Download Effect of Baseline and Changes in Systolic Blood Pressure Over

Effect of Baseline and Changes in Systolic Blood Pressure
Over Time on the Effectiveness of Valsartan in the
Valsartan Heart Failure Trial
Inder S. Anand, MD, DPhil, FRCP; Thomas S. Rector, PhD; Michael Kuskowski, PhD;
Sabu Thomas, MD; N. J. Holwerda, MD; Jay N. Cohn, MD
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 10, 2017
Background—Low systolic blood pressure (SBP) is a risk factor for adverse outcomes in patients with heart failure (HF).
Valsartan improved morbidity rates in the Valsartan Heart Failure Trial (Val-HeFT) despite a reduction in SBP. The aim
of the present study was to investigate the relationship between the SBP-lowering effects of valsartan and its
cardiovascular protective effects in this population.
Methods and Results—Baseline measurements and changes in SBP at 4 months were related to mortality and morbidity rates.
The effects of valsartan on these end points were compared in quartiles of baseline SBP with multivariable Cox proportional
hazards regression models that included a test for interaction between the effects of valsartan treatment and baseline SBP and
examined the effects of changes in SBP on the valsartan effect. The mean⫾SD baseline SBP in all patients (n⫽5010) was
124⫾18 mm Hg. Patients in the lowest quartile of SBP (SBP ⱕ110 mm Hg; mean SBP 102 mm Hg; n⫽940) had more severe
HF and a significantly increased adjusted risk of death (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03 to 1.43;
P⫽0.02), first morbid event (HR, 1.25; 95% CI, 1.10 to 1.40; P⫽0.001), and hospitalization for HF (HR, 1.45; 95% CI, 1.22
to 1.73; P⬍0.001) than did patients in the upper 3 quartiles of baseline SBP (mean SBP 130 mm Hg; n⫽3260). Valsartan
reduced SBP in patients in the upper 3 quartiles but not in patients in the lowest quartile who had a baseline SBP ⬍110 mm Hg.
Valsartan was associated with decreases in the risks of first morbid event (HR, 0.74; 95% CI, 0.60 to 0.91; P⫽0.005) and
hospitalization for HF (HR, 0.60; 95% CI, 0.45 to 0.79; P⬍0.001) in the lowest quartile that were not significantly different than
the valsartan effects in the other 3 quartiles combined (first morbid event HR, 0.90; 95% CI, 0.79 to 1.02; P⫽0.10; and HF
hospitalization HR, 0.77; 95% CI, 0.64 to 0.93; P⫽0.006; nonsignificant interactions). The decrease in SBP from baseline to 4
months was an independent risk factor for subsequent events. When changes in SBP were added to the regression model, the effects
of valsartan in the lowest quartile and in the other 3 quartiles combined did not change substantially.
Conclusion—Baseline SBP and a decrease in SBP over time were risk factors for adverse events in HF. Valsartan reduced
SBP but not in the high-risk group of patients who had a baseline SBP ⬍110 mm Hg. The beneficial effects of valsartan
did not vary significantly with baseline SBP, and decreases in SBP did not counteract the beneficial effects on HF
morbidity rates. (Circ Heart Fail. 2008;1:34-42.)
Key Words: heart failure 䡲 blood pressure 䡲 clinical trial 䡲 valsartan 䡲 outcomes
H
of hypertension, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and a combination of hydralazine and isosorbide, are also effective in reducing mortality and
morbidity rates in patients with HF.12–17 Whether the beneficial
effects of these medications on morbidity and mortality rates in
patients with HF are modified by initially low or drops in blood
pressure is an important clinical issue.
igh blood pressure increases the risk of death in the general
population,1,2 and hypertension is the most important
population-attributable risk factor for the development of heart
failure (HF).3,4 The benefits of treating hypertension on risks of
major cardiovascular events are well established in the absence
of systolic HF, and effective lowering of blood pressure is
associated with an ⬇50% reduction in the incidence of HF.5,6
Once HF develops, however, lower blood pressure becomes a
risk factor for increased mortality and morbidity rates both in
acute decompensated7,8 and chronic HF.9 –11 The risk associated
with elevated blood pressure in patients with systolic dysfunction has not been established. Vasodilators used in the treatment
Clinical Perspective p 42
The present study is a secondary analysis of the Valsartan
Heart Failure Trial (Val-HeFT) database to study the effects
of baseline blood pressure and changes in blood pressure over
Received August 31, 2007; accepted January 18, 2008.
From the VA Medical Center, Minneapolis, Minn (I.S.A., T.S.R.); the University of Minnesota, Minneapolis, Minn (I.S.A., T.S.R., J.N.C., S.T.);
Geriatric Research Education and Clinical Center, VA Medical Center, Minneapolis, Minn (M.K.); and St Elisabeth Hospital, Tilburg, the Netherlands (N.J.H.).
The views expressed in this article are those of the authors and do not necessary represent the views of the Department of Veterans Affairs.
Correspondence to Inder S. Anand, MD, FRCP, DPhil (Oxon), VA Medical Center, Cardiology 111-C, One Veterans Dr, Minneapolis, MN 55417.
E-mail [email protected]
© 2008 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.107.736975
34
Anand et al
Effect of Blood Pressure on Heart Failure Outcomes
time on the effectiveness of treatment with valsartan on
morbidity and mortality in patients with moderate to severe
HF. First, we sought to confirm that both lower baseline
systolic blood pressure (SBP) and a decrease in SBP over
time were independently associated with an increased risk of
morbidity and mortality. The interaction between the effects
of valsartan and baseline SBP was then examined, controlling
for several other known prognostic variables. Finally, to
determine whether adjusting for any potentially deleterious
drops in SBP during treatment would enhance the apparent
beneficial effects of valsartan, we examined how controlling
for changes in SBP affected the beneficial effects of
valsartan.
