Journal Club
Eklind-Cervenka M, Benson L, Dahlström U, Edner M, Rosenqvist M, Lund
LH.
Association of candesartan vs losartan with all-cause mortality in patients
with heart failure.
JAMA. 2011 Jan 12;305(2):175-82.
Heart Protection Study Collaborative Group.
C-reactive protein concentration and the vascular benefits of statin therapy:
an analysis of 20 536 patients in the Heart Protection Study.
Lancet. 2011 Jan 27. [Epub ahead of print]
2011年2月3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
Losartan (rINN) (pronounced /loʊˈsɑrtən/) is an angiotensin II
receptor antagonist drug used mainly to treat high blood
pressure (hypertension). Losartan was the first angiotensin II
receptor antagonist to be marketed. It is currently marketed
by Merck & Co. under the trade name Cozaar. As of 2010
Losartan is now available in generic form.
Candesartan (rINN) (pronounced /ˌkændɨˈsɑrtən/) is an
angiotensin II receptor antagonist used mainly for the
treatment of hypertension. The prodrug candesartan cilexetil
is marketed by AstraZeneca and Takeda Pharmaceuticals,
commonly under the trade names Blopress, Atacand, Amias,
and Ratacand.
Candesartan has 4 binding sites on the
AT1 receptor and losartan has 2 binding
sites.
Department of Cardiology, South Hospital, Stockholm
(Drs Eklind-Cervenka and Rosenqvist); Karolinska
Institutet, Department of Clinical Science and Education,
SöS, Stockholm (Drs Eklind-Cervenka and Rosenqvist
and Ms Benson); Department of Cardiology, Linköping
University Hospital, and Department of Medical and
Health Sciences, Linköping University, Linköping (Dr
Dahlström); Division of Cardiovascular Medicine,
Danderyd Hospital, and Karolinska Institutet,
Department of Clinical Sciences, Danderyd, Stockholm
(Dr Edner); and Department of Cardiology, Karolinska
University Hospital, and Karolinska Institutet,
Department of Medicine, Stockholm (Dr Lund), Sweden.
JAMA. 2011;305(2):175-182
Context Angiotensin II receptor blockers
(ARBs) reduce combined mortality and
hospitalization in patients with heart failure
(HF) with reduced left ventricular ejection
fraction. Different agents have different
affinity for the AT1 receptor and may have
different clinical effects, but have not been
tested against each other in HF.
Objective To assess the association of
candesartan vs losartan with all-cause
mortality in patients with HF.
Design, Setting, and Patients
An HF registry (the Swedish Heart Failure Registry) of
30 254 unique patients registered from 62 hospitals and
60 outpatient clinics between 2000 and 2009. A total of
5139 patients (mean [SD] age, 74 [11] years; 39%
women) were treated with candesartan (n=2639) or
losartan (n=2500). Survival as of December 14, 2009,
by ARB agent was analyzed by Kaplan-Meier method
and predictors of survival determined by univariate and
multivariate proportional hazard regression models,
with and without adjustment for propensity scores and
interactions. Stratified analyses and quantification of
residual confounding were also performed.
Main Outcome Measures
All-cause mortality at 1 and 5 years.
In statistics, imputation is the substitution of some value for
a missing data point or a missing component of a data
point.
To avoid bias due to missing baseline characteristics,
multiple imputation (n=10) was performed for variables
with missing data using predictive mean matching. All
subsequent analyses, except for descriptive statistics,
were performed on the imputed data. To adjust for
selection bias, propensity scores for each patient were
estimated with logistic regression. Quintiles of the
estimated propensity scores were used to divide the
patients into 5 strata.
