CVD Critical Pathways Group  2006 Teleconferences March 22, 2006 This activity is supported by an educational grant from t...
Faculty Gregg C. Fonarow, MD Eliot Corday Professor of Medicine  and Cardiovascular Science Director, Ahmanson-UCLA Cardio...
The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the e...
Gregg C. Fonarow, MD, has served as a consultant to and has received research support and honoraria from Bristol-Myers Squ...
Polling Question #1 <ul><li>Did you attend the American College of Cardiology 2006 Annual Scientific Session? </li></ul><u...
Highlights From the American College of Cardiology 2006 Annual Scientific  Session Gregg C. Fonarow, MD
Highlights From ACC 2006 <ul><li>CHARISMA :  C lopidogrel for  H igh  A therothrombotic  R isk and  I schemic  S tabilizat...
Highlights From ACC 2006 (cont.) <ul><li>OASIS-6 : Sixth  O rganization to  A ssess  S trategies in Acute  I schemic  S yn...
CHARISMA
C lopidogrel for  H igh  A therothrombotic  R isk and  I schemic  S tabilization,  M anagement, and  A voidance (CHARISMA)...
Overall Population: Primary Efficacy  Outcome (MI, Stroke, or CV Death) † †   First Occurrence of  MI (fatal or non-fatal)...
Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization) † Placebo + ASA * 17.9% Clop...
Overall Population:  Secondary Efficacy Results *Intention to treat analysis † First occurrence of MI (fatal or not), stro...
Overall Population: Safety Results *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt...
Primary Efficacy Results (MI/Stroke/CV Death)  by Pre-Specified Entry Category Population RR (95% CI) P  value  Qualifying...
Primary Efficacy Results (MI/Stroke/CV Death)*  by Category of Inclusion Criteria Population N RR (95% CI) P  value  Quali...
Multiple Risk Factor Population:  Secondary Efficacy Results *Intention to treat analysis † First occurrence of MI (fatal ...
Multiple Risk Factor Population:  Safety Results *Adjudicated outcomes by intention to treat analysis Bhatt DL, et al.  N ...
Documented CV Disease Population: Safety Results *Adjudicated outcomes by Intention to treat analysis Bhatt DL, et al.  N ...
CHARISMA: Conclusions <ul><li>7.1% RRR for the primary endpoint (MI/Stroke/CV Death) in the overall population did not rea...
CHARISMA: Clinical Implications <ul><li>In the acute setting, prior studies have shown the benefit of dual antiplatelet th...
REACH
The REACH Registry <ul><li>The REACH (REduction of Atherothrombosis for Continued Health) Registry has recruited outpatien...
REACH Registry: >67,000 Patients From  5,473 Sites* in 44 Countries North America Latin America Eastern Europe Middle East...
A Broad Range of the  At-Risk Population Is Included Must include Signed Written Informed Consent Patients aged 45 years o...
1-Year Results: Single vs Multiple and Overlapping Atherothrombotic Locations: The Example of CAD Rates adjusted for age a...
Major Endpoints as a Function of Single  vs Multiple and Overlapping Locations 1  p<0.05;  2  p<0.01;  3  p<0.001 (ref cla...
Clinical Implications <ul><li>These results suggest the need to address atherothrombosis as a “global disease” rather than...
ACUITY
Study Design – First Randomization Moderate- high risk ACS Aspirin in all clopidogrel dosing and timing per local practice...
Study Design – Second Randomization Moderate- high risk ACS Angiography within 72h Aspirin in all clopidogrel dosing and t...
Primary Endpoint Measures (ITT) 11.7% 7.3% 5.7% 5.3% 11.8% 7.7% Net clinical outcome Ischemic composite Major bleeding 30 ...
Primary Endpoint Measures (ITT) 0 1 2 11.7% 11.8% 1.01 (0.90-1.12) <0.001 0.93 Risk ratio ±95% CI Primary endpoint Net cli...
Primary Endpoint Measures (ITT) 11.7% 7.3% 5.7% 3.0% 10.1% 7.8% Net clinical outcome Ischemic composite Major bleeding 30 ...
Primary Endpoint Measures (ITT) Bivalirudin alone better UFH/Enox + IIb/IIIa better Risk ratio ±95% CI Primary endpoint Bi...
Components of the Ischemic Composite 7.3% 1.3% 4.9% 2.3% 2.7% 2.4% 5.0% 7.7% 1.5% 1.6% 7.8% 5.4% Ischemic composite Death ...
Major Bleeding Endpoints P Sup = 0.38 P Sup < 0.0001 P Sup = 0.31 P Sup  < .001 UFH/Enoxaparin + GPI vs Bivalirudin + GPI ...
Conclusions: Primary Results NI = noninferiority; Sup = superiority Stone G. Presented at: 55th Annual Scientific Session ...
Clinical Implications <ul><li>In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP...
ExTRACT-TIMI 25
Protocol Design STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) UFH 60 U / kg bolus (4000 U)  Inf 12 U /...
Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%)  ENOX  UFH  Relative Risk 0.83 (0.77 to 0.90) P <0.001 ...
Major Secondary End Point Death or Nonfatal MI or Urgent Revascularization (ITT) Secondary End Point (%)  Days   ENOX  UFH...
Death or Nonfatal MI  –  Day 30  Major Subgroups Adapted with permission from Antman EM, et al.  N Engl J Med . 2006;354. ...
Bleeding Endpoints (TIMI)  30 Days UFH ENOX % Events Major Bleed (fatal + nonfatal) ICH  ARD 0.7% RR 1.53 P<0.001   ARD 0....
Net Clinical Benefit at 30 Days 1 1.25 0.9 0.8 Death or Nonfatal MI or  Nonfatal ICH Death or Nonfatal MI or  Nonfatal Maj...
Clinical Implication A strategy of  enoxaparin is preferable to the current standard of unfractionated heparin as the anti...
OASIS-6
OASIS – 6 Trial: Study Design 12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hour...
OASIS – 6 Trial: Primary Endpoint <ul><li>The primary endpoint was lower in the fondaparinux group compared with the contr...
OASIS – 6 Trial: Primary Endpoint (cont.) Reduction in Death/MI: Stratum 1 (No UFH indicated) P <0.05 Reduction in Death/M...
