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USC CardioVascular Thoracic Institute

CLINICAL TRIALSThe USC CardioVascular Thoracic Institute at Keck Medicine of USC is participating in two clinical trials sponsored by Edwards LifeSciences. The COMMENCE trial is evaluating the safety and efficacy of a new tissue treatment platform for aortic and mitral valve bioprostheses (NCT01757665). The TRANSFORM trial is evaluating the safety and efficacy of a rapid deployment system for surgical aortic valve replacement to facilitate smaller incisions and faster procedures (NCT01700439).

Transcatheter Aortic Valve Replacement in patients with severe aortic stenosis who cannot undergo surgeryYour patients deserve exceptional care for their cardiac valve conditions. At the USC CardioVascular Thoracic Institute (CVTI) at Keck Medicine of USC, physicians treat patients who have the most complicated conditions, using one of the most advanced skill sets in the nation.

The CVTI physicians use a full spectrum of devices and techniques to treat diseased cardiac valves. CVTI physicians are specialists in the Ross procedure, in which a pulmonary autograft replaces a diseased aortic valve. The Bentall procedure is commonly used to repair an ascending aortic or aortic root aneurysm that occurs in combination with aortic valve disease. A composite aortic valve graft replaces the proximal ascending aorta and aortic valve. When possible, aortic root aneurysms can

be treated surgically with a valve-sparing aortic root replacement, which will preserve the hemodynamics and function of a healthy native aortic valve.

Several options exist to repair mitral valves instead of replacing them. Depending on the nature of the mitral valve condition (e.g., regurgitant or stenotic), the surgical treatment will be tailored to the patient (see page 5 for details).

Within the last three years, transcatheter aortic valve implantation was approved in the United States to treat patients with severe native aortic stenosis who are deemed high risk or extreme risk to undergo surgical aortic valve replacement. In that time, physicians at CVTI have trained to become specialists in

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Figure 2Bioprosthetic valve used in transcatheter aortic valve implantation procedures. The CoreValve® device includes tissue leaflets and a pericardial cuff that are mounted to a metal mesh stent.

Photo courtesy of Medtronic.

TECHNOLOGY SPOTLIGHTNONPROFIT ORG

U.S. POSTaGe

PaIDUNIveRSITy OF

SOUTheRN CalIFORNIa

THE LEADING EDGEUSC CardioVascular Thoracic Institute

Features and specifications for current TAVI devices

All of the valves currently used for TAVI are bioprostheses, comprising a metal stent and tissue leaflets (Figure 2). The valves are enclosed in a catheter that can be introduced through the femoral artery, subclavian artery, ascending aorta or the left ventricular apex (see table 1 for specifications).

Because CVTI has participated in many clinical trials to evaluate TAVI devices, the physicians have extensive experience using all three valves designed for TAVI. This includes the most recently

developed system from St. Jude Medical, which is only available to patients in the United States by participating in a clinical trial. The TAVI system from St. Jude Medical has the first valve that is retrievable and repositionable until the valve is fully deployed.

The Medtronic CoreValve® is the most recently approved valve available in the United States (January 2014). The CoreValve® expands the range of aortic annulus diameters that can be treated with TAVI over the Edwards SAPIEN valve, the first valve to be FDA approved. Because CVTI participated in a large clinical trial for the CoreValve®, the CVTI physicians have amassed three years of experience with this device and have gone on to teach other physicians the implantation procedure.

Interventional cardiologists and cardiothoracic surgeons examine each case carefully to choose the TAVI system that is most appropriate to treat the

patient. A particular valve may be chosen because of a patient’s unfavorable arterial anatomy or aortic annulus diameter, for instance. TAVI device manufacturers are continuing to improve upon the existing devices, with smaller diameter sheaths and easier valve delivery and placement.

University of Southern California SST-2830, 2011 N. Soto Street Los Angeles, CA 90032

© 2014 Keck Medicine of USC

For more information, call the USC CardioVascular Thoracic Institute at: (323) 442-5849 Or visit: cvti.KeckMedicine.orgFor urgent patient referrals, call: (866) 65-AORTA (866-652-6782)

For emergent cardiac transfers to Keck Hospital of USC, call: (855) USC-BEDS (855-872-2337)

Transcatheter Aortic Valve Replacement (continued from page 1)

MESSAGE FROM THE EXECUTIVE DIRECTOR

It is a lifelong dream to be given the opportunity to advance cardiovascular care at the University of Southern California to the highest attainable levels. In keeping with the continuing challenge posed by that dream and with support from USC leadership, I formed the CardioVascular Thoracic Institute (CVTI) in 2006 to bring together cardiothoracic surgeons, vascular surgeons, cardiologists, anesthesiologists and a host of associated health care specialists to form an integrated model of care that puts patients first.

