ERICAEfficacy of Ranolazine In Chronic Angina trial

Does ranolazine reduce angina in CAD patientsdespite treatment with the maximum dose of a conventional

antianginal agent (amlodipine)?

Background and hypothesis

• Incidence of symptomatic angina in stable CAD patients remains high despite the use of conventional agents and/or revascularization

• Traditional pharmacologic therapies determinants of MVO2 (heart rate, myocardial contractility, wall stress)– Combinations of these therapies may provide incremental antianginal

efficacy but may also produce side effects

• Ranolazine is a new antianginal agent with a novel mechanism of action that does not significantly affect HR or wall stress

MVO2 = Myocardial oxygen consumption Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: Study design

Ranolazine extended-release 500 mg bid

(1 week) then 1000 mg bidn = 281

Placebon = 284

History of CAD* Stable angina (≥3 angina episodes/week) Amlodipine

10 mg/dayN = 565

7 weeks

Primary efficacy variable:Angina frequency (weekly average)

RandomizedDouble-blind

Evaluation of Ranolazine In Chronic Angina

*≥60% stenosis, previous MI, and/or stress-induced perfusion defect Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: Concomitant medications

Placebo n (%)

Ranolazine 1000 mg bidn (%)

Aspirin 244 (86) 245 (87)

ACE inhibitors 144 (51) 152 (54)

Long-acting nitrates* 123 (43) 130 (46)

Statins 93 (33) 109 (39)

Diuretics 77 (27) 89 (32)

Antidiabetics(including insulin)

29 (10) 33 (12)

*All other antianginals were proscribed

N = 564 on amlodipine 10 mg/day

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: Ranolazine reduces angina frequency and nitrate consumption

Placebo Ranolazine 1000 mg bid

Nitroglycerin useAngina episodes

P = 0.028

P = 0.014

N = 564 on amlodipine 10 mg/day

0

1

2

3

4

5

6

Baseline Week 7 Baseline Week 7

Mean number

per week

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

0

0.5

1

1.5

2

2.5

3

3.5

4

Women Men <65 years ≥65 years LAN use No LAN

Meanangina

episodes per

week

ERICA: Consistent treatment effect regardless of gender, age, and concomitant long-acting nitrates

LAN = long-acting nitrates

N = 564 on amlodipine 10 mg/day; week 7

Placebo Ranolazine 1000 mg bid

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

0

1

2

3

4

5

6

0

10

20

30

Anginafrequency

NTGuse

Anginafrequency

NTGuse

Seattle Angina Questionnaire(angina frequency domain)

P < 0.001P = 0.57P < 0.001

P = 0.029

P = 0.036

P = 0.28

≤4.5 >4.5 ≤4.5 >4.5

Number/week SAQ score

( baseline)

ERICA subgroup analyses: Frequency of angina

Placebo Ranolazine 1000 mg bid

N = 564 on amlodipine 10 mg/day

Angina episodes per week

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: No significant effect on heart rate or BP

Placebo Ranolazine 1000 mg bid P

Heart rate (bpm)

↓1.6 ↓2.0 0.66

Systolic BP (mm Hg)

↓1.7 ↓2.0 0.72

Diastolic BP (mm Hg)

↓0.6 ↓1.0 0.61

N = 564 on amlodipine 10 mg/day; Supine measurement

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: Safety and tolerability

Ranolazine 1000 mg bid (%)

Placebo (%)

Any adverse event 39.9 35.3

Constipation 8.9 1.8

Peripheral edema 5.7 2.8

Dizziness 3.9 2.5

Nausea 2.8 0.7

Headache 2.8 2.5

Discontinued 1.1 1.4

N = 564 on amlodipine 10 mg/day

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

ERICA: Summary

• Added to maximum-dose amlodipine, ranolazine extended-release 1000 mg bid for 6 weeks significantly reduced angina frequency and nitroglycerin use– Treatment effect appeared to be greater in patients with

>4.5 angina episodes weekly

• No significant change in HR or BP; no cases of torsades de pointes reported

• Low withdrawal rate due to adverse events in both groups– 1.1% ranolazine – 1.4% placebo

Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

Implications

• ERICA efficacy parameters are in agreement with previous studies using antianginal agents

• SAQ* provides an appealing feature to assess disease-specific measures of quality of life

• Because ranolazine can prolong QTc, the daily dose should not exceed 1000 mg/day; use should be limited to patients unresponsive to other antianginal agents

Cairns JA. J Am Coll Cardiol. 2006;48:576-8.Stone PH et al. J Am Coll Cardiol. 2006;48:566-75.

Ranolazine provides additional, well-tolerated antianginal efficacy in patients who remain symptomatic despite maximal CCB therapy

*Seattle Angina Questionnaire