New Therapeutic Options for Chronic Stable Angina
New mechanistic approaches to chronic stable angina
Sinus node inhibition (ivabradine)
Late INa inhibition (ranolazine)
Rho kinase inhibition (fasudil) Metabolic modulation (trimetazidine)
Preconditioning (nicorandil)
OH3C O
H3C O
N
CH3
O CH3
O CH3
NO
N
CH3
H
CH3
CH3 O
O H
N
SO2 NHN
O
O NO2H
N
O
OHCH3
CH3
OCH3HN N N O
N
N
Evaluation of fasudil in stable angina: Trial design
Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.
2 weeks
2 weeks
2 weeks
2 weeks
Fasudil20 mg tid(n = 41)
40 mg tid
60 mg tid
80 mg tid
Placebo (n = 43)
Run-in(Class II or III angina)
3 weeksET*
ET*
ET*
ET*
ET
N = 84
ET = exercise test (treadmill) *ET at trough and 1 and 4 hours post-dose
0
50
100
150
Mean change from baseline
(seconds)
Results: Fasudil improves exercise durationN = 84
Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.
(20 mg) (40 mg) (60 mg) (80 mg)
2 4 6 8
Visit (fasudil dose tid)Placebo Fasudil
Weeks
Results: Fasudil improves exercise time to ≥1 mm ST depressionN = 84
Vicari RM et al. J Am Coll Cardiol. 2005;46:1803-11.*P = 0.001
0
50
100
150
200
Mean change from baseline
(seconds)
(20 mg) (40 mg) (60 mg) (80 mg)
2 4 6 8
Visit (fasudil dose tid)Placebo Fasudil
*
Weeks
TACT: Study design
Chazov EI et al. Am J Ther. 2005;12:35-42.
N = 166 menET = exercise test (treadmill/bicycle)
Run-in(CCS class I–III)
≥2 weeks
Trimetazidine 20 mg tid (n = 90)
Placebo (n = 87)
ET ET
12 weeks
2 x ET (weeks -1, 0)
Trimetazidine in Angina Combination Therapy
• 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
Primary outcomes
Anginal attacks
012345678
Beforestudy
Run-in 1 2 3
Mean number
perweek
TACT: Trimetazidine reduces angina episodes
Chazov EI et al. Am J Ther. 2005;12:35-42.
N = 166 men with CCS class I–III angina
P < 0.05
Placebo Trimetazidine 20 mg tid
Months
IONA: Study design
Stable angina on optimum antianginal therapyN = 5126
1.6 years mean follow-up
Primary outcome:CHD death, nonfatal MI, hospitalization for chest pain
IONA Study Group. Lancet. 2002;359:1269-75.
RandomizedDouble-blind
Impact Of Nicorandil in Angina
Nicorandil 20 mg bidn = 2565
Placebon = 2561
IONA: Reduction in primary outcome
CHD death, nonfatal MI, hospitalization for chest pain
IONA Study Group. Lancet. 2002;359:1269-75.
RRR 17%HR 0.83 (0.72–0.97)P = 0.014
Proportionevent-free
1.0
0.9
0.8
0.7
0
Follow-up (years)
0 1.5 3.0
Nicorandil
Placebo
0.5 1.0 2.0 2.5
INITIATIVE: Study design
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.ET = exercise test (treadmill) *ET at trough and 4 hours post-dose
4 weeks 12 weeks 2 weeks
Atenolol50 mg(n = 307)
Ivabradine5 mg bid(n = 315)
Ivabradine5 mg bid(n = 317)
10 mg bid
7.5 mg bid
100 mg50 mg
25 mg
Placebo
Placebo
7 days2–7 days
Washout Run-in
Selection ET
Inclusion ET ET* ET*
Placebo
International Trial on the Treatment of Angina with Ivabradine vs. Atenolol
INITIATIVE: Effects of ivabradine vs β-blockade on primary outcome
78.8
86.8
91.7
0
75
80
85
90
95
Atenolol Ivabradine Ivabradine
Change in exercise duration
(seconds)
100 mg(n = 286)
7.5 mg bid(n = 300)
10 mg bid(n = 298)
P < 0.001 for noninferiority vs atenolol (both ivabradine doses)
Tardif J-C et al. Eur Heart J. 2005;26:2529-36.Patients completing trial
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
—†————Late Na+ current inhibitors(ranolazine)
— / —Long-acting nitrates
—Non-DHP CCBs
—*DHP CCBs
——β-blockers
Myocardial contractility
Venous return
Arterial pressureHeart rate
Coronary blood flowDrug class
O2 DemandO2 Supply
*Except amlodipine†Ranolazine: No direct effect butmay 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.pdfKerins DM et al. In: Goodman and Gilman’s
The Pharmacological Basis of Therapeutics. 10th ed.
