ARTIKEL 2 Hypertension

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Effi cacy and safety of nebivolol and valsartan as xed-dosecombination in hypertension: a randomised, multicentre studyThomas D Giles, Michael A Weber, Jan Basile, Alan H Gradman, David B Bharucha, Wei Chen, Manoj Pattathil, for the NAC-MD- Study Investigators*

SummaryBackground The xed-dose combination of any two antihypertensive drugs from different drug classes is typicallymore effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the effi cacyand safety of a xed-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 at401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg wererandomly 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-blindtreatment with nebivolol and valsartan xed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubledin weeks 5–8; results are reported according to the nal dose. Participants and research staff were masked to treatmentallocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolicblood pressure, respectively. The primary statistical comparison was between the highest xed-dose combination doseand the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochbergmethod for multiple testing). Effi cacy analyses were by intention to treat. Safety assessments included monitoring ofadverse events. Continuous effi cacy parameters were analysed using an ANCOVA model; binary outcomes wereanalysed 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 554–555to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the xed-dosecombination 20 and 320 mg/day group had signicantly 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) andvalsartan 320 mg/day (−4·4 mm Hg, –5·4 to –3·3; p


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genotyping), BioClinica (Princeton, NY, USA; ambulatory

blood pressure monitoring [ABPM] processing), andKeystone Bioanalytical (North Wales, PA, USA;processing of pharmacokinetic parameters). Men andwomen aged 18 years or older were eligible to participateif they had stage 1 or 2 hypertension (Seventh Report ofthe Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure[JNC7] criteria2) with a recent diastolic blood pressuremeasurement of at least 90 mm Hg and less than110 mm Hg if receiving hypertension treatment or atleast 95 mm Hg and less than 110 mm Hg at screening ifuntreated, a pulse rate of at least 55 beats per min (exceptfor those already taking a β blocker), and a normalphysical examination at screening. Reasons for exclusionincluded secondary hypertension; systolic blood pressureat least 180 mm Hg or diastolic blood pressure at least110 mm Hg; treatment with more than fourantihypertensive drugs (including components of xed-dose combinations); contraindication to discontinuationof present antihypertensive treatment; upper armcircumference greater than 42 cm; presence of coronaryartery disease, reactive airway disease, chronic obstructivepulmonary disease, second-degree or third-degree heartblock or sick sinus syndrome, heart failure, hypertensiveretinopathy (Keith-Wagener-Barker grade III or IV),type 1 diabetes, poorly controlled type 2 diabetes (glycatedhaemoglobin ≥8%), uncontrolled thyroid disease within3 months of screening, inammatory bowel disease oractive gastritis, pancreatitis, or renal impairment(estimated glomerular ltration rate


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baseline in mean trough seated diastolic and systolic

blood pressure at week 4 and changes in 24-h ABPMvalues for diastolic and systolic blood pressure frombaseline to week 8 for participants assigned to the xed-dose combination of 20 and 320 mg/day versus40 mg/day nebivolol and 320 mg/day valsartan; diastolicblood pressure responder rates at week 8 at levels lessthan 90 mm Hg and less than 80 mm Hg, and systolicblood pressure responder rates at week 8 at levels lessthan 140 mm Hg and less than 130 mm Hg (20 and320 mg/day xed-dose combination versus nebivolol40 mg/day and valsartan 320 mg/day).

Additional prespecied effi cacy parameters includedchanges from baseline in mean trough seated diastolicand systolic blood pressure at each visit, changes inpulse rate at week 8, and proportions of participantsachieving treatment goal (blood pressure


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ResultsBetween Jan 6, 2012 (rst participant, rst visit), andMarch 15, 2013 (last participant, last visit), 4161 par-ticipants were randomly assigned to receive double-blindtreatment, 4118 of whom were included in the intention-to-treat population (gure 1). Mean demographic andclinical characteristics (table) and study completion rates(gure 1) were comparable between treatment groups.

Consent withdrawal was the most frequent reason fordiscontinuation in all active-treatment groups, with theexception of nebivolol 40 mg/day (adverse events) andnebivolol 10 mg/day (consent withdrawal; adverse events;gure 1). Adherence at each visit was at least 99% forevery group.

The mean difference in diastolic blood pressurebetween baseline and week 8 ranged from –14·8 mm Hg(SD 9·2) for the 10 and 160 mg/day xed-dosecombination to −15·7 mm Hg (9·6) for the 20 and320 mg/day xed-dose combination; from –12·7 mm Hg(9·0) fo r nebivolol 10 mg/day to −14·4 mm Hg (9·4) fornebivolol 40 mg/day; and from –10·8 mm Hg (9·6) forvalsartan 160 mg/day to −11·2 mm Hg (9·3) for valsartan320 mg/day (gure 2A). At week 8, the xed-dose

combination 20 and 320 mg/day group had signicantlygreater reductions in diastolic blood pressure frombaseline than both nebivolol 40 mg/day (p=0·030) andvalsartan 320 mg/day (p


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for the 10 and 160 mg/day xed-dose combination to−17·8 mm Hg (15·8) for the 20 and 320 mg/day xed-dose combination; from –14·2 mm Hg (14·8) for nebivolol10 mg/day to −15·1 mm Hg (16·5) for nebivolol40 mg/day; and from –14·2 mm Hg (14·4) for valsartan160 mg/day to −14·8 mm Hg (15·1) for valsartan320 mg/day (gure 2B). At week 8, the xed-dosecombination 20 and 320 mg/day group had signicantlygreater reductions in systolic blood pressure frombaseline than both nebivolol 40 mg/day (p=0·001) andvalsartan 320 mg/day (p=0·0005; primary statistical

comparisons); all other comparisons were also signicant,favouring the xed-dose combinations (all p


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Figure : Changes in trough seated diastolic and systolic blood pressure from baseline to week 8 and visit by visit

Analyses were by intention to treat, last observation carried forward. All active-treatment groups were signicantly different from placebo at weeks 4 and 8 (p


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valsartan only, mean pulse rate changes were similar tothose reported in participants receiving placebo (gure 4A).In a post-hoc analysis, the decrease in pulse pressure withthe xed-dose combination 20 and 320 mg/day was greaterthan the decrease noted with nebivolol 40 mg/day(p=0·0053), but seemed to be smaller than the decreasereported with valsartan 320 mg/day (p=0·053; gure 4B).

