Transcript (1%) patients who were lost to follow

Journal Club
Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, Coresh J,
Brancati FL.
Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults.
N Engl J Med. 2010 Mar 4;362(9):800-11.
Bakris GL, Sarafidis PA, Weir MR, Dahlöf B, Pitt B, Jamerson K, Velazquez EJ,
Staikos-Byrne L, Kelly RY, Shi V, Chiang YT, Weber MA; for the ACCOMPLISH Trial
investigators.
Renal outcomes with different fixed-dose combination therapies in patients with
hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified
secondary analysis of a randomised controlled trial.
Lancet. 2010 Feb 17. [Epub ahead of print]
2010年３月11日 8:30-8:55
８階 医局
埼玉医科大学 総合医療センター 内分泌・糖尿病内科
Department of Endocrinology and Diabetes,
Saitama Medical Center, Saitama Medical University
松田 昌文
Matsuda, Masafumi
From the Department of Epidemiology and the Welch Center for Prevention, Epidemiology, and
Clinical Research (E.S., K.M., J.C., F.L.B.), and the Department of Biostatistics (H.Z., J.C.), Johns
Hopkins Bloomberg School of Public Health; and the Division of General Internal Medicine,
Department of Medicine, Johns Hopkins University (E.S., J.C., F.L.B.) — all in Baltimore; the
Department of Laboratory Medicine and Pathology, Medical School (M.W.S.), and the Division of
Epidemiology and Community Health ( J.P.), University of Minnesota, Minneapolis; and the Division
of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC (L.W.).
N Engl J Med 2010;362:800-11.
Background
Fasting glucose is the standard
measure used to diagnose diabetes
in the United States. Recently,
glycated hemoglobin was also
recommended for this purpose.
Method
We compared the prognostic value of
glycated hemoglobin and fasting glucose for
identifying adults at risk for diabetes or
cardiovascular disease. We measured
glycated hemoglobin in whole-blood samples
from 11,092 black or white adults who did not
have a history of diabetes or cardiovascular
disease and who attended the second visit
(occurring in the 1990–1992 period) of the
Atherosclerosis Risk in Communities (ARIC)
study.
* Plus–minus values are means ±SD. To convert the values for fasting glucose to millimoles per liter, multiply by 0.05551. To convert the values for cholesterol to millimoles per liter,
multiply by 0.02586. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. HDL denotes high-density lipoprotein, and LDL low-density lipoprotein.
† The 699 persons (6.3%) with a fasting glucose level of 126 mg per deciliter (7 mmol per liter) or higher at baseline (8, 56, 112, 185, and 338 persons with a glycated hemoglobin category of
<5.0%, 5.0 to <5.5%, 5.5 to <6.0%, 6.0 to <6.5%, and ≥6.5%, respectively) were excluded from the visit-based analysis examining the risk of diabetes with the use of fasting glucose levels
during the first 6 years of follow-up but were included in the interview-based analysis of diagnosed diabetes during the 15 years of follow-up.
‡ Race was self-reported.
§ The body-mass index is the weight in kilograms divided by the square of the height in meters.
¶ Baecke’s physical-activity index is measured with the use of a questionnaire about leisure-time sports activities developed by Baecke et al. 20 The scale ranges from 1 to 4, with a score of 4
indicating the greatest activity.
Model 1a was adjusted for age, sex, and race (black or
white).
Model 2a was adjusted for the variables in model 1a plus
low-density and high-density lipoprotein cholesterol levels,
log-transformed triglyceride level, body-mass index,
waist-to-hip ratio, hypertension (yes or no), family history
of diabetes (yes or no), education (less than high school,
high school or equivalent, or college or above), alcohol
use (currently, formerly, or never), physical-activity index
score, and smoking status (current smoker, former
smoker, or never smoked).
Model 3a was adjusted for all variables in model 2a plus
the baseline fasting glucose level.
Model discrimination was assessed with the use of Harrell’s C statistic.
Model assessment: C = 0.5: not good, C > 0.8: good, C = 1: perfect.
Self-report (Diagnosis or Use of medication)
Figure 2. Adjusted Hazard Ratios for Self-Reported Diagnosed Diabetes and Coronary Heart Disease, Ischemic Stroke, and Death from Any Cause,
According to the Baseline Glycated Hemoglobin Value.
The hazard ratios are per each absolute increase of 1 percentage point in the glycated hemoglobin value at baseline. The shaded area is the 95%
confidence interval from the restricted-cubic-spline model. Both models are centered at the median (5.4%) and the plot was truncated at the 2.5th and
97.5th percentiles of glycated hemoglobin (4.7% and 6.8%, respectively). The hazard ratios were adjusted for age, sex, and race (black or white), lowdensity and high-density cholesterol levels, log-transformed triglyceride level, body-mass index, waist-to-hip ratio, hypertension (yes or no), family
history of diabetes (yes or no), education (less than high school, high school or equivalent, or college or above), alcohol use (currently, formerly, or never),
physical-activity index score, and smoking status (current smoker, former smoker, or never smoked). The data are shown on a natural-log scale.
