Ranolazine in Patients with Incomplete Revascularization After

Percutaneous Coronary Intervention

Giora Weisz, MD Philippe Généreux, Andres Iñiguez, Aleksander Zurakowski, Michael Shechter, Karen P. Alexander, Ovidiu Dressler, Anna

Osmukhina, Stefan James, E. Magnus Ohman, Ori Ben-Yehuda, Ramin Farzaneh-Far, and Gregg W. Stone

For the RIVER-PCI Investigators

The RIVER-PCI Trial

Disclosure Statement of Financial Interest

• Medical advisory board member

• Grant/Research Support

• AngioSlide, AstraZeneca, Calore, Corindus, Medtronic, Medivisor, and M.I. Medical Incentives

• AngioSlide and Corindus

Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Giora Weisz, MD

Background

• Incomplete revascularization (ICR) is common, present in 17-85% of patients following PCI

• ICR has been strongly associated with increased rates of repeat hospitalization, repeat revascularization, and mortality

• Ranolazine is a late Na+ current blocker that reduces ischemia

Primary Objective

To evaluate the efficacy of ranolazine as

compared with placebo when used as part

of standard medical therapy in patients with

a history of chronic angina and with

incomplete revascularization after PCI

245 sites 15 countries

1:1 RandomizationStrata: ACS vs. non-ACS, DM vs. non-DM

Primary EndpointIschemia-driven revascularization or

Ischemia driven hospitalization

Event driven Minimum 1-Year Follow-up

Ranolazine1000 mg BID

Placebo

Patients with history of chronic angina and incomplete revascularization after PCI

N=2600

Weisz G et al. Am Heart J 2013;166:953-959

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IStudy Design

Multicenter, randomized, double-blind, placebo-controlled, event-driven

ClinicalTrials.gov NCT01442038

Major Inclusion Criteria

1. Post-PCI evidence of incomplete revascularization:≥ 50% stenosis in one or more coronary artery with reference vessel diameter of at least 2.0 mm (visual assessment)

2. History of Chronic angina: ≥ 2 anginal episodes 30d to 1yr prior to PCI

• Primary Endpoint:Time from randomization to the first occurrence of either: Ischemia-driven revascularization Ischemia-driven hospitalization

• Secondary Endpoints: Time from randomization to sudden cardiac death Time from randomization to CV death Time from randomization to MI

Efficacy Endpoints

Efficacy analyzed in the full analysis set: Qualifying PCI performed prior to randomization and at least

one dose of study drug administered (ITT analysis)

• All cause mortality• Stroke• Transient ischemic attack (TIA)• MACE (composite of CV death, MI, stroke)• Hospitalization for heart failure

Safety Endpoints

Safety analyzed in the safety analysis set: all randomized patients in whom at least one dose of

study drug was administered

Trial OrganizationPrincipal Investigator

Giora Weisz, MDShaare Zedek Medical CenterColumbia University Medical Center

Study ChairmanGregg W. Stone, MDColumbia University Medical

Executive CommitteeGiora Weisz, MD, Gregg W. Stone, MD, Karen Alexander, MD; Bernard DeBruyne, MD, PhD; Amir Lerman, MD; Ehtisham Mahmud, MD; Gilles Montalescot, MD, PhD; Magnus Ohman, MD; Harvey White, MD.

Data Management and BiostatisticsOri Ben-Yehuda, MD, Ovidiu Dressler, MD, Ray Hang Zhong, Melissa Nichols MSc Cardiovascular Research Foundation

Data Safety Monitoring BoardBernard J. Gersh, MD (Chair); Harold L. Dauerman, MD; Stuart Pocock, BSC, MSc, PhD; David O. Williams, MD; David P. Faxon, MD; David R. Holmes, MD; Tim Clayton, MSc

Clinical Events CommitteeSteven O. Marx, MD (Chairman); Mun Hong, MD; Shing-Chiu Wong, MD; Ozgen Dogan, MD; Jesse Weinberger, MD. Cardiovascular Research Foundation

Angiographic Core LabPhilippe Généreux MDCardiovascular Research Foundation

SponsorRamin Farzaneh-Far, MD (Study Director); Brian McNabb, MD; Anna Osmukhina, PhD; Jenna Scott; Gennyne Walker, PhD; Gilead Inc. , Menarini Group

