American Journal of Hypertension25(3)325[1]

7/29/2019 American Journal of Hypertension25(3)325[1]

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AMERICAN JOURNAL OF HYPERTENSION | VOLUME 25 NUMBER 3 | 325-334 | MaRch 2012 325

original contributionsnatre pbisin rop

See REVIEWER COMMENTARY page 279

Blood pressure (BP) measurements made in the physiciansoce have long been used to diagnose hypertension and evalu-ate treatment ecacy.1,2 However, the correlation between BPlevel and target organ damage, cardiovascular disease (CVD)risk, and long-term prognosis is greater or ambulatory BPmonitoring (ABPM) than clinical BP.3,4 Among the dierentspecic eatures o the 24-h BP pattern that have been assessedas potential prognostic markers o CVD events, numer-

ous studies have consistently shown an association betweenblunted sleep-time relative BP decline (so-called nondipperBP pattern) and increased incidence o atal and nonatal CVDevents, both in subjects without57 as well as with diabetes.811Independent prospective studies have also ound that thenight-time BP mean is a better predictor o CVD risk thanthe daytime or 24-h BP means,6,7,1214 a relevant nding also

documented or patients with diabetes.10,15 A major limitationo all previous ABPM-based prognostic studies is reliance ononly a single baseline prole rom each participant at the timeo inclusion, without accounting or potential changes in thelevel and circadian pattern o ambulatory BP thereaer dur-ing ollow-up, as a consequence o BP-lowering therapy, aging,and/or development o target organ damage and concomitantdiseases. Tus, due to the lack o periodic multiple evalua-

tions with ABPM in all previous reported studies, the poten-tial reduction in CVD risk associated with modication oprognostic ABPM parameters, i.e., reduction o the asleep BPmean, has never beore been evaluated. Apart rom the awake,asleep, and 24-h BP mean values, other ABPM characteristicshave also been investigated in relation to CVD risk, includingthe extent o the BP surge upon awakening,16 or the recentlyproposed ambulatory arterial stiness index.17

Te MAPEC (Monitorizacin Ambulatoria para Prediccinde Eventos Cardiovasculares, i.e., ambulatory blood pressuremonitoring or prediction o cardiovascular events) studywas specically designed to investigate prospectively whetherchanges in the circadian BP prole determined by ABPM

1Bioengineering & cronobiology Lbortories, University of Vigo, cmpus

Universitrio, Vigo, Spin. correspondene: Rmn c. hermid

([email protected])

Received 12 July 2011; first decision 15 August 2011; accepted 27 October 2011.

2012 American Journal of Hyper tension, Ltd.

Sleep-Time Blood Pressure as a Therapeutic Target for

Cardiovascular Risk Reduction in Type 2 DiabetesRamn C. Hermida1, Diana E. Ayala1, Artemio Mojn1 and Jos R. Fernndez1

BACkgROuNd

Independent studies ve found tt elevted sleep-time blood

pressure (BP) is better preditor of rdiovsulr risk tn te

wke or 24- BP mens in ptients witout s well s wit dibetes.

however, te impt of te ltertion over time of mbultory BP

on rdiovsulr risk s never been investigted. We evluted

in subgroup oort of MaPEc (Monitorizin ambultori pr

Prediin de Eventos crdiovsulres, i.e., mbultory bloodpressure monitoring for predition of rdiovsulr events) wit

dibetes weter redued rdiovsulr risk is more relted to te

progressive derese of wke vs. sleep BP.

METhOdS

We studied 607 ptients wit type 2 dibetes during medin 5.4

yers follow-up. Tose wit ypertension t bseline (74%) were

rndomized to ingest ll teir presribed ypertension meditions

upon wkening or 1 of tem t bedtime. BP ws mesured for 48

t bseline, nd gin nnully in ll ptients, or more frequently

(qurterly) fter djustments in tretment.

RESulTS

Using bseline dt, wen sleep BP ws djusted by wke men,

only te former ws signifint preditor of outome in cox

proportionl-zrd model djusted for sex, ge, nemi, nd

roni kidney disese. anlyses of nges in BP during follow-up

reveled 20% rdiovsulr risk redution for e 5 mm hg

derese in sleep systoli BP men (P< 0.001), independently of

nges in lini or ny oter mbultory BP prmeter.

CONCluSIONS

Sleep-time BP is te most signifint independent prognosti mrker

of rdiovsulr events in dibetes. Most importnt, deresing

sleep-time BP, novel terpeuti trget requiring proper ptient

evlution by mbultory monitoring, ws te most signifint

independent preditor of event-free survivl in dibetes.

