Research

Original Investigation

Observational Modeling of Strict vs Conventional Blood

Pressure Control in Patients With Chronic Kidney Disease
Csaba 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

IMPORTANCE The effect of strict blood pressure control on clinical outcomes in patients with

Supplemental content at
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chronic kidney disease (CKD) is unclear.

OBJECTIVE To compare the outcomes associated with a treated systolic blood pressure (SBP)
of less than 120 mm Hg vs those associated with the currently recommended SBP of less than
140 mm Hg in a national CKD database of US veterans.
DESIGN, SETTING, AND PARTICIPANTS Historical cohort study using a nationwide cohort of US
veterans with prevalent CKD, estimated glomerular filtration rate less than 60 mL/min/1.73
m2, and uncontrolled hypertension, who then received 1 or more additional blood pressure
medications with evidence of a decrease in SBP. Propensity scores were calculated to reflect
each individuals probability for future SBP less than 120 vs 120 to 139 mm Hg.
MAIN OUTCOMES AND MEASURES The effect of SBP on all-cause mortality was evaluated by
the log-rank test, and in Cox models adjusted for propensity scores.
RESULTS Using a database of 651 749 patients with CKD, we identified 77 765 individuals
meeting the inclusion criteria. A total of 5760 patients experienced follow-up treated SBP of
less than 120 mm Hg and 72 005 patients had SBP of 120 to 139 mm Hg. During a median
follow-up of 6.0 years, 19 517 patients died, with 2380 deaths in the SBP less than 120 mm
Hg group (death rate, 80.9/1000 patient-years [95% CI, 77.7-84.2/1000 patient-years]) and
17 137 deaths in the SBP 120 to 139 mm Hg group (death rate, 41.8/1000 patient-years [95%
CI, 41.2-42.4/1000 patient-years]; P < .001). The mortality hazard ratio (95% CI) associated
with follow-up SBP less than 120 vs 120 to 139 mm Hg was 1.70 (1.63-1.78) after adjustment
for propensity scores.
CONCLUSIONS AND RELEVANCE Our results suggest that stricter SBP control is associated with
higher all-cause mortality in patients with CKD. Confirmation of these findings by ongoing
clinical trials would suggest that modeling of therapeutic interventions in observational
cohorts 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.2014.3279
Published online August 4, 2014.

ypertension is a major, reversible cause of morbidity and

mortality worldwide, and there have been many retrospective studies and prospective trials that have examined blood pressure.1 Early retrospective studies initially showed
that high blood pressure was asociated with heart disease and
stroke.2 Subsequent prospective clinical trials have sought to determine how agressively to treat elevated blood pressure3 and
have attempted to decrease systolic blood pressure (SBP) to lower
and lower levels.4 Retrospective studies also identified a J-curve
of mortality for both SBP and diastolic blood pressure (DBP) in
certain groups of patients,5 raising concerns about the safe limits of blood pressure lowering in these populations.
1442

Author Affiliations: Division of

Nephrology, Memphis VA Medical
Center, Memphis, Tennessee
(Kovesdy); Division of Nephrology,
University of Tennessee Health
Science Center, Memphis (Kovesdy,
Lu, Molnar, Canada); Division of
Nephrology, University of Virginia,
Charlottesville (Ma); Harold Simmons
Center for Chronic Disease Research
and Epidemiology, Division of
Nephrology and Hypertension,
University of CaliforniaIrvine,
Orange (Streja, Kalantar-Zadeh);
Section on Nephrology, Wake Forest
School of Medicine, Winston-Salem,
North Carolina (Bleyer).
Corresponding Author: Csaba P.
Kovesdy, MD, Division of Nephrology,
Memphis VA Medical Center, 1030
Jefferson Ave, Memphis, TN 38104
(csaba.kovesdy@va.gov).