Austria (total enrolment = 28): Steinwender Clemens, Allgemeines Krankenhaus der Stadt Linz, Linz. Friedrich Guy, Innsbruck Universitaetsklinik, Innsbruck. Mortl Deddo, Landesklinikum Sankt Pölten, Saint Pölten. Schuchlenz Herwig, Landeskrankenhaus Graz West, Graz. Kastner Johannes, Medizinische Universität Wien, Wien. Huber Kurt, Wilhelminenspital der Stadt Wien, Wien. Belgium (total enrolment = 43): Muyldermans Luc, Algemeen Ziekenhuis Sint-Jan, Brugge. Legrand Victor, Centre Hospitalier Universitaire Sart Tilman Liège, Liège. Roosen John, Imelda Ziekenhuis, Bonheiden. Verheye Stefan, Ziekenhuis Netwerk Antwerpen Middelheim, Antwerpen. Vrolix Mathias, ZOL Genk, Campus Saint Jan, Genk. Canada (total enrolment = 166): Kokis André, Centre Hospitalier de l'Universite de Montreal (CHUM), Montreal, Canada. Nguyen Miche, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Canada. Mehta Shamir, Hamilton Health Sciences, General Site, Hamilton, Canada. Schampaert Erick, Hôpital du Sacré-Coeur de Montréal, Montréal, Canada. Rodés-Cabau Josep, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Canada. Jolicoeur Marc, Montreal Heart Institute, Montreal, Canada. Hubacek Jaroslav, New Brunswick Heart Centre, Saint John, Canada. Dorsch Michael, Royal Alexandra Hospital, Edmonton, Canada. Buller Christopher, Saint Michael's Hospital, Toronto, Canada. Mukherjee Ashok, Scarborough Cardiology Research Associates, Scarborough, Canada. Dzavik Vladimir, University Health Network, Toronto, Canada. Welsh Robert, University of Alberta Hospital, Edmonton, Canada. Czech Republic (total enrolment = 75): Kala Petr, Fakultní nemocnice Brno, Brno. Budesinsky Tomas, Fakultní nemocnice Královské Vinohrady, Praha 10. Skvarilová Marcela, Fakultní nemocnice Olomouc, Olomouc. Groch Ladislav, Fakultní nemocnice u sv. Anny v Brne, Brn. Zemanek David, Fakultní Nemocnice v Motole, Praha 5. Ondrejcak Roman, Karlovarská krajská nemocnice a.s., Karlovarská krajská nemocnice a.s., Horak David, Krajská nemocnice Liberec a.s., Liberec. Horak Jan, Všeobecná fakultní nemocnice v Praze, Prague 2. France (total enrolment = 37): Belle Loic, Centre Hospitalier d'Annecy, Pringy. Hannebicque Gery, Centre Hospitalier d'Arras, Arras. Montalescot Gilles, Groupe hospitalier La Pi tié Salpêtrière, Paris Cedex 13. Steg Philippe Gabriel, Hôspital Bichat-Claude Bernard, Paris. Carrie Didier, Hôpital Rangueil, Toulouse Cedex 9. Germany (total enrolment = 64): Olbrich Hans-Georg, Asklepios-Kliniken Langen, Langen. Moellmann Helge, Kerckhoff-Klinik GmbH, Bad Nauheim. vom Dahl, Jurgen, Kliniken Maria Hilf GmbH, Mönchengladbach. Hauptmann Karl Eugen, Krankenhaus der Barmherzigen Brüder, Trier. Schulze-Waltrup Norbert, Sankt Johannes Hospital, Dortmund. Stellbrink Christoph, Städtische Kliniken Bielefeld GmbH, Bielefeld. Licka Manuela, Universitätsklinikum Heidelberg, Heidelberg. Ince Huseyin, Vivantes Klinikum im Friedrichshain, Berlin. Israel (total enrolment = 223): Vered Zvi, Assaf Harofeh Medical Centre, Zerifin. Katz Amos, Barzilai Medical Center, Ashkelon. Rosenschein Uri, Bnei Zion Medical Center, Haifa. Rozenman Yoseph, Edith Wolfson Medical Center, Holon. Danenberg Haim, Hadassah Medical Center, Jerusalem. Turgeman Yoav, HaEmek Medical Center, Afula. Frimerman Aaron, Hillel Yaffe Medical Center, Hadera. Shimoni Sara, Kaplan Medical Center, Rechovot. Mosseri Morris, Meir Medical Center, Kfar Saba. Nikolsky Eugenia, Rambam Medical Center, Haifa. Klutstein Marc, Shaare Zedek Medical Center, Jerusalem. Shechter, Michael, The Chaim Sheba Medical Center at Tel Hashomer, Ramat Gan. Banai Shmuel, Tel Aviv Souraski Medical Center, Tel Aviv. Atar Shaul, Western Galilee Hospital-Nahariya, Nahariya. Halabi Majdi, Ziv Medical Center, Zefat. Italy (total enrolment = 61): Stabile Amerigo, A.R.N.A.S. Civico G. Di Cristina Benfratelli, Palermo. Musumeci Giuseppe, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo. Mascia Franco, Azienda Ospedaliera S. Sebastiano di Caserta, Caserta. De Luca Giuseppe, Azienda