New Therapeutic Options
for Chronic Stable Angina
New mechanistic approaches to chronic
stable angina
Rho kinase inhibition (fasudil)
Metabolic modulation (trimetazidine)
CH3
N
CH3
SO2 N
CH3
O
O
O
N
NH
Sinus node inhibition (ivabradine)
H3C O
H3C O
H
O CH3
N
CH3
N
O CH3
H
N
N
O
O
CH3
OH
N
H
O NO2
Late INa inhibition (ranolazine)
CH3
H
Preconditioning (nicorandil)
O
N
N
N
OCH3
O
Evaluation of fasudil in stable angina:
Trial design
N = 84
80 mg tid
2 weeks
ET*
60 mg tid
2 weeks
40 mg tid
Fasudil
20 mg tid
(n = 41)
Run-in
(Class II or III angina)
ET*
2 weeks
ET*
2 weeks
ET*
3 weeks
Placebo (n = 43)
ET
ET = exercise test (treadmill)
*ET at trough and 1 and 4 hours post-dose
Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.
Results: Fasudil improves exercise duration
N = 84
150
100
Mean change
from baseline
(seconds)
50
0
Weeks
Placebo
2
(20 mg)
Fasudil
4
(40 mg)
6
(60 mg)
8
(80 mg)
Visit (fasudil dose tid)
Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.
Results: Fasudil improves exercise time to
≥1 mm ST depression
N = 84
200
*
150
Mean change
from baseline 100
(seconds)
50
0
Weeks
Placebo
*P = 0.001
2
(20 mg)
Fasudil
4
(40 mg)
6
(60 mg)
8
(80 mg)
Visit (fasudil dose tid)
Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.
TACT: Study design
Trimetazidine in Angina Combination Therapy
Trimetazidine 20 mg tid (n = 90)
•
•
•
•
•
Run-in
(CCS class I–III)
≥2 weeks
2 x ET
(weeks -1, 0)
Placebo (n = 87)
12 weeks
ET
N = 166 men
ET = exercise test (treadmill/bicycle)
Primary outcomes
ET
ET duration
Time to 1 mm ST 
Time to angina onset
Mean no. angina attacks
Mean short-acting nitrate
use
• Change in rate-pressure
product
• Change in CCS angina
class
Chazov EI et al. Am J Ther. 2005;12:35-42.
TACT: Trimetazidine reduces angina episodes
N = 166 men with CCS class I–III angina
Anginal attacks
8
7
6
Mean
5
number
4
per
3
week
2
1
0
P < 0.05
Before
study
Placebo
Run-in
1
2
Months
3
Trimetazidine 20 mg tid
Chazov EI et al. Am J Ther. 2005;12:35-42.
IONA: Study design
Impact Of Nicorandil in Angina
Stable angina on optimum antianginal therapy
N = 5126
Nicorandil 20 mg bid
n = 2565
Randomized
Double-blind
Placebo
n = 2561
1.6 years mean follow-up
Primary outcome:
CHD death, nonfatal MI, hospitalization for chest pain
IONA Study Group. Lancet. 2002;359:1269-75.
IONA: Reduction in primary outcome
CHD death, nonfatal MI, hospitalization for chest pain
1.0
0.9
Proportion
event-free
Nicorandil
RRR 17%
HR 0.83 (0.72–0.97)
P = 0.014
0.8
Placebo
0.7
0
0
0.5
1.0
1.5
2.0
2.5
3.0
Follow-up (years)
IONA Study Group. Lancet. 2002;359:1269-75.
INITIATIVE: Study design
International Trial on the Treatment of Angina with Ivabradine vs. Atenolol
Ivabradine
5 mg bid
(n = 317)
10 mg bid
Ivabradine
5 mg bid
(n = 315)
7.5 mg bid
Placebo
Placebo
Placebo
2–7 days
Washout
7 days
Run-in
Selection ET
4 weeks
Atenolol
50 mg
(n = 307)
Inclusion ET
ET = exercise test (treadmill)
*ET at trough and 4 hours post-dose
12 weeks
100 mg
ET*
2 weeks
50 mg
25 mg
ET*
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
INITIATIVE: Effects of ivabradine vs β-blockade
on primary outcome
95
P < 0.001 for noninferiority vs atenolol
(both ivabradine doses)
90
Change in
85
exercise
duration
80
(seconds)
91.7
86.8
78.8
75
0
Atenolol
100 mg
(n = 286)
Patients completing trial
Ivabradine
7.5 mg bid
(n = 300)
Ivabradine
10 mg bid
(n = 298)
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
INITIATIVE: Summary
• Ivabradine 7.5 mg bid and 10 mg bid were noninferior to atenolol
100 mg as measured by
– Total exercise duration
– Time to limiting angina, angina onset, and 1 mm ST
• Most common adverse events were transient visual symptoms,
mainly increased brightness in limited areas
• Sinus bradycardia occurred in 2.2% (ivabradine 7.5 mg),
5.4% (ivabradine 10 mg), and 4.3% (atenolol) of patients
If current inhibition may be as effective as β-blockade
in treatment of stable angina
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.
Ranolazine: Late Na+ current inhibitor
• First new class of antianginals to be approved in the
US since 1960s
• Antianginal and anti-ischemic effects with no change
in HR or BP
• May be used in patients with slow HR, low BP,
prolonged AV conduction, CHF, diabetes, or asthma
• Modest prolongation of QTc interval with no known
clinical sequelae
Ranolazine: Pathophysiologic effects vs older
antianginals
O2 Supply
Coronary
blood flow
β-blockers
O2 Demand
Heart rate
Arterial
pressure
Venous
return
Myocardial
contractility
—


