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N Engl J Med. 2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27.

Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy.

Collaborators (484)

Van Cleemput JJ, Servaes V, Strijckmans A, Droogne W, Reis G, Melo Silva S, Marengo Garcia de Carvalho L, Cassio Broilo Franca C, Giorgeto FE, Almeida de Moura Deodato J, Souza de Abreu A, Berensztejn AC, Fernandes PC, Coury Pedrosa R, Fine NM, Jackson-Carter L, Ronak K, Maitland Grant AD, Delgado D, Garrard L, Nugaeva N, Ross HJ, Krejci J, Budnakova D, Skalicka E, Hude P, Palecek T, Doucheva J, Rihova J, Kuchynka P, Kubanek M, Novakova T, Placatova L, Lupinek P, Slama MS, Ladeveze C, Algalarrondo V, Dinanian SI, Eliahou L, Statescu CD, Focseneanu C, Kharoubi M, Arrouasse R, Guendouz S, Joseph X, Le Corvoisier P, Plante-Bordeneuve V, Helmut Ehlermann PB, Meng U, Ulbricht H, Wilhelm D, Wittek M, Aurich M, Bauer R, Baumgaertner CM, Hein SJ, Korff S, Mereles D, Riffel JH, aus dem Siepen F, Stypmann J, Kemmann K, Lauterborn MJ, Mueller K, Bruening-Missfelder AC, Engelen MA, Frommeyer G, Iraqi W, Pogoda CA, Schmidt HHJ, Weber P, Weis T, Farina IM, Cinelli MM, Foffi S, Gagliardi C, Longhi S, Milandri A, Faggiano P, Bulgari M, Savoldi D, Guidetti F, Nardi M, Perfetto F, Angelotti P, Cappelli F, Fabbri A, Spini V, Di Buduo E, Roggeri L, Sforzini C, Mussinelli R, Obici L, Perlini S, Tahara N, Dan K, Fumiyo S, Hashimoto M, Inoue S, Kamura A, Miyazaki H, Naitou M, Shiiba M, Takemata N, Yamasaki K, Anegawa T, Enomoto M, Fukami A, Honda A, Kumagai E, Mawatari K, Nagata T, Nakayoshi T, Ohba T, Izumiya Y, Misumi Y, Oda C, Sakamoto Y, Takamura M, Hisamoto K, Kanazawa H, Miyazaki T, Onoue Y, Sugamura K, Ueda M, Yamamuro M, Yamashita T, Sekijima Y, Asakura H, Hatakoshi K, Ito K, Miyazawa C, Watanabe N, Yamauchi K, Fukushima K, Kato N, Koyama J, Tojo K, Van der Meer P, Bokhorst G, Couperus M, Booij HG, Buisman DC, Hazenberg BPC, Liu LCY, Santema BT, Vegter EL, ter Maaten JM, Crespo-Leiro MG, Blanco Calvo M, Grille Cancela Z, Barge Caballero E, Barge Caballero G, Barriales Villa R, Couto Mallon D, Marzoa Rivas R, Paniagua Martin MJ, Perez Fernandez R, Garcia Pavia P, Cordoba M, Gonzalez Segovia A, Amor Salamanca MA, Cobo Marcos M, Dominguez Rodriguez F, Gallego Delgado M, Gonzalez Lopez E, Gonzalez Mirelis J, Lopez Sainz A, Restrepo Cordoba MA, Pascual Figal DA, Perez Martinez T, Garrido Bravo IP, Gimeno Blanes JR, Pastor Perez FJ, de la Morena Valenzuela G, Boman K, Olofsson M, Wikstrom G, Blomqvist SB, Eriksson M L, Hammarlof LP, Kjellstrom K, Lango A, Johansson K, Vedin O, Anderson L, Brown S, Collins A, Dos Santos Jardim V, Dougal K, Fox G, Sookhoo V, Papadopoulou SA, Ray R, Shanmugam N, Baker V, Horan S, Mfuko C, Wynne L, Lorenzini M, Watkinson O, Tallaj JA, Frazier P, Lowe D, Powell L, Tahmaseb T, Acharya D, Bourge RC, Loyaga-Rendon RY, Pamboukian SV, Prabhu SD, Steidley DE, Clarkson M, Eyshou A, Galindo A, Knight BA, Vaughn SG, Watkins A, Patel JK, Durant D, Tavera DG, Guevarra A, Movsisyan G, Sana SA, Azarbal B, Chang DH, Czer LSC, Geft DR, Hage A, Hamilton MA, Kittleson MM, Kobashigawa JA, Moriguchi JD, Vescio RA, Adler ED, Eidemiller L, Schimmel M, Tandon S, Barnard DD, Gibson MA, Greenberg BH, Kim PJ, Mizeracki AM, Silva Enciso J, Tran HA, Yousefzai R, De Marco T, Bravo S, Etheredge C, Hamilton D, Kobishagawa L, McGuire C, Smith M, Stepanyan G, Westcott S, Selby V, Finn E, Kobayashi S, McDonnell L, Ulloa P, Wheeler MT, Hoffman JE, Ahmed J, Dinh Y, Luis N, Martinez M, Pallapati R, Thompson L, Chaparro SV, De Lima Pereira D, Corona-Cox J, Kozyleva A, Mkrdichian H, Pohlman N, Prendergast K, Sanchez C, Freed BH, Cotts WG, Silver MA, Ball C, Doherty C, Gagliardi A, Kozicki M, Pauwaa S, Ventura HO, Boudet K, Gelpi J, Hammons A, Stewart S, Eiswirth CC, Patel HM, Berk JL, Akinbami A, Hankinson E, Lattanzi V, Lazzari V, Pappin S, Rafferty C, Miller EJ, Ruberg FL, Gottlieb SS, Beach D, Bowers-Lash M, Marshall J, Ramani GV, Robinson SW, Sharma K, Ononogbu S, Smith J, Wingo J, Hsu S, Russell SD, Stevens G, Hummel SL, Luciano J, Shah N, Wells J, Koelling TM, Biorn SA, Birgin AM, Graham KK, Leibfried K, Olson E, Rott MA, Sands T, Vrieze DP, Wanek J, Buadi FK, Case JK, Decker SJ, Dingli DD, Dispenzieri A, Gertz MA, Go RS, Grazzini Frantz JG, Habermann TM, Hayman SR, Hwa YL, Kapoor P, Kourelis T, Kumar SK, Lacy MQ, Leung N, Lin G, Lin Y, Miller SK, Miller WL, Rajkumar SV, Schmidt DC, Witzig TE, Zeldenrust SR, Velazquez EJ, Baum M, Lefevre M, Khouri MG, Samad Z, Shah SH, Tuchman SA, Zucker MJ, Brunner G, Di F, Hayat A, Patel B, Policastro P, Wang L, Baran DA, Pieretti J, Gorevic PD, Baez E, Berhanu G, Cotarlan A, Gregory S, Manapat A, Arora D, Bunker DR, Gopalan RS, De Los Santos J, Alvarez-Munoz J, Castano A, Helmke S, Jimenez O, Teruya SL, Reyentovich A, Cobos S, Donehey J, Bouscher P, Doud KL, Fonk T, Gus B, Ives L, Jarosz M, Moore S, Oblak C, Jacob MS, Tang WH, Taylor DO, Heitner SB, Boucher R, Chirpich M, Dean S, Gordon M, Grace A, Van Ness G, Wilson B, Khoury JA, Marburger T, Mott BH, Ravi S, Scott EC, Divito P, Khella SL, Lenihan DJ, Slosky DA, Bowman SD, Dean I, Gordon M, Hale LL, Neal TK, Hung RR, Sawyer DB, Estep JD, Araujo G, Bhosale A, Brown CC, Bung R, Ghosn MG, Karanja E, Moore P, Prystash M, Taylor E, Ashrith G, Bhimaraj A, Trachtenberg B, Nativi-Nicolau JN, Gibbs J, Kirk J, Rooks A, Abraham JD, Gilbert EM, Kovacsovics TJ, Stehlik J, Shah KB, Cei L, Cooke R, Paciulli SC, Smallfield M, Tchoukina I, Baldwin DE, Bischin A, Vogt S, Rho R, Weiss S, Wilder K, Woo S, Januzzi J, Lopez-Sendon J, Miller A, O’Neill B, Blum RH, De Gruttola VG, Goldstein S, Kivel N, Mangum B, Gaffney M, Bassi L, Espino P, Flynn A, Frolova M, Godfrey L, Guattery D, Hahn C, Hoshino Y, Kiszko J, Lee P, McCawley C, Myatt S, Paulukonis J, Purdom K, Ryan C, Takahashi N, Wang Q, Wesley N, Wudel S, Zhang Y.

