Published Online: April 1, 2008 (doi:10.1001/jama.299.13.1547).
Author Contributions: Dr Nissen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Nissen, Cannon, Deanfield, Despres, Kapadia, Gaudin, Job, Tuzcu.
Acquisition of data: Nissen, Nicholls, Rodes-Cabau, Despres, Yasin, Ruzyllo, Tuzcu.
Analysis and interpretation of data: Nissen, Nicholls, Wolski, Cannon, Deanfield, Despres, Kastelein, Steinhubl, Kapadia, Gaudin, Job, Hu, Bhatt, Lincoff, Tuzcu.
Drafting of the manuscript: Nissen, Deanfield, Tuzcu.
Critical revision of the manuscript for important intellectual content: Nissen, Nicholls, Wolski, Rodes-Cabau, Cannon, Deanfield, Despres, Kastelein, Steinhubl, Kapadia, Yasin, Ruzyllo, Gaudin, Job, Hu, Bhatt, Lincoff, Tuzcu.
Statistical analysis: Nissen, Wolski, Cannon, Hu.
Obtained funding: Nissen, Gaudin.
Administrative, technical, or material support: Nissen, Nicholls, Cannon, Deanfield, Despres, Gaudin, Bhatt, Lincoff, Tuzcu.
Study supervision: Nissen, Rodes-Cabau, Cannon, Deanfield, Despres, Kastelein, Kapadia, Yasin, Gaudin, Job.
Financial Disclosures: Dr Nissen reported receiving research support from AstraZeneca, Atherogenics, Eli Lilly, Novartis, Pfizer, Takeda, Daiichi-Sankyo, and sanofi-aventis and consulting for a number of pharmaceutical companies without financial compensation (all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so that neither income nor any tax deduction is received). Dr Nicholls reported receiving honoraria from Pfizer, AstraZeneca, Takeda, and Merck Schering-Plough; consultancy fees from AstraZeneca, Pfizer, Roche, Novo-Nordisk, Liposcience, and Anthera Pharmaceuticals; and research support from AstraZeneca and Lipid Sciences. Dr Rodés-Cabau reported receiving research support from sanofi-aventis, Boston Scientific, St Jude Medical, and Actelion and lecture or consulting fees from AstraZeneca, Medtronic, and Edwards Lifesciences. Dr Cannon reported receiving research grant support from Accumetrics, AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck, sanofi-aventis, and Schering Plough. Dr Deanfield reported receiving grant support from Aspreva Pharmaceuticals, Pfizer, and Merck and receiving lecture or consultancy fees from AstraZeneca, Merck, Novartis, Pfizer, Roche, sanofi-aventis, and Takeda. Dr Després reported receiving honoraria as a consultant or lecturer from AstraZeneca, Eli Lilly, GlaxoSmithKline, Innodia, Merck, Novartis, Pfizer Inc, Pharmacia Corp, sanofi-aventis, and Solvay and receiving research grants from Eli Lilly, GlaxoSmithKline, Innodia, and sanofi-aventis. Dr Kastelein reported receiving research grants from Schering-Plough, Merck, Pfizer, sanofi-aventis, AstraZeneca, Roche, Isis Pharmaceuticals, and Aspreva Pharma and receiving lecture or consulting fees from Schering-Plough, Merck, Pfizer, sanofi-aventis, AstraZeneca, Roche, Isis Pharmaceuticals, Lipid Sciences, Lexicon Pharmaceuticals, Kinemed, and Novartis. Dr Steinhubl reported receiving honoraria for advisory boards from sanofi-aventis, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, AstraZeneca, Portola, and The Medicines Company and receiving research support from Eli Lilly, The Medicines Company, and Regado; beginning February 1, 2008, Dr Steinhubl became an employee of The Medicines Company. Dr Bhatt reported receiving research grants (directly to the institution) from Bristol Myers Squibb, Eisai, Ethicon, Heartscape, sanofi-aventis (including for the CRESCENDO trial of rimonabant, for which he serves as international principal investigator), and The Medicines Company; receiving honoraria (donated to nonprofits for >2 years) from AstraZeneca, Bristol-Myers