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4. A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease

Author

Wun Ted, Soulieres Denis, Frelinger Andrew L, Krishnamurti Lakshmanan, Novelli Enrico M, Kutlar Abdullah, Ataga Kenneth I, Knupp Charles L, McMahon Lillian E, Strouse John J, Zhou Chunmei, Heath Lori E, Nwachuku Chuke E, Jakubowski Joseph A, Riesmeyer Jeffrey S, and Winters Kenneth J

Subjects
Prasugrel, Sickle cell disease, Thienopyridine, Platelet function, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. Methods The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. Results There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. Conclusions Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.

Published
2013
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6. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

Author

Lincoff, A. Michael, Nicholls, Stephen J., Riesmeyer, Jeffrey S., Barter, Philip J., Brewer, H. Bryan, Fox, Keith A. A., Gibson, C. Michael, Granger, Christopher, Menon, Venu, Montalescot, Gilles, Rader, Daniel, Tall, Alan R., McErlean, Ellen, Wolski, Kathy, Ruotolo, Giacomo, Vangerow, Burkhard, Weerakkody, Govinda, Goodman, Shaun G., Conde, Diego, McGuire, Darren K., Nicolau, Jose C., Leiva-Pons, Jose L., Pesant, Yves, Li, Weimin, Kandath, David, Kouz, Simon, Tahirkheli, Naeem, Mason, Denise, Nissen, Steven E. Del Valle M, Finnell JB, Standley J, Poi K, Croaning J, Tong YC, Guerra JL, Guasparini G, Hubert C, Ardissino D, Betteridge J, Borghi C, Bruckert E, Chiang CE, Cinteza M, Dalby AJ, Erlinge D, Fernandez-Ortiz A, Ge J, Gottlieb S, Goudev A, Gratsiansky N, Huber K, Ilavská A, Jeong MH, Jukema JW, Katus H, Keltai M, Krum H, Nielsen H, Ogawa H, Ongen Z, Parkhomenko A, Raugaliene R, Renkin J, Rynkiewicz A, Steinhubl S, White H, Widimsky P, Zhu J, Armstrong P, Ridker P, Mahaffey K, Steg G, Wittes J, Bhargava A, Chenier M, Coleman C, Cremer P, Jellis C, Lahoud R, Lappe J, Min D, Monteleone P, Newton D, Stegman B, Senn T, Katzan I, Sharma J, Uchino K, Vora N, Brown K, Fabec D, Piper P, Preston S, Colombo T, Pagel-Langenickel I, Penev P, Maixing A, Crowley K, Sarkar S, Torosyan N, Castano L, Tran D, Dena V, Blain L, Keenan G, Slade K, Quinlan E, Edwards R, Ren H, Glenny J, Maffei L, Albisu Di Gennaro J, Caccavo A, Prado A, Colombo H, Luquez H, Lobo Marquez L, Hammett C, Blombery P, Colquhoun D, Amerena J, Howes L, Cooke D, Simpson R, Horowitz J, Sullivan D, Proietto J, Yeo W, Hirschl M, Hanusch U, Drexel H, Brodmann M, Wollaert B, De Wolf L, Delforge M, Vanwelden J, Peeters A, Siqueira Bodart J, Montenegro R, Franken M, Eliaschewitz F, Parvanova Z, Raev D, Mincheva V, Kichukov K, Stoyanov M, Apostolova E, Tzekova M, Dimov B, Lazov P, Devedzhiev T, Dion D, Poirier P, Lavoie JP, Lonn E, Shukla D, Chehayeb R, Nault P, Gaudet D, Tardif JC, Beaudry Y, Bakbak A, Wong B, St-Maurice F, Labonte R, Polasek P, Sweet M, Bhargava R, Nawaz S, Pandey S, Tishler S, Peterson S, O’Keefe D, Genest J, Syan R, Leiter L, Li H, Ma W, Ma C, Xu D, Li X, Hala T, Machova V, Smejkalova O, Vodnansky P, Reichert P, Velimsky T, Matuska J, Machkova M, Jerabek O, Kuchar J, Rasmussen T, Lindgren L, Alexandersen P, Bang L, Brønnum-Schou J, Valter I, Soots M, Lanno R, Rosenthal S, Cottin Y, Elbaz M, Lafitte S, Silvain J, Coste P, Rangé G, Gosse P, Morel O, Berrouschot J, Bourhaial H, Toursarkissian N, Appel KF, Rieker W, Stellbrink C, Münzel T, Geisler T, Kadel C, Giannitsis E, Trenk D, vom Dahl J, Dorsel T, Singer O, Schäufele T, Natour M, Ozaki R, Lau E, Chan K, Yeung V, Yu C, Lakatos F, Zólyomi S, Vangel S, Merkely B, Szakal I, Sipos A, Laszloczky A, Kis E, Szocs A, Szántai G, Faludi P, Kancz S, Oroszlan T, Hamoud S, Francis A, Chorin E, Leibowitz D, Kracoff O, Weisz G, Schiff E, Bitzur R, Hussein O, Di Lorenzo L, Visona A, Mos L, De Luca G, Salvioni A, Rubba P, Imberti D, Bucci M, Saku K, Sueyoshi A, Ohshima K, Kazatani Y, Shimizu M, Fujii K, Higa N, Kawamitsu K, Shimomura H, Hoshizaki H, Tashiro H, Baden M, Ueda