Methods
Study Design and Patient Selection
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Val-HeFT was a randomized, placebo-controlled, double-blind, multicenter trial in 5010 men and women with symptomatic HF that
evaluated the efficacy of the angiotensin receptor blocker valsartan.
Details of the study design and protocol have been presented
previously.17 Briefly, patients over 18 years of age who were in
stable New York Heart Association class II-IV HF for at least 3
months and who had a left ventricular (LV) ejection fraction ⬍40%
and LV internal dimension in diastole/body surface area ⬎2.9 cm/m2
on echocardiography were eligible. All patients had to be receiving
stable pharmacological treatment for HF that could include angiotensin-converting enzyme inhibitors, ␤-blockers, digoxin, diuretics,
hydralazine, and/or nitrates. Exclusion criteria included a persistent
mean standing SBP ⬍90 mm Hg and serum creatinine ⬎2.0 mg/dL.
Eligible patients were stratified according to baseline ␤-blocker
therapy and were randomly allocated to receive either oral valsartan
or placebo. Treatment with valsartan was initiated at 40 mg twice
daily and the dose was doubled every 2 weeks to reach the target
dose of 160 mg twice daily, provided SBP was ⱖ90 mm Hg, there
were no signs or symptoms of hypotension, and increases in serum
creatinine levels did not exceed 50% of the baseline value. Blood
pressure was measured at each visit with a sphygmomanometer after
5 minutes of rest in the sitting position. The study had 2 primary end
points: death and the first morbid event, which was defined as either
death, sudden death with resuscitation, hospitalization for HF, or
administration of intravenous inotropic or vasodilatory drugs for ⱖ4
hours without hospitalization. Hospitalization for HF was a secondary end point.
Data Analysis
Baseline variables grouped by quartiles of baseline SBP were
compared with ANOVA for continuous variables and ␹2 tests for
categorical variables. Time to events in various groups were described with Kaplan-Meier curves. Cox proportional-hazards regression models were used to assess the association between time to
death from any cause and baseline SBP, changes in SBP during the
first 4 months of follow-up, and treatment with valsartan. Baseline
SBP values were grouped into quartiles to examine whether baseline
SBP was linearly related to the mortality and hospitalization hazards
and to examine the effects of valsartan on SBP. The quartile analysis
suggested that the relationships between baseline SBP and hazards
were not linear, as most of the increased risk was seen in the lowest
quartile (quartile 1 [Q1]: SBP ⱕ110 mm Hg). Rather than trying to
model a continuous nonlinear relationship, all further analyses were
simply carried out comparing Q1 with the other 3 quartiles (Q2, Q3,
and Q4) combined. Analyses were repeated using time to first
morbid event and first hospitalization for HF as the dependent
variable. All of the regression models included baseline age, New
York Heart Association class, ischemic etiology, history of hypertension, diabetes, body mass index, pulse, LV ejection fraction,
serum sodium, creatinine, uric acid, brain natriuretic peptide, aldosterone, plasma renin activity, hemoglobin, and use of angiotensin-
35
converting enzyme inhibitors, diuretics, digoxin, and ␤-blockers as
covariates. When change in blood pressure over the first 4 months
was included in the models, all subjects with fatal (n⫽154) or
nonfatal events (n⫽332) that occurred during the first 4 months of
follow-up were excluded. The changes in SBP from baseline to
month 4, month 12, and end of study in the 2 treatment groups were
compared at each time point with a 2-sample t test rather than
ANOVA to minimize loss of information over time due to deaths and
censored follow-up. SPSS statistical software (version 15; SPSS Inc,
Chicago, Ill) was used for all analyses. A probability value ⬍0.05
was considered significant without adjustment for making multiple
comparisons.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
Patient Characteristics
The baseline blood pressure (mean⫾standard deviation) in
the overall population was 124⫾18 mm Hg systolic and
76⫾11 mm Hg diastolic (n⫽5010). Comparison of SBP
quartiles in Table 1 indicates that lower SBP was associated
with younger age, lower body mass index, lower LV ejection
fraction, greater LV internal dimension in diastole, higher
levels of aldosterone and plasma renin activity, and lower
hemoglobin levels. Lower SBP was also associated with
worse New York Heart Association class and Minnesota
Living with Heart Failure Questionnaire (MLHF) scores,
along with more prevalent use of diuretics, digoxin, and
spironolactone. The mean SBP of 149 mm Hg among the
large number of patients in Q4 (SBP ⬎135 mm Hg) is
remarkable for patients with documented systolic dysfunction
who were often treated with medications that lower blood
pressure.
Baseline Systolic Blood Pressure Related to
Morbidity and Mortality
Unadjusted time to death, first morbid event, and hospitalization for HF within quartiles of baseline SBP are shown in
Figure 1. The risks of all events were similar in the upper 3
quartiles of SBP and increased only in the Q1, suggesting that
baseline SBP was not linearly related to the risk (hazard) of
death or hospitalization for HF. We did not fit nonlinear
models to this relationship. The Cox multivariable model for
baseline SBP quartiles is shown in Table 2. With Q3 (patients
with normal SBP) as the reference group, only patients in the
Q1 were found to have an increased risk of first morbid event
and hospitalization for HF, with a trend for an increase risk
for death. The upper quartile that contained many patients
with elevated SBP was not associated with increased risk.
