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Lancet. 2014 May 31;383(9932):1889-98. doi: 10.1016/S0140-6736(14)60614-0.

Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.

Collaborators (475)

Anspach RB, Biggs BC, Block BM, Butuk DJ, Calhoun DA, Champlin JJ, Chaykin LB, Davis TL 3rd, Davis LN, DiGregorio MD, Diller PM, Doehring L, Elacion JM, Ericksen C, Essink BJ, Fang C, Fitz-Patrick D, Folkherth SD, Gabra N, Garner A, Gaudiani L, Gimness M, Goldman BH, Gorton SC 2nd, Graff A, Greenberg J, Gregory DM, Guice M, Heinlen LD, Vander Veen BS, Huffman C, Hughes WD, Huling RT Jr, Jasper D, Krause RA, Kulback SJ, Kunz H, Lee K, Link MH, Lorch DG Jr, Medina CC, Meli JV Jr, Montano C, Morelli J, Morrar N, Nakhle S, Naseeruddin S, Noss MJ, Odugbesan AO, Patel D, Patron A, Pemba R, Perry RG, Pettyjohn FS, Phillips AL, Potts JA, Radin DM, Rapo SE, Roth EM, Samson MB, Sandberg JH, Schmidt LM, Schwartz D, Sensenbrenner JW, Randhawa S, Shah SB, Shah AV, Sorin J, Soufer J, Sparks JD, Stamps HB, Stearns P, Streit B, Surowitz RZ, Tejada AQ, Teltser M, Tidman RE, Webster BR, Whitlock LW, Wine AC, Yang DT, Zehnder BK, Bland VJ, Fiel T, Fuchs R, Gutmann JE, Holdeman TA, Lang CR, Ledesma G, Mariano HG Jr, Robinson M, Arif A, Earl JK, Haase G, Howell JW, Jardula MF, Karns AD, Marienau DJ, Maughan GT, McCurley L, Michlin BA, Naccarato TR, Promisloff S, Radbill MK, Schmidt J, Sibille JS, Watkins LS, Bolster DE, Broker RE, Davis MG, Delgado JP, Detweiler RO, Fox B, Stehouwer E, Giusti R, Horton KB, Jones C, Jones SW, Kaner DB, Kerzner B, Koch SW, Mills RE, Morris FH, Poss GE, Rakowski TA, Ramstad D, Renzi MA, Wallace JE Jr, Wombolt DG, Bains PS, Cox SE, Diederich CF, Hearne A, Kmetzo J, Walia JS, van Cleeff M, Bautista JL, Ceimo J, Condit J, Dewan M, Fogarty CM, Guthrie R, Izzo J Jr, Koontz DA, Lara MM, Levinson LK, Nolasco AE, Pratt SE, Sanchez SA, Sokolowicz JH, Zeig S, Adler JL, Alwine LK, Andrawis NS, Beyer RD, Morris D, McCarroll GD, Moro MV, Rohlf J, Rosenberg RA, Slabic SF, Topkis R, Wieskop BD, Blahey MS, Hanlon BC, Maiquez A, McEntire BE, Anderson AG, Armas E, Azizad M, Bardinas-Rodriguez R, Cauthen BB, Ensz D, Garcia RK, Jack DB, Manos P, Mehra PK, Vaughn MS, Young D, Christensen SG, Connery L, Gagianas PJ, Henry DC, Hidalgo HA Jr, Hindman MG, Hippert RK, Isakov T, Julien KA, Rhee M, Riffer E, Sandoval JD, Sastre RF, Seidner MR, Barker BA, Ison RK, Richwine RT, Schreiber AO, Zamora BM, Gothard SJ, Bernstein M, Lowe JE, Civitarese FA, Crump KL, Johnson DM, Maldonado HM, Moretto T, Breton CF, Polner B, Riveland BR, Harris DJ, LaStella P, El Hafi S, Tobin TM, Lanza FL, Bertsch JP, Blemur PR, Castello R, Cox RF Jr, Cruz H, Heigerick GC, Hole S, Lillo JL, Lipetz RS, Quintero LC, Reddy JS, Sanderlin D, Baula G, Braden SA, Bristol PE, Daoul N, DeHart DP, Montenegro CH, Rosen JB, Smith TR, Tessier CR 3rd, Abraham B, Barbel-Johnson KM, Bouda D, Crabtree Y, Evans BD Jr, Jennings WP, Kelly RL, Marquez F, Safirstein BE, Williams T, Kahn B, Joyce JM, Capo JP Jr, Casanova R, Foster RE, Shafik SN, Martin EE, Doolan R, Riser JM, Barker TA, Wood J, Miller RP, O'Connor T, Budoff MJ, Bowen AC, Drosman SR, Fidelholtz JI, Ghosh C, Martinez JE, Pritchett K, Chipman HN 3rd, Walker GS, Engel E, Hartley PA, Johnson-Caldwell J, Lester FM, Lewis D, Morris KA, Shandilya L, Wenocur