Association of age and baseline systolic blood pressure with outcomes in patients hospitalized for acute heart failure syndromes

International Journal of Cardiology 191 (2015) 100–106

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Association of age and baseline systolic blood pressure with outcomes in patients hospitalized for acute heart failure syndromes Katsuya Kajimoto a,⁎, Naoki Sato b, Teruo Takano c, on behalf of the investigators of the Acute Decompensated Heart Failure Syndromes (ATTEND) registry a b c

Division of Cardiology, Sekikawa Hospital, Tokyo, Japan Internal Medicine, Cardiology, and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan Department of Internal Medicine, Nippon Medical School, Tokyo, Japan

a r t i c l e

i n f o

Article history: Received 10 December 2014 Received in revised form 3 April 2015 Accepted 30 April 2015 Available online 1 May 2015 Keywords: Acute heart failure syndromes Age Systolic blood pressure Morbidity Mortality

a b s t r a c t Background: Baseline systolic blood pressure (SBP) is one of the most important prognostic indicators for patients with acute heart failure syndromes (AHFS). However, the association among age, baseline SBP, and outcomes of AHFS is unclear. This study was performed to evaluate the relation between baseline SBP and outcomes to increasing age in patients hospitalized for AHFS. Methods: Of the 4842 patients entered into the Acute Decompensated Heart Failure Syndromes (ATTEND) registry, 4828 patients with in-hospital and postdischarge follow-up data were included. The patients were divided into quartiles of age (b 65, 65 to 75, 76 to 82, and ≥83 years), and each age group was divided into quartiles of baseline SBP. Then the 1-year all-cause mortality was compared among the baseline SBP quartiles in the each age quartile. Results: After adjustment for multiple comorbidities, patients aged b 65 years, 65 to 75 years, and 76 to 82 years showed no significant increase in the relative risk of all-cause mortality as the baseline SBP declined until the lowest SBP quartile (SBP b 112 mm Hg, b120 mm Hg, and b 120 mm Hg, respectively). In contrast, among patients aged ≥ 83 years, the lower three SBP quartiles (SBP b 122 mm Hg, 122 to b142 mm Hg, and 142 to b 165 mm Hg) were associated with a significantly higher risk of all-cause mortality than the highest SBP quartile. Conclusions: In patients hospitalized for AHFS, the relation between baseline SBP and all-cause mortality is markedly associated with increasing age, which means that baseline SBP is more important for very elderly patients with AHFS. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Acute heart failure syndromes (AHFS) are defined as gradual or rapid deterioration of the signs and symptoms of heart failure (HF) that leads to the need for urgent therapy [1–4]. The incidence and prevalence of AHFS increase progressively with advancing age, and increasing age is also associated with an increased risk of mortality for AHFS patients [5–8]. It was recently suggested that systolic blood pressure (SBP) at the time of admission to hospital reflects the interaction between vascular tone and myocardial pump function and is one of the most important prognostic indicators for AHFS, with a higher admission SBP being associated with lower mortality [4,9]. The systolic blood pressure, but not the diastolic blood pressure, increases with aging, resulting in an increase of the pulse pressure, which suggests that the blood pressure profile changes with age [6,10]. Accordingly, the prognostic significance of baseline SBP may differ among young-aged, middle-aged, and ⁎ Corresponding author at: Division of Cardiology, Sekikawa Hospital, 1-4-1, NishiNippori, Arakawa-ku, Tokyo, 116–0013, Japan. E-mail address: [email protected] (K. Kajimoto).

http://dx.doi.org/10.1016/j.ijcard.2015.04.258 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

elderly patients with AHFS. However, the association among age, baseline SBP, and morbidity or mortality after hospitalization for AHFS is unclear. Additionally, it has been reported that very few hospital HF registries collect data on postdischarge outcomes in contrast to in-hospital outcomes, even though the majority of adverse events are known to occur after discharge [11]. In the present study, we evaluated the relation between baseline SBP and outcomes to increasing age in patients hospitalized for AHFS who were evaluated in inpatient and outpatient settings. 2. Methods 2.1. Study design and data collection The Acute Decompensated Heart Failure Syndromes (ATTEND) registry is a nationwide hospital-based prospective multicenter observational cohort study that accumulates data on AHFS patients admitted to 53 hospitals throughout Japan. Patients are enrolled at their first admission for AHFS and then followed, with data collection being patientbased rather than event-based. The study design, study methods, and

