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Clinical Insights, Risk Stratification, and Enhancing Outcomes

Clinical Insights, Risk Stratification, and Enhancing Outcomes. CRUSADE: National quality improvement initiative. C an R apid risk stratification of U nstable angina patients S uppress AD verse outcomes with E arly implementation of the ACC/AHA guidelines.

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Clinical Insights, Risk Stratification, and Enhancing Outcomes

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  1. Clinical Insights, Risk Stratification, and Enhancing Outcomes

  2. CRUSADE: National quality improvement initiative Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines • Academic collaboration among cardiology and emergency medicine initiated in 2001 • Cross collaboration with ACC and AHA • Multi-industry sponsor • Goal: Improve adherence to ACC/AHA guidelines for managing patients with ACS CRUSADE. www.crusadeqi.com

  3. CRUSADE: In-hospital mortality by age and acute treatment 20 Age >75 yrs 17.6 18 Age <75 yrs 16 14 12 10.4 % 10.7 10 8.7 8 6.7 6.5 6 5.2 3.5 3.5 3.1 4 2.7 1.8 1 2 0.6 0 0 1 2 3 4 5 6 Number of recommended therapies *Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa inhibitors, clopidogrel <24 hours, PCI <48 hours N = 105,619 registry patients Boden WE et al. Circulation. 2005;112:II-745.

  4. CRUSADE: Post-admission MI vs use of recommended therapies 7 6.7 6 Adjusted OR 0.91 (95% CI 0.88–0.95) 5 4.2 % 4 3.4 2.9 3 2.6 2.5 2.2 2 1 0 1 2 3 4 5 6 Number of recommended therapies *Aspirin, β-blockers, UFH/LMWH, GP IIb/IIIa inhibitors, clopidogrel <24 hours, PCI <48 hours N = 105,619 registry patients Boden WE et al. Circulation. 2005;112:II-745.

  5. CRUSADE: Impact of early aggressive management strategy on in-hospital mortality N = 17,926 registry patients Acute medical therapy (<24 h) In-hospital mortality  32% P < 0.001 P < 0.001 94 100 89 88 78 74 80 72 8 60 51 51 6 % 40 3.7 % 4 26 2.5 14 20 2 0 0 Aspirin -Blocker Clopidogrel Heparin GP IIb/IIIa inhibitor No early invasive care (n = 9889) Early invasive care (cardiac cath <48 h, n = 8037) Adjusted for clinical differences and propensity score Bhatt DL et al. JAMA. 2004;292:2096-104.

  6. CRUSADE: NSTE ACS dosing of antithrombotics—Study overview Objective: Investigate association between dosing UFH, LMWH, and GP IIb/IIIa inhibitors and major clinical outcomes Design: Prospective observational analysis Population: Registry patients with NSTE ACS receiving antithrombotic agents Primary outcome: Relation between excessive dosing of UFH, LMWH, and GP IIb/IIIa inhibitors and major bleeding, in-hospital mortality, and length of stay NSTE ACS = non–ST-segment elevation acute coronary syndromes Alexander KP et al. JAMA. 2005;294:3108-16.

  7. Major predictors of overdosing Older age(≥65 years) Renalinsufficiency Female Patients vulnerable to overdosing Low bodyweight Diabetes CHF Alexander KP et al. JAMA. 2005;294:3108-16.

  8. Results: Excess dosing by age 70 P < 0.001 for all treatment groups 60 50 Excessdose(%) 40 30 20 10 0 UFH LMWH GP IIb/IIIa inhibitors Patient age (years) 65–74 <65 ≥75 Alexander KP et al. JAMA. 2005;294:3108-16.

  9. Results: Antithrombotic therapy dose and major bleeding 35 30 25 Majorbleeding(%) P < 0.001 P = 0.25 P < 0.001 20 15 10 5 0 UFH LMWH GP IIb/IIIa inhibitors N = 2074 2063 2073 714 2327 3998 922 237 5879 1955 178 Underdosed Recommended Mild excess Major excess Data are for noncoronary bypass grafting and nontransfer population Alexander KP et al. JAMA. 2005;294:3108-16.

  10. Recommended dosing of antithrombotic agents Alexander KP et al. JAMA. 2005;294:3108-16.

  11. Creatinine clearance vs age 80 70 60 Median creatinine clearance (cc/min) 50 40 30 20 10 0 <65 65–74 75–84 >84 Age (years) Peterson ED et al. ACC. March 2005; Orlando, Fla. Data on file at: Duke Clinical Research Institute. Jan 2001–Dec 2004.