Prospective randomized clinical trials have the ability to

establish a cause-effect relationship between a clinical intervention (eg, the lowering of blood pressure to various predefined targets) and morbidity and mortality. Disadvantages
of randomized clinical trials include their immense cost and
the fact that study participants may not be representative of
the general population (limited external validity).6 Retrospective cohort studies and clinical trials are complementary in the
knowledge that they provide, and observational studies can
examine populations that were excluded from clinical trials and
treatments that cannot be tested in clinical trials, and hence
they can offer valuable practical information. It is also true that

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Blood Pressure Control in Chronic Kidney Disease

retrospective studies often are in agreement with the results

of prospective clinical trials.7
Patients with chronic kidney disease (CKD) represent a large
population with a high prevalence of cardiovascular morbidity
and mortality,8 but they have been excluded from most clinical
trials of blood pressure lowering. The few trials that have examined different blood pressure treatment goals in patients with
CKD9-11 were unable to unequivocally establish the benefit vs risk
of stricter blood pressure control, as a result of limitations in
which end points they were powered to examine (primarily progression of kidney disease, with mortality or cardiovascular
events either not examined or examined as part of composite secondary outcomes) and as a result of discrepancies between results from primary and secondary or post hoc analyses.12-15 Therefore, current guidelines about the ideal target blood pressure in
patients with CKD are based on extrapolations from trials performed in healthier populations and on expert opinion. A growing body of observational studies suggests that the association
of blood pressure with clinical events in patients with CKD is
fundamentally different from that in the general population.16
The implication is that strict blood pressure control may not
be advantageous in patients with CKD, and it could even be
deleterious.8 The Systolic Blood Pressure Interventional Trial
(SPRINT) (clinicaltrials.gov Identifier:NCT01206062) is the first
major clinical trial of blood pressure lowering with a primary aim
to prevent cardiovascular events and mortality that specifically
enrolled patients with CKD, but its results will not be available
for several years and its strict inclusion and exclusion criteria may
limit the generalizability of its findings to a narrow spectrum of
the CKD population. Using a large database of US veterans with
a wide spectrum of patients with CKD, we examined outcomes
associated with stricter (SBP, <120 mm Hg) and conventional (SBP,
120-139 mm Hg) treated blood pressure in patients with baseline
uncontrolled hypertension.

Methods
Study Design and Participants
The present study is a historical cohort study that is designed
to examine outcomes associated with strict vs conventional SBP
control in patients with CKD. A nationwide cohort of US veterans with prevalent CKD was used to identify patients with estimated glomerular filtration rate (GFR) less than 60 mL/min/
1.73 m2 and uncontrolled systolic hypertension (using the
definition applied in the ongoing SPRINT: baseline SBP 130180 mm Hg with use of 0 or 1 antihypertensives, or SBP 130-170
mm Hg with use of up to 2 antihypertensives, or SBP 130-160
mm Hg with use of up to 3 antihypertensives, or SBP 130-150
mm Hg with use of up to 4 antihypertensives). The generation
of our CKD cohort was described previously.17-19 Briefly, prevalent CKD was defined on the basis of the presence of a persistent estimated GFR of less than 60 mL/min/1.73 m2 on at least 2
occasions separated by no less than 3 months or the presence
of a spot urine microalbumin-creatinine ratio of at least 30 mg/g
on at least 1 occasion (for those with estimated GFR, 60 mL/
min/1.73 m2)20 between October 1, 2004, and September 30,
2006. The GFR was estimated from serum creatinine measurejamainternalmedicine.com

