg AD, et al. Optimized biventricular pacing in atrioventricular block after cardiac surgery. Ann Thorac Surg 2005;80:870-5.

Flynn MJ, McComb JM, Dark JH: Temporary left ventricular pacing improves haemodynamic performance in patients requiring epicardial pacing post cardiac surgery. Eur J Cardiothorac Surg 2005;28(2):250-253.

Dzemali O, Bakhtiary F, Israel CW, Ackermann H, Moritz A, Kleine P: Impact of different pacing modes on left ventricular function following cardiopulmonary bypass. Thorac Cardiovasc Surg 56: 87-92, 2008.

Muehlschlegel JD, Peng YG, Lobato EB, Hess PJ Jr, Martin TD, Klodell CT Jr. Temporary biventricular pacing post-cardiopulmonary bypass in patients with reduced ejection fraction. J Card Surg 2008;23:324-30.

Evonich RF, Stephens JC, Merhi W, et al. The role of temporary biventricular pacing in the cardiac surgical patient with severely reduced left ventricular systolic function. J Thorac Cardiovasc Surg 2008;136:915-21.

Hamad MA, van Gelder BM, Bracke FA, van Zundert AA, van Straten AH: Acute hemodynamic effects of cardiac resynchronization therapy in patients with poor left ventricular function during cardiac surgery. J Card Surg 24: 585-590, 2009.

Eberhardt F, Heringlake M, Massalme MS, et al. The effect of biventricular pacing after coronary artery bypass grafting: a prospective randomized trial of different pacing modes in patients with reduced left ventricular function. J Thorac Cardiovasc Surg 2009;137:1461-7.

Hanke T, Misfeld M, Heringlake M, Schreuder JJ, Wiegand UK, Eberhardt F. The effect of biventricular pacing on cardiac function after weaning from cardiopulmonary bypass in patients with reduced left ventricular function: a pressure-volume loop analysis. J Thorac Cardiovasc Surg

2009;138:148-56 Dzemali O, Bakhtiary F, Dogan S, Wittlinger T, Moritz A, Kleine P. Perioperative biventricular pacing leads to improvement of hemodynamics in patients with reduced left-ventricular function--interim results. Pacing Clin Electrophysiol 2006;29:1341-5.

Hajiseyedjavadi O, Pasque M, Moon M, Damiano R, Mucha T, Hebert K, Moazami N. Coronary artery bypass grafting and biventricular pacing efficacy: do past trials dictate a change in future practice? J Thorac Cardiovasc Surg. 2006 Oct;132(4):974-5.

Schmidt C, Frielingsdorf J, Debrunner M, et al. Acute biventricular pacing after cardiac surgery has no influence on regional and global left ventricular systolic function. Europace 2007;9:432-6.

Pichlmaier M, Bagaev E, Lichtenberg A, et al. Four-chamber pacing in patients with poor ejection fraction but normal QRS durations undergoing open-heart surgery. Pacing Clin Electrophysiol 2008;31:184-91.

The goal of the Biventricular Pacing After Cardiac Surgery (BiPACS) trial is to define a strategies for postbypass temporary pacing that will optimize hemodynamics in patients with depressed left ventricular function.

Premise: Nuances of temporary pacing are being lost in the face of powerful tools for pharmacologic and mechanical support. This predetermines increased dependence on these tools, increased costs, and an increase in related complications.

Our primary hemodynamic index in these studies is cardiac index, the ultimate determinant of global systemic perfusion.

Presenter Disclosure Information

FINANCIAL DISCLOSURES:NIH/NHLBI: R01; T32 Training GrantDepartment of Surgery Startup GrantGuidant: Pacemaker/ICD FellowshipStrategic Pacing Systems, LLC

Henry M. Spotnitz, M.D,Biventricular Pacing For Acute Heart FailureBrooklyn Hospital Center, February 1, 2011

UNLABELED/UNAPPROVED USES DISCLOSURE:Use of the INSYNC III for temporary pacing after heart surgery is investigational only (FDA/ IDE)