1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2007 年 11 月 1 日 8:20-8:50 B 棟８階 カンファレンス室

2. Original Article Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes Stephen D. Wiviott, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Gilles Montalescot, M.D., Ph.D., Witold Ruzyllo, M.D., Shmuel Gottlieb, M.D., Franz-Joseph Neumann, M.D., Diego Ardissino, M.D., Stefano De Servi, M.D., Sabina A. Murphy, M.P.H., Jeffrey Riesmeyer, M.D., Govinda Weerakkody, Ph.D., C. Michael Gibson, M.D., Elliott M. Antman, M.D., for the TRITON–TIMI 38 Investigators N Engl J Med Volume 357(20):2001-2015 November 15, 2007

3. Abbreviations: AA, arachidonic acid; ASA, aspirin; cAMP, cyclic AMP; COX-1, cyclo-oxygenase 1; CYP P450, cytochrome P450; PI3K, phosphatidylionisitol 3-kinase; PLC, phospholipase C ; TP, thromboxane receptor; TxA 2, thromboxane A 2 ; VASP-P, phosphorylated vasodilator-stimulated phosphoprotein. Gurbel PA and Tantry US (2006) Drug Insight: clopidogrel nonresponsiveness Nat Clin Pract Cardiovasc Med 3: 387–395 doi:10.1038/ncpcardio0602 Mechanism of action of clopidogrel

4. N Engl J Med 2006;355:2297-307. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial

5. Abbildung: CAPRIE: Amplified benefit of clopidogrel in patients with hihger vascular risk In CAPRIE, 8,854 patients had a prior history of any ischemic event, and of these 4,496 had a history of a major acute event – a myocardial infarction or a stroke. The annual event rate per 1,000 patients was reduced in the clopidogrel group vs the ASA group by 34 in patients with a prior history of a major acute event, and by 28 in those with a prior history of any ischemic event, compared with 11 in the overall population. The benefits of clopidogrel over ASA were amplified in the higher vascular risk group

6. Abbildung 59: CAPRIE: Amplified benefit of clopidogrel in patients with diabetes In CAPRIE, 3,837 patients had co-existing diabetes. These patients are at higher risk of myocardial infarction, ischemic stroke, vascular death or hospitalization for ischemic events/bleeding (17.7 % diabetic vs 12.7 % non-diabetic in the ASA group; 15.6 % diabetic vs 11.8 % non-diabetic in the clopidogrel group). The annual event rate per 1,000 patients was reduced in the clopidogrel group vs the ASA group: by 38 in patients receiving insulin at baseline, 21 in diabetic patients who were not receiving insulin, compared with 11 in the overall CAPRIE population. The benefits of clopidogrel over ASA were amplified in the higher risk, insulin-dependent patients.

7. Role of Platelet Activation and Aggregation in Ischemic Syndromes Platelets flow in the blood as smooth disks until they are activated and change their conformation into spiny spheres (Panel A). Healthy endothelium secretes nitric oxide (NO) and prostacyclin (PGI 2 ), which help keep the platelets in an inactive state. CD39 on the endothelial surface converts adenosine diphosphate (ADP) — a powerful activator of platelets — into adenosine monophosphate (AMP); CD73 converts AMP into adenosine, which further prevents the activation of platelets. Injury to the endothelium exposes numerous ligands such as von Willebrand factor and collagen, which can bind their respective receptors, such as glycoprotein Ib/IX/V and glycoprotein VI, on platelets (Panel B). The activated platelet then releases numerous prothrombotic factors, such as thromboxane A2 (TxA2) and ADP, which themselves further activate platelets and amplify the thrombotic process (Panel C). Cross-linking by means of fibrinogen binding to the glycoprotein IIb/IIIa receptor on platelets leads to the formation of platelet aggregates (Panel D). The P2Y 12 subtype of the ADP receptor is the site of action of both prasugrel and clopidogrel, as well as of other compounds currently in development (Panel E). Both prasugrel and clopidogrel are thienopyridines that are prodrugs (Panel F). Their active metabolites bind irreversibly to the P2Y 12 ADP receptor and inhibit platelet activation and subsequent aggregation.

8. Study Overview Antiplatelet therapy with aspirin and a thienopyridine is a key component in the management of acute coronary syndromes This trial compared a novel, potent thienopyridine (prasugrel) with the standard thienopyridine (clopidogrel) in patients with acute coronary syndromes scheduled to have a coronary intervention Prasugrel led to better cardiovascular outcomes, but at the expense of more bleeding, including fatal bleeding 1 ： 56

9. Study Design Subjects: 13,608 subjects with acute coronary syndromes with scheduled PCI, TIMI score ≥ 3 Randomization: Prasugrel 6813 vs Clopidgrel 6795 Medication: A loading dose: 60 mg of prasugrel vs 300 mg clopidgrel (at randomization and 1 hour after leaving the cardiac catheterization lab.) PCI: under the discretion of the teating physicina Maintenance dose: Prasugrel 10mg vs Clopidgrel 75 mg daily Visits: 30 days, 90 days, and at 3-month interval Observation: Total 6 to 15 months

10. TIMI score JAMA 284:835-842, 2000

11. Baseline Characteristics of the Patients

12. Major Efficacy End Points in the Overall Cohort at 15 Months

13. Cumulative Kaplan- Meier Estimates of the Rates of Key Study End Points during the Follow-up Period The treatment of patients with acute coronary syndromes, across the full spectrum of such syndromes, with prasugrel (a 60-mg loading dose, followed by a 10-mg maintenance dose), as compared with clopidogrel at the standard, approved dose resulted in a significant 2.2% absolute reduction and a 19% relative reduction in the rate of the primary efficacy end point (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke).

14. Hazard Ratios and Rates of the Primary End Point, According to Selected Subgroups of Study Patients

15. Thrombolysis in Myocardial Infarction (TIMI) Bleeding End Points in the Overall Cohort at 15 Months

16. The Balance of Efficacy and Safety in Selected Subgroups

17. Conclusion In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding Overall mortality did not differ significantly between treatment groups 0 ： 57

19. Original Article Teriparatide or Alendronate in Glucocorticoid- Induced Osteoporosis Kenneth G. Saag, M.D., Elizabeth Shane, M.D., Steven Boonen, M.D., Ph.D., Fernando Marín, M.D., David W. Donley, Ph.D., Kathleen A. Taylor, Ph.D., Gail P. Dalsky, Ph.D., and Robert Marcus, M.D. N Engl J Med Volume 357(20):2028-2039 November 15, 2007

20. Reviews on Oct 19, 2006

21. Study Overview This study compared teriparatide, an anabolic agent, with alendronate in an 18-month randomized, double-blind, controlled trial involving patients who had received glucocorticoids for at least 3 months and were at high risk for fracture Bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate, though increased calcium levels occurred more often in the teriparatide group Teriparatide may prove to be useful in patients with glucocorticoid-induced osteoporosis 1 ： 34

22. Enrollment and Outcomes

23. Baseline Characteristics of the Patients

24. Percent Change in Mean Bone Mineral Density at the Lumbar Spine and Total Hip from Baseline to 18 Months or the Last Measurement

25. N-terminal propeptide of type 1 procollagen; bone-specific alkaline phosphatase;

26. N-telopeptide of type I human collagen; C-telopeptide

27. Percent Change in Markers of Bone Formation and Resorption

28. Summary of New Fractures and Clinically Relevant Adverse Events

29. Conclusion Among patients with osteoporosis who were at high risk for fracture, bone mineral density increased more in patients receiving teriparatide than in those receiving alendronate 0 ： 54