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CURE, HARM and GIM Academic ½ Day October 24 th 2001

CURE, HARM and GIM Academic ½ Day October 24 th 2001. Dr Hui N. Lee, MD, M.Sc., FRCPC Community GIM, Sault Ste Marie Clinical Assistant Professor McMaster University. Objectives. Practical knowledge of current ACS management (October 2001)

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CURE, HARM and GIM Academic ½ Day October 24 th 2001

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  1. CURE, HARM and GIMAcademic ½ DayOctober 24th 2001 Dr Hui N. Lee, MD, M.Sc., FRCPC Community GIM, Sault Ste Marie Clinical Assistant Professor McMaster University

  2. Objectives • Practical knowledge of current ACS management (October 2001) • Overview of CURE study and role of clopidrogel in ACS therapy • Principles of evaluation of Harm • Understanding of Community GIM role • Invitation for electives Up North

  3. Scenario • 67 year old man, non-Q MI with troponin I 8.2 / CK 300 • Diabetes, HTN, dyslipidemia, ex-smoker • No previous MI or CAD, but GI bleed • Was on ASA, other standard meds • Now 3 days post MI • Rx ASA, clopidrogel, stop enoxaparin, other Rx standard

  4. Non-ST Elevation ACS • When do you add Clopidogrel? • When do you stop Clopidogrel? • How do you place Clopidogrel in relation to other expensive/potentially risky interventions: • angiogram • LMW heparin • IV G2b3 inhibitors • Do you put Clopidogrel on formulary

  5. CURE CURE (OASIS-4) Clopidogrel in Unstable Angina to prevent Recurrent ischemic Events

  6. Atherothrombosis: a Generalized and Progressive Process Unstable angina Plaquerupture/fissure &thrombosis }ACS Athero-scleroticplaque Fattystreak Fibrousplaque MI Normal Ischemic stroke/TIA Critical leg ischemia Clinically silent Stable angina Intermittent claudication Cardiovasculardeath Increasing age ACS, acute coronary syndrome; TIA, transient ischemic attack

  7. Efficacy of Antiplatelet Therapy:Antiplatelet Trialists’ Collaboration MI, stroke, orvascular death Odds ratio andconfidence interval(Antiplatelet:control) No. oftrialswithdata % oddsreduction(SD) Anti-platelet Adjustedcontrols Categoryof trial Prior MI 11 1331/9677 1693/9914 25% (4) Acute MI 9 992/9388 1348/9385 29% (4) Prior stroke/ 18 1076/5837 1301/5870 22% (4)TIA Unstable angina 7 182/1991 285/2027 0 0.5 1.0 1.5 2.0 Antiplatelettherapybetter Antiplatelettherapyworse TIA, transient ischemic attack Antiplatelet Trialists’ Collaboration BMJ 1994;308:81–106

  8. Complementary Mode of Action between Clopidogrel and ASA COX, cyclooxygenase; ADP, adenosine diphosphate; TxA2, thromboxane A2 Schafer AI Am J Med 1996;101:199–209

  9. Trials of ADP-receptor Antagonists vs Placebo in Patients with Atherosclerosis CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

  10. Trials of ADP-receptor Antagonists vs ASA in Patients with Atherosclerosis CURE Study Investigators Eur Heart J 2000; 21: 2033-41.

  11. ASA + Ticlopidine versus ASA after Coronary Artery Stenting Death or MI Study Odds Ratio 95% CI 0.17 0.01-0.72 HALL, 1996 0.25 0.10-0.63 STARS, 1998* TOTAL 0.23 0.11-0.49 P=0.0001 Test for heterogeneity P=0.66 0.1 1.0 10.0 Combination Better ASA Alone Better CURE Study Investigators Eur Heart J 2000; 21:2033-41 Page 30 of 30

  12. Study Design • Randomized, double-blind, parallel group, clinical trial of clopidogrel vs placebo in patients with ACS • All patients receive ASA (75-325 mg) • International trial (28 countries) • 12,562 patients (482 Hospitals) • Central randomization • 3-12 month Rx and follow-up • Main outcomes: -CV death/MI, stroke • -Above + refractory ischemia

  13. Study Objectives • To evaluate if clopidogrel is superior to placebo in preventing • CV death, MI, stroke (Primary at  0.045) • Above and refractory ischemia (Co-primary at  0.01)

  14. Inclusion Criteria • Ischemic symptoms, suspected to represent UA or MI without ST segment elevation • Randomized within 24 hours of onset of CP • and ECG evidence of ischemia at inclusion or already elevated cardiac enzymes or Troponin I or T to at least 2 x ULN* * Prior to June 1999, pts > 60 yrs with normal ECG allowed Revised July, 1999

  15. Outcome Definitions (1/2) CV Death: Excludes clear non-CV deaths MI: Two of three usual criteria (CP, ECG or enzyme changes) Stroke: Neurological deficit  24 hrs (CT/MRI encouraged) Refractory Ischemia: Inhosp*: recurrent ischemia on max med Rx + ECG changes + intervention  1 day After discharge: Rehosp for UA with ECG changes Severe Ischemia*: Changes similar to in hospital Refractory Ischema, but no intervention Recurrent Angina*: All other ischemic CP in hospital