Original Investigation Research

ments and demographic characteristics by means of the Chronic

Kidney Disease Epidemiology Collaboration equation.21
Information about blood pressure, laboratory results, and
other follow-up data was collected from the date of cohort entry until the end of follow-up (death or April 30, 2012). All blood
pressures measured during clinical practice from October 1,
2004, until April 30, 2012, were recorded and grouped by calendar quarters, and their quarterly mean values were used for
analyses to reduce random variability. Exposure to antihypertensive medications was assessed from Veterans Affairs (VA)
Pharmacy dispensation records.22 Antihypertensive medications were classified according to their mechanism of action
(-blockers, -blockers, calcium channel blockers, angiotensinconverting enzyme inhibitors or angiotensin receptor blockers, loop-type and thiazide-type diuretics). Medication classes
used in fewer than 5% of participants (vasodilators, potassiumsparing diuretics, combination antihypertensives, and others) were not recorded. Individual exposure to each antihypertensive class and to the total number of antihypertensive
classes was assessed during each calendar quarter between October 1, 2004, and April 30, 2012.
Information about prevalent comorbidities was collected
from the VA Inpatient and Outpatient Medical SAS Datasets23
using International Classification of Diseases, Ninth Revision,
Clinical Modification diagnostic and procedure codes and Current Procedural Terminology codes recorded from October 1,
2004, until September 30, 2006. Coronary artery disease was
defined as the presence of diagnostic codes for coronary artery disease, angina, or myocardial infarction, or procedure
codes for percutaneous coronary interventions or coronary artery bypass grafting. We calculated the Charlson comorbidity
index using the Deyo et al24 modification for administrative
data sets, without including kidney disease.
There were a total of 651 749 patients with nondialysisdependent CKD and available blood pressure measurements
in our cohort (Figure 1), of whom 301 097 patients had estimated GFR less than 60 mL/min/1.73 m2 and uncontrolled hypertension. To model therapeutic interventions resulting in improved blood pressure control, we categorized patients on the
basis of SBP levels recorded during their follow-up visits. There
were 18 243 patients with SBP less than 120 mm Hg on at least
50% of subsequent visits and 176 034 patients with SBP 120 to
139 mm Hg on at least 50% of subsequent visits. To minimize
chances that lower SBP levels during follow-up occurred as a
result of clinical events and not antihypertensive interventions, we only included patients who experienced an increase in the total number of antihypertensive medications
used during follow-up (5760 patients in the SBP < 120 mm Hg
group and 72 005 patients in the 120-139 mm Hg group). To alleviate the bias caused by differences in baseline clinical characteristics in reference to subsequent SBP levels, we estimated propensity scores for the likelihood of SBP less than 120
vs 120 to 139 mm Hg during follow-up from logistic regression. Older age, white race, lower baseline SBP, prevalent coronary artery disease, chronic heart failure, nondiabetic status,
and higher Charlson comorbidity index were more likely to be
associated with SBP less than 120 mm Hg during follow-up than
with 120 to 139 mm Hg. As secondary analysis, a propensity
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Research Original Investigation

Blood Pressure Control in Chronic Kidney Disease

examined or were only included as part of composite secondary end points. These end points will be primarily examined in the ongoing SPRINT, but it is possible that its results
may not be applicable to all segments of a heterogeneous
group such as the population with CKD. Our study examined
a much wider population with CKD than that typically
included in a clinical trial and hence could provide more
generalizable findings. This could be important if (once completed) the SPRINT confirms our findings, in that it may
allow for wider-ranging recommendations about ideal blood
pressure treatment targets in all patients with CKD.
The results of observational studies can be biased, often
because of markedly different patient characteristics in the
groups compared, and because of different reasons underlying observed events in the 2 types of studies. We tried to minimize these biases by selecting patients according to specific
criteria, by only considering patients whose decrease in blood
pressure levels occurred in parallel with an enhanced antihypertensive regimen, and by using propensity scores to identify and to adjust for clinical characteristics that could bias different blood pressure responses. There were limitations to our
cohort that need to be considered when our results are interpreted. We examined almost exclusively male (97.4%) and predominantly white (91.3%) patients. Fortunately, most prospective blood pressure trials have not shown a significant
difference in intervention effects between male and female
patients.3,4,16 Comorbid conditions in our cohort were not determined by a group of researchers using strict criteria but were
based on medical records generated in the course of clinical
practice. Unmeasured comorbidities could have affected our
outcomes in spite of careful accounting for relevant measured comorbidities. The fact that the number of antihypertensives needed to achieve the strict and conventional SBP outcomes in our study was similar suggests that determinants of

Conclusions
In summary, we have found that in a cohort of patients with
CKD and uncontrolled hypertension, lowering of the SBP to less
than 120 mm Hg was associated with higher all-cause mortality compared with an SBP of 120 to 139 mm Hg. Such an observational approach to estimate treatment targets for blood
pressure lowering in patients with CKD could be a useful
complement to clinical trials.

Conflict of Interest Disclosures: Dr Kovesdy is an

employee of the US Department of Veterans
Affairs. No other disclosures are reported.

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 access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy 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 important
intellectual 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, KalantarZadeh.

1448

individual responsiveness to antihypertensives (eg, relative hypovolemia or decreased ejection fraction) could be important
unmeasured confounders.
To the best of our knowledge prior to our study, a clinical
trial modeling approach has not been attempted for blood pressure lowering in patients with CKD. If our approach is shown
to be successful, this could corroborate the role that observational studies could play in the planning of clinical trials by determining the likelihood of the best treatment targets, by estimating event rates, and by identifying subgroups most or least
likely to respond to certain interventions. In cases in which
clinical trials are not feasible or not ethically possible, observational studies could provide much-needed information about
the treatments most likely to be effective. This could be especially important in patients with CKD, who experience a substantial number of metabolic and other abnormalities. It is likely
that clinical trials will not be available for all the abnormalities found in patients with CKD, in which case the modeling
of clinical trials from large observational data sets may offer
the best evidence toward effective treatments. It is hoped that
these prospective modeling techniques will improve over time,
such that they will be helpful in the selection and design of future clinical trials.