OASIS – 6 Trial:  Primary Composite Endpoint <ul><li>Among the components of the composite at 30 days, mortality was lower...
OASIS  –  6 Trial: PCI Substudy at 30 Days <ul><li>There was no difference in the primary endpoint for patients who were m...
OASIS  –  6 Trial: PCI Substudy (cont.) <ul><li>There was no difference in severe bleeding at 9 days by treatment group (1...
OASIS  –  6 Trial: PCI Substudy (cont.) <ul><li>There was a higher instance of guiding catheter thrombosis in the PCI coho...
OASIS  –  6 Trial: PCI Substudy (cont.) <ul><li>Coronary complications occurred in more patients treated with fondaparinux...
OASIS – 6 Trial: Conclusions <ul><li>In patients with STEMI, particularly those not undergoing primary PCI, fondaparinux s...
ISAR-REACT 2
ISAR-REACT 2 Trial: Study Design <ul><ul><li>Primary Endpoint: Composite of death, MI, and urgent target vessel revascular...
ISAR REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR Adapted with permission from Kastrati A, et al.  JAMA . 200...
ISAR REACT 2: 30-Day Ischemic Events Abbreviations: CI, confidence interval; MI, myocardial infarction; RR, relative risk....
ISAR REACT 2: Cumulative Incidence of Death,  MI, or Urgent TVR in Subsets With and Without Elevated Troponin Levels (>0.0...
ISAR REACT 2: 30-Day Incidence and  Relative Risk of Death, MI, or Urgent  TVR in Subgroups Error bars indicate 95% confid...
ISAR-REACT 2 Trial:  Secondary Endpoint In-hospital Major and Minor Bleeding  (%) p=NS Kastrati A, et al.  JAMA . 2006;295...
ISAR-REACT 2 Trial: Summary <ul><li>For patients undergoing PCI for a non-ST-segment elevation ACS who were treated with h...
ASTEROID
ASTEROID Trial: Study Design Follow-up IVUS at 24 months n=349 <ul><ul><li>Primary Endpoint: 1) Change in percent atheroma...
ASTEROID Trial: Principal Findings <ul><li>LDL Levels were reduced from 130.4 mg/dL at baseline to a mean of 60.8 mg/dL at...
ASTEROID: Example of Regression of Atherosclerosis in a Patient in  the Trial Adapted with permission from Nissen S, et al...
ASTEROID Trial: Primary Endpoint <ul><li>The first co-primary endpoint, change in percent atheroma volume, was reduced by ...
ASTEROID Trial:  Primary Endpoint cont. <ul><li>Regression in percent atheroma volume was observed in 63.6% of patients; w...
ASTEROID Trial:  Primary Endpoint cont. Co-primary Endpoint of nominal atheroma volume in the 10 mm subsegment with the gr...
ASTEROID Trial: Secondary Endpoint Mean Normalized Total atheroma volume (mm 3 ) <ul><li>At follow-up, total atheroma volu...
ASTEROID Trial: Adverse Events <ul><li>Musculoskeletal complaints (3.7%) and cardiovascular disorders (4.3%) were the adve...
Relationship Between Mean LDL-C Levels and Median Change in % Atheroma Volume for  Several Intravascular Ultrasound Trials...
ASTEROID Trial: Limitations <ul><li>No control group </li></ul><ul><li>Those patients with a >50% stenosis within the targ...
ASTEROID Trial: Summary <ul><li>Among patients with angiographic coronary disease, treatment with intensive statin therapy...
Featured Institution Aurora Health Care Milwaukee, Wisconsin
Polling Question #2 <ul><li>1) We are currently on the same item </li></ul><ul><li>2) We have since moved to the next chec...
Progress Checklist: Immediate Goals Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff f...
Progress Checklist: Short-term Goals/Activities Grand rounds/conference: Cardiology/IM  Grand rounds/conference: Emergenc...
Progress Checklist: Long-term Goals/Activities    NRMI    AHA Get With The Guidelines    ACC National Cardiovascular Da...
Question-and-Answer Session
Concluding Remarks Gregg C. Fonarow, MD Next program: Wednesday, April 19, 2006 - 3PM ET (12N PT) Topic: Preliminary Findi...
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Strive Teleconf Presentation March22 2006

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Strive Teleconf Presentation March22 2006

  1. 1. CVD Critical Pathways Group 2006 Teleconferences March 22, 2006 This activity is supported by an educational grant from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.