Use of propensity score: Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative
beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. 2005 Jul 28;353(4):349-61.
http://dr-urashima.jp/pdf/eki-200406-1.pdf
propensity score の概念
最近propensity score という方法が考案された。観察的データのみからランダム化 臨床試験に近い結果
を得る手法として注目されている。Propensity とは性癖、性質、 傾向を意味する。ある治療を行うか否か
は、医師の性癖（好み）に寄る部分が大きい。 ある患者さんがA 医師にかかった場合には治療A が選択さ
れ、同じ患者さんがB 医師に かかれば、治療A は選択されずに経過観察されるだけかもしれない。そこで、
多くの因 子のデータを基に治療A が選択される確率を多ロジスティック解析を用いて算出する。 これを
propensity score と呼ぶ。これは確率であるため0 から1 の間にあり、2 人の患者さんのpropensity
score が0.6 であれば同じ確率（およそ3 人に2 人）でその治 療を受けることになる。そこで、propensity
score が同じ0.6 であったにもかかわら ず、ある患者さんは治療A を受け、ある患者さんは受けなかったと
いう状況が発生する、 そこで、このような2 人をマッチさせる。そうすると、誰がみても治療A が選択される
場合（患者さん）、誰がみても治療A が選択されない場合（患者さん）はpropensity score を用いた解析か
らは除かれることになる。
propensity score でマッチングすると、自然と予後因子が治療A を行わなかった患者群と行った患者群で
一致してくる。この表はあたかもランダム化臨床試験で最初にで てくる表のようである。すなわち、
propensity score を用いた研究は観察であるにも かかわらずランダム化臨床試験のようになるのである。
実際の臨床現場において医師は propensity score が高くてもその治療を行なわなかったり、逆に低い場
合でもその治 療を行なったりする。つまり中間の部分では同じ予後因子を持っていても、ある人はその治
療を受け、またある人は治療を受けない。これはまさにランダム化臨床試験と似ているわけで、同じ背景
因子をもつ患者さんでも医師によって治療方針が異なることを逆 手にとったのがpropensity score を用い
た臨床観察研究ということになる。これを、 一言でいうならば、治療選択バイアスを軽減するためのデザイ
ンである。 しかし、いくつか問題点も存在する。１つは治療群間でマッチングできる対象が少ない場合であ
る。例えば、ある疾患に対して治療A が選択される基準は、医師の裁量に寄 らずほとんど一定していると
きなどがそれに相当する、何故なら、マッチングできる対 象が、例えば全体の数％にまで低下してしまうか
らである。第二に、変数が少ない場合 である。なるべくランダム化臨床試験に近づけたいのであるが、十
分な変数がとれてい ない場合には、通常の多変量解析で補正しても問題ない（多変量解析より
propensity score の方が有用である場合もある）。
target doses (defined as 32 mg/d and 50 mg/d [or 150mg/d] for candesartan and losartan,
respectively) cf. Candesartan (16 mg/d) compared with losartan (100 mg/d) was more effective
at lowering blood pressure, and after a forced missed dose, patients receiving losartan but not
candesartan returned to pretreatment blood pressure.
Results
One-year survival was 90% (95% confidence interval
[CI], 89%-91%) for patients receiving candesartan and
83% (95% CI, 81%-84%) for patients receiving losartan,
and 5-year survival was 61% (95% CI, 54%-68%) and
44% (95% CI, 41%-48%), respectively (log-rank
P<.001). In multivariate analysis with adjustment for
propensity scores, the hazard ratio for mortality for
losartan compared with candesartan was 1.43 (95% CI,
1.23-1.65; P<.001). The results persisted in stratified
analyses.
Conclusion
In this registry of patients with HF, the use
of candesartan compared with losartan was
associated with a lower mortality risk
Message/Comments
ARBどうしのHead-to-Head研究は珍しく、
また差がでている。
観察研究でも論文化される統計手法がある。
しかし、実際の介入が複雑でうまく解析さ
れているのか不安もあるが。
新しいARBの開発が進んでいるようである。
Methods
■ A randomized, double-blind, placebo-controlled,
multicenter trial conducted at 1315 sites in 26 countries
・ intention-to-treat basis
■ Inclusion Criteria
・ did not have a Hx of cardiovascular disease
• LDL≦130 mg/dl and high-sensitivity CRP≧ 2.0 mg/l
• a willingness to participate for the duration of the trial
• TG ≦ 500 mg/dl
Justification for the Use of Statins in
Prevention: an Intervention Trial
Evaluating Rosuvastatin (JUPITER)
N Engl J Med 2008;359:2195-207.