Funding/Support: This study is supported by grant

R01DK078106 from the National Institute of
Diabetes and Digestive and Kidney Diseases,
National Institutes of Health; and by the
Department of Veterans Affairs.
Role of the Sponsor: The Department of Veterans
Affairs reviewed and approved the manuscript but
had no role in the design and conduct of the study;
analysis and interpretation of the data; preparation
of the manuscript; and decision to submit the
manuscript for publication.
Disclaimer: Opinions expressed in this article are
those of the authors and do not represent the
official opinion of the US Department of Veterans
Affairs.
Previous Presentation: Parts of this material were
presented at the American Society of Nephrology
Kidney Week 2013; November 9, 2013; Atlanta,
Georgia.
Correction: This article was corrected on August 13,
2014, to fix an error in the byline.

REFERENCES
1. Banach M, Aronow WS. Blood pressure J-curve:
current concepts. Curr Hypertens Rep. 2012;14(6):
556-566.
2. Svrdsudd K, Wilhelmsen L. Change of blood
pressure in relation to other variables and to
development of hypertensive disease indices in a
longitudinal population study: the study of men
born in 1913. Eur Heart J. 1980;1(5):355-359.
3. SHEP Cooperative Research Group. Prevention
of stroke by antihypertensive drug treatment in
older persons with isolated systolic hypertension:
final results of the Systolic Hypertension in the
Elderly Program (SHEP). JAMA. 1991;265(24):
3255-3264.
4. Cushman WC, Evans GW, Byington RP, et al;
ACCORD Study Group. Effects of intensive
blood-pressure control in type 2 diabetes mellitus.
N Engl J Med. 2010;362(17):1575-1585.
5. Stewart IM. Relation of reduction in pressure to
first myocardial infarction in patients receiving
treatment for severe hypertension. Lancet. 1979;1
(8121):861-865.
6. Kovesdy CP, Kalantar-Zadeh K. Observational
studies versus randomized controlled trials:

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Blood Pressure Control in Chronic Kidney Disease

Original Investigation Research

Table. Characteristics of Patients With Follow-up Systolic Blood Pressure (SBP) Less Than 120 and 120 to 139 mm Hg,
in the Overall and in the Propensity ScoreMatched Cohorts
Overall Cohort

Propensity ScoreMatched Cohort

SBP < 120 mm Hg

(n = 5760)

SBP 120-139 mm Hg
(n = 72 005)

P Value

SBP < 120 mm Hg

(n = 5760)

SBP 120-139 mm Hg
(n = 5760)

Age, mean (SD)

75.0 (9.2)

P Value

73.5 (9.2)

<.001

75.0 (9.2)

75.2 (8.6)

Male sex, No. (%)

.23

5636 (97.9)

70 248 (97.6)

.17

5636 (97.9)

5638 (97.9)

.90

White

5202 (91.1)

62 234 (88.9)

5202 (91.1)

5159 (90.2)

Black

363 (6.4)

5876 (8.3)

363 (6.4)

433 (7.6)

Hispanic

893 (1.3)

57 (1.0)

57 (1.0)

54 (0.9)

Characteristic

Race, No. (%)

Other

<.001

.07

86 (1.5)

1155 (1.6)

86 (1.5)

77 (1.4)

Cardiovascular disease, No. (%)

2917 (50.6)

27 469 (38.2)

<.001

2917 (50.6)

2929 (50.9)

.82

Diabetes mellitus, No. (%)

2196 (38.1)

28 625 (39.8)

.02

2196 (38.1)

2187 (38.0)

.86

Chronic heart failure, No. (%)

1104 (19.2)

6520 (9.1)

<.001

1104 (19.2)

1117 (19.4)

.76

899 (15.6)

9423 (13.1)

<.001

899 (15.6)

903 (15.7)

.92

Cerebrovascular disease, No. (%)

Charlson comorbidity index, mean (SD)

3.9 (1.7)

3.6 (1.6)

<.001

3.9 (1.7)

3.9 (1.8)

.67

48.1 (9.5)

48.8 (9.1)

<.001

48.1 (9.5)