Keywords:ambulatory blood pressure monitoring; blood pressure;

cardiovascular risk; hypertension; sleep-time blood pressure; type 2

diabetes

American Journal of Hypertension, advance online publication 8 December 2011;

doi:10.1038/ajh.2011.231
mailto:[email protected]://www.nature.com/doifinder/10.1038/ajh.2011.231http://www.nature.com/doifinder/10.1038/ajh.2011.231mailto:[email protected]


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326 MaRch 2012| VOLUME 25 NUMBER 3 |AMERICAN JOURNAL OF HYPERTENSION

original contributions Sleep-Time Blood Pressure in Diabetes

results in reduced CVD risk.1820 Herein, we present addi-tional analyses rom the MAPEC study to evaluate whetherchanges o ambulatory BP characteristics during ollow-up,e.g., awake vs. asleep BP, might be related to increased survivalin patients with type 2 diabetes who were systematically evalu-ated by periodic, at least annually, ABPM.

METhOdS

Inclusion and exclusion criteria. An extended version o theMethods is available in the Supplementary Methods online.In summary, the sample represents a population o Spanishpatients with type 2 diabetes, 18 years o age, either untreatednormotensive or essential hypertensive according to theABPM diagnostic values outlined below, and who were amongthe participants in the more extensive MAPEC study.18,19Exclusion criteria included pregnancy, history o drug/alcoholabuse, night/shi-work employment, AIDS, type 1 diabetes,secondary hypertension, CVD disorders (unstable angina pec-toris, heart ailure, lie-threatening arrhythmia, atrial brilla-

tion, kidney ailure, and grade III-IV retinopathy), intoleranceto ABPM, and inability to communicate and comply with allo the study requirements. Hypertensive subjects who wereunder treatment with 2 BP-lowering medications could alsobe included aer washed-out or 2 weeks beore inclusion.Participants represent a consecutive series o patients ulll-ing the exclusion/inclusion criteria, recruited among thosereerred to the hospital or ABPM evaluation. Tis prospectivesingle-center study (registered at http://www.clinicaltrials.gov,with identier code NC00295542) was approved by the stateethics committee o Clinical Research. All participants gavewritten inormed consent.

Subjects and diagnostic criteria. Between 2000 and 2007, weassessed 645 patients ullling the inclusion/exclusion criteria.Among these, 607 (364 men/243 women, 59.7 12.3 (mean s.d.) years o age) provided all required inormation or thestudy. Te remaining 38 subjects were excluded due to inad-equate ABPM sampling at baseline and lack o consent oradditional ABPM evaluations. Diagnosis o hypertension wasbased on accepted ABPM criteria, i.e., an awake systolic (SBP)/diastolic BP (DBP) mean 135/85 mm Hg and/or an asleepSBP/DBP mean 120/70 mm Hg.2 At the time o recruitment,159 patients were normotensive and 448 were hypertensiveaccording to these ABPM criteria.

Study design. Complete details o the rationale and design othe MAPEC study are described in previous publications.1820A major goal o the study was to assess the eect o the treat-ment-time o prescribed BP-lowering medications on CVDrisk. Tus, hypertensive patients participated in a prospective,randomized, open-label, blinded endpoint (PROBE) trial; theywere randomized to ingest all their prescribed BP-loweringmedications upon awakening (232 patients) or 1 o themat bedtime (216 patients). I patients were uncontrolledbased on ABPM criteria aer 3 months o therapy, additionalmedications could be added in keeping with current clinical

practice. Changes in the hypertension therapeutic scheme dur-ing ollow-up in uncontrolled patients, i.e., those with ambu-latory BP above the thresholds specied above, were alwaysbased on the results o the periodic evaluation by ABPM. Teinfuence o hypertension treatment-time on CVD risk waspreviously reported.20

Blood samples were obtained the same week when each48-h ABPM session was initiated. Participants reported tothe hospital between 0800 and 0900 h, aer overnight ast-ing, or blood withdrawal rom an antecubital vein. Just beorecommencing each 48-h ABPM session, the same investigatorobtained six consecutive clinic BP measurements using a vali-dated automatic oscillometric device (HEM-705I; OmronHealth Care, Vernon Hills, IL) aer the patient had rested in aseated position or 10 min.

ABPM assessment. At inclusion, and at each scheduled visit orABPM during ollow-up (see below), SBP and DBP were auto-matically measured every 20 min between 0700 and 2300 h

and every 30 min during the night or 48 consecutive hourswith a calibrated SpaceLabs 90207 ABPM device (SpaceLabs,Issaquah, WA). BP series were considered invalid or analysisi 30% o the measurements were missing, i data were lack-ing or an interval o >2 h, or i the night-time sleep period was12 h during ABPM.