—

DHP CCBs

*

—

Non-DHP CCBs



—

Long-acting nitrates

/—


—
Late Na+ current inhibitors
(ranolazine)
—
—
—
—
—†
Drug class
*Except amlodipine
†Ranolazine: No direct effect but
may prevent ischemia-related decline
Boden WE et al. Clin Cardiol. 2001;24:73-9.
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
Kerins DM et al. In: Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 10th ed.
MARISA: Study overview
Monotherapy Assessment of Ranolazine In Stable Angina
Objective:
Assess the antianginal effects of ranolazine as
monotherapy in stable angina
Design:
Randomized, double-blind, placebo-controlled, crossover
Population:
N = 191 with stable angina
Treatment:
Ranolazine SR 500 mg, 1000 mg, or 1500 mg bid
Placebo
Primary
outcome:
Follow-up:
Total exercise duration at trough
3 active treatment periods, each lasting 1 week;
1-week placebo period
1-year open-label follow-up
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
MARISA: Study design
Single-blind placebo
qualifying phase
Double-blind phase
Post-study
follow-up
1 week
4 weeks
2 weeks
Pre-visit 1
Visit 1
Visit 7
Randomized, 1-week periods, crossover,
placebo, ranolazine SR 500–1500 mg bid
Qualifying
ET
ET = exercise test (treadmill)
ET each week at trough
and 4 hours post-dose
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
MARISA: Dose-related increase in exercise
duration with ranolazine
N = 175 evaluable patients with stable angina
†
560
†
*
540
551.6
539.4
529.5
Exercise
duration
(seconds)
520
505.7
500
0
Placebo
500 mg
1000 mg
1500 mg
Ranolazine SR bid
*P = 0.003 vs placebo; †P < 0.001 vs placebo
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
MARISA: Tolerability of treatments
Dose-related adverse events*
Ranolazine SR (%)
1000 mg bid 1500 mg bid†
Placebo (%)
500 mg bid
Any adverse event
15.6
16.0
21.7
34.2
Dizziness
1.1
1.1
5.0
12.3
0
<1
1.1
8.6
2.2
0
1.7
6.4
0
0
1.7
4.3
5.0
5.0
1.7
3.2
Nausea
Asthenia
Constipation
Angina
*Occurring in ≥3% of patients
†Exceeds recommended dose
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
MARISA: Summary
• Compared with placebo, ranolazine SR 500–1500 mg bid
significantly improved:
– Total exercise duration
– Time to angina onset
– Time to 1 mm ST 
• No clinically significant  in HR or BP at rest or during exercise
• 7% (13/191) of ranolazine patients discontinued due to adverse
events, mostly (11/13) at the highest dose
• No effect on QT dispersion
• No patient discontinued because of QTc prolongation*
Ranolazine monotherapy is associated with increased exercise performance
in the absence of any clinically meaningful pathophysiologic effects
* >30% from baseline
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
Antianginals: Effects on exercise duration
Mean increase in exercise duration
vs placebo (seconds)
Trough
Peak
Ranolazine SR 500 mg*1
23.8
29.3
Ranolazine SR 1000 mg*1
33.7
50.1
Amlodipine 10 mg2
NA
57.0
Atenolol 100 mg2
NA
14.2
Diltiazem 360 mg3
NA
72.0
Diltiazem SR 180–360 mg4
NA
30.0
*bid
1. Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