Results
The glycated hemoglobin value at baseline was associated with newly
diagnosed diabetes and cardiovascular outcomes. For glycated
hemoglobin values of less than 5.0%, 5.0 to less than 5.5%, 5.5 to less
than 6.0%, 6.0 to less than 6.5%, and 6.5% or greater, the multivariableadjusted hazard ratios (with 95% confidence intervals) for diagnosed
diabetes were 0.52 (0.40 to 0.69), 1.00 (reference), 1.86 (1.67 to 2.08), 4.48
(3.92 to 5.13), and 16.47 (14.22 to 19.08), respectively. For coronary heart
disease, the hazard ratios were 0.96 (0.74 to 1.24), 1.00 (reference), 1.23
(1.07 to 1.41), 1.78 (1.48 to 2.15), and 1.95 (1.53 to 2.48), respectively. The
hazard ratios for stroke were similar. In contrast, glycated hemoglobin
and death from any cause were found to have a J-shaped association
curve. All these associations remained significant after adjustment for the
baseline fasting glucose level. The association between the fasting
glucose levels and the risk of cardiovascular disease or death from any
cause was not significant in models with adjustment for all covariates as
well as glycated hemoglobin. For coronary heart disease, measures of
risk discrimination showed significant improvement when glycated
hemoglobin was added to models including fasting glucose.
Conclusion
In this community-based population of
nondiabetic adults, glycated hemoglobin
was similarly associated with a risk of
diabetes and more strongly associated
with risks of cardiovascular disease and
death from any cause as compared with
fasting glucose. These data add to the
evidence supporting the use of glycated
hemoglobin as a diagnostic test for
diabetes.
Message
A1Cを糖尿病の診断基準とすることを支持する
データ：
糖尿病はともかく，FPGより虚血性心臓疾患や
脳卒中や死亡についても予後がA1Cが6.5%以上
だと悪くなる。
(あと
黒人ではA1Cの影響が少ないらしい)
日本は血糖を診断基準に入れているけれど，A1Cだけでもよいかもしれない？
ACEI/ARB + CaB
ACEI/ARB + 利尿薬
どちらを選びますか？
Hypertensive Diseases Unit, Department of Medicine, University of Chicago-Pritzker School of
Medicine, Chicago, IL, USA (Prof G L Bakris MD); Section of Nephrology and Hypertension, 1st
Department of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
(P A Sarafi dis MD); University of Maryland School of Medicine, Baltimore, MD, USA (Prof M R Weir
MD); Sahlgrenska University Hospital, Gothenburg, Sweden (Prof B Dahlof MD); University of
Michigan Health System, Ann Arbor, MI, USA (Prof B Pitt MD, K Jamerson MD); Duke University
School of Medicine, Durham, NC, USA (E J Velazquez MD); Novartis Pharmaceuticals Corporation,
East Hanover, NJ, USA (L Staikos-Byrne PhD, R Y Kelly MS, V Shi MD, Y-T Chiang PhD); and SUNY
Downstate Medical College, Brooklyn, NY, USA (Prof M A Weber MD)
Published Online February 18, 2010 DOI:10.1016/S0140- 6736(09)62100-0
Objective
The Avoiding Cardiovascular Events through
Combination Therapy in Patients Living with
Systolic Hypertension (ACCOMPLISH) trial
showed that initial antihypertensive therapy
with benazepril plus amlodipine was superior
to benazepril plus hydrochlorothiazide in
reducing cardiovascular morbidity and
mortality. We assessed the effects of these
drug combinations on progression of chronic
kidney disease.
Method
ACCOMPLISH was a double-blind, randomised trial undertaken
in five countries (USA, Sweden, Norway, Denmark, and Finland).
11 506 patients with hypertension who were at high risk for
cardiovascular events were randomly assigned via a central,
telephone-based interactive voice response system in a 1:1 ratio
to receive benazepril (20 mg) plus amlodipine (5 mg; n=5744) or
benazepril (20 mg) plus hydrochlorothiazide (12・5 mg; n=5762),
orally once daily. Drug doses were force-titrated for patients to
attain recommended blood pressure goals. Progression of
chronic kidney disease, a prespecified endpoint, was defined as
doubling of serum creatinine concentration or end-stage renal
disease (estimated glomerular filtration rate <15 mL/min/1・73 m2
or need for dialysis). Analysis was by intention to treat (ITT).
This trial is registered with ClinicalTrials.gov, number NCT00170950.
Patients were randomly assigned to receive either a single pill
combination of benazepril (20 mg) plus amlodipine (5 mg) or a
combination of benazepril (20 mg) plus hydrochlorothiazide (12・5 mg)
daily, without washout of previous medications.
1 month after randomisation, the benazepril component in both groups
was force titrated to 40 mg.
2 months after randomisation, investigators could titrate doses of
either drug to the maximum, if needed, to achieve a target blood
pressure of less than 140/90 mm Hg (or <130/80 mm Hg for patients
with diabetes or chronic kidney disease).