  2. 2. Faculty Gregg C. Fonarow, MD Eliot Corday Professor of Medicine and Cardiovascular Science Director, Ahmanson-UCLA Cardiomyopathy Center UCLA Division of Cardiology UCLA Medical Center Los Angeles, California
  3. 3. The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity. Disclosure Statement
  4. 4. Gregg C. Fonarow, MD, has served as a consultant to and has received research support and honoraria from Bristol-Myers Squibb Company, GlaxoSmithKline, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, and Scios, Inc. The team from Aurora Health Care reports no such relationships. Faculty Disclosure Statement
  5. 5. Polling Question #1 <ul><li>Did you attend the American College of Cardiology 2006 Annual Scientific Session? </li></ul><ul><ul><li>Yes, I attended the entire duration of the conference </li></ul></ul><ul><ul><li>Yes, I attended part of the conference </li></ul></ul><ul><ul><li>No, I did not attend </li></ul></ul>
  6. 6. Highlights From the American College of Cardiology 2006 Annual Scientific Session Gregg C. Fonarow, MD
  7. 7. Highlights From ACC 2006 <ul><li>CHARISMA : C lopidogrel for H igh A therothrombotic R isk and I schemic S tabilization M anagement and A voidance </li></ul><ul><li>REACH : Re duction of A therothrombosis for C ontinued H ealth </li></ul><ul><li>ACUITY : A cute C atheterization and U rgent I ntervention T riage strateg Y (ACUITY) trial </li></ul><ul><li>ExTRACT-TIMI 25 : E no x aparin and T hrombolysis R eperfusion for Ac u t e Myocardial Infarction (ExTRACT) – T hrombolysis i n M yocardial I nfarction (TIMI) 25 study </li></ul>
  8. 8. Highlights From ACC 2006 (cont.) <ul><li>OASIS-6 : Sixth O rganization to A ssess S trategies in Acute I schemic S yndromes </li></ul><ul><li>ISAR-REACT 2 : I ntracoronary S tenting and A ntithrombotic R egimen: R apid E arly A ction for C oronary T reatment 2 trial </li></ul><ul><li>ASTEROID : A St udy to E valuate the Effect of R osuvastatin o n I ntravascular Ultrasoun d </li></ul>
  9. 9. CHARISMA
  10. 10. C lopidogrel for H igh A therothrombotic R isk and I schemic S tabilization, M anagement, and A voidance (CHARISMA): Study Design Double-blind treatment up to 1040 primary efficacy events occur* Aspirin 75–162 mg o nce daily Clopidogrel 75 mg o nce daily Placebo 1 tab o nce daily Aspirin 75–162 mg o nce daily Final study visit (fixed study end date) 1-month visit 3-month visit Patients 45 years or older who are at high risk of atherothrombotic events R = randomization. N=15,603 R Bhatt DL, et al. Am Heart J . 2004;148:263-268. *Event-driven trial: primary efficacy outcome of vascular death, MI, stroke Visits every 6 months (12 m, 18 m…), and intermediate phone calls in between (15 m, 21m…) 6-month visit
  11. 11. Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death) † † 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) Adapted with permission from Bhatt DL, et al. N Engl J Med. 2 006;354. Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] P = 0.22 Months since randomization § 0 2 4 6 8 0 6 12 18 24 30 Cumulative event rate (%)
  12. 12. Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization) † Placebo + ASA * 17.9% Clopidogrel + ASA * 16.7% RRR: 7.7% [95% CI: 0.5%, 14.4%] P = 0.04 Cumulative event rate (%) 0 5 10 15 20 Months since randomization § 0 6 12 18 24 30 *All patients received ASA 75-162mg/day † First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization § The number of patients followed beyond 30 months decreases rapidly to zero and there are only 38 primary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo) Adapted with permission from Bhatt DL, et al. N Engl J Med. 2 006;354.
  13. 13. Overall Population: Secondary Efficacy Results *Intention to treat analysis † First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or a revascularization procedure ‡ For UA, TIA, or revascularization Bhatt DL, et al. N Engl J Med. 2006;354. 0.02 0.90 (0.82, 0.98) 957 (12.3) 866 (11.1) Hospitalization ‡ 0.05 0.80 (0.65, 0.997) 185 (2.4) 149 (1.9) Stroke 0.10 0.82 (0.66, 1.04) 160 (2.1) 132 (1.7) Ischemic Stroke 0.48 0.92 (0.74, 1.16) 159 (2.0) 147 (1.9) Myocardial Infarction 0.68 1.04 (0.87, 1.25) 229 (2.9) 238 (3.1) Cardiovascular Mortality 0.90 0.99 (0.86, 1.14) 374 (4.8) 371 (4.8) All Cause Mortality 0.04 0.92 (0.86, 0.995) 1395 (17.9) 1301 (16.7) Principal Secondary Endpoint † P value RR (95% CI) Placebo + ASA (n=7801) Clopidogrel + ASA (n=7802) Endpoint* – N (%)
  14. 14. Overall Population: Safety Results *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, et al. N Engl J Med. 2006;354. <0.001 1.62 (1.27, 2.10) 101 (1.3) 164 (2.1) GUSTO Moderate Bleeding 0.89 0.96 (0.56, 1.65) 27 (0.3) 26 (0.3) Primary ICH 0.17 1.53 (0.83, 2.82) 17 (0.2) 26 (0.3) Fatal Bleeding 0.09 1.25 (0.97, 1.61) 104 (1.3) 130 (1.7) GUSTO Severe Bleeding P value RR (95% CI) Placebo + ASA (n=7801) Clopidogrel + ASA (n=7802) Safety Outcome* – N (%)
  15. 15. 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=3284) Overall Population* 0.93 (0.83, 1.05) 0.22 (n=15,603) 0.6 0.8 1.4 1.2 Clopidogrel Better Placebo Better 1.6 0.4 * A statistical test for interaction showed marginally significant heterogeneity ( P = 0.045) in treatment response for these pre-specified subgroups of patients Bhatt DL, et al. N Engl J Med. 2006;354.
