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Journal Club

Journal Club. Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ. 2009 Aug 18;339:b2942. doi: 10.1136/bmj.b2942.

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Journal Club

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  1. Journal Club Juurlink DN, Gomes T, Lipscombe LL, Austin PC, Hux JE, Mamdani MM. Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohortstudy. BMJ. 2009 Aug 18;339:b2942. doi: 10.1136/bmj.b2942. Takahisa Sawada1*, Hiroyuki Yamada1, Bjo¨ rn Dahlo¨ f 2, and Hiroaki Matsubara1, for the KYOTO HEART Study Group Effects of valsartan on morbidity and mortality inuncontrolled hypertensive patients with high cardiovascular risks: KYOTO HEART Study European Heart Journal doi:10.1093/eurheartj/ehp363 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 2009年10月１日　8:30-8:55 ８階　医局

  2. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Nissen SE.:N Engl J Med.356.2007.May 21.Online

  3. Assessment of the cardiovascular risks and health benefits of rosiglitazone David J. Graham, MD, MPH Office of Surveillance and Epidemiology Food and Drug Administration July 30, 2007

  4. Does CV risk with RSG differ from that with PIO? • Yes • From DREAM, relatively low-risk population: RSG increased risk by ~40% c/w PBO • From PROactive, high risk population: PIO decreased risk by ~15% c/w PBO • From RSG meta-analysis: RSG increased risk of serious IHD by ~40% c/w all comparators & by ~70% c/w PBO • From PIO meta-analysis: PIO decreased risk by ~25% c/w all comparators • From head-to-head GLAI: RSG increased risk 3.5-fold c/w PIO

  5. 10 8 6 4 2 0 アクトスのイベントに及ぼす影響（メタ解析） （%） 総死亡、心筋梗塞、脳卒中 累積イベント発症率 対照群 ピオグリタゾン群 ハザード比 95%信頼区間 p値 ピオグリタゾンvs 対照群 0.82 0.72,0.94 0.005 （週） 0 20 40 60 80 100 120 140 症例数 対照群 アクトス群 7,836 8,554 6,470 6,556 5,509 5,370 4,133 4,026 3,735 3,679 3,534 3,505 2,826 2,810 2,143 2,146 19の臨床試験から16,390例を対象にピオグリタゾン群と対照群（プラセボ、SU薬、BG薬、インスリン）における、イベントの発症率をメタ解析した。 Lincoff A.M. et al.:JAMA,298,1180,2007.

  6. 1Division of Clinical Pharmacology and Toxicology, Department of Medicine, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, ON, Canada M4N 3M5 2Department of Medicine, University of Toronto 3Department of Pediatrics, University of Toronto 4Department of Health Policy, Management, and Evaluation, University of Toronto 5Institute for Clinical Evaluative Sciences, Toronto 6Women’s College Hospital, Toronto 7Department of Public Health Sciences, University of Toronto 8Applied Health Research Centre, Li Ka Shing Knowledge Institute, St Michael’s Hospital, Toronto BMJ 2009;339:b2942

  7. AIM To compare the risk of acute myocardial infarction, heart failure, and death in patients with type 2 diabetes treated with rosiglitazone and pioglitazone.

  8. Method Setting Ontario, Canada. Participants Outpatients aged 66 years and older who were started on rosiglitazone or pioglitazone between 1 April 2002 and 31 March 2008. Main outcome measure Composite of death or hospital admission for either acute myocardial infarction or heart failure. In a secondary analysis, each outcome was also examined individually.

  9. Results 39 736 patients who started on either pioglitazone or rosiglitazone were identified. During the six year study period, the composite outcome was reached in 895 (5.3%) of patients taking pioglitazone and 1563 (6.9%) of patients taking rosiglitazone. After extensive adjustment for demographic and clinical factors and drug doses, pioglitazone treated patients had a lower risk of developing the primary outcome than did patients treated with rosiglitazone (adjusted hazard ratio 0.83, 95% confidence interval 0.76 to 0.90). Secondary analyses revealed a lower risk of death (adjusted hazard ratio 0.86, 0.75 to 0.98) and heart failure (0.77, 0.69 to 0.87) with pioglitazone but no significant difference in the risk of acute myocardial infarction (0.95, 0.81 to 1.11). One additional composite outcome would be predicted to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone.