K. Kajimoto et al. / International Journal of Cardiology 191 (2015) 100–106

patient characteristics have been described previously [12]. In brief, the ATTEND registry study was designed to clarify the profile of AHFS patients in Japan, including their demographic and clinical characteristics, current treatment, in-hospital mortality, and postdischarge morbidity or mortality. For each registered patient, the data obtained include the demographic profile, past history, baseline characteristics, initial evaluation, medical treatment, procedures, hospital course, and disposition. The study is being conducted according to the principles of the Declaration of Helsinki. Institutional review board approval was obtained at each participating hospital prior to study commencement and all patients gave written informed consent. The endpoint classification committee (two experienced cardiologists who are not investigators) reviews all data and obtains confirmation of the cause of death from the primary physician if clarification is required. 2.2. Patients and definitions Patients with AHFS who fit the modified Framingham criteria, which only include variables assessed at admission, are eligible for entry into the registry [13]. However, patients less than 20 years old, those with acute coronary syndrome, and others considered unsuitable for this study by their attending physicians are excluded. The present study was performed to evaluate patients enrolled in the ATTEND registry between April 2007 and December 2011 for whom in-hospital and postdischarge data were available. A preserved ejection fraction (EF) was defined as a left ventricular EF N 40% at admission, or a qualitative assessment of normal or mildly impaired EF (when it was not measured at admission), while a reduced EF was defined as a left ventricular EF ≤40% at admission or moderate/severe systolic dysfunction on qualitative assessment. The patients were divided into quartiles of age (b65 years, 65 to 75 years, 76 to 82 years, and ≥ 83 years), and each age quartile was divided into quartiles of baseline SBP. Next, morbidity and mortality after admission for AHFS were compared among the baseline SBP quartiles in the each age quartile (Age b 65 years: SBP b 112, 112 to b 138, 138 to b168, and ≥ 168 mm Hg; age 65 to 75 years: SBP b 120, 120 to b 142, 142 to b170, and ≥ 170 mm Hg; age 76 to 82 years: SBP b 120, 120 to b 140, 140 to b 169, and ≥ 169 mm Hg; age ≥ 83 years: SBP b 122, 122 to b 142, 142 to b 165, and ≥165 mm Hg). The primary endpoint was all-cause mortality after admission at 1 year, while the secondary endpoint was a composite of allcause mortality and readmission for HF at 1 year. 2.3. Statistical analysis Data are presented as the mean (SD), median with interquartile range, or proportion as appropriate. One-way analysis of variance was used for between-group comparison of continuous variables with a normal distribution, while the Kruskal–Wallis H-test was employed for skewed continuous or discrete variables. The chi-square test was employed to compare nominal scale variables. The cumulative probability of events was estimated by Kaplan–Meier analysis with a log-rank test. Univariate and multivariate Cox's proportional hazards regression analyses were performed to assess the association of variables with morbidity and mortality. The multivariate model included variables that were found to predict of all-cause mortality or the composite endpoint (all-cause mortality and readmission for HF) by univariate analysis as well as other factors known to influence the outcome after hospital admission: gender, body mass index at admission, ischemic etiology, readmission for HF, left ventricular EF, and New York Heart Association functional class at admission. The proportional hazards assumption was confirmed by the log (−log survival function) and the influence of profile, interaction, and multicollinearity in these models was examined by regression diagnostic analysis. A probability (P) value of less than 0.05 (two-tailed) was considered to indicate statistical significance. An independent statistical data center (STATZ Institute, Inc., Tokyo, Japan)