Ospedaliero Universitaria "Maggiore della Carita" di Novara, Novara. Menozzi Alberto, Azienda Ospedaliero Universitaria di Parma, Parma. Antoniucci David, Azienda Ospedaliero-Universitaria Careggi, Firenze. Brunelli Claudio, IRCCS Azienda Ospedaliera Universitaria San Martino, Genova. Terrosu Pierfranco, Ospedale Civile SS Annunziata ASL 1, Sassari. Colombo Antonio, Ospedale San Raffaele-IRCCS, Milano Netherlands (total enrolment = 26): Henriques José, Academisch Medisch Centrum, Amsterdam. Koolen Jacques, Catharina Ziekenhuis, Eindhoven. Smits Pieter, Maasstad Ziekenhuis, Rotterdam. Winkens Mark, TweeSteden Ziekenhuis, Tilburg. Danse Peter, Ziekenhuis Rijnstate Arnhem, Arnhem. Poland (total enrolment = 378): Ponikowski Piotr, 4th Wojskowy Szpital Kliniczny z Poliklinika, Klinika Kardiologii, Wrocław. Buszman Pawel, American Heart of Poland S.A., Ustroń. Gorycki Bogdan, American Heart of Poland S.A., Bielsko-Biała. Kondys, Marek, American Heart of Poland S.A., Dąbrowa Górnicza. Pruski Maciej, American Heart of Poland S.A. Tychy. Mlodziankowski Adam, American Heart of Poland S.A., Mielec. Prokopczuk, Janusz, American Heart of Poland S.A., Kędzierzyn Koźle. Kosmider Maciej, American Heart of Poland S.A., Bełchatów. Zurakowski Aleksander, American Heart of Poland S.A., Chrzanów. Gil Robert, Centralny Szpital Kliniczny Ministerstwa Spraw Wewnetrznych i Administracji w Warszawie, Warszawa. Witkowski Adam, Instytut Kardiologii, Warszawa. Lesiak Maciej, Samodzielny Publiczny Szpital Kliniczny nr. 1 im. Przemienienia Panskiego, Poznań. Opolski Grzegorz, Samodzielny Publiczny Centralny Szpital Kliniczny w Warszawie, Warszawa. Wojakowski Wojciech, Slaskiego Uniwersytetu Medycznego w Katowicach, Górnoslaskie Centrum Medyczne, Katowice. Wujkowski Marek, Szpital Wojewódzki we Wloclawku, Włocławek. Dudek Dariusz, Uniwersytecki Szpital Dzieciecy w Krakowie, Kraków. Jaworska Krystyna, Wojewodzki Szpital Zespolony, Toruń. Russia (total enrolment = 323): Andreev Denis University Clinical Hospital #1, Moscow. Baranov Evgeny, City Clinical Hospital #5, Nizhni Novgorod. Barbarash Olga, Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo. Belenky Dmitry, City clinical emergency hospital # 2, Novosibirsk. Duda Alexey, Altai Regional Cardiological Dispensary, Barnaul. Eltishcheva Vera, Medical Center “Alliance”,Kirovsk. Gordeev Ivan, City Clinical Hospital #15 named after O.M. Filatov, Moscow. Ivanenko Vitaly, Volgograd Regional Clinical Cardiological Center, Volgograd. Kalinina Svetlana, Ural Institute of Cardiology, Ekaterinburg. Kamalov Gadel, Republic Clinical Hospital № 2, Kazan. Karpenko Mikhail, Federal center of heart, blood and endocrinology n.a. V.A.Almazov, Sain-Petersburg. Libov Igor, City Clinical Hospital n.a. S.P.Botkin, Moscow. Linev Kirill, Regional Clinical Hospital, Krasnoyarsk. Markov Valentin, Scientific and Research Institution Of Cardiology, Tomsk. Mazaev Vladimir, National Research Center For Preventive Medicine, Moscow. Oleynikov Valentin, Penza Regional Clinical Hospital n.a. N.N. Burdenko, Penza. Privalova Elena, University Clinical Hospital #1, Moscow. Shutemova Elena, Cardiological Dispensary, Ivanovo. Sokolova Nadejda, Regional Clinical Hospital №3, Chelyabinsk. Vasilieva Elena, City Clinical Hospital # 23 n.a.“Medsantrud”, Moscow.Spain (total enrolment = 174): Moris Cesar, Hospital Central de Asturias, Oviedo. Martin Yuste Victoria, Hospital Clinic I Provincial de Barcelona, Barcelona. Sanchis Juan, Hospital Clinico Universitario de Valencia, Valencia. Hernández José-María, Hospital Clínico Universitario Virgen de la Victoria, Málaga. Iñiguez Andres, Hospital de Meixoeiro, Vigo. Mainar Vicente, Hospital General Universitario de Alicante, Alicante. Nunez Ivan, Hospital San Carlos Madrid, Madrid. Cequier Fillat Ángel Ramon, Hospital Universitario de Bellvitge, L´Hospitalet de Llobregat. Moreno Raul, Hospital Universitario La Paz, Madrid. Zueco Javier, Hospital Universitario Marques de Valdecilla, Santander. Garcia Bruno, Hospital