Supplementary Appendix 1

This appendix has been provided by the authors to give readers additional information about their work. Supplement to: The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-85. DOI: 10.1056/NEJMoa1001286.

Table of Contents
Section
1

Title
Members of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group and DSMB . . . . . . . . . . . . . . . . . . . . . . . . Consort Diagram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACCORD Design and Details of Allocation to Blood Pressure and Lipid Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Eligibility Criteria for the ACCORD BP Trial . . . . . . . . . . . . . . . . . The ACCORD Vanguard Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACCORD Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Serious Adverse Events (SAEs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood Pressure Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Blood Pressure Intervention Medications . . . . . . . . . . . . . . . . . . . . . Results Medications Used at Study Entry . . . . . . . . . . . . . . . . . . . Results Medications Prescribed at 12 Months and Last Visit . . . . Results Visit Adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results Sensitivity Analysis for Systolic Blood Pressures . . . . . . . Results Diastolic Blood Pressures . . . . . . . . . . . . . . . . . . . . . . . . Results Number and Causes of Death . . . . . . . . . . . . . . . . . . . . . Results - Kaplan-Meier Curves . . . . . . . . . . . . . . . . . . . . . . . . . . . . Results Subgroup Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Page
2 10

2 3

11 12 13 16 19 20 22 23 24 25 26 27 28 20 33

4 5 6 7 8 9 10 11 12 13 14 15 16 17

Section 1. Members of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group and DSMB
Steering Committee: W.T. Friedewald (Chair), J.B. Buse (Vice Chair), J.T. Bigger, R.P. Byington, W.C. Cushman, F. Ismail-Beigi, H. C. Gerstein, H. N. Ginsberg, D.C. Goff, Jr, R.H. Grimm, Jr, J.L. Probstfield, D.G. Simons-Morton. Clinical center networks (CCNs) and clinical sites: Canadian CCN: Population Health Research Institute, Hamilton General Hospital, Canadian Diabetes Outcome Researchers (CANDOR Network), Hamilton, Ontario, Canada: H.C. Gerstein, S. Yusuf, Z. Punthakee , R. Russo, S. Anand, K Chrysler*, B. Cracknell, T. Cukierman-Yaffe, A. Gafni, G. Guyatt*, S. Hall, J. Kaszyca, E. Lonn*, P. Mackie*, V. Reiding, N. Shehadeh*, B. Tadeson*, K. Thompson*, M. Vallis, V. Vasudeva, I. Wilderman*, D. Wright Canadian clinical sites: McMaster Medical Centre, Hamilton, Ontario, Canada: Z. Punthakee, A. Smith, I. Stanton, S. Capes*, P. Manjoo*, T. Valla, S. Danby*, W. Harper*, P. Harvey, D. Hunt, Audrey Moroso*, Rose Otto, Ally Prebtani. Six Nations Health Services, Ohsweken, Ontario, Canada: Z. Punthakee, A. Davis, S. Capes*, K.L. Hill, V. McCarthy. Diabetes, Hypertension and Cholesterol Centre, University of Calgary, Calgary, Alberta, Canada: A.L. Edwards, D.J. Mitchell, M.A. Clearwaters, C. Dielissen*, M. Gillam, B. Hammond*, H. Jensen*, A. Kherani*, D. Lau, V. Pringle, D. Rabi, R. Sigal, C. Smith*, M. Walker*, G. Williams*. Memorial University of Newfoundland, St. Johns, Newfoundland, Canada: C. Joyce, M. Parsons, B. Rowe, J. Burton*, V. Chandurkar, S. Coady-McDonald*, D. Gibbons*, C. Kovacs, B. Murphy*, R. Smart*, S. Varghese. University of Alberta, Edmonton, Alberta, Canada: L. Mereu, E. Ryan, P. Senior, P. Kirkland, J. Abe*, K. Dalton, W. Gendall, J. Germsheid*, D. Hartmann*, A. Jeffrys*, U. Kumar*, C. MacDonald, N. Makhani, S. Mawani*, F. Morales, B. Paty*, M. Pick*, B. Schwanke, A. Stark, M. Tennant, S. Varma*, D. WeissAburto , P. Werbiski-Wood, B. Woloschuk, W. Zimmerman*. Centre de Recherche Clinique de Laval, Laval, Quebec, Canada: A. Blanger, S. Gauthier, G. Bahsali*, C. Barbeau*, E. Caponi*, R. Duchesne*, R. Dumas, P. Gauthier, J. Girouard*, N. Kandalaft*, M. Labb, J. Palardy, M. Pilon, J. Raymond, A. Schiffrin. St. Josephs Health Care London, London, Ontario, Canada: I. Hramiak, S. Tereschyn, M. Driscoll, M. Gehring, J. Gonder, C. Lincoln, W. McBeth, C. McDonald, T. McDonald*, P. Pauli*, T.Paul, S. Powers*, N. Ronald, V. Trinh*, L. Vancer*, G. Walsh*. Ottawa Hospital, Division of Endocrinology and Metabolism, Ottawa, Ontario, Canada: H. Lochnan, T.C. Ooi, J. Maranger, L. Bradley*, R. Buhrmann, M. Cyr*, C. Gilchrist*, B. Hanlon*, M. Harley*, K. Jay*, T. Leech, J. Malcolm, M. McLean*, E. Parker*, R. Sigal*, K. Sullivan. Royal Victoria Hospital, Montreal, Quebec, Canada: J.F. Yale, S.A. Segal, G. Al Ansari, N. Renouf*, N. Allaire*, M.A.M.A. Alawadhi*, B. Belfer*, D.W. Blank, F. Bouchard*, S. Buoy-Phang*, J. Carter,

3 L. Coppin*, D. Dalpe*, I. Delpech*, P.M. Doran, F. Emmian*, S. Fortin*, N. Garfield, M. Gosselin*, S. Horan*, M. Kalergis*, S. Koutelias*, C. Lgar*, A. Lombardo*, J.A. Morais, M. Quigley*, N. Renouf*, C. Riopel*, S. Riopel, J.A. Rivera, G. Rochon*, M. Roy, M. Salera*, M.H. Sherman, M. Shingler*, H.E. Staples*, L. Ulyatt*, Z. Yared*. St. Michaels Hospital, Toronto, Ontario, Canada: L.A. Leiter, G. Booth, L. Sparrow*, H. Choi, D.C. Bedard, A. Berger*, L.A. Berndl, A. Cheng*, V. Evalmplev*, J. Goguen, A. Hanna, R.G. Josse, J.A. Kalas*, S. Perry, M. Pike*. Vancouver General Hospital, Vancouver, British Columbia, Canada: T. Elliott, K. Dawson, J. Kong, D. Albiani*, M. Inducil, R. Al Amoudi*, T. Broughton*, L. Hall*, B. Harrison*, N. Hirvi*, R. Lee*, A. Merkur*, E. Norman*, B. Paty, M. Potter, D. Stevenson*, A. Vafadaran. Health Sciences Centre Diabetes Research Group, Winnipeg, Manitoba, Canada: V. Woo, L. Berard, T. Anderlic, K. Austman*, A. Bernard*, D. Catte*, P. Darvill*,D. Hak, K.Hutchison*, L. Janzen*, T. Klopak, C. Mandock, M. Mathen*, S. Mawani*, A. Mawani*, L. Murphy, G. Nyomba, B. Penner*, S. Pockett*, S. Russell*, F. Stockl, J. Studney*, R. Sukkau. Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada: C. Abbott, E. Ur*, M. Yuille, M. Archibald*, D. Clayton, A. Cruess, N. Davis, H. Fong*, S. Frizzell*, B. Hanway*, A. Hoskin-Mott, A. Imran, C. Ingraham*, G. McCarthy, H. Murdock*, T. Palmer, A.M. Patterson*, T. Ransom, D. Shu*, J. Tuttle*. Western CCN: University of Washington, Seattle, WA: J.L. Probstfield, C. Kingry, A.S. Line, M.A. Corson, R. Knopp*, E. Lipkin*, M.D. Sullivan, J. Johnson, C. Griswold*, K. Liebert*, A. Brown*, D. Juliano*, E.M. Kurashige*, S. Moberg*, J. Leader Western clinical sites: Northridge Hospital Medical Center, Cardiovascular Center, Northridge, CA: K. Ariani, K. Karunaratne, M. Azizad*, C. Chow*, H. Gutierrez, J. Partamian*, J. Toven*, J. Toven, J. Mular*, S. Sanders* White Memorial Medical Center, Clinical Hypertension Services, Los Angeles, CA: L.J. Haywood, V. Kamdar*, D.L. DeQuattro, L. Wang, Z. Song, L. Becerra, A. Qi Cai*, C. Pruitt*, V. DeQuattro University of Washington Medical Center at Roosevelt, Family Medical Center, Seattle, WA: R. Failor, A. Ellsworth*, N. Jackson, C. Miller, D. Britt*, S. Dobie*, I. Hirsch*, D. Khakpour*, R. Quaempts*, W. Stoffel*, W. Neighbor*, K. Cappocia*, V.Hawkins*, L.Tapp Idaho State University, Department of Family Medicine, Pocatello, ID: R. Force, M. Macdonald, K. Pettingill, C. Liday*, S. Koester*, T. Pettinger, R. Solbrig, C. Waldron,* W. Woodhouse*, B. Hoover* S.Lusk, T. Wilcox*, D.Hachey* Naval Medical Center San Diego, Cardiology Division, San Diego, CA: P.E. Linz, P.V. Pepper, J. Kozlowski, C. Chase*, C. Griffin, D. Samuelson*, P. Gutierrez*, C. Gonzales, M. Engle*, J. Coopersmith*, S. Griffin, R. Lammers*, J. Leon*, D. Zirkle*, S. Hollingsworth* Oregon Health & Science University, Section of Diabetes, Portland, OR: M.C. Riddle, K.A. Hanavan, P.A. McDaniel, R. Swift, A.J. Ahmann*, S.C. Gammell-Matthews, D.M. Karl, V. Burden*, B. MacNeil, M. MacMurray, J. Weiss*, C. Carlson*, S.K. DesRochers*, D. Negreanu*, E.A. Stephens*, D. Gale* Washington State University, Spokane, WA: C. Wysham, D. Weeks, L. Kuntsmann, L. Maxwell*, S. Yedinak, H. Pena*, J. Kistler*, J. White*