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performed all analyses using SAS system ver. 9.3 software (SAS Institute, Cary, NC, USA). 3. Results 3.1. Baseline characteristics of all patients and groups stratified according to age Of the 4842 patients entered into the ATTEND registry, 4828 patients with in-hospital and postdischarge data were included in the present analysis. The mean age was 73.0 ± 13.8 years and 42.0% were women. Almost half of the patients had a preserved EF (46.1%). The 1-year allcause mortality was 17.0%, while the composite endpoint of all-cause mortality and readmission for HF at 1 year was reached by 31.9% of the subjects. The subjects were divided into quartiles of age (b 65 years, 65 to 75 years, 76 to 82 years, and ≥83 years). The baseline clinical characteristics of these age quartiles are shown in Table 1. Older patients were more likely to be women, to have a valvular etiology, to have a history of hypertension, and to have a preserved EF. They also had lower heart rate, lower body mass index, lower hemoglobin, and higher blood urea nitrogen at baseline than younger patients. Additionally, significant but modest differences were observed regarding baseline SBP, serum creatinine, and serum sodium levels. Furthermore, in the enrolled patients, there was no relationship between increasing age and baseline SBP (r = 0.042). 3.2. Association of age and baseline SBP with outcomes Kaplan–Meier estimates of all-cause mortality after admission in each SBP quartile of the four age groups are shown in Fig. 1. In the b65 years, 65 to 75 years, and 76 to 82 years age groups, the crude relative risk of all-cause mortality was significantly higher for patients with the lowest SBP quartile than for patients with the highest SBP quartile, whereas this risk was not significantly different among the higher two SBP quartiles (Fig. 2). After adjustment for multiple comorbidities, the lowest baseline SBP quartile showed a significant increase of all-cause mortality, with the relative adjusted risk ratio being 4.07 (95% confidence interval [CI], 1.95–8.49; p b 0.001) for patients aged b65 years, 3.52 (95% CI, 2.12–5.83; p b 0.001) for patients aged 65 to 75 years, and 2.68 (95% CI, 1.80–3.98; p b 0.001) for patients aged 76 to 82 years compared with patients having the highest baseline SBP quartile (Fig. 2). However, in patients aged b65 years, 65 to 75 years, or 76 to 82 years, there was no significant increase in the relative adjusted risk of all-cause mortality as baseline SBP declined to the lowest baseline SBP quartile (112 mm Hg, 120 mm Hg, or 120 mm Hg, respectively). On the other hand, in patients aged ≥ 83 years, an SBP of b122 mm Hg, 122 to b 142 mm Hg, or 142 to b 165 mm Hg was associated with a significantly higher adjusted risk of all-cause mortality than an SBP ≥ 165 mm Hg (hazard ratio [HR], 3.37; 95% CI, 2.38–4.76; p b 0.001, HR, 2.39; 95% CI, 1.67–3.43; p b 0.001, and HR, 1.64; 95% CI, 1.12–2.39; p = 0.010, respectively). Kaplan–Meier estimates of the composite endpoint of all-cause mortality and readmission for HF in each SBP quartile of the four age groups are shown in Fig. 3. In Fig. 4, multivariate analysis revealed the same trends for the adjusted risk of this composite endpoint after admission as for the adjusted risk of allcause mortality alone. Furthermore, the associations of baseline SBP with all-cause death and the composite endpoint were markedly different across the four age groups, with a significant age × baseline SBP interaction (p b 0.001 and p = 0.010 for the interaction, respectively). 4. Discussion The present study revealed three main findings in patients hospitalized for AHFS. First, the lowest baseline SBP quartile was associated with a higher risk of morbidity and mortality than the highest SBP quartile in

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Table 1 Baseline characteristics by age quartiles. Age quartile, years Variables

Age, years Gender (% Men) Etiology, % Ischemic Hypertensive Valvular Idiopathic dilated Medical history, % Prior hospitalization for heart failure Hypertension Dyslipidemia Diabetes COPD Stroke Reduced EF (≤40%), % Atrial fibrillation on admission, % Clinical profile on admission, % Paroxysmal nocturnal dyspnea Orthopnea Jugular venous distension Peripheral edema NYHA functional class III IV Body mass index, kg/m2 Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Heart rate, beats/min Blood urea nitrogen, mg/dl Serum creatinine, mg/dl Serum sodium, mEq/l Hemoglobin, g/dl B-type natriuretic peptide, pg/ml Oral medications on admission, % Loop diuretic Spironolactone or eplerenone ACE-I or ARB Beta-blocker Digoxin Aspirin Warfarin Intravenous therapy during hospitalization, % Diuretic Any vasodilator Any inotrope

Total

b65

65 to 75

76 to 82

≥83

(n = 4828)

(n = 1171)

(n = 1237)

(n = 1136)

(n = 1284)

73.0 ± 13.8 58.0

53.6 ± 10.0 73.4

70.5 ± 3.2 65.4

79.0 ± 2.0 54.6

87.7 ± 3.9 39.9

b0.001 b0.001

31.1 17.8 19.4 12.7

23.0 18.1 9.6 26.6

34.5 14.0 17.5 13.3

37.0 16.3 23.2 7.4

30.1 22.5 26.8 4.0

b0.001 b0.001 b0.001 b0.001

36.3 69.5 36.6 33.8 12.3 14.1 53.9 36.0

32.1 57.0 38.6 36.3 6.6 7.0 71.6 27.8

37.3 68.1 42.0 41.2 12.1 13.7 57.4 38.5

39.8 75.6 39.3 35.7 14.4 14.9 48.9 40.8

36.1 76.7 27.3 22.7 15.7 20.2 38.6 36.9

0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001

53.0 63.4 52.8 66.9

57.8 64.6 53.1 64.6

53.4 64.0 51.4 64.3

50.9 61.6 52.1 65.9

50.3 63.2 54.5 72.3

0.003 0.564 0.471 b0.001

37.9 43.7 23.2 ± 4.6 145.4 ± 36.7 82.5 ± 22.6 98.4 ± 29.0 27.8 ± 26.0 1.43 ± 1.57 139.3 ± 4.4 12.0 ± 2.6 706 (362–1280)