O, Tanabe J, Momiyama Y, Hosokawa S, Takahashi N, Kimura K, Fujinaga H, Masutani M, Kuramochi T, Higashikata T, Ichikawa S, Yamagishi M, Sakota S, Sakuragi S, Suzuki M, Taguchi S, Nakamura T, Ozaki Y, Tsujita K, Yasuda S, Ando K, Fujimoto K, Tanabe K, Fukunaga M, Kavaliauskiene R, Motiejuniene L, Slapikas R, Jarasuniene D, De los Rios Ibarra M, Alcocer Gamba M, Nevarez Ruiz L, Fajardo-Campos P, Llamas Esperon G, Violante Ortiz R, Stobschinski de Alba C, Guizar Sanchez C, Guerra Lopez A, Montano E, Miracle S, Fanghanel G, Lenderink T, Troquay R, Van Leendert R, van Eck J, Hamer B, Ronner E, Karalis I, Lok D, Magro M, Westendorp I, Stroes E, De Melker E, Verhave G, Plomp J, Bronzwaer P, Wiersma J, Kooy A, Herrman JP, Imholz B, de Groot M, Devlin G, Elliott J, Benatar J, Harding S, Hart H, Young C, Mirek-Bryniarska E, Gniot J, Broncel M, Kozina M, Kus W, Sciborski R, Lesnik J, Kawka-Urbanek T, Krzyzanowski M, Okopien B, Wierzbicka K, Dyczek A, Ochean V, Copaci I, Matei C, Pruna C, Constantinescu M, Minescu B, Stamate C, Boldueva S, Markov V, Alexeeva N, Chizhov P, Supryadkina T, Petrochenkova N, Zrazhevsky K, Barbarash O, Gurevich V, Hranai M, Gergel V, Dzupina A, Uhliar R, Vinanska D, Fazekas F, Bugan W, Saaiman J, Nortje H, Theron H, Bernhardi D, Ramlachan P, Van-Zyl L, Basson M, Venter T, Kim D, Han S, Park G, Hwang K, Rhee M, Cho B, Jeong J, Hong B, Chang K, Garcia Puig J, Fuentes Jiménez F, Nieto Iglesias LJ, Pintó Sala X, Gamez JM, Sánchez Álvarez J, Hernandez García JM, Olsson A, Mooe T, Tengmark BO, Lindholm CJ, Hansen O, Tyden P, Moccetti T, Binder R, Ueng K, Lai W, Shyu K, Hsieh I, Sheu W, Chen J, Altunkeser B, Erkan A, Karpenko O, Kaydashev I, Yagensky A, Kovalenko V, Brunskill J, Barr C, Cecil J, Cahill T, A Gorog D, Bakhai A, Coulson W, Gorog D, Loftus I, Haddad T, Hotchkiss D, Isserman S, Janik M, Weinstein D, Wilson S, Butman S, Hearne S, Khan F, Nadar V, Zelman R, Benton R, Flores E, Kahn B, Soni A, Asbill B, Singal D, Dy J, Foucauld J, Crenshaw B, Rogers W, Aslam A, Lieber I, Shah P, Durr S, Spencer R, Mahal S, Cheng S, Abadier R, Gilmore R, Staniloae C, Miller G, Seals A, Jetty P, Mathis C, Henry S, Murray A, Felten W, Navas J, Gudipati R, Singh N, West S, Sabatino K, Crater T, Amin J, Dosh K, Earl J, Z Jafar M, Gelernt M, Kutner M, Salazar J, Krantzler J, El-Ahdab F, Lader E, Zakhary B, Miller S, Madder R, Khan T, Khan M, Collis W, Evans J, Prodafikas J, Panchal V, Cohen K, Weiss R, Dietrich D, Vogel C, Mascarenhas V, Seaworth J, Teklinski A, Davalos J, Dehning M, Herzog W, Snyder H, Talano J, Donahoe S, Hunter J, Sandoval J, Batchelor W, Brautigam D, Moriarty K, Siachos A, Kereiakes D, Traboulssi M, Arif I, Kosinski E, Quadrel M, DeHart D, Miller M, Poock J, Loh I, van Cleeff M, Georgeson S, Suryanarayana P, Cohn J, Schmedtje J, Lamas G, DeSantis J, Stahl L, Prashad R, Schuchard T, Schramm E, Rao V, Deen C, Soufer J, Gurbel P, Vazquez-Tanus J, Srivastava S, Ballantyne C, Lotun K, Younis L, Gupta D, Yeoman G, Zebrack J, Knutson T, Whitaker J, Appel M, Koren M, Muneer B, Fairlamb J, Aviles R, Kozlowski L, Rees A, Stephens M, Mays M, Downey H, Almassi H, Peichert D, Rocco M, French W, Bhatia P, Hoch J, Peart B, Carmichael P, Acheatel R, Vo A, Kirtane A, Bhagwat R, Gilchrist I, Labroo A, Pollock S, Bacon J, Karunaratne H, Moursi M, Doshi A, Sethi P, Treasure C, Marple R, Goodwin T, Zayas-Torres C, Loussararian A, Korn D, Paster R, Albirini A, Moretto T, Guarnieri T, White L, Kramer J, Shortal B, Maynard K, Raikhel M, Rohatgi A, Melucci M, Masri B, Krichmar P, Morris F, Canto J, Wali A, Comerota A, Ellison W, Degregorio M, Chandrika Parameswaran A, Goldscher D, George W, Mulkay A, Maynard R, Ziada K, Strain J, Hermiller J, Ennis B, Desai V, Al-Joundi B, Azocar J, Claudio J, Perez Vargas E, Loy J, Albert M, Chandler G, Maislos F, Graf R, Rama P, Studeny M, Gimple L, Pytlewski G, Simon H, Islam A, Dillon W, Shah S, Geohas