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Reverse J-Curve Relationship Between On-Treatment Blood Pressure and Mortality in Patients With Heart Failure
JACC: HEART FAILURE
VOL. 5, NO. 11, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2017.08.015
CLINICAL RESEARCH
Reverse J-Curve Relationship Between On-Treatment Blood Pressure and Mortality in Patients With Heart Failure Sang Eun Lee, MD,a Hae-Young Lee, MD,b Hyun-Jai Cho, MD,b Won-Seok Choe, MD,b Hokon Kim, MS,b Jin-Oh Choi, MD,b Eun-Seok Jeon, MD,c Min-Seok Kim, MD,a Kyung-Kuk Hwang, MD,d Shung Chull Chae, MD,e Sang Hong Baek, MD,f Seok-Min Kang, MD,g Dong-Ju Choi, MD,h Byung-Su Yoo, MD,i Kye Hun Kim, MD,j Myeong-Chan Cho, MD,d Jae-Joong Kim, MD,a Byung-Hee Oh, MDb
ABSTRACT OBJECTIVES This study aimed to assess the relationship between on-treatment blood pressure (BP) and clinical outcomes of patients with heart failure (HF). BACKGROUND Lower BP has been reported to be related to increased mortality in various cardiovascular diseases. The optimal BP level for patients already experiencing HF is contentious. METHODS The Korean Acute Heart Failure registry prospectively enrolled a total of 5,625 consecutive patients hospitalized for acute HF in 10 tertiary university hospitals in Korea between March 2011 and February 2014. Clinical profiles including BP were collected at admission, discharge, and during outpatient follow-up. Mean on-treatment BP was calculated from BP at discharge and at each follow-up visit. We evaluated the effects of mean on-treatment BP on the clinical outcomes of patients. RESULTS Patients were followed up for a median 2.2 years. One-year mortality after discharge was 18.2%. The relationship between on-treatment BP and all-cause mortality followed a reversed J-curve relationship. A nonlinear, multivariable Cox proportional hazard model identified a nadir of systolic and diastolic BPs of 132.4/74.2 mm Hg in patients, for whom the mortality rate was lowest (p < 0.0001). The relationship with increased mortality above and below the reference BP was more definitive for diastolic BP and for HF with a preserved ejection fraction. CONCLUSIONS Systolic and diastolic BPs <130/70 mm Hg at discharge and during follow-up was associated with worse survival in HF patients. These data suggest that the lowest BP possible might not be an optimal target for HF patients. Further studies should establish a proper BP goal in HF patients. (Registry [Prospective Cohort] for Heart Failure in Korea [KorAHF]; NCT01389843) (J Am Coll Cardiol HF 2017;5:810–9) © 2017 by the American College of Cardiology Foundation.
From the aDepartment of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; b
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; cSungkyunkwan University College of
Medicine, Seoul, South Korea; dChungbuk National University College of Medicine, Cheongju, South Korea; eKyungpook National University College of Medicine, Daegu, South Korea; fThe Catholic University of Korea, Seoul, South Korea; gYonsei University College of Medicine, Seoul, South Korea;
h
Seoul National University Bundang Hospital, Seongnam, South Korea; iYonsei
University Wonju College of Medicine, Wonju, South Korea; and the jHeart Research Center of Chonnam National University, Gwangju, South Korea. This work was supported by grants from Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013-E63003-00, 2013-E63003-01, 2013-E63003-02, 2016-ER6303-00, and 2016-ER6303-01). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 5, 2017; revised manuscript received August 21, 2017, accepted August 21, 2017.
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
H
igh blood pressure (BP) is the single most
10 tertiary university hospitals throughout the
ABBREVIATIONS
important modifiable factor for develop-
country were consecutively enrolled from
AND ACRONYMS
ment of heart failure (HF) (1–4). Clinical
March 2011 to February 2014. Among these AA = aldosterone antagonist
trials have shown that treatment of hypertension re-
patients,
duces the risk of HF by approximately 50% (5,6). How-
without heart transplantation in this analysis,
ever, the effect of BP levels on the prognosis of
and those with malignancy and infiltrative
patients with HF is unclear. In several observational
disease were excluded. Information on pa-
studies, lower BP at baseline for both acute and
tient demographics, medical history, signs
chronic HF was related to higher mortality (7–13),
and symptoms, results of laboratory tests,
blocker
whereas higher BP was also related to higher mortality
electrocardiographic results, echocardiogra-
BB = beta-blocker
in other studies (10,14). Yet, initiation and continua-
phy results, medications, procedures, and
BP = blood pressure
tion
outcomes
of
811
Blood Pressure and Long-Term Mortality in Heart Failure
neurohormonal
blockade,
including
we
included
were
those
collected
at
discharged
admission,
angiotensin-converting enzyme inhibitors (ACEIs),
discharge, and during follow-up (30 days, 3
angiotensin receptor blockers (ARBs), beta-blockers
and 6 months, 1 to 5 years annually). The pri-
(BBs), or
mary
aldosterone
antagonists
(AAs),
before
outcome
was
all-cause
mortality.
hospital discharge are strongly recommended in HF
The secondary outcome was readmission due
with reduced ejection fraction (HFrEF) according to
to HF aggravation. The study protocol was
current HF guidelines, regardless of the baseline BP
approved
(15,16). No target BP has yet been recommended to
institutional review board at each hospital.
adjust the dose of neurohormonal blockade. Rather, the maximal tolerable dose used in randomized controlled trials is recommended. It is generally accepted that there is a J- or U-curve association between BP and mortality, especially among older adults and those with vascular or other diseases (17–19). SEE PAGE 820
However, few studies have robustly investigated the association between on-treatment BP and the clinical outcome of HF. It is unclear whether or in what range of BP a J-curve relationship occurs in patients with HF. Thus, clinicians face a dilemma whether to start or increase neurohormonal blockade in patients with marginally low BP. The situation is more complicated in Korea because Korean patients with acute HF tend to have lower BP during hospitalization compared with other countries, which may lead to less use of neurohormonal blocking agents before discharge (20). We analyzed the relationship between ontreatment BP during follow-up and the long-term mortality of patients to describe whether there is a J-curve relationship in Korean patients with HF.
METHODS
by
STATISTICAL
the
ethics
ANALYSES. BPs
committee/
at admission,
discharge, and at each follow-up (<1, 3, and 6 months, and 1 year) were determined. The differences were tested with a paired Student
ACEI = angiotensin-converting enzyme inhibitor
ANOVA = 1-way analysis of variance model
ARB = angiotensin receptor
DBP = diastolic blood pressure df = degrees of freedom HF = heart failure HFpEF = heart failure with preserved ejection fraction
HFrEF = heart failure with reduced ejection fraction
HR = hazard ratio LV = left ventricle LVEF = left ventricle ejection fraction
SBP = systolic blood pressure
t-test or linear mixed models, and p values were adjusted using the Hochberg method. Average ontreatment BP was calculated from BP at discharge and at each follow-up before the occurrence of an event. BPs were categorized in 10 mm Hg intervals from 90 to 160 mm Hg for systolic BP (SBP) and from 50 to 90 mm Hg for diastolic BP (DBP). Demographic and clinical profiles were compared among the groups using a 1-way analysis of variance model (ANOVA) for continuous variables and chi-square statistics for categorical variables. Trend was tested with ANOVA with contrast for continuous variables and with the Cochran-Armitage trend test for categorical variables. For exploratory purposes, the adjusted hazard ratios (HRs) for each category of BP were estimated with the previous
multivariable
Cox
proportional
hazard
model in reference to the SBP group ($130 to <140 mm Hg) or DBP group ($70 to <80 mm Hg), when the HR was considered to be 1. The variables for adjustment were identified from the multivariable Cox proportional hazard model described in Online
PATIENTS, DATA COLLECTION, AND OUTCOME. The
Tables 1 to 6. The adjusted relationship between on-
KorAHF (Korean Acute Heart Failure) registry is a
treatment BP and clinical outcomes was confirmed
prospective, multicenter cohort study designed to
by a nonlinear Cox proportional hazard model in
describe demographic and clinical profiles, current
which linear and quadratic terms of mean on-
diagnostic approaches and treatments, and short- and
treatment BP measurements were included in the
long-term patient outcomes of acute HF in Korea.
model as the major predictor variable. The nonlinear
Detailed information on the study design and the main
relationships were depicted based on this model with
results are described in our previous papers (20,21).
restricted cubic splines (a SAS macro, SAS Institute,
Briefly, 5,625 patients hospitalized for acute HF from
Cary, North Carolina). Three knots were placed at the
812
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
F I G U R E 1 BP at Admission, Discharge, and Each Follow-Up
(A) Systolic blood pressure (SBP). (B) Diastolic blood pressure (DBP).
1st, 50th, and 99th percentiles (at 86, 117, and 155
Prescription of ACEIs/ARBs were unrelated to SBP
mm Hg for SBP and at 49, 68, and 92 mm Hg for DBP,
categories,
respectively). The variables, which were significant in
prescribed for those with lower SBP, whereas AAs,
the multivariable Cox regression model to predict all-
loop diuretics, and warfarin were prescribed more
cause mortality and considered to be important clin-
often (Table 1, Online Table 7). Patients with lower
ically, were involved in an interaction analysis. The
DBP were older, less likely to be men, and more likely
although
BBs
were
less
frequently
statistical analyses were performed using SAS version
to have a history of HF or atrial fibrillation, but
9.3 (SAS Institute) by professional statisticians affili-
more likely to have ischemic heart disease, lung
ated with the Medical Research Collaborating Center
congestion, left bundle branch block found on an
at the Seoul National University College of Medicine
electrocardiogram, and a lower serum sodium level.
and the Seoul National University Hospital.