This rich experience has allowed everyone involved to provide individualized care with the most advanced technologies and therapies. It has led to excellent outcomes and patient experiences, both of which continue to improve.

My colleagues and I take great pride in creating this publication to describe our singular achievements.

To our patients with cardiovascular disease and those who are at risk, we dedicate our energies to providing the best care attainable with modern medicine.

To our colleagues in the community of physicians, we pledge to partner with you to develop individualized treatment plans to facilitate continual communication and the exchange of ideas, all directed to providing the best care possible for your patients.

The USC CardioVascular Thoracic Institute has built a reputation for clinical excellence, conducting tomorrow’s research and employing highly advanced technology since its inception. Our multidisciplinary physician model allows CVTI specialists to leverage their broad and deep expertise toward making superior treatment decisions for each patient. Our expanding team now numbers in excess of 200 clinical specialists whose skills span the spectrum of cardiovascular medicine.

Patient care is shaped by everyone. Advancing technologies, coupled with dedicated operating rooms and imaging suites, have allowed us to adopt, adapt and complete a range of minimally invasive procedures that have led to improved outcomes with minimal postoperative morbidity. These procedures are supported by state-of-the-art screening tests, diagnostic imaging technologies and innovative noninvasive therapies.

We push boundaries. Advanced robotic procedures, minimally invasive and percutaneous heart valve replacement, endovascular aortic intervention and ablation therapies for complex arrhythmias are but a few examples of the treatments our specialists now provide.

Vaughn A. Starnes, MD

Hastings Distinguished Professor and Chair Department of SurgeryKeck School of Medicine of USC

Surgeon-in-chief

Keck Hospital of USC and USC Norris Cancer Hospital

H. Russell Smith Foundation Chair for Stem Cell and CardioVascular Thoracic Research

Executive DirectorUSC CardioVascular Thoracic Institute

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transcatheter aortic valve implantation (TAVI). (Transcatheter aortic valve implantation is synonymous with transcatheter aortic valve replacement and percutaneous aortic valve replacement). TAVI devices combine an expandable metal mesh and tissue valve leaflets (see Table 1).

The Centers for Medicare and Medicaid Services (CMS) mandate that two cardiac surgeons determine that a patient with severe aortic stenosis has a high or extreme risk of mortality by treatment with a traditional surgical procedure and that TAVI is the best treatment option. The high-risk analysis includes the Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) estimate. Long before

Medicare mandated it, CVTI surgeons and interventional cardiologists had established comprehensive collaboration in patient care. As a result, CVTI has seamlessly complied with the CMS guidelines.

The outcomes from randomized, controlled clinical trials show a statistically significant reduction in the rate of death at one year for patients treated with TAVI. In the PARTNER trial, the rate of death from any cause was 30.7 percent with TAVI, compared with 50.7 percent with standard surgical therapy (hazard ratio with TAVI, 0.55; 95 percent confidence interval, 0.40 to 0.74; P<0.001).1 In the CoreValve® High-Risk population, the rate of death in the as-treated group from any cause at one

year was 14.2 percent in the TAVI group vs. 19.1 percent in the surgical group, for an absolute reduction in risk of 4.9 percentage points (upper boundary of the 95 percent confidence interval, −0.4; P<0.001 for noninferiority; P=0.04 for superiority).2 CVTI participated in the clinical trial that resulted in this publication and the CoreValve® Extreme-Risk publication.3 Preliminary results from the PORTICO European trial show the rate of death from any cause was 7.8 percent in the TAVI group (n=102).4 The earliest TAVI patients have had the bioprostheses in place for four to six years, and all valves are functioning as expected with few complications.

