1. N Engl J Med. 2018 Mar 29;378(13):1200-1210. doi: 10.1056/NEJMoa1710895. Epub
2018 Mar 12.

Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout.

White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo 
M, Gunawardhana L; CARES Investigators.

Collaborators: Aggarwal N, Bell A, Belle Isle J, Brown J, Cividino A, Dion D,
Dzongowski P, Kelly A, Luton R, Misik K, Morin F, O'Mahony W, Pesant Y, Toma A,
Van den Berg L, Wilderman I, Abud Mendoza C, Aguilera Real M, Alcocer Gamba MA,
Aldrete‐Velasco J, Alpizar Salazar M, Avila Zapata F, Carmona Furusho L, Carrillo
Vazquez SM, Chavez Paez JG, De la Garza Ramos E, Enkerlin Pauwells HL, Esquivel
Valerio J, Fajardo Campos P, Garcia Olivera I, Garcia Reza R, Lopez Ruiz OM, Luna
Ceballos RI, Maldonado Hernandez H, Del Rosario Marrufo M, Miracle Lopez S,
Montano Gonzalez E, Montes Cruz E, Nevarez Ruiz L, Ramos Lopez G, Rodriguez
Briones I, Sanchez Mijangos H, Sanchez Vazquez JC, Silveira Torre LH, Solis
Morales L, Stobschinski de Alba CA, Vazquez Mellado Cervantes NJ, Vega Elguezabal
JF, Villeda Espinosa E, Violante R, Zazueta Montiel BE, Abalos‐Galito M, Abboy C,
Abraham W, Adams M, Aelion J, Alvarado O, Alwine L, Amin K, Anderson A, Anderson 
C, Andrawis N, Archuleta M, Arif A, Azorr M, Babich J, Baraf H, Barag S, Barker
B, Barksdale W, Barreto A, Bartkowiak A, Batongmalaque J, Bays H, Bedel G, Berg
I, Bernstein R, Bertsch J, Bhat A, Bland V, Bornfreund J, Bowling B, Box E,
Branum R, Brewer M, Bright C, Britt D, Broker R, Bruce T, Buchanan P, Burack D,
Burbano De Lara J, Burke D, Buynak R, Byars W, Bybee K, Campbell J, Canlas D,
Canosa R, Captain A, Carlos E, Carpenter K, Carter M, Cauthen B, Cha G, Chang K, 
Chaykin L, Cheung D, Chilito A, Chiong R, Chipman H, Choi S, Christensen J,
Chuang R, Claassen D, Clark G, Clower J, Coburn NJ, Collins H, Corder C, Cox R,
Crawford P, Cunnar J, Davila W, Davit R, Dayon D, DeBusk C, Delgado J, Delmont J,
DeMatteo D, Demetry K, Dennis D, DeSantis D, Diab I, Diener C, Dobrusin R, Dodd
J, Drummond W, Dulgeroff A, Durrence H, Mari Elacion J, Ellison W, Elzi W,
Escalante D, Ettlinger R, Fakih F, Fandino A, Fang M, Farooq O, Farrington C,
Farris N, Feinman M, Feld L, Ferro F, Fields H, First B, Fitz‐Patrick D, Flint K,
Flippo G, Folkerth S, Fowler F, Fox D, Frandsen B, Freeman J, Freyne B, Fritzhand
M, Fung E, Funk G, Gabra N, Gagianas P, Gamarra L, Gaona R, Garcia R, Garner A,
Gaston P, Ghanekar H, Ghosh C, Gladstein G, Goldfischer E, Gorman T, Gottschlich 
G, Grant D, Gray J, Green C, Green B, Gregory D, Griffin R, Guice M, Gupta R,
Hahn G, Halter D, Halter M, Hansen V, Harris A, Harris M, Headley D, Hejeebu S,
Hendrix E, Herman L, Herrera C, Herring C, Herrod J, Ho G, Hole S, Hollister R,
Holt P, Hopkins J, Horton K, Howard T, Howell M, Huff J, Huffman C, Huling R,
Hyers T, Hymowitz R, Ibraheem M, Idarraga S, Iranmanesh A, Isakov T, Jack D,
Jacks R, Jackson R, Jackson R, Jackson B, Jain M, Janovitz R, Jeereddi P, Johary 
A, Johnson C, Johnson W, Johnson C, Jones S, Jones R, Jordan R, June J, Kafka S, 
Kalen V, Karl J, Kaufmann R, Kavanaugh A, Kaveh K, Keane J, Kerzner B, Khan J,
Kidokoro Y, Kirstein J, Kivitz A, Klein S, Klein T, Knight H, Knutson T, Koch S, 
Koilpillai R, Kolettis E, Koontz D, Kopp J, Koshy N, Kotek L, Krause R, LaFata J,
Lang C, Lano M, Lasala G, Lawless A, Lee K, Lee D, Lefebvre G, Lester F, Levins
P, Lewis D, Lieberman D, Lillestol M, Lillo J, Littlefield R, Lockwood M, Lohr K,
Look M, Lorch D, Ludivico C, Luna B, Lutskiy M, Mabaquiao A, Maggiacomo F, Makam 
S, Maletz L, Malik A, Martin E, Martinez J, Marx P, May P, Maynard K, McConnehey 
D, McConnehey B, McGettigan J, McGuire M, McIlwain H, McKenzie W, McLean B,
McNeil D, Mehta D, Meisner C, Meli J, Metyas S, Metzger F, Meyers P, Michlin B,
Mihills C, Miller K, Miller A, Minton S, Mohart A, Montenegro C, Montgomery R,
Morelli J, Morin D, Morita C, Morris F, Mortensen S, Movafagh S, Multani P,
Murphy D, Muse D, Myerson G, Nagrani M, Naidu J, Natividad MB, Neutel J, Nolen T,
Nussbaum A, Olson R, Ong S, Osborne J, Pace M, Paez H, Palatnik M, Palmer W,
Pappas J, Paster Z, Patel M, Patel M, Patel B, Patton W, Pema K, Peniston J,
Peppin G, Petit C, Phillips C, Phillips A, Piatek M, Pick M, Pillinger M, Pogue
B, Posey M, Poss G, Preston K, Prupas H, Pullman J, Raikhel M, Randall W,
Rangaraj M, Rapo S, Rapoport R, Rastogi P, Reddy J, Reddy R, Reed L, Reeves M,
Reiff M, Reynolds M, Rhee M, Rhudy J, Richter R, Ries D, Roberson K, Roberts D,
Robinson D, Rock K, Roer D, Rosen R, Rosenblum G, Rosenfeld J, Rosenthal A, Ross 
D, Rothberg M, Rubino J, Rudolph L, Ruoff G, Ryan E, Sadler C, Samson M, Sanders 
R, Scarsella A, Schmidt J, Schoenwalder M, Schreiber A, Schreiman R, Schultz D,
Schwartz A, Sensenbrenner J, Serfer G, Seshadri N, Severa L, Shah S, Shanes J,
Sharma M, Sharpe C, Shergy W, Sherman H, Shlotzhauer T, Shoffner S, Shore K, Sims
J, Singh H, Smallow S, Smith MT, Snyder B, Soo A, Sprague A, Stamps H, Stearns P,
Sudano D, Sugimoto D, Suleman A, Sunkureddi P, Tan R, Tan A, Tannenbaum A, Tawney
K, Teixeira G, Teltser M, Torres A, Tran C, Trapp R, Trevino M, Tsai Y, Tuan W,
Vaid B, Valente R, Van Camp K, Van Ginkel E, Varano S, Vaughn M, Velderman P,
Viera E, Vijay N, Vincent S, Von Feldt J, Vora K, Vora S, Vukotic G, Waller P,
Walton M, Wayne J, Weinstein D, Weiss D, Weiss E, Whitlock L, Wiesenhutter C,
Williams R, Williams T, Williams D, Wilson S, Wolfe S, Wombolt D, Wood J, Yarows 
S, Yetman C, Yiannias C, Yood R, Young VL, Young D, Zuzarte K, Gibofsky A, Carson
PE, Lakatos E, Ryan LM, Waikar SS, Morris DD, Jackson R, McLean L, Qin Y,
Kisfalvi K, MacDonald P, Palmer R, Yang T, Tsymbalov S, Alkawass N, Keeter K,
Koziol M, Schickedanz B, Evans B, Chefo S, Xie B, Song E, Dong X, Zhang W, Chen
Y, Loke R, Li D, Li X, Max E, Dabholkar A, Makaratzi M, Schulz P, Khursheed M,
Marcinak J, Geiger C, Henning E, Harrigan P, Ludwig P, Idemoto C, Bronson C, Gans
J, Kennedy JE, Villinski A, Koehler L, Parker J, Desai E.

