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Redefining Treatment Strategies for Optimal Medical Care in CAD

Redefining Treatment Strategies for Optimal Medical Care in CAD. COURAGE and MERLIN-TIMI 36. COURAGE. Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation. COURAGE: Background and objective. In patients with stable CAD.

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Redefining Treatment Strategies for Optimal Medical Care in CAD

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  1. Redefining Treatment Strategies for Optimal Medical Care in CAD COURAGE and MERLIN-TIMI 36

  2. COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

  3. COURAGE: Background and objective In patients with stable CAD • Elective PCI procedures are common in the US (~85% of all PCI) • PCI decreases angina frequency but long-term prognostic effects on CV events are not known • Antianginal agents also provide symptom relief whereas ACEIs, ASA, β-blockers, and statins have been shown to prevent MI and death COURAGE was designed to evaluate whether PCI plus optimal medical therapy, as initial management strategy, reduces risk of major CV events compared with optimal medical therapy alone in stable CAD patients Boden WE et al. N Engl J Med. 2007;356:1503-16.Boden WE et al. Am Heart J. 2006;151:1173-9.

  4. COURAGE: Study design AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia (or ≥80% stenosis + CCS class III angina without provocation testing) Optimal medical therapy* + PCI (n = 1149) Optimal medical therapy(n = 1138) Randomized Primary outcomes: All-cause mortality, nonfatal MI Secondary outcomes: Death, MI, stroke; ACS hospitalization Follow-up: Median 4.6 years *Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

  5. Smoking cessation Exercise program ≥30 min moderately intensive exercise 5x/week Nutrition counseling Total dietary fat <30% of calories Saturated fat <7% of calories Dietary cholesterol <200 mg/day Weight control BMI <25 kg/m2 (if baseline BMI 25.0-27.5) 10% relative weight loss (if baseline BMI >27.5) LDL-C (mg/dL) 60-85 HDL-C (mg/dL) ≥40 Triglycerides (mg/dL) <150 BP (mm Hg) <130/85 <130/80 if diabetes or renal disease present A1C (%) <7.0 Lifestyle intervention and risk factor goals Boden WE et al. Am Heart J. 2006;151:1173-9.

  6. Antiplatelet Aspirin Clopidogrel in accordance with established practice standards Dyslipidemia Simvastatin ± ezetimibe or ER niacin ACEI or ARB Lisinopril or losartan -blocker ER metoprolol succinate Calcium channel blocker Amlodipine Nitrate Isosorbide 5-mononitrate Pharmacologic therapy Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

  7. COURAGE: Baseline demographics Boden WE et al. N Engl J Med. 2007;356:1503-16.

  8. COURAGE: Baseline angiographic data *Patients who underwent previous CABG†P = 0.01 Boden WE et al. N Engl J Med. 2007;356:1503-16.

  9. COURAGE: Baseline angina Boden WE et al. N Engl J Med. 2007;356:1503-16.

  10. COURAGE: Inducible ischemia at baseline Boden WE et al. N Engl J Med. 2007;356:1503-16.

  11. COURAGE: Change in lifestyle factors PCI + medical therapy(n = 1149) Medical therapy(n = 1138) Boden WE et al. N Engl J Med. 2007;356:1503-16.

  12. COURAGE: Improvement in CV risk factors Boden WE et al. N Engl J Med. 2007;356:1503-16.

  13. Angiographic outcomes • PCI attempted on 1688 lesions in 1077 patients • 590 patients (59%) received 1 stent • 416 (41%) received ≥2 stents • Reduction in stenosis diameter • 83% (± 14%) to 31% (± 34%) in 244 non-stented lesions • 82% (± 12%) to 1.9% (± 8%) in 1444 stented lesions • Angiographic success rate* of 93% *<50% residual stenosis after balloon angioplasty; <20% residual stenosis in stented artery Boden WE et al. N Engl J Med. 2007;356:1503-16.

  14. COURAGE: Treatment effect on primary outcome All-cause death, MI (time to first event) 1.0 0.9 0.8 Survival free of primary outcome HR 1.05 (0.87-1.27) P = 0.62* 0.7 0.6 0.5 0 0 1 2 3 4 5 6 7 Years Medical therapy PCI + medical therapy No. at risk Medical therapy 1138 1017 959 834 638 408 192 30 PCI 1149 1013 952 833 637 417 200 35 *Unadjusted Boden WE et al. N Engl J Med. 2007;356:1503-16.

  15. COURAGE: Treatment effects All-cause death Myocardial infarction 1.0 1.0 0.9 0.9 Overall survival Survival free of MI 0.8 0.8 HR 0.87 (0.65-1.16) P = 0.38* HR 1.13 (0.89-1.43) P = 0.33* 0.7 0.7 0 0 0 1 2 3 4 5 6 7 0 1 2 3 4 5 6 7 Years Years No. at risk Medical therapy 1138 1073 1029 917 717 468 302 38 1138 1019 962 834 638 409 192 120 PCI 1149 1094 1051 929 733 488 312 44 1149 1015 954 833 637 418 200 134 Medical therapy PCI + medical therapy *Unadjusted Boden WE et al. N Engl J Med. 2007;356:1503-16.