2. Davies RF et al. J Am Coll Cardiol. 1995;25:619-25.
3. Go M et al. Am J Cardiol. 1984;53:669-73.
4. Stone PH et al. Circulation. 1990;82:1962-72.
CARISA: Study overview
Combination Assessment of Ranolazine In Stable Angina
Objective:
Assess the antianginal effects of ranolazine when added
to standard antianginal therapy
Design:
Randomized, double-blind, placebo-controlled,
parallel-group
Population:
N = 823 with angina/ischemia despite standard qd doses
of amlodipine 5 mg, atenolol 50 mg, or diltiazem 180 mg
Treatment:
Ranolazine SR 750 mg or 1000 mg bid
Placebo
Primary
outcome:
Total exercise duration at trough
Follow up:
12 weeks
Chaitman BR et al. JAMA. 2004;291:309-16.
CARISA: Study design
Background CCB or -blocker plus nitrates prn
Ranolazine SR 1000 mg bid (n = 275)
Single-blind placebo
qualifying phase
Ranolazine SR 750 mg bid (n = 279)
1 week
ET
Placebo (n = 269)
2 weeks
ET
4 weeks
ET*
ET = Exercise test (treadmill)
*ET at trough and 4 hours post-dose
6 weeks
ET*
ET*
Chaitman BR et al. JAMA. 2004;291:309-16.
CARISA: Ranolazine increases exercise duration
Background CCB or -blocker plus nitrates prn
540
*
*
531.8
530.5
750 mg
1000 mg
(n = 272)
(n = 261)
530
Exercise
duration
(seconds)
520
510
510
0
Placebo
(n = 258)
Ranolazine SR bid
*P = 0.03 vs placebo
Chaitman BR et al. JAMA. 2004;291:309-16.
CARISA: Ranolazine reduces angina frequency
Background CCB or -blocker plus nitrates prn
P < 0.001
5
4.6
4.3
4.5
4
P = 0.006
3.3
Anginal
episodes 3
per
2
week
2.5
2.1
1
0
Baseline
Placebo
Ranolazine SR
750 mg bid
Week 12
Ranolazine SR
1000 mg bid
Chaitman BR et al. JAMA. 2004;291:309-16.
CARISA: Ranolazine reduces nitrate
consumption
Background CCB or -blocker plus nitrates prn
P < 0.001
5
P = 0.02
4.0
4.0
4
Number
per
week
3.7
3.1
3
2.1
2
1.8
1
0
Baseline
Week 12
Nitroglycerin use
Placebo
Ranolazine SR
750 mg bid
Ranolazine SR
1000 mg bid
Chaitman BR et al. JAMA. 2004;291:309-16.
CARISA: Summary
• Ranolazine SR added to standard therapy significantly improved:
– Total exercise duration, time to angina onset, time to 1 mm ST 
– Anginal frequency and nitroglycerin consumption
• No clinically significant changes in HR or BP at rest or during
exercise
• Small QTc increases with no effect on QT dispersion
Ranolazine provides additional antianginal and anti-ischemic efficacy
in patients who remain symptomatic on standard therapies
Chaitman BR et al. JAMA. 2004;291:309-16.
ERICA: Study design
Evaluation of Ranolazine in Chronic Angina
Stable angina on amlodipine 10 mg
N = 565
Ranolazine SR 1000 mg bid
Randomized
Double-blind
Placebo
7 weeks
Primary outcome:
Angina frequency
Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.
ERICA: Ranolazine reduces angina frequency
and nitrate consumption
N = 565
6
5
P = 0.028
Mean 4
number
3
per
week 2
P = 0.014
1
0
Baseline
Week 7
Anginal attacks
Placebo
Baseline
Week 7
Nitroglycerin use
Ranolazine SR 1000 mg bid
Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.
ERICA: Summary
• Added to maximum-dose amlodipine, ranolazine SR
1000 mg bid significantly reduced anginal frequency
and nitroglycerin use