4 Kaiser Endocrine Clinic, San Diego, CA: J. Dudl, L. Lyons, B. House, M. Murray, R. Stevenson*, P. Wu*, A. Palma*, S. Briere*, T. Wilson*, D. Becker*, K. Harden*, C. Hawley* Whittier Institute for Diabetes, Clinical Trials Department, La Jolla, CA: G. Dailey, M. Baron, A. Gianella, M. Jacobson*, E. Farro*, A. Philis-Tsimikas*, A. Banares*, A. Bravo-Medina*, J. Horne*, E. Esquer*, R. Morrissey* Minnesota-Iowa CCN: Berman Center for Outcomes & Clinical Research, Minneapolis, MN: R.H. Grimm, Jr, B.R. Kirpach, M.M. Bartkoske, C.M. Boyce*, N. Druckman*, A.M. Gillett*, J.A. Levin, G.J. Livingston, A.M. Murray, H. Wood*, HealthPartners Research Foundation, Minneapolis, MN: K.L. Margolis. Minnesota-Iowa clinical sites: Hennepin ACCORD Clinic, Minneapolis, MN: S. Kempainen, M. Madden, M.Tariq Fareed*, K. Hall*, R. Moor*, K.Wood. International Diabetes Center, Minneapolis, MN: R. Bergenstal, R. Cuddihy, B. Davick*, J. Hokanson*, M. Johnson, M. Lausch*, S. List, A. Monk, R. Robinson*, K. Smith*, D. Whipple, G. Damberg, R. Hahn*, V. Koenig*, M. Magadan, S. Sabin- Smith*, P. Stewart*, E. Strock, D. Peremislov, K. Gunyou, R. Passi . C. Ashanti, L. Thomas, D. Stoffels. University of Minnesota, Minneapolis, MN: E.R. Seaquist, M.V. Mech, L.E. Benedict*, D.J. Demmon*, D. Kendall*, A.F. Kumar*, S.M. Martinson*, S.A. Miller*, C. Pease*, J.P. Rao*, J.B. Redmon*, J.E. Swanson, J.K. Wimmer*, Y. Okorocha, M. Stiles*, C. Kodl*, C. Chadha* University of Minnesota, Phalen Village Clinic, St. Paul, MN: KA.. Peterson, L.A. Seaquist, C. Boese*, M. Cruciani*, E. Dodds, F. Parenteau Ek*, J.L. Feldman*, P. Fontaine*, C.J. Lange, T.J. Mendenhall*, A.M. Peterson*, A. Rudelt* T.M. Schrock*, D.P. Spielman*, S. Velasco*, J.C. Weinhand*. Riverside Health Partners Clinic, Department of Endocrinology, Minneapolis, MN: J.M. Sperl-Hillen, P.J. OConnor, M.E. Busch, A. Chung*, B.K. Klein*, N. Krugen*, T. Bunkers-Lawson*, H.L. Ekstrom*, H.S. Gunderson*, B.M. Johnson*, J.H. MacIndoe*, D.J. Prewedo*, J.L. Rawl*, C.M. Roethke*, Mary Quinlan, C.R. Fox, B.M. Bate, Q.T. Cao*. M.M. Ohnstad, P.J. Meyers*. University of Iowa, Health Care Diabetes Clinical Research and Programs, Iowa City, IA: W.I. Sivitz, S.M. Wayson, T.A. Lower*, L. Larson, L.A. Ahrens*, M. Bayless, S.E. Beck*, J. Chahal, C. Chenard, G.C. Doelle, V.M. Guzman, U.M. Kabadi*, K.A. Ochs*, A. Rahhal, R.G. Spanheimer*, L. Snetselaar*, K. Smith*, D. Wells*. Ohio-Michigan CCN: Case Western Reserve University, Division of Clinical and Molecular Endocrinology, Cleveland, OH: S. Genuth, F. Ismail-Beigi, M. Thibonnier*, L. Vargo*, C. Kelly*, T. Bongorno*, A. Dolish*, L. Pavlik, M. Tiktin, S. Isteitieh* A. Bartlett, T. Kulow. Ohio-Michigan clinical sites: University Hospitals of Cleveland, Division of Endocrinology, and University Hospitals Westlake Medical, Cleveland, OH: F. Ismail-Beigi, A. Krikorian, L. Moore, L. Richardson, E. Coles-Herman*, K. Yee*, J. Frankino, M. Jing*, A. Sood, L. Hustak*, M. Julius*, L. Pavlik*, T. Ross*, L. Long*, W. Schwing*, M. Tiktin*, M.K. Sullivan*, L. Strauss*, K. Behm*, F. Eskandari*, C. Hall*, D. Hayes*, K. Horowitz, S. Isteitieh*, Z. Madhun*, E. Seeholzer*, J. Shina*, H. Taylor*, A. Schnall*, S. Huang, M. Heeg, J. Tang, J. Belkin*, M.S. Lee*, T. Joly*.

5 St. Vincent Charity Hospital, Lipid Research Center, Cleveland, OH: L.S. Sadler, M. Griffith*, A. Hornsby*, K. Klyn, E. Ospelt, L. Long, M. DeSmit*, P. McCann, N.P. Schmidt*, C. Gottfried, T. Kulow, J. Zaletal*, M.S. Kapadia, L.Smith*.

