1

Stable Coronary Syndrome:Old and New Antianginal Drugs

•Marginal and tedious topic

•PCI is the cure of angina, not drugs!

•Antianginal drugs are obsolete and do not have any impact on survival

Burden of Chronic Angina in the United States

9.1 million American adults have chronic

angina1

500,000 new cases diagnosed per year

50% experience angina as the initial sign of

ischemic heart disease

213 per 100,000 annual US angina incidence

in people >30 years of age

~50% of patients presenting with MI at the

hospital have preceding angina2

1 Rosamond W, et al. Heart Disease and Stroke Statistics – 2008 Update. Circulation. 2008;117:e25-e146.2 Gibbons RJ, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina. p5

Available at: http://acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf3 Boden WE, et al. Optimal Medical Therapy with or without PCI for Stable Coronary Disease. N Engl J Med

2007;356:1510.

The Cost of Chronic Angina

Outpatient;

38,3%

Nursing Home;

12,0%Home Health;

6,2%

Prescription

Drugs; 15,1%

Hospitalization;

16,3%

Emergency

Department,

12.1%

Adapted from Javitz H, et al. Am J Managed Care. 2004;10(11):S367.

Direct Costs 2004 Estimates: $1.9 – $8.9 Billion (US)*

* Direct costs for angina $1.9 billion when it is the first-listed diagnosis and $8.9 billion when it is listed in any position

Angina Symptoms Predict

Total Mortality in Patients with CAD

Prospective study with 8900 VA patients with CAD, greater physical limitations due to angina had higher mortality rates:

Mozaffarian D, et al. Am Heart J. 2003;146:1015-1022.

Years

COURAGE:

Treatment Effect on Primary Outcome

HR 1.05*

(0.87-1.27)

P = 0.62

All-Cause Mortality, MI

* Unadjusted

PCI + OMT

No. at risk

Medical therapy 1138 1017 959 834 638 408 192 30

PCI 1149 1013 952 833 637 417 200 35

Survival

free of

primary

outcome

0 2 4 7

0

0.5

0.6

0.7

0.8

1.0

0.9

Years

6531

Optimal Medical Therapy (OMT)

Boden WE et al. N Engl J Med. 2007;356:1503-16.

Angina Symptoms Persist in Many

Patients Despite Revascularization

Serruys PW, et al. N Engl J Med. 2001;344:1117-1124.

Continued angina and antianginal medication use 12 months after revascularization for angina (n=1205)

100%

Stenting groupSurgery group

Pre

vale

nce (

% o

f p

ati

en

ts)

21%*

79%* 81%*

11%

59% 62%

0%

20%

40%

60%

80%

Continued

angina

Continued

antianginal

medication

Continued angina

and/or antianginal

medication*p < 0.001

7

Stable Coronary Syndrome:Old and New Antianginal Drugs

•Marginal and tedious topic

•PCI is the cure of angina, not drugs!

•Antianginal drugs are obsolete and do not have any impact on survival

Treatments

DihydropyridineCCBs

Nicorandil

Beta-blockers

Others (nitrates,diltiazem, verapamil)

Studies in patientswith stable CAD

CAMELOTACTION

IONA

Meta regression analysisCIBIS-II

-

Findings

No impact on mortality or MI in CAMELOTACTION: no reduction in CV events

Primary endpoint reduced, but no impact on mortality or non fatal MI

Evidence only in post-MI and CHF

No prognositic data in stable CAD patients

Effects of antischemic drugs on outcome

Draft ~ CVT Confidential ~ Do not distribute 9

Oxygen Supply and Demand Are

Mismatched During Ischemia

Chaitman BR. Circulation. 2006;113:2462-2472. Belardinelli L, et al. Eur Heart J. 2004;6(suppl I):I3-I7. Opie LH, et al. In: Opie LH, Gersh BJ, eds. Drugs for the Heart. 6th ed. Philadelphia, Pa: Elsevier Saunders; 2005:5,33,56,58,280,323.

