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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

Welcome Ask The Experts March 24-27, 2007 New Orleans, LA. Christopher P. Cannon, MD Senior Investigator, TIMI Study Group Cardiovascular Division Brigham and Women's Hospital Associate Professor of Medicine Harvard Medical School Boston, MA. Year in Review 2006.

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Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

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  1. Welcome Ask The Experts March 24-27, 2007 New Orleans, LA

  2. Christopher P. Cannon, MDSenior Investigator, TIMI Study GroupCardiovascular DivisionBrigham and Women's HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA Year in Review 2006 C. Michael Gibson, MS, MDAssociate Professor of MedicineHarvard Medical SchoolChief of Clinical ResearchCardiology DivisionBeth Israel Deaconess Medical CenterBoston, MA

  3. Top Ten Clinical Trials of the Year

  4. BASKET LATE Trial Basel Stent Cost-effectiveness Trial-Late Thrombotic Events (BASKET LATE) Trial Presented at The American College of Cardiology Scientific Session 2006 Presented by Dr. Matthias E. Pfisterer

  5. BASKET LATE Trial: Primary Composite Endpoint Composite of Cardiac death or nonfatal MI (%) p=0.01 • In the year following clopidogrel discontinuation, the primary composite endpoint of cardiac death or MI occurred significantly more frequently in the DES group than in the BMS group (4.9% vs. 1.3%, p=0.01). % patients Presented at ACC 2006

  6. BASKET LATE Trial: “Thrombosis-Related Events” Additional endpoint of “thrombosis-related events” (%) p=0.23 • There was no significant difference in the occurrence of late stent thrombosis (combination of angiographic documented thrombosis and thrombotic clinical events) between the DES and BMS groups (2.6% vs. 1.3%, p=0.23). • The median time of the late thrombotic event was 116 days following clopidogrel discontinuation, but events occurred throughout the one year follow-up (range 362 days). % patients Presented at ACC 2006

  7. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance(CHARISMA) The Cleveland Clinic Foundation Deepak L. Bhatt M.D., Keith A. A. Fox M.B.Ch.B., Werner Hacke M.D., Peter B. Berger M.D., Henry R. Black M.D., William E. Boden M.D., Patrice Cacoub M.D., Eric A. Cohen M.D., Mark A. Creager M.D., J. Donald Easton M.D., Marcus D. Flather M.D., Steven M. Haffner M.D., Christian W. Hamm M.D., Graeme J. Hankey M.D., S. Claiborne Johnston M.D., Koon-Hou Mak M.D., Jean-Louis Mas M.D., Gilles Montalescot M.D., Ph.D., Thomas A. Pearson M.D., P. Gabriel Steg M.D., Steven R. Steinhubl M.D., Michael A. Weber M.D., Danielle M. Brennan M.S., Liz Fabry-Ribaudo M.S.N., R.N., Joan Booth R.N., Eric J. Topol M.D., on behalf of the CHARISMA Investigators

  8. 8 6 4 2 0 Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)† Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% Cumulative event rate (%) RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 0 6 12 18 24 30 Months since randomization§ † First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA 75-162 mg/day §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

  9. Overall Population: Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17 Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.10) <0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

  10. Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) p value Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.046 (n=12,153) Multiple Risk Factors 1.20 (0.91, 1.59) 0.20 (n=3,284) Overall Population* 0.93 (0.83, 1.05) 0.22 (n=15,603) 1.2 1.4 1.6 0.4 0.6 0.8 Clopidogrel Better Placebo Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-specified subgroups of patients Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

  11. Nordman AJ, et al. Hot Line Session. World Congress of Cardiology, September 3, 2006, Barcelona.

  12. 7 6 5 4 3 2 1 0 DES/BMS SES/BMS PES/BMS Incidence of Late Stent Thrombosis: > 1 Year Per 1,000 pts RR = 5.7 p = 0.049 RR = 5.0 p = 0.02 p = 0.22 0 0 0 Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006.

  13. ISAR-REACT 2 Trial Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) Trial Presented at The American College of Cardiology Scientific Session 2006 Presented by Dr. Adnan Kastrati

  14. ISAR-REACT 2 Trial: Primary Composite Endpoint Composite of death, MI, or urgent TVR due to Myocardial Ischemia within 30 days (%) p=0.03 • The primary composite endpoint occurred less frequently in the abciximab group compared to placebo (8.9% vs 11.9%; relative risk [RR] 0.75 p=0.03) Presented at ACC 2006

  15. 20 15 10 5 0 ISAR REACT 2: Benefit of IIb/IIIa in Tn+ Patients, even after Pretreatment with Clopidogrel 600 mg Death,MI, or Urg TVR by Troponin (>0.03 µg/L) Placebo Group Abciximab Group Troponin >0.03 µg/L Log-Rank P = .02 Cumulative Rate of Primary End Point, % Troponin <0.03 µg/L Log-Rank P = .98 0 5 10 15 20 25 30 Days After Randomization Adapted with permission from Kastrati A, et al. JAMA. 2006;295:1531-1538.