C., Lincoff, Am, Nicholls, Sj, Riesmeyer, J, Barter, Pj, Brewer, Hb, Fox, Kaa, Gibson, Cm, Granger, C, Menon, V, Montalescot, G, Rader, D, Tall, Ar, Mcerlean, E, Wolski, K, Ruotolo, G, Vangerow, B, Weerakkody, G, Goodman, Sg, Conde, D, Mcguire, Dk, Nicolau, Jc, Leiva-Pons, Jl, Pesant, Y, Li, W, Kandath, D, Kouz, S, Tahirkheli, N, Mason, D, Nissen, Se, Del Valle, M, Finnell, Jb, Standley, J, Poi, K, Croaning, J, Tong, Yc, Guerra, Jl, Guasparini, G, Hubert, C, Ardissino, D, Betteridge, J, Borghi, C, Bruckert, E, Chiang, Ce, Cinteza, M, Dalby, Aj, Erlinge, D, Fernandez-Ortiz, A, Ge, J, Gottlieb, S, Goudev, A, Gratsiansky, N, Huber, K, Ilavská, A, Jeong, Mh, Jukema, Jw, Katus, H, Keltai, M, Krum, H, Nielsen, H, Ogawa, H, Ongen, Z, Parkhomenko, A, Raugaliene, R, Renkin, J, Rynkiewicz, A, Steinhubl, S, White, H, Widimsky, P, Zhu, J, Armstrong, P, Ridker, P, Mahaffey, K, Steg, G, Wittes, J, Bhargava, A, Chenier, M, Coleman, C, Cremer, P, Jellis, C, Lahoud, R, Lappe, J, Min, D, Monteleone, P, Newton, D, Stegman, B, Senn, T, Katzan, I, Sharma, J, Uchino, K, Vora, N, Brown, K, Fabec, D, Piper, P, Preston, S, Colombo, T, Pagel-Langenickel, I, Penev, P, Maixing, A, Crowley, K, Sarkar, S, Torosyan, N, Castano, L, Tran, D, Dena, V, Blain, L, Keenan, G, Slade, K, Quinlan, E, Edwards, R, Ren, H, Glenny, J, Maffei, L, Albisu Di Gennaro, J, Caccavo, A, Prado, A, Colombo, H, Luquez, H, Lobo Marquez, L, Hammett, C, Blombery, P, Colquhoun, D, Amerena, J, Howes, L, Cooke, D, Simpson, R, Horowitz, J, Sullivan, D, Proietto, J, Yeo, W, Hirschl, M, Hanusch, U, Drexel, H, Brodmann, M, Wollaert, B, De Wolf, L, Delforge, M, Vanwelden, J, Peeters, A, Siqueira Bodart, J, Montenegro, R, Franken, M, Eliaschewitz, F, Parvanova, Z, Raev, D, Mincheva, V, Kichukov, K, Stoyanov, M, Apostolova, E, Tzekova, M, Dimov, B, Lazov, P, Devedzhiev, T, Dion, D, Poirier, P, Lavoie, Jp, Lonn, E, Shukla, D, Chehayeb, R, Nault, P, Gaudet, D, Tardif, Jc, Beaudry, Y, Bakbak, A, Wong, B, St-Maurice, F, Labonte, R, Polasek, P, Sweet, M, Bhargava, R, Nawaz, S, Pandey, S, Tishler, S, Peterson, S, O’Keefe, D, Genest, J, Syan, R, Leiter, L, Li, H, Ma, W, Ma, C, Xu, D, Li, X, Hala, T, Machova, V, Smejkalova, O, Vodnansky, P, Reichert, P, Velimsky, T, Matuska, J, Machkova, M, Jerabek, O, Kuchar, J, Rasmussen, T, Lindgren, L, Alexandersen, P, Bang, L, Brønnum-Schou, J, Valter, I, Soots, M, Lanno, R, Rosenthal, S, Cottin, Y, Elbaz, M, Lafitte, S, Silvain, J, Coste, P, Rangé, G, Gosse, P, Morel, O, Berrouschot, J, Bourhaial, H, Toursarkissian, N, Appel, Kf, Rieker, W, Stellbrink, C, Münzel, T, Geisler, T, Kadel, C, Giannitsis, E, Trenk, D, vom Dahl, J, Dorsel, T, Singer, O, Schäufele, T, Natour, M, Ozaki, R, Lau, E, Chan, K, Yeung, V, Yu, C, Lakatos, F, Zólyomi, S, Vangel, S, Merkely, B, Szakal, I, Sipos, A, Laszloczky, A, Kis, E, Szocs, A, Szántai, G, Faludi, P, Kancz, S, Oroszlan, T, Hamoud, S, Francis, A, Chorin, E, Leibowitz, D, Kracoff, O, Weisz, G, Schiff, E, Bitzur, R, Hussein, O, Di Lorenzo, L, Visona, A, Mos, L, De Luca, G, Salvioni, A, Rubba, P, Imberti, D, Bucci, M, Saku, K, Sueyoshi, A, Ohshima, K, Kazatani, Y, Shimizu, M, Fujii, K, Higa, N, Kawamitsu, K, Shimomura, H, Hoshizaki, H, Tashiro, H, Baden, M, Ueda, O, Tanabe, J, Momiyama, Y, Hosokawa, S, Takahashi, N, Kimura, K, Fujinaga, H, Masutani, M, Kuramochi, T, Higashikata, T, Ichikawa, S, Yamagishi, M, Sakota, S, Sakuragi, S, Suzuki, M, Taguchi, S, Nakamura, T, Ozaki, Y, Tsujita, K, Yasuda, S, Ando, K, Fujimoto, K, Tanabe, K, Fukunaga, M, Kavaliauskiene, R, Motiejuniene, L, Slapikas, R, Jarasuniene, D, De los Rios Ibarra, M, Alcocer Gamba, M, Nevarez Ruiz, L, Fajardo-Campos, P, Llamas Esperon, G, Violante Ortiz, R, Stobschinski de Alba, C, Guizar Sanchez, C, Guerra Lopez, A, Montano, E, Miracle, S, Fanghanel, G, Lenderink, T, Troquay, R, Van Leendert, R, van Eck, J, Hamer, B, Ronner, E, Karalis, I, Lok, D, Magro, M, Westendorp, I, Stroes, E, De Melker, E, Verhave, G, Plomp, J, Bronzwaer, P, Wiersma, J, Kooy, A, Herrman, Jp, Imholz, B, de