Impaired DiastolicRelaxation

Sodium-InducedCalcium Overload

Ischemia

DiastolicWall Tension

MicrovascularFlow

O2

SupplyO2

Demand

Vasospasm

Thrombus

Atherosclerosis

Heart rate

Contractility

LV wall tension

Despite β-blockers, many CAD

patients have a heart rate >70 bpmMean resting HR at initial assessment in the overall patient population (n = 3 674)

and in patients with β-blockers (n= 2 005) from The Euro Heart Survey

ESC 2008, C. Daly, L. Tavazzi, K. Fox. Abstract P1354.

53

39

0

25

50

75

Total on BB

Resting Heart Rate and

Beta-blocking therapy

69±8

73±8

p<0.001

Heart

rate

(b

pm

)

62%38%

With BB Without BB

Lorgis L. et al. Arch of Cardiovasc Dis 2009, 102, 541-547

12

New Antianginal Drugs

PathophysiologicTarget

Old (HR)

“New” (Ca overload)

Ivabradine

Ranolazine

Mechanism ofAction

New (If inhibition)

New(late I Na inhibition)

13

RANOLAZINE (Ranexa®)

13

FIRST “LATE CARDIAC SODIUM CURRENT” INHIBITOR

NEW CLASS OF ANTI-ANGINAL AGENTS

film-coated prolonged release tablets containing

375 mg, 500 mg or 750 mg

HN

NO

N

OH

OOMe

14

Late Na current and Intracellular Ca

15

Pathophysiology of Myocardial IschemiaFocus on LV Wall Tension and Late I Na current

Ranolazine Inhibits Late INa of the Human Heart in vivo

Effect of Ranolazine in Patients with

the Congenital Long-QT Syndrome Type 3

16

Study (CVT 3114) carried out by:

Dr. Arthur Moss

Dr. Wojciech Zareba

University of Rochester, Rochester, NY

17

Sudden

death

Effect of Ranolazine in the Congenital Long-QT Syndrome Type 3 Patients

• LQT3 syndrome is a monogenetic disorder

characterized by an abnormally prolonged QT

interval and by life-threatening arrhythmias.

Genotype

Mutant SCN5A

Δ KPQ

Molecular

phenotype

Increased late INa

Cellular

phenotype

Prolonged action

potential; early

afterdepolarizations;

delayed relaxation

Organ

phenotype

Prolonged QT

interval; torsade de

pointes

delayed relaxation

(not shown)

Clinical

phenotype

Syncope

Sudden death

Pathogenetic

pathwayLate INa

Peak INa

control

mutant

TdP

SyncopeSuddendeath

EAD

I II III IV

18Time and dose-dependent effect of

Ranolazine on QTc interval1 in patients with LQT3 syndrome2

Time and dose-dependent effect of Ranolazine on QTc interval1 in

patients with LQT3 syndrome2

Source: teg_QTCF (11JUN2007 17:24) S:\CVT-303\cvt3114\Statistics\Final|Table_Graph\TEG_QTCF.RTF

tpc (11jun2007 18:14) S:\cvt-303\CVT3114\Statistics\Final\Table_Graph\TPC.RTF

Values are mean SE from 5 patients1QTc (Fridericia) change from baseline2 KPQ

0 4 8 12 16 20 24

Time (hrs)

1000

2000

3000

-10

-20

-30

-40

-50

** *

§ ‡

§

‡ †

†

‡

*

*

‡

*p < 0.05†p < 0.01‡p < 0.001§p < 0.0001

repeated measures ANOVA

On Ranolazine, IV Off

Ch

an

ge

in

QT

c

(ms

ec

)

[Ra

no

lazi

ne]

(ng

/ml)

45 mg/hr 90 mg/hr

QTc vs. [RAN] plasma

r = 0.7 ± 0.22

slope = 24.1 msec/1,000 ng/ml

(P = 0.008)

Draft ~ CVT Confidential ~ Do not distribute 19

Ranolazine: Key Clinical Trials

Chaitman BR, et al. JAMA. 2004;291:309-316.Stone PH, et al. J Am Coll Cardiol. 2006;48:566-575.Morrow DA, et al. JAMA. 2007;297:1775-1783.