38.8 42.3 25.3 ± 5.7 143.1 ± 41.2 87.8 ± 26.1 105.6 ± 28.8 24.9 ± 26.1 1.47 ± 2.14 138.9 ± 4.3 13.5 ± 2.6 709 (370–1287)

38.6 41.9 23.6 ± 4.1 147.5 ± 38.5 83.1 ± 23.3 99.4 ± 29.6 27.3 ± 21.7 1.51 ± 1.63 139.5 ± 4.1 12.3 ± 2.6 666 (356–1240)

37.2 43.8 22.6 ± 3.9 145.8 ± 34.9 80.4 ± 20.8 97.1 ± 28.8 28.1 ± 16.7 1.39 ± 1.07 139.4 ± 4.4 11.5 ± 2.2 687 (352–1259)

37.2 46.8 21.5 ± 3.6 145.2 ± 31.6 79.0 ± 18.8 92.2 ± 27.1 30.7 ± 34.8 1.35 ± 1.23 139.3 ± 4.8 10.9 ± 2.3 760 (378–1354)

0.786 0.053 b0.001 0.029 b0.001 b0.001 b0.001 0.049 0.006 b0.001 0.063

46.3 19.8 47.5 33.8 12.7 32.4 24.5

38.9 22.9 37.7 32.0 12.0 20.3 22.1

46.2 19.2 49.5 37.3 13.6 33.4 28.5

51.6 20.2 53.5 38.2 14.5 38.3 30.6

48.4 17.1 49.1 28.0 11.0 37.4 17.6

b0.001 0.004 b0.001 b0.001 0.041 b0.001 b0.001

76.3 78.4 18.2

71.6 76.4 22.5

75.8 79.1 19.0

78.6 78.5 16.5

79.1 79.5 15.1

b0.001 0.257 b0.001

p value

Values are the mean ± SD, percentage (%), or median (interquartile range). SBP = systolic blood pressure; COPD = chronic obstructive pulmonary disease; EF = ejection fraction; NYHA = New York Heart Association; ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker.

patients of all age quartiles. Second, in patients aged b65 years, 65 to 75years, or 76 to 82 years, there was no significant increase in the relative risk of adverse events as baseline SBP declined to the lowest baseline SBP quartile. Third, in patients aged ≥ 83 years, the risk of adverse events after admission declined significantly with an increase of baseline SBP across the entire blood pressure spectrum that we examined. Accordingly, the relation between baseline SBP and morbidty or mortality at 1 year was markedly associated with advancing age, suggesting a greater importance of baseline SBP in very elderly patients hospitalized for AHFS. There is a well-known inverse relationship between baseline SBP and mortality, but this has mainly been described in the overall AHFS population, and the influence of age combined with baseline SBP on clinical outcomes has been unclear [1–4,8,9]. We found that the association between baseline SBP and outcomes differs markedly for patients aged b 80 years old or ≥80 years old, suggesting that the baseline SBP might have different prognostic implications depending on age. The mechanism underlying this association is not clear, but some assumptions can be made. The main determinants of SBP are cardiac output

and peripheral vascular resistance, and the ability to maintain an adequate SBP may reflect sympathetic and neurohormonal activation (i.e., reactive hypertension), representing functional cardiovascular reserve in the setting of acute stress [14–16]. It was also reported that a preserved EF increases dramatically in prevalence with increasing age, while the efficiency of post-synaptic beta-adrenergic signaling declines with age [17–21]. Thus, the ability of elderly patients to maintain SBP in the acute phase of AHFS may reflect a cardiovascular reserve that is mediated by a stronger vasoconstrictor response rather than a larger contractile reserve. In addition, it was reported that low SBP may lead to non-cardiac effects that result in the development or worsening of new non-cardiac comorbidities, including renal failure, cerebral dysfunction, and peripheral vascular disease [22]. Moreover, the majority of adverse events in elderly patients are related to non-cardiac comorbidities, since the existence of multiple non-cardiac comorbidities impedes appropriate access to acute primary care that could forestall acute adverse events [23–25]. On the basis of previous reports and our findings, it seems possible that an elevated baseline SBP may have a protective effect in elderly patients rather than younger patients, since it

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Fig. 1. Kaplan–Meier estimates of all-cause mortality after hospitalization stratified according to baseline SBP. (A) Patients aged b65 years. (B) Patients aged from 65 to 75 years. (C) Patients aged from 76 to 82 years. (D) Patients aged ≥83 years. SBP = systolic blood pressure.