Groot, M, Devlin, G, Elliott, J, Benatar, J, Harding, S, Hart, H, C, Young, Mirek-Bryniarska, E, Gniot, J, Broncel, M, Kozina, M, Kus, W, Sciborski, R, Lesnik, J, Kawka-Urbanek, T, Krzyzanowski, M, Okopien, B, Wierzbicka, K, Dyczek, A, Ochean, V, Copaci, I, Matei, C, Pruna, C, Constantinescu, M, Minescu, B, Stamate, C, Boldueva, S, Markov, V, Alexeeva, N, Chizhov, P, Supryadkina, T, Petrochenkova, N, Zrazhevsky, K, Barbarash, O, Gurevich, V, Hranai, M, Gergel, V, Dzupina, A, Uhliar, R, Vinanska, D, Fazekas, F, Bugan, W, Saaiman, J, Nortje, H, Theron, H, Bernhardi, D, Ramlachan, P, Van-Zyl, L, Basson, M, Venter, T, Kim, D, Han, S, Park, G, Hwang, K, Rhee, M, Cho, B, Jeong, J, Hong, B, Chang, K, Garcia Puig, J, Fuentes Jiménez, F, Nieto Iglesias LJ, Pintó Sala, X, Gamez, Jm, Sánchez Álvarez, J, Hernandez García JM, Olsson, A, Mooe, T, Tengmark, Bo, Lindholm, Cj, Hansen, O, Tyden, P, Moccetti, T, Binder, R, Ueng, K, Lai, W, Shyu, K, Hsieh, I, Sheu, W, Chen, J, Altunkeser, B, Erkan, A, Karpenko, O, Kaydashev, I, Yagensky, A, Kovalenko, V, Brunskill, J, Barr, C, Cecil, J, Cahill, T, A Gorog D, Bakhai, A, Coulson, W, Gorog, D, Loftus, I, Haddad, T, Hotchkiss, D, Isserman, S, Janik, M, Weinstein, D, Wilson, S, Butman, S, Hearne, S, Khan, F, Nadar, V, Zelman, R, R, Benton, E, Flore, Kahn, B, Soni, A, Asbill, B, Singal, D, Dy, J, Foucauld, J, Crenshaw, B, Rogers, W, Aslam, A, Lieber, I, Shah, P, Durr, S, Spencer, R, Mahal, S, Cheng, S, Abadier, R, Gilmore, R, Staniloae, C, Miller, G, Seals, A, Jetty, P, Mathis, C, Henry, S, Murray, A, Felten, W, Navas, J, Gudipati, R, Singh, N, West, S, Sabatino, K, Crater, T, Amin, J, Dosh, K, Earl, J, Z Jafar M, Gelernt, M, Kutner, M, J, Salazar, Krantzler, J, El-Ahdab, F, Lader, E, Zakhary, B, Miller, S, Madder, R, Khan, T, Khan, M, Collis, W, Evans, J, Prodafikas, J, Panchal, V, Cohen, K, Weiss, R, Dietrich, D, Vogel, C, Mascarenhas, V, Seaworth, J, Teklinski, A, Davalos, J, Dehning, M, Herzog, W, Snyder, H, Talano, J, Donahoe, S, Hunter, J, Sandoval, J, Batchelor, W, Brautigam, D, Moriarty, K, Siachos, A, Kereiakes, D, Traboulssi, M, Arif, I, Kosinski, E, Quadrel, M, Dehart, D, Miller, M, Poock, J, Loh, I, van Cleeff, M, Georgeson, S, Suryanarayana, P, Cohn, J, Schmedtje, J, Lamas, G, Desantis, J, Stahl, L, Prashad, R, Schuchard, T, Schramm, E, Rao, V, Deen, C, Soufer, J, Gurbel, P, Vazquez-Tanus, J, Srivastava, S, Ballantyne, C, Lotun, K, Younis, L, Gupta, D, Yeoman, G, Zebrack, J, Knutson, T, Whitaker, J, Appel, M, Koren, M, Muneer, B, Fairlamb, J, Aviles, R, Kozlowski, L, Rees, A, Stephens, M, Mays, M, Downey, H, Almassi, H, Peichert, D, Rocco, M, French, W, Bhatia, P, Hoch, J, Peart, B, Carmichael, P, Acheatel, R, Vo, A, Kirtane, A, Bhagwat, R, Gilchrist, I, Labroo, A, Pollock, S, Bacon, J, Karunaratne, H, Moursi, M, Doshi, A, Sethi, P, Treasure, C, Marple, R, Goodwin, T, Zayas-Torres, C, Loussararian, A, Korn, D, Paster, R, Albirini, A, Moretto, T, Guarnieri, T, White, L, Kramer, J, Shortal, B, Maynard, K, Raikhel, M, Rohatgi, A, Melucci, M, Masri, B, Krichmar, P, Morris, F, Canto, J, Wali, A, Comerota, A, Ellison, W, Degregorio, M, Chandrika Parameswaran, A, Goldscher, D, George, W, Mulkay, A, Maynard, R, Ziada, K, Strain, J, Hermiller, J, Ennis, B, Desai, V, Al-Joundi, B, Azocar, J, Claudio, J, Perez Vargas, E, Loy, J, Albert, M, Chandler, G, Maislos, F, Graf, R, Rama, P, Studeny, M, Gimple, L, Pytlewski, G, Simon, H, Islam, A, Dillon, W, Shah, S, Geohas, C., Lincoff, A. Michael, Nicholls, Stephen J., Riesmeyer, Jeffrey S., Barter, Philip J., Brewer, H. Bryan, Fox, Keith A. A., Gibson, C. Michael, Granger, Christopher, Menon, Venu, Montalescot, Gille, Rader, Daniel, Tall, Alan R., Mcerlean, Ellen, Wolski, Kathy, Ruotolo, Giacomo, Vangerow, Burkhard, Weerakkody, Govinda, Goodman, Shaun G., Conde, Diego, Mcguire, Darren K., Nicolau, Jose C., Leiva-Pons, Jose L., Pesant, Yve, Li, Weimin, Kandath, David, Kouz, Simon, Tahirkheli, Naeem, Mason, Denise, Nissen, Steven E., Del Valle M, Young, C, Nieto Iglesias, Lj, Hernandez García, Jm, A Gorog, D, Benton, R, Flores, E, Z Jafar, M, and Salazar, J