CARISA

N=823

Chronic

angina

Ranexa vs placebo

on top of

standard therapy

ERICA

N=565

Chronic

angina

Ranexa vs placebo

on top of

amlodipine 10mg

MERLIN

TIMI-36

N=6560

Non-STE

ACS

Ranexa vs placebo

on top of

standard care

19

ERICA/CARISA Efficacy Summary

Ranolazine is an effective antianginal therapy in combination with ß-blockers, amlodipine and nitrates

Increases ETT exercise duration, time to angina and ST depression

Decreases rate of angina attacks

Decreases NTG consumption

Provides significant antianginal efficacy on top of maximum approved doses of amlodipine

Antianginal and anti-ischemic effects do not depend on changes in BP or HR

Modified from Stone P, et al. J Am Coll Cardiol. 2006;48(3):566-75

MERLIN:

Components of Primary Endpoint

Recurrent Ischemia (%*) CV Death or MI (%*)

Days from Randomization

Ranolazine 13.9%

(N=3,279)

Placebo 16.1%

(N=3,281)

0 180 360 540

HR 0.87 (95% CI 0.76 to 0.99)

P =0.030 0

5

10

15

20

0

5

10

15

0 180 360 540

Ranolazine 10.4%

Placebo 10.5%

HR 0.99 (95% CI 0.85 to 1.15)

P =0.87

20

Days from Randomization

*KM Cumulative Incidence at 12 months

Morrow D, et al. JAMA 2007;297:1775-83

22

New Antianginal Drugs

PathophysiologicTarget

Old (HR)

“New” (Ca overload)

Ivabradine

Ranolazine

Mechanism ofAction

New (If inhibition)

New(late I Na inhibition)

Ivabradinea prototype of a new class of drugs, the If inhibitors

a new concept for a drug providing anatomical (sinus node cell) and functional (Ifchannel) selectivity

If Current: What is it ? f for funny

Observed (1979) by Brown, Di Francesco

and Noble

Present only in the sinus node (and retina)

Important for pacemaker depolarisation

(heart rate)

Mixed, conducts sodium and potassium

Controlled by sympathetic and vagal

systems

mV

pA

500

-50

-50

ICaL

50

I K

ms0

-50

INaCa

-50

ICaT

-50

If

Sinus node action potential and currents

Ca channel

T- type

Ca channel

L- type

K channel

f-channel

Sinus node

Robinson RB, DiFrancesco D. Fundamental and Clinical Cardiology; NY; Marcel Decker; 2001:151-170.

Sinus node channels

If current in the sinus node: the determinant of heart rate

Simon L et al. J Pharmacol Exp Ther. 275:659-666, 1995

Heart rate

* P <0.05

*

**

**

*

Baseline Rest Ex 5 Ex 10 Ex 12

0

100

200

-100

(km/h)

Baseline Rest Ex 5 Ex 10 Ex 12

**

* * *

50

0

100

75

25

- 20

**

*

125

(km/h)

(%

)Ivabradine, contrary to β-blockers,

maintains cardiac contractilityPropranolol (1 mg/kg)Saline Ivabradine (0.5 mg/kg)

No negative inotropic effect

HR decrease (at rest) versus other HR lowering agents

* 1 Weiss. 1993. 2 Frances. 1995.

**Tardif J-C, et al. 2005.

0

-5

-10

-15

, bpm

Ivabradine**

5 mg bid 7.5 mg bid

Atenolol**

50 mg od 100 mg od

Diltiazem*

200 & 300 mg od2

n=182

180-240 mg bid1

n=208 n=286n=595 n=300

Effects of ivabradine on heart rate

Extracellular

side

Closed Open Inihibited

Na+ K+Ivabradine

Intracellular

side

Bucchi A, Baruscotti M, DiFrancesco D. J Gen Physiol. 2002;120:1-13

When the channel is in closed state

(bradicardia) ivabradine is inactive.

