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Methods Conclusions
Elderly hypertensive patients (65–85 years old) were randomly MS was associated with cardiovascular risk in elderly hypertensive
assigned to strict (target systolic BP <140 mm Hg) or mild (140– patients <75 years old, and strict BP control was beneficial for those
159 mm Hg) BP target, and were treated for 2 years with efonidipine- with MS. However, MS and intensive control of BP may have little
based regimen. MS was defined according to the National effect on cardiovascular events in elderly patients ≥75 years old.
Cholesterol Education Program Adult Treatment Panel III criteria,
Keywords: aged; blood pressure; calcium antagonist;
except for the use of body mass index (BMI) ≥25 kg/m2 instead of
cardiovascular disease; hypertension; metabolic syndrome
waist circumference. Primary endpoint was combined incidence
of cardiovascular and renal events. Data were obtained from 2,865 American Journal of Hypertension, advance online publication 4 August 2011;
patients. doi:10.1038/ajh.2011.138
Results
The prevalence of MS was 31.4%. The incidence of primary endpoint
in patients with and without MS was 4.0% and 3.1%, respectively.
The benefit of antihypertensive treatment in elderly patients tial hypertension.5,6 The incidence of cardiovascular and renal
with hypertension is well documented,1–3 and the beneficial events was similar in both groups, however, the incidence of
effect has also been shown in very old subjects.4 However, the the primary endpoint tended to be lower with strict treatment
implication of lowering systolic blood pressure (SBP) below than with mild treatment in younger (65–74 years old) patients,
140 mm Hg has not been clearly shown in clinical trials. The whereas the opposite trend was observed in older (75–85 years
Japanese Trial to Assess Optimal Systolic Blood Pressure in old) patients. The interaction between age and treatment for
Elderly Hypertensive Patients (JATOS) compared the thera- the primary endpoint was statistically significant.
peutic effects of strict treatment to reduce SBP to <140 mm Hg The metabolic syndrome (MS) is a complex of abdominal obes-
with that of mild treatment to maintain SBP at 140–160 mm Hg ity, hypertension, impaired glucose tolerance, and dyslipidemia,
over a period of 2 years using efonidipine hydrochloride, a and is recognized to confer high cardiovascular risk.7–10 The car-
long-acting calcium antagonist, in elderly patients with essen- diovascular risk associated with MS has been observed in mid-
dle-aged and elderly populations,11–15 as well as in hypertensive
1Division of Hypertension and Nephrology, National Cerebral and
patients.16,17 It has been suggested that strict control of BP substan-
Cardiovascular Center, Osaka, Japan; 2Department of Geriatric Medicine,
tially reduces the risk of coronary events in patients with MS.18
Osaka University Graduate School of Medicine, Osaka, Japan; 3Department of However, the benefit of antihypertensive treatment on car-
Internal Medicine, School of Medicine, Keio University, Tokyo, Japan; diovascular outcomes in elderly patients with MS is not clear.