Fig. 2. Hazard ratios for all-cause death after admission stratified according to baseline SBP and age. SBP = systolic blood pressure. HR = hazard ratios.

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Fig. 3. Kaplan–Meier estimates of the composite endpoint (all-cause mortality and readmission for heart failure) stratified according to baseline SBP. (A) Patients aged b65 years. (B) Patients aged from 65 to 75 years. (C) Patients aged from 76 to 82 years. (D) Patients aged ≥83 years. SBP = systolic blood pressure.

reflects an adequate response to acute stress and prevents the development of non-cardiac comorbidities. However, further prospective investigations will be necessary to clarify the mechanism. It was recently suggested that predicting the risk of mortality is more accurate than predicting readmission for HF and that there are few predictors of readmission after hospitalization for AHFS [11]. Indeed, it was reported that the short-term readmission rate is high regardless of baseline SBP [4,9]. In our study, the endpoint of readmission for HF alone was not evaluated because readmission should be considered in the context of mortality since patients who die are not at risk for readmission [26, 27]. Interestingly, we found the same trend for the adjusted risk of our composite endpoint (mortality and readmission for HF) as for the risk of all-cause mortality among patients aged ≥80 years. That is, among AHFS patients aged ≥80 years but not patients aged b 80 years, baseline SBP may help to identify an elevated risk of readmission for HF as well as all-cause death. However, further prospective investigations will be needed to clarify the association of age and baseline SBP with the risk of subsequent morbid events, such as readmission for HF, in patients with AHFS. There are several limitations of the present study that need to be considered. First, it has been reported that under-prescription of recommended HF drugs occurs in elderly HF patients [28,29]. We observed that baseline use of spironolactone, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, and beta-blocker was significantly lower in patients aged ≥80 years than in those aged b80 years. Moreover, the proportion treated and doses used in these patients were unclear and we could not determine reasons for non-prescription of standard HF therapy. Accordingly, the influence of treatment on the short-

term outcome must be interpreted cautiously since this was an observational study and was not designed to evaluate the impact of medications. Second, the presence of comorbidities is clearly dependent on advancing age. However, we did not have data on all of the comorbidities associated with age, such as depression, thyroid disorders, osteoporosis, ocular disorders, or dementia [24]. Accordingly, we did not evaluate the association of age and comorbidities with the outcomes after hospitalization for AHFS, so further investigation will be needed to clarify the relation between age, cardiac or non-cardiac comorbidities, and clinical outcomes in the setting of AHFS. Third, as previously reported [30], the longer hospital stay of our registry population may influence both in-hospital mortality and postdischarge outcomes. Therefore, caution must be exercised when applying these results to different cohorts. Fourth, in the setting of AHFS, whether the relation of baseline SBP to clinical outcomes differs between short-term and long-term is unclear. Accordingly, further investigation is needed to clarify the association among baseline SBP, time after hospitalization, and clinical outcomes in AHFS patients. In conclusion, the relation between baseline SBP and the risk of adverse events after admission for AHFS was markedly associated with increasing age. However, in the setting of AHFS, the prognostic interaction between advancing age and baseline SBP is complex. Therefore, further research will be needed to clarify the association among age, baseline SBP and outcomes in patients hospitalized for AHFS.

Conflict of interest None declared.

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Fig. 4. Hazard ratios for the composite endpoint (all-cause mortality and readmission for heart failure) stratified according to baseline SBP and age. SBP = systolic blood pressure. HR = hazard ratios.

Acknowledgments We thank the study investigators for their contributions. We also express our appreciation to Katsunori Shimada, PhD (STATZ Institute, Inc., Tokyo, Japan) for his expert assistance with the statistical analysis. Funding sources: This work was supported by the Japan Heart Foundation, which had no role in the conduct of the study, but provided funding for statistical support and administration. Prior to commencing the ATTEND registry, information on the objectives of this study, its social significance, and an abstract were provided for clinical trial registration with the University Hospital Medical Information Network (UMIN; Clinical Trial Registration ID UMIN000000736). Role of the sponsor: The funding organization did not participate in the design and conduct of this study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.ijcard.2015.04.258.

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