Effect of baseline and changes in systolic blood pressure over time on the effectiveness of...

Effect of Baseline and Changes in Systolic Blood PressureOver Time on the Effectiveness of Valsartan in the

Valsartan Heart Failure TrialInder S. Anand, MD, DPhil, FRCP; Thomas S. Rector, PhD; Michael Kuskowski, PhD;

Sabu Thomas, MD; N. J. Holwerda, MD; Jay N. Cohn, MD

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 aimof the present study was to investigate the relationship between the SBP-lowering effects of valsartan and itscardiovascular 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 proportionalhazards regression models that included a test for interaction between the effects of valsartan treatment and baseline SBP andexamined the effects of changes in SBP on the valsartan effect. The mean�SD baseline SBP in all patients (n�5010) was124�18 mm Hg. Patients in the lowest quartile of SBP (SBP �110 mm Hg; mean SBP 102 mm Hg; n�940) had more severeHF 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, 1.22to 1.73; P�0.001) than did patients in the upper 3 quartiles of baseline SBP (mean SBP 130 mm Hg; n�3260). Valsartanreduced 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) andhospitalization for HF (HR, 0.60; 95% CI, 0.45 to 0.79; P�0.001) in the lowest quartile that were not significantly different thanthe 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 HFhospitalization HR, 0.77; 95% CI, 0.64 to 0.93; P�0.006; nonsignificant interactions). The decrease in SBP from baseline to 4months was an independent risk factor for subsequent events. When changes in SBP were added to the regression model, the effectsof 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 reducedSBP but not in the high-risk group of patients who had a baseline SBP �110 mm Hg. The beneficial effects of valsartandid not vary significantly with baseline SBP, and decreases in SBP did not counteract the beneficial effects on HFmorbidity rates. (Circ Heart Fail. 2008;1:34-42.)

Key Words: heart failure � blood pressure � clinical trial � valsartan � outcomes

High blood pressure increases the risk of death in the generalpopulation,1,2 and hypertension is the most important

population-attributable risk factor for the development of heartfailure (HF).3,4 The benefits of treating hypertension on risks ofmajor cardiovascular events are well established in the absenceof systolic HF, and effective lowering of blood pressure isassociated with an �50% reduction in the incidence of HF.5,6

Once HF develops, however, lower blood pressure becomes arisk factor for increased mortality and morbidity rates both inacute decompensated7,8 and chronic HF.9–11 The risk associatedwith elevated blood pressure in patients with systolic dysfunc-tion has not been established. Vasodilators used in the treatment

of hypertension, such as angiotensin-converting enzyme inhibi-tors, angiotensin receptor blockers, and a combination of hydral-azine and isosorbide, are also effective in reducing mortality andmorbidity rates in patients with HF.12–17 Whether the beneficialeffects of these medications on morbidity and mortality rates inpatients with HF are modified by initially low or drops in bloodpressure is an important clinical issue.

Clinical Perspective p 42The present study is a secondary analysis of the Valsartan

Heart Failure Trial (Val-HeFT) database to study the effectsof 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

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time on the effectiveness of treatment with valsartan onmorbidity and mortality in patients with moderate to severeHF. First, we sought to confirm that both lower baselinesystolic blood pressure (SBP) and a decrease in SBP overtime were independently associated with an increased risk ofmorbidity and mortality. The interaction between the effectsof valsartan and baseline SBP was then examined, controllingfor several other known prognostic variables. Finally, todetermine whether adjusting for any potentially deleteriousdrops in SBP during treatment would enhance the apparentbeneficial effects of valsartan, we examined how controllingfor changes in SBP affected the beneficial effects ofvalsartan.