Comment in
    N Engl J Med. 2018 Oct 18;379(16):1582.
    N Engl J Med. 2018 Oct 18;379(16):1583.
    N Engl J Med. 2018 Oct 18;379(16):1583-4.
    Internist (Berl). 2018 Nov;59(11):1224-1228.

BACKGROUND: Cardiovascular risk is increased in patients with gout. We compared
cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase 
inhibitor, with those associated with allopurinol, a purine base analogue
xanthine oxidase inhibitor, in patients with gout and cardiovascular disease.
METHODS: We conducted a multicenter, double-blind, noninferiority trial involving
patients with gout and cardiovascular disease; patients were randomly assigned to
receive febuxostat or allopurinol and were stratified according to kidney
function. The trial had a prespecified noninferiority margin of 1.3 for the
hazard ratio for the primary end point (a composite of cardiovascular death,
nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent
revascularization).
RESULTS: In total, 6190 patients underwent randomization, received febuxostat or 
allopurinol, and were followed for a median of 32 months (maximum, 85 months).
The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued
follow-up. In the modified intention-to-treat analysis, a primary end-point event
occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients
(10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the
one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority).
All-cause and cardiovascular mortality were higher in the febuxostat group than
in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI,
1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to
1.73]). The results with regard to the primary end point and all-cause and
cardiovascular mortality in the analysis of events that occurred while patients
were being treated were similar to the results in the modified intention-to-treat
analysis.
CONCLUSIONS: In patients with gout and major cardiovascular coexisting
conditions, febuxostat was noninferior to allopurinol with respect to rates of
adverse cardiovascular events. All-cause mortality and cardiovascular mortality
were higher with febuxostat than with allopurinol. (Funded by Takeda Development 
Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).

DOI: 10.1056/NEJMoa1710895 
PMID: 29527974  [Indexed for MEDLINE]