Subjects
Male, 0301 basic medicine, Cardiovascular Outcome, Cholesterol Ester Transfer Protein, Myocardial Ischemia, 030204 cardiovascular system & hematology, Coronary artery disease, cholesteryl ester transfer protein inhibitor, Benzodiazepines, chemistry.chemical_compound, 0302 clinical medicine, Cardiovascular Disease, Anticholesteremic Agent, Intracranial Arteriosclerosi, Treatment Failure, Evacetrapib, Peripheral Vascular Diseases, Benzodiazepine, biology, Medicine (all), Anticholesteremic Agents, Diabetes Mellitu, General Medicine, Middle Aged, Intracranial Arteriosclerosis, High-Risk Vascular Disease, Editorial, Cardiovascular Diseases, Cardiology, Female, lipids (amino acids, peptides, and proteins), Human, Risk, medicine.medical_specialty, Acute coronary syndrome, 03 medical and health sciences, Double-Blind Method, Internal medicine, Diabetes mellitus, Cholesterylester transfer protein, Diabetes Mellitus, Journal Article, medicine, Humans, Aged, Cholesterol, Vascular disease, business.industry, Cholesterol, HDL, Biomarker, Cholesterol, LDL, medicine.disease, Cholesterol Ester Transfer Proteins, Surgery, 030104 developmental biology, Peripheral Vascular Disease, chemistry, biology.protein, business, Biomarkers, Lipoprotein
Abstract