Edwards LifeSciences, Sapien XT

Medtronic, CoreValve®

St. Jude Medical, Portico™

Frame material Cobalt chromium Nitinol Nitinol

Valve material Bovine leaflets, fabric skirt

Porcine leaflets and cuff

Bovine leaflets, porcine pericardial cuff

Insertion options Direct aortic, transapical, transfemoral

Direct aortic, subclavian, transfemoral

Direct aortic, transapical, transfemoral

Deployment Balloon expandable Self-expanding Self-expanding

Valve diameter(s) 23 mm, 26 mm, 29 mm 23 mm, 26 mm, 29 mm, 31 mm 23 mm, 25 mm, 27 mm, 29 mm

Retrievable If not deployed If partially deployed, no redeployment

Retrievable and repositional until fully deployed

FDA-approved June 2014 January 2014 Clinical trials only

2 USC CardioVascular Thoracic Institute: (323) 442-5849 cvti.KeckMedicine.org 3

THE LEADING EDGEUSC CardioVascular Thoracic Institute

Table 1 Technical specifications for TAVI valves used to treat severe aortic stenosis

Dr. Beverly Gates was referred to CVTI for worsening symptoms of mitral regurgitation. A 67-year-old female weighing 130 lbs and standing 5'8" tall, she presented with frequent premature ventricular contractions, shortness of breath, exercise intolerance and fatigue. She also had a history of multiple sclerosis.

A master’s-level swimmer, Dr. Gates had been swimming almost a mile and a half each morning for many years. As her mitral regurgitation worsened, she found she couldn’t maintain the same swimming pace as before. She would need to stop at the top of the stairs in her home because she was so short of breath.

“I felt much, much older [than I was] and that scared me,” Dr. Gates said.

A coronary angiogram ordered by Dr. Gates’ referring cardiologist was negative for coronary artery disease. An echocardiogram showed severe mitral regurgitation on a myxomatous mitral valve with prolapse of leaflet segments A2, P2 and P3. No atrial fibrillation was present.

After a clinical evaluation at CVTI, Dr. Starnes recommended that Dr. Gates undergo a minimally invasive mitral valve repair. By choosing a minimally invasive incision over a sternotomy, she could ambulate sooner, so there was no aggravation of her MS symptoms.

For the mitral valve repair, a small, anterolateral thoracotomy was made based on the anterior axillary line. Dr. Starnes performed a quadrangular resection of a large segment of P2, a folding

valvuloplasty of P1 to P3, insertion of chordae to A2 and A3, and placement of a 34-mm annuloplasty band. Following the procedure, the patient spent one day in the ICU and was discharged from the hospital on postoperative day 3. Her recovery was typical.

Dr. Gates, a practicing pediatrician, returned to work shortly after the procedure, and she also resumed master’s-level swimming.

“By three months [after the procedure], I was going up and down the stairs without any shortness of breath. People wouldn’t have to wait for me anymore. In swimming, I can keep up with my teammates now,” Dr. Gates exclaimed.

Transcatheter Aortic Valve Replacement (continued from page 3) PROCEDURE SHOWCASE AND OUTCOMES

Mitral valve repair instead of replacement

The CVTI physicians perform several types of mitral valve repair procedures to preserve valve function and restore the surface of coaptation. Surgeons perform a quadrangular resection of prolapsed posterior mitral valve leaflets to remove the prolapsed section. Mitral valve leaflets can be resuspended by inserting artificial chordae. An annuloplasty can correct annulus-to-leaflet mismatch in size and placement. The annuloplasty may be performed as a stand-alone procedure or following a quadrangular resection or artificial chordae insertion.

There are numerous benefits of mitral valve repair instead of replacement for the patient. The mortality rate is lower for repair when compared to replacement, with 1.5 percent vs. 5.5 percent, respectively, according to the STS database. There is no need for chronic anticoagulation therapy. In addition, patients undergoing mitral valve repair have lower rates of endocarditis and thromboembolism than patients undergoing valve replacement.

In the near future, transcatheter valves will be used to treat a wider array of patients and conditions. Clinical trials are underway to examine TAVI in expanded patient populations, specifically patients with moderate aortic stenosis and patients at intermediate surgical risk (see Clinical Trials for more details).

Instead of repeating cardiac surgery for a failed bioprosthetic valve, transcatheter valves are beginning to be used for a “valve-in-valve” procedure to replace the degraded bioprosthesis.5,6 TAVI is also being explored to treat patients with bicuspid aortic valve disease, traditionally considered an exclusion for TAVI.7,8

Ray V. Matthews, MD, professor of medicine, Keck School of Medicine of USC, and director of interventional cardiology, believes that valve repair and replacement will be “the area of greatest change and advancement in all of cardiovascular medicine in the next decade.” He sees new transcatheter and surgical techniques for other cardiac valves, not just the aortic valve, on the horizon. “We’re absolutely committed to be at the forefront of all those techniques.”