Ivabradine interacts internaly with

the If channel: a safety issue

Expected clinical benefits from pure HR reduction

stable angina / ischemia

CAD and LV dysfunction

CHF

Ivabradine and angina

Against amlodipine

Against placebo

Against atenolol

Ivabradine versus beta-blockade: Clinical efficiency for angina reduction

Tardif JC, et al. Drugs Today. 2008;44:171-181.

Increase in exercise capacity per 1 beat of heart rate reduction

(after 4-month treatment)

atenolol 100 mg

Changes in TED

(Total Exercise

Duration,

sec)

Ivabradine 7.5 mg0

2

4

6

8

10

12

X 2

Dog

Subendocardial blood flow (% anterior wall)

Rest

Exercise without

medication

Normalized wall

thickening (% rest)

Matsuzaki et al., Am J Physiol 247: H52-H60, 1984

Regional myocardial blood flow and function

Coronary stenosis

Dog

Subendocardial blood flow (% anterior wall)

Rest

Exercise without

medication

Exercise with

medication

Normalized wall

thickening (% rest)

Matsuzaki et al., Am J Physiol 247: H52-H60, 1984

ß-Blockade and regional myocardial blood flow and function

Coronary stenosis

Subendocardial blood flow (ml/min/g)

10

20

30Rest

Exercise

Exercise + Atenolol / Pace

0.2 0.4 0.6 0.8 1.0 1.2

Systolic wall

thickening (%)

Guth et al., Circ Res 60: 738-746, 1987

Dog

Coronary stenosis

ß-Blockade and regional myocardial blood flow and function

8Change from

baseline (%)

Simon L, et al. J Pharmacol Exp Ther. 1995;275:659-666.

*

*

++

++

+

++ ++

++

Baseline Exercise 5 min 10 min 12 min

6

4

2

0

-2

-4

-6

-8

Saline

0.5 mg/kg Ivabradine

1.0 mg/kg Propranolol

* p<0.05 vs. Baseline

p<0.05 vs. Saline

p<0.05 vs. Propranolol

++

+

Ivabradine, contrary to β-blockers

allows coronary dilatationEXERCISE

b-blockade unmasking a-adrenergic

vasoconstriction

Ivabradine reduces heart rate in

patients already receiving β-blockers

54

56

58

60

62

64

66

68

Baseline M2 M4

Ivabradine

5 mg bid

Ivabradine 7.5 mg bid (90% of pts) or 5 mg bid (10%)

67

60 (- 7 bpm)

58 (- 9 bpm)

Ivabradine +

atenolol

atenolol

Placebo +

889 stable angina patients, 20 countries

Ivabradine

7.5 mg bid

Tardif JC, et al. Eur Heart J. 2009;30:540-548.

Ivabradine + atenolol

Placebo + atenolol

0

10

20

30

40

50

60

Total exercise

duration

Time to limiting

angina

Time to angina

onset

Time to 1mm ST

segment

depression

P<0.001 P<0.001

P<0.001 P<0.001

Ivabradine increases all ETT parameters

in patients already receiving BBs further

*Evaluated at trough of drug activity

889 stable angina patients, 20 countries

Tardif JC, et al. Eur Heart J. 2009;30:540-548.