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .).

Published
2017

7. Designing, Conducting, Monitoring, and Analyzing Data from Pragmatic Randomized Clinical Trials: Proceedings from a Multi-stakeholder Think Tank Meeting.

Author

Lentz TA, Curtis LH, Rockhold FW, Martin D, Andersson TLG, Arias C, Berlin JA, Binns C, Cook A, Cziraky M, Dent R, Desai M, Emmett A, Esserman D, George J, Hantel S, Heagerty P, Hernandez AF, Hucko T, Khan N, Lee SF, LoCasale R, Mardekian J, McCall D, Monda K, Normand SL, Riesmeyer J, Roe M, Roessig L, Scott R, Siedentop H, Waldstreicher J, Wang L, Weerakkody G, Wolf M, and Ellenberg SS

Subjects
Humans, Patient Safety, Randomized Controlled Trials as Topic, Research Design
Abstract

In late 2018, the Food and Drug Administration (FDA) outlined a framework for evaluating the possible use of real-world evidence (RWE) to support regulatory decision-making. This framework was created to facilitate studies that would generate high-quality RWE, including pragmatic clinical trials (PCTs), which are randomized trials designed to inform clinical or policy decisions by assessing the real-world effectiveness of an intervention. There is general agreement among experts that the use of existing healthcare and patient-generated data holds promise for making randomized trials more efficient, less costly, and more generalizable. Yet the benefits of relying on real-world data sources must be weighed against difficulties with ensuring data integrity and completeness. Additionally, appropriately monitoring patient safety in randomized trials of new drugs using healthcare system data that might not be available in real time can be quite difficult. Recognizing that these and other concerns are critical to the development and acceptability of PCTs, a group of stakeholders from academia, industry, professional organizations, regulatory bodies, government agencies, and patient advocates discussed a path forward for PCT growth and sustainability at a think tank meeting entitled "Monitoring and Analyzing Data from Pragmatic Streamlined Randomized Clinical Trials," which took place in January 2019 (Washington, DC). The goals of this meeting were to: (1) evaluate study design and methodological options specific to PCTs that have the potential to yield high-quality evidence; (2) discuss best practices to ensure data quality in PCTs; and (3) identify appropriate methods for study monitoring. Proceedings from the think tank meeting are summarized in this manuscript.

Published
2020
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8. Effect of CETP inhibition with evacetrapib in patients with diabetes mellitus enrolled in the ACCELERATE trial.