Given these findings, the upper 3 quartiles were collapsed
into 1 group for further analyses comparing Q1 with Q2, Q3,
and Q4 combined. Patients with baseline SBP in the lowest
quartile (Q1: ⱕ110 mm Hg) had a significantly increased
adjusted risk of death (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03 to 1.43; P⫽0.02), first morbid event
(HR, 1.25; 95% CI, 1.10 to 1.40; P⫽0.001), and hospitalization for HF (HR, 1.45; 95% CI, 1.22 to 1.73; P⬍0.001)
compared with patients in the upper 3 quartiles (Table 2).
Thus, a low baseline SBP was an independent risk factor for
morbidity and mortality in this patient population.
36
Circ Heart Fail
Table 1.
May 2008
Baseline Characteristics by Quartile of SBP
Quartile 1
Quartile 2
Quartile 3
Quartile 4
No.
1156
1304
1323
1227
Quartiles 2, 3, and 4 Combined
3854
Age, y†
60⫾12
62⫾11
64⫾11
66⫾10
64⫾11§
Female
19
19
20
22
20
White
88
91
91
92
91§
Ischemic etiology
56
58
58
56
58
Nonischemic etiology
44
42
42
44
42
Diabetes
23
23
28
28
26‡
Atrial fibrillation
14
14
13
15
14
Mean SBP, mm Hg†
102⫾6
115⫾4
128⫾4
149⫾12
130⫾16§
Mean DBP, mm Hg†
67⫾8
73⫾8
77⫾9
84⫾10
78⫾10§
Heart rate, bpm
74⫾13
74⫾12
73⫾13
73⫾13
73⫾13
44
39
34
36
36§
36⫾23
33⫾23
30⫾22
30⫾23
31⫾23§
History of PND
11
9
8
8
8†
Elevated JVP
14
13
14
14
13
Peripheral edema
16
18
17
19
18
79⫾15
79⫾15
80⫾16
79⫾15
79⫾15
26.4⫾4.6
26.8⫾4.4
27.2⫾4.5
27.2⫾4.4
27⫾4§
NYHA III/IV†
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MLHFQ†
Weight, kg
BMI, kg/m2†
eGFR
57⫾17
58⫾16
58⫾15
58⫾15
58⫾15§
Serum albumin, g/dL
4.2⫾0.4
4.2⫾0.3
4.2⫾0.3
4.2⫾0.3
4.2⫾0.3
S3 presence†
LVEF§
LVIDd/BSA§
29
28
24
23
25§
25⫾8
26⫾7
27⫾7
28⫾7
27⫾7§
3.76⫾0.6
3.67⫾0.5
3.62⫾0.5
3.57⫾0.5
3.60⫾0.5§
Background therapy
ACE inhibitors
94
94
91
92
92‡
␤-Blockers
38
34
33
35
34
Diuretics†
89
86
83
84
84
Digoxin*
74
68
65
64
65§
Aspirin
40
39
41
42
41
Statins
33
33
32
29
32
Spironolactone†
7
5
4
3
13.6⫾1.5
13.7⫾1.4
13.8⫾1.5
13.8⫾1.4
13.8⫾1.4§
lnCRP
1.6⫾0.9
1.6⫾0.9
1.6⫾0.8
1.5⫾0.8
1.6⫾0.8
lnNorepinephrine
6.0⫾0.6
6.0⫾0.6
5.9⫾0.6
6.0⫾0.5
5.9⫾0.6
lnBNP
4.6⫾1.4
4.5⫾1.3
4.3⫾1.4
4.5⫾1.3
4.4⫾1.4§
lnaldosterone*
4.8⫾0.9
4.7⫾0.9
4.6⫾0.8
4.5⫾0.8
4.6⫾0.8§
lnPRA*
2.5⫾1.4
1.9⫾1.5
1.4⫾1.5
0.7⫾1.5
4.4⫾1.6§
Hemoglobin, g/dL*
4§
Values are expressed as mean⫾SD or %. DBP indicates diastolic blood pressure; NYHA, New York Heart Association functional
class; MLHFQ, Minnesota Living with Heart Failure Questionnaire; PND, paroxysmal nocturnal dyspnea; JVP, jugular venous pressure;
BMI, body mass index; eGFR, estimated glomular filtration rate; LVEF, left ventricular ejection fraction; LVIDd, left ventricle internal
dimension in diastole; BSA, body surface area; ACE, angiotensin-converting enzyme; CRP, C-reactive protein; BNP, brain natriuretic
peptide; and PRA, plasma renin activity.
*P⬍0.05, †Pⱕ0.001 for differences between quartiles.
‡P⬍0.05, §P⬍0.01 between Q1 and Q2, Q3, and Q4 combined.
Effect of Baseline Systolic Blood Pressure on
Effectiveness of Valsartan
In the overall population, valsartan use was not associated
with a reduction in the risk of death but it did cause a 13.3%
reduction in risk of first morbid event (HR, 0.87; 95% CI,
0.77 to 0.97) and a 27.5% reduction in risk for first hospitalization for worsening HF (HR, 0.73; 95% CI, 0.64 to 0.84).17
When the effects of valsartan were estimated separately in
patients with baseline SBP in Q1 and in those with baseline
SBP the upper 3 SBP quartiles combined, use of valsartan
was associated with a 26% decrease in risk of first morbid
event in the Q1 patients (HR, 0.74; 95% CI, 0.60 to 0.91;
P⫽0.005), compared with a 10% decrease in the combined
Q2, Q3, and Q4 group (HR, 0.90; 95% CI, 0.79 to 1.02;
Anand et al
100
Effect of Blood Pressure on Heart Failure Outcomes
Effect of Valsartan on Systolic Blood Pressure
Time to Death
% Survival
90
80
SBP <110 mmHg
SBP >110 <121 mmHg
SBP >121 <135 mmHg
SBP >135 mmHg
70
60
0
10
20
30
40
Months Since Randomization
Time to First Morbid Event
90
80
70
Overall, treatment with valsartan caused a significant placebo
corrected decrease in SBP (mean, [95% CI]) of ⫺4.0 (⫺3.1 to
⫺4.6), ⫺3.9 (⫺2.9 to ⫺4.9), and ⫺3.4 (⫺2.4 to
⫺4.3) mm Hg at 4 months, 12 months, and the end point,
respectively (P⬍0.001 at all time points). The change in SBP
at 4 months with valsartan by quartiles of baseline SBP is
shown in Table 4. Treatment with valsartan did not lower
SBP in Q1 (ⱕ110 mm Hg). In fact, the mean SBP increased
in both the placebo and valsartan groups as one might expect
with regression to the mean. However, the increase in SBP in
Q1 was significantly greater in the placebo group (P⬍0.001).