20 mg
End points
■Primary outcome
• occurrence of a first major cardiovascular event,
defined as nonfatal MI, nonfatal stroke,
hospitalization for unstable angina,
an arterial revascularization procedure,
or confirmed death from cardiovascular causes.
■Secondary end points
• the components of the primary end point
considered individually and death from any cause.
Results
■Effect of Rosuvastatin
・Compliance; 75%
-37%
-50%
+4%
-17%
20 mg
NNT:
N Engl J Med 2008;359:2195-207.
95
(2years)
31
･･25
(4years) (5years)
Heart Protection Study
An outline of the study protocol was published in 1999.[1] Initial results[2] were
published in 2002, which indicated that vitamins made little difference in modifying
cardiovascular risk, but that simvastatin could significantly reduce the risk of
cardiovascular events. Further results, from 2003 and 2004, focused on the role of
simvastatin in diabetics[3] and preventing stroke.[4] A 2005 paper analyses the costeffectiveness of a prescribing strategy similar to the one employed in the study.[5]
^ MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of
antioxidant vitamin supplementation in a wide range of patients at
increased risk of coronary heart disease death: early safety and efficacy
experience. Eur Heart J 1999;20:725-41. PDF. PMID 10329064.
^ Heart Protection Study Collaborative Group. MRC/BHF Heart Protection
Study of cholesterol lowering with simvastatin in 20,536 high-risk
individuals: a randomised placebo-controlled trial. Lancet 2002;360:7-22.
doi:10.1016/S0140-6736(02)09327-3 PMID 12114036.
^ Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study
Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised
placebo-controlled trial. Lancet 2003;361:2005-16. PMID 12814710
^ Collins R, Armitage J, Parish S, Sleight P, Peto R; Heart Protection Study
Collaborative Group. Effects of cholesterol-lowering with simvastatin on
stroke and other major vascular events in 20536 people with
cerebrovascular disease or other high-risk conditions. Lancet
2004;363:757-67. PMID 15016485.
^ Mihaylova B, Briggs A, Armitage J, Parish S, Gray A, Collins R; Heart
Protection Study Collaborative Group. Cost-effectiveness of simvastatin in
people at different levels of vascular disease risk: economic analysis of a
randomised trial in 20,536 individuals. Lancet 2005;365:1779-85. PMID
15910950.
Lancet 2004;363:757-67.
LDL-Cholesterol and Coronary event rate
30
25
20
4S - Placebo
Rx - Statin therapy
PRA – pravastatin
ATV - atorvastatin
Secondary Prevention
4S - Rx
LIPID - Placebo
15
CARE - Placebo
LIPID - Rx
CARE - Rx
HPS - Placebo Primary Prevention
HPS - Rx
TNT – ATV10
10
PROVE-IT - PRA
WOSCOPS – Placebo
TNT – ATV80
PROVE-IT – ATV
AFCAPS - Placebo
5
AFCAPS - Rx
ASCOT - Rx
0
40
(1.0)
6
WOSCOPS - Rx
ASCOT - Placebo
60
(1.6)
80
(2.1)
100
(2.6)
120
(3.1)
140
(3.6)
160
(4.1)
180
(4.7)
200
(5.2)
LDL-C achieved mg/dL (mmol/L)
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:1425-1435
27
CRP C-reactive protein
C-reactive protein (CRP) is a protein found in the blood, the
levels of which rise in response to inflammation (i.e. C-reactive
protein is an acute-phase protein). Its physiological role is to
bind to phosphocholine expressed on the surface of dead or
dying cells (and some types of bacteria) in order to activate
the complement system via the C1Q complex. CRP is
synthesized by the liver in response to factors released by fat
cells (adipocytes). It is a member of the pentraxin family of
proteins. It is not related to C-peptide or protein C.