  12. Clinical implications • Early use of antithrombotic agents plays a key role in management of NSTE ACS, but dosing errors are common • Dosing errors occur more often in elderly and others already vulnerable to bleeding • Dosing errors predict an increased risk of major bleeding • Altering dosing based on weight and renal function minimizes bleeding while preserving therapeutic benefit • Patients receiving recommended doses of heparin and GP IIb/IIIa inhibitors alone or in combination have the lowest rates of bleeding Proper dosing of antithrombotic therapies is necessary to prevent bleeding complications in vulnerable patients Alexander KP et al. JAMA. 2005:294:3108-16.

  13. Clinical Insights, Risk Stratification, and Enhancing Outcomes Combination Therapy

  14. INTERACT: Study design INTegrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment Evaluate safety and efficacy of GP IIb/IIIa inhibitors + enoxaparin vs UFH N = 746 with ischemic chest symptoms and ECG or CK-MB evidence of ACS Prospective, randomized multicenter study Enoxaparin 1 mg/kg per 12 h for 48 h UFH 70 U/kg IV bolus, then 15 U/kg per h for 48 h Eptifibatide 180 µg/kg bolus, then 2.0 µg/kg per min for 48 h Primary safety outcome:96 h non–CABG-related major hemorrhage Primary efficacy outcome:Recurrent ischemia detected by continuous ECG evaluation within 96 h UFH = unfractionated heparin Goodman SG et al. Circulation. 2003;107:238-44.

  15. INTERACT: LMWH/UFH plus GP IIb/IIIa inhibitor in UA/NSTEMI—Primary outcomes Ischemia Bleeding (96 h) 35 5 35 P = 0.03 P = 0.003 30 30 P = 0.0002 P < 0.0001 4 25 25 3 20 20 Patients (%) 15 15 2 10 10 1 5 5 0 0 0 Initial 48 h 48–96 h Minor‡ Major‡ n = 357 357 322 302 n = 380 366 380 366 Enoxaparin* Heparin† *Enoxaparin 1 mg/kg SC q 12 h for 48 h †UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 h All patients: Eptifibatide 180-g/kg bolus + 2-g/kg per min infusion ‡Non–CABG-related Goodman SG et al. Circulation. 2003;107:238-44.

  16. INTERACT: LMWH/UFH plus GP IIb/IIIa inhibition in UA/NSTEMI Effect on 30-day death/MI 0.10 UFH† + GP IIb/IIIa inhibitor 0.08 P = 0.031 0.06 Proportion of patients 0.04 Enoxaparin* + GP IIb/IIIa inhibitor 0.02 0 15 20 25 30 10 5 0 Days since randomization *Enoxaparin 1 mg/kg SC q 12 h for 48 h†UFH 70-U/kg bolus + 15-U/kg per h infusion for 48 h All patients: Eptifibatide 180-g/kg bolus + 2-g/kg per min infusion Goodman SG et al. Circulation. 2003;107:238-44.

  17. SYNERGY: Study design Superior Yield of the New Strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa Inhibitors Compare enoxaparin vs UFH and define role of enoxaparin N = 10,027 high-risk NSTEMI patients managed with early PCI Prospective, randomized, open-label, multicenter study Enoxaparin UFH GP IIb/IIIa inhibitor, aspirin, and clopidogrel Primary outcome:Death or MI ≤30 days Primary safety outcome:Major bleeding or stroke SYNERGY Trial Investigators. JAMA. 2004;292:45-54.

  18. SYNERGY: Enoxaparin vs UFH with GP IIb/IIIa inhibition in ACS with early PCI Primary outcome (death or MI) Concomitant medications (%) Aspirin 95.2 94.7 Clopidogrel 62.5 63.3 GP IIb/IIIa inhibitor 56.5 58.2 b-Blocker 86.4 85.9 ACE inhibitor 63.8 62.2 Statin 69.2 70.0 0.2 Enoxn = 4993 UFHn = 4985 UFH Enoxaparin 14.5% 14.0% Proportion of patients 0.1 HR 0.96(95% Cl 0.86–1.06) 0 10 20 30 0 Days from randomization No. at Risk 4920 4458 4343 4301 4279 4261 3509 UFH 4936 4508 4375 4338 4313 4300 3550 Enoxaparin SYNERGY Trial Investigators. JAMA. 2004;292:45-54.