• No change in HR or BP
• Early withdrawal rate due to adverse events was
comparably low in both groups
– 1.1% ranolazine
– 1.4% placebo
Ranolazine provides additional, well-tolerated antianginal efficacy in
patients who remain symptomatic despite maximal CCB therapy
Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.
Ranolazine: Long-term use
Exercise-induced chronic angina
Successfully completed 1 of 2 treadmill studies
N = 746
Open label
Ranolazine titrated to 1000 mg bid
2.96 years mean follow-up
Results:
Overall mortality: 2.8% per patient year (PPY)
SCD mortality: 0.6% PPY
QTc >500msec: 10 patients; Torsade de Pointes: 0 patients
Ranolazine discontinuation due to AEs: 9.7% in first 2 years
Age >64 years and prior Hx of HF were significant predictors
of AE-associated discontinuation
SCD = sudden cardiac death
Koren MJ et al. J Am Coll Cardiol.
2006;47(suppl A):Abstract 999-253.
Ranolazine extended-release tablets:
Approved Jan 31, 2006
• Ranolazine is indicated for the treatment of chronic angina
• Because ranolazine prolongs the QT interval, it should be
reserved for patients who have not achieved an adequate
response with other antianginal drugs
• Ranolazine should be used in combination with amlodipine,
β-blockers or nitrates
• Effects on angina rate and exercise tolerance appear to be
smaller in women
FDA. http://www.fda.gov/bbs/topics/news/2006/NEW01306.html.
Ranolazine extended-release tablets prescribing information.
Ranolazine: Drug interactions
Inhibitors of CYP3A increase ranolazine plasma levels and
QTc prolongation and should not be coadministered with
ranolazine:
• Ketoconazole and other azole antifungals
• Diltiazem
• Verapamil
• Macrolide antibiotics
• HIV protease inhibitors
• Grapefruit juice or grapefruit-containing products
Ranolazine extended-release tablets prescribing information.
Ranolazine extended-release tablets: Dosing
• Dosing should be initiated at 500 mg bid and increased
to 1000 mg bid, as needed, based on clinical symptoms
• The maximum recommended daily dose of ranolazine
is 1000 mg bid
Ranolazine extended-release tablets prescribing information.
Electrophysiologic
effects of ranolazine
Late INa effect mitigates IKr effect
Ranolazine
potency IC50
Effect on
action potential
Effect on
ECG
IKr inhibition
12 µM*
Lengthens
 QT
Late INa inhibition
6 µM*
Shortens
 QT
Ion current
*At 500–1000 mg bid,
mean concentration range ~2–6 µM
Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut.
2004;9(suppl 1):S65-83.
Antzelevitch C et al. Circulation. 2004;110:904-10.
Cobbe S. Eur Heart J Suppl. 2004;6(suppl I):I9-11.
Overview of torsade de pointes
 Net repolarizing current
(IKr or INa)
Action potential duration
and QT interval
 Dispersion of ventricular
repolarization (ΔAPD)
Early afterdepolarizations
(EADs)
Trigger
Substrate
Torsade de pointes
APD = action potential duration
Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut.
2004;9(suppl 1):S65-83.
Ranolazine: No apparent proarrhythmic
characteristics
• No potential for early afterdepolarizations (EADs)
– Did not cause EADs