MethodsStudy Design and Patient SelectionVal-HeFT was a randomized, placebo-controlled, double-blind, mul-ticenter trial in 5010 men and women with symptomatic HF thatevaluated the efficacy of the angiotensin receptor blocker valsartan.Details of the study design and protocol have been presentedpreviously.17 Briefly, patients over 18 years of age who were instable New York Heart Association class II-IV HF for at least 3months 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 receivingstable pharmacological treatment for HF that could include angio-tensin-converting enzyme inhibitors, �-blockers, digoxin, diuretics,hydralazine, and/or nitrates. Exclusion criteria included a persistentmean standing SBP �90 mm Hg and serum creatinine �2.0 mg/dL.Eligible patients were stratified according to baseline �-blockertherapy and were randomly allocated to receive either oral valsartanor placebo. Treatment with valsartan was initiated at 40 mg twicedaily and the dose was doubled every 2 weeks to reach the targetdose of 160 mg twice daily, provided SBP was �90 mm Hg, therewere no signs or symptoms of hypotension, and increases in serumcreatinine levels did not exceed 50% of the baseline value. Bloodpressure was measured at each visit with a sphygmomanometer after5 minutes of rest in the sitting position. The study had 2 primary endpoints: death and the first morbid event, which was defined as eitherdeath, sudden death with resuscitation, hospitalization for HF, oradministration of intravenous inotropic or vasodilatory drugs for �4hours without hospitalization. Hospitalization for HF was a second-ary end point.

Data AnalysisBaseline variables grouped by quartiles of baseline SBP werecompared with ANOVA for continuous variables and �2 tests forcategorical variables. Time to events in various groups were de-scribed with Kaplan-Meier curves. Cox proportional-hazards regres-sion models were used to assess the association between time todeath from any cause and baseline SBP, changes in SBP during thefirst 4 months of follow-up, and treatment with valsartan. BaselineSBP values were grouped into quartiles to examine whether baselineSBP was linearly related to the mortality and hospitalization hazardsand to examine the effects of valsartan on SBP. The quartile analysissuggested that the relationships between baseline SBP and hazardswere not linear, as most of the increased risk was seen in the lowestquartile (quartile 1 [Q1]: SBP �110 mm Hg). Rather than trying tomodel a continuous nonlinear relationship, all further analyses weresimply carried out comparing Q1 with the other 3 quartiles (Q2, Q3,and Q4) combined. Analyses were repeated using time to firstmorbid event and first hospitalization for HF as the dependentvariable. All of the regression models included baseline age, NewYork Heart Association class, ischemic etiology, history of hyper-tension, diabetes, body mass index, pulse, LV ejection fraction,serum sodium, creatinine, uric acid, brain natriuretic peptide, aldo-sterone, plasma renin activity, hemoglobin, and use of angiotensin-

converting enzyme inhibitors, diuretics, digoxin, and �-blockers ascovariates. When change in blood pressure over the first 4 monthswas included in the models, all subjects with fatal (n�154) ornonfatal events (n�332) that occurred during the first 4 months offollow-up were excluded. The changes in SBP from baseline tomonth 4, month 12, and end of study in the 2 treatment groups werecompared at each time point with a 2-sample t test rather thanANOVA to minimize loss of information over time due to deaths andcensored follow-up. SPSS statistical software (version 15; SPSS Inc,Chicago, Ill) was used for all analyses. A probability value �0.05was considered significant without adjustment for making multiplecomparisons.

The authors had full access to and take full responsibility for theintegrity of the data. All authors have read and agree to themanuscript as written.

ResultsPatient CharacteristicsThe baseline blood pressure (mean�standard deviation) inthe overall population was 124�18 mm Hg systolic and76�11 mm Hg diastolic (n�5010). Comparison of SBPquartiles in Table 1 indicates that lower SBP was associatedwith younger age, lower body mass index, lower LV ejectionfraction, greater LV internal dimension in diastole, higherlevels of aldosterone and plasma renin activity, and lowerhemoglobin levels. Lower SBP was also associated withworse New York Heart Association class and MinnesotaLiving with Heart Failure Questionnaire (MLHF) scores,along with more prevalent use of diuretics, digoxin, andspironolactone. The mean SBP of 149 mm Hg among thelarge number of patients in Q4 (SBP �135 mm Hg) isremarkable for patients with documented systolic dysfunctionwho were often treated with medications that lower bloodpressure.

Baseline Systolic Blood Pressure Related toMorbidity and MortalityUnadjusted time to death, first morbid event, and hospital-ization for HF within quartiles of baseline SBP are shown inFigure 1. The risks of all events were similar in the upper 3quartiles of SBP and increased only in the Q1, suggesting thatbaseline SBP was not linearly related to the risk (hazard) ofdeath or hospitalization for HF. We did not fit nonlinearmodels to this relationship. The Cox multivariable model forbaseline SBP quartiles is shown in Table 2. With Q3 (patientswith normal SBP) as the reference group, only patients in theQ1 were found to have an increased risk of first morbid eventand hospitalization for HF, with a trend for an increase riskfor death. The upper quartile that contained many patientswith elevated SBP was not associated with increased risk.Given these findings, the upper 3 quartiles were collapsedinto 1 group for further analyses comparing Q1 with Q2, Q3,and Q4 combined. Patients with baseline SBP in the lowestquartile (Q1: �110 mm Hg) had a significantly increasedadjusted risk of death (hazard ratio [HR], 1.21; 95% confi-dence 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 hospitaliza-tion 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 formorbidity and mortality in this patient population.