Across all treatment groups, subgroup analysesrevealed no signicant interactions between treatmentand sex, race, diabetes status, or diastolic blood pressurestatus at baseline (


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During the 8-week treatment phase, discontinuationrates because of an adverse event ranged from nineof 555 (2%) for those in the 10 and 320 mg/day and 20 and320 mg/day xed-dose combination groups to 22 of555 (4%) in the nebivolol 40 mg/day group (gure 1). Therates of experiencing at least one treatment-emergentadverse event in the safety population were similar acrosstreatment groups: 100 of 277 (36%) in the placebo group,193 of 555 (35%) in the xed-dose combination 10 and160 mg/day group, 185 of 555 (33%) in the xed-dosecombination 10 and 320 mg/day group, 189 of 554 (34%) in

the xed-dose combination 20 and 320 mg/day group,

196 of 555 (35%) in the nebivolol 10 mg/day group,198 of 554 (36%) in the nebivolol 40 mg/day group, 165 of555 (30%) in the valsartan 160 mg/day group, and 190of 554 (34%) in the valsartan 320 mg/day group. Mosttreatment-emergent adverse events were judged to be mildor moderate in severity. The appendix lists treatment-emergent adverse events that occurred in at least 2% of thesafety population.

During double-blind treatment, 27 serious adverseevents were reported by three of 277 (1%) participants inthe placebo group (spontaneous abortion, cerebrovascularaccident, and transient ischaemic attack), two of555 (


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The absence of a dose response in the xed-dosecombination groups (gure 2) could be attributed to theat dose responses for both nebivolol 8 and valsartan. 17 Thewell-established tolerability of nebivolol 8 and valsartan 18 monotherapies was shown in a favourable tolerabilityprole of the combination. Adverse events commonlyassociated with β-blocker use (eg, bradycardia, fatigue,and dizziness) 19,20 were noted with the highest nebivololdose (40 mg/day, which is rarely used in clinical practiceand is associated with a loss of β 1 selectivity10), but notwith clinically common doses (5–20 mg/day; appendix).

Finally, post-hoc and exploratory ndings suggest thatthe nebivolol and valsartan xed-dose combination has a

haemodynamic effect that includes reductions in bothpulse rate and pulse pressure (consistent with pharmaco-logical properties of individual components) 10,15 and thatthis combination would be effective in a wide variety ofpatients. The absence of a systolic blood pressure effectin participants at least 65 years old is probably an artifactof subdivision of the sample and the small number ofparticipants in that category.

Data interpretation is limited by several factors,including the size of the ABPM substudy, which mighthave been too small to capture a signicant difference in24-h ABPM data between the groups treated with xed-dose combination 20 and 320 mg/day and nebivolol40 mg/day. Moreover, available data suggest that bothincreases in dose and treatment duration for nebivolol 8

Figure : Antihypertensive effects of xed-dose combination 20 and 320 mg/day (placebo-subtracted values) by subgroupAnalyses were by intention to treat, last observation carried forward. BMI=body-mass index. FDC=xed-dose combination. LSMD=least-squares mean difference.

SexMenWomen

BMI

≥30 kg/m2


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and valsartan 21 would be expected to ultimately play a

part in effi cacy. Additionally, a stron g placebo response,especially among Hispanics and participants at least65 years old, and also among the small number of elderlyparticipants, makes assessment of the effi cacy of thecombination in those subgroups diffi cult. Finally, adesign following a perfect Latin square, similar to theone used in combination studies of nebivolol and hydro-chlorothiazide, 17,18 might have provided better insightinto a potential dose response of the nebivolol andvalsartan combination.ContributorsTDG designed the study; collected, analysed, and interpreted data; andwrote and reviewed the manuscript. MAW, JB, AHG, DBB, andMP designed the study, interpreted data, and revised the manuscript.WC designed the study, analysed data, and revised the manuscript.

Declaration of interestsIn the past 36 months, TDG has received personal fees from ForestLaboratories. MAW has received speaker, consultant, or research feesfrom Forest, Boehringer-Ingelheim, Daiichi-Sankyo, Takeda, Medtronic,Boston Scientic, AstraZeneca, and Arbor. JB has received consultantfees from Forest. AHG has received grants, personal fees or non-nancialsupport from Forest, Novartis, Daiichi-Sankyo, Takeda, the AmericanSociety for Hypertension, and the American College of Cardiology.DBB, WC, and MP are employees of Forest Research Institute.

AcknowledgmentsKristen Andersen, Autumn Kelly, Vojislav Pejović, Leah Richmond, andBill Sterling of Prescott Medical Communications Group (Chicago, IL,USA) assisted with literature searches, editing, creation of graphs andtables, circulation of drafts among the authors, and formatting of themanuscript for submission.

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ARTIKEL 2 Hypertension