  16. Outcome Definitions (2/2) Major Bleeds: Significantly disabling, intraocular (vision loss), or transfusion of  2 units Classified as Life Threatening if: Hb  > 5g/dl, hypotension needing IV inotropes, surgery to stop bleeding, symptomatic ICH or transfusion or  4 units of blood

  17. Patient Schedule 300 mg loading + 75 mg o.d. dose Clopidogrel(~6,250 patients) Patients with Acute CoronarySyndrome Aspirin 75-325mg R 3 months £double-blind treatment£ 12 months (UA or MI Without STelevation) Aspirin 75-325mg Placebo 1 tab o.d.(~6,250 patients) Day 1 1 m. Visit 6 m. Visit 3 m. Visit 9 m. Visit Discharge Visit loading dose 12 m.or Final Visit

  18. Baseline Characteristics (1)

  19. Baseline Characteristics (2)

  20. Medications After Randomization in Hospital

  21. Outcomes 1 /2

  22. Cumulative Hazard Rates for CV Death/MI/Stroke up to 30 Days Placebo Cumulative Hazard Rates Clopidogrel P = 0.003 0 10 20 30 Days of Follow-up No. Plac No. Clop 6303 6259 6108 6103 5998 6035 5957 5984

  23. Placebo Cumulative Hazard Rates Clopidogrel P < 0.001 0 3 6 9 12 No of Pts Months of Follow-up Plac Clop 6303 6259 5780 5866 4664 4779 3600 3644 2388 2418 Cumulative Hazard Rates for CV Death/MI/Stroke

  24. Outcomes 2/2

  25. Bleeding Complications

  26. TIMI Major Bleeding / GUSTO Severe-Life-Threatening Bleeding Criteria

  27. Major/Life-Threatening Bleeds within 7 Days of CABG Surgery

  28. Thrombocytopenia and Neutropenia

  29. Scenario • 67 year old man, non-Q MI • Diabetes, HTN, dyslipidemia, ex-smoker • No previous MI or CAD, but GI bleed • Was on ASA, other standard meds • Now 3 days post MI • Rx ASA, clopidogrel, stop enoxaparin, other Rx standard • Do you stop Clopidogrel?

  30. Users’ Guides for an Article about Harm • Are the results valid? • Similarity of all known determinants of outcome or adjustments for differences in analysis? • Were exposed patients equally identified? • Outcome assessment similar? • Was follow-up sufficiently complete?

  31. Harm: Different Study Designs

  32. Harm: Results and Applicability • What are the results? • How strong is the association between exposure and outcome? • How precise is the estimate of the risk? • How can I apply the results to patient care? • Were the study patients similar to mine? • Was f/u duration adequate? • What is the magnitude of the risk? • Should I attempt to stop the exposure?

  33. Scenario • 67 year old man, non-Q MI • Diabetes, HTN, dyslipidemia, ex-smoker • No previous MI or CAD, but GI bleed • Was on ASA, other standard meds • Now 3 days post MI • Rx ASA, clopidogrel, stop enoxaparin, other Rx standard • Do you stop Clopidogrel?

  34. Who would …. • Stop Clopidogrel? • Continue it? • Don’t know….

  35. Clopidogrel: NNT and NNH

  36. Clopidogrel: NNT and NNH

  37. Clopidogrel: NNT and NNH

  38. TIMI Score for ACSwww.timi.tv or www.timi.org • Age >= 65 years • 3 CRF: (DM, HTN, Fam Hx, Lipid, smoker, ) • Known CAD • Prior chronic ASA use • >= 2 episodes rest angina in 24h • Elevated Cardiac enzymes • ST deviation >= .5mm

  39. TIMI Score for ACS • Age >= 65 years • 3 CRF: (DM, HTN, Fam Hx, Lipid, smoker, ) • Known CAD • Prior chronic ASA use • >= 2 episodes rest angina in 24h • Elevated Cardiac enzymes • ST deviation >= .5mm

  40. TIMI clinical prediction score(14 days)

  41. Clopidogrel: NNT and NNH WHAT ARE THE CONFIDENCE INTERVALS AROUND NNT?

  42. Clopidogrel: NNT and NNH

  43. Clopidogrel: NNT and NNH

  44. Placebo Cumulative Hazard Rates Clopidogrel P < 0.001 0 3 6 9 12 No of Pts Months of Follow-up Plac Clop 6303 6259 5780 5866 4664 4779 3600 3644 2388 2418 Cumulative Hazard Rates for CV Death/MI/Stroke Initial benefit then 20% relative over 11 months

  45. TIMI clinical prediction score(14 days)

  46. Clopidogrel: NNT and NNH

  47. TIMI in TACTICS (6mo)

  48. TIMI and PRISM-PLUS

  49. Non-ST Elevation ACS • When do you add Clopidogrel? • When do you stop Clopidogrel? • How do you place Clopidogrel in relation to other expensive/potentially risky interventions: • angiogram • LMW heparin • IV G2b3 inhibitors • Do you put Clopidogrel on formulary

  50. QUESTIONS?

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