Actigraphy. All participants wore an actigraph (Mini-Motion-Logger, Ambulatory Monitoring, Ardsley, NY) on the domi-nant wrist to quantiy physical activity at 1-min intervals duringeach 48-h ABPM. Te actigraphy data, combined with patientdiaries, were used to corroborate absence o daytime nap-

ping and to dene the commencement and termination o thedaytime awake and night-time asleep spans so the respectiveSBP and DBP means o each participant could be accuratelydetermined.

Follow-up. Te same evaluation procedure described above,including conventional clinic BP measurement, 48-h ABPMand wrist activity monitoring, was scheduled annually in allparticipants, or more requently (3 months aer any change intherapy in treated patients) i the therapeutic scheme was mod-ied to improve ambulatory BP control. Investigators blindedto the timed-treatment scheme o each participant (excludingthose perorming clinic evaluation at each visit to the hospi-tal, clinic and ambulatory BP measurement, and/or statisticalanalyses) reviewed at least annually, as well as or a year aerthe last ABPM evaluation was perormed, the complete clinicalrecords o all enrolled patients to assess CVD morbidity andmortality. Registered events included: death rom all causes,myocardial inarction, angina pectoris, coronary revascu-larization, heart ailure, acute arterial occlusion o the lowerextremities, thrombotic occlusion o the retinal artery, hemor-rhagic stroke, ischemic stroke, and transient ischemic attack.

Statistical methods. Te awake and asleep BP means were cal-culated as the average o all valid readings obtained during
http://www.clinicaltrials.gov%2C/http://www.clinicaltrials.gov%2C/


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AMERICAN JOURNAL OF HYPERTENSION | VOLUME 25 NUMBER 3 | MaRch 2012 327

original contributionsSleep-Time Blood Pressure in Diabetes

either the hours o daytime activity or night-time sleep, respec-tively, as determined by wrist actigraphy, during the 48-hABPM. Te sleep-time relative BP decline (an index o BPdipping), dened as the percent decrease in mean BP duringnight-time sleep relative to the mean BP during daytime activ-ity, was calculated as: ((awake BP mean asleep BP mean)/

awake BP mean) 100, using all the data sampled by 48-hABPM. For comparative purposes, a patient was dened as adipper i the sleep-time relative SBP decline was 10%, andas a nondipper otherwise. Te morning BP surge was calcu-lated as the dierence between the average BP during the rst2 h aer wake-up time and the hourly average centered on thelowest night-time sleep-time BP reading.16 Te ambulatoryarterial stiness index was calculated as 1 minus the regressionslope o DBP on SBP rom ABPM.17

Te relationship between the ABPM-derived characteristicsand CVD risk was evaluated on the basis o the: (i) baselineABPM evaluation rom every participant; and (ii) changes in anytested ABPM characteristic per participant during ollow-up.

Te primary outcomes o study endpoint was total CVD mor-bidity and mortality, which included all the events listed above.We also used the additional endpoint o major CVD events,i.e., a composite o CVD deaths, myocardial inarction, andstroke. Demographic and clinical characteristics were com-pared among groups o patients experiencing or not experienc-ing an event byt-test (continuous variables) or nonparametric2 test (proportions). Te Cox proportional-hazard model, withadjustment or signicant conounding variables, was used toestimate hazard ratios (HR) with 95% condence intervals (CI)or events associated with each tested potential prognostic BPparameter at baseline; we standardized these HRs by calculating

them or 1-s.d. increments or each BP parameter. On the otherhand, the prognostic value o BP reduction during ollow-upwas evaluated by entering the change in the tested ABPMparameter as a time-dependent covariate in the Cox regres-sion analysis. We additionally compared the prognostic valueo the dierent tested ABPM parameters plus clinic BP by theAkaike Inormation Criteria (AIC).21 Model selection was per-ormed by evaluating dierences in AIC between tested ABPMparameters, according to the rules proposed by Burnham andAnderson.22 For survival analysis, ollow-up was established aseither the time to the rst documented event or the time to thelast evaluation in event-ree patients.

