Journal Club 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 2010 年６月３日 8:30-8:55 ８階 医局 Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee DE, Cass A, Chalmers J, Perkovic V. Effects of fibrates on cardiovascular outcomes: a systematic review and meta- analysis. Lancet May 29;375(9729): Epub 2010 May 10. Boutron I, Dutton S, Ravaud P, Altman DG. Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes. JAMA May 26;303(20):

Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med Mar 14. [Epub ahead of print]PMID: [PubMed - as supplied by publisher] Effects of Intensive Blood-Pressure Control in Type 2 Diabetes Mellitus. The ACCORD Study Group. N Engl J Med Mar 14. [Epub ahead of print]PMID: [PubMed - as supplied by publisher] Effect of Valsartan on the Incidence of Diabetes and Cardiovascular Events. The NAVIGATOR Study Group. N Engl J Med Mar 14. [Epub ahead of print]PMID: [PubMed - as supplied by publisher] Effect of Nateglinide on the Incidence of Diabetes and Cardiovascular Events. The NAVIGATOR Study Group. N Engl J Med Mar 14. [Epub ahead of print]PMID: [PubMed - as supplied by publisher]

primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317: Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102:21-7. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus Lancet 2005;366: Not Significant

Lancet 2010; 375: 1875–84 The George Institute for International Health, University of Sydney, Sydney, Australia (M Jun MSc, C Foote MBBS, J Lv MD, Prof B Neal MBChB, A Patel MD, Prof A Cass MBBS, Prof J Chalmers MBBS, V Perkovic MBBS); Peking University First Hospital, Beijing, China (J Lv); Departments of Cardiovascular Medicine and Cell Biology, Cleveland Clinic, Cleveland, OH, USA (S J Nicholls MBBS); and Julius Centre, University Medical Centre, Utrecht, Netherlands (Prof D E Grobbee MD) Funding National Health and Medical Research Council of Australia.

Background Several clinical trials have reported inconsistent findings for the effect of fibrates on cardiovascular risk. We undertook a systematic review and meta-analysis to investigate the effects of fibrates on major clinical outcomes. Trials of gemfibrozil, such as the Helsinki Heart Study and VA-HIT, have shown clear benefits, whereas the FIELD and ACCORD-Lipid trials with fenofibrate did not reach the primary endpoints.

We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and March, We included prospective randomised controlled trials assessing the effects of fibrates on cardiovascular outcomes compared with placebo. Summary estimates of relative risk (RR) reductions were calculated with a random effects model. Outcomes analysed were major cardiovascular events, coronary events, stroke, heart failure, coronary revascularisation, all-cause mortality, cardiovascular death, non-vascular death, sudden death, new onset albuminuria, and drug-related adverse events. Methods

Figure 1: Identification process for eligible studies *Article identified with ClinicalTrials.gov. The literature search yielded 1555 articles, of which 27 were reviewed in full text (figure 1). Of these studies, 18 randomised controlled trials met the inclusion criteria. These trials included a total of patients, in whom 2870 major cardiovascular events were reported from five studies, 3880 deaths from 15 studies, and 4552 coronary events from 16 studies.

IV= inverse variance. -C

TG 1 mg/dl = mmol/L, 0.1 mmol/L = 8.85 mg/dl Cholesterol 1 mg/dl = mmol/L, 0.1 mmol/L = 3.86 mg/dl -C

Results We identified 18 trials providing data for participants, including 2870 major cardiovascular events, 4552 coronary events, and 3880 deaths. Fibrate therapy produced a 10% RR reduction (95% CI 0–18) for major cardiovascular events (p=0 ・ 048) and a 13% RR reduction (7–19) for coronary events (p<0 ・ 0001), but had no benefit on stroke (–3%, –16 to 9; p=0 ・ 69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, –8 to 7; p=0 ・ 92), cardiovascular mortality (3%, –7 to 12; p=0 ・ 59), sudden death (11%, –6 to 26; p=0 ・ 19), or non-vascular mortality (–10%, –21 to 0 ・ 5; p=0 ・ 063). Fibrates reduced the risk of albuminuria progression by 14% (2–25; p=0 ・ 028). Serious drug related adverse events were not significantly increased by fibrates ( participants, 225 events; RR 1 ・ 21, 0 ・ 91–1 ・ 61; p=0 ・ 19), although increases in serum creatinine concentrations were common (1 ・ 99, 1 ・ 46–2 ・ 70; p<0 ・ 0001).