In contrast to the lowest baseline SBP quartile, SBP fell in the
other 3 combined quartiles in both treatment groups at 4
months, with a significantly greater decrease in the valsartan
group. Because the use of valsartan in patients with extremely
low SBP may be a concern to the clinicians, we also
compared the response to valsartan with the response to
placebo in 317 patients whose baseline SBP was
ⱕ100 mm Hg (valsartan group mean SBP 95⫾3 mm Hg,
n⫽170; placebo group mean SBP 95⫾3 mm Hg, n⫽147). In
this group as well, SBP increased in both the valsartan
(5⫾13 mm Hg) and placebo (8⫾12 mm Hg) groups, and the
increase was significantly greater in the placebo group (Table 4).
Safety Profile of Valsartan in Patients With Low
Versus High Baseline SBP
60
0
10
20
30
40
30
40
Months Since Randomization
Time to Hospitalization
100
% Hospitalizations for Heart Failure
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% Event Free Survival
100
37
90
80
70
60
0
10
20
Overall, the mean change from baseline to 4 months was
greater in the valsartan group than in the placebo group for
blood urea nitrogen (1.4⫾3.6 versus 0.7⫾2.2 mmol/dL
P⬍0.001), serum creatinine (0.9⫾2.2 versus 0.2⫾1.3 mmol/
dL, P⬍0.001), and serum potassium (0.13⫾0.65 versus
decrease of 0.06⫾0.6 mmol/dL, P⬍0.001). However, the
effect of valsartan on these parameters was similar in low
(Q1) and high (Q2, Q3, and Q4) SBP groups (blood urea
nitrogen 1.6⫾4.4 versus 1.4⫾3.3 mmol/L; creatinine
0.12⫾0.28 versus 0.10⫾0.24 mmol/dL; and potassium
0.7⫾0.6 versus 0.12⫾0.7 mmol/L; all P⫽not significant).
More patients discontinued the randomized treatment because
of hypotension in Q1 (2.9% in valsartan group versus 1.4% in
placebo group; P⬍0.001) than in the other quartiles combined (0.7% in valsartan group versus 0.2% in placebo group;
P⬍0.001).
Months Since Randomization
Figure. Kaplan-Meier curves for time to death, first morbid
event, and hospitalization for HF by quartile of baseline systolic
blood pressure.
P⫽0.10). The test for interaction between the effects of
valsartan treatment and baseline SBP was not significant,
however, as shown in Table 3. Similarly, valsartan caused a
40% decrease in risk of first hospitalization for HF in Q1
patients (HR, 0.60; 95% CI, 0.45 to 0.79, P⬍0.001) and a
23% decrease in patients in the upper 3 quartiles (HR, 0.77;
95% CI, 0.64 to 0.93; P⫽0.006), with interaction that was
again not significant.
Changes in Systolic Blood Pressure Related to
Morbidity and Mortality
When the change in SBP over the first 4 months was analyzed
as a continuous variable in a multivariable Cox regression
model ignoring treatment, a 1-mm Hg increase in SBP was
associated with a significant decrease in the risk of death, first
morbid event, and hospitalizations for HF in the entire
population (Table 5). The interaction between the baseline
SBP quartile groups and the change in SBP was not significant for any end point, suggesting that the beneficial effect
associated with an increase in SBP over time was not
different in the 2 groups defined by baseline SBP (Table 5).
Thus, both low baseline SBP and a decrease in SBP over time
were associated with an increase in subsequent HF morbidity.
38
Circ Heart Fail
May 2008
Table 2. Adjusted Hazard Ratios (95% Confidence Interval) for Mortality, First Morbid Event, and Hospitalizations for HF
in Patients Grouped by Baseline SBP
Mean Baseline SBP,
Mean⫾SD
102⫾5
No. of Patients
Mortality,
HR (95% CI)
First Morbid
Event, HR
(95% CI)
Hospitalization
for HF, HR
(95% CI)
940
1.12 (0.98 to 1.47)
1.24 (1.05 to 1.45)
1.44 (1.16 to 1.79)
0.08
0.01
0.001
0.97 (0.83 to 1.14)
1.01 (0.81 to 1.26)
SBP Quartiles
Q1: ⱕ110 mm Hg
P
Q2: ⬎110 mm Hg and ⱕ121 mm Hg
115⫾4
1110
1.01 (0.82 to 1.23)
0.96
0.71
0.91
128⫾4
1116
Reference group
Reference group
Reference group
149⫾11
1034
0.94 (0.76 to 1.16)
0.99 (0.84 to 1.17)
0.95 (0.71 to 1.20)
0.58
0.90
0.67
1.21 (1.03 to 1.43)
1.25 (1.10 to ⫺1.4)
1.45 (1.22 to 1.73)
0.02
0.001
⬍0.001
Reference group
Reference group
Reference group
P
Q3: ⬎121 mm Hg and ⱕ135 mm Hg
P
Q4: ⬎135 mm Hg
P
Q1 versus Q2, Q3, and Q4 combined
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Q1
102⫾6
940
P
Q2, Q3, and Q4 combined
130⫾16
3260
Covariates used in the Cox regression model: age, New York Heart Association class, origin, history of hypertension, diabetes, body mass index,
pulse, LV ejection fraction, serum sodium, creatinine, uric acid, brain natriuretic peptide, aldosterone, plasma renin activity, hemoglobin, and use of
an angiotensin-converting enzyme inhibitor, diuretics, digoxin, or ␤-blockers. No. in each groups is for those with all covariates. P values are against
the reference groups. HR indicates hazard ratio.