  10. Conclusion Among older patients with diabetes, pioglitazone is associated with a significantly lower risk of heart failure and death than is rosiglitazone. Given that rosiglitazone lacks a distinct clinical advantage over pioglitazone, continued use of rosiglitazone may not be justified.

  11. Message Rosiglitazoneとpioglitazoneの比較では両者の差が存在する。Pioglitazoneが有利であればrosiglitazoneを使う理由がない。

  12. 主要降圧薬の積極的適応 *1少量から開始し、注意深く漸増する　　*2非ジヒドロピリジン系Ca拮抗薬　　*3冠攣縮性狭心症には注意 *4ループ利尿薬　　*5メタボリックシンドローム　　*6ジヒドロピリジン系Ca拮抗薬 高血圧治療ガイドライン2009.

  13. 糖尿病を合併する高血圧の治療計画 治療開始血圧　130/80mmHg以上 生活習慣の修正・血糖管理と同時に薬物療法* 第一選択薬：ACE阻害薬、ARB 効果不十分 用量を増加 Ca拮抗薬、利尿薬を併用 効果不十分 3剤併用：ARBあるいはACE阻害薬、Ca拮抗薬、利尿薬 降圧目標　130/80mmHg未満 * 血圧が130-139/80-89mmHgで生活習慣の修正で降圧目標が見込める場合は、3か月を超えない範囲で生活習慣の修正により降圧を図る 高血圧治療ガイドライン2009.

  14. AⅡ PI 3-kinase AT-R P85 P-Ser- P110 Insulin Receptor P-Ser- -Tyr-P -Tyr-P β α -Tyr-P -Tyr-P -Tyr-P P-Ser- IRS-1 Diagram of AⅡsignaling interactions with the insulin receptor, IRS-1, and PI 3 kinase in RASMC Folli et al:J. Clin. Invest.100:2158–2169, 1997

  15. ARBの種類と糖尿病の発症（２型糖尿病治療におけるARBの意義）ARBの種類と糖尿病の発症（２型糖尿病治療におけるARBの意義） (%) (2004) (2002) (2002) (2005) (2004) (2001) (2003) VALUE, LIFE, SCOPE, CHARMのメタ解析の発症リスクは-23% NAVIGATOR, ONTARGET, TRANSCENDが進行中

  16. 糖尿病予防効果 ONTARGET 2008 4.7 ARB 399 8542 10.0 ACEI 366 8576 9.2 ONTARGET 2008 4.7 ARB+ACEI 323 8502 8.1 ACEI 366 8576 9.2 松田昌文：DREAM study 内分泌・糖尿病科 26(1):35-41, 2008.

  17. JIKEI HEART 1 • 従来治療群（Ca拮抗剤やACE阻害薬の増量・新規使用などによる）のサブ解析がされていない。（解析中と思われるがCa拮抗剤、ACE阻害薬あるいは両方使用の３群の差を知りたい） • バルサルタン群にはACE阻害薬がすでに投与されている患者も入っている。従ってACEIとARBの併用という患者のバイアスがかかっていないか。　（参考）バルサルタン群とは　　　　従来治療群にバルサルタンを追加投与する群 • 従来治療群でACE阻害薬使用群と非使用群の比較検討は？ • CKD予防としてのARBの観点から腎不全進行抑制ができなかったのは不思議である。 （従来治療群にACE阻害薬が多く使われていて、そのために差が出なかった？） • 腎機能低下例でのサブ解析でACE阻害薬and/orARB群と非ACE阻害薬and/orARB群で差が出るかも知れない。　　（Solomon SDCirculation１１４;26：2006） • 患者数がスタートから終了時点で　バルサルタン群　１５４１例から３６８例　従来治療群　　　１５４０例から３４３例　　　に減少している。この減少数は一般的な数なのか？ • http://blog.m3.com/reed/20070910/JIKEI__HEART_Study_2_