– Suppressed EADs induced by proarrhythmic agents
• Does not cause  dispersion of ventricular
repolarization
– Concentration-dependent  transmural dispersion of APD
(cardiomyocytes)
– No effect on QT dispersion in humans
– No torsade de pointes reported in clinical trials
Antzelevitch C et al. Circulation. 2004;110:904-10.
Cobbe S. Eur Heart J Suppl. 2004;6(suppl I):I9-11.
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
Current nonpharmacologic antianginal strategies
• Exercise Training
• Enhanced external
counterpulsation (EECP)
–  Endothelial function
– Promotes coronary collateral
formation
–  Peripheral vascular
resistance
–  Ventricular function
– Placebo effect
• Transmyocardial
revascularization (TMR)
– Sympathetic denervation
– Angiogenesis
• Spinal cord stimulation (SCS)
–  Neurotransmission
of painful stimuli
–  Release of
endogenous opiates
– Redistributes myocardial
blood flow to ischemic areas
Allen KB et al. N Engl J Med. 1999;341:1029-36.
Bonetti PO et al. J Am Coll Cardiol. 2003;41:1918-25.
Murray S et al. Heart. 2000;83:217-20.
Potential cardioprotective benefits of exercise
NO
production
ROS
generation
Vasculature
ROS
scavenging
Myocardium
Other
mechanisms
Thrombosis
Domenech R. Circulation. 2006;113:e1-3.
Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72.
Exercise vs PCI in low-risk CAD
N = 101 men with CCS class I–III angina*
PCI
20 min bicycle ergometry daily
Assessed at 12 months
Exercise vs PCI
Lower resting HR (P < 0.01)
Fewer rehospitalizations
Greater improvement in maximal
O2 uptake (P < 0.001)
Lower cost
*>80% had 1- or 2-vessel disease
Hambrecht R et al. Circulation. 2004;109:1371-8.
EECP improves angina class
N = 2289 consecutive EECP Clinical Consortium patients
80
73.4
70
60
50
Patients
(%)
39.5
40
30
22.0
20
10
0
≥1 class
≥2 classes
≥3 classes
Improvement in CCS angina class
EECP = enhanced external counterpulsation
Lawson WE et al. Cardiology. 2000;94:31-5.
Surgical laser TMR improves angina class
N = 275 with CCS class IV angina
100
87
83
60
Improvement*
(% of patients) 40
P < 0.001
TMR vs medical
(both time points)
78
76
80
32
13
20
0
3
12
Time (months)
TMR
Medical
*Reduction of ≥2 CCS classes
†Due to treatment failure
TMR = transmyocardial revascularization
†
Crossover from medical
Allen KB et al. N Engl J Med. 1999;341:1029-36.
SCS vs CABG: Equivalent symptom relief in
high-risk patients
N = 104 with CCS class III or IV angina
18
16
14
Mean 12
number 10
per
8
week
6
70%
73%
*
*
68%
77%
*
*
4
2
0
Anginal attacks
Nitrate consumption
SCS
Baseline
Anginal attacks
Nitrate consumption
CABG
6 months
SCS = spinal cord stimulation
*P < 0.0001
Mannheimer C et al. Circulation. 1998;97:1157-63.
Summary
• Many patients continue to experience angina despite
medical therapy and/or revascularization
• Late Na+ blockade is a potentially effective new
antianginal option with a mechanism of action
complementary to traditional agents
• Potential clinical application in broad range of patients
unresponsive to current treatment options
– Elderly
– Diabetes
– LV dysfunction or heart failure