48.0 (9.5)

.78

SBP

140.8 (8.7)

142.1 (9.0)

<.001

140.8 (8.7)

141.1 (8.5)

.05

DBP

74.4 (9.9)

74.7 (9.8)

.01

74.4 (9.9)

73.3 (9.7)

<.001

SBP

119.1 (5.5)

133.1 (5.6)

<.001

119.1 (5.5)

132.7 (5.6)

<.001

DBP

66.2 (6.6)

71.1 (7.1)

<.001

66.2 (6.6)

70.1 (7.1)

<.001

At baseline

2 (1-2)

2 (1-2)

.43

2 (1-2)

2 (1-2)

<.001

During follow-up

3 (2-4)

3 (2-4)

<.001

3 (2-4)

3 (2-4)

<.001

eGFR, mean (SD), mL/min/1.73 m2

Baseline, mean (SD), mm Hg

Follow-up, mean (SD), mm Hg

BP medications, median (IQR), No.

Baseline use, No. (%)

ACEI and/or ARB

2155 (37.4)

27 843 (38.7)

.06

2155 (37.4)

2292 (39.8)

.009

-Blocker

1068 (18.5)

12 745 (17.7)

.11

1068 (18.5)

1027 (17.7)

.32

-Blocker

2578 (44.8)

28 775 (40.0)

<.001

2578 (44.8)

2616 (45.4)

.48

Calcium channel blocker

1175 (20.4)

20 333 (28.2)

<.001

1175 (20.4)

1658 (28.8)

<.001

Loop diuretic

1363 (23.7)

10 283 (14.3)

<.001

1363 (23.7)

1174 (20.4)

<.001

788 (13.7)

15 129 (21.0)

<.001

788 (13.7)

1154 (20.0)

<.001

Serum albumin level, mean (SD), g/dL

3.99 (0.41)

4.02 (0.40)

<.001

3.99 (0.41)

4.02 (0.40)

.04

Serum cholesterol level, mean (SD), mg/dL

168 (38)

172 (38)

<.001

168 (38)

169 (37)

.18

Thiazide diuretic

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor;

ARB, angiotensin receptor blocker; BP, blood pressure; DBP, diastolic blood
pressure; eGFR, estimated glomerular filtration rate; IQR, interquartile range;
SBP, systolic blood pressure.

SI conversion factors: To convert serum albumin to grams per liter, multiply by

10; to convert serum cholesterol level to millimoles per liter, multiply by 0.0259.

examined separately in subgroups of patients of the overall cohort, after categorization by age, sex, race, the level of the Charlson comorbidity index and estimated GFR, and the presence
or absence of key comorbid conditions.
Analyses were repeated in a cohort of 5000 propensity
scorematched patients (2500 in both SBP groups) defined
using the inclusion and exclusion criteria of the CKD portion
of the SPRINT (eBox and eFigure 1 in the Supplement), with
the exception of the proteinuria criterion. Sensitivity analyses were performed by comparing all patients with decreased
SBP during follow-up irrespective of the number of antihypertensive medications used and by considering a stricter definition of follow-up SBP of at least 75% of measurements falling in the desired target categories (<120 and 120-139 mm Hg,
respectively). Statistical analyses were performed using Stata

MP, versions 11 and 12 (StataCorp). The study protocol was approved by the Research and Development Committee at the
Memphis VA Medical Center.

jamainternalmedicine.com

Results
Baseline characteristics of the patients with follow-up SBP
less than 120 and 120 to 139 mm Hg in the overall and the
propensity-matched cohorts are shown in the Table.
Patients with follow-up SBP less than 120 mm Hg in the
overall cohort were older and in general had a higher prevalance of comorbid conditions except for diabetes mellitus.
These differences were not present in the propensity score
matched cohort. The SBP less than 120 mm Hg group had
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Research Original Investigation

Blood Pressure Control in Chronic Kidney Disease

Figure 2. Follow-up Systolic Blood Pressure (SBP) and Diastolic Blood Presure (DBP) in Patients
With SBP Less Than 120 vs 120 to 139 mm Hg
A

SBP 120-139 mm Hg group

SBP <120 mm Hg group

150
140

Blood Pressure, mm Hg

130
120
110
100
90
80
70
60
50
0

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Follow-up Time, Calendar Quarters