Anand et al Effect of Blood Pressure on Heart Failure Outcomes 35

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Effect of Baseline Systolic Blood Pressure onEffectiveness of ValsartanIn the overall population, valsartan use was not associatedwith 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 hospital-ization for worsening HF (HR, 0.73; 95% CI, 0.64 to 0.84).17

When the effects of valsartan were estimated separately inpatients with baseline SBP in Q1 and in those with baselineSBP the upper 3 SBP quartiles combined, use of valsartanwas associated with a 26% decrease in risk of first morbidevent in the Q1 patients (HR, 0.74; 95% CI, 0.60 to 0.91;P�0.005), compared with a 10% decrease in the combinedQ2, Q3, and Q4 group (HR, 0.90; 95% CI, 0.79 to 1.02;

Table 1. Baseline Characteristics by Quartile of SBP

Quartile 1 Quartile 2 Quartile 3 Quartile 4 Quartiles 2, 3, and 4 Combined

No. 1156 1304 1323 1227 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

NYHA III/IV† 44 39 34 36 36§

MLHFQ† 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

Weight, kg 79�15 79�15 80�16 79�15 79�15

BMI, kg/m2† 26.4�4.6 26.8�4.4 27.2�4.5 27.2�4.4 27�4§

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† 29 28 24 23 25§

LVEF§ 25�8 26�7 27�7 28�7 27�7§

LVIDd/BSA§ 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 4§

Hemoglobin, g/dL* 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§

Values are expressed as mean�SD or %. DBP indicates diastolic blood pressure; NYHA, New York Heart Association functionalclass; 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 internaldimension in diastole; BSA, body surface area; ACE, angiotensin-converting enzyme; CRP, C-reactive protein; BNP, brain natriureticpeptide; and PRA, plasma renin activity.

*P�0.05, †P�0.001 for differences between quartiles.‡P�0.05, §P�0.01 between Q1 and Q2, Q3, and Q4 combined.

36 Circ Heart Fail May 2008



P�0.10). The test for interaction between the effects ofvalsartan treatment and baseline SBP was not significant,however, as shown in Table 3. Similarly, valsartan caused a40% decrease in risk of first hospitalization for HF in Q1patients (HR, 0.60; 95% CI, 0.45 to 0.79, P�0.001) and a23% decrease in patients in the upper 3 quartiles (HR, 0.77;95% CI, 0.64 to 0.93; P�0.006), with interaction that wasagain not significant.

Effect of Valsartan on Systolic Blood PressureOverall, treatment with valsartan caused a significant placebocorrected 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 SBPat 4 months with valsartan by quartiles of baseline SBP isshown in Table 4. Treatment with valsartan did not lowerSBP in Q1 (�110 mm Hg). In fact, the mean SBP increasedin both the placebo and valsartan groups as one might expectwith regression to the mean. However, the increase in SBP inQ1 was significantly greater in the placebo group (P�0.001).In contrast to the lowest baseline SBP quartile, SBP fell in theother 3 combined quartiles in both treatment groups at 4months, with a significantly greater decrease in the valsartangroup. Because the use of valsartan in patients with extremelylow SBP may be a concern to the clinicians, we alsocompared the response to valsartan with the response toplacebo in 317 patients whose baseline SBP was�100 mm Hg (valsartan group mean SBP 95�3 mm Hg,n�170; placebo group mean SBP 95�3 mm Hg, n�147). Inthis group as well, SBP increased in both the valsartan(5�13 mm Hg) and placebo (8�12 mm Hg) groups, and theincrease was significantly greater in the placebo group (Table 4).