  19. PCI-CURE: Substudy design Percutaneous Coronary Intervention substudy of Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Evaluate pre/post-PCI benefit of clopidogrel N = 2658 with NSTEMI Double-blind, placebo-controlled, multicenter prespecified post-randomization analysis Clopidogrel 300 mg pre-PCI, Open-label thienopyridine 2–4 wk, Clopidogrel 3–12 mo Placebo pre-PCI,Open-label thienopyridine 2–4 wk, Placebo 3–12 mo Aspirin 75–325 mg (all patients) Primary outcome:CV death, MI, revascularization at 30 days Follow-up: 1 month Mehta SR et al. Lancet. 2001;358:527-33.

  20. PCI-CURE: Reduction in primary outcome at 30 days CV death, MI, or urgent target vessel revascularization 0.08 30% RRR*P = 0.03 Placebo 0.06 Cumulative hazard rates 0.04 Clopidogrel 0.02 P = 0.03 0 0 5 10 15 20 25 30 Days of follow-up *Unadjusted Mehta SR et al. Lancet. 2001;358:527-33.

  21. ISAR-REACT: Study design Intracoronary Stenting and Antithrombotic Regimen–Rapid Early Action for Coronary Treatment Evaluate abciximab + clopidogrel loading dose in PCI N = 2159 undergoing elective PCI Double-blind, randomized, placebo-controlled multicenter study Clopidogrel 600 mg ≥2 h prior to PCIAspirin 325–500 mg Abciximab 0.25 mg/kg bolus, then0.125 µg/kg per min for 12 h+ UFH 70 U/kg Placebo+ UFH 140 U/kg Primary outcome:All-cause death, MI, urgent revascularization Follow-up: 1 month Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.

  22. ISAR-REACT: Timing of loading dose and primary outcome All-cause death, MI, urgent revascularization Major bleeding (%) 1.6 0.5 0.4 1.1 10 <3 h 3–6 h 8 6–12 h Death, MI, urgent revascularization(%) 6 >12 h 4 2 P = 0.79 0 0 5 10 15 20 25 30 Time from randomization (days) Kandzari DE et al. J Am Coll Cardiol. 2004;44:2133-6.

  23. ISAR-CHOICE: No additional platelet effect with doses >600 mg Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect Maximal ADP-induced platelet aggregation after 4 hours 120 P = 0.001 100 ADP(5 µmol/L)-inducedaggregation(%) 80 60 40 20 P = 0.01 P = 0.59 0 300 mg 600 mg 900 mg Clopidogrel (loading dose) von Beckerath N et al. Circulation. 2005;112:2946-50.

  24. ISAR-SWEET: Study design Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics Evaluate abciximab + clopidogrel loading dose in PCI N = 701 with diabetes, undergoing elective PCI Double-blind, randomized, placebo-controlled multicenter study Clopidogrel 600 mg ≥2 h prior to PCI Placebon = 350 Clopidogrel 600 mg ≥2 h prior to PCIAbciximab 0.25 mg/kg bolus, then0.125 µg/kg per min for 12 hn = 351 Aspirin 500 mg and heparin Primary outcome:All-cause death and MI at 1 year TVR = target vessel revascularization Mehilli J et al. Circulation. 2004;110:3627-35.

  25. ISAR-SWEET: Neutral effect on primary outcome in diabetes 10 RR 0.97(0.58–1.62)P = 0.91 8 6 All-cause death, MI(%) Abciximab 4 Placebo 2 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time from randomization (months) Mehilli J et al. Circulation. 2004;110:3627-35.

  26. ISAR-SWEET: Reduction in restenosis and target vessel revascularization in diabetes RRR = 24% P = 0.01 RRR = 22% 37.8 40 P = 0.03 30.4 28.9 30 23.2 Incidence(%) 20 10 0 Angiographicrestenosis Target lesionrevascularization Abciximab Placebo Mehilli J et al. Circulation. 2004;110:3627-35.