C-reactive protein, pentraxin-related
Heart Protection Study, Clinical Trial
Service Unit, Richard Doll Building,
University of Oxford, Oxford OX3 7LF, UK
The Heart Protection Study was a large randomized controlled trial run by the
Clinical Trial Service Unit, and funded by the Medical Research Council (MRC) and
the British Heart Foundation (BHF) in the United Kingdom. It studied the use of
statin (simvastatin 40 mg) medication and vitamin supplementation (vitamin E,
vitamin C and beta carotene) in patients that are at risk for cardiovascular disease.
www.thelancet.com Published online January 28, 2011 DOI:10.1016/S0140-6736(10)62174-5
Background
It has been suggested that inflammation status,
as assessed by C-reactive protein (CRP)
concentration, modifies the vascular protective
effects of statin therapy. In particular, there have
been claims that statins might be more
beneficial in people with raised CRP
concentrations, and might even be ineffective in
people with low concentrations of both CRP and
LDL cholesterol. This study aimed to test this
hypothesis.
Methods
In 69 UK hospitals, 20 536 men and women aged
40–80 years at high risk of vascular events were
randomly assigned to simvastatin 40 mg daily
versus matching placebo for a mean of 5・0 years.
Patients were categorised into six baseline CRP
groups (<1・25, 1・25–1・99, 2・00–2・99, 3・00–4・
99, 5・00–7・99, and ≥8・00 mg/L). The primary
endpoint for subgroup analyses was major
vascular events, defined as the composite of
coronary death, myocardial infarction, stroke, or
revascularisation. Analysis was by intention to
treat.
This study is registered, number ISRCTN48489393.
Panel: Research in context
Systematic review
Electronic searches of Medline, PubMed, and Scopus, supplemented by hand
searches of reference lists of review articles and meta-analyses, identified four
trials6–8,11 that had previously estimated the effect of statin therapy by
baseline concentration of C-reactive protein (CRP). These studies were all of
high quality based on blinding of patients, use of intention-to-treat analyses,
details about completeness of follow-up, the type of intervention, reporting of
the patient population, and outcome reporting. However, they each included
small numbers of cardiovascular events.
Interpretation
The large numbers of major vascular events in the Heart Protection Study
(HPS) allows a reliable test of the hypothesis that the effects of statin therapy
differ according to baseline CRP concentration. The results do not lend
support to the suggestion that the beneficial effects of statin therapy are
affected by baseline CRP concentration or, more generally, by inflammation
status. The results could be applicable to all statins (not only simvastatin) and
are likely to be applicable to a wide range of people with and without preexisting vascular disease.
Findings
Overall, allocation to simvastatin resulted in a significant 24%
(95% CI 19–28) proportional reduction in the incidence of first
major vascular event after randomisation (2033 [19・8%] allocated
simvastatin vs 2585 [25・2%] allocated placebo). There was no
evidence that the proportional reduction in this endpoint, or its
components, varied with baseline CRP concentration (trend p=0・
41). Even in participants with baseline CRP concentration less
than 1・25 mg/L, major vascular events were significantly reduced
by 29% (99% CI 12–43, p<0・0001; 239 [14・1%] vs 329 [19・4%]).
No significant heterogeneity in the relative risk reduction was
recorded between the four subgroups defined by the combination
of low or high baseline concentrations of LDL cholesterol and CRP
(p=0・72). In particular, there was clear evidence of benefit in
those with both low LDL cholesterol and low CRP (27% reduction,
99% CI 11–40, p<0・0001; 295 [15・6%] vs 400 [20・9%]).
Interpretation
Evidence from this large-scale randomised
trial does not lend support to the
hypothesis that baseline CRP
concentration modifies the vascular
benefits of statin therapy materially.
Funding: UK Medical Research Council, British Heart
Foundation, Merck, Roche Vitamins, and
GlaxoSmithKline.
Message/Comments
過去にJUPITER研究（ロスバスタチンをCRPが高
いがコレステロール正常者に投与）でよい結果
が出たが、コレステロールが高い場合にはCRP
はあまり関係ないのかもしれない。