University Suburban Health Center, South Euclid, OH: A.M. Schnall, L. Dragmen, R. Ellert*, J. Smith, J. Leksan, T. Sussman, S. Huang, M. Heeg, J. Tang, J. Belkin*, M.S. Lee*, T. Joly*.
Cleveland Veterans Affairs (VA) Medical Center (VAMC), Department of Medicine, and Ravenna Community Based Outpatient Clinic, Cleveland, OH: F. Ismail-Beigi, L. Hustak*, M. Julius*, W. Schwing, M. Tiktin*, J. Anselmo*, F. Eskandari*, S. Daymeyer*, C. Hall*, D. Hayes*, K. Horowitz*, S. Isteitieh*, C. Johnson*, E. Kern, M.A. Richmond*, L. Richardson, K. Roberts*, J. Shina*, A. Sood, P. Suhan*, H. Taylor*, S. Watts*, J. Martin, L. Moor*, B. Burtch*, S. Ober, G.J. Strauss, A. Leone, J. Belkin*, S. Huang*, K. Frank*, D. Stephens*, M.S. Lee*, T. Joly*. The Cleveland Clinic Foundation, Cleveland, OH: B.J. Hoogwerf*, J. Brakeman, M. Matzinger *, J. Newsome*, J. Becker*, S. Bizjack*, B. Clingman*, S. Curtas-Thomas, G. Depietro*, R. Ellert*, C. Horner, G. Bunae * , A. Hamrahian*, A. Hawkins*, T. Head*, S. Iannica*, L. Jones*, P. Kaiser, R. McCoy, A. Mehta, L. Olansky, A. Orasko, S. Reddy *, D. Ross*, L. Shockley*, E. Siraj*, M. Williams*, R. Zimmerman M.Hamaty.

Your Diabetes Endocrine Nutrition Group, Mentor, OH: D. Weiss, K.A. Fagan, T.M. Hanslik*, J. Farrell*, P. Brys*, M. Oligny, K. Prokop, K. Lenardic*, T. Karapanzcik*, S. Huang, M. Heeg, J. Tang, J. Belkin*, M.S. Lee*, T. Joly*.
Medical University of Ohio, Department of Medicine, Ruppert Health Center, Toledo, OH: B. Akpunonu, R. Franco-Saenz, J. Gilmore, M. Gilmore, L. Godfrey*, P. Ross*, B. Bauer, M. Chrisstie*, A. Lopez, P. Mulrow, C. Peters*, R. Pop-Busui*, J. Roman*, C. Smith*, J. Bick*, Z. Blust*, P.T. Nelsen, D. Marcus*. The Ohio State University Medical Center, Division of Endocrinology, Diabetes and Metabolism, Columbus, OH: K. Osei, E.A. Dziengelewski*, H. Breedlove, D. Boland*, C. Casey Boyer, S. Cataland, P. A. Kearns, J.E. Irwin, D.P. Schuster, J.L. Varga-Spangler*, T. Bowles, K. Weiland, K. Arnold; T. Evans*, J. Bouttamy, A. Letson, E. Craig, F. Davidorf. University of Cincinnati/VA Medical Center, Research Service, Cincinnati, OH: R.M. Cohen, K. Burton, J. Craig, B. Carter*, J. Harrer*, R. Hurd*, D. Lopez-Stickney*, C. Pritchard*, A. Pfefferman*, B.A. RamloHalsted*, C. McCormick, C. Riley, M. Strominger*, A. Knittel, G. Groff*, C. Bailey, A. Howald , N. Anderson, J. Laver Bierschbach, M. Tyzinski*, B. Smith*, S. Krug, V. Hershberger*, R.K. Hutchins*, L.A. Raymond*. Henry Ford Health SystemNew Center One, Detroit, MI: A.Thomas, D.M. Kahkonen*, T. Cushman, M. Roman, A.M. Stys, K. White, M. Austin*, C. Chatterton, J.K. Francis*, C. Jones*, D. Kruger, A. McLellan*, F. Whitehouse, E. Higgins*, S. Levy, A. Schoenherr*, P. Edwards. Grunberger Diabetes Institute, Bloomfield Hills, MI: G. Grunberger, L.C. Aman*, A.H. Bandagi*, K.M. Russell*, C. Tucker, Y. Abidova*, A. Amirikia, M. Narduccio, B. Billingsly. Northeastern CCN: Columbia University College of Physicians and Surgeons, New York, NY: J.T. Bigger, C.R. Lopez-Jimenez, R. Bornholdt, L. Busaca, H.N. Ginsberg, P. Gonzales, D. Gosh*, P. Love, A. Kosok*, E. Robinson*, R. Steinman, C. Watson, G. Reyes.

6 Northeastern clinical sites: Jacobi Medical Center, Bronx, NY: U.K. Schubart, M. Mendoza, G. Goswami, A. Laufer*, J. Russo, N. Vincenty. Albert Einstein General Clinical Research Center, Bronx, NY: M.H. Alderman, L. Carroll, M.J. Sanguily*, J.U. Gorkin, A.C. Mayer, L. Ramos, V. Sessoms, A. Fritts Stewart*. Cornell Internal Medicine Associates, New York, NY: D. Brillon, J. Cordero, M.A. Richardson, E. Wei, F. Ganz, B.R. Meyer, J. Paley*, S. Anderson*, C. Charles*, A. Dwoskin*, R. Chiong*, K. Hyams. The Diabetes Care and Information Center of New York, Flushing, NY: D.L. Lorber, T. Arenstein*, P. Depree, A.A. Elmorsy*, J.M. Wendel, L.L. Zintl*, P. August, M. Beck*, M.D. Goldberg, M.J. Hofacker*, M. Marotta-Kollarus*, E.J.L. Ocampo, C.A. Resta, J.M. Tibaldi. The Cooper Health System, Cherry Hill, NJ: A. Bastien*, S. Grudzinski*, P. Niblack, L. Abreu*, T. Brobyn, K. Brown*, M. Casale*, D. Dougherty*, G. Haddad, K. Heintz, M. Kelly,* D. Linneman*, C. Olivia, M.A. Salvador*, P. Zee*, D. Hyman. The Cooper Health System, Cherry Hill, NJ: A. Bastien*, S. Grudzinski*, P. Niblack, L. Abreu*, T. Brobyn, K. Brown*, M. Casale*, D. Dougherty*, G. Haddad, K. Heintz, M. Kelly,* D. Linneman*, C. Olivia, M.A. Salvador*, P. Zee*, D. Hyman. Great Lakes Medical Clinic Research, Westfield, NY: D.F. Brautigam, R. Fischer, J.M. Chiarot, D.M. Scharf*, B. Nunn*, J. Carlson, C. Flanders*, M.R. Hagen, S. Newman, T.A. Gordon. Naomi Berrie Diabetes Center, New York, NY: R. Goland, C.H. Tuck, P. Kringas, J. Hey-Hadavi*, J. Montes*, J. Vargas-Jerez, J. Salas-Spiegel. Ambulatory Care Network at Columbia University, New York, NY: A. Getaneh, J. Ramirez*, E.F. Vasquez*, G. Kranwinkel*, S.A. Durant. Irving Diabetes Research Unit, New York, NY: D.S. Donovan, G. Febres*, C. Hernandez*, M.A. Jonaitis, L. Mesa*. State University of New York Downstate Medical Center, Brooklyn, NY: M.A. Banerji, M. Norton, P. Patel*, V. Daly, S. Hirsch, C. Jazmin, R. Khillan, D. Mendonca, A. Relingado, E. Sandoval, M. Tiewala. Kings County, Brooklyn, NY: M.A. Banerji, M. Norton, P. Patel*, V. Daly, S. Hirsch, C. Jazmin, R. Khillan, D. Mendonca, A. Relingado, E. Sandoval, M. Tiewala. The Cooper Health System, Cherry Hill, NJ: A. Bastien*, S. Grudzinski*, P. Niblack, L. Abreu*, T. Brobyn, K. Brown*, M. Casale*, D. Dougherty*, G. Haddad, K. Heintz, M. Kelly,* D. Linneman*, C. Olivia, M.A. Salvador*, P. Zee*, D. Hyman. Southeastern CCN: Wake Forest University School of Medicine, Department of Public Health Sciences, Winston-Salem, NC: D.C. Goff, Jr, J.H. Summerson, L. Crago, C.S. Blackwell*, A. Bertoni*, R.L. Blaine*, J.K. Kirk, R.L. Spach, J. Williamson, J. Calles, J. Katula, D.B. Wishnietsky*. Southeastern clinical sites: Duke University Medical Center, Durham, NC: M.N. Feinglos, J. Jones, M.B. Mason, M.A. Furst, W.J. Bean*, G. Gedon-Lipscomb, J.B. Green, T. Parham*, B.M. Satterwhite*, C.R. Thacker.