4Japan Physicians Association, Tokyo, Japan; 5Yokohama City University
Table 2 | Baseline clinical characteristics of patients with and without metabolic syndrome (MS) according to treatment received
MS Non-MS
Strict treatment Mild treatment Strict treatment Mild treatment
Variables (n = 457) (n = 443) P (n = 988) (n = 977) P
Male (%) 159 (34.8) 149 (33.6) 0.71 436 (44.1) 393 (40.2) 0.08
Age, years 72.8 ± 5.1 73.3 ± 5.2 0.14 73.7 ± 5.3 73.5 ± 5.2 0.32
Systolic blood pressure, mm Hg 172 ± 9 172 ± 10 0.77 172 ± 10 172 ± 10 0.31
Diastolic blood pressure, mm Hg 89 ± 10 89 ± 10 0.63 90 ± 9 90 ± 9 0.69
Body mass index, kg/m2 25.8 ± 3.2 25.6 ± 3.5 0.28 22.5 ± 3.0 22.6 ± 3.1 0.21
Fasting blood glucose, mg/dl 114.7 ± 29.0 114.9 ± 28.2 0.90 98.8 ± 17.4 97.4 ± 16.1 0.07
HDL-cholesterol, mg/dl 47.6 ± 12.1 47.3 ± 11.8 0.66 60.4 ± 14.3 61.1 ± 14.9 0.31
Triglyceride, mg/dl 195.0 ± 105.6 187.0 ± 100.0 0.25 109.8 ± 54.7 109.1 ± 48.2 0.76
LDL-cholesterol, mg/dl 127.0 ± 32.9 127.9 ± 33.4 0.69 120.8 ± 30.4 121.7 ± 30.7 0.50
Enlarged heart or LVH (%) 256 (56.0) 250 (56.4) 0.90 450 (45.5) 468 (47.9) 0.30
History of cerebrovascular disease (%) 12 (2.6%) 27 (6.1%) 0.01 43 (4.4%) 38 (3.9%) 0.61
History of cardiac and vascular disease (%) 14 (3.1%) 9 (2.0%) 0.33 30 (3.0%) 19 (1.9%) 0.12
Renal diseasea (%) 67 (14.7%) 71 (16.0%) 0.57 117 (11.8%) 114(11.7%) 0.90
Diabetes mellitus (%) 105 (23.0%) 94 (21.2%) 0.53 68 (6.9%) 60 (6.1%) 0.51
Dyslipidemia (%) 360 (78.8%) 329 (74.3%) 0.11 396 (40.1%) 411 (42.1%) 0.37
Current smoking (%) 59 (12.9%) 44 (9.9%) 0.16 148 (15.0%) 144 (14.7%) 0.88
Prior antihypertensive treatment (%) 254 (55.6%) 248 (56.0%) 0.90 476 (48.2%) 497 (50.9%) 0.23
Data are expressed as means ± s.d., or n (percentage) of patients.
HDL, high-density lipoprotein; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy.
aProteinuria or elevated serum creatinine (men ≥1.3, women ≥1.2 mg/dl).
slightly younger, and showed comparable SBP but lower treatment group (146 ± 11/79 ± 9 mm Hg) (P < 0.0001). At the
diastolic BP, higher low-density lipoprotein cholesterol, and end of study, antihypertensive drugs other than efonidipine
higher prevalence of left ventricular hypertrophy compared were more frequently used in the strict treatment group than
with patients without MS. History of cardiovascular disease in the mild treatment group (P < 0.001), but the number of
was similar between the two groups, but renal disease was antihypertensive drugs was not different between the MS and
more common in patients with MS than in patients without non-MS groups (percentage of combination therapy: strict
MS. The prevalence of smokers was lower and that of prior treatment MS group 37%, non-MS group 34% (P = 0.18), mild
antihypertensive treatment was higher in patients with MS treatment MS group 28%, non-MS group 27% (P = 0.19)).
than in those without MS. The rate of discontinuation from the study was 20% in the MS
Table 2 shows the clinical characteristics of patients with group and 18% in the non-MS group. This difference was of
and without MS in the strict and mild treatment groups. In borderline significance (P = 0.06). It was not different between
patients with MS, there were no significant differences in sex, the strict and mild control groups (P = 0.90).
age, baseline BP, BMI, metabolic parameters, and other risk
factors, except for history of cerebrovascular disease between Primary endpoint
the strict and mild control groups. In patients without MS, The incidence of the primary endpoint in the total popula-
these parameters were not significantly different between the tion, in patients with MS, and in those without MS is shown
two groups. in Table 3. There was no significant difference in the incidence
of primary endpoint as well as its components between the MS
BP control during the treatment period group and non-MS group. The impact of MS was also not sig-
BP decreased in both treatment groups, and average BP was nificant both in men and women. However, in the mild treat-
controlled within the target levels (Figure 1). The difference ment group, the incidence of the primary endpoint was higher
in SBP and diastolic BP between the two groups was signifi- in patients with MS (5.2%) than in patients without MS (2.5%)
cant after 3 months and thereafter. In patients with MS, BP (P = 0.008). In the strict control group, the difference was not
after 24 months was significantly lower in the strict treatment significant (2.8% vs. 3.7%, P = 0.38). There was a significant
group (137 ± 13/75 ± 10 mm Hg) than in the mild treatment difference in the influence of MS between the treatment groups
group (146 ± 11/78 ± 9 mm Hg) (P < 0.0001). Similarly, in in terms of the primary endpoint (P = 0.02).
