Association of systolic blood pressure with mortality in patients with heart failure with reduced ejection fraction: A complex

relationship
Sameer Ather, MD, a Wenyaw Chan, PhD, b Annirudha Chillar, MD, c David Aguilar, MD, a Allison M. Pritchett, MD, a,d Kumudha Ramasubbu, MD, a,e Xander H. T. Wehrens, MD, PhD, FHRS, a Anita Deswal, MD, MPH, a,e,f and Biykem Bozkurt, MD, PhD, FACC, FAHA a,e,f Houston, TX

Background In ambulatory patients with heart failure with reduced ejection fraction (HFrEF), high systolic blood pressure (SBP) is associated with better outcomes. However, it is not known whether there is a ceiling beyond which high SBP has a detrimental effect. Thus, our aim was to assess the linearity of association between SBP and mortality. Methods We used the External Peer Review Program (EPRP) and Digitalis Investigation Group (DIG) trial databases of HFrEF patients. Linearity of association of SBP with mortality was assessed by plotting Martingale residuals against SBP. To assess the patterns of relationship of SBP with mortality, we used restricted cubic spline analysis with Cox proportional hazards model. Results In patients with mild-to-moderate left ventricular systolic dysfunction (LVSD) (30% LVEF b 50%), SBP had a nonlinear association with mortality in both EPRP (n = 3,693) and DIG (n = 3,263) databases. In these patients, SBP had a significant U-shaped association with mortality in EPRP and a trend toward U-shaped relationship in DIG database. In patients with severe LVSD (LVEF b30%), SBP had a linear association with mortality in both EPRP (n = 2,906) and DIG (n = 3,537) databases, with lower SBP being associated with increased mortality. Conclusions Systolic blood pressure has a complex nonlinear association with mortality in patients with heart failure. Whereas it has a U-shaped association in patients with mild-to-moderate LVSD, it has a linear association with mortality in patients with severe LVSD. Recognition of this pattern of association of blood pressure profile may help clinicians in providing better care for their patients and help improve existing prediction models. (Am Heart J 2011;161:567-73.)

The relationship of systolic blood pressure (SBP) with long-term outcomes in patients with heart failure with reduced ejection fraction (HFrEF) is complex. Although, hypertension is associated with development of incident HFrEF,1-5 once the HFrEF is established, it has a protective survival effect.6-14 Advanced HFrEF is usually associated with low SBP, and the ability to generate high SBP in severe HFrEF patients is accepted as an indicator of a relatively preserved pump function in the presence of appropriate peripheral compensation.

From the aBaylor College of Medicine, Houston, TX, bUniversity of Texas School of Public Health, Houston, TX, cUniversity of Houston, Houston, TX, dBen Taub General Hospital, Houston, TX, eMichael E. DeBakey Veterans Affairs Medical Center, Houston, TX, and f Winters Center for Heart Failure Research, Houston, TX. Submitted October 5, 2010; accepted December 6, 2010. Reprint requests: Biykem Bozkurt, MD, PhD, FACC, FAHA, Division of Cardiology, Department of Medicine; Winter's Center for Heart Failure, Cardiology 3C-310 F, Michael E. DeBakey VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail: bbozkurt@bcm.edu 0002-8703/$ - see front matter 2011, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2010.12.009

Accordingly, SBP is used as one of the parameters for prediction of survival in patients with established HFrEF. Every 10-mm Hg rise in SBP has been shown to be associated with a 13% reduction in mortality.15 This model, however, assumes a continuous linear inverse protective relationship of SBP with mortality and does not account for a potential increased risk at higher SBP.15 Although Lee et al16 recently identified a U-shaped relationship between discharge SBP and long-term mortality in patients with acute decompensated heart failure (HF), data on such an association in stable chronic HF are lacking. We hypothesized that there is a range of SBP associated with better survival in HFrEF patients and that an SBP above or below this range will be associated with worse outcomes in this population. We further hypothesized that this relationship is different with varying degrees of left ventricular systolic dysfunction (LVSD). Thus, our aims were to assess the linearity of association between SBP and mortality and the profile of the relationship of SBP with mortality and to examine the patterns of association in different degrees of LVSD.