Advantages of ivabradine as an anti-ischemic agent

• Novel pharmacodynamic profile• pure heart rate reduction, no negative inotropism

• preservation of blood pressure, LV relaxation, A-V and ventricular conduction

• no coronary vasoconstriction

• Identical clinical efficacy of atenolol and amlodipine

• Long-term efficacy without tolerance

• None of the β-blockers limitation

• Useful on top of β-blockers

• Documented coronary artery

disease

• Documented left ventricular

systolic dysfunction (EF<40%)

• Sinus rhythm and resting heart

rate ≥60 bpm

Inclusion criteria

Am Heart J. 2006;152:860-66

•Cardiovascular death

•Hospitalization for acute MI

•Hospitalization for new-onset or worsening HF

Primary end point

All end points analyzed for total

population (HR >60 bpm) and for

patients with HR >70 bpm

Clinical: composite of

Pathophysiological

Heart rate as a predictor of

CARDIOVASCULAR DEATH HOSPITALIZATION FOR HF

HOSPITALIZATION FOR MI REVASCULARIZATION

Fox et al. Lancet. 2008;372:817-21.

• In patients with heart rate > 70 bpm,

ivabradine was shown to reduce the

composite of fatal and non fatal MI

• In patients with heart rate > 70 bpm,

ivabradine reduced the need for

revascularisation

Conclusion

Angina sub analysis

1507 randomized

with angina

734 to ivabradine 773 to placebo

773 analyzed734 analyzed

12 138 screened

10 917 randomized

Fox K, et al. Eur Heart J. 2009 FASTTRACK.

Effect of ivabradine on primary

composite end point

HR (95% CI), 0.76 (0.58–1.00),

P=0.05

Years

HR (95% CI),

0.69 (0.47–1.01), P=0.06

Years

0

5

10

15

20

25

30

0 0.5 1 1.5 2

Eve

nt ra

te (

%)

0

5

10

15

20

25

30

0 0.5 1 1.5 2

Eve

nt ra

te (

%)

All angina patients HR >70 bpm

24% 31%Placebo

Ivabradine

Placebo

Ivabradine

* Composite of cardiovascular mortality or hospitalization for fatal and

nonfatal myocardial infarction or heart failure Fox et al. Eur Heart J. 2009. FASTTRACK.

Placebo

Ivabradine

HR (95% CI), 0.27 (0.11–0.66),

P=0.002

Years

Placebo

Ivabradine

HR (95% CI), 0.58 (0.37–0.92),

P=0.021

Years

0

5

10

15

0 0.5 1 1.5 2

Even

t ra

te (

%)

0

5

10

15

0 0.5 1 1.5 2

Event ra

te (

%)

42% 73%

Effect of ivabradine on

hospitalization for MI

All angina patients HR >70 bpm

* Fatal and nonfatal events Fox et al. Eur Heart J. 2009. FASTTRACK.

Intolerant or contraindicationβ-Blockers

Add If inhibitor

Consider suitability for

revascularization

If inhibitor

Substitute

calcium antagonist or

long-acting nitrate

Treatment aimed at symptom relief

Modified from: Fox K. Recommendations of the Task Force of the ESC on stable angina. Eur Heart J. 2006;27:1341-1381.

Symptoms not controlled after dose optimization

Symptoms not controlled after dose optimizationAdd long-acting

nitrate, calcium

antagonist, or K-

channel opener

Symptoms not controlled after

dose optimizationIntolerant

Symptoms not controlled on 2 drugs after dose optimization

HR > 60bpm

HR > 60bpm

FROM

TO

• Outpatients with stable CAD

• Age > 55 years

• With at least one other CV risk factor

• Without LVSD (LVEF > 40%) or clinical signs of HF

Population

• With resting HR>70 bpm (two

consecutive ECG recordings at

5 min apart, at selection and

inclusion visits) and in sinus

rhythm

• Receiving appropriate guide-

lines driven CV medication

Population

50

Stable Coronary Syndrome:Old and New Antianginal Drugs

• Chronic angina in still a very relevant epidemiologic and clinical issue

• PCI is still a long way from eliminating angina/ischemia in the vast majority of patients with CAD

• At least two drugs (Ivabradine and Ranolazine) offer an intriguing opportunity to improve treatment of chronic myocardial ischemia and, possibly, to reduce MI and revascularization