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Observational Modeling of Strict vs Conventional BloodPressure
Control in PatientsWith Chronic Kidney DiseaseCsaba P. Kovesdy, MD;
Jun L. Lu, MD; Miklos Z. Molnar, MD, PhD; Jennie Z. Ma, PhD; Robert
B. Canada, MD;Elani Streja, PhD; Kamyar Kalantar-Zadeh, MD, MPH,
PhD; Anthony J. Bleyer, MD, MS
H ypertensionisamajor,
reversiblecauseofmorbidityandmortalityworldwide, and
therehavebeenmanyretro-spective studiesandprospective trials
thathaveexam-inedbloodpressure.1Earlyretrospectivestudies
initiallyshowedthat high blood pressurewas asociatedwith heart
disease andstroke.2Subsequentprospectiveclinical
trialshavesoughttode-termine how agressively to treat elevated
blood pressure3
andhaveattemptedtodecreasesystolicbloodpressure(SBP)tolowerandlower
levels.4Retrospectivestudiesalso identifiedaJ-curveofmortality for
both SBP and diastolic blood pressure (DBP)
incertaingroupsofpatients,5 raisingconcernsabout the safe lim-its
of blood pressure lowering in these populations.
Prospective randomized clinical trials have the ability
toestablish a cause-effect relationship between a clinical
inter-vention (eg, the lowering of blood pressure to various
pre-defined targets) and morbidity and mortality. Disadvantagesof
randomized clinical trials include their immense cost andthe fact
that study participants may not be representative ofthe general
population (limited external validity).6 Retrospec-tive cohort
studies andclinical trials are complementary in theknowledge that
they provide, and observational studies canexaminepopulations
thatwereexcludedfromclinical trialsandtreatments that cannot be
tested in clinical trials, and hencetheycanoffervaluablepractical
information. It is also true that
IMPORTANCE The effect of strict blood pressure control on
clinical outcomes in patients withchronic kidney disease (CKD) is
unclear.
OBJECTIVE To compare the outcomes associated with a treated
systolic blood pressure (SBP)of less than 120mmHg vs those
associated with the currently recommended SBP of less than140mmHg
in a national CKD database of US veterans.
DESIGN, SETTING, AND PARTICIPANTS Historical cohort study using
a nationwide cohort of USveterans with prevalent CKD, estimated
glomerular filtration rate less than 60mL/min/1.73m2, and
uncontrolled hypertension, who then received 1 or more additional
blood pressuremedications with evidence of a decrease in SBP.
Propensity scores were calculated to reflecteach individuals
probability for future SBP less than 120 vs 120 to 139mmHg.
MAIN OUTCOMES ANDMEASURES The effect of SBP on
all-causemortality was evaluated bythe log-rank test, and in
Coxmodels adjusted for propensity scores.
RESULTS Using a database of 651 749 patients with CKD, we
identified 77 765 individualsmeeting the inclusion criteria. A
total of 5760 patients experienced follow-up treated SBP ofless
than 120mmHg and 72 005 patients had SBP of 120 to 139mmHg. During
a medianfollow-up of 6.0 years, 19 517 patients died, with 2380
deaths in the SBP less than 120mmHg group (death rate, 80.9/1000
patient-years [95% CI, 77.7-84.2/1000 patient-years]) and17 137
deaths in the SBP 120 to 139mmHg group (death rate, 41.8/1000
patient-years [95%CI, 41.2-42.4/1000 patient-years]; P < .001).
Themortality hazard ratio (95% CI) associatedwith follow-up SBP
less than 120 vs 120 to 139mmHgwas 1.70 (1.63-1.78) after
adjustmentfor propensity scores.
CONCLUSIONS AND RELEVANCE Our results suggest that stricter SBP
control is associated withhigher all-cause mortality in patients
with CKD. Confirmation of these findings by ongoingclinical trials
would suggest that modeling of therapeutic interventions in
observationalcohorts may offer useful guidance for the treatment of
conditions that lack clinical trial data.
JAMA Intern Med. 2014;174(9):1442-1449.
doi:10.1001/jamainternmed.2014.3279Published online August 4,
2014.
Supplemental content atjamainternalmedicine.com
Author Affiliations:Division ofNephrology, Memphis
VAMedicalCenter, Memphis, Tennessee(Kovesdy); Division of
Nephrology,University of Tennessee HealthScience Center, Memphis
(Kovesdy,Lu, Molnar, Canada); Division ofNephrology, University of
Virginia,Charlottesville (Ma); Harold SimmonsCenter for Chronic
Disease Researchand Epidemiology, Division ofNephrology and
Hypertension,University of CaliforniaIrvine,Orange (Streja,
Kalantar-Zadeh);Section on Nephrology, Wake ForestSchool of
Medicine, Winston-Salem,North Carolina (Bleyer).