Abstract

BACKGROUND:

Transthyretin amyloid cardiomyopathy is caused by the deposition of transthyretin amyloid fibrils in the myocardium. The deposition occurs when wild-type or variant transthyretin becomes unstable and misfolds. Tafamidis binds to transthyretin, preventing tetramer dissociation and amyloidogenesis.

METHODS:

In a multicenter, international, double-blind, placebo-controlled, phase 3 trial, we randomly assigned 441 patients with transthyretin amyloid cardiomyopathy in a 2:1:2 ratio to receive 80 mg of tafamidis, 20 mg of tafamidis, or placebo for 30 months. In the primary analysis, we hierarchically assessed all-cause mortality, followed by frequency of cardiovascular-related hospitalizations according to the Finkelstein-Schoenfeld method. Key secondary end points were the change from baseline to month 30 for the 6-minute walk test and the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS), in which higher scores indicate better health status.

RESULTS:

In the primary analysis, all-cause mortality and rates of cardiovascular-related hospitalizations were lower among the 264 patients who received tafamidis than among the 177 patients who received placebo (P<0.001). Tafamidis was associated with lower all-cause mortality than placebo (78 of 264 [29.5%] vs. 76 of 177 [42.9%]; hazard ratio, 0.70; 95% confidence interval [CI], 0.51 to 0.96) and a lower rate of cardiovascular-related hospitalizations, with a relative risk ratio of 0.68 (0.48 per year vs. 0.70 per year; 95% CI, 0.56 to 0.81). At month 30, tafamidis was also associated with a lower rate of decline in distance for the 6-minute walk test (P<0.001) and a lower rate of decline in KCCQ-OS score (P<0.001). The incidence and types of adverse events were similar in the two groups.

CONCLUSIONS:

In patients with transthyretin amyloid cardiomyopathy, tafamidis was associated with reductions in all-cause mortality and cardiovascular-related hospitalizations and reduced the decline in functional capacity and quality of life as compared with placebo. (Funded by Pfizer; ATTR-ACT ClinicalTrials.gov number, NCT01994889 .).

PMID:
30145929
DOI:
10.1056/NEJMoa1805689
[Indexed for MEDLINE]

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