Vall d´Hebrón, Barcelona.Sweden (total enrolment = 44): Hagström Lars, Falu lasarett, Falun. Carlsson, Roland, Karlstad Central Hospital, Karlstad. Omerovic Elmir, Sahlgrenska Universitetsjukhuset, Göteborg. Kellerth Thomas, Mölnlycke. Universitetssjukhuset Örebro, Mölnlycke. James Stefan, Uppsala University Hospital, Uppsala.United Kingdom (total enrolment = 33): Fluck David, Ashford and Saint Peter's Hospital NHS Trust, Surrey. Zaman Azfar, Freeman Hospital, Newcastle upon Tyne. Hildick-Smith David, Royal Sussex County Hospital, Brighton. Spence Mark, Royal Victoria Hospital, Belfast. Wong Yuk-Ki, Saint Richards Hospital, West Sussex. De Belder Mark, The James Cook University Hospital, Middlesbrough.United States (total enrolment = 976): Abbott J. Dawn, Rhode Island Hospital, Providence, RI. Abu-Fadel Mazen, Oklahoma City Veterans' Affairs Medical Center, Oklahoma City, OK. Albirini Abdulah, Cardiology Associates of Southeast Ohio, Inc., Zanesville, OH. Al-Joundi Bassam, Gateway Cardiology, PC, Saint Louis, MO. Anderson R. David, University of Florida, Gainesville, FL. Angiolillo Dominick, University of Florida Health Sciences Center-Jacksonville, Jacksonville, FL. Applegate Robert, Wake Forest University School of Medicine, Winston-Salem, NC. Assi Nizar, Gateway Cardiology, PC, Saint Louis, MO. Atanasoski-McCormack Violet, Broward General Medical Center, Fort Lauderdale, FL. Atassi Keith, Northwest Indiana Cardiovascular Physicians, Valparaiso, IN. Banerjee Subhash, North Texas Healthcare System, Dept. of Veteran's Affairs, Dallas, TX. Bansal Manish, Baptist Heart Specialists, Jacksonville Beach, FL. Bansal Sharad, Mercy Medical Research Institute, Springfield, MO. Barsness Gregory, Mayo Clinic, Rochester, MN. Batchelor Wayne, Tallahassee Research Institute, Tallahassee, FL. Bavry Anthony, North Florida/South Georgia Veterans Health System, Gainsville, FL. Beohar Nirat, Mount Sinai Medical Center, Miami Beach, FL. Bertolet Barry, Cardiology Associates of North Mississippi, Tupelo, MS. Blankenship James, Geisinger Medical Center, Danville, PA. Bouchard Alain, Cardiology, PC, Birmingham, AL. Brener Sorin, New York Methodist Hospital, Brooklyn, NY. Brott Brigitta, University of Alabama at Birmingham, Birmingham, AL. Caputo Ronald, SJH Cardiology Associates, Liverpool, NY. Carrozza Jr. Joseph, Saint Elizabeth's Medical Center, Boston, MA. Chandna Harish, Victoria Heart and Vascular Center, Victoria, TX. Cohen Martin, Westchester Medical Center, Valhalla, NY. Daniel Kurt, Carolina Cardiology Associates, High Point, NC. Dauber Ira, South Denver Cardiology Associates, PC, Littleton, CO. Davis Scott, Arkansas Cardiology, Little Rock, AR. Devries James, Dartmouth Hitchcock Medical Center, Lebanon, NH. D'Urso Michael, Black Hills Cardiovascular Cardiology Associates P.C., Rapid City, SD. Ellis Stephen, The Cleveland Clinic Foundation, Cleveland, OH. Erickson Bernard, Saint Cloud Hospital,, Saint Cloud, MN. Flores Angel, The Heart and Vascular Center, Beaver, PA. Garas Samer, Saint Vincent's Ambulatory Care, Jacksonville, FL. Gershony Gary, John Muir Medical Center Concord Campus, Concord, CA. Ghali Magdi, Iowa Heart Center, West Des Moines, IA. Ginete Wilson, Essential Health, Duluth, MN. Gogo Jr. Prospero, University of Vermont Medical Center, Fletcher Allen Health Care, Burlington, VT. Gruberg Luis, Stony Brook University Medical Center, Stony Brook, NY. Guidera Steven, Central Bucks Cardiology, Doylestown, PA. Gumina Richard, The Ohio State University Wexner Medical Center, Columbus, OH. Gurbel Paul, Baltimore Heart Associates, Baltimore, MD. Hahn Harvey, Southwest Cardiology, Inc, Kettering, OH. Hahn Richard, The Indiana Heart Hospital, Indianapolis, IN. Hamroff Glenn, Hudson Valley Cardiology Group, PC, Cortlandt Manor, NY. Henderson David, Cardiology Research Associates, Daytona Beach, FL. Iwaoka Robert, Novant Health Heart and Vascular Institute, Charlotte, NC. Izzo Mark, Saint Vincent Health Care Center, Erie, PA. Jafar M. Zubair, Hudson