Squibb, Centocor, Daiichi- Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL, sanofi-aventis, Schering Plough, The Medicines Company, and tns Healthcare; serving on the speakers bureau (>2 years ago) of Bristol-Myers Squibb, sanofi-aventis, and The Medicines Company; serving on the consultant/advisory board (donated to nonprofits for >2 years) of Astellas, AstraZeneca, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, McNeil, Medtronic, Millennium, Molecular Insights, Otsuka, Paringenix, PDL, Philips, Portola, sanofi-aventis, Schering-Plough, Scios, The Medicines Company, tns Healthcare, and Vertex; and providing expert testimony regarding clopidogrel (>2 years ago; compensation donated to a nonprofit organization). The Cleveland Clinic Coordinating Center currently receives or has received research funding from Abraxis, Alexion Pharma, AstraZeneca, Atherogenics, Aventis, Biosense Webster, Biosite, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardionet, Centocor, Converge Medical Inc, Cordis, Dr Reddy’s, Edwards Lifesciences, Esperion, GE Medical, Genentech, Gilford, GlaxoSmithKline, Guidant, Johnson & Johnson, Kensey-Nash, Lilly, Medtronic, Merck, Mytogen, Novartis, Novo Nordisk, Orphan Therapeutics, P & G Pharma, Pfizer, Roche, Sankyo, sanofi-aventis, Schering-Plough, Scios, St Jude Medical, Takeda, TMC, VasoGenix, and Viacor. Dr Lincoff reported consulting for a number of pharmaceutical companies but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor tax deduction. Dr Tuzcu reported receiving consultancy fees from Pfizer and honoraria from Pfizer and Merck. No other disclosures were reported.
Funding/Support: This study was funded by sanofi-aventis.
Role of the Sponsor: sanofi-aventis participated in discussions regarding study design and protocol development and provided logistical support during the trial. Monitoring of the study was performed by the sponsor, who also maintained the trial database. The intravascular ultrasound end points were measured by the Cleveland Clinic Cardiovascular Coordinating Center. Statistical analyses were performed independently by both the sponsor and the coordinating center, with results cross-checked for accuracy between the 2 statistical teams. The manuscript was prepared by the corresponding author and modified after consultation with the other authors. The sponsor was permitted to review the manuscript and suggest changes, but the final decision on content was exclusively retained by the academic authors.
Independent Statistical Analysis: An independent statistical analysis was conducted by Kathy Wolski, MPH, of the Department of Cardiovascular Medicine at the Cleveland Clinic Foundation. Ms Wolski received the trial database from the sponsor, which included all raw data, not just derived data sets, and independently computed the intravascular ultrasound efficacy parameters, safety measures, laboratory parameters, and demographic variables. Ms Wolski is employed by the Cleveland Clinic Cardiovascular Coordinating Center, which received compensation from the sponsor for conducting the trial, including reimbursement for statistical services. An additional independent statistical analysis was performed by Bo Hu, PhD, of the Department of Quantitative Health Sciences at the Cleveland Clinic. Dr Hu is also affiliated with the Department of Statistics at Case Western Reserve University. Dr Hu received the entire trial database and independently confirmed Ms Wolski's findings. Dr Hu received compensation from the coordinating center, but not from the sponsor, for statistical services. The results reported in this article are based on the independent analyses.