Prescriptions of ACEIs/ARBs were unrelated to DBP, although BBs were less frequently prescribed in those
RESULTS
with lower DBP, whereas AAs and loop diuretics were
BP AND PATIENT PROFILES. BP measurements at
ventricular (LV) systolic function measured by ejec-
prescribed more often (Table 2, Online Table 8). Left baseline, at discharge, and at each follow-up (<1, 3,
tion fraction (LVEF) was significantly decreased with
and 6 months, and 1 year) are presented in Figure 1A
lower SBP but was not related to DBP.
for SBP and Figure 1B for DBP. BP dropped signifi-
BP AND CLINICAL OUTCOMES. A total 1,319 deaths
cantly after admission (SBP/DBP 133.0 29.9/79.6
occurred during 9,947 person-years (13,260 deaths
18.6 mm Hg at admission vs. 115.0 17.5/67.2
per 100,000 person-years). A total 1,419 HF read-
11.4 mm Hg at discharge; p < 0.0001) and steadily
missions
increased thereafter. The baseline characteristics of
(16,100 HF readmissions per 100,000 person-years).
the patients by average on-treatment SBP and DBP
Multivariable Cox proportional hazard models were
categories (in 10 mm Hg increments) are listed in
constructed for all-cause mortality and hospital
Tables 1 and 2, respectively. Patients with lower SBP
readmission for HF aggravation, and HRs were
were leaner, less likely to be diabetic, or to have
adjusted for potential confounders (Online Tables 1 to 6).
ischemic heart disease and a history of chronic renal
The relationship between BP and adjusted HRs for all-
failure, but they were more likely to have atrial
cause mortality followed a reversed J-shaped curve
fibrillation, idiopathic dilated cardiomyopathy, and a
with increased HRs at lower and higher BPs (Online
history of HF compared with those with higher SBP.
Figures 1A and 1D, Table 3). The event rate increased
They had lower serum creatinine levels, lower serum
significantly below and above the reference BP range,
sodium levels, and higher plasma hemoglobin levels
except for SBP above the reference BP range. How-
at discharge compared with those with higher SBP.
ever, there was also a trend of increased mortality for
occurred
during
8,814
person-years
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
813
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 1 Baseline Characteristics of the Population by Average On-Treatment SBP Categories
SBP 90 # SBP 100 # SBP 110 # SBP 120 # SBP 130 # SBP 140 # SBP 150 # SBP 160 mm Hg Total <90 mm Hg < 100 mm Hg < 110 mm Hg < 120 mm Hg < 130 mm Hg < 140 mm Hg < 150 mm Hg < 160 mm Hg #SBP (N ¼ 4,487) (n ¼ 102) (n ¼ 437) (n ¼ 922) (n ¼ 1,156) (n ¼ 1,001) (n ¼ 560) (n ¼ 221) (n ¼ 67) (n ¼ 21) p Value*†
p Value‡
Demographics Age (yrs) Male
68 15
62 15
65 15
68 14
69 14
69 14
69 14
69 15
69 16
66 18
<0.0001†
0.2460
2,370 (53)
61 (60)
236 (54)
494 (54)
607 (53)
527 (53)
304 (54)
99 (45)
32 (48)
10 (48)
0.2927*
0.0559
22.4 3.4
22.9 3.6
23.4 3.7
24.0 4.0
24.3 4.3
24.2 4.0
24.5 4.2
Body mass 23.5 3.9 22.0 3.6 index (kg/m2)
25.1 6.4 <0.0001†
0.0211
Comorbidities Hypertension§
2,831 (63)
30 (29)
176 (40)
454 (49)
688 (60)
735 (73)
468 (84)
198 (90)
63 (94)
19 (90)
<0.0001* <0.0001
Diabetes§
1,781 (40)
27 (26)
133 (30)
311 (34)
445 (38)
429 (43)
271 (48)
117 (53)
36 (54)
12 (57)
<0.0001* <0.0001
Previous HF
1,908 (43)
72 (71)
222 (51)
435 (47)
501 (43)
386 (39)
199 (36)
67 (30)
18 (27)
8 (38)
<0.0001* <0.0001
Atrial fibrillation§
2,025 (45)
39 (38)
194 (44)
469 (51)
574 (50)
444 (44)
216 (39)
65 (29)
19 (28)
5 (24)
<0.0001* <0.0001
Chronic renal failure
603 (13)
5 (5)
38 (9)
72 (8)
142 (12)
146 (15)
118 (21)
51 (23)
22 (33)
9 (43)
<0.0001* <0.0001
1,919 (43)
33 (32)
170 (39)
362 (39)
482 (42)
459 (46)
275 (49)
97 (44)
31 (46)
10 (48)
710 (16)
36 (35)
113 (26)
166 (18)
179 (15)
135 (13)
50 (9)
24 (11)
6 (9)
1 (5)
Heart ratek (beats/min)
76 14
79 16
77 14
77 14
76 14
76 14
75 13
75 11
73 13
81 13
0.0053†
0.1375
NYHA functional classk IIIIV
382 (9)
6 (6)
31 (7)
78 (9)
107 (10)
83 (9)
51 (10)
20 (9)
5 (8)
1 (5)
0.8201*
0.3564
Etiology Ischemic CMP Idiopathic DCMP
0.0010* <0.0001 <0.0001* <0.0001
Clinical status
Laboratory tests LBBB
237 (5)
5 (5)
27 (6)
55 (6)
62 (5)
46 (5)
32 (6)
10 (5)
0 (0)
0 (0)
0.4413*
0.0782
LVEF (%)
38 15
31 15
32 15
36 15
38 15
40 16
42 14
42 15
44 14
44 15
<0.0001†
0.0162
Creatininek
1.4 1.4
1.1 0.8
1.1 0.9
1.1 1.0
1.2 1.1
1.4 1.4
1.8 1.7
2.0 2.2
2.3 2.2
Sodiumk
138 4
136 4
137 4
138 4
138 4
138 4
139 4
138 4
137 4
12.2 2.1
11.9 1.9
12.4 2.1
12.4 2.1
12.3 2.1
12.2 2.2
12.0 2.2
11.7 2.3
11.2 2.3
Hemoglobink
2.9 3.0 <0.0001† <0.0001 137 4
<0.0001†
0.0456
11.3 2.1 <0.0001† <0.0001
Management ACEIs/ARBsk
3,201 (71)
74 (73)
314 (72)
640 (69)
803 (69)
728 (73)
412 (74)
167 (76)
46 (69)
17 (81)
0.3247*
0.0817
Beta-blockersk
2,427 (54)
45 (44)
225 (51)
490 (53)
617 (53)
532 (53)
328 (59)
142 (64)
35 (52)
13 (62)
0.0085*
0.0006
AAk
2,154 (48)
74 (73)
287 (66)
521 (57)
554 (48)
424 (42)
203 (36)
73 (33)
14 (21)
4 (19)
<0.0001* <0.0001
Loop diureticsk
3,292 (73)
87 (85)
367 (84)
741 (80)
858 (74)
684 (68)
359 (64)
149 (67)
34 (51)
13 (62)
<0.0001* <0.0001
Values are mean SD or n (%). All SBP measured in mm Hg. *p value by chi-square test. †p value by Kruskal-Wallis test. ‡p value for linear trend test. §Including those first diagnosed at the index admission. kAt discharge. AA ¼ aldosterone antagonists; ACEI ¼ angiotensin converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CMP ¼ cardiomyopathy; DCMP ¼ dilated cardiomyopathy; HF ¼ heart failure; LBBB ¼ left bundle branch block; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure.
SBP above the reference BP range. This nonlinear
BP AND CLINICAL OUTCOMES IN SUBGROUPS. There
relationship was assessed by restricted cubic splines
were 2,581 (59.4%) patients with HFrEF (LVEF #40%)
(Figures 2A and 2D) and was confirmed by a nonlinear
and 1,130 (26.0%) patients with HF with preserved EF
Cox proportional hazard model (chi-square: 49.3;
(HFpEF; LVEF $50%) in our cohort. Their character-
degrees of freedom [df]: 1, p < 0.0001 for SBP; chi-
istics are summarized in Online Table 9. The reverse
square: 30.4; df: 1; p < 0.0001 for DBP). Based on
J-curve relationship was observed in both HFrEF and
the latter model, we identified a nadir of SBP of 132.4
HFpEF for all-cause mortality, with the risk lowest
mm Hg and DBP of 74.2 mm Hg when the event rate
at a SBP/DBP of 136.0/76.6 mm Hg for HFrEF
was the lowest. For readmission for HF aggravation,
(chi-square: 12.1; df: 1; p ¼ 0.0005 for SBP; chi-square:
the HRs followed a nonlinear model for SBP, with a
10.3; df: 1; p ¼ 0.0013 for DBP) (Figures 2B and 2E,
nadir of 143.6 mm Hg (chi-square: 8.1; df: 1; p ¼
Online Figures 1B and 1E, Table 3) and at 127.9/72.7
0.0044) (Figure 3A, Online Figure 2A) and a linear
mm Hg for HFpEF, respectively (chi-square: 32.9,
relationship for DBP, with risks increased with lower
df: 1; p < 0.0001 for SBP; chi-square: 15.7, df: 1;
DBP (chi-square: 5.2; df: 1; p ¼ 0.023) (Figure 3D,
p < 0.0001 for DBP) (Figures 2C and 2F, Online
Online Figure 2D).