Safety Profile of Valsartan in Patients With LowVersus High Baseline SBPOverall, the mean change from baseline to 4 months wasgreater in the valsartan group than in the placebo group forblood urea nitrogen (1.4�3.6 versus 0.7�2.2 mmol/dLP�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 versusdecrease of 0.06�0.6 mmol/dL, P�0.001). However, theeffect of valsartan on these parameters was similar in low(Q1) and high (Q2, Q3, and Q4) SBP groups (blood ureanitrogen 1.6�4.4 versus 1.4�3.3 mmol/L; creatinine0.12�0.28 versus 0.10�0.24 mmol/dL; and potassium0.7�0.6 versus 0.12�0.7 mmol/L; all P�not significant).More patients discontinued the randomized treatment becauseof hypotension in Q1 (2.9% in valsartan group versus 1.4% inplacebo group; P�0.001) than in the other quartiles com-bined (0.7% in valsartan group versus 0.2% in placebo group;P�0.001).

Changes in Systolic Blood Pressure Related toMorbidity and MortalityWhen the change in SBP over the first 4 months was analyzedas a continuous variable in a multivariable Cox regressionmodel ignoring treatment, a 1-mm Hg increase in SBP wasassociated with a significant decrease in the risk of death, firstmorbid event, and hospitalizations for HF in the entirepopulation (Table 5). The interaction between the baselineSBP quartile groups and the change in SBP was not signifi-cant for any end point, suggesting that the beneficial effectassociated with an increase in SBP over time was notdifferent in the 2 groups defined by baseline SBP (Table 5).Thus, both low baseline SBP and a decrease in SBP over timewere associated with an increase in subsequent HF morbidity.

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Time to Death

Figure. Kaplan-Meier curves for time to death, first morbidevent, and hospitalization for HF by quartile of baseline systolicblood pressure.




Effects of Valsartan Treatment Adjusted forChange in Systolic Blood PressureBecause valsartan caused a significant decrease in SBP inbaseline Q2, Q3, and Q4 and a smaller increase in SBP in Q1compared with placebo throughout the study, and because adecrease in SBP was associated with worse outcomes regard-less of baseline SBP, we examined whether controlling forthe change in SBP after 4 months would alter the apparenteffectiveness of valsartan from 4 months to the end offollow-up. When the change in SBP was added to theregression model, the beneficial effects of valsartan on firstmorbid event and hospitalizations for HF tended to increasein Q1, and to a lesser extent in Q2, Q3, and Q4 (Table 6);however, the blood pressure–lowering effect of valsartan didnot deeply undermine its beneficial effects. Furthermore,there was no significant interaction between treatment and

change in blood pressure on any of the outcomes, suggestingthat the effect of valsartan was not greatly modified bychanges in SBP.

DiscussionThe present analysis of Val-HeFT data confirms that low SBPis independently associated with an increase in the risk ofmortality and morbidity in patients with moderate to severechronic HF.7,9–11 The increased risk did not appear to belinear across all levels of baseline SBP and was observedmainly in patients with a SBP in the lowest quartile(�110 mm Hg). A decrease in SBP over time was also foundto increase the subsequent risk of adverse outcomes.

It is noteworthy that approximately 25% of patients in thepresent study, all of whom had documented LV systolicdysfunction and were being treated with a diuretic (84%), an

Table 2. Adjusted Hazard Ratios (95% Confidence Interval) for Mortality, First Morbid Event, and Hospitalizations for HFin Patients Grouped by Baseline SBP

Mean Baseline SBP,Mean�SD No. of Patients

Mortality,HR (95% CI)

First MorbidEvent, HR(95% CI)

Hospitalizationfor HF, HR(95% CI)

SBP Quartiles

Q1: �110 mm Hg 102�5 940 1.12 (0.98 to 1.47) 1.24 (1.05 to 1.45) 1.44 (1.16 to 1.79)

P 0.08 0.01 0.001

Q2: �110 mm Hg and �121 mm Hg 115�4 1110 1.01 (0.82 to 1.23) 0.97 (0.83 to 1.14) 1.01 (0.81 to 1.26)

P 0.96 0.71 0.91

Q3: �121 mm Hg and �135 mm Hg 128�4 1116 Reference group Reference group Reference group

P

Q4: �135 mm Hg 149�11 1034 0.94 (0.76 to 1.16) 0.99 (0.84 to 1.17) 0.95 (0.71 to 1.20)

P 0.58 0.90 0.67

Q1 versus Q2, Q3, and Q4 combined

Q 1 102�6 940 1.21 (1.03 to 1.43) 1.25 (1.10 to �1.4) 1.45 (1.22 to 1.73)

P 0.02 0.001 �0.001

Q2, Q3, and Q4 combined 130�16 3260 Reference group Reference group Reference group

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 ofan angiotensin-converting enzyme inhibitor, diuretics, digoxin, or �-blockers. No. in each groups is for those with all covariates. P values are againstthe reference groups. HR indicates hazard ratio.