RESulTS

demograpic caracteristics an aboratory variabes in

event an nonevent sbjects

During the median ollow-up period o 5.4 years (range0.58.4 years), we documented 107 events (35 major events),including 18 deaths (10 CVD deaths), 16 myocardial inarc-tions, 9 angina pectoris, 6 coronary revascularizations, 11cerebrovascular events, 25 heart ailures, 9 cases o aortoiliacocclusive disease, and 13 thrombotic occlusions o the retinalartery. At baseline, event-patients were predominantly men,o older age, and likely to have chronic kidney disease (CKD),anemia, and/or obstructive sleep apnea (Table 1). In addition,

they had higher clinic SBP (but not DBP), HbA1c, creatinine,low-density lipoprotein-cholesterol, plasma brinogen, anderythrocyte sedimentation rate, but lower estimated glomeru-lar ltration rate, high-density lipoprotein-cholesterol, andhemoglobin (Table 1). All dierences between groups reportedin Table 1 with a Pvalue


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Cox regression analysis indicated that clinic BP was not a sig-nicant predictor o outcome in the models already includingthe ABPM-derived asleep or 48-h BP mean; thus, clinic BPwas not an independent predictor o CVD events when resultswere properly corrected by ABPM-derived characteristics. Teanalysis also indicated that the best joint ully adjusted modelor predicting CVD events in diabetes included only the asleepSBP mean (1.43 (1.161.76), P < 0.001) and the sleep-timerelative SBP decline (0.72 (0.580.99), P < 0.01). Other vari-ables, including awake or 48-h BP means, morning surge, ands.d. o SBP, the ambulatory arterial stiness index, and param-eters derived rom DBP and pulse pressure, were not statisti-cally signicant when the asleep SBP mean was simultaneouslyincluded in the Cox regression models. Te sleep-time relativeheart rate decline was not a signicant predictor o outcome

Tabe 1 | Baseine caracteristics of investigate patients wit

type 2 iabetes

Variablea No event EventPbetween

groups

Demographic characteristics

Ptients, n 500 107

Sex, % men 57.6 71.0 0.01

Metboli syndrome, % 81.8 80.4 0.73

cigrette smoking, % 11.0 5.6 0.09

Obesity, % 58.2 57.0 0.82

Obstrutive sleeppne, %

9.8 20.6


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when the model was adjusted by the asleep SBP mean and thesleep-time relative SBP decline. Finally, when the asleep andawake SBP means were used jointly in the same Cox regressionmodel, only the ormer was a signicant predictor o outcome.Most important, the asleep BP mean was also the most signi-cant predictor o major CVD events (HR 2.14 (1.642.79) or1-s.d. elevation in asleep SBP mean; P < 0.001; Table 2, rightcolumns).

In order to urther investigate the clinical impact o awakeand asleep BP on the risk o CVD events, we divided the stud-ied population into our groups according to BP level, i.e.,normal or elevated, using the diagnostic ABPM thresholdsprovided above. Te results, as depicted in Figure 1, indicatethat the: (i) adjusted HR was comparable in patients witheither normal or elevated asleep BP, independently o awakeBP; and (ii) patients with elevated asleep BP had signicantly

Tabe 2 | hR of tota an major CVd events associate wit baseine cinic an ambatory BP in patients wit type 2 iabetes

Total CVD events Major CVD events

Parameter Adjusted HRFurther adjustment

by clinic BP Adjusted HRFurther adjustment

by clinic BP

SBP

clini 1.44 (1.191.74)* 1.93 (1.382.70)*

awke men 1.38 (1.171.63)* 1.22 (0.991.50) 1.75 (1.362.26)* 1.27 (0.911.76)

asleep men 1.71 (1.452.01)* 1.74 (1.402.17)* 2.23 (1.682.95)* 1.80 (1.252.58)*

48 men 1.51 (1.281.77)* 1.41 (1.141.75)** 1.90 (1.472.46)* 1.43 (1.022.02)***

Sleeptime reltive deline 0.58 (0.490.69)* 0.62 (0.520.74)* 0.48 (0.350.65)* 0.58 (0.420.79)*

s.d., wke 1.52 (1.271.81)* 1.40 (1.151.71)** 1.90 (1.422.54)* 1.54 (1.112.13)***

s.d., sleep 1.33 (1.121.57)** 1.20 (0.991.44) 1.59 (1.202.11)** 1.28 (0.941.74)

s.d., 48 1.34 (1.121.59)** 1.18 (0.971.45) 1.65 (1.212.24)** 1.25 (0.881.76)

Morning surge 0.79 (0.720.86)* 0.69 (0.590.82)* 0.59 (0.430.81)** 0.69 (0.530.92)**

DBP

clini 1.10 (0.901.34) 1.83 (1.252.68)**

awke men 1.03 (0.841.26) 0.95 (0.731.22) 1.75 (1.212.52)** 1.21 (0.761.91)asleep men 1.38 (1.161.66)* 1.47 (1.191.81)* 1.98 (1.472.67)* 1.72 (1.212.43)*