STRADIVARIUS Investigators:Executive Committee: Steven Nissen (Chair), Cleveland Clinic, Cleveland, Ohio; Christopher Cannon, Brigham & Women's Hospital, Boston, Massachusetts; John Deanfield, University College, London, England; Jean-Pierre Després, Laval Hospital Research Center, Quebec City, Quebec, Canada; Christophe Gaudin (nonvoting) and Bernard Job (nonvoting), sanofi-aventis, Paris, France; John Kastelein, Academic Medical Center, Amsterdam, the Netherlands; Josep Rodès-Cabau, Laval Hospital, Quebec City, Quebec, Canada; Steven Steinhubl, MD, University of Kentucky, Lexington. Data and Safety Monitoring Board: Robert Frye (Chair), Mayo Clinic, Rochester, Minnesota; Robert Harrington and Kerry Lee, Duke University, Durham, North Carolina; Marc Buyse, International Drug Development Institute, Belgium. Investigators (*indicates sites that were activated but no screening of patients was performed during the study): Australia:New South Wales: John Hunter Hospital, New Lambton (G. Bellamy, MD); Royal Prince Alfred Hospital, Camperdown (M. Adams, PR); Queensland: Core Research Group, Milton (D. Colquhoun, PR); Victoria: Monash Medical Centre Cardiovascular Research, Clayton (J. Cameron, PR). Belgium: Cliniques Universitaires Saint Luc Service de Pharmacie, Bruxelles (J. Renkin, PR); Ziekenhuis Oost-Limburg Dienst Apotheek, Genk (M. Vrolix, MD); UZ Antwerpen Dienst Apotheek, Edegem (C. Vrints, PR); OLV Ziekenhuis Dienst Apotheek, Aalst (B. De Bruyne, MD); Hôpital de Charleroi Service, Charleroi (J. Lalmand, MD)*. Canada:Quebec: Hopital Laval Cardiologie, Sainte-Foy (J. Rodes-Cabau, MD); Hopital Maisonneuve-Rosemont Recherche Clinique Polyclinique, Montreal (C. Constance, MD); Montreal Heart Institute Research Center, Montreal (R. Gallo, MD); Alberta: Foothills Medical Centre, Calgary (M. Curtis, MD); Ontario: Toronto General Hospital University Health Network, Toronto (L. Schwartz, MD); British Columbia: Victoria Heart Institute Foundation, Victoria (W.P. Klinke, MD). France: Hôpital Rangueil, Toulouse (J. Puel, PR); Hôpital Europeen G. Pompidou, Paris (A. Lafont, PR)*; Chu Henri Mondor, Creteil (E. Teiger, PR); Hôpital Claude Galien Service Angiographie, Quincy Sous Senart (P. Garot, MD); Hôpital Louis Pradel Pharmacie, Bron (G. Finet, PR)*; Hôpital Marie Lannelongue, Le Plessis Robinson (C. Caussin, MD); Hopital Haut-Lévêque, Pessac (P. Coste, PR, MD). Italy: Ospedale San Raffaele Unità Di Emodinamica E Cardiologia Interventistica, Milano (A. Colombo, MD); Ospedale S. Maria Della Misericordia Strutt, Udine (G. Bernardi, MD); Centro Cardiologico Monzino, Milan (A. Bartorelli, MD); Ospedale Cisanello, Pisa (A. Petronio, PR); Ospedale S. Giovanni Addolorata, Roma (F. Prati, MD); Policlinico San Matteo, Pavia (G. De Ferrari, MD); Isitituto Clinico Humanitas, Rozzano (P. Presbitero, MD). The Netherlands: Olvg, Amsterdam (J.P.R. Herrman, MD, PhD); Catharina Ziekenhuis, Eindhoven (J.J. Koolen, MD, PhD); Medisch Spectrum Twente, Enschede (C. Von Birgelen, PR, MD, PhD); Umc St Radboud, Nijmegen (W.R.M. Aengevaeren, MD, PhD); Amphia Ziekenhuis, Breda (P. Den Heijer, MD, PhD); Isala Klinieken, Zwolle (A.T.M. Gosselink, MD, PhD); St Antonius Ziekenhuis, Nieuwegein (B.J.W.M. Rensing, MD). Poland: Instytut Kardiologii I Klinika Warszawa, Anin (W. Ruzyllo, PR, MD, PhD); Gornoslaskie Centrum Medyczne Sam Oddzial Ostrych Zespolow Wiencowych, Katowice (Pawel Buszman, MD, PhD); Gornoslaskie Centrum Medyczne Sam Iii Klinika Kardiologii, Katowice (A. Ochala, MD, PhD). Spain: Hospital De Bellvitge Hemodinámica Feixa, Llarga (A. Cequier, MD); Hospital