HS, Mays ME, Sandercock DJ, Jordan RS, Terrelong AE, Samuels BS, Karns R, Adler F, Alpizar S, Atieh M, Christensen T, Cole J, DeSantis M, Flippo G, Jones E, Karl J, Laurent A, Longshaw K, McKnight T, Pearlstein R, Powers C, Pucillo RM, Ratner PH, Reiff M, Rosen RD, Varano S, Williams DG, Wise JK, Zarich S, Allaw MA, Cone C, DeGarmo RG, Devenport SB, Duong CQ, Haffizulla JM, Kalen V, Rahimi AR, Sellers GA, Zaidi SM, Ball EM, Yarows S, Thompson TA, Segal I, Patton WS, Maynard KM, Oudeh IN, Pomposini DL, Sanders R, Crater T, Lindenbaum JA, Navayogarajah S, Pinches JL 3rd, Allison D, Beavins JE, Dawson MC, Lentz JD 3rd, Hood RG, Tse A, Spierings E, McGill LJ, Willette RC, Neskovic SM, Quigley JF, Durrence HD, Garcia LM, Borders JL, Bakhtiar K, Bellingar B, Schlau A, Aish B, Davis PW, Doshi AA, Eaton CB, Verma SP, Wolfson E, Bowden R, Canaan YA, Morris LA, El Sayad NI, Margulies JA, Martinez GJ, Pharr WD, Ponce GA, Riske TA, Sullivan JL, Weil AJ, Yazdi FM, Brown CL, Huehnergarth KV, Prince CJ, Tamayo RA, Weiner GR, Beckett PL, Chappel CM, Testori A, Olds SG, Chandra L, Tarleton GP, Andersen JL, Anderson CG, Calatayud G, Cannon KD, Cheung DG, Chiong R, Cohen LM, Collins H, Dao MM, Dawson CH, DeSantis DM, Dunmyer SL, El-Harazi SM, Farrington CM, Ferrera R, Funk GS, Gottschlich GM, Hart TT, Kalafer M, Kereiakes DJ, Khan B, Lefebvre GC, Laliotis AT, Mattar PN, McCartney MJ, McConnehey DO, Mello CJ, Neutel JM, Burke DA, Pritchard J, Raad GL, Rankin BG, Reed JC, Samudrahla S, Schramm EL, Schreiman R, Schwartz HI, Segall N, Shoemaker JR, Sial V, Sligh T, Smith WB, Stewart RB, Streja DA, Sugimoto D, White A, Williams HT, Abraham W, Ahmed AA, Beasley RL, Gruener DM, Hsu CC, Klein RM, Soo AM, Andrews CP, Corder CN, Hurley DP, Bretton EM, Martinez RE, Morin DJ, Trevino M, Arora S, Horn CS, Lovell CF Jr, Nussdorfer TC, Weiss RJ, Bays HE, Rhudy JM, Almaguer EM, Woolley JH, Miller VE, Moya-Hechevarria J, Punzi HA, Taylor AA, Wilson JP, Alper AB, Buchanan PP, Dobrusin RS, Forker AD, Krumian R, Oberstein SF, Lewin AJ, Natividad MB, Segui A, Harper WL, Lawless A, Levinson L, Shah S, Blair-Britt L, Carmichael PR, Giles TD, Winer N, Grant D, Pragalos AA, Rickner K, Tilley AH, Wagner RJ, Harper LS, Maddock S, Boscia JA 3rd, Khronusova YA, Reed LD, Abboy C.

Author information

1
Department of Medicine, Tulane University, New Orleans, LA, USA. Electronic address: tgiles4@cox.net.
2
Division of Cardiovascular Medicine, State University of New York, Downstate College of Medicine, Brooklyn, NY, USA.
3
Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA.
4
Department of Medicine, Temple University School of Medicine, Pittsburgh, PA, USA.
5
Department of Clinical Development, Forest Research Institute, Jersey City, NJ, USA.
6
Department of Biostatistics, Forest Research Institute, Jersey City, NJ, USA.

Erratum in

Abstract

BACKGROUND:

The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension.

METHODS:

We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026.

FINDINGS:

Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group.

INTERPRETATION:

Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension.

FUNDING:

Forest Research Institute.

PMID:
24881993
DOI:
10.1016/S0140-6736(14)60614-0
[Indexed for MEDLINE]
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