  16. Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial InfarctionExTRACT-TIMI 25 ACC 2006 Atlanta, GA Disclosure Statement: Dr. Antman received research grant support via the Brigham and Women’s Hospital from sanofi-aventis

  17. Primary End Point (ITT)Death or Nonfatal MI UFH 12.0% 17% RRR 9.9% Primary End Point (%) ENOX Relative Risk0.83 (0.77 to 0.90)P<0.0001 Lost to follow up = 3 Days

  18. For Every 1000 Pts Treated with Enoxaparin + (No increase in nonfatal ICH) Events / 1000 Pts Nonfatal reMI Urgent Revasc. Death Nonfatal TIMI Major Bleed

  19. OASIS-6 Trial: Primary EndpointDeath/MI Reduction in Death/MI: Stratum I (No UFH indicated) P<.05 Reduction in Death/MI: Stratum II (UFH Indicated) P=NS p=0.97 • There was no difference in Stratum 2, comparing those patients who received fondaparinux vs those who received UFH (8.3% vs 8.7%; HR 0.96, P=NS). The reduction in the primary endpoint at 30 days in the fondaparinux group was driven by Stratum 1, where death/MI occurred less frequently among fonda. pts than placebo (11.2 vs 14%; HR 0.79, P<.05). The OASIS-6 Trial Group. JAMA. 2006;295:E1-E12.

  20. ASSENT- 4 PCI Trial The Assessment of the Safety and Efficacy of a New Treatment Strategy for Acute Myocardial Infarction (ASSENT-4 PCI) Trial Presented at The European Society of Cardiology Hot Line Session 2005 Presented by Dr. Frans Van de Werf

  21. ASSENT- 4 PCI Trial: Mortality at 30 days Analysis of mortality at 30 days (%) p = 0.04 • The primary endpoint of mortality was higher in the • TNK + PCI treatment group compared with the PCI alone group (6.0% vs 3.8%, p=0.04) at 30 days n=50 n=32 Presented at ESC 2005

  22. ASSENT-4: In-Hospital Cardiac Events Thrombolysis immediately pre-PCI van de Werf F. Lancet 2006

  23. Prospective, Randomized Comparison of Heparin Plus IIb/IIIa Inhibition and Bivalirudin With or Without IIb/IIIa Inhibition in Patients with Acute Coronary Syndromes Gregg W. Stone MD for the ACUITY Investigators

  24. Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI p value(non inferior)(superior) UFH/Enox + IIb/IIIa Primary endpoint Risk ratio ±95% CI Bival + IIb/IIIa RR (95% CI) <0.001 0.93 Net clinical outcome 11.8% 11.7% 1.01 (0.90-1.12) 0.015 0.39 Ischemic composite Upper boundary non-inferiority 7.7% 7.3% 1.07 (0.92-1.23) <0.001 0.38 Major bleeding 5.3% 5.7% 0.93 (0.78-1.10) Bivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa better

  25. Primary Endpoint Measures (ITT) UFH/Enoxaparin + GPI vs. Bivalirudin Alone p value(non inferior)(superior) UFH/Enox + IIb/IIIa Primary endpoint Risk ratio ±95% CI Bival alone RR (95% CI) <0.001 0.015 Net clinical outcome 10.1% 11.7% 0.86 (0.77-0.97) 0.02 0.32 Ischemic composite 7.8% 7.3% 1.08 (0.93-1.24) Upper boundary non-inferiority <0.001 <0.001 Major bleeding 3.0% 5.7% 0.53 (0.43-0.65) Bivalirudin alone better UFH/Enox + IIb/IIIa better

  26. Primary Endpoint Measures (ITT) Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa p value(non inferior)(superior) Deferred IIb/IIIa Primary endpoint Risk ratio ±95% CI Upstream IIb/IIIa RR (95% CI) <0.001 0.93 Net clinical outcome 11.7% 11.7% 1.00 (0.89-1.11) Ischemic composite 0.06 0.13 Upper boundary non-inferiority 7.1% 7.9% 1.12 (0.97-1.29) <0.001 0.01 Major bleeding 6.1% 4.9% 0.80 (0.67-0.95) Deferred PCI GPI better Routine Upstream GPI better