patients without MS, BP was significantly lower in the strict The incidence of the primary endpoint was higher in patients
treatment group (135 ± 11/74 ± 9 mm Hg) than in the mild ≥75 years old than in those <75 years old (P = 0.003). Table 4
a Patients with MS
180
160
* * * * * * * *
Blood pressure (mm Hg) Mild treatment
140 Strict treatment
120
100
80
* * * * * * * * Mild treatment
Strict treatment
60
0 3 6 9 12 15 18 21 24 (Months)
Mild treatment (n) 443 394 374 350 343 326 314 294 296
Strict treatment (n) 457 412 381 372 359 340 336 325 303
b Patients without MS
180
160
Blood pressure (mm Hg)
* * * * * * * * Mild treatment
140 Strict treatment
120
100
* * * * * * * * Mild treatment
80
Strict treatment
60
0 3 6 9 12 15 18 21 24 (Months)
Mild treatment (n) 977 871 832 800 788 736 727 710 704
Strict treatment (n) 988 883 862 816 804 762 747 718 709
Figure 1 | Time course of changes in blood pressure in the strict control group and the mild control group among patients (a) with or (b) without metabolic
syndrome (MS). *P < 0.05 strict vs. mild treatment group.
Table 3 | Incidence of the primary endpoint and its components according to treatment in patients with and without metabolic
syndrome (MS)
Strict treatment group Mild treatment group Overall
MS Non-MS MS Non-MS MS Non-MS
(n = 457) (n = 988) Pa (n = 443) (n = 977) P (n = 900) (n = 1965) P Pb
Primary endpoint 13 (2.8) 37 (3.7) 0.38 23 (5.2) 24 (2.5) 0.008 36 (4.0) 61 (3.1) 0.22 0.02
Cerebrovascular disease 6 (1.3) 26 (2.6) 0.11 13 (2.9) 15 (1.5) 0.08 19 (2.1) 41 (2.1) 0.97 0.02
Cardiac and vascular disease 5 (1.1) 8 (0.8) 0.59 8 (1.8) 6 (0.6) 0.04 13 (1.4) 14 (0.7) 0.06 0.32
Renal failure 2 (0.4) 3 (0.3) 0.69 2 (0.5) 3 (0.3) 0.67 4 (0.4) 6 (0.3) 0.56 0.99
Results are expressed as n (percentage) of patients. Primary endpoint: the combined incidence of cerebrovascular disease , cardiac and vascular disease, and renal failure.
aMS vs. without MS. bInteraction between the MS status and the treatment group.