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 bidPlacebo
Primary outcome: Total exercise duration at trough
Follow-up: 3 active treatment periods, each lasting 1 week; 1-week placebo period 1-year open-label follow-up
Monotherapy Assessment of Ranolazine In Stable Angina
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
MARISA: Study overview
MARISA: Study design
Pre-visit 1 Visit 1 Visit 7
Qualifying ET
Single-blind placeboqualifying phase
Double-blind phasePost-study
follow-up
1 week 2 weeks
Randomized, 1-week periods, crossover,
placebo, ranolazine SR 500–1500 mg bid
ET each week at trough and 4 hours post-dose
4 weeks
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.ET = exercise test (treadmill)
MARISA: Dose-related increase in exercise duration with ranolazine
505.7
529.5
539.4
551.6
0
500
520
540
560
Placebo 500 mg 1000 mg 1500 mg
Exercise duration
(seconds)
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
Ranolazine SR bid
N = 175 evaluable patients with stable angina
*P = 0.003 vs placebo; †P < 0.001 vs placebo
*
†
†
MARISA: Tolerability of treatments
Ranolazine SR (%)
Placebo (%) 500 mg bid 1000 mg bid 1500 mg bid†
Any adverse event 15.6 16.0 21.7 34.2
Dizziness 1.1 1.1 5.0 12.3
Nausea 0 <1 1.1 8.6
Asthenia 2.2 0 1.7 6.4
Constipation 0 0 1.7 4.3
Angina 5.0 5.0 1.7 3.2
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.
Dose-related adverse events*
*Occurring in ≥3% of patients†Exceeds recommended dose
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
Chaitman BR et al. J Am Coll Cardiol. 2004;43:1375-82.* >30% from baseline
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
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.*bid
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 bidPlacebo
Primary outcome: Total exercise duration at trough
Follow up: 12 weeks
Combination Assessment of Ranolazine In Stable Angina
Chaitman BR et al. JAMA. 2004;291:309-16.
CARISA: Study overview
CARISA: Study design
Chaitman BR et al. JAMA. 2004;291:309-16.
Single-blind placeboqualifying phase
1 week
ET
ET
Placebo (n = 269)
Ranolazine SR 750 mg bid (n = 279)
Ranolazine SR 1000 mg bid (n = 275)
ET* ET*ET*
2 weeks 4 weeks 6 weeks
ET = Exercise test (treadmill)*ET at trough and 4 hours post-dose
Background CCB or -blocker plus nitrates prn
CARISA: Ranolazine increases exercise duration
510
531.8 530.5
0
510
520
530
540
Placebo 750 mg 1000 mg
Exercise duration
(seconds)
Ranolazine SR bid
Chaitman BR et al. JAMA. 2004;291:309-16.*P = 0.03 vs placebo
*
(n = 258) (n = 272) (n = 261)
*
Background CCB or -blocker plus nitrates prn
CARISA: Ranolazine reduces angina frequency
4.6
3.3
4.3
2.5
4.5
2.1
0
1
2
3
4
5
Baseline Week 12
Chaitman BR et al. JAMA. 2004;291:309-16.
P < 0.001
P = 0.006
Anginal episodes
perweek
Placebo Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Background CCB or -blocker plus nitrates prn
CARISA: Ranolazine reduces nitrate consumption
4.0
3.1
4.0
2.1
3.7
1.8
0
1
2
3
4
5
Baseline Week 12
Chaitman BR et al. JAMA. 2004;291:309-16.