Effects of Valsartan Treatment Adjusted for
Change in Systolic Blood Pressure
Because valsartan caused a significant decrease in SBP in
baseline Q2, Q3, and Q4 and a smaller increase in SBP in Q1
compared with placebo throughout the study, and because a
decrease in SBP was associated with worse outcomes regardless of baseline SBP, we examined whether controlling for
the change in SBP after 4 months would alter the apparent
effectiveness of valsartan from 4 months to the end of
follow-up. When the change in SBP was added to the
regression model, the beneficial effects of valsartan on first
morbid event and hospitalizations for HF tended to increase
in Q1, and to a lesser extent in Q2, Q3, and Q4 (Table 6);
however, the blood pressure–lowering effect of valsartan did
not deeply undermine its beneficial effects. Furthermore,
there was no significant interaction between treatment and
change in blood pressure on any of the outcomes, suggesting
that the effect of valsartan was not greatly modified by
changes in SBP.
Discussion
The present analysis of Val-HeFT data confirms that low SBP
is independently associated with an increase in the risk of
mortality and morbidity in patients with moderate to severe
chronic HF.7,9 –11 The increased risk did not appear to be
linear across all levels of baseline SBP and was observed
mainly in patients with a SBP in the lowest quartile
(⬍110 mm Hg). A decrease in SBP over time was also found
to increase the subsequent risk of adverse outcomes.
It is noteworthy that approximately 25% of patients in the
present study, all of whom had documented LV systolic
dysfunction and were being treated with a diuretic (84%), an
Table 3. Effect of Valsartan Versus Placebo on Mortality, First Morbid Event, and Hospitalizations for HF in Patients
Grouped by Baseline SBP
Mean Baseline SBP, mm Hg
Mean⫾SD
Q1
P
First Morbid
Event, HR
(95% CI)
Hospitalization
for HF, HR
(95% CI)
0.74 (0.60 to
0.91)
0.60 (0.45 to
0.79)
Placebo
Valsartan
Placebo
Valsartan
102⫾5
101⫾6
474
466
0.82 (0.63 to
1.06)
0.13
0.005
⬍0.001
131⫾16
130⫾15
1657
1623
1.04 (0.88 to
1.23)
0.90 (0.79 to
1.02)
0.77 (0.64 to
0.93)
P
Q2, Q3, and Q4
combined
Mortality,
HR (95% CI)
No. of Patients
0.64
0.10
0.006
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䡠䡠䡠
䡠䡠䡠
0.15
0.29
0.36
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
䡠䡠䡠
The Hs (95% CIs) have been adjusted for all covariates. Covariates used in the Cox regression model: age, New York Heart Association class, origin,
history of hypertension, diabetes, body mass index, pulse, LV ejection fraction, serum sodium, creatinine, uric acid, brain natriuretic peptide,
aldosterone, plasma renin activity, hemoglobin, and use of an angiotensin-converting enzyme inhibitor, diuretics, digoxin, or ␤-blockers. No. in each
groups is for those with all covariates. HR indicates hazard ratio.
Interaction P
䡠䡠䡠
Anand et al
Table 4.
Effect of Blood Pressure on Heart Failure Outcomes
39
Effects of Valsartan on SBP at 4 Months by Quartile of Baseline SBP
No. of Patients
Mean Baseline SBP
Mean Change in SBP
Placebo-Corrected Change
⫺4.9 (⫺6.4 to ⫺3.5) †
Quartiles of Baseline Systolic Blood Pressure
Q1: ⱕ110 mm Hg
Valsartan
509
101⫾5
1.2⫾12
Placebo
539
102⫾5
6.1⫾12
Valsartan
629
115⫾4
⫺2.1⫾14
Placebo
574
115⫾4
1.2⫾13
Q2: ⬎110 mm Hg and ⱕ121 mm Hg
⫺3.2 (⫺4.8 to ⫺1.7) †
Q3: ⬎121 mm Hg and ⱕ135 mm Hg
Valsartan
617
128⫾4
⫺7.2⫾15
Placebo
616
127⫾4
⫺2.1⫾14
⫺5.1 (⫺6.7 to ⫺3.5) †
Q4: ⬎135 mm Hg
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Valsartan
543
149⫾12
⫺12.5⫾18
Placebo
601
149⫾11
⫺9.1⫾16
⫺3.4 (⫺5.4 to ⫺1.4) †
Q1 versus Q2⫹Q3⫹Q4
Q1
Valsartan
509
101⫾5
1.2⫾12.3
Placebo
539
102⫾5
6.1⫾11.8
⫺4.9 (⫺6.4 to ⫺3.5†
Q2⫹Q3⫹Q4
Valsartan
1789
130⫾16
⫺7.0⫾16.2
Placebo
1791
131⫾16
⫺3.4⫾14.9
Valsartan
170
95⫾3
4.7⫾13
Placebo
147
95⫾3
8.0⫾12.3
⫺3.6 (⫺4.6 to ⫺2.6) †
SBP ⱕ 100 mm Hg
⫺3.4 (⫺6.2 to ⫺0.5)*
Values are expressed as n, mean⫾SD.