shows the incidence of the primary endpoint in younger and ment group (P = 0.003), but not in the strict treatment group
older patients in relation to MS. In patients <75 years old, the (P = 0.84). This relationship in the mild treatment group was
incidence was significantly higher in those with MS than in evident in patients <75 years old, but was not significant in
those without MS. The association of MS with cardiovascular patients ≥75 years old (Figure 2). It was not observed in either
events in this age group was highly significant in mildly treated age group of strictly treated patients. Regarding the influence
patients but was not significant in strictly treated patients. On of each component of MS (other than BP), high blood glu-
the other hand, in patients ≥75 years old, there was no difference cose was significantly associated with the cardiovascular out-
in the incidence of events between those with and those without come (HR 1.63, 95% CI: 1.06–2.50, P = 0.03). The HR of BMI
MS either in the strict treatment group or mild treatment group. (0.92, 95% CI: 0.59–1.44, P = 0.72), high triglyceride (1.13,
A significant trend was observed between the number of 95% CI: 0.72–1.78, P = 0.59), and low high-density lipopro-
MS components and the incidence of events in the mild treat- tein cholesterol (1.28, 95% CI: 0.81–2.04, P = 0.29) was not
Table 4 | Incidence of the primary endpoint in patients with and without metabolic syndrome (MS) according to treatment and age
Strict treatment group Mild treatment group Overall
MS Non-MS Pa MS Non-MS P MS Non-MS P
<75 years old, n 291 558 271 569 562 1127
Primary endpoint, n (%) 5 (1.7) 13 (2.3) 0.56 16 (5.9) 9 (1.6) 0.0006 21 (3.7) 22 (2.0) 0.03
≥75 years old, n 166 430 172 408 338 838
Primary endpoint, n (%) 8 (4.8) 24 (5.6) 0.71 7 (4.1) 15 (3.7) 0.82 15 (4.4) 39 (4.7) 0.87
Pb 0.10
aMS vs. without MS. bInteraction between the MS status and the age group on the primary endpoint.
4.0
4 4 4 4 3.6 3.8
3.1 3.2
2.5
2.1
2 1.7 2 2 2
1.1
1.0
0 0 0 0
Number of
1 2 3 ≥4 1 2 3 ≥4 1 2 3 ≥4 1 2 3 ≥4
components
n = 260 298 198 93 281 288 178 93 234 196 100 66 222 186 118 54
Strict treatment Mild treatment Strict treatment Mild treatment
Patients <75 years old Patients ≥75 years old
Figure 2 | Number of metabolic syndrome components and the incidence of the primary endpoint according to age of patients and treatment received. P values
mean “P values for trend.” Primary endpoint: the combined incidence of cerebrovascular disease, cardiac and vascular disease, and renal failure.
Patients
n
Non MS/MS P* 95%CI
treatment group (HR: 3.80), but not in the strict treatment
group (HR: 0.99). In patients ≥75 years old, the presence of MS
0.01 1.17–4.02
Patients <75 years old 1,127/562 did not affect cardiovascular or renal outcomes (adjusted HR:
Strict treatment 558/291 0.99 0.35–2.85
0.98). MS was not associated with these outcomes in either the
Mild treatment 569/271 0.002 1.65–8.74 strict (HR: 0.94) or mild (HR: 1.00) treatment groups.
the National Cholesterol Education Program Adult Treatment components of MS in the mild treatment group. These results
Panel III with BMI instead of waist circumference. The rela- indicate that MS has a marked influence when the control of
tively low prevalence of MS among the JATOS participants BP is insufficient, but not under strict BP control in elderly
who had high BP can be explained by the smaller number of hypertensive patients. However, the benefit of strict control
overweight and obese subjects compared with western and of SBP to <140 mm Hg in patients with MS was evident in
other Asian populations. patients aged <75 years, but not in those aged ≥75 years.
The cardiovascular risk associated with MS has been The mechanism(s) of the diverse effects of the strict BP con-
observed in middle-aged subjects and in elderly popula- trol on the cardiovascular risk between age groups or MS sta-
tions.11–15 According to a recent meta-analysis, the presence tuses cannot be clarified from this study. However, it has been
of MS is associated with a twofold increase in cardiovascu- shown that the relative risk of high BP on cardiovascular out-
lar outcomes and a 1.5-fold increase in all-cause mortality.11 come is remarkable in middle-aged and early elderly subjects
Regarding elderly population, the Health, Aging, and Body but is attenuated in late elderly subjects.26 Therefore, the effect
Composition study showed that patients with MS had signifi- of strict BP control may be weak in late elderly patients with
cantly higher incidence of ischemic heart disease (HR 1.56).12 hypertension. Although our study supports the importance of
In the Cardiovascular Health Study, there were 20–30% more BP control for elderly hypertensive patients with MS, further
cardiovascular events among elderly participants with MS than studies are needed to determine appropriate treatment goals.