Table 3. Effect of Valsartan Versus Placebo on Mortality, First Morbid Event, and Hospitalizations for HF in PatientsGrouped by Baseline SBP

Mean Baseline SBP, mm HgMean�SD No. of Patients

Mortality,HR (95% CI)

First MorbidEvent, HR(95% CI)

Hospitalizationfor HF, HR(95% CI)Placebo Valsartan Placebo Valsartan

Q1 102�5 101�6 474 466 0.82 (0.63 to1.06)

0.74 (0.60 to0.91)

0.60 (0.45 to0.79)

P 0.13 0.005 �0.001

Q2, Q3, and Q4combined

131�16 130�15 1657 1623 1.04 (0.88 to1.23)

0.90 (0.79 to1.02)

0.77 (0.64 to0.93)

P � � � � � � � � � � � � 0.64 0.10 0.006

Interaction P � � � � � � � � � � � � 0.15 0.29 0.36

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 eachgroups is for those with all covariates. HR indicates hazard ratio.




angiotensin-converting enzyme inhibitor (92%), and some-times a �-blocker (35%), still had SBP �135 mm Hg (mean149 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 thestudy. Interestingly, these patients did not have a significantlyincreased risk of adverse events. In the African AmericanHeart Failure Trial (A-HeFT), approximately 25% patientswith systolic dysfunction had similarly elevated blood pres-sure at baseline.12 Similar findings of elevated SBP have also

been reported recently in patients admitted with acute HFfrom the Organized Program To Initiate life-saving treatmentin hospitalized patients with Heart Failure (OPTIMIZE-HF)registry. In this registry, the majority of patients with elevatedSBP had preserved LV function. Although the pathophysiol-ogy of systolic hypertension might be different in patientswith preserved LV systolic function, if elevated SBP iscommon among patients with chronic HF and LV systolicdysfunction and the elevated SBP is not associated withincreased risk of adverse events (although the risk of stroke

Table 4. 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

Quartiles of Baseline Systolic Blood Pressure

Q1: �110 mm Hg

Valsartan 509 101�5 1.2�12 �4.9 (�6.4 to �3.5) †

Placebo 539 102�5 6.1�12

Q2: �110 mm Hg and �121 mm Hg

Valsartan 629 115�4 �2.1�14 �3.2 (�4.8 to �1.7) †

Placebo 574 115�4 1.2�13

Q3: �121 mm Hg and �135 mm Hg

Valsartan 617 128�4 �7.2�15 �5.1 (�6.7 to �3.5) †

Placebo 616 127�4 �2.1�14

Q4: �135 mm Hg

Valsartan 543 149�12 �12.5�18 �3.4 (�5.4 to �1.4) †

Placebo 601 149�11 �9.1�16

Q1 versus Q2�Q3�Q4

Q1

Valsartan 509 101�5 1.2�12.3 �4.9 (�6.4 to �3.5†

Placebo 539 102�5 6.1�11.8

Q2�Q3�Q4

Valsartan 1789 130�16 �7.0�16.2 �3.6 (�4.6 to �2.6) †

Placebo 1791 131�16 �3.4�14.9

SBP � 100 mm Hg

Valsartan 170 95�3 4.7�13 �3.4 (�6.2 to �0.5)*

Placebo 147 95�3 8.0�12.3

Values are expressed as n, mean�SD.*P�0.05, †P�0.01 for change in SBP comparing valsartan to placebo groups.

