new therapeutic options for chronic stable angina

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)


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


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


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)

*


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


P < 0.001

P = 0.006

Anginal episodes

perweek

Placebo Ranolazine SR750 mg bid

Ranolazine SR1000 mg bid


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


P = 0.02

Nitroglycerin use

Numberper

week

Placebo Ranolazine SR750 mg bid

Ranolazine SR1000 mg bid

P < 0.001


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


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


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


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.


• 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

new therapeutic options for chronic stable angina

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