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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
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