48 men 1.15 (0.941.39) 1.14 (0.881.47) 1.91 (1.342.72)* 1.46 (0.932.29)

Sleeptime reltive deline 0.59 (0.490.72)* 0.58 (0.480.71)* 0.54 (0.390.75)* 0.52 (0.360.73)*

s.d., wke 1.44 (1.191.75)* 1.46 (1.191.78)* 2.14 (1.572.92)* 1.88 (1.352.62)*

s.d., sleep 1.15 (0.971.36) 1.14 (0.961.35) 1.24 (0.921.66) 1.16 (0.871.56)

s.d., 48 1.11 (0.911.35) 1.08 (0.881.33) 1.41 (0.991.99) 1.22 (0.851.75)

Morning surge 0.75 (0.680.83)* 0.60 (0.500.71)* 0.61 (0.430.85)** 0.58 (0.420.79)**

PP

clini 1.46 (1.241.71)* 1.67 (1.232.26)**

awke men 1.45 (1.241.71)* 1.25 (0.991.59) 1.55 (1.202.01)** 1.07 (0.711.62)

asleep men 1.55 (1.351.80)* 1.61 (1.232.09)* 1.86 (1.422.42)* 1.58 (1.012.08)***48 men 1.51 (1.301.77)* 1.39 (1.091.78)** 1.65 (1.282.13)* 1.22 (0.801.86)

Sleeptime reltive deline 0.65 (0.550.77)* 0.71 (0.600.85)* 0.55 (0.410.74)* 0.63 (0.470.85)**

s.d., wke 1.46 (1.221.75)* 1.25 (1.001.57)*** 2.07 (1.502.85)* 1.73 (1.192.51)**

s.d., sleep 1.32 (1.101.59)** 1.18 (0.961.44) 1.50 (1.132.00)** 1.29 (0.941.77)

s.d., 48 1.44 (1.231.68)* 1.25 (1.011.55)*** 1.86 (1.422.44)* 1.54 (1.092.17)***

Morning surge 0.89 (0.810.98)*** 0.81 (0.680.97)*** 0.74 (0.531.03) 0.80 (0.591.07)

aaSI 1.41 (1.111.79)** 1.29 (1.011.66)*** 1.44 (0.962.15) 1.14 (0.731.77)

HRs (95% CI) were standardized by calculating them for 1-s.d. increments. Adjustments were applied for significant influential characteristics of age, sex, anemia, and chronic kidneydisease. Major events included cardiovascular death, myocardial infarction, and stroke. The sleep-time relative BP decline, an index of BP dipping, is defined as the percent decline inmean BP during night-time sleep relative to the mean BP during daytime activity, and calculated as: ((awake BP mean asleep BP mean)/awake BP mean) 100. The morning BP surgewas calculated as the difference between the average BP during the first 2 h af ter wake-up time and the hourly average centered on the lowest BP reading recorded during night-timesleep.

AASI, ambulatory arterial stiffness index; BP, blood pressure; CI, confidence interval; CVD, cardiovascular disease; DBP, diastolic blood pressure; HR, hazard ratio; PP, pulse pressure;SBP, systolic blood pressure.*P< 0.001; **P< 0.01; ***P< 0.05.


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higher HR than patients with normal asleep BP, independ-ently o awake BP. We urther compared the prognostic valueo ABPM-derived asleep BP mean with that o clinic BP meas-

urements. Accordingly, we additionally divided the studiedpopulation into our groups according to BP level, i.e., nor-mal or elevated, o clinic BP and asleep BP mean. Results inFigure 2indicate that, in patients with type 2 diabetes, CVDrisk is strongly associated with elevated asleep BP mean inde-pendently o the level o clinic BP measurements.

Canges in cinic an ambatory BP ring foow-p as

preictors of CVd risk

Table 3 gives the results o the time-dependent Cox regres-sion analysis (adjusted by age, sex, anemia, CKD, baseline BP,and number o hypertension medications) or total and majorCVD events. Le columns provide results in raw units, e.g.,HR or each 5 mm Hg decrease in BP. Right columns (stand-ardized HR) allow direct comparison on the prognostic valueo changing dierent BP parameters. Te progressive decreasein the awake, asleep, and 48-h SBP and DBP means was asso-ciated with signicantly increased survival. Changes in otherABPM parameters during ollow-up were less or not sig-nicantly associated with reduced/increased CVD risk. Tedecrease in the asleep BP mean during ollow-up was also themost signicant predictor o survival rom major events (HR0.76 (0.630.91), P< 0.001 or each 5 mm Hg decrease in asleepSBP mean;Table 3). When the changes in the asleep and awakeBP mean were used jointly in the same Cox regression model,

only the decrease in the asleep BP mean was signicantly asso-ciated with increased survival. Te right columns inTable 3,providing results based on standardized units, corroborate the

progressive decrease in the asleep BP mean was the most sig-nicant predictor o event-ree survival. Te Cox regressionmodel with the change in asleep SBP mean rom baseline hadthe lowest AIC among all parameters tested in Table 3. Tedierence in AIC with this best model was 14 or the changein asleep DBP mean, and 27 or every other tested param-eter, indicating considerably worst prognostic models than thechange in asleep SBP mean or all the variables inTable 3.