  16. 16. Primary Efficacy Results (MI/Stroke/CV Death)* by Category of Inclusion Criteria Population N RR (95% CI) P value Qualifying CV Disease 12,153 0.88 (0.77, 0.998) 0.046 Coronary 5,835 0.86 (0.71, 1.05) 0.13 Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09 PAD 2,838 0.87 (0.67, 1.13) 0.29 Multiple Risk Factors 3,284 1.20 (0.91, 1.59) 0.20 Overall Population 15,603 0.93 (0.83, 1.05) 0.22 0.6 0.8 1.4 1.2 Clopidogrel Better Placebo Better 1.6 0.4 * First occurrence of MI (fatal or not), Stroke (fatal or not), or CV Death Bhatt DL. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  17. 17. Multiple Risk Factor Population: Secondary Efficacy Results *Intention to treat analysis † First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or a revascularization procedure ‡ For UA, TIA, or revascularization Bhatt DL, et al. N Engl J Med. 2006;354. 0.55 0.93 (0.74, 1.18) 147 (9.0) 140 (8.4) Hospitalization ‡ 0.84 0.95 (0.60, 1.52) 36 (2.2) 35 (2.1) Stroke 0.73 0.91 (0.54, 1.54) 29 (1.8) 27 (1.6) Ischemic Stroke 0.45 1.19 (0.75, 1.89) 33 (2.0) 40 (2.4) Myocardial Infarction 0.01 1.74 (1.16, 2.62) 36 (2.2) 64 (3.9) Cardiovascular Mortality 0.04 1.41 (1.02, 1.95) 62 (3.8) 89 (5.4) All Cause Mortality 0.88 1.01 (0.84, 1.22) 216 (13.3) 224 (13.5) Principal Secondary Endpoint † P value RR (95% CI) Placebo + ASA (n=1625) Clopidogrel + ASA (n=1659) Endpoint* – N (%)
  18. 18. Multiple Risk Factor Population: Safety Results *Adjudicated outcomes by intention to treat analysis Bhatt DL, et al. N Engl J Med. 2006;354. 0.08 1.60 (0.95, 2.71) 22 (1.4) 36 (2.2) GUSTO Moderate Bleeding 0.81 1.14 (0.38, 3.39) 6 (0.4) 7 (0.4) Primary ICH 0.38 1.71 (0.50, 5.84) 5 (0. 2) 7 (0.4) Fatal Bleeding 0.07 1.67 (0.96, 2.88) 20 (1.2) 34 (2.0) GUSTO Severe Bleeding P value RR (95% CI) Placebo + ASA (n=1625) Clopidogrel + ASA (n=1659) Safety Outcome* – N (%)
  19. 19. Documented CV Disease Population: Safety Results *Adjudicated outcomes by Intention to treat analysis Bhatt DL, et al. N Engl J Med. 2006;354. <0.001 1.63 (1.23, 2.15) 79 (1.3) 128 (2.1) GUSTO Moderate Bleeding 0.65 0.87 (0.47, 1.60) 21 (0.3) 19 (0.3) Primary ICH 0.28 1.47 (0.73, 2.97) 13 (0.2) 19 (0.3) Fatal Bleeding 0.39 1.14 (0.85, 1.52) 84 (1.4) 95 (1.6) GUSTO Severe Bleeding P value RR (95% CI) Placebo + ASA (n=6091) Clopidogrel + ASA (n=6062) Safety Outcome* – N (%)
  20. 20. CHARISMA: Conclusions <ul><li>7.1% RRR for the primary endpoint (MI/Stroke/CV Death) in the overall population did not reach statistical significance </li></ul><ul><li>7.7% RRR for the secondary endpoint, which included hospitalizations, was statistically significant </li></ul><ul><li>The overall outcome was influenced by divergent findings in the two main sub-groups enrolled in the trial </li></ul><ul><li>In patients with multiple risk factors only, without clearly established CV disease, dual antiplatelet therapy was not beneficial - excess in CV mortality as well as an increase in bleeding </li></ul><ul><li>In patients with documented CV disease (CAD, CVD, or PAD) long-term clopidogrel plus ASA resulted in a significant 12.5% RRR in MI/Stroke/CV Death with no significant increase in severe bleeding compared to ASA alone </li></ul>Bhatt DL. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  21. 21. CHARISMA: Clinical Implications <ul><li>In the acute setting, prior studies have shown the benefit of dual antiplatelet therapy for 1 year post ACS or PCI </li></ul><ul><li>For stable patients, CHARISMA failed to demonstrate a reduction in CV death/MI/stroke with dual antiplatelet therapy </li></ul><ul><li>CHARISMA may suggest differential long-term effects of dual antiplatelet therapy by patient type: </li></ul><ul><ul><li>NOT Recommended for Primary Prevention </li></ul></ul><ul><ul><li>Potential benefit in Secondary Prevention (CAD, CVD, or PAD) </li></ul></ul><ul><ul><ul><li>CV death/MI/stroke - 10 events prevented per 1000 patients treated </li></ul></ul></ul><ul><ul><ul><li>Balanced by 2 severe GUSTO bleeds per 1000 patients treated </li></ul></ul></ul><ul><li>These data and future trials will help physicians decide which non-acute/stable patients should receive long-term dual antiplatelet therapy </li></ul>Bhatt DL. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  22. 22. REACH
  23. 23. The REACH Registry <ul><li>The REACH (REduction of Atherothrombosis for Continued Health) Registry has recruited outpatients who have had, or are at high risk of having, symptoms of atherothrombosis </li></ul><ul><li>The Registry aims to study a contemporary stable patient population from various regions of the world in order to: </li></ul><ul><ul><li>Describe the characteristics and management of these patients and of each subgroup </li></ul></ul><ul><ul><li>Assess the long-term risk of atherothrombotic events in the global population and in each subgroup </li></ul></ul><ul><ul><li>Assess the amount of “cross-risk” across subgroups </li></ul></ul><ul><ul><li>Compare outcomes within different subject profiles </li></ul></ul><ul><ul><li>Define predictors of risk for subsequent atherothrombotic events </li></ul></ul><ul><li>Follow-up planned at 12 and 21 months, extended to 3 and 4 years </li></ul>Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  24. 24. REACH Registry: >67,000 Patients From 5,473 Sites* in 44 Countries North America Latin America Eastern Europe Middle East Asia (incl. Japan) Australia 27,746 1,931 17,886 846 5,903 2,872 Western Europe 5,048 5,656 *Up to 15 patients/site (up to 20 in the US) Bhatt DL, et al. JAMA . 2006;295:180-189.
  25. 25. A Broad Range of the At-Risk Population Is Included Must include Signed Written Informed Consent Patients aged 45 years or more At least 1 of four criteria <ul><li>Documented cerebrovascular disease ischemic stroke or transient ischemic attack </li></ul><ul><li>Documented coronary disease angina, MI, angioplasty/ stent/bypass </li></ul><ul><li>Documented historical or current intermittent claudication associated with ABI < 0.9 </li></ul>At least 3 atherothrombotic risk factors <ul><li>Male  65 years or female  70 years </li></ul><ul><li>Current smoking > 15 cigarettes/day </li></ul><ul><li>Type 1 or Type 2 diabetes </li></ul><ul><li>Hypercholesterolemia </li></ul><ul><li>Diabetic nephropathy </li></ul><ul><li>Hypertension </li></ul><ul><li>Ankle Brachial Index (ABI) < 0.9 in either leg at rest </li></ul><ul><li>Asymptomatic carotid stenosis  70% </li></ul><ul><li>Presence of at least one carotid plaque </li></ul>REACH Registry Inclusion Criteria Bhatt DL, et al. JAMA . 2006;295:180-189.