3 months after randomisation and until the end of the trial, add-on
antihypertensive agents, consisting of β blockers, α blockers,
clonidine, and spironolactone, were allowed. β blockers were
recommended as a second agent in both groups to achieve blood
pressure targets.
Once-daily loop diuretics could be given for volume management. After
the initial 3-month titration period, patients returned at 6 months and
then at 6-month intervals until the end of the trial.12 Patient follow-up
for assessment of endpoints continued until the end of the trial, even if
study medication had been permanently discontinued.
Endpoints
The primary endpoint of the main ACCOMPLISH trial was time to first
event of composite cardiovascular morbidity and mortality (sudden
cardiac death, myocardial infarction, stroke, coronary intervention,
congestive heart failure, or other cardiovascular causes).
The prespecified, intention-to-treat, chronic kidney disease endpoint was
time to first event of doubling of serum creatinine concentration or endstage renal disease, defined as eGFR less than 15 mL/min/1・73 m2 or
need for chronic dialysis. This endpoint was defined before the data and
safety monitoring board recommended early termination of the trial.
(Because of this early termination, the follow-up period in this trial is
about 1 year shorter than that in previous trials reporting chronic kidney
disease outcomes. )
Other endpoints were progression of chronic kidney disease plus death
(all-cause or cardiovascular), change in albuminuria, and change in eGFR.
Additionally, progression of chronic kidney disease was assessed in the
subset of patients with more advanced chronic kidney disease at baseline.
60%：diabetes mellitus
Patients with chronic kidney disease had a similar rate of diabetes to those without the disease (58・9% vs 60・5%; p=0・302).
Results
The trial was terminated early (mean follow-up 2・9 years [SD 0・4])
because of superior efficacy of benazepril plus amlodipine compared with
benazepril plus hydrochlorothiazide. At trial completion, vital status was
not known for 143 (1%) patients who were lost to follow-up (benazepril
plus amlodipine, n=70; benazepril plus hydrochlorothiazide, n=73). All
randomised patients were included in the ITT analysis. There were 113 (2・
0%) events of chronic kidney disease progression in the benazepril plus
amlodipine group compared with 215 (3・7%) in the benazepril plus
hydrochlorothiazide group (HR 0・52, 0・41–0・65, p<0・0001). The most
frequent adverse event in patients with chronic kidney disease was
peripheral oedema (benazepril plus amlodipine, 189 of 561, 33・7%;
benazepril plus hydrochlorothiazide, 85 of 532, 16・0%). In patients with
chronic kidney disease, angio-oedema was more frequent in the
benazepril plus amlodipine group than in the benazepril plus
hydrochlorothiazide group. In patients without chronic kidney disease,
dizziness, hypokalaemia, and hypotension were more frequent in the
benazepril plus hydrochlorothiazide group than in the benazepril plus
amlodipine group.
Conclusion
Initial antihypertensive treatment
with benazepril plus amlodipine
should be considered in
preference to benazepril plus
hydrochlorothiazide since it
slows progression of
nephropathy to a greater extent.
Message
ACEIとCa拮抗薬がACEIと利尿薬より腎臓に対し
てよかった という結果。
ARBでもおそらく
Ca拮抗薬
との併用から？
一応 糖尿病があるとABCD研究では 差はなし。
また，GUARD研究では 利尿薬の方が微量アル
ブミンは減少効果はよいとされた。
CARTER試験概要
Cilnidipine versus Amlodipine Randomized Trial for Evaluation in Renal Disease
● デ ザ イ ン : 多施設無作為化オープン比較試験
● 対 象 患 者 : 1. 尿蛋白300mg/gCr以上
2. 血清クレアチニン3.0mg/dL以下
3. 血圧130/85mmHg以上
4. 2～3ヵ月間RAS阻害薬で治療中
●方
法:
前観察期間
治療期間 1年間
RAS阻害薬+シルニジピン
339例
RAS阻害薬
（5-20mg/日）
179例
160例
RAS阻害薬+アムロジピン
（2.5-7.5mg/日）
● 目 標 血 圧 : 130/85mmHg未満
※ シルニジピン又はアムロジピンにて降圧目標値に到達しない場合は、
RAS阻害薬又はCa拮抗薬以外の第三の薬剤を追加投与。
● エンドポイント : 尿蛋白/クレアチニン比の変化
Fujita T, et al. Kidney Int 2007; 72: 1543-9
試験期間中の尿蛋白／Cr比の変化
20
*
*
15
2000
†
†
10
変化率 （%）
尿蛋白・クレアチニン比（mg/gCr）
2500
1500
1000
5
0
-5
-10
-15
500
-20
0
-25
投与前
1
3
6
12
観察期間（月）
147
168
142
168
137
160
3
6
12
観察期間（月）
*：p<0.05 vs シルニジピン群
ｱﾑﾛｼﾞﾋﾟﾝ群 160
ｼﾙﾆｼﾞﾋﾟﾝ群 179
1
130
146
*：p<0.05， †：p<0.01 vs シルニジピン群
アムロジピン群
シルニジピン群
Fujita T, et al. Kidney Int 2007; 72: 1543-9