  16. COURAGE: Treatment effect on hospitalization for ACS 1.0 0.9 Survival 0.8 free of ACS HR 1.07 (0.84-1.37) P = 0.56* 0.7 0 0 1 2 3 4 5 6 7 Years No. at risk Medical therapy 1138 1025 956 833 662 418 236 127 PCI 1149 1027 957 835 667 431 246 134 Medical therapy PCI + medical therapy *Unadjusted Boden WE et al. N Engl J Med. 2007;356:1503-16.

  17. COURAGE: Treatment effect on angina NS P = 0.02 P < 0.001 Angina-free(%) NS Boden WE et al. N Engl J Med. 2007;356:1503-16.

  18. Treatment effect in CV and diabetes subgroups Baseline characteristics PCI better Medical therapy better Myocardial infarction Yes No Extent of CAD Multivessel disease Single-vessel disease Diabetes Yes No Angina CCS 0-I CCS II-III Ejection fraction ≤50% >50% Previous CABG No Yes 0.25 0.50 1.00 1.50 1.75 2.00 Hazard ratio (95% CI) Boden WE et al. N Engl J Med. 2007;356:1503-16.

  19. COURAGE: Summary and implications • PCI added to optimal medical therapy did not reduce risk of death, MI, or other major CV events compared with optimal medical therapy alone • Findings reinforce existing clinical practice guidelines • Optimal medical therapy and aggressive management of multiple treatment targets without initial PCI can be implemented safely in the majority of patients with chronic stable angina, even those with objective evidence of ischemia and significant multivessel CAD Boden WE et al. N Engl J Med. 2007;356:1503-16.

  20. MERLIN-TIMI 36 Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis In Myocardial Infarction 36

  21. MERLIN-TIMI 36: Background In non-ST-elevation ACS • Current management is designed to ↑myocardial O2 supply (antithrombotic therapy, revascularization) and ↓myocardial O2 demand (↓HR) • Ion current modulation is under evaluation in ACS management • Prolongation of the late Na+ current during myocardial ischemia may contribute to deleterious cellular effects • Ranolazine, an inhibitor of the late Na+ current, exerts an anti-ischemic action without any clinically significant effect on HR or BP in stable CAD patients, but has not been studied in ACS patients Morrow DA et al. JAMA. 2007;297:1775-83.

  22. MERLIN-TIMI 36: Objective Non-ST-elevation ACS MERLIN-TIMI 36 was designed to evaluate the efficacy and safety of ranolazine in reducing CV death, MI, and recurrent ischemia in ACS patients receiving standard therapy Morrow DA et al. JAMA. 2007;297:1775-83.

  23. MERLIN-TIMI 36: Study design Patients with non-ST-elevation ACStreated with standard medical/interventional therapiesN = 6560 RandomizedDouble-blind IV/oral ranolazine Placebo Primary efficacy endpoint:CV death, MI, recurrent ischemia Safety endpoints:All-cause death, CV hospitalization, symptomatic documented arrhythmia, clinically significant arrhythmia on Holter during first 7 days Morrow DA et al. JAMA. 2007;297:1775-83.

  24. MERLIN-TIMI 36: Effect on primary endpoint N = 6560 with non-STE ACS; Ranolazine vs placebo ≤48hrs of ischemic symptom onset 30 CV death, MI, or recurrent ischemia (%) 20 HR 0.92(95% CI 0.83-1.02)Log-rank P = 0.11 10 0 0 180 360 540 Days Placebo Ranolazine No. at risk Placebo Ranolazine 3281 3279 2454 2450 1223 1223 268 269 Morrow DA et al. JAMA. 2007;297:1775-83.

  25. MERLIN-TIMI 36: Effect on efficacy outcomes Ranolazinebetter Placebobetter 0.5 1 1.5 Hazard ratio(95% CI) Morrow DA et al. JAMA. 2007;297:1775-83.

  26. MERLIN-TIMI 36: Major safety outcomes Morrow DA et al. JAMA. 2007;297:1775-83.

  27. MERLIN-TIMI 36: Summary and implications • In patients with ACS, ranolazine added to standard therapy was associated with • No difference in composite efficacy endpoint of CV death, MI, or recurrent ischemia • No difference in safety endpoints of all-cause death, all-cause death or CV hospitalization, or symptomatic documented arrhythmia • Significant reduction in arrhythmias detected by Holter monitoring during first 7 days • Findings do not support use of ranolazine in ACS but add to previous safety data and provide additional support for ranolazine as antianginal therapy in stable CAD Morrow DA et al. JAMA. 2007;297:1775-83.

  28. COURAGE, MERLIN-TIMI 36: Optimal medical therapy for patients with CAD • Establish aggressive treatment goals • Utilize intensive, multifaceted therapy to achieve and maintain treatment goals • Lifestyle modification • Risk factor reduction • Antianginal therapy

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