Figures 1C and 1F, Table 3). The HR increased
814
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 2 Baseline Characteristics of the Population by Average On-Treatment DBP Categories
Total (N ¼ 4,487)
DBP <50 mm Hg (n ¼ 63)
50 # DBP < 60 mm Hg (n ¼ 661)
60 # DBP < 70 mm Hg (n ¼ 1,948)
70 # DBP < 80 mm Hg (n ¼ 1,319)
80 # DBP < 90 mm Hg (n ¼ 417)
DBP $90 mm Hg (n ¼ 79)
p Value*†
p Value‡
Demographics 68 15
73 16
72 14
69 14
67 14
61 15
58 19
<0.0001†
0.0010
Male
2,370 (53)
26 (41)
308 (47)
1,024 (53)
709 (54)
256 (61)
47 (59)
<0.0001*
<0.0001
Body mass index (m/kg2)
23.5 3.9
20.9 3.6
22.5 3.4
23.2 3.6
23.9 3.9
25.1 4.3
26.3 5.9
<0.0001†
0.3266 <0.0001
Age (yrs)
Comorbidities Hypertension§
2,831 (63)
34 (54)
343 (52)
1,156 (59)
909 (69)
318 (76)
71 (90)
<0.0001*
Diabetes§
1,781 (40)
22 (35)
257 (39)
763 (39)
554 (42)
162 (39)
23 (29)
0.1700*
0.7543
Previous HF
1,908 (43)
35 (56)
328 (50)
877 (45)
505 (38)
141 (34)
22 (28)
<0.0001*
<0.0001
Atrial fibrillation§
2,025 (45)
28 (44)
311 (47)
888 (46)
606 (46)
168 (40)
24 (30)
0.0297*
0.0156
603 (13)
9 (14)
79 (12)
241 (12)
193 (15)
72 (17)
9 (11)
0.0658*
0.0173
1,919 (43)
31 (49)
292 (44)
863 (44)
572 (43)
131 (31)
30 (38)
<0.0001*
0.0002
710 (16)
9 (14)
111 (17)
314 (16)
187 (14)
79 (19)
10 (13)
0.2182*
0.7415
Heart ratek (beats/min)
76 14
73 14
74 14
76 14
76 13
78 14
81 13
<0.0001†
0.2095
NYHA functional classk IIIIV
382 (9)
7 (11)
64 (10)
162 (9)
113 (9)
28 (7)
8 (11)
0.6374*
0.3372
Chronic renal failure Etiology Ischemic CMP Idiopathic DCMP Clinical status
Laboratory tests LBBB
237 (5)
2 (3)
47 (7)
104 (5)
74 (6)
9 (2)
1 (1)
0.0070*
0.0042
LVEF (%)
38 15
37 16
37 16
38 15
39 15
38 16
38 15
0.0758†
0.9888
Creatininek
1.4 1.4
1.3 1.2
1.2 0.9
1.3 1.2
1.5 1.6
1.6 1.7
1.7 2.2
<0.0001†
0.0559
Sodiumk
138 4
138 5
137 4
138 4
138 4
139 4
139 3
<0.0001†
0.0034
12.2 2.1
11.3 1.9
11.8 1.9
12.1 2.0
12.4 2.2
12.9 2.5
13.1 2.5
<0.0001†
0.4595
Hemoglobink Management ACEIs/ARBsk
3,201 (71)
45 (71)
466 (71)
1,392 (71)
945 (72)
294 (71)
59 (75)
0.9719*
0.7166
Beta-blockersk
2,427 (54)
28 (44)
328 (50)
1,034 (53)
735 (56)
254 (61)
48 (61)
0.0018*
<0.0001
AAk
2,154 (48)
30 (48)
379 (57)
989 (51)
571 (43)
158 (38)
27 (34)
<0.0001*
<0.0001
Loop diureticsk
3,292 (73)
46 (73)
541 (82)
1,497 (77)
895 (68)
260 (62)
53 (67)
<0.0001*
<0.0001
Values are mean SD or n (%). All DBPs measured in mm Hg. *p value by chi-square test. †p value by Kruskal-Wallis test. ‡p value for linear trend test. §Including those first diagnosed at the index admission. kAt discharge. DBP ¼ diastolic blood pressure; other abbreviations as in Table 1.
significantly at lower and higher BPs for both SBP
(younger than 70 years) were detected (p for
and DBP in HFpEF. However, in HFrEF, the mortality
interaction ¼ 0.0016) (Online Figure 3).
rate increased significantly only at lower BP, and a trend for an increased mortality rate at a higher
DISCUSSION
SBP was observed. For readmission, the HR followed a nonlinear model only for SBP in HFpEF, with a nadir
ON-TREATMENT BP AND OUTCOME IN PATIENTS
of 127.6 mm Hg (chi-square: 7.3; df: 1; p ¼ 0.0068)
WITH HF. The J-curve phenomenon has been robustly
(Figure 3C, Online Figure 2C, Table 4). Readmission
evaluated in hypertensive patients, patients with
risk increased with lower DBP in HFpEF and with
coronary artery disease or cerebrovascular disease,
lower SBP/DBP in HFrEF (Figures 3B, 3E, and 3F;
and recently in healthy subjects, in whom the
Online Figures 2B, 2E, and 2F, Table 4).
existence of the phenomenon is generally accepted
Interaction analyses revealed no significant effect
(17–19,22). However, it has not been evaluated in HF
heart
patients. The J-curve phenomenon is defined as the
disease, history of HF or chronic lung disease; heart
shape of the relationship between BP and the risk of
rate at discharge, New York Heart Association
cardiovascular morbidity and mortality, which means
functional class at discharge; LVEF, serum creati-
that the risk of cardiovascular events may increase at
nine levels, serum sodium level, or hemoglobin
both too high and too low levels of BP (22). The shape
level at discharge; prescription of BBs, ACEIs/ARBs,
can be that of a J-curve, U-curve, or a reverse J-curve,
AAs,
coronary
depending on where the point of inflection is and
artery bypass graft at index admission. However,
where the risk increases more deeply. However, the
significant
important point in the J-curve phenomenon is not its
modification
or
by
sex,
diuretics
at
interactions
diabetes,
discharge; between
ischemic
and DBP
and
age
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 3 Adjusted Hazard Ratio for All-Cause Mortality According to Blood Pressure
LVEF #40%
Total Population Adjusted HR (95% CI)
p Value
Adjusted HR (95% CI)
LVEF $50% p Value
Adjusted HR (95% CI)
p Value
On-treatment SBP (mm Hg) SBP <90 mm Hg
2.2 (1.6–3.2)
<0.0001
2.0 (1.3–3.1)
0.0014
4.7 (1.9–11.2)
0.0006
SBP $90 to <100 mm Hg
1.7 (1.3–2.1)
<0.0001
1.7 (1.2–2.3)
0.0011
2.1 (1.3–3.4)
0.0032
SBP $100 to <110 mm Hg
1.2 (1.0–1.5)
0.0518
1.3 (1.0–1.7)
0.0969
1.3 (0.9–1.9)
0.2151
SBP $110 to <120 mm Hg
1.0 (0.8–1.2)
0.9604
1.0 (0.8–1.3)
0.9650
1.0 (0.7–1.5)
0.9927 0.6928
SBP $120 to <130 mm Hg
1.0 (0.8–1.2)
0.7026
1.0 (0.7–1.3)
0.9772
0.9 (0.6–1.4)
SBP $130 to <140 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
SBP $140 to <150 mm Hg
1.0 (0.7–1.3)
0.9194
0.6 (0.4–1.0)
0.0683
1.4 (0.8–2.3)
0.2455
SBP $150 to <160 mm Hg
1.3 (0.8–2.1)
0.3268
1.3 (0.6–2.8)
0.4669
1.0 (0.4–2.5)
0.9542
SBP $160 mm Hg
1.4 (0.7–2.9)
0.3240
1.0 (0.3–3.1)
0.9743
2.2 (0.8–6.3)
0.1334
On-treatment DBP (mm Hg) DBP <50 mm Hg
1.6 (1.1–2.3)
0.0100
1.8 (1.2–2.9)
0.0096
1.7 (0.8–3.5)
0.1761
DBP $50 to <60 mm Hg
1.3 (1.1–1.5)
0.0111
1.3 (1.0–1.6)
0.0495
1.6 (1.2–2.2)
0.0054 0.5356
DBP $60 to <70 mm Hg
1.0 (0.9–1.2)
0.9411
1.1 (0.9–1.3)
0.3087
0.9 (0.7–1.2)
DBP $70 to <80 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
DBP $80 to <90 mm Hg
1.1 (0.9–1.4)
0.2909
1.0 (0.7–1.4)
0.9436
1.3 (0.8–2.0)
0.3176
DBP $90 mm Hg
2.0 (1.3–3.1)
0.0031
1.6 (0.8–3.1)
0.2009
2.5 (1.2–5.2)
0.0138
CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.
existence or exact shape, but whether such a point of
high-risk patients, although the population was
inflection occurs within a physiological range of BP
different from ours.
(19). Our study was unique in describing a reverse J-curve association between on-treatment BP and
SYSTOLIC AND DIASTOLIC BP AND OUTCOME IN
long-term mortality in HF patients with a nadir of SBP/
PATIENTS WITH HFrEF AND HFpEF. The association
DBP of 132.4/74.2 mm Hg. This result suggested that
between on-treatment BP and outcomes had several
SBP/DBP <130/70 mm Hg at discharge and during
implications for treatment strategies in HF, which
follow-up was associated with worse survival in HF
might be different from HFrEF to HFpEF. For HFrEF,
patients, and, therefore, the lowest BP possible might
prescribing neurohormonal blockades to reduce the
not be an optimal target for HF patients. The rela-
mortality is necessary. Because patients with HFrEF
tionship between SBP and outcome was more linear
often present with low BP, which is associated with
compared with DBP, especially in HFrEF, whereas the
poor outcomes, there is an important issue of whether
J-curve was more prominent in HFpEF. This might be
there is an optimal BP level so the dose of neurohor-
partially explained because the lower SBP could
monal blockades can be adjusted or whether the
be related to a reduced stroke volume in HFrEF.
maximal tolerable dose should be always pursued,
Several studies examined the association between
as discussed in randomized controlled trials. Previous
BP and outcomes in HF, but their analyses were
post hoc analysis of COPERNICUS (Carvedilol Pro-
mostly limited to baseline BP (10–13), which could
spective
not be extrapolated to the BP level achieved under
CHARM (Candesartan in Heart Failure: Assessment of
treatment. Furthermore, most previous studies were
Reduction in Mortality and Morbidity) trials, as well as
not able to evaluate nonlinearity of the relationship
a recent analysis of the PARADIGM-HF (Prospective
between BP and clinical outcome, and failed to
Comparison
describe a J-point in the relationship, although a few
Neprilysin
of them included follow-up BP achieved under treat-
Converting-Enzyme Inhibitor] to Determine Impact on
ment as well (23,24). Our association between on-
Global Mortality and Morbidity in Heart Failure)
treatment BP and mortality agreed with the recent
trial revealed that the study drugs had benefit even in
analysis by Böhm et al. (25), which described that the
those patients with lower initial SBP (26–28). In the
mean achieved SBP/DBP of <120/70 mm Hg was
post hoc analysis of the PARADIGM-HF trial, the
associated with increased all-cause mortality in
authors also brilliantly adjusted time-updated and
pooled data of large randomized controlled trials with
on-treatment BP. All together, these studies encourage
Randomized
of
ARNI
Inhibitor]
Cumulative
Survival)
[Angiotensin with
ACEI
and
Receptor-
[Angiotensin-
815
816
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
F I G U R E 2 Restricted Cubic Splines Model for All-Cause Mortality According to On-Treatment BP
(A) SBP: all population. (B) SBP: heart failure with reduced ejection fraction (EF). (C) SBP: heart failure with preserved EF. (D) DBP: all population. (E) DBP: heart failure with reduced EF. (F) DBP: heart failure with preserved EF. Abbreviations as in Figure 1.