dISCuSSION

Tis study is the rst to assess prospectively the prognosticvalue o changes in ABPM parameters during a ollow-uptime o sucient duration by systematic periodic evaluation,using highly reproducible 48-h ABPM and wrist actigraphy,in a relatively large cohort o patients with type 2 diabeteswith baseline BP ranging rom normotension to hyperten-sion. Te results corroborate the higher prognostic value oABPM over clinic BP measurements documented in previousstudies.3,4,6,11 Analyses based on a single ABPM prole romeach patient obtained at baseline, as customary in all previousstudies on this topic, indicate that the asleep SBP mean wasthe most signicant predictor o total and major CVD events(Table 2), both individually as well as jointly when combinedwith other ABPM-derived potential prognostic markers inthe best possible Cox proportional-hazard model. In act,

Normal awake BP

Normal asleep BP High asleep BP

High awake BP

AdjustedHR

1.0

5(0.3

72.9

9)

2.7

7(1.7

34.4

1)

3.1

7(2.1

94.5

8)

3.5

3.0

2.5

1.00

n= 159 n= 37 n= 109 n= 302

2.0

1.5

1.0

0.5

0.0

P< 0.001

P= 0.922

P= 0.021

P= 0.122

Figre 1 | adjusted hR of totl cVD events. adjustments were pplied for ge, sex, nemi, nd roni kidney disese. Ptients were divided in four tegories

ording to te level, i.e., norml or elevted, of aBPMderived wke nd sleep BP. awke BP men ws onsidered norml if


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only the sleep-time relative SBP decline added prognosticvalue to the model that already included the asleep SBP meanand corrected or relevant conounding variables. Moreover,

when the asleep SBP mean was adjusted by either the awakeSBP mean (Figure 1) or by clinic SBP (Figure 2), only theormer was a signicant predictor o outcome. Interestingly, avery large 94% o event-patients in this study had a nondipperBP pattern at baseline; the sleep-time relative BP decline was,apart rom the asleep BP mean, a most signicant predictoro CVD events (Table 2). Most important, rom a therapeu-tic point o view, the evaluation o changes in ABPM-derivedvariables during ollow-up documented that the progressivedecrease in the asleep SBP mean was signicantly associatedwith event-ree survival (Table 3). Altogether, these resultsnot only corroborate that the asleep SBP mean is the most sig-nicant prognostic marker o CVD morbidity and mortalityin patients with type 2 diabetes, as previously suggested,10,15but they also document or the rst time that decreasingasleep SBP mean signicantly reduces the risk o total andmajor CVD events.

Apart rom the asleep BP mean and the sleep-time relativeBP decline, other specic eatures o the circadian BP patternhave been assessed as potential sources o injury to target tis-sues and as triggers o CVD events in hypertensive patients.For example, the level o BP immediately aer awakening andthe rate o BP rise coincident with the commencement o day-time activity have been hypothesized to be triggers or the doc-umented higher incidence o myocardial inarction and stroke

at this time o day.23 However, the ndings o prospectivestudies that investigated the prognostic signicance o themorning BP surge are inconsistent.16,2426 In our study, we

ound (Table 2) a larger morning BP surge was associatedwith a signicantly lower CVD risk, in line with the lower riskassociated with increased dipping o the circadian BP pattern.Te largest CVD risk was, indeed, ound in patients with a ris-ing pattern (asleep BP mean greater than awake BP mean),characterized by a morning BP decline (3.5 1.1 mm Hg onaverage in our study), not surge. Moreover, the morning BPsurge was no longer signicantly associated with CVD riskin the Cox regression models already including the asleep BPmean.