*P⬍0.05, †P⬍0.01 for change in SBP comparing valsartan to placebo groups.
angiotensin-converting enzyme inhibitor (92%), and sometimes a ␤-blocker (35%), still had SBP ⬎135 mm Hg (mean
149 mm Hg). The reason for the high SBP is not obvious.
These patients tended to be older, to have better LV function,
and to have slightly less medication use than others in the
study. Interestingly, these patients did not have a significantly
increased risk of adverse events. In the African American
Heart Failure Trial (A-HeFT), approximately 25% patients
with systolic dysfunction had similarly elevated blood pressure at baseline.12 Similar findings of elevated SBP have also
been reported recently in patients admitted with acute HF
from the Organized Program To Initiate life-saving treatment
in hospitalized patients with Heart Failure (OPTIMIZE-HF)
registry. In this registry, the majority of patients with elevated
SBP had preserved LV function. Although the pathophysiology of systolic hypertension might be different in patients
with preserved LV systolic function, if elevated SBP is
common among patients with chronic HF and LV systolic
dysfunction and the elevated SBP is not associated with
increased risk of adverse events (although the risk of stroke
Table 5. Effect of Change in SBP From Baseline to 4 Months on the Adjusted HRs (95% CIs) for Mortality, First Morbid Event, and
Hospitalizations for HF Analyzed as a Continuous Variable in Patients Grouped by Quartile
No. of Patients
Mortality, HR (95% CI)
First Morbid Event, HR
(95% CI)
Hospitalization for HF,
HR (95% CI)
3897
0.993 (0.988 to 0.999)
0.992 (0.987 to 0.996)
0.989 (0.983 to 0.995)
0.024
⬍0.001
⬍0.001
853
1.0 (0.986 to 1.01)
0.994 (0.983 to 1.004)
0.986 (0.972 to 0.999)
0.90
0.23
0.035
3044
0.992 (0.986 to 0.998)
0.991 (0.986 to 0.996)
0.989 (0.983 to 0.996)
P
0.014
0.001
0.001
Interaction P
0.35
0.50
0.88
Continuous variable
P
Q1 versus Q2 ⫹Q3⫹Q4
Q1
P
Q2 ⫹Q3⫹Q4
Covariates used in the Cox regression model: baseline SBP, age, New York Heart Association class, origin, history of hypertension, diabetes, body mass index, pulse,
LV ejection fraction, serum sodium, creatinine, uric acid, brain natriuretic peptide, aldosterone, plasma renin activity, hemoglobin, and use of an angiotensin-converting
enzyme inhibitor, diuretics, digoxin, or ␤-blockers. No. in each groups is for those with all covariates. HR indicates hazard ratio.
40
Circ Heart Fail
May 2008
Table 6. Effect of Controlling for Changes in SBP on the Effect of Valsartan on Mortality, First Morbid Event, and
Hospitalizations for HF
Placebo Versus
Valsartan, Mean
Difference in
SBP, mm Hg
Mortality*
First Morbid Event*
Hospitalization for HF*
0.82 (0.63 to 1.06)
0.74 (0.60 to 0.91)
0.60 (0.45 to 0.79)
Baseline SBP Q1 (n⫽853)
Without change in SBP in model
P
With change in SBP in model
⫺4.9
P
0.13
0.005
⬍0.001
0.75 (0.54 to 1.03)
0.63 (0.49 to 0.82)
0.52 (0.37 to 0.73)
0.08
0.001
⬍0.001
1.07 (0.87 to 1.29)
0.88 (0.76 to 1.02)
0.75 (0.62 to 0.91)
0.48
0.08
0.003
1.05 (0.86 to 1.28)
0.83 (0.71 to 0.97)
0.69 (0.56 to 0.84)
0.65
0.015
⬍0.001
Baseline SBP Q2⫹Q3⫹Q4 (n⫽3044)
Without change in SBP in model
P
With change in SBP in model
⫺3.6
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P
*HR (95% CI) from Cox regression model; see Data Analysis section for a list of covariates.
Groups include only those who had a value for all covariates.
could not be assessed), one wonders whether the high SBP
should or could be decreased. This important question needs
to be addressed by further research.
Although the beneficial effects of valsartan in reducing the
number of morbid events over time and of hospitalizations for
HF tended to be relatively higher in the patients with the
baseline SBP ⬍110 mm Hg (Q1) as compared with those
with SBP above 110 mm Hg, statistical test for interaction
between treatment and baseline SBP did not detect a significant difference in effect in the 2 subgroups. Interestingly,
valsartan did not actually decrease SBP in patients with the
lowest pretreatment values, including those in Q1 with a SBP
⬍110 mm Hg or even the subgroup with a SBP
ⱕ100 mm Hg, even though valsartan was associated with a
smaller increase in SBP as compared with placebo. In
contrast, valsartan did cause a significant decrease in SBP in
patients with higher baseline SBP that could have potentially
counteracted its beneficial effects on morbidity rates. However, the present analysis did not indicate that the benefits of
valsartan depended on baseline SBP or changes in SBP
during the first 4 months of treatment, suggesting dissociation
between the effects of valsartan on SBP and clinical outcomes. It should be emphasized, however, that these conclusions are based on the lack of significance for interaction.
Although interaction tests can be useful exploratory tools, the
lack of statistical significance for interaction tests may be
partially due to their relatively low power. Thus, any inference based on interaction test results should be made with
caution.