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Methods
Patient cohort External Peer Review Program (EPRP) database.
We performed a retrospective study of a national cohort of veterans with HFrEF treated in ambulatory clinics at Veterans Affairs medical centers using the Veteran Affairs EPRP data between October 2000 and September 2002 (n = 6,608), as described previously.17,18 This database contained qualitative left ventricular (LV) function assessments of mild-to-moderate (30% LVEF b 50%) or severe LV systolic dysfunction (LVEF b 30%), and not specific LVEF measurements. Only patients for whom LVEF was determined to be b50% within 1 year before or 3 months after the clinic visit were included. Four patients were excluded due to missing SBP value, and 5 patients were excluded due to missing outcomes. For variables with b20% missing values, imputation procedures were applied, and variables with missing values of more than 20% were excluded from the analyses. Missing values for serum sodium (6.1%), hemoglobin (15.9%), and blood urea nitrogen (7.8%) were imputed. For these continuous variables, the missing values were imputed using linear regression with baseline variables as predictors and constraints applied based on observed minimum and maximum values. All analyses were also repeated by excluding observations with imputed values, and the results were found to be concordant. Thus, results using imputed data are shown. Digitalis Investigation Group (DIG) database. The database used for this study was a public-use copy of the main DIG study from the National Heart, Lung, and Blood Institute (NHLBI) (Bethesda, MD). The main DIG study recruited patients from February 1991 through September 1993 to test the effects of effects of digoxin on mortality and hospitalization in patients with HFrEF (LVEF 45%).19 Of note, the DIG trial did not exclude patients based on their blood pressure profile, although patients with acute HF were excluded.19 Three patients with missing SBP values were excluded from the analyses. None of the other variables had missing values N0.3% that were addressed as described above. For categorical variables, categories were imputed based on the predicted probability of occurrence of a particular level generated from logistic regression.

variable; age; BMI; duration of HF; cardiothoracic index; diastolic blood pressure; gender; New York Heart Association (NYHA) class; presence or absence of edema, third heart sound, congestion on x-ray, and DM; and use of potassium-sparing diuretics such as spironolactone, nonpotassium-sparing diuretics, nitrates, and hydralazine. Clinically significant variables (SBP, etiology of HFrEF, and use of ACEIs/ARBs) were forced into the model. Data on the use of cardiac resynchronization therapy and or implantable cardioverter defibrillator were not available in either of the databases.

Statistical analyses
Survival analyses were done using Cox PH model with all the covariates described above for the end point of all-cause mortality. Both accelerated failure time models and PH model were assessed, and PH model was found to have a better fit, which has been used throughout the article. Nonlinearity in the relationship between the log hazard and SBP was assessed by plotting Martingale residuals against SBP. Fractional polynomial curve fitting was done for the plot, and nonlinearity was described as 95% CI not overlapping 0. To evaluate the functional form of the SBP effect on the log hazard of mortality, restricted cubic spline analysis for Cox PH model was performed with all the covariates, using knots at the 5th, 25th, 50th, 75th, and 95th percentiles of SBP.20 Continuous variables are reported using mean SD. Continuous variables were compared using t test, and categorical variables were compared using 2 test. A 2-sided P value less than .05 for comparisons was considered statistically significant. All analyses were performed using SAS statistical software version 9.1.3 (SAS Institute, Cary, NC). D.A. is a recipient of a NIH Mentored Career Development Award (5K01-HL092585-02). X.H.T.W. is a W.M. Keck Foundation Distinguished Young Scholar in Medical Research, and is also supported by NIH/NHLBI grants R01-HL089598 and R01HL091947. DA is supported by VA Health Services Research and Development Service grant IIR02-082-1. B.B. is supported by NIH 3U01DE017793 and 9K30RR02229. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.

Covariates EPRP database. Covariates were identified using backward stepwise Cox proportional hazards (PH) analysis with exclusion set at 0.05 for the end point of all-cause mortality. Significant factors included LVSD, categorized as mild-tomoderate (30% LVEF b 50%) and severe systolic dysfunction (LVEF b30%); age; body mass index (BMI); SBP; hemoglobin level; serum blood urea nitrogen levels; and serum sodium levels; presence or absence of peripheral arterial disease, cerebrovascular accident, metastatic cancer, dementia, past hospitalization for HF, chronic obstructive pulmonary disease, diabetes mellitus (DM); and use of -blockers, angiotensin converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and statins. Clinically significant variables (gender and history of myocardial infarction) were forced into the model. DIG database. Covariates were identified as described above. Significant factors included LVEF as a continuous