Conclusion Fibrates can reduce the risk of major cardiovascular events predominantly by prevention of coronary events, and might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia.

Editorial Comments They reported that patients with high triglycerides benefit most from fibrate treatment, whereas baseline HDL cholesterol did not affect outcome. The results show that the highest benefit of fibrates is achieved in patients with high triglycerides and low HDL cholesterol, who make up about a fifth of the diabetic population. Bart Staels Fibrates in CVD: a step towards personalised medicine Lancet 2010; 375:

Message フィブラート系薬物は脳梗塞には効果はなさそ う。心血管障害には 10% 程度のリスク減少があ るというが，．．． 中性脂肪が高く，おそらく HDL-C が低値の場合 に（糖尿病などのように）効果がありそうだが 検討する余地があるだろう。

JAMA. 2010;303(20): Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom (Drs Boutron and Altman and Ms Dutton); INSERM, U738, Paris, France (Drs Boutron and Ravaud); Assistance Publique des Hoˆ pitaux de Paris, Hoˆ pital Hoˆ - tel Dieu, Centre d’E´ pide´miologie Clinique, Paris (Drs Boutron and Ravaud); and Universite´ Paris Descartes, Faculte´ deMe´ decine, Paris (Drs Boutron and Ravaud).

Context Previous studies indicate that the interpretation of trial results can be distorted by authors of published reports. Objective To identify the nature and frequency of distorted presentation or “spin” (ie, specific reporting strategies, whatever their motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results) in published reports of randomized controlled trials (RCTs) with statistically nonsignificant results for primary outcomes.

Data Sources March 2007 search of MEDLINE via PubMed using the Cochrane Highly Sensitive Search Strategy to identify reports of RCTs published in December Study Selection Articles were included if they were parallel-group RCTs with a clearly identified primary outcome showing statistically nonsignificant results (ie, P ≧.05). Data Extraction Two readers appraised each selected article using a pretested, standardized data abstraction form developed in a pilot test. Methods

spin was defined as use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite a statistically nonsignificant difference for the primary outcome, or to distract the reader from statistically nonsignificant results.

Figure. Study Selection RCT indicates randomized controlled trial.

Abbreviations: CI, confidence interval; NA, not applicable. a All these articles also reported the statistically nonsignificant results for the primary outcome in the abstract and in the main text. bOne article also associated with other spin strategies. cOne article associated with particular focus on overall within- group analyses. dOne article associated with other spin (focuses on overall within- group assessment). e Three articles associated respectively with particular focus on overall within-group analyses, acknowledgment of negative primary outcome plus focus on positive secondary outcomes, and focus only on statistically significant results.

Results From the 616 published reports of RCTs examined, 72 were eligible and appraised. The title was reported with spin in 13 articles (18.0%; 95% confidence interval [CI], 10.0%- 28.9%). Spin was identified in the Results and Conclusions sections of the abstracts of 27 (37.5%; 95% CI, 26.4%- 49.7%) and 42 (58.3%; 95% CI, 46.1%-69.8%) reports, respectively, with the conclusions of 17 (23.6%; 95% CI, 14.4%-35.1%) focusing only on treatment effectiveness. Spin was identified in the main-text Results, Discussion, and Conclusions sections of 21 (29.2%; 95% CI, 19.0%- 41.1%), 31 (43.1%; 95% CI, 31.4%-55.3%), and 36 (50.0%; 95% CI, 38.0%- 62.0%) reports, respectively. More than 40% of the reports had spin in at least 2 of these sections in the main text.

Conclusion In this representative sample of RCTs published in 2006 with statistically nonsignificant primary outcomes, the reporting and interpretation of findings was frequently inconsistent with the results.

Message プライマリーエンドポイントが統計的に有意で なかった場合に論文で間違ったことが書かれて いないか注意が必要かもしれない。 「嘘つき論文に注意！」