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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 .

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journal club
Journal Club

Eklind-CervenkaM, 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]

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

2011年2月3日8:30-8:55

8階 医局

slide2

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.

slide3

Department of Cardiology, South Hospital, Stockholm (DrsEklind-Cervenka and Rosenqvist); KarolinskaInstitutet, Department of Clinical Science and Education, SöS, Stockholm (DrsEklind-Cervenka and Rosenqvist and Ms Benson); Department of Cardiology, Linköping University Hospital, and Department of Medical and Health Sciences, Linköping University, Linköping (DrDahlström); Division of Cardiovascular Medicine, Danderyd Hospital, and KarolinskaInstitutet, Department of Clinical Sciences, Danderyd, Stockholm (DrEdner); and Department of Cardiology, Karolinska University Hospital, and KarolinskaInstitutet, Department of Medicine, Stockholm (Dr Lund), Sweden.

JAMA. 2011;305(2):175-182

slide4

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.

slide5

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.

slide6

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.

slide7

Use of propensity score: LindenauerPK, 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.

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)。

http://dr-urashima.jp/pdf/eki-200406-1.pdf

slide10

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.

slide16

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.

slide17

Conclusion

In this registry of patients with HF, the use of candesartan compared with losartan was associated with a lower mortality risk

slide18

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
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.

end points
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
Results

■Effect of Rosuvastatin

・Compliance; 75%

-37%

-50%

+4%

-17%

slide25

20 mg

NNT:95 31 ・・25

(2years)(4years)(5years)

N Engl J Med 2008;359:2195-207.

slide26

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 cost-effectiveness 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)09327-3PMID 12114036.

^ Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering 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.

slide27

30

4S - Placebo

25

Rx - Statin therapy

PRA – pravastatin

ATV - atorvastatin

Secondary Prevention

4S - Rx

20

Event rate (%)

LIPID - Placebo

15

CARE - Placebo

LIPID - Rx

CARE - Rx

Primary Prevention

HPS - Placebo

HPS - Rx

TNT – ATV10

10

PROVE-IT - PRA

WOSCOPS – Placebo

TNT – ATV80

PROVE-IT – ATV

AFCAPS - Placebo

6

5

AFCAPS - Rx

WOSCOPS - Rx

ASCOT - Placebo

ASCOT - Rx

0

40

(1.0)

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)

LDL-Cholesterol and Coronary event rate

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

slide28

CRPC-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

slide29

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

slide30

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.

slide31

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.

slide37

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 pre-existing vascular disease.

slide38

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 vs2585 [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%] vs329 [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%] vs400 [20・9%]).

slide39

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.

slide40

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。

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