Valley Heart Center, Poughkeepsie, NY. Jayasuriya Sasanka, The University of Arizona, Tucson, AZ. Jenkins J. Stephen, Ochsner Clinic Foundation, New Orleans, LA. Jobe Robert, Wake Heart Research, Raleigh, NC. Jones William, Veterans Affairs Medical Center, Duke University Medical Center, Durham, NC. Kaluski Edo, University Medical and Denistry of New Jersey, Newark, NJ. Kander Nathan, Ohio Health Research Institute, Columbus, OH. Kelberman Michael, Central New York Cardiology, Utica, NY. Kiesz Radoslaw, San Antonio Endovascular and Heart Institute, San Antonio, TX. Kim Christopher, Utah Cardiology, PC, Layton, UT. Klag Joseph, Scottsdale Healthcare, Scottsdale, AZ. Krawczyk Justine, Buffalo Cardiology and Pulmonary Associates, PC, Williamsville, NY. Lane Gary, Mayo Clinic Jacksonville, Jacksonville, FL. Langevin Eugene, Freeman West Hospital, Joplin, MO. Lansky Alexandra, Yale University, New Haven, CT. Londono Juan, Future Care Solution, LLC, Hialeah, FL. Lui Henry, Research Associates of Jackson, Jackson, TN. Mahmud Ehtisham, University of California, San Diego, La Jolla, CA. Maini Brijeshwar, Pinnacle Health System, Wormleysburg, PA. Marques Vasco, Pepin Heart Hospital and Dr. Kiran C. Patel Research Institute, Tampa, FL. Martinelli Michael, Albany Associates in Cardiology, Albany, NY. Masud A.R. Zaki, Buffalo Heart Group, Buffalo, NY. McLaurin Brent, AnMed Health, Anderson, SC. Moreno Pedro, Mount Sinai Medical Center, New York, NY. Mulkay Angel, Holy Name Medical Center, Teaneck, NJ. Munuswamy, Karan, Holy Cross Hospital, Fort Lauderdale, FL. Nathan Sandeep, University of Chicago Medical Center, Chicago, IL. Nolan Brian, Saint Luke's Clinic - Idaho Cardiology Associates, Boise, ID. Oswood Bradley, Scottsdale Healthcare, Scottsdale, AZ. Parikh Manish, Columbia University Medical Center, New York, NY. Patel Samir, Cardiovascular Institute of Northwest Florida, Panama City, FL. Pattanayak Jan, Asheville Cardiology Associates, Asheville, NC. Penny William, Veterans Affairs San Diego Healthcare System, San Diego, CA. Petersen John, Swedish Medical Center, Seattle, WA. Ponce George, Spectrum Clinical Research Institute, Inc, Moreno Valley, CA. Portnay Edwardmart, Cardiology Associates of Fairfield County, PC, Stamford, CT. Quintana Ofsman, Valley Central Research, Inc., Mission, TX. Qureshi Mansoor, Michigan Heart, PC, Ypsilanti, MI. Rabah Maher, William Beaumont Hospital, Royal Oak, MI. Rahman, Aref, Veterans Administration Medical Center, Pittsburgh, PA. Revana Madaiah, Humble Cardiology Associates, Humble, TX. Riba Arthur, Oakwood Hospital and Medical Center, Dearborn, MI. Riddick John, Centennial Heart Cardiovascular Consultants, LLC, Nashville, TN. Rouch Carl, Indiana Heart Physicians, Inc., Indianapolis, IN. Rozeman Phillip, Clinical Trials of America, Inc., Minden, LA. Scott, J. Christopher, University of Tennessee, Knoxville, TN. Seals Albert, East Coast Institute for Research, Jacksonville, FL. Seifein Hani, Florida Heart Institute, Orlando, FL. Sharma Mukesh, Parkway Cardiology Associates, Oak Ridge, TN. Shunk Kendrick, San Francisco Veterans Affairs Medical Center, San Francisco, CA. Stine Ronald, Sentara Cardiovascular Research Institute, Norfolk, VA. Tahirkheli Naeem, South Oklahoma Heart Research, Oklahoma City, OK. Talreja Deepak, Cardiovascular Associates, Ltd., Virginia Beach, VA. Teirstein Paul, Scripps Health, La Jolla, CA. Traverse Jay, Minneapolis Heart Institute, Minneapolis, MN. Vasquez Alejandro, Heart Center Research, LLC, Huntsville, AL. Waksman Ron, Washington Hospital Center, Washington, DC. Waltman Jonathan, Saint Joseph Cardiology Associates, KY. Wang John, Union Memorial Hospital, Baltimore, MD. Weinstein Debra, Zasa Clinical Research, Atlantis, FL. Weintraub Andrew, Tufts Medical Center Neely Center for Cancer Research, Boston, MA. Wiseman Alan, Northeast Cardiology Associates, Bangor, ME. Zelman Richard, Cape Cod Research Institute, Hyannis, MA. Zhang Wenwu, Clinical Trials of America, Inc., Shreveport, LA.