Corresponding Author: Csaba P.Kovesdy, MD, Division of
Nephrology,Memphis VAMedical Center, 1030Jefferson Ave, Memphis, TN
38104([email protected]).
Research
Original Investigation
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retrospective studies often are in agreement with the resultsof
prospective clinical trials.7
Patientswithchronickidneydisease (CKD)representa
largepopulationwithahighprevalenceof
cardiovascularmorbidityandmortality,8 but theyhavebeenexcluded
frommost clinicaltrialsofbloodpressure lowering.The fewtrials
thathaveexam-ined different blood pressure treatment goals in
patients
withCKD9-11wereunabletounequivocallyestablishthebenefitvsriskof
stricter blood pressure control, as a result of limitations
inwhichendpoints theywerepoweredtoexamine(primarilypro-gression of
kidney disease, with mortality or
cardiovasculareventseithernotexaminedorexaminedaspartofcompositesec-ondary
outcomes) and as a result of discrepancies between
re-sultsfromprimaryandsecondaryorposthocanalyses.12-15There-fore,
currentguidelinesabout the ideal targetbloodpressure inpatients
with CKD are based on extrapolations from trials per-formed
inhealthierpopulationsandonexpertopinion.Agrow-ingbodyof
observational studies suggests that the associationof blood
pressure with clinical events in patients with CKD isfundamentally
different from that in the general population.16
The implication is that strict blood pressure control may notbe
advantageous in patients with CKD, and it could even
bedeleterious.8 The Systolic Blood Pressure Interventional
Trial(SPRINT) (clinicaltrials.gov Identifier:NCT01206062) is the
firstmajorclinical trialofbloodpressure
loweringwithaprimaryaimtopreventcardiovasculareventsandmortality
that specificallyenrolled patientswith CKD, but its resultswill not
be availableforseveralyearsanditsstrict
inclusionandexclusioncriteriamaylimit thegeneralizabilityof its
findings toanarrowspectrumoftheCKDpopulation.Usinga
largedatabaseofUSveteranswithawide
spectrumofpatientswithCKD,weexaminedoutcomesassociatedwithstricter(SBP,
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scorematchedcohortwasgeneratedbya
1-to-1nearestneigh-bormatchingwithout replacementusing
thepsmatch2com-mand suite in Stata. The propensity-matched cohort
con-sisted of 11 520 patients, 5760 in each group (Figure 1).
Statistical AnalysesData were expressed as mean (SD), median
(interquartilerange),
andproportion.Baselinecharacteristicsofpatientswithfollow-up SBP
less than 120 and 120 to 139mmHgwere com-pared using t tests,
nonparametric tests, and 2 tests, as ap-propriate. The start of the
follow-upperiodwas thedateof
thebaselineSBPmeasurement.Patientswereobserveduntildeathor were
censored at the date of the last health care or admin-istrative VA
encounter, as documented in the VA Vital StatusFiles (a
registrycontainingdatesofdeathor lastmedical and/oradministrative
encounter from all available sources in the VAsystem).The
sensitivity andspecificityof theVital StatusFiles
using theUSNationalDeath Indexasgoldstandard,were foundto be
98.3% and 99.8%, respectively.25 The association of fol-low-up SBP
of less than 120 vs 120 to 139 mm Hg with all-cause mortality was
examined by the Kaplan-Meier methodand the log-rank test, according
to the intention-to-treat prin-ciple. Associations were examined
first in the overall cohortof 77 765 patients and then in the
propensity-matched cohortof 11 520 patients using Cox models. The
association of fol-low-up SBP less than 120 vs 120 to 139 mm Hg in
the overallcohort was examined before and after adjustment for
indi-vidual propensity scores and for baseline characteristics
(age,sex, race, estimated GFR, SBP and DBP, Charlson comorbid-ity
index, diabetes mellitus, coronary artery disease, chronicheart
failure, serum albumin and cholesterol levels, and useof -blockers,
-blockers, calciumchannel blockers,
angioten-sin-convertingenzymeinhibitorsorangiotensinreceptorblock-ers,andloop-typeor
thiazide-typediuretics).Associationswere
Figure 1. AlgorithmUsed to Define the Study Cohort
5760 Patients with SBP
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examinedseparately in subgroupsofpatientsof theoverall co-hort,
aftercategorizationbyage, sex, race, the levelof theCharl-son
comorbidity index and estimated GFR, and the presenceor absence of
key comorbid conditions.