At CVTI, a team of physicians, nurse practitioners and supporting staff collaborate to evaluate each patient thoroughly for TAVI. Interventional cardiologists, such as Dr. Matthews, and cardiovascular surgeons, such as Mark J. Cunningham, MD, associate professor of cardiothoracic surgery, Keck School of Medicine of USC, meet with the patient concurrently to review all of the clinical data and discuss the best treatment option with the patient and family. CVTI employs a highly personal approach where the patient is the focus.

Nurse practitioners navigate each patient through the pre-procedure testing and are in constant communication with the patient before, during, and after each procedure. CVTI physicians keep an open line of communication with referring physicians, reaching out after the patient’s initial office visit, after any procedure, and after the patient has been discharged from the hospital. The referring physician typically receives a phone call immediately following the procedure to be informed in real-time about the status of the patient.

Figure 1Transcatheter aortic valve implantation The transcatheter delivery system is introduced at the femoral artery (transfemoral method) and enters the aorta retrograde to blood flow. This image shows the SAPIEN XT valve after it has been deployed with a balloon expander at the level of the native aortic valve. Image courtesy of Edwards LifeSciences.

CASE STUDY

Mitral valve repair for severe, symptomatic mitral regurgitation

4 USC CardioVascular Thoracic Institute: (323) 442-5849 cvti.KeckMedicine.org 5

THE LEADING EDGEUSC CardioVascular Thoracic Institute

USC CardioVascular Thoracic Team

References1. Leon MB, Smith CR, Mack M, et al. Transcatheter aortic valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med.

2010;363(17):1597-1607.

2. Adams DH, Popma JJ, Reardon MJ, et al. Transcatheter aortic valve replacement with a self-expanding prosthesis. N Engl J Med. 2014;370(19):1790-1798.

3. Popma JJ, Adams DH, Reardon MJ, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. J Am Coll Cardiol. 2014;63(19):1972-1981.

4. Manoharan G. Portico CE Trial Preliminary Results: Acute and 1-year outcomes. 2014; http://professional-intl.sjm.com/products/sh/tissue-valves/aortic-mitral/portico. Accessed September 15, 2014.

5. Webb JG, Wood DA, Ye J, et al. Transcatheter valve-in-valve implantation for failed bioprosthetic heart valves. Circulation. 2010;121:1848-1857.

6. Eggebrecht H, Schafer U, Treede H, et al. Valve-in-valve transcatheter aortic valve implantation for degenerated bioprosthetic heart valves. J Am Coll Cardiol Intv. 2011;4:1218-1227.

7. Wijesinghe N, Ye J, Rodes-Cabau J, et al. Transcatheter aortic valve implantation in patients with bicuspid aortic valve stenosis. J Am Coll Cardiol Intv. 2010;3(11):1122-1125.

8. Yousef A, Simard T, Pourdjabbar A, et al. Performance of transcatheter aortic valve implantation in patients with bicuspid aortic valve: systematic review. Int J Cardiol. in press.

Dr. Matthews was recently selected as a proctor to train U.S. physicians to use the Medtronic CoreValve® system for TAVI. He travels to medical centers across the country to teach interventional cardiologists from his own experience with the device. This appointment recognizes Dr. Matthews as an expert in the implantation technique.

Data from a recent clinical trial of the Medtronic CoreValve® system were published in the New England Journal of Medicine. CVTI was a top recruiting center for this trial. The paper showed a significantly lower death rate in the TAVI group than in the surgical group (14.2 percent vs. 19.1 percent, respectively; P<0.001 for non-inferiority, P=0.04 for superiority). (Adams et al, N Engl J Med. 2014;370: 1790-1798.)

Dr. Matthews was the lead author on a recent review paper that was published in Cardiology Clinics. The paper reviews the use of the Medtronic CoreValve® system to treat severe aortic stenosis. (Matthews and Shavelle, Cardiol Clin. 2013 Aug;31(3):351-61.)