Results
Patient characteristics The baseline demographic, laboratory characteristics, and comorbidities of the patients with HFrEF in the EPRP database are summarized in Table I. The follow-up duration was 631 201 days. All-cause mortality was 25% in the overall group, which was significantly higher in patients with severe LVSD (29%), in comparison with patients with mild-to-moderate LVSD (23%; P b .001). Most of the baseline parameters were different between the 2 groups as detailed in Table I. The baseline demographic, laboratory characteristics, and comorbidities of the patients with HFrEF in the DIG database are summarized in Table II. The follow-up duration was 1,064 455 days. All-cause mortality was

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Table I. Baseline profile of patients in the EPRP database

Mild-to-moderate LVSD (n = 3,693) Age (y) Male (%) SBP BMI (kg/m2) DM (%) History of MI (%) COPD (%) PAD (%) CVA (%) Past HF hospitalization (%) Dementia (%) Metastatic cancer (%) BUN (mg/dL) -Blockers (%) Hemoglobin (g/dL) Serum sodium (mEq/L) ACEI/ARB (%) Statins (%) 70.4 10.0 95.5 127.8 20.8 29.3 6.1 42.1 40 29.3 28.1 21.1 19.5 3.0 1.4 26.2 14.8 64.6 13.3 1.9 139.2 3.3 82.6 64.6 Severe LVSD (n = 2,906) 68.4 10.6 97.6 120.4 20.3 27.6 5.5 37.3 41 23.2 27.5 21.5 27.2 2.1 1.6 26.7 14.4 65.1 13.5 1.9 138.8 3.7 89.3 65.1 P b.001 b.001 b.001 b.001 b.001 .42 b.001 .58 .74 b.001 .03 .68 .19 .69 b.001 b.001 b.001 .68

Data are represented as mean SD for continuous variables and as percentage for categorical variables. MI, Myocardial infarction; COPD, chronic obstructive pulmonary disease; PAD, peripheral arterial disease; CVA, cerebrovascular accident; BUN, blood urea nitrogen.

Table II. Baseline characteristics in DIG database

Mild-to-moderate LVSD (n = 3,263) Age (y) Male (%) EF (%) Duration of HFrEF (m) SBP (mm Hg) DBP (mm Hg) BMI (kg/m2) DM (%) Edema (%) Third heart sound (%) Congestion on x-ray (%) Cardiothoracic index NYHA class Ischemic etiology (%) ACEI/ARB (%) Potassium-sparing diuretics (%) Nonpotassium-sparing diuretics (%) Nitrates (%) Hydralazine (%) 64.0 73.7 36.2 4.6 29.5 37.3 129.4 19.9 75. 6 11.0 27.4 5.3 29.3 18.8 20.2 11.5 0.52 0.07 2.1 0.7 73.2 93.3 7.7 73.7 41.8 2.1 Severe LVSD (n = 3,537) 63.0 81.3 21.5 5.2 30.8 36.4 122.5 19.4 74.3 11.4 26.8 5.1 27.6 21.1 30.7 17.9 0.54 0.07 2.3 0.7 68.6 95.5 7.5 82.6 43.4 2.1 P .001 b.001 b.001 .13 b.001 b.001 b.001 .13 .02 b.001 b.001 b.001 b.001 b.001 b.001 .82 b.001 .18 .93

Data are represented as mean SD for continuous variables and as percentage for categorical variables. EF, Ejection fraction; DBP, diastolic blood pressure.

35% in the overall group, which was significantly higher in patients with severe LVSD (41.9%), in comparison with patients with mild-to-moderate LVSD (27.4%; P b .001). Most of the baseline parameters were different between the 2 groups as detailed in Table II.

Effect of SBP on survival in patients with mild-to-moderate LVSD In the EPRP database, SBP was found to have a nonlinear association with all-cause mortality both at

lower and upper ranges of SBP. On restricted cubic spline analysis adjusted for covariates, SBP was found to have a significant U-shaped association with all-cause mortality (Figure 1, A). The lowest morality was found at around 130 mm Hg, which increased significantly both below 120 and above 150 mm Hg. Based on the spline curves, we divided the database into 4 groups: SBP b 110 mm Hg, 110 mm Hg SBP b 130 mm Hg, 130 mm Hg SBP b150, and SBP 150 mm Hg. Based on Martingale plots, we found that SBP was linearly associated with the log hazard of all-cause mortality in each of the 4 subgroups.

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Figure 1

Figure 2

Restricted cubic spline analysis for Cox PH model, in patients with heart failure with mild-to-moderate LVSD, showing significantly increased all-cause mortality for SBP below 120 mm Hg and above 150 mm Hg in EPRP database (A) and significantly increased mortality for SBP below 110 mm Hg and a nonsignificant increase above 150 mm Hg in DIG trial (B). Solid line represents the estimated logarithmic hazard ratio of all-cause mortality with 95% point-wise confidence band represented by broken lines.