Analyses were repeated in a cohort of 5000
propensityscorematched patients (2500 in both SBP groups)
definedusing the inclusion and exclusion criteria of the CKD
portionof the SPRINT (eBox and eFigure 1 in the Supplement),
withthe exception of the proteinuria criterion. Sensitivity
analy-seswere performed by comparing all patientswith
decreasedSBPduring follow-up irrespectiveof thenumberof
antihyper-tensive medications used and by considering a stricter
defi-nition of follow-up SBP of at least 75% of measurements
fall-ing in the desired target categories (
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lower baseline SBP and similar (albeit statistically
different)baseline DBP levels.
Subsequent SBP and DBP levels throughout thefollow-up period
were significantly lower in the less than 120compared with the 120
to 139 mm Hg group, in both theoverall and the propensity
scorematched cohorts (Figure 2).Patients increasingly used more
antihypertensive medica-tions over time. Specifically, the median
(interquartile range)number of antihypertensive medications
increased from 2(1-2) at baseline to 3 (2-4) during follow-up in
both SBPgroups and in both cohorts.
A total of 19 517 patients died (death rate, 44.4/1000
pa-tient-years [95%CI,43.8-45.0/1000patient-years])duringame-dian
follow-up of 6.0 years. In the SBP less than 120 mm Hggroup, 2380
deaths occurred (death rate, 80.9/1000 patient-years [95% CI,
77.7-84.2/1000 patient-years]), whereas 17 137deathsoccurred in
theSBP120 to 139mmHggroup (death rate,
41.8/1000 patient-years [95% CI, 41.2-42.4/1000
patient-years]).Mortalitywas significantly higher in the SBP less
than120 mm Hg group compared with the SBP 120 to 139 mm Hggroup, in
both the overall and the propensity scorematchedcohorts (P <
.001 for both) (Figure 3). The unadjusted hazardratio (HR) (95%CI)
ofmortality associatedwith follow-upSBPless than 120vs 120 to
139mmHg in theoverall cohortwas2.08(1.99-2.17), which was
attenuated but remained significantafter adjustment for propensity
scores (1.70 [1.63-1.78]), afteradjustment fordifferences
inbaselinecharacteristics (1.74[1.65-1.83]), and in the propensity
scorematched cohort (1.61 [1.51-1.71]). The risk associated with
SBP less than 120 mmHg wassignificantly higher in all examined
subgroups (Figure4). Theresults remained consistent in the cohort
defined accordingto SPRINT inclusion and exclusion criteria
(eFigure 2 in theSupplement) and in sensitivity analyses including
all pa-tients irrespective of antihypertensive medication use,
and
Figure 2. Follow-up Systolic Blood Pressure (SBP) and Diastolic
Blood Presure (DBP) in PatientsWith SBP Less Than 120 vs 120 to
139mmHg
150
90
100
110
120
140
130
80
70
60
50
150
90
100
110
120
140
130
80
70
60
50
Bloo
d Pr
essu
re, m
m H
g
Follow-up Time, Calendar Quarters
A
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
24
Bloo
d Pr
essu
re, m
m H
g
Follow-up Time, Calendar Quarters
B
SBP 120-139 mm Hg group SBP
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when target SBP levels for both groups were required to
bepresent on more than 75% of follow-up measurements (re-sults not
shown).
DiscussionIn our database containing more than 650 000 patients
withCKD,wewere able to identify 77 765
individualswithCKDandbaseline uncontrolled hypertension and who
experiencedblood pressure changes similar to what would be expected
ina clinical trial or in clinical practice. During follow-up,
pa-tients in the lower (
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examined or were only included as part of composite sec-ondary
end points. These end points will be primarily exam-ined in the
ongoing SPRINT, but it is possible that its resultsmay not be
applicable to all segments of a heterogeneousgroup such as the
population with CKD. Our study examineda much wider population with
CKD than that typicallyincluded in a clinical trial and hence could
provide moregeneralizable findings. This could be important if
(once com-pleted) the SPRINT confirms our findings, in that it
mayallow for wider-ranging recommendations about ideal
bloodpressure treatment targets in all patients with CKD.
The results of observational studies can be biased, oftenbecause
of markedly different patient characteristics in thegroups
compared, and because of different reasons underly-ing observed
events in the 2 types of studies.We tried tomini-mize these biases
by selecting patients according to specificcriteria, by only
consideringpatientswhosedecrease in bloodpressure levels occurred
in parallel with an enhanced antihy-pertensive regimen, and by
using propensity scores to iden-tify and to adjust for clinical
characteristics that couldbiasdif-ferent bloodpressure responses.