RECENT ACCOMPLISHMENTS

USC CardioVascular Thoracic Institute: (323) 442-5849 cvti.KeckMedicine.org 7

Ray V. Matthews, MD Professor of Clinical MedicineDepartment of MedicineKeck School of Medicine of USC

Director, Interventional CardiologyUSC CardioVascular Thoracic Institute

St. Jude Medical is sponsoring three studies in which Keck Medicine of USC is participating. The PORTICO™ trial is a prospective, randomized, controlled study designed to evaluate the safety and effectiveness of the Portico™ TAVI system via transfemoral and transapical delivery (NCT02000115). Two post-approval studies are further evaluating the safety and efficacy of Biocor™ valves and Trifecta™ aortic valves (NCT00636987 and NCT01514162, respectively).

There are six clinical trials currently sponsored by Medtronic. The CoreValve® Pivotal trial is a prospective, randomized study for safety and efficacy of the CoreValve® system to treat severe aortic stenosis in high-risk and extreme-risk patients (NCT01240902). The CoreValve® SURTAVI trial is a prospective, randomized

trial to evaluate the safety and efficacy of TAVI in patients with severe aortic stenosis at intermediate surgical risk (NCT01586910).

In addition to the Pivotal trial, two extension CoreValve® trials are underway. The CoreValve® Continued Access trial is analyzing a subset of patients designated as extreme risk (NCT015313740). The CoreValve® Expanded Use trial is evaluating the safety and effectiveness of the CoreValve® system in a subset of subjects who were excluded from Pivotal trial population due to co-morbidities (NCT01675440).

The EVOLUT R trial is a non-randomized trial to evaluate the CoreValve® Evolut R TAVI system, which offers the possibility of recapturing and repositioning the CoreValve® during deployment

(NCT02207569). Finally, the PERIGON trial is a non-randomized trial to determine the safety and efficacy of an aortic valve bioprosthesis in patients with aortic valve disease (NCT02088554).

CLINICAL TRIALS (continued from page 1)

For more information on any of the clinical trials or to inquire about enrolling a patient, please contact Stephanie Mullin, RN, Research Coordinator Supervisor, at (323) 442-6226 or: stephanie.mullin@med.usc.edu

THE LEADING EDGEUSC CardioVascular Thoracic Institute

Cardiothoracic SurgeryVaughn A. Starnes, MDHastings Distinguished Professor and ChairDepartment of SurgeryExecutive Director, USC CardioVascular Thoracic Institute

Craig J. Baker, MDAssociate Professor of Cardiothoracic Surgery

Mark L. Barr, MDAssociate Professor of Cardiothoracic SurgeryCo-director, Cardiothoracic Transplantation

Michael E. Bowdish, MDAssistant Professor of Cardiothoracic SurgeryDirector, Mechanical Circulatory Support

Robbin G. Cohen, MDAssociate Professor of Clinical Cardiothoracic Surgery

Mark J. Cunningham, MDAssociate Professor of Cardiothoracic SurgerySurgical Director, Heart Transplant Program

Fernando Fleischman, MDAssistant Professor of Clinical Cardiothoracic SurgeryDirector, USC Comprehensive Aortic Center

Guangqiang Gao, MDAssistant Professor of Clinical Cardiothoracic Surgery

Amy Hackmann, MDAssistant Professor of Clinical Cardiothoracic Surgery

Ming Lu Huang, MDAssistant Professor of Clinical Cardiothoracic Surgery

Sophia Lam, RN, MSN, CNS, ACNP-BCNurse Practitioner

6

RadiologyFarhood Saremi, MDProfessor of Radiology

Alison G. Wilcox, MDAssistant Professor of Radiology Director, Cardiothoracic Imaging

NeurologyNerses Sanossian, MDAssistant Professor of Neurology

CardioVascular MedicineRay V. Matthews, MDProfessor of Clinical MedicineDirector, Interventional Cardiology

Leonardo C. Clavijo, MD, PhDAssistant Professor of Clinical MedicineDirector, Vascular Medicine and Peripheral Interventions

Tracy D. Lawrence, MDAssistant Professor of Clinical Medicine

Vivian Y. Mo, MDAssistant Professor of Clinical MedicineDirector, Women’s CardioVascular Center

David M. Shavelle, MDAssociate Professor of Clinical Medicine

Jerold S. Shinbane, MDAssociate Professor of Clinical MedicineDirector, USC Arrhythmia Center

Mary Schoenbaum, RN, ACNPNurse Practitioner, TAVR Program