Restricted cubic spline analysis for Cox PH model, in patients with HF with severe LVSD, showing a relatively linear association of SBP with all-cause mortality in EPRP database (A) and DIG trial (B). Solid line represents the estimated logarithmic hazard ratio of all-cause mortality with 95% point-wise confidence band represented by broken lines.

In the DIG database, SBP was found to have a nonlinear association with all-cause mortality at the lower range of SBP but not at the upper range of SBP. On restricted cubic spline analysis, SBP was found to have a significantly increased mortality at pressures below 110 mm Hg but only a trend toward an increase at pressures above 150 mm Hg (Figure 1, B). Based on the spline curves, we divided the database into 3 groups: SBP b 110 mm Hg, 110 mm Hg SBP b 140 mm Hg, and SBP 140 mm Hg. Based on Martingale plots, we found that SBP was linearly associated with the log hazard of all-cause mortality in the second and third subgroups, but in the first subgroup, there was a nonlinear association of SBP with all-cause mortality below 90 mm Hg. When the analyses were repeated with further subcategorization of the mild/moderate LVSD into 2 groups of patients with mild LVSD (LVEF 40%) and moderate LVSD (40% N LVEF 30%), the U-shaped profile of the

association of SBP with mortality in these subgroups (ie, patients with mild or moderate LV systolic dysfunction) remained similar to the overall mild/moderate LV systolic dysfunction group. However, this relationship did not reach significance by restricted cubic spline analysis or by Martingale plots.

Effect of SBP on survival in patients with severe LVSD In both the databases, SBP was found to have a linear association with all-cause mortality throughout the range. This was also confirmed by restricted cubic spline analysis, where SBP was found to have a linear association, with lower SBP being associated with worse mortality in both databases (Figure 2). In the EPRP database, SBP had a linear association with mortality at SBP b 120 mm Hg and SBP N 140 mm Hg, with no association with mortality between 120 and 140 mm Hg.

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Discussion
This study shows that in ambulatory HFrEF patients with mild-to-moderate LVSD, SBP had a nonlinear relationship with mortality. The lowest mortality was in the SBP range of 130 to 140 mm Hg, with a significantly increased mortality in patients with SBP below 110 mm Hg. In the more recent EPRP database, there was a significantly increased mortality above 150 mm Hg, whereas in the DIG database, there was only a trend toward increased mortality at similar SBP range. On the other hand, in HFrEF patients with severe LVSD, SBP had a linear association with mortality, with higher SBP being associated with better outcomes. Previous studies have shown that in patients with established HFrEF, low SBP is associated with worse outcomes.14,21-30 In a recent meta-analysis, there was a 13% reduction in the mortality for every 10-mm Hg rise in SBP in stable chronic HF patients.6,14,21,22-30 However, there is lack of information whether this relationship is linear or not. Although, a recent study showed that in patients admitted with acute HFrEF, discharge SBP had a U-shaped relationship with long-term mortality,16 such data for chronic HFrEF patients is lacking. In addition, even though Lee et al6 demonstrated that SBP has a significant nonlinear association with mortality, this study did not address the characteristics or shape of this nonlinearity. Also, in some of these studies, the inverse relationship of SBP with mortality was demonstrated in patient population with relatively low SBP (which is an established risk factor for higher mortality), rather than normal SBP ranges.2,6,13 The second important finding of our study is that the association of SBP with mortality varies with the severity of LVSD. We found a U-shaped relationship of SBP with mortality in patients with mild-to-moderate LVSD. In contrast, in patients with severe LVSD, higher SBP was associated with decreased mortality throughout the range of SBP. In the absence of any previous literature on the same, our study is the first to reveal different patterns of relationship of SBP with mortality, according to the severity of LVSD. We believe that the U-shaped relationship of SBP with mortality may be potentially attributable to 2 interrelated mechanisms. Whereas, on one hand, hypertension is a well-known risk factor for worse outcomes,31,32 SBP is also dependent on cardiac output, and thus, lower SBP indicates pump failure or poor contractile reserve in the setting of decompensated or advanced LVSD. In severe LVSD, the second factor may be more dominant resulting in higher SBP having a protective effect on HF outcomes. On the other hand, in the general population, the first factor is more dominant resulting in higher SBP having a detrimental effect on survival. Mild-to-moderate LVSD straddles both these populations and, as shown by us, has a symmetrical U-shaped relationship of SBP with mortal-