  18. JIKEI HEART 2 • http://rockymuku.sakura.ne.jp/zyunnkannkinaika/JIKEI%20HEART%20STUDY%20to%20PROBEhou.pdf • PROBEを用いた時は　「入院」のような介入方法はエンドポイントにいれてはいけない。

  19. Aim The objective was to assess the add-on effect of valsartan on top of the conventional treatment for high-risk hypertension in terms of the morbidity and mortality.

  20. Method The KYOTO HEART Study was of a multicentre, Prospective Randomised Open Blinded Endpoint (PROBE) design, and the primary endpoint was a composite of fatal and non-fatal cardiovascular events (clintrials.gov NCT00149227). A total of 3031 Japanese patients (43% female, mean 66 years) with uncontrolled hypertension were randomized to either valsartan add-on or non-ARB treatment.

  21. Procedure After confirming eligibility, patients were randomized in accordance with the minimization method with eight factors (age, gender, dyslipidaemia, diabetes mellitus, smoking, obesity, history of CAD and/or cerebrovascular disease, and history of congestive heart failure), either to the valsartan add-on group or to the conventional treatment group. For the valsartan add-on group, valsartan 80 mg once daily in the morning was administered to the patient as an initial dose, the dose was doubled after 4 weeks if the initial dose could not achieve the target blood pressure of less than 140/ 90 mmHg (in patients with diabetes or renal disease, target blood pressure was set to less than 130/80 mmHg). After 8 weeks, an additional administration of other antihypertensive drugs with flexible dosing regimen other than ARBs and ACE inhibitors was allowed if necessary. Meanwhile, for the conventional treatment group, the antihypertensive drugs other than ARB and ACE inhibitors were provided for the patients to reach the target blood pressure. The periodical follow-up was implemented every 6 months after setting the sustainable dose.

  22. Blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study

  23. stroke (hospitalization and diagnosed by CT and/or MRI), new or recurrent TIA (hospitalization and diagnosed by CT and/or MRI and sudden onset of neurological deficit persisting for less than 24 h without the history of atrial arrhythmia that causes embolism), new or recurrent acute myocardial infarction (hospitalization, ECGchange, and biomarkers for myocardial infarction), new occurrence or exacerbation of angina pectoris (hospitalization and diagnosed by both ECG changes corresponding with chest symptoms and coronary angiography showing .75% stenosis according to AHA/ACC guidelines), new occurrence or exacerbation of heart failure (hospitalization and clinical symptoms together with left ventricular dysfunction by echocardiography according to the guidelines of the AHA/ACC), dissecting aneurysm of the aorta (hospitalization and diagnosed by imaging technique), lower limb arterial obstruction, emergency thrombosis, transition to dialysis, and doubling of plasma Cr levels. The first of any of these events to occur in a specific patient was classified as an event to be counted in the primary endpoint by the Endpoint Committee.

  24. Results Median follow-up period was 3.27 years. In both groups, blood pressure at baseline was 157/88 and 133/76 mmHg at the end of study. Compared with non-ARB arm, valsartan add-on arm had fewer primary endpoints (83 vs. 155; HR 0.55, 95% CI 0.42–0.72, P . 0.00001).

  25. Conclusion Valsartan add-on treatment to improve blood pressure control prevented more cardiovascular events than conventional non-ARB treatment in high-risk hypertensive patients in Japan. These benefits cannot be entirely explained by a difference in blood pressure control.

  26. Message PROBE法(まぁ色々問題点もあるが)で血圧が同じにもかかわらずvalsartanの優位性がしめされた。 糖尿病の発症も減少！（JIKEI HEARTはどうだったの？）

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