Table 5. Effect of Change in SBP From Baseline to 4 Months on the Adjusted HRs (95% CIs) for Mortality, First Morbid Event, andHospitalizations 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)

Continuous variable 3897 0.993 (0.988 to 0.999) 0.992 (0.987 to 0.996) 0.989 (0.983 to 0.995)

P 0.024 �0.001 �0.001

Q1 versus Q2 �Q3�Q4

Q1 853 1.0 (0.986 to 1.01) 0.994 (0.983 to 1.004) 0.986 (0.972 to 0.999)

P 0.90 0.23 0.035

Q2 �Q3�Q4 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

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-convertingenzyme inhibitor, diuretics, digoxin, or �-blockers. No. in each groups is for those with all covariates. HR indicates hazard ratio.




could not be assessed), one wonders whether the high SBPshould or could be decreased. This important question needsto be addressed by further research.

Although the beneficial effects of valsartan in reducing thenumber of morbid events over time and of hospitalizations forHF tended to be relatively higher in the patients with thebaseline SBP �110 mm Hg (Q1) as compared with thosewith SBP above 110 mm Hg, statistical test for interactionbetween treatment and baseline SBP did not detect a signif-icant difference in effect in the 2 subgroups. Interestingly,valsartan did not actually decrease SBP in patients with thelowest pretreatment values, including those in Q1 with a SBP�110 mm Hg or even the subgroup with a SBP�100 mm Hg, even though valsartan was associated with asmaller increase in SBP as compared with placebo. Incontrast, valsartan did cause a significant decrease in SBP inpatients with higher baseline SBP that could have potentiallycounteracted its beneficial effects on morbidity rates. How-ever, the present analysis did not indicate that the benefits ofvalsartan depended on baseline SBP or changes in SBPduring the first 4 months of treatment, suggesting dissociationbetween the effects of valsartan on SBP and clinical out-comes. It should be emphasized, however, that these conclu-sions are based on the lack of significance for interaction.Although interaction tests can be useful exploratory tools, thelack of statistical significance for interaction tests may bepartially due to their relatively low power. Thus, any infer-ence based on interaction test results should be made withcaution.

The observation that blood pressure did not actuallydecrease in the group with low initial SBP suggests that theaddition of valsartan was usually well tolerated by patientswith moderate to severe chronic HF. Low SBP blood pressureshould not preclude a trial of these agents that appear tobenefit all patients. Is there a threshold SBP below which theuse of an angiotensin receptor blocker is associated withdeleterious outcomes? Although the present study was notdesigned to address this question, we did find that even in the

small subgroup of 317 patients with a SBP between 90 and100 mm Hg, valsartan appeared to have been well tolerated,on average, without frequent deleterious drops in bloodpressure. Because patients with low initial SBP are at agreater risk of HF morbidity and mortality, and because atrend for greater risk reduction in morbidity was seen withvalsartan for the low SBP patients (even though the riskreduction for HF hospitalization was significant for both lowand high SBP patients), patients with low SBP could beexpected to be more likely to benefit from this treatment.Moreover, the increases in serum creatinine, blood ureanitrogen, and potassium were no different in patients inbaseline SBP Q1 or than those in Q2, Q3, and Q4, suggestingthat introduction of valsartan even in patients with low SBPmay not precipitate major adverse effects. However, a pa-tient’s baseline SBP had to be �90 mm Hg to be eligible forthis clinical trial or for an increase in the dose of the studymedication. Thus, these data cannot address the use orbenefits of valsartan in patients with HF and a SBP less thanthis level.

If low baseline SBP and a decrease in SBP over time areassociated with worse outcomes, how can we explain theapparent dissociation between the blood pressure–loweringeffects of valsartan and clinical outcomes? The fact thatvalsartan did not lower blood pressure in patients with a lowbaseline SBP could be explained by an improvement in thehemodynamics, although these were not measured in thepresent study. In patients with chronic HF, a low strokevolume threatens the arterial blood pressure and leads to abaroreceptor-mediated activation of several vasoconstrictiveneurohormones that help to preserve blood pressure byincreasing arterial impedance.19 The increase in impedance is,however, deleterious to the failing heart and further reducesthe stroke volume, worsening hypotension. Vasodilators suchas sodium nitroprusside reverse the functional abnormalitiesacutely by improving stroke volume and may increase bloodpressure.10,20,21 Thus, the vasodilatory effects of valsartanmight have lowered arterial impedance in patients with the

Table 6. Effect of Controlling for Changes in SBP on the Effect of Valsartan on Mortality, First Morbid Event, andHospitalizations for HF

Placebo VersusValsartan, Mean

Difference inSBP, mm Hg Mortality* First Morbid Event* Hospitalization for HF*

Baseline SBP Q1 (n�853)