Te ndings summarized inTable 3suggest the asleep BPmean should be considered a novel therapeutic target orreduction o CVD risk in diabetes. Along these lines, a numbero previous prospective trials reviewed elsewhere27,28 havedetected meaningul morningevening, treatment-time di-erences in BP-lowering ecacy, duration o action, saetyprole and/or eects on the circadian BP pattern o dierentclasses o hypertension medications. Te impact o hyperten-sion treatment-time on sleep-time BP regulation might thusbe clinically relevant. Te previously reported results o therandomized part o the MAPEC study indicate that treatmentwith 1 BP-lowering medications at bedtime was signicantlyassociated with greater asleep BP reduction and signicantlylower CVD risk than treatment with all hypertension medica-tions upon awakening.19,20

Normal clinic BP

Normal asleep BP High asleep BP

AdjustedHR

High clinic BP

4

3

2

1

0

P< 0.001

P< 0.001

P= 0.713

P= 0.223

n= 82 n= 114 n= 54 n= 357

1.00

0

.61(0.2

71.3

6)

3

.95(1.7

19.0

8)

3

.74(2.1

26.5

8)

Figre 2 | adjusted hR of totl cVD events. adjustments were pplied for ge, sex, nemi, nd roni kidney disese. Ptients were divided in four tegories

ording to te level, i.e., norml or elevted, of lini BP nd aBPMderived sleep BP. clini BP ws onsidered norml if


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Our study has some potential limitations. Compared toother larger multicenter clinical trials on hypertensive patientsentailing only clinic BP measurement during ollow-up, thesample size o the single-center MAPEC study might seemsmall. However, the number o participants was considerablygreater than that o other published trials on the prognosticvalue o ABPM in patients with diabetes.811,15 Te design othe MAPEC study also has several strengths. While all previous

trials on the prognostic value o ABPM had relied on a sin-gle baseline prole rom each patient at the time o recruit-ment, the MAPEC study is the rst to provide results that arebased on systematic periodic and multiple ABPM evaluations.Tis so-ar unique approach enabled rst-time determina-tion o the infuence on CVD risk o specic changes duringollow-up in relevant ABPM parameters. Further strengths othe MAPEC study are the use o: (i) 48 h, instead o the most

Tabe 3 | Ajste hR of tota an major CVd events associate wit rection in cinic an ambatory BP ring foow-p in patientswit type 2 iabetes

Raw units Standardized units

Parameter Total CVD events Major CVD events Total CVD events Major CVD events

SBP

clini 0.94 (0.871.02) 0.98 (0.831.15) 0.81 (0.601.10) 0.91 (0.491.69)awke men 0.83 (0.750.93)* 0.80 (0.650.99)*** 0.61 (0.460.82)** 0.56 (0.330.96)***

asleep men 0.80 (0.730.89)* 0.76 (0.630.91)* 0.55 (0.420.73)* 0.48 (0.290.80)*

48 men 0.82 (0.730.91)* 0.78 (0.640.95)*** 0.60 (0.450.78)* 0.53 (0.320.87)***

Sleeptime reltive deline 0.80 (0.660.98)*** 0.74 (0.491.10) 0.72 (0.540.97)*** 0.64 (0.351.15)

s.d., wke 0.91 (0.840.98)*** 0.91 (0.791.04) 0.71 (0.540.92)*** 0.70 (0.431.14)

s.d., sleep 0.87 (0.810.94)** 0.88 (0.751.03) 0.59 (0.430.81)** 0.58 (0.301.12)

s.d., 48 0.86 (0.800.94)* 0.85 (0.721.00) 0.60 (0.450.80)* 0.56 (0.310.99)***

Morning surge 1.01 (0.991.03) 1.03 (0.991.08) 1.18 (0.851.63) 1.65 (0.863.17)

DBP

clini 0.89 (0.761.05) 0.93 (0.661.29) 0.79 (0.571.11) 0.85 (0.431.70)

awke men 0.70 (0.570.86)* 0.70 (0.471.05) 0.56 (0.400.78)** 0.55 (0.281.06)asleep men 0.61 (0.500.74)* 0.60 (0.410.88)** 0.44 (0.320.61)* 0.42 (0.220.80)**

48 men 0.62 (0.500.77)* 0.64 (0.420.96)*** 0.49 (0.350.68)* 0.49 (0.260.94)***

Sleeptime reltive deline 0.77 (0.640.92)** 0.73 (0.511.04) 0.64 (0.470.87)** 0.58 (0.321.06)

s.d., wke 0.86 (0.770.95)** 0.82 (0.671.01) 0.66 (0.500.88)** 0.60 (0.351.03)

s.d., sleep 0.88 (0.790.98)*** 0.78 (0.630.96)*** 0.68 (0.490.94)*** 0.45 (0.230.89)***

s.d., 48 0.88 (0.780.99)*** 0.81 (0.641.02) 0.72 (0.520.99)*** 0.57 (0.311.06)