physicians to not avoid prescribing neurohormonal
manner as those without hypertension, no definitive
blockades for HFrEF patients, even in those with lower
evidence supports controlling BP in patients with HF
BPs. However, apart from the limitations of a post hoc
(15,29). The guidelines are based on evidence that
and explorative analysis, this could not be extrapo-
management of hypertension reduces development
lated to the notion that the maximal tolerable
of HF, but not that such management might improve
dosage of the drugs was more beneficial for HFrEF
the outcome of the patients with HF. In hypertensive
patients even with lower BPs because initiation of
patients, recent evidence suggested that achieving
the drug and up-titration might not be the same at
lower BP targets might carry a better outcome as
all. Whether the highest dose possible and the
validated by the SPRINT (Systolic Blood Pressure
lowest BP thereafter are safe and necessary should be
Intervention Trial) (6). However, no study has
tested.
assessed optimal BP in HFpEF. Our study described a
Because it is not mandatory to prescribe neuro-
J-curve association between on-treatment BP and
hormonal blockades in patients with HFpEF, and
long-term mortality in HFpEF patients with a nadir of
hypertension is one of the important etiologies of
SBP/DBP of 127.9/72.7 mm Hg, with increased mor-
HFpEF, there is an issue of BP control and its optimal
tality above and below the point. This suggested that
target.
the lowest BP possible was not necessarily the
Although
current
guidelines
recommend
treating hypertension in HF patients in the same
optimal target for HFpEF.
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
F I G U R E 3 Restricted Cubic Splines Model for Heart Failure Readmission Due to Heart Failure Aggravation According to On-Treatment BP
(A) SBP: all population. (B) SBP: heart failure with reduced EF. (C) SBP: heart failure with preserved EF. (D) DBP: all population. (E) DBP: heart failure with reduced EF. (F) DBP: heart failure with preserved EF. Abbreviations as in Figures 1 and 2.
POTENTIAL MECHANISM OF
related to poor outcomes, including age, body mass
REVERSE J-CURVE RELATIONSHIP BETWEEN
index, etiology, comorbidities, laboratory tests (e.g.,
ON-TREATMENT BP AND MORTALITY
serum creatinine and serum sodium), LVEF, and even
Low BP could lead to poor tissue perfusion, which
ond, low SBP might only be a marker of poor cardiac
treatments as described in Online Tables 1 to 7. Secresults in further deterioration of cardiac function,
function, which increases mortality (33,34). However,
and, finally, in multiorgan failure. However, the
lower SBP was also a significant predictor of events
J-curve associations do not directly imply a causal
even after adjustment for LV function in terms of
relationship.
noncausal
LVEF. Moreover, lower DBP, which is not directly
mechanisms were proposed to explain the phenome-
related to systolic function, was also a significant
non (19). First, it might be an epiphenomenon of a
predictor of events. Third, lower DBP might be caused
Several
other
potential
more severe and debilitating underlying condition
by increased pulse pressure, reflecting advanced
(30–32). However, we excluded cancer patients and
vascular disease and arterial stiffness, which are
those with infiltrative disease who have poor short-
related to increased mortality (35–38). In our analyses,
term
aggressively
we noticed a reverse J-curve phenomenon for both
adjusted for other potential compounding factors
DBP and SBP; for the latter, the pulse pressure theory
prognosis.
In
addition,
we
817
818
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 4 Adjusted Hazard Ratio for Readmission for Heart Failure Aggravation According to Blood Pressure
LVEF #40%
Total Population Adjusted HR (95% CI)
p Value
Adjusted HR (95% CI)
LVEF $50% p Value
Adjusted HR (95% CI)
p Value
On-treatment SBP (mm Hg) SBP <90 mm Hg
1.8 (1.3–2.6)
0.0012
1.9 (1.2–2.8)
0.0033
1.9 (0.6–6.3)
0.2820
SBP $90 to <100 mm Hg
1.6 (1.3–2.1)
<0.0001
1.6 (1.2–2.1)
0.0036
1.5 (0.9–2.6)
0.1198
SBP $100 to <110 mm Hg
1.3 (1.1–1.7)
0.0056
1.3 (1.0–1.7)
0.0841
1.5 (1.0–2.2)
0.0557
SBP $110 to <120 mm Hg
1.2 (1.0–1.4)
0.1077
1.2 (0.9–1.6)
0.1996
1.0 (0.7–1.5)
0.9560
SBP $120 to <130 mm Hg
1.1 (0.9–1.4)
0.2335
1.3 (1.0–1.7)
0.0900
0.9 (0.6–1.4)
0.6932
SBP $130 to <140 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
SBP $140 to <150 mm Hg
1.0 (0.8–1.4)
0.7752
1.0 (0.6–1.5)
0.8454
1.2 (0.7–2.1)
0.4281
SBP $150 to <160 mm Hg
1.4 (0.9–2.3)
0.1698
1.7 (0.9–3.5)
0.1233
1.3 (0.6–2.8)
0.5003
SBP $160 mm Hg
1.5 (0.6–3.6)
0.3897
2.3 (0.7–7.5)
0.1546
1.3 (0.3–5.6)
0.6886
On-treatment DBP (mm Hg) DBP <50 mm Hg
1.2 (0.8–1.8)
0.4920
1.1 (0.6–2.0)
0.6790
1.2 (0.5–2.8)
0.6711
DBP $50 to <60 mm Hg
1.3 (1.1–1.5)
0.0069
1.2 (1.0–1.5)
0.0937
1.4 (1.0–2.0)
0.0304 0.6364
DBP $60 to <70 mm Hg
1.1 (1.0–1.3)
0.1433
1.2 (1.0–1.4)
0.0789
0.9 (0.7–1.2)
DBP $70 to <80 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
DBP $80 to <90 mm Hg
0.9 (0.7–1.1)
0.2205
0.9 (0.7–1.2)
0.4463
0.8 (0.5–1.4)
0.5034
DBP $90 mm Hg
1.0 (0.6–1.7)
0.9883
1.2 (0.6–2.2)
0.6511
0.7 (0.2–2.2)
0.5255
Abbreviations as in Tables 1 to 3.
would not be applicable. Fourth, hypoperfusion of the
CONCLUSIONS
coronary arteries by low DBP might lead to increased mortality in patients with compromised coronary flow
On-treatment BP and all-cause mortality showed a
reserve, such as those with coronary artery disease
reverse J-curve relationship in patients with HF.
(18,39). However, even after adjustment for ischemic
Lower BP portends an increased risk of readmission
heart disease, or even in a subgroup without ischemic
for HF. Our findings suggested that the lowest BP
heart disease, the relationship persisted, and the same
possible might not be optimal for HF patients. Further
relationship was observed with SBP. Finally, lower BP
studies should establish a proper BP goal in patients
might
with HF.
interrupt
prescription
of
neurohormonal
blocking agents that promote survival. Although this hypothesis is not applicable for HFpEF, the J-curve ADDRESS FOR CORRESPONDENCE: Dr. Hae-Young
was more definitive in HFpEF in our analysis. STUDY LIMITATIONS. Because this was an observa-
tional study, our results did not support a causal relationship between low BP and risk of cardiovascular mortality, and the mechanism by which the J curve occurred. We could not consider all the drug prescriptions during the follow-up. Although our analyses were adjusted for baseline confounders, any unmeasured confounders could have been missed. We also did not adjust our analyses for dosage of antihypertensive
agents
received
(because
of
complexity) or for other confounders (because of lack of data), especially those that were predictors of poor health, socioeconomic status, job stress, or mental health. Finally, issues of multiple comparisons should be considered, because multiple statistical tests were conducted to increase type I error and false positive results.
Lee,
Department
of
Internal
Medicine,
Seoul
National University College of Medicine, 101, Daehak-ro, Jongno-gu,
Seoul
110-744,
South
Korea.
E-mail:
[email protected]. PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Both high and low blood pressure can be deleterious in patients with heart failure. Controlling blood pressure beyond the indication of neurohormonal blockades for heart failure should be cautious. TRANSLATIONAL OUTLOOK: Additional research is needed to determine optimal target blood pressure for patients with heart failure.
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
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30. Hakala SM, Tilvis RS. Determinants and significance of declining blood pressure in old age. A prospective birth cohort study. Eur Heart J 1998; 19:1872–8. 31. Langer RD, Criqui MH, Barrett-Connor EL, Klauber MR, Ganiats TG. Blood pressure change and survival after age 75. Hypertension 1993;22: 551–9. 32. Boutitie F, Gueyffier F, Pocock S, et al. J-shaped relationship between blood pressure and mortality in hypertensive patients: new insights from a meta-analysis of individual-patient data. Ann Intern Med 2002;136:438–48. 33. Tuomilehto J, Ryynanen OP, Koistinen A, Rastenyte D, Nissinen A, Puska P. Low diastolic blood pressure and mortality in a populationbased cohort of 16913 hypertensive patients in North Karelia, Finland. J Hypertens 1998;16: 1235–42. 34. Oakley C. Diagnosis and natural history of congested (dilated) cardiomyopathies. Postgrad Med J 1978;54:440–50. 35. Boutouyrie P, Tropeano AI, Asmar R, et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: a longitudinal study. Hypertension 2002; 39:10–5. 36. Franklin SS, Lopez VA, Wong ND, et al. Single versus combined blood pressure components and risk for cardiovascular disease: the Framingham Heart Study. Circulation 2009;119: 243–50. 37. Vaccarino V, Holford TR, Krumholz HM. Pulse pressure and risk for myocardial infarction and heart failure in the elderly. J Am Coll Cardiol 2000;36:130–8. 38. Benetos A, Thomas F, Safar ME, Bean KE, Guize L. Should diastolic and systolic blood pressure be considered for cardiovascular risk evaluation: a study in middle-aged men and women. J Am Coll Cardiol 2001;37:163–8. 39. Messerli FH, Mancia G, Conti CR, et al. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med 2006;144: 884–93.