  26. 26. 1-Year Results: Single vs Multiple and Overlapping Atherothrombotic Locations: The Example of CAD Rates adjusted for age and risk factors *TIA, unstable angina, other ischemic arterial event including worsening of PAD Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga. (%)
  27. 27. Major Endpoints as a Function of Single vs Multiple and Overlapping Locations 1 p<0.05; 2 p<0.01; 3 p<0.001 (ref class: CAD alone) 1 p<0.05; 2 p<0.01; 3 p<0.001 (ref class: CAD + CVD) *TIA, unstable angina, other ischemic arterial event including worsening of PAD Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga. Polyvascular disease Single arterial bed 26.9 (3) 7.4 4.0 1.8 3.6 (3) CAD + CVD + PAD 24.4 (1) 7.0 4.8 1.3 1.8 CVD + PAD 23.3 (3) 4.8 (3) 1.3 (3) 1.4 2.9 (2) CAD + PAD 20.0 6.4 3.7 1.6 2.0 CAD + CVD 22.0 6.0 3.1 1.5 2.4 Overall 18.2 (3) 10.0 (3) 13.3 12.8 CV death/MI/ stroke/ hospitalization 2.3 4.5 (3) 3.1 3.4 CV death/MI/stroke 0.6 3.5 (3) 0.9 1.5 Non-fatal stroke 1.0 0.5 (3) 1.4 1.2 Non-fatal MI 1.2 1.4 1.5 1.5 CV death PAD alone CVD alone CAD alone Overall
  28. 28. Clinical Implications <ul><li>These results suggest the need to address atherothrombosis as a “global disease” rather than separately for each vascular bed </li></ul><ul><li>All-out efforts are needed to reduce the high event rates experienced by atherothrombotic patients </li></ul><ul><li>A more in-depth discussion of REACH will take place during next month’s STRIVE Champion teleconference. </li></ul>
  29. 29. ACUITY
  30. 30. Study Design – First Randomization Moderate- high risk ACS Aspirin in all clopidogrel dosing and timing per local practice Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) *Stratified by pre-angiography thienopyridine use or administration Stone GW, et al. Am Heart J . 2004;148:764-775. Angiography within 72h UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone R* Medical management PCI CABG
  31. 31. Study Design – Second Randomization Moderate- high risk ACS Angiography within 72h Aspirin in all clopidogrel dosing and timing per local practice Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Stone GW, et al. Am Heart J . 2004;148:764-775. Medical management PCI CABG Bivalirudin alone UFH or enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only R Bivalirudin R Routine upstream GPI in all pts GPI started in CCL for PCI only
  32. 32. Primary Endpoint Measures (ITT) 11.7% 7.3% 5.7% 5.3% 11.8% 7.7% Net clinical outcome Ischemic composite Major bleeding 30 day events (%) UFH/Enoxaparin+GPI (N=4603) Bivalirudin+GPI (N=4604) P NI < 0.0001 P Sup = 0.93 P NI = 0.007 P Sup = 0.39 P NI = 0.0001 P Sup = 0.38 UFH/Enoxaparin + GPI vs Bivalirudin + GPI Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  33. 33. Primary Endpoint Measures (ITT) 0 1 2 11.7% 11.8% 1.01 (0.90-1.12) <0.001 0.93 Risk ratio ±95% CI Primary endpoint Net clinical outcome Ischemic composite Major bleeding Bivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa better Bival + IIb/IIIa UFH/Enox + IIb/IIIa RR (95% CI) P value (noninferior) (superior) 7.3% 7.7% 1.07 (0.92-1.23) 0.015 0.39 5.7% 5.3% 0.93 (0.78-1.10) <0.001 0.38 Upper boundary noninferiority UFH/Enoxaparin + GPI vs Bivalirudin + GPI Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  34. 34. Primary Endpoint Measures (ITT) 11.7% 7.3% 5.7% 3.0% 10.1% 7.8% Net clinical outcome Ischemic composite Major bleeding 30 day events (%) UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612) P NI <0.0001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.0001 P Sup <0.0001 UFH/Enoxaparin + GPI vs Bivalirudin Alone Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  35. 35. Primary Endpoint Measures (ITT) Bivalirudin alone better UFH/Enox + IIb/IIIa better Risk ratio ±95% CI Primary endpoint Bival alone UFH/Enox + IIb/IIIa RR (95% CI) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.7% 10.1% 0.86 (0.77-0.97) <0.001 0.015 7.3% 7.8% 1.08 (0.93-1.24) 0.02 0.32 5.7% 3.0% 0.53 (0.43-0.65) <0.001 <0.001 P value (non inferior) (superior) UFH/Enoxaparin + GPI vs Bivalirudin Alone 0 1 2 Upper boundary noninferiority Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  36. 36. Components of the Ischemic Composite 7.3% 1.3% 4.9% 2.3% 2.7% 2.4% 5.0% 7.7% 1.5% 1.6% 7.8% 5.4% Ischemic composite Death Myocardial infarction Unplanned revasc for ischemia 30 day events (%) UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612) UFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin Alone Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga. P Sup = 0.32 P Sup = 0.34 P Sup = 0.35 P Sup = 0.78
  37. 37. Major Bleeding Endpoints P Sup = 0.38 P Sup < 0.0001 P Sup = 0.31 P Sup < .001 UFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin Alone 11.8% 5.7% 11.1% 5.3% 3.0% 9.1% All major bleeding Non-CABG major bleeding (primary endpoint) 30 day events (%) Heparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612) Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  38. 38. Conclusions: Primary Results NI = noninferiority; Sup = superiority Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga. P Value Rate P Value Rate Rate Observed <0.001 Sup 3.0% 0.001 NI 5.3% 5.7% Major bleeding 0.011 NI 7.8% 0.007 NI 7.7% 7.3% Ischemic events 0.015 Sup 10.1% <0.001 NI 11.8% 11.7% Net clinical outcome Endpoint Bivalirudin alone Bivalirudin + GP IIb/IIIa UFH/Enox + GP IIb/IIIa
  39. 39. Clinical Implications <ul><li>In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors </li></ul><ul><ul><li>Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin </li></ul></ul><ul><li>However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition </li></ul><ul><ul><li>A bivalirudin-alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days </li></ul></ul>Stone G. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga.
  40. 40. ExTRACT-TIMI 25
  41. 41. Protocol Design STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1 ° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage Antman EM, et al. N Engl J Med . 2006;354.
  42. 42. Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%) ENOX UFH Relative Risk 0.83 (0.77 to 0.90) P <0.001 Days after Randomization 9.9% 12.0% Lost to follow-up = 3 17% RRR Adapted with permission from Antman EM, et al. N Engl J Med . 2006;354.