Morning surge 1.01 (0.981.04) 1.02 (0.951.09) 1.08 (0.761.52) 1.22 (0.582.58)

PP

clini 0.93 (0.811.06) 0.99 (0.751.30) 0.86 (0.631.16) 0.98 (0.521.83)

awke men 0.86 (0.721.03) 0.91 (0.641.30) 0.82 (0.641.06) 0.88 (0.541.44)

asleep men 0.84 (0.691.02) 0.85 (0.591.22) 0.79 (0.591.04) 0.79 (0.461.34)

48 men 0.87 (0.721.05) 0.90 (0.631.30) 0.84 (0.651.07) 0.87 (0.541.41)

Sleeptime reltive deline 0.99 (0.841.16) 0.89 (0.641.23) 0.97 (0.711.33) 0.79 (0.411.51)

s.d., wke 0.87 (0.760.99)*** 0.83 (0.661.04) 0.73 (0.550.98)*** 0.65 (0.391.09)

s.d., sleep 0.96 (0.841.10) 0.98 (0.761.25) 0.91 (0.651.28) 0.94 (0.491.78)

s.d., 48 0.83 (0.730.95)*** 0.79 (0.621.01) 0.69 (0.510.92)*** 0.60 (0.351.02)

Morning surge 1.02 (0.981.05) 1.05 (0.981.13) 1.18 (0.851.62) 1.66 (0.833.33)

aaSI 0.96 (0.741.24) 1.12 (0.651.92) 0.95 (0.661.35) 1.18 (0.572.44)

HR (95% CI) for each 5 mm Hg decrease in BP, 5% increase in sleep-time relative BP decl ine, 1 mm Hg decrease in morning surge, and 0.1 decrease in ambulatory arterial stiffness index (AASI)during follow-up. Right columns provide HR standardized by calculating them for 1-s.d. change in any given ABPM parameter during follow-up. Adjustments were applied for the influentialcharacteristics of age, sex, anemia, chronic kidney disease, baseline BP, and number of hypertension medications used for treatment. Change in BP was entered as a time-dependent covariatein the Cox regression models. Major events included cardiovascular death, myocardial infarction, and stroke. The sleep-time relative BP decline, an index of BP dipping, is defined as the percentdecline in mean BP during night-time sleep relative to the mean BP during daytime activity, and calculated as: ((awake BP mean asleep BP mean)/awake BP mean) 100. The morning BP surge

was calculated as the difference between the average BP during the first 2 h after wake-up time and the hourly average centered on the lowest BP reading recorded during night-time sleep.ABPM, ambulatory blood pressure monitoring; BP, blood pressure; CI, confidence interval; CVD, cardiovascular disease; DBP, diastolic blood pressure; HR, hazard ratio; SBP, systolic bloodpressure.*P< 0.001; **P< 0.01; ***P< 0.05.


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common 24-h, ABPM sampling to increase the reproducibilityo the BP ndings29; and (ii) wrist actigraphy to precisely andindividually determine the beginning and end o the activityand sleep spans or each patient to derive the awake and asleepBP means accurately.

International guidelines recognized the prognostic value o

ABPM, but at this time it is recommended only in a limitednumber o clinical circumstances.1,2 Te recent update o theguidelines or clinical management o primary hypertensionin adults rom the National Institute or Health and ClinicalExcellence, however, proposes or the very rst time the needor ABPM as a requirement or corroborating the diagnosiso hypertension in all adults with elevated clinic BP.30 Ourndings urther support ABPM or CVD risk assessment inpatients with type 2 diabetes, independently o their clinic BPmeasurements, taking into account the prognostic value o theasleep BP mean, a novel validated therapeutic target that canbe assessed only by ABPM.

Supplementry mteril is linked to te online version of te pper tttp://www.nture.om/j

aknowledgment: Tis independent investigtorpromoted reser

ws supported by unrestrited grnts from Ministerio de cieni e

Innovin (SaF20066254FEDER; SaF20097028FEDER); conseller de

Presideni, Relins Instituionis e administrin Pbli, Seretr

Xerl de Investigin e Desenvolvemento, Xunt de Glii (PGIDIT03

PXIB32201PR); conseller de Eonom e Industri, Direin Xerl de

Investigin e Desenvolvemento, Xunt de Glii (INcITE07PXI322003ES;

INcITE08E1R322063ES; INcITE09E2R322099ES; IN845B2010/114;

09cSa018322PR); nd Vierretordo de Investigin, University of Vigo.

Dislosure: Te utors delred no onflit of interest.

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Documents

American Journal of Hypertension25(3)325[1]