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KEY WORDS blood pressure, heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, J-curve, mortality
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A PP END IX For supplemental tables and figures, please see the online version of this paper.
819
VOL. 5, NO. 11, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
ISSN 2213-1779/$36.00 http://dx.doi.org/10.1016/j.jchf.2017.08.015
CLINICAL RESEARCH
Reverse J-Curve Relationship Between On-Treatment Blood Pressure and Mortality in Patients With Heart Failure Sang Eun Lee, MD,a Hae-Young Lee, MD,b Hyun-Jai Cho, MD,b Won-Seok Choe, MD,b Hokon Kim, MS,b Jin-Oh Choi, MD,b Eun-Seok Jeon, MD,c Min-Seok Kim, MD,a Kyung-Kuk Hwang, MD,d Shung Chull Chae, MD,e Sang Hong Baek, MD,f Seok-Min Kang, MD,g Dong-Ju Choi, MD,h Byung-Su Yoo, MD,i Kye Hun Kim, MD,j Myeong-Chan Cho, MD,d Jae-Joong Kim, MD,a Byung-Hee Oh, MDb
ABSTRACT OBJECTIVES This study aimed to assess the relationship between on-treatment blood pressure (BP) and clinical outcomes of patients with heart failure (HF). BACKGROUND Lower BP has been reported to be related to increased mortality in various cardiovascular diseases. The optimal BP level for patients already experiencing HF is contentious. METHODS The Korean Acute Heart Failure registry prospectively enrolled a total of 5,625 consecutive patients hospitalized for acute HF in 10 tertiary university hospitals in Korea between March 2011 and February 2014. Clinical profiles including BP were collected at admission, discharge, and during outpatient follow-up. Mean on-treatment BP was calculated from BP at discharge and at each follow-up visit. We evaluated the effects of mean on-treatment BP on the clinical outcomes of patients. RESULTS Patients were followed up for a median 2.2 years. One-year mortality after discharge was 18.2%. The relationship between on-treatment BP and all-cause mortality followed a reversed J-curve relationship. A nonlinear, multivariable Cox proportional hazard model identified a nadir of systolic and diastolic BPs of 132.4/74.2 mm Hg in patients, for whom the mortality rate was lowest (p < 0.0001). The relationship with increased mortality above and below the reference BP was more definitive for diastolic BP and for HF with a preserved ejection fraction. CONCLUSIONS Systolic and diastolic BPs <130/70 mm Hg at discharge and during follow-up was associated with worse survival in HF patients. These data suggest that the lowest BP possible might not be an optimal target for HF patients. Further studies should establish a proper BP goal in HF patients. (Registry [Prospective Cohort] for Heart Failure in Korea [KorAHF]; NCT01389843) (J Am Coll Cardiol HF 2017;5:810–9) © 2017 by the American College of Cardiology Foundation.
From the aDepartment of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; b
Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; cSungkyunkwan University College of
Medicine, Seoul, South Korea; dChungbuk National University College of Medicine, Cheongju, South Korea; eKyungpook National University College of Medicine, Daegu, South Korea; fThe Catholic University of Korea, Seoul, South Korea; gYonsei University College of Medicine, Seoul, South Korea;
h
Seoul National University Bundang Hospital, Seongnam, South Korea; iYonsei
University Wonju College of Medicine, Wonju, South Korea; and the jHeart Research Center of Chonnam National University, Gwangju, South Korea. This work was supported by grants from Research of Korea Centers for Disease Control and Prevention (2010-E63003-00, 2011-E63002-00, 2012-E63005-00, 2013-E63003-00, 2013-E63003-01, 2013-E63003-02, 2016-ER6303-00, and 2016-ER6303-01). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 5, 2017; revised manuscript received August 21, 2017, accepted August 21, 2017.
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
H
igh blood pressure (BP) is the single most
10 tertiary university hospitals throughout the
ABBREVIATIONS
important modifiable factor for develop-
country were consecutively enrolled from
AND ACRONYMS
ment of heart failure (HF) (1–4). Clinical
March 2011 to February 2014. Among these AA = aldosterone antagonist
trials have shown that treatment of hypertension re-
patients,
duces the risk of HF by approximately 50% (5,6). How-
without heart transplantation in this analysis,
ever, the effect of BP levels on the prognosis of
and those with malignancy and infiltrative
patients with HF is unclear. In several observational
disease were excluded. Information on pa-
studies, lower BP at baseline for both acute and
tient demographics, medical history, signs
chronic HF was related to higher mortality (7–13),
and symptoms, results of laboratory tests,
blocker
whereas higher BP was also related to higher mortality
electrocardiographic results, echocardiogra-
BB = beta-blocker
in other studies (10,14). Yet, initiation and continua-
phy results, medications, procedures, and
BP = blood pressure
tion
outcomes
of
811
Blood Pressure and Long-Term Mortality in Heart Failure
neurohormonal
blockade,
including
we
included
were
those
collected
at
discharged
admission,
angiotensin-converting enzyme inhibitors (ACEIs),
discharge, and during follow-up (30 days, 3
angiotensin receptor blockers (ARBs), beta-blockers
and 6 months, 1 to 5 years annually). The pri-
(BBs), or
mary
aldosterone
antagonists
(AAs),
before
outcome
was
all-cause
mortality.
hospital discharge are strongly recommended in HF
The secondary outcome was readmission due
with reduced ejection fraction (HFrEF) according to
to HF aggravation. The study protocol was
current HF guidelines, regardless of the baseline BP
approved
(15,16). No target BP has yet been recommended to
institutional review board at each hospital.
adjust the dose of neurohormonal blockade. Rather, the maximal tolerable dose used in randomized controlled trials is recommended. It is generally accepted that there is a J- or U-curve association between BP and mortality, especially among older adults and those with vascular or other diseases (17–19). SEE PAGE 820
However, few studies have robustly investigated the association between on-treatment BP and the clinical outcome of HF. It is unclear whether or in what range of BP a J-curve relationship occurs in patients with HF. Thus, clinicians face a dilemma whether to start or increase neurohormonal blockade in patients with marginally low BP. The situation is more complicated in Korea because Korean patients with acute HF tend to have lower BP during hospitalization compared with other countries, which may lead to less use of neurohormonal blocking agents before discharge (20). We analyzed the relationship between ontreatment BP during follow-up and the long-term mortality of patients to describe whether there is a J-curve relationship in Korean patients with HF.
METHODS
by
STATISTICAL
the
ethics
ANALYSES. BPs
committee/
at admission,
discharge, and at each follow-up (<1, 3, and 6 months, and 1 year) were determined. The differences were tested with a paired Student
ACEI = angiotensin-converting enzyme inhibitor
ANOVA = 1-way analysis of variance model
ARB = angiotensin receptor
DBP = diastolic blood pressure df = degrees of freedom HF = heart failure HFpEF = heart failure with preserved ejection fraction
HFrEF = heart failure with reduced ejection fraction
HR = hazard ratio LV = left ventricle LVEF = left ventricle ejection fraction
SBP = systolic blood pressure
t-test or linear mixed models, and p values were adjusted using the Hochberg method. Average ontreatment BP was calculated from BP at discharge and at each follow-up before the occurrence of an event. BPs were categorized in 10 mm Hg intervals from 90 to 160 mm Hg for systolic BP (SBP) and from 50 to 90 mm Hg for diastolic BP (DBP). Demographic and clinical profiles were compared among the groups using a 1-way analysis of variance model (ANOVA) for continuous variables and chi-square statistics for categorical variables. Trend was tested with ANOVA with contrast for continuous variables and with the Cochran-Armitage trend test for categorical variables. For exploratory purposes, the adjusted hazard ratios (HRs) for each category of BP were estimated with the previous
multivariable
Cox
proportional
hazard
model in reference to the SBP group ($130 to <140 mm Hg) or DBP group ($70 to <80 mm Hg), when the HR was considered to be 1. The variables for adjustment were identified from the multivariable Cox proportional hazard model described in Online
PATIENTS, DATA COLLECTION, AND OUTCOME. The
Tables 1 to 6. The adjusted relationship between on-
KorAHF (Korean Acute Heart Failure) registry is a
treatment BP and clinical outcomes was confirmed
prospective, multicenter cohort study designed to
by a nonlinear Cox proportional hazard model in
describe demographic and clinical profiles, current
which linear and quadratic terms of mean on-
diagnostic approaches and treatments, and short- and
treatment BP measurements were included in the
long-term patient outcomes of acute HF in Korea.
model as the major predictor variable. The nonlinear
Detailed information on the study design and the main
relationships were depicted based on this model with
results are described in our previous papers (20,21).
restricted cubic splines (a SAS macro, SAS Institute,
Briefly, 5,625 patients hospitalized for acute HF from
Cary, North Carolina). Three knots were placed at the
812
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
F I G U R E 1 BP at Admission, Discharge, and Each Follow-Up
(A) Systolic blood pressure (SBP). (B) Diastolic blood pressure (DBP).
1st, 50th, and 99th percentiles (at 86, 117, and 155
Prescription of ACEIs/ARBs were unrelated to SBP
mm Hg for SBP and at 49, 68, and 92 mm Hg for DBP,
categories,
respectively). The variables, which were significant in
prescribed for those with lower SBP, whereas AAs,
the multivariable Cox regression model to predict all-
loop diuretics, and warfarin were prescribed more
cause mortality and considered to be important clin-
often (Table 1, Online Table 7). Patients with lower
ically, were involved in an interaction analysis. The
DBP were older, less likely to be men, and more likely
although
BBs
were
less
frequently
statistical analyses were performed using SAS version
to have a history of HF or atrial fibrillation, but
9.3 (SAS Institute) by professional statisticians affili-
more likely to have ischemic heart disease, lung
ated with the Medical Research Collaborating Center
congestion, left bundle branch block found on an
at the Seoul National University College of Medicine
electrocardiogram, and a lower serum sodium level.
and the Seoul National University Hospital.