P = 0.02
Nitroglycerin use
Numberper
week
Placebo Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
P < 0.001
Background CCB or -blocker plus nitrates prn
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
Ranolazine SR 1000 mg bid Placebo
Stable angina on amlodipine 10 mgN = 565
7 weeks
Primary outcome:Angina frequency
RandomizedDouble-blind
Evaluation of Ranolazine in Chronic Angina
Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.
ERICA: Ranolazine reduces angina frequency and nitrate consumption
N = 565
Nitroglycerin useAnginal attacks
P = 0.028P = 0.014
Stone PH et al. Circulation. 2005;112(suppl II):II-748-9.
0
1
2
3
4
5
6
Baseline Week 7 Baseline Week 7
Meannumber
perweek
Placebo Ranolazine SR 1000 mg bid
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
Koren MJ et al. J Am Coll Cardiol.2006;47(suppl A):Abstract 999-253.SCD = sudden cardiac death
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 yearsAge >64 years and prior Hx of HF were significant predictors of AE-associated discontinuation
Open label
Ranolazine titrated to 1000 mg bid2.96 years mean follow-up
Exercise-induced chronic angina Successfully completed 1 of 2 treadmill studies
N = 746
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
• Ketoconazole and other azole antifungals
• Diltiazem
• Verapamil
• Macrolide antibiotics
• HIV protease inhibitors
• Grapefruit juice or grapefruit-containing products
Inhibitors of CYP3A increase ranolazine plasma levels and QTc prolongation and should not be coadministered with ranolazine:
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
Ion currentRanolazine potency IC50
Effect on action potential
Effect on ECG
IKr inhibition 12 µM* Lengthens QT
Late INa inhibition 6 µM* Shortens QT
*At 500–1000 mg bid,mean concentration range ~2–6 µM
Late INa effect mitigates IKr effect
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
Dispersion of ventricular repolarization (ΔAPD)
Torsade de pointes
Early afterdepolarizations (EADs)
Net repolarizing current (IKr or INa)
Action potential duration and QT interval
Trigger Substrate
Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut. 2004;9(suppl 1):S65-83.APD = action potential duration
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.
• Exercise Training
• Enhanced external counterpulsation (EECP) Endothelial function– Promotes coronary collateral formation Peripheral vascular
resistance Ventricular function– Placebo effect
Current nonpharmacologic antianginal strategies
• 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
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.
NO production
ROS generation
ROS scavenging
Other mechanisms
Vasculature ThrombosisMyocardium
Exercise vs PCI in low-risk CAD
N = 101 men with CCS class I–III angina*
20 min bicycle ergometry daily PCI
Assessed at 12 months
Lower resting HR (P < 0.01)
Greater improvement in maximal O2 uptake (P < 0.001)
Hambrecht R et al. Circulation. 2004;109:1371-8.
Fewer rehospitalizations
Lower cost
Exercise vs PCI
*>80% had 1- or 2-vessel disease
EECP improves angina class
73.4
39.5
22.0
0
10
20
30
40
50
60
70
80
≥1 class ≥2 classes ≥3 classes
Improvement in CCS angina class
Patients(%)
Lawson WE et al. Cardiology. 2000;94:31-5.
N = 2289 consecutive EECP Clinical Consortium patients
EECP = enhanced external counterpulsation
Surgical laser TMR improves angina class
8376
13
32
8778
0
20
40
60
80
100
3 12Time (months)
Improvement*(% of patients)
TMR Medical Crossover from medical
Allen KB et al. N Engl J Med. 1999;341:1029-36.
N = 275 with CCS class IV angina
*Reduction of ≥2 CCS classes†Due to treatment failureTMR = transmyocardial revascularization
P < 0.001 TMR vs medical
(both time points)
†
SCS vs CABG: Equivalent symptom relief in high-risk patients
SCS CABG
N = 104 with CCS class III or IV angina
Mannheimer C et al. Circulation. 1998;97:1157-63.
70% 73% 68% 77%
* * **
SCS = spinal cord stimulation*P < 0.0001
0
2
4
6
8
10
12
14
16
18
Anginal attacks Nitrate consumption Anginal attacks Nitrate consumption
Mean number
perweek
Baseline 6 months
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
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