  27. DREAM Diabetes REduction Assessment with ramipril and rosiglitazone Medication

  28. Primary Outcome: Rosiglitazone HR = 0.40 (0.35-0.46); P<0.0001 Placebo Rosiglitazone DREAM Year

  29. DREAM Primary Outcome: Ramipril HR 0.91 (CI 0.81-1.03); P=0.15 Placebo Ramipril Year

  30. Cardiovascular Outcomes Following Long-term Treatment with Etoricoxib vs Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis Multinational Etoricoxib and Diclofenac ArthritisLong-term (MEDAL) Study Program Christopher P. Cannon, MD, Sean P. Curtis, MD, Amarjot Kaur, PhD, Loren Laine, MD, for the MEDAL Steering Committee

  31. Diclofenac (323 events) Etoricoxib (320 events) Primary Endpoint: Cumulative Incidence of Thrombotic CV Events 7.0 6.0 Etoricoxib vs diclofenacHR = 0.95 95% CI = (0.81-1.11) 5.0 4.0 Cumulative incidence (%) with 95% CI 3.0 2.0 1.0 0 0 6 12 18 24 30 36 42 Months No. of patients at risk* Etoricoxib 16,819 13,359 10,733 8277 6427 4024 805 Diclofenac 16,483 12,800 10,142 7901 6213 3832 815 *Per protocol population.

  32. Etoricoxib (176 events) POBs† No. of patients at risk Etoricoxib 17412 13704 10972 8400 6509 4063 821 Diclofenac 17289 13190 10396 8027 6306 3867 820 Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)* 3.0 Diclofenac (246 events) 2.5 Etoricoxib vs diclofenacHR = 0.69 95% CI = (0.57-0.83) 2.0 1.5 Cumulative incidence (%) with 95% CI 1.0 0.5 0 0 6 12 18 24 30 36 42 Months *ITT (14 days) population. 50.6% of patients were on gastroprotective agents. †No significant difference in perforations, obstructions, or major bleeds.

  33. ASTEROID Steven E. Nissen MD Disclosure Consulting: AstraZeneca, Abbott, Atherogenics, Bayer, Lipid Sciences, Wyeth, Novartis, Pfizer, Sankyo, Haptogard, Hoffman-LaRoche, Kemia, Takeda, Kowa, Sanofi-Aventis, Protevia, Novo-Nordisk, Eli Lilly, Kos, GlaxoSmithKline, Forbes Medi-tech, Vasogenix,Vascular Biogenics, Isis Pharma, Viron Therapeutics, Roche, and Merck–Schering Plough Lectures:AstraZeneca and Pfizer Clinical Trials:AstraZeneca, Eli Lilly, Takeda, Sankyo, Sanofi-Aventis, Pfizer, Atherogenics, and Lipid Sciences. Companies are directed to pay any honoraria directly to charity. No personal reimbursement is accepted for directing or participating in clinical trials. The Effect of Very High-Intensity Statin Therapyon Regression of Coronary Atherosclerosis

  34. ASTEROID: Percent Atheroma Volume 80 Regression63.6% Progression36.4% 60 Number of Patients 40 20 0 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 Change in Percent Atheroma Volume (%)

  35. Recent Coronary IVUS Progression Trials Relationship between LDL-C and Progression Rate 1.8 CAMELOT placebo REVERSAL pravastatin 1.2 Median Change In Percent AtheromaVolume (%) ACTIVATE placebo 0.6 REVERSAL atorvastatin A-Plus placebo 0 r2= 0.95 p<0.001 -0.6 ASTEROID rosuvastatin -1.2 50 60 70 80 90 100 110 120 Mean Low-Density Lipoprotein Cholesterol (mg/dL)

  36. ILLUMINATE: Torcetrapib Trial Halted ILLUMINATE trial, a randomized, double-blind evaluation of the effect of torcetrapib/atorvastatin vs atorvastatin alone on the occurrence of major cardiovascular events in 15 000 subjects with coronary heart disease or risk equivalents. The Data Safety Monitoring Board (DSMB) recommended the trial be halted due to an "imbalance of mortality and cardiovascular events." Overall, 82 patients taking the combination of torcetrapib and atorvastatin died, compared with 51 patient deaths in the atorvastatin-alone arm.

  37. C. Michael Gibson, MS, MDAssociate Professor of MedicineHarvard Medical SchoolChief of Clinical ResearchCardiology DivisionBeth Israel Deaconess Medical CenterBoston, MA Preview of ACC CTR agenda

  38. Question & Answer

  39. Thank You! Please make sure to hand in your evaluation and pick up a ClinicalTrialResults.org flash drive

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