7 Constant Care, Inc., Valdosta, GA: D. Padhiar, R. Noel*, N. Padhiar, S. West*, J. Braden, A Francis*. Wake Forest University School of Medicine, Department of Geriatrics/Gerontology, Winston-Salem, NC: H.H. Atkinson, M. Dibari*, J. Allen, J. Stanfield, T. Delvalle-Fagan, L.J. Gordineer, L. Gordon, M. Gordon*, S.L. Smith*, H. Yates.* Downtown Health Plaza, Winston-Salem, NC: C.F. Pedley, G. Zurek, M. Baird, B. Dunn*, W. Kinder*, S. Mauney. University of North Carolina, Diabetes Care Center, Chapel Hill, NC: J.B. Buse, M.D. Duclos, R.E. Kirby*, J.F. Largay, N.M. McDermott*, A. Goley, S.S. Braithwaite*, J.M. Dostou, E.A. Fasy*, D.C. Kelly*, C.E. Metz*, J. Jeffries*, D. Rubin*, K. Vukojicik. Holston Medical Group, Kingsport, TN: J.L. Miller, W. Besterman, S.M. Norton*, J. Weatherly*, S. Bishop*, B. Cross, K. Nuss*, M. Surgenor*, D. Alley*, A. Farmer*, J. Foard, J. White, Y. Wood*. Carolinas Medical Center Family Practice, Charlotte, NC: M. Dulin, J. Konen*, T. Barringer*, K. Andrews*, C. Hoffman*, C. Morris*, S. Norton, P. Tochiki*, G. Reinblatt*, P. Bruner*. Robeson Health Care Corporation, Fairmont Clinic, Fairmont, NC: R. Peace, D.O. Stuart*, J. Strickland, L. Cummings*, D. Craig*, J. Stanfield*, J. Morgan*. Robeson Health Care Corporation, Julian T. Pierce Clinic, Pembroke, NC: R. Peace, D.O. Stuart*, J. Strickland, L. Cummings*, D. Craig*, J. Stanfield*, G. Williams*. Wake Forest University School of Medicine, Departments of Internal Medicine and Endocrinology, Winston-Salem, NC: J.R. Crouse, L. Menon, S. Marion*, D. Davis*, B. Cabrera*, J. Calles, T. Chandler, J. Ellis, E. Kouba, P. Riddle, E. Myers*. Tulane University Health Science Center, New Orleans, LA: V. Fonseca, J. John-Kalarickal*, R.H. McDuffie, N.O. Asafu-Adjaye, S.M. Leger, P. Reilly, G. Afner, F. Arrey*, S. Asnani, E. Borshard*, D. Boyd*, A.Cemo, S. Chennur*, P. Dupart, R. Garg*, G.P. Girindra*, B. Gouda*, W. Itoua-NGanongo*, I. Innocent-Ituah*, C. Johnson*, N. Kuhadiya, M. Kukreja*, I. Mangan-Mbondi*, S. Mason*, C. McLain, J. Naylyanya*, K. Nazereth*, S. Nazereth*, S. Singh, T. Thethi, K. Varnado*, R. Williams*. Kaiser Permanente, Clinic Atlanta Crescent Medical Center, Tucker, GA: J.I. Barzilay, M. Eley*, K. Bader, D. Curry-Ball, S. Goodman*, M. Stevens. VA CCN: Memphis VAMC, Memphis, TN: William C. Cushman, Therese S. Geraci, Sandra M. Walsh, Linda G. Coley, Marshall B. Elam, Diane I. Pickering*, C.Huff. VA clinical sites: Memphis VAMC, Hypertension/Lipid Research Clinic, Memphis, TN: M.B. Elam, C.W. Thompson*, L. Lichtermann, S. Peeples, J. Turner-Bates*, M. Heimberg, D. Childress, J. Turner, J. Jasper*, J. Coley. Baltimore VAMC, Baltimore, MD: B.P. Hamilton, J. Hamilton, G. Kuzbida*, W. Hatten, Jr, A. Lancaster, J. Haywood, J.Luck, D. Bannerman-Wood*. Carl T. Hayden VAMC, Phoenix, AZ: J. Felicetta, M. Bourne- Collo*, M.E. Svoboda, D. Clothier*, M. Deitz, C. Flaugher*, P. Hayward*, T. Scheibe*, S. Velarde, S. Heritage*, J.P. Nelson, D. Heritage*, C.Martinez* .

8 Atlanta VAMC Medical Service, Decatur, GA: M.E. Sweeney, D. Harrelson*, S. McConnell, F. Watson, R. Johnson, L. Whittington, M. Nanes, M. Salles, C Rice*, C. Cowden*. Ralph H. Johnson VAMC, Primary Care, Charleston, SC: J. Basile, S.U. Rehman, D.B. Ham, B. North-Lee*, H.A. Baig, J. Mixson, D Nelson*. G. V. (Sonny) Montgomery VAMC, Research Department, Jackson, MS: K.A. Kirchner, L.A. Hinton, L. Mack*, C. Adair*, B. James*, A. Spencer, A. Jones. VA NY Harbor Healthcare System, New York, NY: L. Katz, E.A. Richardson, A.G. Goldberg*, A. Nieves*, J.E. Russo*, J. Adams*, S.A. Sochalski*, M.Coles*, S. Anderson*, M. Williams*D. Hoffman. Washington VAMC, Washington, DC: V. Papademetriou, B. Gregory, R. Alignay*, E. Nylen, B. Rajendran, R. Hodges, S. Amodeo, A. Ross*, A. Notargiacomo*, M. Metcalfe*, P. Narayan*, D. Wojackovski* St. Louis VAMC, St. Louis, MO: S. Giddings, E. Clark, A. Pittler, R. Davis*, P. Harris, K. Waidmann, L. Conwill, S. Felton, A. Chen. Central Arkansas Clinic Healthcare System, Little Rock, AR: D.L. Simmons, J.J. Cooper*, K. Dishongh, R. Bates*, K. Bhaghayath*, P. Choksi*, S. Conley*, S. Elbein*, F. Faas, Z. Hamid*, J. Johnson, P. Johnson*, A. Mayo*, M.S. Moriarty*, G. Nair*, D. Rani*, N. Rasouli*, S. Said*, N. Rassouli*, M. Rodriguez*, K. Thomas*, K. Watson*, D. Williams*, A. Makdissi. Coordinating Center: Wake Forest University School of Medicine, Winston-Salem, NC: R.P. Byington, W.T. Ambrosius, R.T. Anderson*, J. Barnes, J. Beal, C. Bell*, D.E. Bonds*, S. Burton,* C. Collins, D. Cook, B. Craven, T. Craven, D. Dunbar*, G. W. Evans, P. Feeney*, C. D. Furberg, C. M. Greven, J. Griffin, L. Harvin, J. Hepler, L. Howard*, L.T. Howard-Perdue, M. Hough, W. Hwang*, A. Kimel, D. Lefkowitz, A. Lopina*, J. Lovato, L.C. Lovato, M.E. Miller, D. Reboussin*, S. Rushing, L. Sanders, L. Sims, C. Stowe, M. Walkup*, S. Wilmoth, K. Wilson, N. Woolard. Drug Distribution Center: VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, Albuquerque, NM: D. Raisch, R. Ringer, M. Sather, B. DelCurto, D. Garnand. ECG Reading Center: Wake Forest University School of Medicine, Winston-Salem, NC: R. Prineas*, C. Campbell, Z. Zhang, L. Kesler, S. Hall*, S. Hensley, Y. Li, E. Solomon, D. Milne Central Chemistry Laboratory: Northwest Lipid Research Laboratories, Seattle, WA: S. Marcovina, J. Chmielewski, K. Gadbois, V. Gaur, G. Strylewicz, M. Ramirez, S. Waddell, M. Mehan*. ACCORD-MIND MRI Reading Center: University of Pennsylvania, Philadelphia, PA: R.N. Bryan, C. Davatzkios, G. Moonis, L. Desiderio, S. DArcy*. Fundus Photograph Reading Center: University of Wisconsin Medical School, Madison, WI: M. Davis, R. Danis, S. Johnson*, N. Robinson, L. Hubbard, B. Esser, D. Thayer, M. Neider, K. Glander, M. Burger, V. Gama, G. Guilfoil, M. Schiffman, H. Wabers, J. Dingledine, T. Graham*. Project Office: National Heart, Lung, and Blood Institute (NHLBI), Bethesda, MD: D.G. Simons-Morton, L. Cooper*, M. Domanski, C. Nwachuku*, Y. Rosenberg, M. Salive*, P. Savage, J.L. Fleg, J.A. Cutler, N. Geller, D. Follmann*, M. Proschan*, C. Jennings, E. Schaeffer*, P. Mills,* J. Bittner*, R. Kirby, P. Frommer, L. Fine, J. Chan*.