  43. 43. Major Secondary End Point Death or Nonfatal MI or Urgent Revascularization (ITT) Secondary End Point (%) Days ENOX UFH 11.7% (1199) 14.5% (1479) 5.3% 6.1% RR 0.88 (0.79 to 0.98) P =0.02 48 h UFH ENOX 280 events 19% RRR RR 0.81 (0.75 to 0.87) P <0.001 12% RRR Adapted with permission from Antman EM, et al. N Engl J Med . 2006;354.
  44. 44. Death or Nonfatal MI – Day 30 Major Subgroups Adapted with permission from Antman EM, et al. N Engl J Med . 2006;354.    > Median < Median Fibrin-specific Streptokinase Prior MI No Prior MI DM No DM Other Anterior 0.5 1 2 PRIOR MI OVERALL DIABETES FIBRINOLYTIC INFARCT LOCATION ENOX Better UFH Better Relative Risk TIME TO Rx 20,479 11 23 17 21 17 20 13 18 23 12 17 Reduction In Risk (%) > 75 < 75 AGE (y) 20 6 Female Male SEX 18 16 All Interaction Tests P = NS P < 0.0001
  45. 45. Bleeding Endpoints (TIMI) 30 Days UFH ENOX % Events Major Bleed (fatal + nonfatal) ICH ARD 0.7% RR 1.53 P<0.001 ARD 0.1% RR 1.27 P = 0.14 Nonfatal Major Bleed ARD 0.4% RR 1.39 P = 0.014 Antman EM, et al. N Engl J Med . 2006;354.
  46. 46. Net Clinical Benefit at 30 Days 1 1.25 0.9 0.8 Death or Nonfatal MI or Nonfatal ICH Death or Nonfatal MI or Nonfatal Major Bleed Death or Nonfatal MI or Nonfatal Disabl. Stroke ENOX Better UFH Better RR UFH (%) ENOX (%) RRR (%) 12.3 10.1 18 12.8 11.0 14 12.2 10.1 17 Prespecified Definitions P <0.001 P <0.001 P <0.001 Antman EM, et al. N Engl J Med . 2006;354.
  47. 47. Clinical Implication A strategy of enoxaparin is preferable to the current standard of unfractionated heparin as the antithrombin to support fibrinolysis, the most common form of reperfusion for STEMI used worldwide.
  48. 48. OASIS-6
  49. 49. OASIS – 6 Trial: Study Design 12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial) Randomized. Blinded. Factorial. 28% female, mean age 62 years, mean follow-up 3-6 months Fondaparinux 2.5 mg/day for up to 8 days or hospital discharge Placebo Fondaparinux 2.5 mg/day for up to 8 days or hospital discharge UFH <ul><ul><li>Primary Endpoint: Composite of death or reinfarction at 30 days </li></ul></ul><ul><ul><li>Secondary Endpoint: Composite of death or reinfarction at 9 days and at final follow-up </li></ul></ul>Stratum 1 (No UFH) Stratum 2 (UFH) Yusuf S, et al. JAMA . 2006;295.
  50. 50. OASIS – 6 Trial: Primary Endpoint <ul><li>The primary endpoint was lower in the fondaparinux group compared with the control group (9.7% vs.11.2%, HR 0.86, P =0.008) </li></ul><ul><li>The results were similar at 9 days (HR 0.83, P =0.003) and at study end (HR 0.88, P =0.008) </li></ul>Primary Endpoint: Death/Reinfarction (%) P =0.008 P =0.003 P =0.008 Frequency Yusuf S, et al. JAMA . 2006;295.
  51. 51. OASIS – 6 Trial: Primary Endpoint (cont.) Reduction in Death/MI: Stratum 1 (No UFH indicated) P <0.05 Reduction in Death/MI: Stratum 2 (UFH Indicated) P =NS <ul><li>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<0.05) </li></ul><ul><li>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) </li></ul>p=0.97 Yusuf S, et al. JAMA . 2006;295.
  52. 52. OASIS – 6 Trial: Primary Composite Endpoint <ul><li>Among the components of the composite at 30 days, mortality was lower in the fondaparinux group compared to the control group (7.8% vs. 8.9%, HR 0.87, P =0.03). </li></ul><ul><li>Reinfarction was also lower in the fondaparinux group compared to the control group (2.5% vs. 3.0% HR 0.81, P =0.06). </li></ul>Components of Primary Composite Endpoint (%) P =0.03 P =0.06 Yusuf S, et al. JAMA . 2006;295. 7.8% 2.5% 8.9% 3.0% 0% 2% 4% 6% 8% 10% Death Reinfarction Fondaparinux Control
  53. 53. OASIS – 6 Trial: PCI Substudy at 30 Days <ul><li>There was no difference in the primary endpoint for patients who were managed with primary PCI (6.1% vs 5.1%, p=0.19). </li></ul><ul><li>Guiding catheter thrombosis in the primary PCI cohort occurred more often with fondaparinux compared with control (n=22 vs. n=0, p<0.001) </li></ul>Primary Endpoint of Death or MI in PCI Cohort (%) p=0.19 Yusuf S, et al. JAMA . 2006;295.
  54. 54. OASIS – 6 Trial: PCI Substudy (cont.) <ul><li>There was no difference in severe bleeding at 9 days by treatment group (1.0% fondaparinux vs. 1.3% control, P =NS) </li></ul><ul><li>Intracranial hemorrhage occurred in 0.2% in each group </li></ul>Severe Bleeding at 9 days (%) P =NS Yusuf S, et al. JAMA . 2006;295.
  55. 55. OASIS – 6 Trial: PCI Substudy (cont.) <ul><li>There was a higher instance of guiding catheter thrombosis in the PCI cohort treated with fondaparinux compared to control (n=22 vs. n=0, P <0.001) </li></ul>Guiding Catheter Thrombosis P <0.001 Yusuf S, et al. JAMA . 2006;295. Number of instances
  56. 56. OASIS – 6 Trial: PCI Substudy (cont.) <ul><li>Coronary complications occurred in more patients treated with fondaparinux compared to control (n=270 vs. n=225, P =0.04) </li></ul><ul><li>Coronary complications include abrupt closure, no reflow, dissection, new angiographic thrombus, perforation, or catheter thrombus </li></ul>Coronary Complications P =0.04 Yusuf S, et al. JAMA . 2006;295.