in those without MS.13 Wang et al. reported that MS, defined There are several limitations in this study. First, the MS pop-
by various criteria, was significantly associated with incident ulation in the present study consisted of hypertensive patients
stroke (HR: 1.5–1.7) in Finnish subjects aged 65–74 years.14 with initial SBP ≥160 mm Hg. This characteristic of the study
Several other studies have also showed associations between subjects may influence the prevalence of MS and the incidence
MS and cardiovascular disease in elderly subjects.15,22,23 of cardiovascular disease in the JATOS. The generalizability
However, MS did not significantly increase cardiovascu- of the findings from JATOS is also limited because it is not a
lar risk in some studies. In a sub-analysis of the Prospective community-based study. Second, BMI ≥25 kg/m2 was substi-
Study of Pravastatin in the Elderly at Risk, no association was tuted for waist circumference as a component of MS. Although
found between MS and cardiovascular risk (HR: 1.07) in sub- BMI is recognized as a good index of obesity, waist circum-
jects aged >70 years with a history of vascular disease or at ference may be better index of abdominal obesity and related
high risk for vascular disease.24 In the British Regional Heart cardiovascular diseases. Third, the study was performed in
Study, the association was weak and not significant (relative Japanese subjects, in whom cardiovascular risk is relatively low
risk 1.27) among subjects aged 60–79 years.24 In the JATOS, and stroke accounts for a higher proportion of the composite
the impact of MS on composite cardiovascular and renal out- endpoint than would be expected in other ethnic populations.
come was not significant among elderly hypertensive patients Fourth, the treatment and follow-up period in the JATOS
although patients with MS had a 29% higher risk for the pri- might not be sufficient to determine the influence of MS or
mary endpoint. Reasons for the discrepancy among the stud- the effect of antihypertensive therapy on the outcomes. Finally,
ies are not clear, however, the characteristics of study subjects the study was not designed to address the hypothesis tested in
such as age, race and clinical background may be responsible this post hoc, subgroup analysis. Further studies with longer
for the differences. Taken together, it appears that the pres- follow-up periods may be required to confirm the findings of
ence of MS modestly increases cardiovascular risk in elderly this study.
population. In conclusion, the present study showed that the cardiovas-
The influence of age on the impact of MS on cardiovascular cular risk associated with MS was evident in elderly patients
disease has not been investigated in elderly populations. Our with hypertension aged <75 years, but not in those aged ≥75
findings suggest that the impact of MS on cardiovascular dis- years. The increased cardiovascular risk associated with MS
ease is apparent in subjects aged <75 years old, but diminishes was apparent when SBP was controlled mildly but not under
beyond 75 years of age. In a recent cohort study of very old strict SBP control, although this difference was not observed in
(mean age 85 years) high-risk subjects, low BMI, low diasto- patients aged ≥75 years. Therefore, strict control of BP appears
lic BP, low total and high-density lipoprotein cholesterol, and to be desirable for elderly hypertensive patients with MS,
high insulin sensitivity were associated with total mortality.25 particularly for those <75 years old. However, the benefit of
Further studies are required to clarify the significance of MS in aggressive antihypertensive therapy is not obvious for patients
the very old population. aged ≥75 years, even if they have MS.
In this study, the incidence of the primary endpoint was not
significantly different between patients with MS and those Acknowledgments: Japan Physicians Association and Japanese Society of
without MS in the strict treatment group, but the incidence Hypertension supported this study. Shionogi & Co., Ltd., Japan supplied
research fund. We thank all the members and researchers of the JATOS
was higher in patients with MS than in patients without MS in group.
the mild treatment group. In terms of the number of MS com-
ponents and the primary endpoint, the association was not Disclosure: Y.K., T.O., and T.S. received honorarium for lectures from several
significant in the strict treatment group, but cardiovascular pharmaceutical companies including Shionogi & Co., Ltd. Y.G. and M.I.
and renal events increased linearly with increasing number of declared no conflict of interest.
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