9 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD: J. Fradkin, S. Malozowski, C. Meyers, T. Hostetter*. National Institute on Aging (NIA), Bethesda, MD: L. Launer. National Eye Institute (NEI), Bethesda, MD: E.Y. Chew. Centers for Disease Control and Prevention (CDC), Atlanta, GA: A. Albright, K.M.V. Narayan, M. Engelgau*, P. Zhang. DSMB: Antonio M. Gotto. Jr. (chair), Kent Bailey, Dorothy Gohdes, Steven Haffner, Roland Hiss, Kenneth Jamerson, Kerry Lee, David Nathan, James Sowers, LeRoy Walters.

* No longer affiliated with study unit. Deceased.

10

Section 2. Consort Diagram

Screened N = 19,716

Did not meet eligibility criteria: N = 1915 Screen incomplete: N = 6774

Enrolled in Overarching Glycemia Trial N = 10,251

Eligible, but ultimately not randomized: N = 776

Eligible for Blood Pressure Trial Only N =4725

Eligible for Both BP and Lipid Trials N=2773

Eligible for Lipid Trial Only N = 2753

Allocated to/Enrolled in BP Trial N = 4733

Randomized to Intensive Therapy N = 2362

Randomized to Standard Therapy N = 2371

Lost to Follow-up: N = 29 Discontinued Intervention: N = 72

Lost to Follow-up: N = 29 Discontinued Intervention: N = 61

Analyzed: N = 2362 Excluded from Analysis: N = 0

Analyzed: N = 2371 Excluded from Analysis: N = 0

11

Section 3. ACCORD Design and Details of Allocation to Blood Pressure and Lipid Trials (Details from ACCORD Protocol, found on
www.accordtrial.org) ACCORD was designed as a double 2X2 factorial trial of 10,000 eligible participants. The factors employed in the design were: intensive versus standard glycemic control, intensive versus standard blood pressure control, and, in the presence of LDL-C lowering, fibrate versus placebo. As shown in the figure below, all 10,000 required participants were randomized to one or the other glycemic treatment groups, and to either blood pressure or lipid trial treatment groups in two non-overlapping 2 X 2 layouts. Specifically, and based upon the sample size requirements for the separate blood pressure and lipid trials, it was planned that 4200 blood pressure-eligible participants would assigned to and randomized within the blood pressure trial and 5800 lipid participants to and within the lipid trial.

Blood Pressure Trial Glycemia Trial A1c < 6.0% SBP < 120 SBP < 140 mm Hg mm Hg

Lipid Trial Fibrate Placebo

1050 1050 2100 4200

1050 1050 2100

1450 1450 2900

1450 1450 2900

5000 5000

7.0% < A1c < 7.9%

5800

10000

All 10,000 participants had to be eligible for the overarching glycemia trial and for either the blood pressure and/or lipid trial. Participants eligible for the lipid trial but not the blood pressure trial were randomized to one of the four cells in the lipid and glycemic control 2 X 2 layout; similarly for those eligible for the blood pressure intervention but not the lipid intervention. Participants eligible for both the lipid and the blood pressure interventions were randomly assigned to one or the other trial using probabilistic weights designed to ensure that the 4200 BP/5800 Lipid split was efficiently achieved. Because progress towards the BP goal of 4200 subjects was more rapid than progress towards the Lipid goal of 5800, the vast majority of participants eligible for both trials were allocated to the Lipid trial (see consort diagram). Furthermore, the BP trial was allowed to over-recruit in order to efficiently meet the goal of 10,000 subjects enrolled for the glycemia trial. Ultimately, when recruitment was finished for the overarching glycemia trial, recruitment stopped for the BP and lipid trials. Overall, 10,251 participants were recruited for the glycemia trial, with 4733 also enrolled in the BP trial and the remaining 5518 enrolled in the Lipid trial.

12

Section 4. Eligibility Criteria for the ACCORD BP Trial (Details from

ACCORD Protocol, found on www.accordtrial.org)

1. Eligible for the glycemia trial. 2. Systolic BP was: a. 130160 mm Hg, inclusive, if the participant is on 0, 1, 2, or 3 antihypertensive medications, b. 161170 mm Hg, inclusive, if the participant is on 0, 1, or 2 antihypertensive medications, or c. 171180 mm Hg, inclusive, if the patient is on 0 or 1 antihypertensive medication 3. The dipstick protein in a spot urine test must have been <2+, or the protein/creatinine ratio in a spot urine test must have been <700 mg/g creatinine, or the 24-hr protein excretion must have been <1.0 g/24 hr. 4. For screenees who were not on BP-lowering medication at screening, there must have been documentation of systolic BP 130 mm Hg on at least 2 occasions within 3 months prior to randomization.

13

Section 5. The ACCORD Vanguard Period

(Details from ACCORD Protocol, found on www.accordtrial.org) Because of the complexity of the planned protocol, the ACCORD Data and Safety Monitoring Board (DSMB) recommended in 2000 that various aspects of the protocol be tested during the first two years of recruitment, treatment, and follow-up. This period (January 2001 through December 2002) was designated as the ACCORD Vanguard Phase. The overall purpose of this phase was to assess the feasibility of recruitment, achievement of glycemia and blood pressure treatment goals, and achievement of an acceptable level of adherence in the masked lipid trial. The following were the specific goals of the Vanguard phase, which were used to judge its success.

Recruitment. The goal was to randomize 1,000 Vanguard participants within four months after the first randomization. Glycemia control. There were two glycemia control goals, which were analyzed in participants with at least 8 and 12 months of post-randomization follow-up: a) the median achieved HbA1c in the intensive group would be less than 6.5%, and b) the difference in median HbA1c between the standard and intensive groups would be at least 1.3%. Blood Pressure. The study target is 20 mm Hg difference between the two BP arms. Evidence suggests that a 10-12 mm Hg difference may produce a 20% effect on CVD events. The target for the end of the Vanguard period was 10 mm Hg, which allowed time to titrate medications. An achieved mean SBP < 130 mm Hg in the intensive BP group was considered adequate for the Vanguard phase, if it also was 10 mm Hg lower than the less intensive group. Lipid. Targets for assessment of the fibrate intervention were based on adherence. The target adherence rate to fibrate and to statin was at least 80% as measured by simple self-report. During this period, 1174 participants were randomized over a 5-month period (1000 of them within 4 months and one day) and treated/followed for the next year and a half. On the basis of the outcomes of the targeted measures noted above, protocol changes were proposed, reviewed, and approved in the winter of 2002. To achieve the total sample size goal of 10,000 participants, it was planned that approximately 8800 additional participants would be randomized during the main component of ACCORD study (i.e., Vanguard participants would continue to be treated and followed until the planned end of the trial in 2009). Main trial randomizations began in February 2003. The ACCORD recruitment goal of 10,000 participants (Vanguard + Main Trial) was reached on September 30, 2005. The last patient (the 10,251st) was randomized on October 29, 2005. Exit visits for all participants occurred between March and June 2009.