North America:

• Canada: 12• United States: 113

Asia

• Israel: 15

Europe

• Austria: 6 • Belgium: 5 • Czech Republic: 8

France: 5 • Germany: 8 • Italy: 9

• Netherlands: 5 • Poland: 17 • Russia: 20 • Spain: 11 • Sweden: 5 • United Kingdom: 6

245 Sites in 15 Countries

Enrollment and Randomization

10 Excluded 7 not treated 3 scientific misconduct

22 Excluded 9 not treated 3 scientific misconduct

5 Excluded (no PCI) 10 Excluded (no PCI)

1322 Ranolazine 1297 Placebo

Safety Analysis SetN=2619

All patients dosed with study drug

1287 Placebo1317 Ranolazine

ICR post-PCI

2651 Randomized

2604 Full Analysis SetN=2604

Median follow-up 643 days (1.8 years)

Baseline CharacteristicsRanolazine

(n=1,317)Placebo (n=1,287)

Age, years 63.4 ± 10.5 63.4 ± 10.0

Age ≥75 years 15.6% 14.9%

Female 20.8% 20.0%

Body mass index (kg/m2) 29.6 ± 5.5 29.6 ± 5.2

Diabetes Mellitus 33.6% 33.4%

- Type 1 1.5% 1.0%

- Type 2 32.1% 32.4%

Hypertension 85.1% 87.8%

Hyperlipidemia 86.9% 85.2%

Reason for PCI

- ACS 32.9% 35.4%

- Non-ACS 67.1% 64.6%

Extent of CAD and ICRRanolazine

(n=1,317)Placebo (n=1,287)

Number of diseased vessels    

- 1-vessel disease 8.7% 9.3%

- 2-vessel disease 43.6% 43.0%

- 3-vessel disease 44.0% 44.4%

Number of treated lesions 1.5 ± 0.8 1.5 ± 0.8

Untreated CTO 33.5% 32.9%

Untreated small vessel or diffuse ds. 15.6% 16.0%

Post CABG 14.0% 14.3%

Syntax score    

- Baseline 17.0 ± 8.6 16.8 ± 8.0

- Residual (post-PCI) 10.6 ± 7.3 10.4 ± 6.9

- Change from baseline to post PCI 6.5 ± 4.9 6.6 ± 4.9

Primary Endpoint

0 3 6 9 12 15 18 21 24 27 30

100

90

80

70

60

Months since randomization

Fre

edo

m f

rom

p

rim

ary

end

po

int

even

t (%

)

No. at riskRanolazine 1317 1164 1101 1018 945 891 813 500 266 134 30Placebo 1287 1165 1098 1028 960 879 788 461 271 128 45

Time to first ischemia-driven revascularization orischemia-driven hospitalization without revascularization

Hazard ratio [95%CI] = 0.95 [0.82, 1.10]p-value = 0.48

RanolazinePlacebo

Primary Endpoint

Ranolazine (N=1,317)

Placebo (N=1,287) HR [95% CI]

P-value

Primary endpoint 345 (26.2%) 364 (28.3%) 0.95 [0.82, 1.10] 0.48

Ischemia-driven revascularization

201 (15.3%) 200 (15.5%) 1.01 [0.83, 1.23] 0.91

Ischemia-driven hospitalization

201 (15.3%) 230 (17.9%) 0.87 [0.72, 1.05] 0.14

Secondary EndpointsRanolazine (N=1,317)

Placebo (N=1,287)

HR [95% CI] P-value

Sudden cardiac death 0.5% 0.9% 0.67 [0.24, 1.69] 0.40

Cardiovascular death 1.6% 1.6% 1.07 [0.58, 1.99)] 0.82

Myocardial infarction 8.4% 9.0% 0.97 [0.75, 1.26] 0.81

- Q-wave 0.5% 0.5% 1.05 [0.36, 3.07] 0.93

- Non-Q-wave 7.9% 8.5% 0.96 [0.74, 1.27] 0.81

- Spontaneous 7.7% 8.0% 0.99 [0.76, 1.31] 0.97

- Peri-procedural 0.8% 1.2% 0.72 [0.32, 1.56] 0.41

Safety Events

Ranolazine (N=1,322)

Placebo (N=1,297)

HR [95% CI]P-

value

MACE* 10.7% 11.1% 1.0 [0.79, 1.26] 0.99

All-cause mortality 3.2% 2.8% 1.17 [0.75, 1.83] 0.49

Stroke 1.7% 1.5% 1.10 [0.60, 2.04] 0.75

TIA 1.0% 0.2% 4.36 [1.40, 19.0] 0.02

CHF hospitalization 2.9% 1.9% 1.55 [0.94, 2.60] 0.09

Ischemia-related 1.4% 1.5% 0.95 [0.49, 1.81] 0.87

Non-ischemia-related 1.7% 1.0% 1.72 [0.88, 3.51] 0.12

* MACE = CV death, MI, or stroke

Conclusions (1)