Clínco San Carlos, Madrid (C. Macaya, MD); Hospital Del Mar Hemodinámica, Barcelona (A. Serra, MD); Hospital San Juan De Alicante Hemodinámica, San Juan (J. Miguel Ruiz, MD); Hospital Gregorio Marañon Hemodinámica, Madrid (J. Soriano, MD); Hospital Clínico De Málaga Hemodinámica, Malaga (J.M. Hernandez, MD); Hospital Central De Asturias Hemodinámica, Oviedo (I. Lozano, MD); Hospital Vall D´Hebron Hemodinámica, Barcelona (J. Angel, MD). United States:Alabama: The Heart Group, Mobile (C. Alford, MD); California: Northern California Medical Associates, Santa Rosa (P. Coleman, MD); VA Medical Center Division of Cardiology, Los Angeles (R. Ebrahimi, MD); St Joseph´s Medical Center, Stockton (D. Primack, MD)*; Radiant Research, Santa Rosa (S. Dhar, MD); Los Angeles Cardiology Associates, Los Angeles (R. Matthews, MD); Kaiser Permanente, San Francisco (M. Tawadrous, MD); Golden Gate Cardiology, San Francisco (G. Milechman, MD); Sacramento Heart and Vascular Research, Sacramento (D. Roberts, MD); VA San Diego Healthcare System, San Diego (W. Penny, MD); University of California San Diego (E. Mahmud, MD); Colorado: University of Colorado Health Sciences Center, Denver (J. C. Messenger, MD); Florida: Orlando Heart Center, Orlando (R. Dalton, MD); Florida Cardiovascular Research at JFK Medical Center, Atlantis (M. Rothenberg, MD); The Heart and Vascular Institute of Florida, Safety Harbor (M. Krolick, DO); Cardiology Consultants, Pensacola (W. Pickens, MD); St Vincent´s Medical Center, Jacksonville (G. Pilcher, MD); Clearwater Cardiovascular & International Consultants, Clearwater (J.T. Zelenka, MD); Sarasota Memorial Health Care System Clinical Research Center, Sarasota (S. Culp, MD); Miami International Cardiology Consultants, Miami Beach (J. Margolis, MD); Florida Cardiovascular Institute, Tampa (F. Matar, MD); Mima Century Research Associates, Melbourne (R. Vicari, MD); University of Florida Health Science Center, Jacksonville (M. Costa, MD); Pasco Cardiology, Hudson (P. Rossi, MD); Heart Center, Port Charlotte (V. Howard, MD); Illinois: Heart Care Research Foundation, Blue Island (R. Iaffaldano, MD); Indiana: Cardiovascular Clinics, Merrillville (T. Nguyen, MD); Midwest Medical Group, Elkhart (D. Westerhausen, MD); Iowa: Iowa Heart Center, Des Moines (M. Ghali, MD); Kansas: Cardiovascular Research Shawnee Mission Medical Center, Shawnee Mission (P. Kramer, MD); Kentucky: Cardiology Associates Research, Edgewood (M. Jordan, MD); University of Louisville University Cardiology Research, Louisville (M. Leesar, MD); Gill Heart Institute University of Kentucky, Lexington (K. Ziada, MD); Louisiana: TCA Research, Covington (G. Lasala, MD); Maryland: HPV Heart, Columbia (W. Herzog, MD); Peninsula Cardiology Associates, Salisbury (J. Raffetto, MD); John Hopkins University, Baltimore (J. Resar, MD); Washington Adventist Hospital, Takoma Park (M. Turco, MD); Sinai Hospital, Baltimore (P. Gurbel, MD); Michigan: Michigan Heart, Ypsilanti (J. Wilks, MD); Cardiac and Vascular Research Center of Northern Michigan, Petoskey (L. Cannon, MD); Covenant Medical Center Cardiovascular Research, Saginaw (W. Felten, MD); Borgess Research Institute Borgess Medical Center, Kalamazoo (A.J. Carter, MD); University of Michigan Health Systems, Ann Arbor (S.J. Chetcuti, MD); Cardiology Research, Road Royal Oak (G. Hanzel, MD); Michigan Cardiovascular Institute, Saginaw (R. Gudipati, MD); Minnesota: 225 North Smith Avenue Suite 400, St Paul (K. Baran, MD); Central Minnesota Heart Center, St Cloud (B. Erickson, MD). Mississippi: Memphis Heart Clinic, Southaven (S. Himmelstein, MD); Missouri: Kansas City Heart Foundation, Kansas City (E. Hockstad, MD); Nebraska: Nebraska Heart Institute, Lincoln (P. Dionisopoulos, MD); New Mexico: New Mexico Heart Institute, Albuquerque (J. Batty, MD); New York: Buffalo Cardiology & Pulmonary Associates, Williamsville (J. Corbelli, MD); Capital Cardiology, Troy (A. Delago, MD); Metropolitan Cardiology Consultants, LLC, Pomono (C. Hirsch, MD); Strong Memorial Hospital University of Rochester Medical Center, Rochester (F. Ling, MD); Buffalo Heart Group, Buffalo (A. R. Zaki Masud, MD); South Bay Cardiovascular, Islip (D. Reich, MD); NYU Medical Center, New York (M. Attubato, MD); Hudson Valley Heart Center Vassar Brothers Medical Center, Poughkeepsie (M. Zubair Jafar, MD); North Carolina: Wake Forest University Health Sciences Department of Cardiology Medical Center, Winston-Salem (T. Baki, MD)*; East Carolina University School of Medicine Division of Cardiology, Greenville (J. Babb, MD); Lebauer Cardiovascular Research Foundation, Greensboro (B. Brodie, MD); Ohio: Davies Heart and Lung Research Institute, Columbus (R. Magorien, MD)*; University Hospitals of Cleveland, Cleveland (R. Nair, MD); Cardiovascular Medicine Associates, Middleburg Heights (M. Schrode, DO); Medical College of Ohio, Toledo (W. Colyer, MD); Cleveland Clinic, Cleveland (R. Raymond, DO); Oklahoma: Oklahoma Heart Institute, Tulsa (W. Leimbach, MD); Southwest Cardiology, Oklahoma City (M. Yasin, MD); Oregon: Oregon Cardiology, Eugene (S. Cook, MD); Hillsboro Cardiology, Hillsboro (S. Promisloff, MD); Pennsylvania: The Heart Group, Lancaster (P. Casale, MD); University of PA Medical Center-Presbyterian Division of Cardiology, Philadelphia (R.H. Li, MD); Moffitt Heart & Vascular Group, Wormleysburg (W. Bachinsky, MD); University of Pittsburgh Medical Center, Pittsburgh (O. Marroquin, MD); Penn State Milton S. Hershey Medical Center, Hershey (I. Gilchrist, MD); Geisinger Clinic, Danville (J. Blankenship, MD); South Carolina: Upstate Cardiology, Greenville (J. Cebe, MD); Tennessee: VA Memphis, Memphis (K.B. Ramanathan, MD); Parkway Cardiology Associates, Oak Ridge (M. Sharma, MD); Texas: University of Texas Health Science Center at San Antonio (D. Patel, MD); Virginia: Sentara Norfolk General Hospital, Norfolk (P. Mahoney, MD); University of Virginia Health System Hospital, Charlottesville (M. Ragosta, MD); Inova Research Center, Falls Church (B. Raybuck, MD)*; Washington: The Hope Heart Institute, Bellevue (T. Amidon, MD); Wisconsin: Milwaukee Cardiovascular Research Foundation, Milwaukee (A. Arnold, DO). National Coordinators:Australia: James Cameron, MD; Belgium: Jean Renkin, MD; Canada: Josep Rodes, MD; France: Jacques Puel, MD; Italy: Antonio Colombo, MD; Poland: Witold Ruzyllo, MD, PhD; Spain: Angel R. Cequier, MD; The Netherlands: Gert-Jan Laarman, MD; United States: Ian Gilchrist, MD; Stanley Chetcuti, MD.
Intravascular Ultrasound Core Laboratory Staff: Tim Crowe, William Magyar, Jordan Andrews, Tammy Churchill, Anne Colagiovanni, Jessica Fox, Teresa Fonk, Karilane King, Aaron Loyd, Erin Mayock, Kara McInturff, Rhiannon Regal, Andrea Winkhart and Jay Zhitnik.
Previous Presentation: Presented in part at the American College of Cardiology 57th Annual Scientific Session; April 1, 2008; Chicago, Illinois.
Additional Contributions: We thank Marilyn Borgman, RN (project manager), Craig Balog, BS, and Amy Hsu, MS (statistical support). These individuals are employed by the Cleveland Clinic Cardiovascular Coordinating Center and were not compensated for participation in the study.