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
• 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.
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 Optimal medical therapy
Randomized
(n = 1149) (n = 1138)
Primary outcomes: All-cause mortality, nonfatal MI
Secondary outcomes: Death, MI, stroke; ACS hospitalization
Follow-up: Median 4.6 years
*Intensive pharmacologic therapy + lifestyle intervention Boden WE et al. Am Heart J. 2006;151:1173-9.
CCS = Canadian Cardiovascular Society Boden WE et al. N Engl J Med. 2007;356:1503-16.
Lifestyle intervention and risk factor goals
• Smoking cessation • LDL-C (mg/dL)
60-85
• Exercise program
– ≥30 min moderately intensive exercise • HDL-C (mg/dL)
5x/week ≥40
• Nutrition counseling • Triglycerides (mg/dL)
– Total dietary fat 27.5) • A1C (%)
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.
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.
MERLIN-TIMI 36
Metabolic Efficiency With Ranolazine for Less Ischemia
in Non-ST-Elevation Acute Coronary Syndromes-
Thrombolysis In Myocardial Infarction 36
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.
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.
MERLIN-TIMI 36: Study design
Patients with non-ST-elevation ACS
treated with standard medical/interventional therapies
N = 6560
Randomized
IV/oral ranolazine Placebo
Double-blind
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.
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 20
recurrent HR 0.92
ischemia (95% CI 0.83-1.02)
(%) 10
Log-rank P = 0.11
0
0 180 360 540
Days
Placebo Ranolazine
No. at risk
Placebo 3281 2454 1223 268
Ranolazine 3279 2450 1223 269
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Effect on efficacy outcomes
Ranolazine Placebo
better better P
Primary endpoint 0.11
Major secondary endpoint 0.50
Cardiovascular death 0.98
MI 0.76
Recurrent ischemia 0.03
Failure of therapy 0.16
Hospitalization for heart failure 0.68
0.5 1 1.5
Hazard ratio
(95% CI)
Morrow DA et al. JAMA. 2007;297:1775-83.
MERLIN-TIMI 36: Major safety outcomes
Event rate (%)
Ranolazine Placebo
(n = 3268) (n = 3273) P
All-cause death 5.3 5.4 0.91
All-cause death or CV hospitalization 33.2 33.4 0.53
Symptomatic documented arrhythmia 3.0 3.1 0.84
Clinically significant arrhythmia on Holter 73.7 83.1 <0.001
Morrow DA et al. JAMA. 2007;297:1775-83.
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.
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