Prescriptions of ACEIs/ARBs were unrelated to DBP, although BBs were less frequently prescribed in those
RESULTS
with lower DBP, whereas AAs and loop diuretics were
BP AND PATIENT PROFILES. BP measurements at
ventricular (LV) systolic function measured by ejec-
prescribed more often (Table 2, Online Table 8). Left baseline, at discharge, and at each follow-up (<1, 3,
tion fraction (LVEF) was significantly decreased with
and 6 months, and 1 year) are presented in Figure 1A
lower SBP but was not related to DBP.
for SBP and Figure 1B for DBP. BP dropped signifi-
BP AND CLINICAL OUTCOMES. A total 1,319 deaths
cantly after admission (SBP/DBP 133.0 29.9/79.6
occurred during 9,947 person-years (13,260 deaths
18.6 mm Hg at admission vs. 115.0 17.5/67.2
per 100,000 person-years). A total 1,419 HF read-
11.4 mm Hg at discharge; p < 0.0001) and steadily
missions
increased thereafter. The baseline characteristics of
(16,100 HF readmissions per 100,000 person-years).
the patients by average on-treatment SBP and DBP
Multivariable Cox proportional hazard models were
categories (in 10 mm Hg increments) are listed in
constructed for all-cause mortality and hospital
Tables 1 and 2, respectively. Patients with lower SBP
readmission for HF aggravation, and HRs were
were leaner, less likely to be diabetic, or to have
adjusted for potential confounders (Online Tables 1 to 6).
ischemic heart disease and a history of chronic renal
The relationship between BP and adjusted HRs for all-
failure, but they were more likely to have atrial
cause mortality followed a reversed J-shaped curve
fibrillation, idiopathic dilated cardiomyopathy, and a
with increased HRs at lower and higher BPs (Online
history of HF compared with those with higher SBP.
Figures 1A and 1D, Table 3). The event rate increased
They had lower serum creatinine levels, lower serum
significantly below and above the reference BP range,
sodium levels, and higher plasma hemoglobin levels
except for SBP above the reference BP range. How-
at discharge compared with those with higher SBP.
ever, there was also a trend of increased mortality for
occurred
during
8,814
person-years
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
813
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 1 Baseline Characteristics of the Population by Average On-Treatment SBP Categories
SBP 90 # SBP 100 # SBP 110 # SBP 120 # SBP 130 # SBP 140 # SBP 150 # SBP 160 mm Hg Total <90 mm Hg < 100 mm Hg < 110 mm Hg < 120 mm Hg < 130 mm Hg < 140 mm Hg < 150 mm Hg < 160 mm Hg #SBP (N ¼ 4,487) (n ¼ 102) (n ¼ 437) (n ¼ 922) (n ¼ 1,156) (n ¼ 1,001) (n ¼ 560) (n ¼ 221) (n ¼ 67) (n ¼ 21) p Value*†
p Value‡
Demographics Age (yrs) Male
68 15
62 15
65 15
68 14
69 14
69 14
69 14
69 15
69 16
66 18
<0.0001†
0.2460
2,370 (53)
61 (60)
236 (54)
494 (54)
607 (53)
527 (53)
304 (54)
99 (45)
32 (48)
10 (48)
0.2927*
0.0559
22.4 3.4
22.9 3.6
23.4 3.7
24.0 4.0
24.3 4.3
24.2 4.0
24.5 4.2
Body mass 23.5 3.9 22.0 3.6 index (kg/m2)
25.1 6.4 <0.0001†
0.0211
Comorbidities Hypertension§
2,831 (63)
30 (29)
176 (40)
454 (49)
688 (60)
735 (73)
468 (84)
198 (90)
63 (94)
19 (90)
<0.0001* <0.0001
Diabetes§
1,781 (40)
27 (26)
133 (30)
311 (34)
445 (38)
429 (43)
271 (48)
117 (53)
36 (54)
12 (57)
<0.0001* <0.0001
Previous HF
1,908 (43)
72 (71)
222 (51)
435 (47)
501 (43)
386 (39)
199 (36)
67 (30)
18 (27)
8 (38)
<0.0001* <0.0001
Atrial fibrillation§
2,025 (45)
39 (38)
194 (44)
469 (51)
574 (50)
444 (44)
216 (39)
65 (29)
19 (28)
5 (24)
<0.0001* <0.0001
Chronic renal failure
603 (13)
5 (5)
38 (9)
72 (8)
142 (12)
146 (15)
118 (21)
51 (23)
22 (33)
9 (43)
<0.0001* <0.0001
1,919 (43)
33 (32)
170 (39)
362 (39)
482 (42)
459 (46)
275 (49)
97 (44)
31 (46)
10 (48)
710 (16)
36 (35)
113 (26)
166 (18)
179 (15)
135 (13)
50 (9)
24 (11)
6 (9)
1 (5)
Heart ratek (beats/min)
76 14
79 16
77 14
77 14
76 14
76 14
75 13
75 11
73 13
81 13
0.0053†
0.1375
NYHA functional classk IIIIV
382 (9)
6 (6)
31 (7)
78 (9)
107 (10)
83 (9)
51 (10)
20 (9)
5 (8)
1 (5)
0.8201*
0.3564
Etiology Ischemic CMP Idiopathic DCMP
0.0010* <0.0001 <0.0001* <0.0001
Clinical status
Laboratory tests LBBB
237 (5)
5 (5)
27 (6)
55 (6)
62 (5)
46 (5)
32 (6)
10 (5)
0 (0)
0 (0)
0.4413*
0.0782
LVEF (%)
38 15
31 15
32 15
36 15
38 15
40 16
42 14
42 15
44 14
44 15
<0.0001†
0.0162
Creatininek
1.4 1.4
1.1 0.8
1.1 0.9
1.1 1.0
1.2 1.1
1.4 1.4
1.8 1.7
2.0 2.2
2.3 2.2
Sodiumk
138 4
136 4
137 4
138 4
138 4
138 4
139 4
138 4
137 4
12.2 2.1
11.9 1.9
12.4 2.1
12.4 2.1
12.3 2.1
12.2 2.2
12.0 2.2
11.7 2.3
11.2 2.3
Hemoglobink
2.9 3.0 <0.0001† <0.0001 137 4
<0.0001†
0.0456
11.3 2.1 <0.0001† <0.0001
Management ACEIs/ARBsk
3,201 (71)
74 (73)
314 (72)
640 (69)
803 (69)
728 (73)
412 (74)
167 (76)
46 (69)
17 (81)
0.3247*
0.0817
Beta-blockersk
2,427 (54)
45 (44)
225 (51)
490 (53)
617 (53)
532 (53)
328 (59)
142 (64)
35 (52)
13 (62)
0.0085*
0.0006
AAk
2,154 (48)
74 (73)
287 (66)
521 (57)
554 (48)
424 (42)
203 (36)
73 (33)
14 (21)
4 (19)
<0.0001* <0.0001
Loop diureticsk
3,292 (73)
87 (85)
367 (84)
741 (80)
858 (74)
684 (68)
359 (64)
149 (67)
34 (51)
13 (62)
<0.0001* <0.0001
Values are mean SD or n (%). All SBP measured in mm Hg. *p value by chi-square test. †p value by Kruskal-Wallis test. ‡p value for linear trend test. §Including those first diagnosed at the index admission. kAt discharge. AA ¼ aldosterone antagonists; ACEI ¼ angiotensin converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CMP ¼ cardiomyopathy; DCMP ¼ dilated cardiomyopathy; HF ¼ heart failure; LBBB ¼ left bundle branch block; LVEF ¼ left ventricular ejection fraction; NYHA ¼ New York Heart Association; SBP ¼ systolic blood pressure.
SBP above the reference BP range. This nonlinear
BP AND CLINICAL OUTCOMES IN SUBGROUPS. There
relationship was assessed by restricted cubic splines
were 2,581 (59.4%) patients with HFrEF (LVEF #40%)
(Figures 2A and 2D) and was confirmed by a nonlinear
and 1,130 (26.0%) patients with HF with preserved EF
Cox proportional hazard model (chi-square: 49.3;
(HFpEF; LVEF $50%) in our cohort. Their character-
degrees of freedom [df]: 1, p < 0.0001 for SBP; chi-
istics are summarized in Online Table 9. The reverse
square: 30.4; df: 1; p < 0.0001 for DBP). Based on
J-curve relationship was observed in both HFrEF and
the latter model, we identified a nadir of SBP of 132.4
HFpEF for all-cause mortality, with the risk lowest
mm Hg and DBP of 74.2 mm Hg when the event rate
at a SBP/DBP of 136.0/76.6 mm Hg for HFrEF
was the lowest. For readmission for HF aggravation,
(chi-square: 12.1; df: 1; p ¼ 0.0005 for SBP; chi-square:
the HRs followed a nonlinear model for SBP, with a
10.3; df: 1; p ¼ 0.0013 for DBP) (Figures 2B and 2E,
nadir of 143.6 mm Hg (chi-square: 8.1; df: 1; p ¼
Online Figures 1B and 1E, Table 3) and at 127.9/72.7
0.0044) (Figure 3A, Online Figure 2A) and a linear
mm Hg for HFpEF, respectively (chi-square: 32.9,
relationship for DBP, with risks increased with lower
df: 1; p < 0.0001 for SBP; chi-square: 15.7, df: 1;
DBP (chi-square: 5.2; df: 1; p ¼ 0.023) (Figure 3D,
p < 0.0001 for DBP) (Figures 2C and 2F, Online
Online Figure 2D).