Without change in SBP in model 0.82 (0.63 to 1.06) 0.74 (0.60 to 0.91) 0.60 (0.45 to 0.79)

P 0.13 0.005 �0.001

With change in SBP in model �4.9 0.75 (0.54 to 1.03) 0.63 (0.49 to 0.82) 0.52 (0.37 to 0.73)

P 0.08 0.001 �0.001

Baseline SBP Q2�Q3�Q4 (n�3044)

Without change in SBP in model 1.07 (0.87 to 1.29) 0.88 (0.76 to 1.02) 0.75 (0.62 to 0.91)

P 0.48 0.08 0.003

With change in SBP in model �3.6 1.05 (0.86 to 1.28) 0.83 (0.71 to 0.97) 0.69 (0.56 to 0.84)

P 0.65 0.015 �0.001

*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.




lowest SBP who would be expected to have the highestimpedance, thereby increasing the cardiac output and main-taining blood pressure. Over the long term, valsartan use wasassociated with an improvement in LV ejection fraction22 anda decrease in the levels of several neurohormones, includingbrain natriuretic peptide, norepinephrine, and aldosterone.23,24

Thus, the dual effects of lowering impedance (BP-loweringeffect) and improving LV structural remodeling might havecontributed to the beneficial effects of valsartan on hemody-namics and subsequently to reduced morbidity and mortality.

In conclusion, the present secondary analysis of data froma randomized controlled clinical trial suggests that patientswith low systolic blood pressure can benefit from valsartantherapy without an inordinate risk of deleterious hypotension.Patients with low SBP are at least as likely as and perhapsmore likely to benefit from valsartan therapy as those withnormal or high pretreatment blood pressures. Patients withlow blood pressure are at the highest risk and, therefore, havethe greatest need for aggressive therapy. Judicious use ofvalsartan in such patients is more likely to produce benefitthan use in those with higher blood pressures, althoughpatients with low or high SBP appear to benefit. However, thedata were not sufficient to determine whether these findingsare generalizable to patients with SBP well below100 mm Hg. Regardless, blood pressure reduction does notseem to greatly counteract the favorable effects of valsartanon hospitalization for HF and morbidity and cannot be usedas a surrogate for efficacy. Many patients in the presentanalysis had HF, systolic dysfunction, and prescriptions forantihypertensive medications but still had elevated SBP;however, they were not at increased risk of adverse events.Because reductions in SBP tended to be associated withincreased risk, further research is needed to determinewhether the SBP should be reduced in patients with thesecharacteristics and how this might be achieved, if desirable.Finally, it is important to emphasize that findings of thepresent study do not apply to patients with acute decompen-sated HF.

Sources of FundingNovartis Pharmaceutical provided a grant for the study. Resources ofthe Minneapolis VA Medical Center supported this analysis in part.Dr Rector was supported by VA Clinical Science and HealthServices Research & Development Grants 04S-CRCOE-001 andHFP-98-001.

DisclosuresDrs Anand, Holwerda, and Cohn received research grants andhonoraria from Novartis. The other authors report no conflicts.

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CLINICAL PERSPECTIVELowering high blood pressure greatly reduces the incidence of heart failure. In the presence of heart failure with systolicdysfunction, however, low blood pressure and drops in blood pressure are associated with increased risk of hospitalizationand death. Many effective medications that are used for heart failure, including those that decrease angiotensin II, reduceblood pressure, which could reduce their beneficial effects. Concerns about hypotensive effects often limit use of thesemedications. The present secondary analysis of data from the Valsartan Heart Failure trial indicates that neither a lowpretreatment 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 baselineSBP between 90 and 110 mm Hg. Valsartan reduced the risk of hospitalization for heart failure and the first morbid eventin the lowest SBP quartile and the other 3 quartiles. Adjustments for the changes in SBP on therapy did not substantiallyreduce these beneficial effects. Judicious use of valsartan should be considered for patients who present with low SBP andhave the highest risk of hospitalization and death.




N. CohnInder S. Anand, Thomas S. Rector, Michael Kuskowski, Sabu Thomas, N.J. Holwerda and Jay

of Valsartan in the Valsartan Heart Failure TrialEffect of Baseline and Changes in Systolic Blood Pressure Over Time on the Effectiveness

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