14

Section 6. ACCORD Outcomes

The primary and secondary outcomes presented in the ACCORD Blood Pressure Results paper are described in the ACCORD Protocol (www.accordtrial.org). A) Primary Outcome: a composite of nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular disease (CVD) death: (1) Cardiovascular causes of death include fatal MI, congestive heart failure, documented arrhythmia, death after invasive cardiovascular interventions, death after noncardiovascular surgery, fatal stroke, unexpected death presumed to be due to ischemic CVD occurring <24 hours after the onset of symptoms, and death due to other vascular diseases (e.g., pulmonary emboli, abdominal aortic aneurysm rupture). (2) The diagnosis of MI is based on the occurrence of a compatible clinical syndrome associated with diagnostic elevation of cardiac enzymes (i.e., an increase in troponin T or troponin I to a level indicating myonecrosis and/or an increase in creatine kinase myocardial band to a level more than twice the upper limit of normal). Q-wave MI is defined as the development of new significant Q waves. Silent MI is diagnosed when new (compared with the previous 12-lead electrocardiogram) significant Q waves are detected by surveillance electrocardiography performed every 2 years and at study end in all participants. (3) Stroke is diagnosed by a focal neurologic deficit that lasts >24 hours, associated with evidence of brain infarction or hemorrhage by computed tomography, MRI, or autopsy. Specifics describing the above are presented in Part D below. B) The Secondary Outcomes are: (1) Expanded macrovascular outcome: the combination of the primary end point plus any revascularization and hospitalization for congestive heart failure (2) Major coronary artery disease events: fatal events, nonfatal MI, and unstable angina (3) Nonfatal Myocardial Infarction (4) Total stroke: combined fatal and nonfatal stroke (5) Nonfatal Stroke (6) Total mortality (7) Cardiovascular mortality (8) Congestive heart failure: death or hospitalization for heart failure (with documented clinical and radiologic evidence)

15 C) Prespecified Subgroups We examined consistency of the intervention effect on the primary outcome among nine prespecified subgroups using statistical tests of interaction between the treatment effect and the subgroup within the Cox models. Pre-specified subgroups included gender, age, ethnicity, prior CVD, glycemia-group assignment, baseline A1C, SBP and DBP tertiles at baseline, and number of BP medications at screening D) Multiple Comparisons Since we conducted 17 statistical tests of hypotheses related to secondary endpoints and subgroups, there was a 58% chance (i.e., 1 [1 0.05]17) that at least one of these tests would be statistically significant at an alpha level of 0.05, assuming independence between tests E) ACCORD Event Ascertainment and Adjudication Processes

Events ascertainment was performed at 4 month visits common to all treatment groups and was based on participant self-report in response to a series of questions concerning hospitalization, emergency room visits and out of hospital procedures occurring since the last clinic visit. When participants missed clinic visits, sites attempted to contact the participant and perform events ascertainment by phone. Ascertainment for silent (unrecognized) MI was based on 12-lead ECG readings obtained at baseline and at the biennial follow-up visits (i.e., every 2 years) and close-out visit. For participants lost to follow-up or refusing further contact, ascertainment of vital status was supplemented in 2009 with a National Death Index (NDI) search of deaths that occurred through 2007 (the latest data available) . For total mortality and cardiovascular deaths, the censoring time was the date of the last participant contact, whether or not events ascertainment was performed, or the last date checked in National Death Index search, whichever was later. For non-fatal events, the censoring time was taken as the date of the last visit at which events ascertainment was performed (Q4 month visits, closeout visits).
ACCORD utilized a centralized adjudication process for all deaths, and hospitalizations

for myocardial infarction and strokes. Upon identification of a potential outcome, clinical site staff obtained medical records (if the outcome was a hospitalization) or details regarding the case (if the case was an out-of-hospital death). Personal identifiers and information that may have alerted adjudicators to treatment assignment (e.g. A1C values) were masked by the clinical site and the medical records sent to the Coordinating Center. At the Coordinating Center, the case was assigned to two reviewers who completed their adjudication independently. Two criteria were followed when making assignment. First, the reviewers must be in different Clinical Center Networks, and second, the reviewer could not be affiliated with a clinical site within the Clinical Center Network of the clinical site submitting the case. Reviewers consisted of physicians (general internists, cardiologists, and endocrinologists) associated with the study and serving on the Morbidity and Mortality committee. Stroke cases were also independently reviewed by an experienced stroke adjudicator in addition to the two primary reviewers. Cases in which the original reviewers agreed on the primary

16

outcome (myocardial infarction, stroke, or cause of death) were considered closed. If there was disagreement between the two (or three in the case of stroke) primary reviewers, the case was presented to the entire Morbidity and Mortality committee and consensus obtained on the outcome.
F) Components of the ACCORD Primary Outcome

Each component of the ACCORD Primary Outcome (the first occurrence of a nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular death) had a prespecified definition that was described in the protocol and used for adjudication. These outcomes are described here.
Cardiovascular Death

Unexpected death: Unexpected death presumed to be due to ischemic cardiovascular disease, occurring within 24 hours of the onset of symptoms without confirmation of cardiovascular disease, and without clinical or post mortem evidence of other etiology. Fatal Myocardial infarction (MI): death within 7 days of the onset of documented MI (see below for definition of MI). Congestive heart failure (CHF): death due to clinical, radiological or postmortem evidence of CHF without clinical or postmortem evidence of an acute ischemic event (cardiogenic shock to be included). Death after invasive cardiovascular interventions: death associated with the intervention, i.e., within 30 days of cardiovascular surgery, or within 7 days of cardiac catheterization, arrhythmia ablation, angioplasty, atherectomy, stent deployment, or other invasive coronary or peripheral vascular intervention. Documented arrhythmia: death due to bradyarrhythmias or tachyarrhythmias not associated with an acute cardiac ischemic event. Death following non-cardiovascular surgery: death due to cardiovascular causes as defined above within 30 days of surgery. Stroke: death due to stroke occurring within 7 days of the signs and symptoms of a stroke (see below for definition of stroke). Other cardiovascular diseases: death due to other vascular diseases including pulmonary emboli and abdominal aortic aneurysm rupture. Presumed cardiovascular death: Suspicion of cardiovascular death with supporting clinical evidence that may not fulfill criteria otherwise stated. Example: Patient admitted with typical chest pain of 3 hours duration and treated as an MI, but without ECG and enzymatic documentation to meet usual criteria.

17 Myocardial Infarction

The definitions for MI are presented below. If necessary for a definition, prolonged ischemic symptoms must last 20 minutes, and the cardiac enzymes of interest are Troponin T or I and/or serum CK-MB mass. Silent MIs will be identified by the ACCORD ECG Reading Center. Q-wave MI: Diagnosis based on the occurrence of a compatible clinical syndrome with prolonged ischemic symptoms, associated with the development of new significant Q waves (defined in the ECG Reading Center Manual of Procedures). Diagnostic elevation of cardiac enzymes will include: increase in CK-MB mass to a level > twice the upper limit of normal, and/or and increase in Troponin T or I to a level that indicates myonecrosis in the laboratory performing the study. Non Q-wave MI: Diagnosis based on the occurrence of a compatible clinical syndrome with prolonged ischemic symptoms, associated with elevation of serum enzymes, as for Q-wave MI. Only in the case that both Troponin and CK-MB mass measurements are not available, would the elevation of total CK to > twice the upper limit of normal qualify for diagnosis. Silent (unrecognized) MI: development of new significant Q waves without other evidence of myocardial infarction (the date of event will be assigned halfway between the date of discovery and last normal ECG). Probable non Q-wave MI: Diagnosis based on the occurrence of a compatible clinical syndrome with prolonged ischemic symptoms, without documentation of cardiac enzyme elevation, but associated with the development of new and persistent significant ST-T changes (>24 hr in duration). (Changes are defined in the ECG Reading Center Manual of Procedures). MI after cardiovascular invasive interventions Diagnosis based upon the occurrence of CK-MB (or Troponin) elevations to a level increased 3-5 times normal for the laboratory performing the studies, occurring within 7 days of cardiac catheterization, arrhythmia ablation, angioplasty, atherectomy, stent deployment or other invasive coronary, carotid or peripheral vascular intervention. MI after coronary bypass graft surgery: Diagnosis based upon the occurrence of CK-MB (or Troponin) elevations to a level increased > 5-10 times normal for the laboratory performing the studies, occurring within 30 days of cardiac surgery. MI after non-cardiovascular surgery: MI (as defined above), occurring within 30 days of non-cardiovascular surgery.
Stroke