The observation that blood pressure did not actually
decrease in the group with low initial SBP suggests that the
addition of valsartan was usually well tolerated by patients
with moderate to severe chronic HF. Low SBP blood pressure
should not preclude a trial of these agents that appear to
benefit all patients. Is there a threshold SBP below which the
use of an angiotensin receptor blocker is associated with
deleterious outcomes? Although the present study was not
designed to address this question, we did find that even in the
small subgroup of 317 patients with a SBP between 90 and
100 mm Hg, valsartan appeared to have been well tolerated,
on average, without frequent deleterious drops in blood
pressure. Because patients with low initial SBP are at a
greater risk of HF morbidity and mortality, and because a
trend for greater risk reduction in morbidity was seen with
valsartan for the low SBP patients (even though the risk
reduction for HF hospitalization was significant for both low
and high SBP patients), patients with low SBP could be
expected to be more likely to benefit from this treatment.
Moreover, the increases in serum creatinine, blood urea
nitrogen, and potassium were no different in patients in
baseline SBP Q1 or than those in Q2, Q3, and Q4, suggesting
that introduction of valsartan even in patients with low SBP
may not precipitate major adverse effects. However, a patient’s baseline SBP had to be ⬎90 mm Hg to be eligible for
this clinical trial or for an increase in the dose of the study
medication. Thus, these data cannot address the use or
benefits of valsartan in patients with HF and a SBP less than
this level.
If low baseline SBP and a decrease in SBP over time are
associated with worse outcomes, how can we explain the
apparent dissociation between the blood pressure–lowering
effects of valsartan and clinical outcomes? The fact that
valsartan did not lower blood pressure in patients with a low
baseline SBP could be explained by an improvement in the
hemodynamics, although these were not measured in the
present study. In patients with chronic HF, a low stroke
volume threatens the arterial blood pressure and leads to a
baroreceptor-mediated activation of several vasoconstrictive
neurohormones that help to preserve blood pressure by
increasing arterial impedance.19 The increase in impedance is,
however, deleterious to the failing heart and further reduces
the stroke volume, worsening hypotension. Vasodilators such
as sodium nitroprusside reverse the functional abnormalities
acutely by improving stroke volume and may increase blood
pressure.10,20,21 Thus, the vasodilatory effects of valsartan
might have lowered arterial impedance in patients with the
Anand et al
Effect of Blood Pressure on Heart Failure Outcomes
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lowest SBP who would be expected to have the highest
impedance, thereby increasing the cardiac output and maintaining blood pressure. Over the long term, valsartan use was
associated with an improvement in LV ejection fraction22 and
a decrease in the levels of several neurohormones, including
brain natriuretic peptide, norepinephrine, and aldosterone.23,24
Thus, the dual effects of lowering impedance (BP-lowering
effect) and improving LV structural remodeling might have
contributed to the beneficial effects of valsartan on hemodynamics and subsequently to reduced morbidity and mortality.
In conclusion, the present secondary analysis of data from
a randomized controlled clinical trial suggests that patients
with low systolic blood pressure can benefit from valsartan
therapy without an inordinate risk of deleterious hypotension.
Patients with low SBP are at least as likely as and perhaps
more likely to benefit from valsartan therapy as those with
normal or high pretreatment blood pressures. Patients with
low blood pressure are at the highest risk and, therefore, have
the greatest need for aggressive therapy. Judicious use of
valsartan in such patients is more likely to produce benefit
than use in those with higher blood pressures, although
patients with low or high SBP appear to benefit. However, the
data were not sufficient to determine whether these findings
are generalizable to patients with SBP well below
100 mm Hg. Regardless, blood pressure reduction does not
seem to greatly counteract the favorable effects of valsartan
on hospitalization for HF and morbidity and cannot be used
as a surrogate for efficacy. Many patients in the present
analysis had HF, systolic dysfunction, and prescriptions for
antihypertensive medications but still had elevated SBP;
however, they were not at increased risk of adverse events.
Because reductions in SBP tended to be associated with
increased risk, further research is needed to determine
whether the SBP should be reduced in patients with these
characteristics and how this might be achieved, if desirable.
Finally, it is important to emphasize that findings of the
present study do not apply to patients with acute decompensated HF.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Sources of Funding
Novartis Pharmaceutical provided a grant for the study. Resources of
the Minneapolis VA Medical Center supported this analysis in part.
Dr Rector was supported by VA Clinical Science and Health
Services Research & Development Grants 04S-CRCOE-001 and
HFP-98-001.
15.
16.
Disclosures
Drs Anand, Holwerda, and Cohn received research grants and
honoraria from Novartis. The other authors report no conflicts.
17.
References
18.
1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective
Studies Collaboration. Age-specific relevance of usual blood pressure to
vascular mortality: a meta-analysis of individual data for one million
adults in 61 prospective studies (published correction appears in Lancet.
2003;361:1060). Lancet. 2002;360:1903–1913.
2. World Health Organization. World Health Report 2002; Reducing Risk,
Promoting Healthy Life. Geneva, Switzerland: World Health Organization; 2002.
3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL
Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; Joint
National Committee on Prevention, Detection, Evaluation, and Treatment
of High Blood Pressure. National Heart, Lung, and Blood Institute;
19.
20.
21.
41
National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206 –1252.
Lloyd-Jones DM, Larson MG, Leip EP, Beiser A, D’Agostino RB,
Kannel WB, Murabito JM, Vasan RS, Benjamin EJ, Levy D; Framingham Heart Study. Lifetime risk for developing congestive heart
failure: the Framingham Heart Study. Circulation. 2002;106:3068 –3072.
Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester PO.
Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet. 1991;338:1281–1285.
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;265:3255–3264.
Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ;
ADHERE Scientific Advisory Committee, Study Group, and Investigators. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA.
2005;293:572–580.
Lee DS, Austin PC, Rouleau JL, Liu PP, Naimark D, Tu JV. Predicting
mortality among patients hospitalized for heart failure: derivation and
validation of a clinical model. JAMA. 2003;290:2581–2587.
Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM.
Development and prospective validation of a clinical index to predict
survival in ambulatory patients referred for cardiac transplant evaluation.
Circulation. 1997;95:2660 –2667.
Anand IS, Tam SW, Rector TS, Taylor AL, Sabolinski ML, Archambault
WT, Adams KF, Olukotun AY, Worcel M, Cohn JN. Influence of blood
pressure on the effectiveness of a fixed-dose combination of isosorbide
dinitrate and hydralazine in the African-American Heart Failure Trial.
J Am Coll Cardiol. 2007;49:32–39.
Levy WC, Mozaffarian D, Linker DT, Sutradhar SC, Anker SD, Cropp
AB, Anand I, Maggioni A, Burton P, Sullivan MD, Pitt B, Poole-Wilson
PA, Mann DL, Packer M. The Seattle Heart Failure Model: prediction of
survival in heart failure. Circulation. 2006;113:1424 –1433.
Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino R Jr, Ferdinand K,
Taylor M, Adams K, Sabolinski M, Worcel M, Cohn JN; AfricanAmerican Heart Failure Trial Investigators. Combination of isosorbide
dinitrate and hydralazine in blacks with heart failure (published correction
appears in N Engl J Med. 2005;352:1276). N Engl J Med. 2004;351:
2049 –2057.
Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson
EL, Olofsson B, Ostergren J, Yusuf S, Pocock S; CHARM Investigators
and Committees. Effects of candesartan on mortality and morbidity in
patients with chronic heart failure: the CHARM-Overall programme.
Lancet. 2003;362:759 –766.
The CONSENSUS Trial Study Group. Effects of enalapril on mortality in
severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;
316:1429 –1435.
The SOLVD Investigators. Effect of enalapril on survival in patients with
reduced left ventricular ejection fractions and congestive heart failure.
N Engl J Med. 1991;325:293–302.
Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani
FE, Dunkman WB, Jacobs W, Francis GS, Flohr KH, et al. Effect of
vasodilator therapy on mortality in chronic congestive heart failure:
results of a Veterans Administration Cooperative Study. N Engl J Med.
1986;314:1547–1552.
Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor
blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:
1667–1675.
Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O’Connor
CM, She L, Stough WG, Yancy CW, Young JB, Fonarow GC;
OPTIMIZE-HF Investigators and Coordinators. Systolic blood pressure at
admission, clinical characteristics, and outcomes in patients hospitalized
with acute heart failure. JAMA. 2006;296:2217–2226.
Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson PA, Harris PC.
Edema of cardiac origin: studies of body water and sodium, renal
function, hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation. 1989;80:299 –305.
Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure (second of
two parts). N Engl J Med. 1977;297:254 –258.
Cohn JN, Franciosa JA. Vasodilator therapy of cardiac failure: (first of
two parts). N Engl J Med. 1977;297:27–31.
42
Circ Heart Fail
May 2008
22. Wong M, Staszewsky L, Latini R, Barlera S, Volpi A, Chiang YT, Benza
RL, Gottlieb SO, Kleemann TD, Rosconi F, Vandervoort PM, Cohn JN;
Val-HeFT Heart Failure Trial Investigators. Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study. J Am Coll Cardiol. 2002;40:970 –975.
23. Cohn JN, Anand IS, Latini R, Masson S, Chiang YT, Glazer R; Valsartan
Heart Failure Trial Investigators. Sustained reduction of aldosterone in
response to the angiotensin receptor blocker valsartan in patients with
chronic heart failure: results from the Valsartan Heart Failure Trial.
Circulation. 2003;108:1306 –1309.
24. Latini R, Masson S, Anand I, Judd D, Maggioni AP, Chiang YT, Bevilacqua M, Salio M, Cardano P, Dunselman PH, Holwerda NJ, Tognoni
G, Cohn JN; Valsartan Heart Failure Trial Investigators. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in
symptomatic chronic heart failure: the Valsartan Heart Failure Trial
(Val-HeFT). Circulation. 2002;106:2454 –2458.
CLINICAL PERSPECTIVE
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Lowering high blood pressure greatly reduces the incidence of heart failure. In the presence of heart failure with systolic
dysfunction, however, low blood pressure and drops in blood pressure are associated with increased risk of hospitalization
and death. Many effective medications that are used for heart failure, including those that decrease angiotensin II, reduce
blood pressure, which could reduce their beneficial effects. Concerns about hypotensive effects often limit use of these
medications. The present secondary analysis of data from the Valsartan Heart Failure trial indicates that neither a low
pretreatment systolic blood pressure (SBP) nor changes in SBP reduced the beneficial effects of valsartan. As expected,
valsartan did reduce SBP in patients in the upper 3 quartiles of SBP but not those in the lowest quartile who had a baseline
SBP between 90 and 110 mm Hg. Valsartan reduced the risk of hospitalization for heart failure and the first morbid event
in the lowest SBP quartile and the other 3 quartiles. Adjustments for the changes in SBP on therapy did not substantially
reduce these beneficial effects. Judicious use of valsartan should be considered for patients who present with low SBP and
have the highest risk of hospitalization and death.
Effect of Baseline and Changes in Systolic Blood Pressure Over Time on the Effectiveness
of Valsartan in the Valsartan Heart Failure Trial
Inder S. Anand, Thomas S. Rector, Michael Kuskowski, Sabu Thomas, N.J. Holwerda and Jay
N. Cohn
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Circ Heart Fail. 2008;1:34-42
doi: 10.1161/CIRCHEARTFAILURE.107.736975
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Copyright © 2008 American Heart Association, Inc. All rights reserved.
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