B

150
140

Blood Pressure, mm Hg

130
120
110
100
90
80
70
60
50
0

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Follow-up Time, Calendar Quarters

lower baseline SBP and similar (albeit statistically different)

baseline DBP levels.
Subsequent SBP and DBP levels throughout the
follow-up period were significantly lower in the less than 120
compared with the 120 to 139 mm Hg group, in both the
overall and the propensity scorematched cohorts (Figure 2).
Patients increasingly used more antihypertensive medications 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 SBP
groups and in both cohorts.
A total of 19 517 patients died (death rate, 44.4/1000 patient-years [95% CI, 43.8-45.0/1000 patient-years]) during a median follow-up of 6.0 years. In the SBP less than 120 mm Hg
group, 2380 deaths occurred (death rate, 80.9/1000 patientyears [95% CI, 77.7-84.2/1000 patient-years]), whereas 17 137
deaths occurred in the SBP 120 to 139 mm Hg group (death rate,
1446

A, In the overall cohort; B, in the

propensity scorematched cohort.
Upper symbols show SBP, and lower
symbols, DBP. Symbols indicate
mean, and error bars, standard
deviation.

41.8/1000 patient-years [95% CI, 41.2-42.4/1000 patientyears]). Mortality was significantly higher in the SBP less than
120 mm Hg group compared with the SBP 120 to 139 mm Hg
group, in both the overall and the propensity scorematched
cohorts (P < .001 for both) (Figure 3). The unadjusted hazard
ratio (HR) (95% CI) of mortality associated with follow-up SBP
less than 120 vs 120 to 139 mm Hg in the overall cohort was 2.08
(1.99-2.17), which was attenuated but remained significant
after adjustment for propensity scores (1.70 [1.63-1.78]), after
adjustment for differences in baseline characteristics (1.74 [1.651.83]), and in the propensity scorematched cohort (1.61 [1.511.71]). The risk associated with SBP less than 120 mm Hg was
significantly higher in all examined subgroups (Figure 4). The
results remained consistent in the cohort defined according
to SPRINT inclusion and exclusion criteria (eFigure 2 in the
Supplement) and in sensitivity analyses including all patients irrespective of antihypertensive medication use, and

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Blood Pressure Control in Chronic Kidney Disease

Original Investigation Research

Figure 3. Kaplan-Meier Survival Curves of Patients With Follow-up Systolic Blood Pressure (SBP) Less Than 120 vs 120 to 139 mm Hg
A Overall cohort

1.00

Propensity scorematched cohort

1.00
SBP 120-139 mm Hg

0.75

Survivors, Proportion

Survivors, Proportion

SBP 120-139 mm Hg

SBP <120 mm Hg
0.50

0.25

0.75

SBP <120 mm Hg
0.50

0.25

0
0

Analysis Time, y

Analysis Time, y

Figure 4. Propensity ScoreAdjusted Hazard Ratios of All-Cause Mortality Associated With Systolic Blood
Pressure Less Than 120 vs 120 to 139 mm Hg in Various Subgroups of Patients in the Overall Cohort
Overall
Age, y
<75
75
Sex
Female
Male
Race
Black
White
CCI
<3
3
eGFR, mL/min/1.73 m2
<30
30
Diabetes mellitus
Yes
No
Coronary artery disease
Yes
No
Chronic heart failure
Yes
No
1.00

1.25

1.50

1.75

2.00

2.25

2.50

2.75

3.00

Hazard Ratio (95% CI)

when target SBP levels for both groups were required to be

present on more than 75% of follow-up measurements (results not shown).

Discussion
In our database containing more than 650 000 patients with
CKD, we were able to identify 77 765 individuals with CKD and
baseline uncontrolled hypertension and who experienced
blood pressure changes similar to what would be expected in
a clinical trial or in clinical practice. During follow-up, patients in the lower (<120 mm Hg) SBP arm had significantly
lower SBP and DBP and experienced significantly higher mortality compared with patients in the SBP 120 to 139 mm Hg arm.
These results were consistent in various subgroups of patients and also in a subcohort modeled on the basis of the injamainternalmedicine.com

CCI indicates Charlson comorbidity

index; and eGFR, estimated
glomerular filtration rate. Symbols
indicate hazard ratio, and error bars,
95% confidence interval.

clusion and exclusion criteria of the currently ongoing SPRINT.