1. RIVER-PCI is the first trial to have prospectively studied patients with incomplete revascularization after PCI, and to examine the potential role of adjunctive anti-ischemic pharmacotherapy

2. Incomplete revascularization was associated with a high event rate (27% ischemia-driven revascularization or hospitalization at a median follow-up of 1.8 years)

3. Routine treatment with ranolazine did not reduce the composite rate of ischemia-driven revascularization or hospitalization in patients with a history of chronic angina who had incomplete revascularization after PCI

4. There were no major safety concerns with ranolazine, although a higher rate of mild adverse events resulted in more frequent study drug discontinuation

Conclusions (2)

Ranolazine in Patients with Incomplete Revascularization After

Percutaneous Coronary Intervention

Giora Weisz, MD Philippe Généreux, Andres Iñiguez, Aleksander Zurakowski, Michael Shechter, Karen P. Alexander, Ovidiu Dressler, Anna

Osmukhina, Stefan James, E. Magnus Ohman, Ori Ben-Yehuda, Ramin Farzaneh-Far, and Gregg W. Stone

For the RIVER-PCI Investigators

The RIVER-PCI Trial

Why Was Ranolazine Ineffective?

• Lesions that were left untreated may have been of little clinical consequence, consisting of relatively small vessels supplying limited myocardium

• No assessment of ischemia

• ICR may represent a surrogate for the severity of atherosclerosis and future events unrelated to ischemia

• Ranolazine does not prevent ischemia but reduces its severity

Concomitant Medical Therapy at Randomization

Ranolazine (n=1,317)

Placebo (n=1,287)

P-value

Aspirin 93.9% 94.9% 0.29

ADP receptor antagonist 95.7% 95.1% 0.49

ACE inhibitor or ARB 78.5% 80.0% 0.34

Statins 93.8% 92.3% 0.12

Beta blocker 85.6% 85.6% 0.99

Calcium channel blocker 24.7% 25.2% 0.77

Long-acting nitrate 21.0% 20.0% 0.57

Number of anti-ischemic drugs

- 0 7.7% 7.8% 0.98

- 1 59.5% 58.4% 0.57

- 2 26.4% 29.0% 0.14

- 3 6.3% 4.8% 0.10

3 Most Common Reasons for ICR(Site Reported)

Ranolazine (n=1,317)

Placebo (n=1,287)

P-value

Medical therapy is an accepted approach for this level of ICR

47.8% 44.9% 0.03

Extent of ICR is unlikely to be clinically significant

17.9% 19.6% 0.35

PCI of lesion would have a low likelihood of acute success

11.7% 11.7% 0.76

Revascularization During Follow-upRanolazine (N=1,317)

Placebo (N=1,287)

HR [95% CI]

P-value

Ischemia-driven revascularization* 15.3% 15.5% 1.01 [0.83, 1.23] 0.91

- Untreated lesion responsible for ICR 7.0% 7.2% 0.98 [0.74, 1.31] 0.91

- Successfully treated PCI lesion which recurred** 7.0% 8.6% 0.83 [0.63, 1.09] 0.18

- New, progressive lesion1.2% 1.9% 0.65 [0.34, 1.21] 0.18

* 90% of all revascularizations were ischemia-driven** i.e. target lesion revascularization

EndpointRanolazine

(n=472)Placebo(n=442) HR P-value

Primary endpoint* 24.5% 33.7% 0.71 (0.55, 0.91) 0.01

- CV death 1.7% 3.8% 0.39 (0.16, 0.93) 0.03

- MI 7.8% 8.2% 0.91 (0.57, 1.44) 0.68

- Recurrent Ischemia 17.6% 25.6% 0.69 (0.51, 0.92) 0.01

Recurrent Ischemia Leading to Hospitalization

9.9% 16.5% 0.62 (0.43, 0.90) 0.01

Recurrent Ischemia Requiring Revascularization

6.2% 11.0% 0.60 (0.38, 0.95) 0.03

Gutierrez JA, Clinical Cardiology. Aug 2015;38(8):469-475

MERLIN: Ad-hoc Sub-group AnalysisPatients with history of angina treated with PCI for ACS

Primary endpoint = CV death, MI, or recurrent ischemia

Study Drug Discontinuation

Ranolazine

(n=1322)

Placebo

(n=1297)

P

Value

Follow-up duration, median (IQR) 644 (575-757) 642 (575-761) 0.49

On study-drug duration, median (IQR) 579 (229-674) 586 (361-688) 0.004

Drug discontinuation 529 (40.0%) 463 (35.7%) 0.006

- Due to an adverse event 189 (14.3%) 137 (10.6%) 0.004

Drug discontinuation ≤12 months 373 (28.2%) 295 (22.7%) 0.01

Pre-specified Subgroups

SubgroupN patients N (%) events

HR (95% CI) HR (95% CI)P-value

interactionRan Plac Ran Plac

Gender

Male104

31030 258 (24.7%) 281 (27.3%)

