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

Redefining Treatment Strategies for Optimal Medical Care in CAD

COURAGE and MERLIN-TIMI 36

COURAGEClinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

COURAGE: Background and objective

• 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

Boden WE et al. N Engl J Med. 2007;356:1503-16.Boden WE et al. Am Heart J. 2006;151:1173-9.

In patients with stable CAD

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

COURAGE: Study design

Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

Optimal medical therapy* + PCI (n = 1149)

Optimal medical therapy(n = 1138)

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)

Primary outcomes: All-cause mortality, nonfatal MI

Follow-up: Median 4.6 years

Randomized

*Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society

Secondary outcomes: Death, MI, stroke; ACS hospitalization

Lifestyle intervention and risk factor goals

• 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

Boden WE et al. Am Heart J. 2006;151:1173-9.

Pharmacologic therapy

• 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

Boden WE et al. Am Heart J. 2006;151:1173-9.Boden WE et al. N Engl J Med. 2007;356:1503-16.

COURAGE: Baseline demographics

PCI + medical therapy(n = 1149)

Medical therapy(n = 1138)

Age (years) 61.5 61.8

Male (%) 85 85

Race (%) White Black Hispanic Other

86563

86554

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

COURAGE: Baseline angiographic data



Vessels with disease (%) 1 2 3

313930

303931

Disease in graft vessel* (%) 62 69

Proximal LAD disease (%) 31 37†

Ejection fraction (%) 60.8 60.9


*Patients who underwent previous CABG†P = 0.01

COURAGE: Baseline angina



CCS class (%) 0 I II III

12303623

13303719

Median duration (mo) Interquartile range

51-15

51-15

Median episodes/week Interquartile range

31-6

31-6


COURAGE: Inducible ischemia at baseline



Nuclear imaging, % (n) 70 (685) 72 (708)

Single reversible defect, % (n) 22 (154) 23 (161)

Multiple reversible defect, % (n) 65 (444) 68 (483)


COURAGE: Change in lifestyle factors

0

20

40

60

80

100

Smoking AHA step 2diet

Moderateactivity

Patients (%)

Baseline 1 year




0

20

40

60

80

100

Smoking AHA step 2diet

Moderateactivity

Treatment targets

Baseline 1 year

PCI +medical therapy

Medical therapy

PCI + medical therapy

Medical therapy

SBP (mm Hg) 131 130 126 124

DBP (mm Hg) 74 74 72 70

Total cholesterol (mg/dL) 172 177 156 150

LDL-C (mg/dL) 100 102 84 81

HDL-C (mg/dL) 39 39 42 41

TG (mg/dL) 143 149 129 133

BMI (kg/m²) 28.7 28.9 28.5 29.0

Moderate activity, 5x/week (%) 25 25 46 43


COURAGE: Improvement in CV risk factors

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

COURAGE: Treatment effect on primary outcome

HR 1.05(0.87-1.27)P = 0.62*


All-cause death, MI (time to first event)

*Unadjusted

No. at riskMedical therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Medical therapy PCI + medical therapy

Survival free of primaryoutcome

0 2 4 70

0.5

0.6

0.7

0.8

1.0

0.9

Years6531

No. at riskMedical therapyPCI

3844

302312

468488

717733

917929

10291051

10731094

11381149

120134

192200

409418

638637

834833

962954

10191015

11381149

COURAGE: Treatment effects

Boden WE et al. N Engl J Med. 2007;356:1503-16.*Unadjusted

All-cause death Myocardial infarction

Overall survival

Survival free of MI

PCI + medical therapy

1.0

0.9

0.7

0.8

Medical therapy

1.0

0.9

0.7

0.8

0 1 2 3 4 5 6 7

0

YearsYears

0 1 2 3 4 5 6 7

0

HR 0.87(0.65-1.16)P = 0.38*

HR 1.13(0.89-1.43)P = 0.33*

COURAGE: Treatment effect on hospitalization for ACS

Boden WE et al. N Engl J Med. 2007;356:1503-16.*Unadjusted

HR 1.07(0.84-1.37)P = 0.56*

No. at riskMedical therapyPCI

127134

236246

418431

662667

833835

956957

10251027

11381149

Survival free of ACS

Years

00 1 2 3 4 5 6 7

1.0

0.9

0.7

0.8

PCI + medical therapyMedical therapy

COURAGE: Treatment effect on angina

0

10

20

30

40

50

60

70

80

Baseline 1 year 3 years 5 years

PCI + medical therapy Medical therapy


P < 0.001P = 0.02 NS

Angina-free(%)

NS


Treatment effect in CV and diabetes subgroups

0.25 0.50 1.00 2.001.751.50

Medical therapy betterPCI betterMyocardial infarctionYesNo

Extent of CADMultivessel diseaseSingle-vessel disease

DiabetesYesNo

AnginaCCS 0-ICCS II-III

Ejection fraction

>50%Previous CABG

NoYes

≤50%

Baseline characteristics

Hazard ratio (95% CI)

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


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

• 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.

In non-ST-elevation ACS

MERLIN-TIMI 36: Objective

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


Non-ST-elevation ACS

MERLIN-TIMI 36: Study design

IV/oral ranolazine Placebo

Patients with non-ST-elevation ACStreated with standard medical/interventional therapies

N = 6560

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

RandomizedDouble-blind


MERLIN-TIMI 36: Effect on primary endpoint


N = 6560 with non-STE ACS; Ranolazine vs placebo ≤48hrs of ischemic symptom onset

No. at riskPlaceboRanolazine

32813279

24542450

12231223

268269

HR 0.92(95% CI 0.83-1.02)Log-rank P = 0.11

30

20

10

00 180 360 540

Days

Placebo Ranolazine

CV death, MI, or

recurrent ischemia

(%)

MERLIN-TIMI 36: Effect on efficacy outcomes


P

Primary endpoint

Major secondary endpoint

Cardiovascular death

MI

Recurrent ischemia

Failure of therapy

Hospitalization for heart failure

0.11

0.50

0.98

0.76

0.03

0.16

0.68

0.5 1 1.5Hazard ratio

(95% CI)

Ranolazinebetter

Placebobetter

MERLIN-TIMI 36: Major safety outcomes

Event rate (%)

Ranolazine(n = 3268)

Placebo(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


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


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

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

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