Definite ischemic stroke: CT or MRI scan within 14 days of onset of a focal neurological deficit lasting more than 24 hours with evidence of brain infarction (mottled cerebral

18

pattern or decreased density in a compatible location), no intraparenchymal hemorrhage by CT/MRI, no significant blood in the subarachnoid space by CT/MRI or by lumbar puncture, or autopsy confirmation. A nonvascular etiology must be absent. Definite primary intracerebral hemorrhage: Focal neurological deficit lasting more than 24 hours. Confirmation of intraparenchymal hemorrhage in a compatible location with CT/MRI scan within 14 days of the deficit onset, or at autopsy, or by lumbar puncture. Subarachnoid hemorrhage: Sudden onset of a headache, neck stiffness, loss of consciousness. There may be a focal neurological deficit, but neck stiffness is more prominent. Blood in the subarachnoid space by CT/MRI or lumbar puncture or intraventricular by CT/MRI. Stroke of unknown type etiology: Definite stroke of unknown etiology when CT, MRI, or autopsy are not done. Information is inadequate to diagnose ischemic (infarction), intracerebral hemorrhage, or subarachnoid hemorrhage. Non-fatal stroke after cardiovascular invasive interventions: stroke associated to the intervention within 30 days of cardiovascular surgery, or within 7 days of cardiac catheterization, arrhythmia ablation, angioplasty, atherectomy, stent deployment or other invasive coronary or peripheral vascular interventions. Non-fatal stroke post non-cardiovascular surgery: stroke (as defined above) occurring within 30 days of non-cardiovascular surgery.

19

Section 7: Serious Adverse Events (SAEs)

Serious Adverse Events (SAEs) were reported to the ACCORD Coordinating Center by the investigator. SAEs in ACCORD were defined as any adverse experience that was significantly life threatening and/or resulted in permanent disability, hospitalization or prolongation of hospitalization and were considered by the investigators to be possibly, probably, or definitely related to antihypertensive medications. If an event met the definition for a SAE, a Serious Adverse Event Form was completed and reported within 24 hours of discovering the event. The five specific types of serious adverse experience that were reported for the ACCORD BP trial were: Death Any life threatening event any event that posed a significant risk of death Any event resulting in persistent or significant disability Any hospitalization Any prolongation of hospital stay Events that were part of the primary and secondary ACCORD outcomes (examples: deaths, MI, stroke, unstable angina) were NOT considered SAEs unless the Investigator believed that an ACCORD study drug or device caused the event or contributed to the immediate cause of the event.

20

Section 8: Blood Pressure Management

The BP management approach used in the ACCORD BP trial has been described in detail elsewhere.1 Visit schedules for BP management differed by treatment group. For intensive participants, BP assessment visits occurred monthly for 4 months and every 2 months thereafter. For standard participants, BP assessment visits occurred at months 1, 4, and every 4 months thereafter. Additional visits occurred as needed in both groups to monitor and assure appropriate implementation of the study intervention strategies. During management visits , SBP, DBP, and pulse rate were based on the average of three measurements using an automated device (Omron 907) after 5 minutes rest with the participant seated in a chair. For standard BP group participants, medication dose titration or addition of another drug was indicated if SBP was >160 mm Hg at a single visit or >140 mm Hg at two successive visits. Down-titration was encouraged if SBP was <135 mm Hg on two successive visits or <130 mmHg at any single visit. For intensive group participants, medication dose titration or addition of another drug was indicated whenever SBP was 120 mm Hg. For participants not at goal, addition of another drug from a different class was required during Milepost visits occurring every 4 months during the first 2 years and annually thereafter, unless there was a compelling reason not to do so. The ACCORD BP trial tested a strategy of treatment to specific SBP goals, rather than testing any specific drug regimen. All major classes of antihypertensive drugs and many combination medications were provided by the study (see Table). All antihypertensive regimens were to include a drug class that had demonstrated reduced cardiovascular events in participants with diabetes: diuretic, beta-blocker, calcium channel blocker (CCB), angiotensin converting-enzyme (ACE) inhibitor, or angiotensin receptor blocker (ARB).2-6 For intensive participants, a combination of a diuretic and either an ACE inhibitor or a beta-blocker was recommended as initial therapy.7
REFERENCES 1. Cushman WC, Grimm RH, Cutler JA, et al, for the ACCORD Study Group. Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99(suppl):44i55i. 2. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560 2571. 3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ, for the National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206 1252.

21 4. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-2997. 5. Whelton PK, Barzilay J, Cushman WC, Davis BR, Ilamathi E, Kostis JB, Leenen FHH, Louis GT, Margolis K, Mathis DE, et al, for the ALLHAT Collaborative Research Group. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005;165:14011409. 6. Wright JT Jr, Probstfield JL, Cushman WC, Pressel SL, Cutler JA, Davis BR, Einhorn PT, Rahman M, Whelton PK, Ford CE, Haywood LJ, Margolis KL, Oparil S, Black HR, Alderman MH; ALLHAT Collaborative Research Group. 7. Materson BJ, Reda DJ, Cushman WC, Henderson WG, for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. Results of combination antihypertensive therapy after failure of each of the components. J Hum Hypertens 1995;9:791796.

22

Section 9. Blood Pressure Intervention Medications

Class ACE-inhibitor ACE-inhibitor ACE-inhibitor Diuretic Beta-Blocker CCB non-DHP CCB-DHP Alpha blocker ARB ARB Loop Diuretic Sympatholytic Vasodilator Alpha-Beta Blocker K-sparing / Diuretic BBL / Diuretic ACE-I / Diuretic ACE-I / Diuretic ARB / Diuretic ARB / Diuretic CCB-DHP / ACE-I Potassium Agent Benazepril (Lotensin) Lisinopril (Zestril) Ramipril (Altace) Chlorthalidone (Thalitone) Metoprolol (Toprol XL) Diltiazem (Tiazac) Plendil (Felodipine) Terazosin (Hytrin) Candesartan (Atacand) Valsartan (Diovan) Furosemide Reserpine Hydralazine Carvedilol (Coreg) Triamterene / HCTZ (Dyazide) Metoprolol / HCTZ (Lopressor HCT) Benazepril / HCTZ (Lotensin HCT) Lisinopril / HCTZ (Zestoretic) Candesartan / HCTZ (Atacand HCT) Valsartan / HCTZ (Diovan HCT) Amlodipine / Benazepril (Lotrel) Potassium Chloride Doses 10mg, 20mg 10mg, 20mg, 40mg 2.5mg, 5mg, 10mg 15mg, 25mg 50mg, 100mg, 200mg 120mg, 180mg, 240mg, 300mg 2.5mg, 5mg, 10mg 1mg, 5mg, 10mg 8mg, 16mg, 32mg 80mg, 160mg 20mg, 40mg, 80mg 0.1mg, 0.25mg 25mg, 50mg, 100mg 3.125mg, 6.25mg, 12.5mg, 25mg 37.5 / 25mg 50 / 25 mg, 100 / 25 mg 10 / 12.5 mg, 20 / 12.5 mg, 20 / 25 mg 10 / 12.5 mg, 20 / 12.5 mg, 20 / 25 mg 16 / 12.5 mg, 32 / 12.5 mg 80 / 12.5 mg, 160 / 12.5 mg 5 / 10 mg, 5 / 20 mg, 5 / 40 mg, 10 / 40 mg 20mEq

Other drugs not supplied by the trial could be used as the investigator deemed appropriate.