Therewere limitations toourcohort that need to be considered when
our results are inter-preted.Weexaminedalmost exclusivelymale
(97.4%)andpre-dominantlywhite
(91.3%)patients.Fortunately,mostprospec-tive blood pressure trials
have not shown a significantdifference in intervention effects
between male and femalepatients.3,4,16 Comorbid conditions in our
cohortwerenot de-terminedbyagroupof researchersusingstrict
criteriabutwerebased on medical records generated in the course of
clinicalpractice. Unmeasured comorbidities could have affected
ouroutcomes in spite of careful accounting for relevant mea-sured
comorbidities. The fact that the number of
antihyper-tensivesneededtoachieve thestrict
andconventionalSBPout-comes in our studywas similar suggests that
determinants of
individual responsiveness toantihypertensives (eg,
relativehy-povolemia or decreased ejection fraction) could be
importantunmeasured confounders.
To the best of our knowledge prior to our study, a
clinicaltrialmodelingapproachhasnotbeenattempted forbloodpres-sure
lowering in patients with CKD. If our approach is shownto be
successful, this could corroborate the role that observa-tional
studies couldplay in theplanningof clinical trials byde-termining
the likelihood of the best treatment targets, by es-timatingevent
rates,andby identifyingsubgroupsmostor leastlikely to respond to
certain interventions. In cases in whichclinical trials are not
feasible or not ethically possible, obser-vational
studiescouldprovidemuch-neededinformationaboutthe treatmentsmost
likely to be effective. This could be espe-cially important in
patients with CKD, who experience a
sub-stantialnumberofmetabolicandotherabnormalities. It is
likelythat clinical trials will not be available for all the
abnormali-ties found in patients with CKD, in which case the
modelingof clinical trials from large observational data sets may
offerthebest evidence towardeffective treatments. It is hoped
thattheseprospectivemodeling techniqueswill improveover time,such
that theywill behelpful in the selection anddesignof fu-ture
clinical trials.
ConclusionsIn summary, we have found that in a cohort of
patients withCKDanduncontrolledhypertension, loweringof theSBPto
lessthan 120mmHgwas associatedwith higher all-causemortal-ity
compared with an SBP of 120 to 139 mm Hg. Such an ob-servational
approach to estimate treatment targets for bloodpressure lowering
in patients with CKD could be a usefulcomplement to clinical
trials.
ARTICLE INFORMATION
Accepted for Publication: April 9, 2014.
Published Online: August 4,
2014.doi:10.1001/jamainternmed.2014.3279.
Author Contributions:Dr Kovesdy had full accessto all of the
data in the study and takesresponsibility for the integrity of the
data and theaccuracy of the data analysis.Study concept and design:
Kovesdy, Kalantar-Zadeh,Bleyer.Acquisition, analysis, or
interpretation of data:Kovesdy, Lu, Molnar, Canada,
Streja,Kalantar-Zader.Drafting of the manuscript: Kovesdy, Molnar,
Ma,Kalantar-Zadeh, Bleyer.Critical revision of the manuscript for
importantintellectual content: Lu, Molnar, Ma, Canada,
Streja,Kalantar-Zadeh, Bleyer.Statistical analysis: Kovesdy, Lu,
Ma, Streja,Kalantar-Zadeh, Bleyer.Obtained funding: Kovesdy,
Kalantar-Zadeh.Administrative, technical, or material
support:Kovesdy, Lu, Molnar, Kalantar-Zadeh, Bleyer.Study
supervision: Kovesdy, Canada, Kalantar-Zadeh.
Conflict of Interest Disclosures:Dr Kovesdy is anemployee of the
US Department of VeteransAffairs. No other disclosures are
reported.
Funding/Support: This study is supported by grantR01DK078106
from the National Institute ofDiabetes and Digestive and Kidney
Diseases,National Institutes of Health; and by theDepartment of
Veterans Affairs.
Role of the Sponsor: The Department of VeteransAffairs reviewed
and approved themanuscript buthad no role in the design and conduct
of the study;analysis and interpretation of the data; preparationof
themanuscript; and decision to submit themanuscript for
publication.
Disclaimer:Opinions expressed in this article arethose of the
authors and do not represent theofficial opinion of the US
Department of VeteransAffairs.
Previous Presentation: Parts of this material werepresented at
the American Society of NephrologyKidneyWeek 2013; November 9,
2013; Atlanta,Georgia.
Correction: This article was corrected on August 13,2014, to fix
an error in the byline.
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Blood Pressure Control in Chronic Kidney Disease Original
Investigation Research
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