  27. CLEAR PLATELETS: Study design Clopidogrel Loading with Eptifibatide to Arrest the Reactivity of PLATELETS Compare effects of antiplatelet regimens on platelet reactivity and occurrence of myocardial necrosis N = 120 undergoing elective stenting 2 x 2 factorial study Clopidogrel 300 mg* Clopidogrel 300 mg*+ eptifibatide† Clopidogrel 600 mg* Clopidogrel 600 mg*+ eptifibatide† Primary aim:Compare effects of four regimens Secondary aim:Effect of treatment on platelet reactivity and postprocedural myocardial necrosis *Loading dose immediately after stenting, then 75 mg/d †Double bolus (180 g/kg) followed by infusion (2 g/kg per min) for 18–24 hours postprocedure Gurbel PA et al. Circulation. 2005;111:1153-9.

  28. CLEAR PLATELETS: Platelet effects vs clopidogrel dose and GP IIb/IIIa inhibition Platelet inhibition* Platelet reactivity* 70 120 60 † † † § 100 D 50 C Relative inhibition (%) Aggregation (%) 80 40 ‡ 60 30 ‡ B ‡ 20 40 A  10 20 0 0 A B C D 3 h 8 h 18–24 h Group Time (post-stenting) †P ≤ 0.001 C or D vs A or B ‡P = 0.001 A vs B §P = 0.002 A vs B P < 0.001 C or D vs A or B A: Clopidogrel 300 mg B: Clopidogrel 600 mg C: Clopidogrel 300 mg + eptifibatide D: Clopidogrel 600 mg + eptifibatide *Response to adenosine diphosphate 5 mol/L Gurbel PA et al. Circulation. 2005;111:1153-9.

  29. CLEAR PLATELETS: Effect of clopidogrel dose and GP IIb/IIIa inhibition on cardiac biomarkers CK-MB release Troponin release 20 30 20 Patients (%) 10 † 10 ‡ * * 0 0 CK-MB (>3x ULN) Troponin-I (> ULN) Clopidogrel 300 mg Clopidogrel 600 mg Clopidogrel 300 mg + eptifibatide Clopidogrel 600 mg + eptifibatide *P < 0.05 vs clopidogrel 300 or 600 mg †P = 0.04 vs clopidogrel 300 mg ‡P = 0.08 vs clopidogrel 600 mg ULN = upper limit of normal Gurbel PA et al. Circulation. 2005;111:1153-9.

  30. Clopidogrel response variability: 300 mg vs 600 mg N = 190 33 300 mg clopidogrel Resistance 600 mg = 8% 30 600 mg clopidogrel Resistance 300 mg = 28% 27 24 Nonresponsiveness 21 Patients(%) 18 15 12 9 6 3 0 ≤-30 (-20,-10] (0,10] (20,30] (40,50] (60,70] (-30,-20] (10,20] (30,40] (50,60] > 70 (-10,0] D Platelet aggregation (5 µM ADP-induced) at 24 hours Gurbel PA. J Am Coll Cardiol. 2005;45:1392-96.

  31. Clopidogrel resistance associated with increased CV risk ADP-induced platelet aggregation Recurrent CV events at 6 months 40 Clopidogrel resistance 40 120 P = 0.007 35 1st Q 100 30 80 25 2nd Q % 60 % 20 3rd Q 15 40 4th Q 6.7 10 20 5 0 0 0 0 1stn = 15 2ndn = 15 3rdn = 15 4thn = 15 1 2 3 4 5 6 Days Quartiles Matetzky S et al. Circulation. 2004;109:3171-5.

  32. REPLACE-2: Study design Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events Evaluate bivalirudin vs heparin + GP IIb/IIIa blockade post-PCI N = 6010 undergoing PCI Randomized, double-blind multicenter study Bivalirudin 0.75 mg/kg bolus, 1.75 mg/kg per h during PCIProvisional GP IIb/IIIa inhibitor Heparin 65 U/kg bolusPlanned GP IIb/IIIa inhibitor Primary outcome:Death, MI, repeat revascularization, or in-hospital major bleeding in ≤30 days Secondary outcome:Death, MI, repeat revascularization ≤30 days Lincoff AM et al. JAMA. 2003;289:853-63.

  33. REPLACE-2: Death, MI, urgent revascularization, major bleeding P = 0.32 P = 0.26 P = 0.23 P = 0.44 P < 0.001 10.0 10 9.2 Heparin + GP IIb/IIIa inhibitor(n = 3008) 8 7.0 6.2 Bivalirudin(n = 2994) 6 % 4.1 4 2.4 2 1.4 1.2 0.4 0.2 0 Composite Death MI Urgent revasc Major bleed Lincoff AM et al. JAMA. 2003;289:853-63.

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