23

Section 10. Results Medications Used by Participants at Study Entry

Medications

Overall (N=4733) 87.3 52.1 16.9 68.2 26.1 25.5 18.5 1.8 36.9 57.4 47.4 21.3 52.3 54.4 64.8 11.7 70.0

Intensive Therapy (N=2362) 88.0 52.9 16.2 68.4 25.3 26.2 19.2 1.9 36.4 56.9 48.9 21.1 53.5 56.0 63.9 12.4 69.6

Standard Therapy (N=2371) 86.7 51.3 17.6 68.1 27.0 24.8 17.7 1.7 37.4 57.8 45.9 21.5 51.0 52.8 65.6 11.0 70.4

P-value 0.16 0.26 0.19 0.85 0.18 0.27 0.18 0.65 0.48 0.56 0.04 0.75 0.08 0.03 0.21 0.12 0.57

Any anti-hyperensive agent (%) Antiotensin-converting enzyme (ACE) inhibitor (%) Angiotensin receptor blocker (ARB) (%) ACE or ARB (%) Any thiazide type diuretic (%) Beta-blocker (%) Calcium Channel Blocker (%) Alpha Blocker (%) Insulin (%) Metformin (%) Any sulfonylurea (%) Any thiazolidinedione (%) Aspirin (%) Platelet inhibitors (including Aspirin) (%) Statin (%) Other lipid-lowering agent (%) Any lipid-lowering agent (%)

24

Section 11: Results Medications Prescribed at 12 Months and Last Visit

12 Months Medication ACE inhibitor Angiotensin-receptor blocker (ARB) ACE inhibitor or ARB Diuretic Beta blocker Calcium channel blocker Alpha blocker Reserpine Other Anti-hypertensive Intensive % 66 35 93 83 54 41 16 8 4 Standard % 54 24 76 52 33 18 6 1 1 Last Visit Intensive % 60 41 90 80 61 42 23 7 8 Standard % 52 30 80 56 43 24 11 1 4

Insulin Metformin Any sulfonylurea Any thiazolidinedione

56 77 53 57

56 78 53 59

62 63 39 24

63 69 39 26

Aspirin Any platelet inhibitor (including Aspirin) Statin Other lipid-lowering agent Any lipid-lowering agent

57 57 56 14 61

56 60 59 18 64

56 58 57 13 62

59 62 58 18 63

Number of Anti-Hypertensive Classes 0 1 2 3 4 5 1 8 24 32 23 12 12 28 29 21 7 2 1 8 20 30 23 18 7 24 30 23 12 4

12 Month Visit, Intensive Therapy group N=2170, Standard Group N=2208 Last Visit for each Pariticpant, Intensive Group N=2303 and Standard Group N=2306

25

Section 12: Results Visit Adherence in ACCORD BP Trial by Months Post-Randomization

Number of Expected* Visits 2357 2350 2342 2333 2325 2317 2306 2294 2284 2275 2268 2092 1851 1602 1385 1110 833 528 232 209 208 206 205 203 Intensive Number (% ) of Number (% ) of Completed Missed^ Visits Visits 2224 (94.4) 133 (5.6) 2200 (93.6) 150 (6.4) 2184 (93.3) 158 (6.7) 2128 (91.2) 205 (8.8) 2102 (90.4) 223 (9.6) 2096 (90.5) 221 (9.5) 2025 (87.8) 281 (12.2) 2003 (87.3) 291 (12.7) 2016 (88.3) 268 (11.7) 1960 (86.2) 315 (13.8) 1963 (86.6) 305 (13.4) 1843 (88.1) 249 (11.9) 1601 (86.5) 250 (13.5) 1390 (86.8) 212 (13.2) 1205 (87) 180 (13) 964 (86.8) 146 (13.2) 720 (86.4) 113 (13.6) 469 (88.8) 59 (11.2) 195 (84.1) 37 (15.9) 170 (81.3) 39 (18.7) 170 (81.7) 38 (18.3) 163 (79.1) 43 (20.9) 162 (79) 43 (21) 181 (89.2) 22 (10.8) Number of Expected* Visits 2369 2368 2359 2351 2342 2338 2327 2319 2310 2300 2292 2106 1870 1638 1415 1129 862 571 282 244 240 239 235 235 Standard Number (% ) of Completed Visits 2261 (95.4) 2221 (93.8) 2200 (93.3) 2162 (92) 2139 (91.3) 2144 (91.7) 2074 (89.1) 2088 (90) 2100 (90.9) 2065 (89.8) 2029 (88.5) 1895 (90) 1684 (90.1) 1460 (89.1) 1289 (91.1) 1009 (89.4) 780 (90.5) 522 (91.4) 249 (88.3) 207 (84.8) 213 (88.8) 200 (83.7) 195 (83) 209 (88.9) Number (% ) of Missed^ Visits 108 (4.6) 147 (6.2) 159 (6.7) 189 (8) 203 (8.7) 194 (8.3) 253 (10.9) 231 (10) 210 (9.1) 235 (10.2) 263 (11.5) 211 (10) 186 (9.9) 178 (10.9) 126 (8.9) 120 (10.6) 82 (9.5) 49 (8.6) 33 (11.7) 37 (15.2) 27 (11.3) 39 (16.3) 40 (17) 26 (11.1)

Months PostRandomization 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96

*Expected = Number of surviving participants expected to reach visit based on their randomization date ^Missed = Includes participants who withdrew consent or were lost to follow-up at that visit.

26

Section 13. Results Sensitivity Analysis Systolic Blood Pressures

Compares Maximum Likelihood Repeated Measures Analysis (ML) under MAR assumptions with analysis of observed data (MCAR) presented in manuscript

27

Section 14. Results Diastolic Blood Pressures

28

Section 15. Results Number and Causes of Death

NUMBER AND CAUSES OF DEATH BY TREATMENT GROUP

Causes of Death

Intensive 150 43 7 11 2 2 3 3 4 44 10 36 6 14 5 2 1 3 0 5

Standard 144 38 5 10 5 2 2 8 3 44 14 28 5 8 2 2 2 1 2 2

Total Mortality Unexpected/Presumed Cardiovascular Disease* Fatal Myocardial Infarction* Fatal Congestive Heart Failure* Fatal Cardiovascular Disease Procedure* Fatal Arrhythmia* Fatal Non-cardiovascular Disease Procedure* Fatal Stroke* Other Cardiovascular Disease* Cancer Death Indeterminate Not Cancer or Cardiovascular Disease, with breakdown: Respiratory Causes (excluding pneumonia) Infectious Accident/Trauma Renal Failure Liver Disease Gastrointestinal Neurologic Disease Other

Data within rows are not mutually exclusive, and individuals who were classified as having more than 1 possible cause of death are listed in the relevant rows. *Components of the fatal cardiovascular disease outcome

29

Section 16: Results Kaplan-Meier Curves (page 1 of 4)

30

Results Kaplan-Meier Curves (continued, page 2 of 4)

31

Results Kaplan-Meier Curves (continued, page 3 of 4)

32

Results Kaplan-Meier Curves (continued, page 4 of 4)

33

Section 17: Results Hazard Ratios for Primary Outcome in Pre-specified Subgroups
Intensive Events N (% / yr)
Overall Gender Male Fem ale Age <65 >=65 Ethnicity White Nonw hite Prior CVD No Yes Glycem ia Standard Intensive HbA1c <= 8.0 > 8.0 SBP Tertiles < 133 133 - 144 > 144 DBP Tertiles < 72 72 - 80 > 80 Screening Meds 0-1 2-3 1568 (1.54) 794 (2.53) 1452 (1.97) 910 (1.72) 1548 (1.72) 823 (2.79) 1414 (2.34) 957 (1.74) 0.98 2362 (1.87)

Standard Events N (% / yr)

2371 (2.09)

INT / STD Hazard Ratio

Interaction P-value

1234 (2.15) 1128 (1.56)

1241 (2.41) 1130 (1.75)

0.98

0.44

1558 (1.33) 804 (2.98)

1582 (1.46) 789 (3.43)

0.78

1184 (1.89) 1178 (1.85) 1050 (1.34) 1309 (2.31)

1178 (2.47) 1193 (1.73) 1160 (1.82) 1201 (2.35)

0.08

0.11

828 (1.89) 733 (1.7) 800 (2.01)

784 (2.08) 798 (1.82) 789 (2.38)

0.99

796 (2.34) 803 (1.65) 762 (1.62) 1154 (1.49) 1208 (2.24)

784 (2.76) 830 (1.72) 757 (1.81) 1174 (1.53) 1197 (2.67)

0.7

0.44

0.5
Intensive Better

1.0

1.5
Standard Better