  57. 57. OASIS – 6 Trial: Conclusions <ul><li>In patients with STEMI, particularly those not undergoing primary PCI, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes </li></ul><ul><li>Benefits of fondaparinux were observed in Stratum 1 where placebo or no antithrombin was administered </li></ul><ul><li>Fondaparinux was not superior to active control UFH overall, but was more beneficial in those patients not undergoing direct PCI </li></ul><ul><li>Fondaparinux trended to produce less severe bleeding </li></ul><ul><li>Fondaparinux was associated with a hazard in those patients who underwent PCI, including guiding catheter thrombosis </li></ul>
  58. 58. ISAR-REACT 2
  59. 59. ISAR-REACT 2 Trial: Study Design <ul><ul><li>Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 days </li></ul></ul><ul><ul><li>Secondary Endpoint: In-hospital major and minor bleeding </li></ul></ul>2022 patients with an episode of angina within the preceding 48 hours and an elevated troponin T level or new ST-segment depression of ≥ 0.1 mV or transient ( <20 minutes) ST-segment elevation of ≥0.1 mV or new or presumed new bundle-branch block; significant angiographic lesions in a native coronary vessel or venous bypass graft amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded. 24% female, mean age 66 years, mean follow-up 30 days Abciximab (usual bolus or infusion dose) n=1012 Placebo n=1010 Pre-treatment with high dose (600mg) clopidogrel at least 2 hours pre-procedure Kastrati A, et al. JAMA . 2006;295.
  60. 60. ISAR REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR Adapted with permission from Kastrati A, et al. JAMA . 2006;295. Published online March 13, 2006. 20 15 10 5 0 0 5 10 15 20 25 30 Days After Randomization Cumulative Rate of Primary End Point, % Placebo Group Abciximab Group Log-Rank P =.03
  61. 61. ISAR REACT 2: 30-Day Ischemic Events Abbreviations: CI, confidence interval; MI, myocardial infarction; RR, relative risk. Adapted with permission from Kastrati A, et al. JAMA . 2006;295. Published online March 13, 2006. No. (%) 0.64 (0.25-1.63) 11 (1.1) 7 (0.7) PCI 2.99 (0.24-157) 1 (0.1) 3 (0.3) Aortocoronary bypass surgery 0.83 (0.36-1.92) 12 (1.2) 10 (1.0) Urgent target vessel revascularization 0.78 (0.36-1.72) 14 (1.4) 11 (1.1) Q-wave MI 0.77 (0.59-1.02) 106 (10.5) 82 (8.1) MI 0.69 (0.32-1.47) 16 (1.6) 11 (1.1) Death 0.75 (0.57-0.97) 116 (11.5) 87 (8.6) Death or MI 0.75 (0.58-0.97) 120 (11.9) 90 (8.9) Death, MI, or urgent target vessel revascularization RR (95% CI) Placebo (n=1010) Abciximab (n=1012) Event
  62. 62. ISAR REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without Elevated Troponin Levels (>0.03 µg/L) Adapted with permission from Kastrati A, et al. JAMA . 2006;295. Published online March 13, 2006. 20 15 10 5 0 0 5 10 15 20 25 30 Days After Randomization Cumulative Rate of Primary End Point, % Placebo Group Abciximab Group Troponin >0.03 µg/L Log-Rank P = .02 Troponin < 0.03 µg/L Log-Rank P = .98
  63. 63. ISAR REACT 2: 30-Day Incidence and Relative Risk of Death, MI, or Urgent TVR in Subgroups Error bars indicate 95% confidence intervals. Adapted with permission from Kastrati A, et al. JAMA . 2006;295. Published online March 13, 2006. Abciximab Placebo All Participants 90/1012 (8.9) 120/1010 (11.9) Troponin Level >0.03 µg/L 67/513 (13.1) 98/536 (18.3) ≤ 0.03 µg/L 23/499 (4.6) 22/474 (4.6) Clopidogrel Pretreatment Duration >3 h 27/475 (5.7) 35/461 (7.6) ≤ 3 h 63/537 (11.7) 85/549 (15.5) Diabetes Yes 26/252 (10.3) 32/284 (11.3) No 64/760 (8.4) 88/726 (12.1) Primary End Point, No. of Events/Total No. (%) 0.4 1 2 Relative Risk
  64. 64. ISAR-REACT 2 Trial: Secondary Endpoint In-hospital Major and Minor Bleeding (%) p=NS Kastrati A, et al. JAMA . 2006;295. Published online March 13, 2006.
  65. 65. ISAR-REACT 2 Trial: Summary <ul><li>For patients undergoing PCI for a non-ST-segment elevation ACS who were treated with high dose clopidogrel (600 mg) at least 2 hours before the procedure, treatment with abciximab was associated with a reduction in death, MI, or urgent target vessel revascularization within 30 days. </li></ul><ul><li>A subgroup analysis showed that the benefit of abciximab therapy was largely confined to patients with an elevated troponin level as there was no significant difference in the incidence of the primary endpoint among patients without an elevated troponin level. </li></ul><ul><li>There were no significant differences in in-hospital TIMI major bleeding (1.4% in each group, P = NS) or TIMI minor bleeding (4.2% abciximab vs 3.3% placebo, P = NS) </li></ul>
  66. 66. ASTEROID
  67. 67. ASTEROID Trial: Study Design Follow-up IVUS at 24 months n=349 <ul><ul><li>Primary Endpoint: 1) Change in percent atheroma volume and 2) change in nominal atheroma volume in the 10 mm subsegment with the greatest disease severity at baseline. </li></ul></ul><ul><ul><li>Secondary Endpoint: Change in normalized total atheroma volume for the entire artery. </li></ul></ul>Withdrawn during treatment (n=125) 1,183 patients screened for the presence of a coronary angiographic evaluated lesion >20%; IVUS target vessel stenosis <50% and not being treated with angioplasty with a minimum length of 40 mm; and statin-naïve. Excluding those with: Uncontrolled triglyceride levels ( ≥500mg/dL) or poorly controlled diabetes (glycosylated hemoglobin levels ≥10%). Open-label; mean age 58.5 years; mean follow-up at 2 years; 29% female. All enrolled patients: 40 mg rosuvastatin, IVUS of a single vessel not intervened upon at baseline n=507 Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006.