Our results suggest that SBP levels that are lower than currently recommended treatment targets may not be beneficial
and may even be harmful. These findings are in concordance
with other recent observational studies that showed a J-shaped
association between SBP and major clinical outcomes.1,8
Ideal blood pressure targets in patients with CKD remain
a matter of lively debate. The recently released guidelines by
the Eighth Joint National Committee26 for the management
of high blood pressure in adults has advocated less stringent
treatment targets in patients with CKD compared with previous guidelines, largely because of the lack of conclusive data
from clinical trials to support stricter blood pressure targets.
Previous trials in patients with CKD have primarily examined the renoprotective effects of various blood pressure
treatment targets on progression of CKD,9-11 but outcomes
such as mortality or cardiovascular events either were not
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Research Original Investigation

Blood Pressure Control in Chronic Kidney Disease

examined or were only included as part of composite secondary end points. These end points will be primarily examined in the ongoing SPRINT, but it is possible that its results
may not be applicable to all segments of a heterogeneous
group such as the population with CKD. Our study examined
a much wider population with CKD than that typically
included in a clinical trial and hence could provide more
generalizable findings. This could be important if (once completed) the SPRINT confirms our findings, in that it may
allow for wider-ranging recommendations about ideal blood
pressure treatment targets in all patients with CKD.
The results of observational studies can be biased, often
because of markedly different patient characteristics in the
groups compared, and because of different reasons underlying observed events in the 2 types of studies. We tried to minimize these biases by selecting patients according to specific
criteria, by only considering patients whose decrease in blood
pressure levels occurred in parallel with an enhanced antihypertensive regimen, and by using propensity scores to identify and to adjust for clinical characteristics that could bias different blood pressure responses. There were limitations to our
cohort that need to be considered when our results are interpreted. We examined almost exclusively male (97.4%) and predominantly white (91.3%) patients. Fortunately, most prospective blood pressure trials have not shown a significant
difference in intervention effects between male and female
patients.3,4,16 Comorbid conditions in our cohort were not determined by a group of researchers using strict criteria but were
based on medical records generated in the course of clinical
practice. Unmeasured comorbidities could have affected our
outcomes in spite of careful accounting for relevant measured comorbidities. The fact that the number of antihypertensives needed to achieve the strict and conventional SBP outcomes in our study was similar suggests that determinants of

Conclusions
In summary, we have found that in a cohort of patients with
CKD and uncontrolled hypertension, lowering of the SBP to less
than 120 mm Hg was associated with higher all-cause mortality compared with an SBP of 120 to 139 mm Hg. Such an observational approach to estimate treatment targets for blood
pressure lowering in patients with CKD could be a useful
complement to clinical trials.

Conflict of Interest Disclosures: Dr Kovesdy is an

employee of the US Department of Veterans
Affairs. No other disclosures are reported.

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 access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy 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 important
intellectual 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, KalantarZadeh.

1448

individual responsiveness to antihypertensives (eg, relative hypovolemia or decreased ejection fraction) could be important
unmeasured confounders.
To the best of our knowledge prior to our study, a clinical
trial modeling approach has not been attempted for blood pressure lowering in patients with CKD. If our approach is shown
to be successful, this could corroborate the role that observational studies could play in the planning of clinical trials by determining the likelihood of the best treatment targets, by estimating event rates, and by identifying subgroups most or least
likely to respond to certain interventions. In cases in which
clinical trials are not feasible or not ethically possible, observational studies could provide much-needed information about
the treatments most likely to be effective. This could be especially important in patients with CKD, who experience a substantial number of metabolic and other abnormalities. It is likely
that clinical trials will not be available for all the abnormalities found in patients with CKD, in which case the modeling
of clinical trials from large observational data sets may offer
the best evidence toward effective treatments. It is hoped that
these prospective modeling techniques will improve over time,
such that they will be helpful in the selection and design of future clinical trials.

Funding/Support: This study is supported by grant

R01DK078106 from the National Institute of
Diabetes and Digestive and Kidney Diseases,
National Institutes of Health; and by the
Department of Veterans Affairs.
Role of the Sponsor: The Department of Veterans
Affairs reviewed and approved the manuscript but
had no role in the design and conduct of the study;
analysis and interpretation of the data; preparation
of the manuscript; and decision to submit the
manuscript for publication.
Disclaimer: Opinions expressed in this article are
those of the authors and do not represent the
official opinion of the US Department of Veterans
Affairs.
Previous Presentation: Parts of this material were
presented at the American Society of Nephrology
Kidney Week 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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