Author

Menon V, Kumar A, Patel DR, St John J, Riesmeyer J, Weerakkody G, Ruotolo G, Wolski KE, McErlean E, Cremer PC, Nicholls SJ, Lincoff AM, and Nissen SE

Subjects
Aged, Cardiovascular Diseases prevention & control, Cholesterol, HDL analysis, Cholesterol, LDL analysis, Female, Humans, Male, Middle Aged, Treatment Outcome, Anticholesteremic Agents administration & dosage, Benzodiazepines administration & dosage, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Diabetes Complications prevention & control, Diabetes Mellitus drug therapy, Hypoglycemic Agents administration & dosage
Abstract

Background: High-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition with evacetrapib results in a marked increase in HDL and reduction in low-density lipoprotein (LDL) levels. We evaluated the impact of treatment with evacetrapib versus placebo in the subset of 8236 patients with diabetes mellitus (DM) enrolled in the Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes trial., Methods and Results: Time to first occurrence of any component of the primary composite endpoint of cardiovascular death, myocardial infarction, stroke, revascularization, and hospitalization for unstable angina was compared among patients with DM randomized to treatment with evacetrapib (n=4127) or placebo (n=4109) over a median of 26 months of follow-up. The mean baseline LDL at initiation was 80 mg/dL with a mean baseline HDL of 44 mg/dL. In patients with DM, evacetrapib resulted in a 131% mean increase in HDL levels and a 32% mean decrease in LDL at 3 months that was sustained during the course of the trial. At 6 months, hemoglobin A1c (HbA1c) levels were lower with evacetrapib than placebo (7.08% vs 7.15%, p=0.023). Composite event rates were higher in patients with DM than without DM (Kaplan-Meier estimates: 15.2% vs 10.6%, HR 1.46, 95% CI 1.30 to 1.64, p<0.001). In the DM group, event rates for the composite endpoint (14.5% evacetrapib vs 16% placebo, HR 0.95, 95% CI 0.85 to 1.07, p=0.38) and individual components of the composite were similar for both evacetrapib and placebo groups. No significant treatment interaction between treatment assignment and diabetes status was noted., Conclusion: Despite a favorable increase in HDL, and decreases in LDL and HbA1c levels in patients with DM, we observed no benefits of treatment with evacetrapib on prespecified clinical outcomes in this high-risk population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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9. Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference.

Author

Povsic TJ, Scott R, Mahaffey KW, Blaustein R, Edelberg JM, Lefkowitz MP, Solomon SD, Fox JC, Healy KE, Khakoo AY, Losordo DW, Malik FI, Monia BP, Montgomery RL, Riesmeyer J, Schwartz GG, Zelenkofske SL, Wu JC, Wasserman SM, and Roe MT

Subjects
Animals, Cardiovascular Agents pharmacology, Cardiovascular Diseases physiopathology, Drug Discovery methods, Drug Evaluation, Preclinical methods, Drug Industry, Humans, Cardiovascular Agents therapeutic use, Cardiovascular Diseases drug therapy, Drug Design
Abstract

Purpose: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease., Methods: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe., Results: We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development., Conclusions: The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

Published
2017
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10. Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: Rationale and design of the ACCELERATE trial.

Author

Nicholls SJ, Lincoff AM, Barter PJ, Brewer HB, Fox KA, Gibson CM, Grainger C, Menon V, Montalescot G, Rader D, Tall AR, McErlean E, Riesmeyer J, Vangerow B, Ruotolo G, Weerakkody GJ, and Nissen SE

Subjects
Anticholesteremic Agents administration & dosage, Anticholesteremic Agents adverse effects, Cerebrovascular Disorders diagnosis, Cerebrovascular Disorders metabolism, Cholesterol, HDL blood, Cholesterol, LDL blood, Coronary Artery Disease diagnosis, Coronary Artery Disease metabolism, Double-Blind Method, Drug Monitoring, Female, Humans, Male, Middle Aged, Outcome Assessment, Health Care, Peripheral Vascular Diseases diagnosis, Peripheral Vascular Diseases metabolism, Risk Assessment, Benzodiazepines administration & dosage, Benzodiazepines adverse effects, Cerebrovascular Disorders prevention & control, Cholesterol Ester Transfer Proteins antagonists & inhibitors, Cholesterol Ester Transfer Proteins metabolism, Coronary Artery Disease prevention & control, Peripheral Vascular Diseases prevention & control
Abstract

Background: Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease., Study Design: ACCELERATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients qualified for enrollment if they have experienced an acute coronary syndrome within the prior 30 to 365 days, cerebrovascular accident, or transient ischemic attack; if they have peripheral vascular disease; or they have diabetes with coronary artery disease. A total of 12,092 patients were randomized to evacetrapib 130 mg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to first event of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. Treatment will continue until 1,670 patients reached the primary end point; at least 700 patients reach the key secondary efficacy end point of CV death, myocardial infarction, and stroke, and the last patient randomized has been followed up for at least 1.5 years., Conclusions: ACCELERATE will establish whether the cholesteryl ester transfer protein inhibition by evacetrapib improves CV outcomes in patients with high-risk vascular disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Published
2015
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11. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38).