  68. 68. ASTEROID Trial: Principal Findings <ul><li>LDL Levels were reduced from 130.4 mg/dL at baseline to a mean of 60.8 mg/dL at 2 year follow-up ( P <0.001), with 75% of patients achieving an LDL <70 mg/dL. </li></ul><ul><li>HDL levels were increased from 43.1 mg/dL at baseline to a mean of 49.0 mg/dL at follow-up ( P <0.001). </li></ul>LDL/HDL mg/dL Mean LDL level decrement and HDL level increment (mg/dL) p<0.001 p<0.001 Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006. 43.1 60.8 49.0 130.4 0 22 44 66 88 110 132 LDL Levels HDL Levels Baseline Follow-up
  69. 69. ASTEROID: Example of Regression of Atherosclerosis in a Patient in the Trial Adapted with permission from Nissen S, et al. JAMA . 2006;295. Published online March 13, 2006.
  70. 70. ASTEROID Trial: Primary Endpoint <ul><li>The first co-primary endpoint, change in percent atheroma volume, was reduced by a mean of 0.98% (from 39.6% at baseline to 38.6% at 2 year follow-up, absolute change of -0.98%, P <0.001). </li></ul>Co-primary Endpoint of change in % atheroma volume (%) % Atheroma Volume p<0.001 Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006. 38.6% 39.6% 0 10 20 30 40 Baseline Follow-up
  71. 71. ASTEROID Trial: Primary Endpoint cont. <ul><li>Regression in percent atheroma volume was observed in 63.6% of patients; whereas, progression was observed in 34.6%. </li></ul>Regression vs. progression change in % atheroma volume (%) % patients Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006.
  72. 72. ASTEROID Trial: Primary Endpoint cont. Co-primary Endpoint of nominal atheroma volume in the 10 mm subsegment with the greatest disease severity at baseline (mm 3 ) mm 3 P <0.001 <ul><li>The other co-primary endpoint, change in nominal atheroma volume in the 10 mm subsegment with the greatest disease severity at baseline, was also reduced (from 65.1 mm 3 at baseline to 59.0 mm 3 at 2 year follow-up, an absolute change of -6.1 mm 3 , P <0.001). </li></ul>Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006.
  73. 73. ASTEROID Trial: Secondary Endpoint Mean Normalized Total atheroma volume (mm 3 ) <ul><li>At follow-up, total atheroma volume was reduced from 212.2 mm 3 at baseline to 197.5 mm 3 (an absolute change of -14.7 mm 3 ). </li></ul>mm 3 Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006.
  74. 74. ASTEROID Trial: Adverse Events <ul><li>Musculoskeletal complaints (3.7%) and cardiovascular disorders (4.3%) were the adverse events that resulted in study drug discontinuation. </li></ul><ul><li>There were no cases of rhabdomyolysis. </li></ul>Adverse events resulting in study drug discontinuation (%) % Nissen SE, et al. JAMA . 2006;295. Published online March 13, 2006.
  75. 75. Relationship Between Mean LDL-C Levels and Median Change in % Atheroma Volume for Several Intravascular Ultrasound Trials Adapted with permission from Nissen S, et al. JAMA . 2006;295. Published online March 13, 2006. REVERSAL Pravastatin CAMELOT Placebo A-Plus Placebo REVERSAL Atorvastatin ASTEROID Rosuvastatin r 2 = 0.97 P <.001
  76. 76. ASTEROID Trial: Limitations <ul><li>No control group </li></ul><ul><li>Those patients with a >50% stenosis within the target segment were excluded. </li></ul><ul><li>It is unknown whether statin-naïve patients are more likely to have a larger amount of atheroma regression compared to those already receiving statin therapy. </li></ul>Nissen S, et al. JAMA . 2006;295. Published online March 13, 2006.
  77. 77. ASTEROID Trial: Summary <ul><li>Among patients with angiographic coronary disease, treatment with intensive statin therapy with rosuvastatin 40 mg was associated with atherosclerosis regression on IVUS at 2 year follow-up. </li></ul><ul><li>Prior IVUS studies have shown a reduction in atherosclerosis progression with intensive statin therapy compared with a more moderate lipid lowering regimen. </li></ul><ul><li>The authors attribute the regression in atheroma volume to the very large reductions in LDL and increases in HDL. </li></ul><ul><li>It should be noted that regression in atheroma volume in the most diseased 10 mm subsegment was observed even in patients with an average LDL of 100mg/dL (-6.9 mm 3 , P<0.001 ) and in those with an average HDL <35 mg/dL (-5.9 mm 3 , P <0.001). </li></ul><ul><li>The impact of aggressive lipid lowering on clinical events was not fully evaluated in this trial. </li></ul>Nissen S, et al. JAMA . 2006;295. Published online March 13, 2006.
  78. 78. Featured Institution Aurora Health Care Milwaukee, Wisconsin
  79. 79. Polling Question #2 <ul><li>1) We are currently on the same item </li></ul><ul><li>2) We have since moved to the next checkbox on the checklist </li></ul><ul><li>3) We have progressed by more than one item on the checklist </li></ul><ul><li>4) ACS pathways are up-to-date and regularly followed </li></ul>If you participated in a previous teleconference, how much progress have you made since then? (Please refer to the checklists on the next 3 slides.)
  80. 80. Progress Checklist: Immediate Goals Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff for comments  Circulate pathways to all cardiology, ED, and CV nursing staff for comments  Develop draft pathways  Assemble team and set up meeting of working group 
  81. 81. Progress Checklist: Short-term Goals/Activities Grand rounds/conference: Cardiology/IM  Grand rounds/conference: Emergency Dept.  Grand rounds/conference: Nursing  Circulate memo  Launch critical pathways  Finalize critical pathways 
  82. 82. Progress Checklist: Long-term Goals/Activities  NRMI  AHA Get With The Guidelines  ACC National Cardiovascular Data Registry  CRUSADE  GRACE  REACH  Other Monitor data: which registry? 
  83. 83. Question-and-Answer Session
  84. 84. Concluding Remarks Gregg C. Fonarow, MD Next program: Wednesday, April 19, 2006 - 3PM ET (12N PT) Topic: Preliminary Findings From the REACH Registry Faculty: Gregg C. Fonarow, MD

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