0.91 (0.77, 1.08)

0.38 Female 274 257 87 (31.8%) 83 (32.3%)

1.07 (0.79, 1.44)

Age (years)

<65 709 715 193 (27.2%) 205 (28.7%)0.94 (0.77,

1.15)0.91

≥65 608 572 152 (25.0%) 159 (27.8%)0.96 (0.77,

1.20)

<75 1111 1095 296 (26.6%) 320 (29.2%)0.92 (0.78,

1.07)0.28

≥75 206 192 49 (23.8%) 44 (22.9%)1.17 (0.78,

1.76)North America

No 742 742 175 (23.6%) 190 (25.6%)0.95 (0.77,

1.17)0.94

Yes 575 545 170 (29.6%) 174 (31.9%)0.94 (0.76,

1.16)Diabetes mellitus

No 874 857 205 (23.5%) 229 (26.7%)0.90 (0.74,

1.08)0.34

Yes 443 430 140 (31.6%) 135 (31.4%)1.04 (0.82,

1.32)PCI for ACS indication

No 884 832 228 (25.8%) 241 (29.0%)0.91 (0.76,

1.10)0.50

Yes 433 455 117 (27.0%) 123 (27.0%)1.02 (0.79,

1.31)Vessel disease

Triple 579 572 157 (27.1%) 163 (28.5%)0.97 (0.78,

1.21)0.79

Single or double 689 674 174 (25.3%) 186 (27.6%)0.93 (0.76,

1.15)

Ranolazine better Placebo better

0.50 0.75 1.50 2.001.00

Ischemia-driven revascularization or hospitalization

SubgroupN subjects N (%) events

HR (95% CI) HR (95% CI)P-value

interactionRan Plac Ran Plac

Residual SYNTAX score

< median (9) 499 493 119 (23.8%) 139 (28.2%) 0.82 (0.64, 1.05)0.34

≥ median (9) 554 555 135 (24.4%) 146 (26.3%) 0.97 (0.77, 1.22)PCI device BMS or PTCA 319 331 82 (25.7%) 87 (26.3%) 0.99 (0.73, 1.35)

0.76 DES 961 914 257 (26.7%) 266 (29.1%) 0.94 (0.79, 1.12)Total occlusion No 843 827 215 (25.5%) 225 (27.2%) 0.94 (0.78, 1.13)

0.91 Yes 441 423 120 (27.2%) 128 (30.3%) 0.95 (0.74, 1.22)Prior CABG No 1108 1091 269 (24.3%) 300 (27.5%) 0.90 (0.76, 1.06)

0.12 Yes 209 196 76 (36.4%) 64 (32.7%) 1.20 (0.86, 1.68)Baseline BNP (pg/mL) ≥ 80 545 524 141 (25.9%) 151 (28.8%) 0.90 (0.71, 1.13)

0.70 > 80 691 711 180 (26.0%) 201 (28.3%) 0.95 (0.78, 1.16)Baseline LVEF (%) ≥ 50 651 637 171 (26.3%) 190 (29.8%) 0.87 (0.71, 1.08)

0.19 < 50 225 205 64 (28.4%) 56 (27.3%) 1.16 (0.81, 1.66)

All subjects 1317 1287 345 (26.2%) 364 (28.3%) 0.95 (0.82, 1.10)

Ranolazine better Placebo better

0.50 0.75 1.50 2.001.00

Pre-specified SubgroupsIschemia-driven revascularization or hospitalization

1. Future planned revascularization

2. Unprotected LM ≥50% diameter stenosis

3. Major complications during the index PCI

4. NYHA Class III-IV CHF

5. Stroke within 90 days or major disability

6. eGFR <30 mL/min/1.73m2

7. Cirrhosis

8. Previous ranolazine use for >7d within 30d

9. Hypersensitivity or intolerance to ranolazine

10. Use of class Ia, Ic, or class III antiarrhythmic (except amiodarone)

11. Strong CYP3A inhibitors, CYP3A4 or P-gp inducers

12. >20mg simvastatin, >40mg lovastatin, or >1000mg metformin qd

Major Exclusion Criteria

Limitations

• The definition of ICR was anatomy-based with no requirement to prove ischemia

• Anti-anginal medication use (other than ranolazine) was left to local standards, and most patients were on one or two additional anti-ischemic agents

• There was a high rate of study drug discontinuation in both arms which may have biased the results toward the null

Statistical Analysis

• Event-driven with accrual of ~720 primary endpoints

• Assuming 20% event rate in the placebo group, conservatively based on MERLIN

• Follow-up of at least 1 year

• 20% risk reduction with ranolazine

• 2600 pts → 85% power at a 2-sided α=0.05