ity. When we examined the subgroups of patients with mild LVSD (LVEF 40%) and moderate LVSD (40% N LVEF 30%) separately, the U-shaped profile of the association of SBP with mortality persisted but did not reach significance probably due to smaller sample size and limited power in these subgroups. With the use of spline analysis, we found that in patients with mild-to-moderate LVSD, the trough of association of SBP with mortality was lower in EPRP database than in DIG trial. Specifically, we found that SBP associated with the lowest mortality in the EPRP database is around 130 mm Hg, whereas in the DIG trial, it was around 140 mm Hg. At the time of the DIG trial,33 -blocker therapy was not widespread, but during the EPRP database collection, more HF patients were being treated with -blockers (Table II). We believe that the addition of -blocker therapy may have affected the optimal SBP range that is associated with survival in patients with HFrEF. We clarify that although this particular range is associated with better prognosis, the goal of this study was not to prove a causal relationship between SBP and mortality and/or define a target for treatment. Our results do emphasize the need for prospective trials addressing safety and efficacy of different SBP targets in patients with HFrEF, with or without hypertension. To improve generalizability of our results, we examined 2 databases. Although, on one hand, DIG trial offered us patients who were prospectively enrolled and underwent close scrutiny during enrollment and follow-up, it represented a historically older HFrEF population enrolled in a clinical trial with certain inclusion and exclusion criteria. In contrast, the EPRP database represents a more recent HFrEF population, examining real world and not clinical trial patients, including all ranges of comorbidities and renal function. However, this database also has the limitations of representing a predominantly male veteran population and data compilation by chart review. Importantly, in both the EPRP database and DIG trial, there were no exclusions based on SBP levels. This offers unique possibilities to explore the effect of SBP on outcomes as the SBP ranged from 74 to 220 mm Hg in DIG trial and from 66 to 214 mm Hg in EPRP database. Many of the HF trials since then have excluded patients based on their blood pressure profile,34,35 and thus, by using EPRP database and DIG trial, we could explore the relationship of SBP profile with outcomes throughout the range.

Limitations It is important to note that these were post hoc analyses of 2 databases. Our analyses were limited by covariates collected by design in the 2 databases, and residualunmeasured confounding factors may exist. Among the variables significantly associated with mortality in HFrEF,

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we did not have information on important variables such as the -blocker use, diuretic dose, hemoglobin, sodium, BNP levels in DIG database; and NYHA class and specific numeric EF measurements in EPRP database.15 In addition, DIG trial did not document other noncardiac comorbidities, which could have contributed to all-cause mortality. We believe that our results were strengthened by validating our results in the EPRP database, which included noncardiac comorbidities and had -blocker use, hemoglobin levels, and sodium levels that were not available in DIG database. Also, the cutoff for diagnosing HFrEF in the 2 databases was slightly different. Although, this introduces heterogeneity, but by conducting analyses in both the databases separately, we believe that our results are both reproducible and generalizable. Furthermore, spline analysis has an inherent limitation of overfitting the data. Thus, we used 2 large databases to confirm our findings and moreover limited the fitting to 5th and 95th percentiles.

2. 3. 4.

5.

6.

7.

8.

Conclusion
Systolic blood pressure has a complex relationship with outcomes in HFrEF patient that varies with the severity of systolic dysfunction. Specifically, SBP has a U-shaped association with mortality in mild-to-moderate LVSD patients, with better outcomes in the range of 130 to 140 mm Hg. On the other hand, in severe LVSD patients, SBP has a relatively linear association with mortality with higher SBP portending better prognosis. Identification of these patterns of association of SBP with mortality may help in better prognostication and management of these patients.
9.

10.

11.

12. 13.

Acknowledgements
The Digitalis Investigation Group (DIG) study is conducted and supported by the NHLBI in collaboration with the DIG Investigators. This manuscript was not prepared in collaboration with investigators of the DIG, and the views expressed in this article are those of the authors and do not necessarily reflect the opinions or views of the DIG, NHLBI, or Department of Veteran Affairs. The authors thank the Office of Quality and Performance of the Veterans Health Administration for Providing External Peer Review Program data and NHLBI for providing the DIG database.

14.

15. 16.

17.

Disclosures
Conflicts of interest: None of the authors have any financial or other relations that could lead to a conflict of interest.

18.

19.

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