Author

Wiviott SD, Antman EM, Gibson CM, Montalescot G, Riesmeyer J, Weerakkody G, Winters KJ, Warmke JW, McCabe CH, and Braunwald E

Subjects
Acute Disease, Aged, Angioplasty, Balloon, Coronary adverse effects, Clopidogrel, Coronary Disease therapy, Dose-Response Relationship, Drug, Double-Blind Method, Follow-Up Studies, Humans, Piperazines administration & dosage, Platelet Aggregation Inhibitors administration & dosage, Prasugrel Hydrochloride, Syndrome, Thiophenes administration & dosage, Thrombosis prevention & control, Ticlopidine administration & dosage, Ticlopidine therapeutic use, Treatment Outcome, Coronary Disease drug therapy, Myocardial Infarction drug therapy, Piperazines therapeutic use, Platelet Aggregation Inhibitors therapeutic use, Research Design, Thiophenes therapeutic use, Thrombolytic Therapy, Ticlopidine analogs & derivatives
Abstract

Background: Dual antiplatelet therapy with aspirin and clopidogrel is standard for prevention of thrombotic complications of percutaneous coronary intervention (PCI). Prasugrel is a thienopyridine that is more potent, more rapid in onset, and more consistent in inhibition of platelets than clopidogrel. TRITON-TIMI 38 is designed to compare prasugrel with clopidogrel in moderate to high-risk patients with acute coronary syndrome (ACS)., Study Design: TRITON-TIMI 38 is a phase 3, randomized, double-blind, parallel-group, multinational, clinical trial. Approximately 13,000 patients with moderate to high-risk ACS undergoing PCI (9500 unstable angina/non-ST-segment elevation myocardial infarction [MI], 3500 ST-segment elevation MI) will be randomized to prasugrel 60 mg loading dose followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months. The primary end point is the time of the first event of cardiovascular death, MI, or stroke. Analyses will be performed first in the unstable angina/non-ST-segment elevation MI cohort and, conditionally, on the whole ACS population. Major safety end points include TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery., Conclusions: TRITON-TIMI 38 is a phase 3 comparison of prasugrel versus clopidogrel in patients with moderate to high-risk ACS undergoing PCI. In addition, it is the first large-scale clinical events trial to assess whether a thienopyridine regimen that achieves a higher level of inhibition of platelet aggregation than the standard therapy results in an improvement in clinical outcomes.

Published
2006
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12. Acute hemodynamic changes during intravenous dipyridamole thallium imaging early after infarction.

Author

Miller DD, Scott RA, Riesmeyer JS, Chaudhuri TK, Blumhardt R, Boucher CA, and O'Rourke RA

Subjects
Aminophylline pharmacology, Electrocardiography, Humans, Infusions, Intravenous adverse effects, Length of Stay economics, Monitoring, Physiologic, Myocardial Infarction physiopathology, Radionuclide Imaging, Dipyridamole administration & dosage, Dipyridamole adverse effects, Hemodynamics drug effects, Myocardial Infarction diagnostic imaging, Thallium Radioisotopes adverse effects
Abstract

In order to determine the safety and hemodynamic effects of intravenous dipyridamole infusion for thallium-201 scinitigraphy in patients with acute ischemic syndromes, 10 patients with recent uncomplicated myocardial infarction (7 +/- 2 days pre-test) had central pressures and cardiac output values measured serially in a coronary care unit during and after the administration of dipyridamole (0.56 mg/kg over 4 minutes) and following aminophylline reversal (50 to 150 mg intravenously) of dipyridamole effect. Cardiac medications were not discontinued. Double product did not change significantly (8522 +/- 1811 versus 9044 +/- 1701; p = NS). Serious ischemic events did not occur, although 20% of patients had noncardiac side effects and 30% developed greater than or equal to 1 mm ST segment depression with associated angina in one-third of these cases. The peripheral blood pressure and heart rate response did not predict the occurrence of myocardial ischemia. Dipyridamole significantly reduced systemic vascular resistance (1218 +/- 302 to 739 +/- 166 dyne/sec-1/cm-5; p less than 0.05) and increased cardiac index (3.1 +/- 0.7 to 4.7 +/- 1.0 L/min/m2; p less than 0.05) within approximately 10 minutes, in association with a significant increase in pulmonary capillary wedge pressure (13 +/- 5 to 17 +/- 6 mm Hg; p less than 0.05). Three patients developed silent new "V" waves in their pulmonary capillary wedge pressure tracing, associated with anterior thallium redistribution. All three patients with newly elevated wedge pressures (greater than 15 mm Hg) had both thallium-201 redistribution and multivessel coronary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Published
1989
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