Figures 1C and 1F, Table 3). The HR increased
814
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 2 Baseline Characteristics of the Population by Average On-Treatment DBP Categories
Total (N ¼ 4,487)
DBP <50 mm Hg (n ¼ 63)
50 # DBP < 60 mm Hg (n ¼ 661)
60 # DBP < 70 mm Hg (n ¼ 1,948)
70 # DBP < 80 mm Hg (n ¼ 1,319)
80 # DBP < 90 mm Hg (n ¼ 417)
DBP $90 mm Hg (n ¼ 79)
p Value*†
p Value‡
Demographics 68 15
73 16
72 14
69 14
67 14
61 15
58 19
<0.0001†
0.0010
Male
2,370 (53)
26 (41)
308 (47)
1,024 (53)
709 (54)
256 (61)
47 (59)
<0.0001*
<0.0001
Body mass index (m/kg2)
23.5 3.9
20.9 3.6
22.5 3.4
23.2 3.6
23.9 3.9
25.1 4.3
26.3 5.9
<0.0001†
0.3266 <0.0001
Age (yrs)
Comorbidities Hypertension§
2,831 (63)
34 (54)
343 (52)
1,156 (59)
909 (69)
318 (76)
71 (90)
<0.0001*
Diabetes§
1,781 (40)
22 (35)
257 (39)
763 (39)
554 (42)
162 (39)
23 (29)
0.1700*
0.7543
Previous HF
1,908 (43)
35 (56)
328 (50)
877 (45)
505 (38)
141 (34)
22 (28)
<0.0001*
<0.0001
Atrial fibrillation§
2,025 (45)
28 (44)
311 (47)
888 (46)
606 (46)
168 (40)
24 (30)
0.0297*
0.0156
603 (13)
9 (14)
79 (12)
241 (12)
193 (15)
72 (17)
9 (11)
0.0658*
0.0173
1,919 (43)
31 (49)
292 (44)
863 (44)
572 (43)
131 (31)
30 (38)
<0.0001*
0.0002
710 (16)
9 (14)
111 (17)
314 (16)
187 (14)
79 (19)
10 (13)
0.2182*
0.7415
Heart ratek (beats/min)
76 14
73 14
74 14
76 14
76 13
78 14
81 13
<0.0001†
0.2095
NYHA functional classk IIIIV
382 (9)
7 (11)
64 (10)
162 (9)
113 (9)
28 (7)
8 (11)
0.6374*
0.3372
Chronic renal failure Etiology Ischemic CMP Idiopathic DCMP Clinical status
Laboratory tests LBBB
237 (5)
2 (3)
47 (7)
104 (5)
74 (6)
9 (2)
1 (1)
0.0070*
0.0042
LVEF (%)
38 15
37 16
37 16
38 15
39 15
38 16
38 15
0.0758†
0.9888
Creatininek
1.4 1.4
1.3 1.2
1.2 0.9
1.3 1.2
1.5 1.6
1.6 1.7
1.7 2.2
<0.0001†
0.0559
Sodiumk
138 4
138 5
137 4
138 4
138 4
139 4
139 3
<0.0001†
0.0034
12.2 2.1
11.3 1.9
11.8 1.9
12.1 2.0
12.4 2.2
12.9 2.5
13.1 2.5
<0.0001†
0.4595
Hemoglobink Management ACEIs/ARBsk
3,201 (71)
45 (71)
466 (71)
1,392 (71)
945 (72)
294 (71)
59 (75)
0.9719*
0.7166
Beta-blockersk
2,427 (54)
28 (44)
328 (50)
1,034 (53)
735 (56)
254 (61)
48 (61)
0.0018*
<0.0001
AAk
2,154 (48)
30 (48)
379 (57)
989 (51)
571 (43)
158 (38)
27 (34)
<0.0001*
<0.0001
Loop diureticsk
3,292 (73)
46 (73)
541 (82)
1,497 (77)
895 (68)
260 (62)
53 (67)
<0.0001*
<0.0001
Values are mean SD or n (%). All DBPs measured in mm Hg. *p value by chi-square test. †p value by Kruskal-Wallis test. ‡p value for linear trend test. §Including those first diagnosed at the index admission. kAt discharge. DBP ¼ diastolic blood pressure; other abbreviations as in Table 1.
significantly at lower and higher BPs for both SBP
(younger than 70 years) were detected (p for
and DBP in HFpEF. However, in HFrEF, the mortality
interaction ¼ 0.0016) (Online Figure 3).
rate increased significantly only at lower BP, and a trend for an increased mortality rate at a higher
DISCUSSION
SBP was observed. For readmission, the HR followed a nonlinear model only for SBP in HFpEF, with a nadir
ON-TREATMENT BP AND OUTCOME IN PATIENTS
of 127.6 mm Hg (chi-square: 7.3; df: 1; p ¼ 0.0068)
WITH HF. The J-curve phenomenon has been robustly
(Figure 3C, Online Figure 2C, Table 4). Readmission
evaluated in hypertensive patients, patients with
risk increased with lower DBP in HFpEF and with
coronary artery disease or cerebrovascular disease,
lower SBP/DBP in HFrEF (Figures 3B, 3E, and 3F;
and recently in healthy subjects, in whom the
Online Figures 2B, 2E, and 2F, Table 4).
existence of the phenomenon is generally accepted
Interaction analyses revealed no significant effect
(17–19,22). However, it has not been evaluated in HF
heart
patients. The J-curve phenomenon is defined as the
disease, history of HF or chronic lung disease; heart
shape of the relationship between BP and the risk of
rate at discharge, New York Heart Association
cardiovascular morbidity and mortality, which means
functional class at discharge; LVEF, serum creati-
that the risk of cardiovascular events may increase at
nine levels, serum sodium level, or hemoglobin
both too high and too low levels of BP (22). The shape
level at discharge; prescription of BBs, ACEIs/ARBs,
can be that of a J-curve, U-curve, or a reverse J-curve,
AAs,
coronary
depending on where the point of inflection is and
artery bypass graft at index admission. However,
where the risk increases more deeply. However, the
significant
important point in the J-curve phenomenon is not its
modification
or
by
sex,
diuretics
at
interactions
diabetes,
discharge; between
ischemic
and DBP
and
age
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 3 Adjusted Hazard Ratio for All-Cause Mortality According to Blood Pressure
LVEF #40%
Total Population Adjusted HR (95% CI)
p Value
Adjusted HR (95% CI)
LVEF $50% p Value
Adjusted HR (95% CI)
p Value
On-treatment SBP (mm Hg) SBP <90 mm Hg
2.2 (1.6–3.2)
<0.0001
2.0 (1.3–3.1)
0.0014
4.7 (1.9–11.2)
0.0006
SBP $90 to <100 mm Hg
1.7 (1.3–2.1)
<0.0001
1.7 (1.2–2.3)
0.0011
2.1 (1.3–3.4)
0.0032
SBP $100 to <110 mm Hg
1.2 (1.0–1.5)
0.0518
1.3 (1.0–1.7)
0.0969
1.3 (0.9–1.9)
0.2151
SBP $110 to <120 mm Hg
1.0 (0.8–1.2)
0.9604
1.0 (0.8–1.3)
0.9650
1.0 (0.7–1.5)
0.9927 0.6928
SBP $120 to <130 mm Hg
1.0 (0.8–1.2)
0.7026
1.0 (0.7–1.3)
0.9772
0.9 (0.6–1.4)
SBP $130 to <140 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
SBP $140 to <150 mm Hg
1.0 (0.7–1.3)
0.9194
0.6 (0.4–1.0)
0.0683
1.4 (0.8–2.3)
0.2455
SBP $150 to <160 mm Hg
1.3 (0.8–2.1)
0.3268
1.3 (0.6–2.8)
0.4669
1.0 (0.4–2.5)
0.9542
SBP $160 mm Hg
1.4 (0.7–2.9)
0.3240
1.0 (0.3–3.1)
0.9743
2.2 (0.8–6.3)
0.1334
On-treatment DBP (mm Hg) DBP <50 mm Hg
1.6 (1.1–2.3)
0.0100
1.8 (1.2–2.9)
0.0096
1.7 (0.8–3.5)
0.1761
DBP $50 to <60 mm Hg
1.3 (1.1–1.5)
0.0111
1.3 (1.0–1.6)
0.0495
1.6 (1.2–2.2)
0.0054 0.5356
DBP $60 to <70 mm Hg
1.0 (0.9–1.2)
0.9411
1.1 (0.9–1.3)
0.3087
0.9 (0.7–1.2)
DBP $70 to <80 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
DBP $80 to <90 mm Hg
1.1 (0.9–1.4)
0.2909
1.0 (0.7–1.4)
0.9436
1.3 (0.8–2.0)
0.3176
DBP $90 mm Hg
2.0 (1.3–3.1)
0.0031
1.6 (0.8–3.1)
0.2009
2.5 (1.2–5.2)
0.0138
CI ¼ confidence interval; HR ¼ hazard ratio; other abbreviations as in Tables 1 and 2.
existence or exact shape, but whether such a point of
high-risk patients, although the population was
inflection occurs within a physiological range of BP
different from ours.
(19). Our study was unique in describing a reverse J-curve association between on-treatment BP and
SYSTOLIC AND DIASTOLIC BP AND OUTCOME IN
long-term mortality in HF patients with a nadir of SBP/
PATIENTS WITH HFrEF AND HFpEF. The association
DBP of 132.4/74.2 mm Hg. This result suggested that
between on-treatment BP and outcomes had several
SBP/DBP <130/70 mm Hg at discharge and during
implications for treatment strategies in HF, which
follow-up was associated with worse survival in HF
might be different from HFrEF to HFpEF. For HFrEF,
patients, and, therefore, the lowest BP possible might
prescribing neurohormonal blockades to reduce the
not be an optimal target for HF patients. The rela-
mortality is necessary. Because patients with HFrEF
tionship between SBP and outcome was more linear
often present with low BP, which is associated with
compared with DBP, especially in HFrEF, whereas the
poor outcomes, there is an important issue of whether
J-curve was more prominent in HFpEF. This might be
there is an optimal BP level so the dose of neurohor-
partially explained because the lower SBP could
monal blockades can be adjusted or whether the
be related to a reduced stroke volume in HFrEF.
maximal tolerable dose should be always pursued,
Several studies examined the association between
as discussed in randomized controlled trials. Previous
BP and outcomes in HF, but their analyses were
post hoc analysis of COPERNICUS (Carvedilol Pro-
mostly limited to baseline BP (10–13), which could
spective
not be extrapolated to the BP level achieved under
CHARM (Candesartan in Heart Failure: Assessment of
treatment. Furthermore, most previous studies were
Reduction in Mortality and Morbidity) trials, as well as
not able to evaluate nonlinearity of the relationship
a recent analysis of the PARADIGM-HF (Prospective
between BP and clinical outcome, and failed to
Comparison
describe a J-point in the relationship, although a few
Neprilysin
of them included follow-up BP achieved under treat-
Converting-Enzyme Inhibitor] to Determine Impact on
ment as well (23,24). Our association between on-
Global Mortality and Morbidity in Heart Failure)
treatment BP and mortality agreed with the recent
trial revealed that the study drugs had benefit even in
analysis by Böhm et al. (25), which described that the
those patients with lower initial SBP (26–28). In the
mean achieved SBP/DBP of <120/70 mm Hg was
post hoc analysis of the PARADIGM-HF trial, the
associated with increased all-cause mortality in
authors also brilliantly adjusted time-updated and
pooled data of large randomized controlled trials with
on-treatment BP. All together, these studies encourage
Randomized
of
ARNI
Inhibitor]
Cumulative
Survival)
[Angiotensin with
ACEI
and
Receptor-
[Angiotensin-
815
816
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
F I G U R E 2 Restricted Cubic Splines Model for All-Cause Mortality According to On-Treatment BP
(A) SBP: all population. (B) SBP: heart failure with reduced ejection fraction (EF). (C) SBP: heart failure with preserved EF. (D) DBP: all population. (E) DBP: heart failure with reduced EF. (F) DBP: heart failure with preserved EF. Abbreviations as in Figure 1.
physicians to not avoid prescribing neurohormonal
manner as those without hypertension, no definitive
blockades for HFrEF patients, even in those with lower
evidence supports controlling BP in patients with HF
BPs. However, apart from the limitations of a post hoc
(15,29). The guidelines are based on evidence that
and explorative analysis, this could not be extrapo-
management of hypertension reduces development
lated to the notion that the maximal tolerable
of HF, but not that such management might improve
dosage of the drugs was more beneficial for HFrEF
the outcome of the patients with HF. In hypertensive
patients even with lower BPs because initiation of
patients, recent evidence suggested that achieving
the drug and up-titration might not be the same at
lower BP targets might carry a better outcome as
all. Whether the highest dose possible and the
validated by the SPRINT (Systolic Blood Pressure
lowest BP thereafter are safe and necessary should be
Intervention Trial) (6). However, no study has
tested.
assessed optimal BP in HFpEF. Our study described a
Because it is not mandatory to prescribe neuro-
J-curve association between on-treatment BP and
hormonal blockades in patients with HFpEF, and
long-term mortality in HFpEF patients with a nadir of
hypertension is one of the important etiologies of
SBP/DBP of 127.9/72.7 mm Hg, with increased mor-
HFpEF, there is an issue of BP control and its optimal
tality above and below the point. This suggested that
target.
the lowest BP possible was not necessarily the
Although
current
guidelines
recommend
treating hypertension in HF patients in the same
optimal target for HFpEF.
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
F I G U R E 3 Restricted Cubic Splines Model for Heart Failure Readmission Due to Heart Failure Aggravation According to On-Treatment BP
(A) SBP: all population. (B) SBP: heart failure with reduced EF. (C) SBP: heart failure with preserved EF. (D) DBP: all population. (E) DBP: heart failure with reduced EF. (F) DBP: heart failure with preserved EF. Abbreviations as in Figures 1 and 2.
POTENTIAL MECHANISM OF
related to poor outcomes, including age, body mass
REVERSE J-CURVE RELATIONSHIP BETWEEN
index, etiology, comorbidities, laboratory tests (e.g.,
ON-TREATMENT BP AND MORTALITY
serum creatinine and serum sodium), LVEF, and even
Low BP could lead to poor tissue perfusion, which
ond, low SBP might only be a marker of poor cardiac
treatments as described in Online Tables 1 to 7. Secresults in further deterioration of cardiac function,
function, which increases mortality (33,34). However,
and, finally, in multiorgan failure. However, the
lower SBP was also a significant predictor of events
J-curve associations do not directly imply a causal
even after adjustment for LV function in terms of
relationship.
noncausal
LVEF. Moreover, lower DBP, which is not directly
mechanisms were proposed to explain the phenome-
related to systolic function, was also a significant
non (19). First, it might be an epiphenomenon of a
predictor of events. Third, lower DBP might be caused
Several
other
potential
more severe and debilitating underlying condition
by increased pulse pressure, reflecting advanced
(30–32). However, we excluded cancer patients and
vascular disease and arterial stiffness, which are
those with infiltrative disease who have poor short-
related to increased mortality (35–38). In our analyses,
term
aggressively
we noticed a reverse J-curve phenomenon for both
adjusted for other potential compounding factors
DBP and SBP; for the latter, the pulse pressure theory
prognosis.
In
addition,
we
817
818
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
T A B L E 4 Adjusted Hazard Ratio for Readmission for Heart Failure Aggravation According to Blood Pressure
LVEF #40%
Total Population Adjusted HR (95% CI)
p Value
Adjusted HR (95% CI)
LVEF $50% p Value
Adjusted HR (95% CI)
p Value
On-treatment SBP (mm Hg) SBP <90 mm Hg
1.8 (1.3–2.6)
0.0012
1.9 (1.2–2.8)
0.0033
1.9 (0.6–6.3)
0.2820
SBP $90 to <100 mm Hg
1.6 (1.3–2.1)
<0.0001
1.6 (1.2–2.1)
0.0036
1.5 (0.9–2.6)
0.1198
SBP $100 to <110 mm Hg
1.3 (1.1–1.7)
0.0056
1.3 (1.0–1.7)
0.0841
1.5 (1.0–2.2)
0.0557
SBP $110 to <120 mm Hg
1.2 (1.0–1.4)
0.1077
1.2 (0.9–1.6)
0.1996
1.0 (0.7–1.5)
0.9560
SBP $120 to <130 mm Hg
1.1 (0.9–1.4)
0.2335
1.3 (1.0–1.7)
0.0900
0.9 (0.6–1.4)
0.6932
SBP $130 to <140 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
SBP $140 to <150 mm Hg
1.0 (0.8–1.4)
0.7752
1.0 (0.6–1.5)
0.8454
1.2 (0.7–2.1)
0.4281
SBP $150 to <160 mm Hg
1.4 (0.9–2.3)
0.1698
1.7 (0.9–3.5)
0.1233
1.3 (0.6–2.8)
0.5003
SBP $160 mm Hg
1.5 (0.6–3.6)
0.3897
2.3 (0.7–7.5)
0.1546
1.3 (0.3–5.6)
0.6886
On-treatment DBP (mm Hg) DBP <50 mm Hg
1.2 (0.8–1.8)
0.4920
1.1 (0.6–2.0)
0.6790
1.2 (0.5–2.8)
0.6711
DBP $50 to <60 mm Hg
1.3 (1.1–1.5)
0.0069
1.2 (1.0–1.5)
0.0937
1.4 (1.0–2.0)
0.0304 0.6364
DBP $60 to <70 mm Hg
1.1 (1.0–1.3)
0.1433
1.2 (1.0–1.4)
0.0789
0.9 (0.7–1.2)
DBP $70 to <80 mm Hg
1.0 (ref.)
—
1.0 (ref.)
—
1.0 (ref.)
—
DBP $80 to <90 mm Hg
0.9 (0.7–1.1)
0.2205
0.9 (0.7–1.2)
0.4463
0.8 (0.5–1.4)
0.5034
DBP $90 mm Hg
1.0 (0.6–1.7)
0.9883
1.2 (0.6–2.2)
0.6511
0.7 (0.2–2.2)
0.5255
Abbreviations as in Tables 1 to 3.
would not be applicable. Fourth, hypoperfusion of the
CONCLUSIONS
coronary arteries by low DBP might lead to increased mortality in patients with compromised coronary flow
On-treatment BP and all-cause mortality showed a
reserve, such as those with coronary artery disease
reverse J-curve relationship in patients with HF.
(18,39). However, even after adjustment for ischemic
Lower BP portends an increased risk of readmission
heart disease, or even in a subgroup without ischemic
for HF. Our findings suggested that the lowest BP
heart disease, the relationship persisted, and the same
possible might not be optimal for HF patients. Further
relationship was observed with SBP. Finally, lower BP
studies should establish a proper BP goal in patients
might
with HF.
interrupt
prescription
of
neurohormonal
blocking agents that promote survival. Although this hypothesis is not applicable for HFpEF, the J-curve ADDRESS FOR CORRESPONDENCE: Dr. Hae-Young
was more definitive in HFpEF in our analysis. STUDY LIMITATIONS. Because this was an observa-
tional study, our results did not support a causal relationship between low BP and risk of cardiovascular mortality, and the mechanism by which the J curve occurred. We could not consider all the drug prescriptions during the follow-up. Although our analyses were adjusted for baseline confounders, any unmeasured confounders could have been missed. We also did not adjust our analyses for dosage of antihypertensive
agents
received
(because
of
complexity) or for other confounders (because of lack of data), especially those that were predictors of poor health, socioeconomic status, job stress, or mental health. Finally, issues of multiple comparisons should be considered, because multiple statistical tests were conducted to increase type I error and false positive results.
Lee,
Department
of
Internal
Medicine,
Seoul
National University College of Medicine, 101, Daehak-ro, Jongno-gu,
Seoul
110-744,
South
Korea.
E-mail:
[email protected]. PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Both high and low blood pressure can be deleterious in patients with heart failure. Controlling blood pressure beyond the indication of neurohormonal blockades for heart failure should be cautious. TRANSLATIONAL OUTLOOK: Additional research is needed to determine optimal target blood pressure for patients with heart failure.
Lee et al.
JACC: HEART FAILURE VOL. 5, NO. 11, 2017 NOVEMBER 2017:810–9
Blood Pressure and Long-Term Mortality in Heart Failure
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KEY WORDS blood pressure, heart failure, heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, J-curve, mortality
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A PP END IX For supplemental tables and figures, please see the online version of this paper.
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