John Parissis

Athens, Greece

New Therapeutic Approaches in the

Management of Stable Angina and

Ischemic Heart Disease

AGENDA

Drawbacks of old anti-anginal drugs

Anti-anginal effect of ranolazine

Anti-ischemic effect of ranolazine

Metabolic effects/effects on diastolic function

Anti-arrhythmic effects/safety issues

Clinical scenarios

Take home messages

Anti-ischaemic strategies in stable

coronary artery disease

COURAGE

Courage trial: Freedom from Angina

12 13

66

58

7267

74 72

0

10

20

30

40

50

60

70

80

Baseline 1 Year 3 Year 5 Year

PCI + OMT

OMTPerc

ent

*P<0.001†P=0.02

P=NS at baseline and 5 years

*†

Boden et al. N Engl J Med 2007; 356: 1503-1516.

Alleviation of angina symptoms –ESC guidelines 2006

Beta blockers first line therapy

Inadequate control of

symptoms – add a

calcium channel

blocker

Sublingual GTN tablets or

spray for immediate relief

& before activities known to

bring on angina

A

A

If intolerant of beta blockers

treat with a rate limiting

calcium channel blocker, long

acting nitrates or nicorandil

Consider referral to a cardiologist if symptoms not controlled

on maximum therapeutic doses of two drugs

Class I Level C

Older antianginal drugs: Clinical conditions that may limit use

Drug class

β-blockers NitratesCalcium channel

blockers†

Asthma/Severe COPD

Severe bradycardia

AV block

Severe depression

Raynaud’s syndrome

Sick sinus syndrome

Severe aortic stenosis

Hypertrophic obstructive

cardiomyopathy

Erectile dysfunction*

AV block

Bradycardia

Heart failure

Left ventricular

dysfunction

Sinus node

dysfunction

*Treated with PDE5 inhibitors†Nondihydropyridine CCBs Gibbons RJ et al. ACC/AHA 2002 guidelines

New concepts on nitrate tolerance

Side effects:

Headache, Flushing, Palpitations, Hypotension, Tolerance

Nitrate tolerance has multifactorial etiology.

Main causes:

Abnormalities in organic nitrate biotransformation

Increased production of free radicals

Endothelial dysfunction

Plasma volume expansion

Neurohormonal activation

Gori and Parker, Circulation 2002, 106:2510-2513

Molecular mechanisms of nitrate tolerance.

Münzel T et al. Circulation Research 2005;97:618-628

Long-term nitrate use may be deleterious in ischemic heart disease: A study using the

databases from two large-scale postinfarction studies.

BACKGROUND:

Secondary coronary prevention studies have generally focused on specific medications, often to the exclusion of commonly used therapies. To date, long-term nitrate use has not been investigated in large-scale clinical trials.

METHODS AND RESULTS:

Data were analyzed prospectively acquired in a large, observational study involving 1042 patients enrolled for the Multicenter Study of Myocardial Ischemia (MSMI) as well as 1779 patients enrolled for the Multicenter Diltiazem Post Infarction Trial (MDPIT).

The Cox analyses with all the variables retained revealed that nitrates were associated with a significantly increased mortality risk (MSMI: hazard ratio 3.78, P =.011; MDPIT: hazard ratio 1.61, P =.019) in patients who had recovered from an acute coronary event.

CONCLUSION:

These analyses raise concern about the potential adverse effects of long-acting nitrate therapy in chronic coronary disease.

Am Heart J. 1999;138:577

Pathophysiology of Angina

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.

14 A Pathological Paradigm: Sodium Channelopathy

Ca2+

Overload

Na Ch inactivation failure

Enhanced late INa Na+i

Na Ch inactivation failure

Enhanced late INa

Adapted from Belardinelli L. et al. Heart. 92 (Suppl. IV):IV6-IV14, 2006.

Pathological

Conditions

• Acquired

• Congenital

VG

VG: voltage-gated

15 Diastolic relaxation failure increases O2

consumption and reduces O2 supply

Na+ and Ca2+ overload Increased wall tension during diastole:

− Increases MVO2

− Compresses intramural small vessels

− Reduces myocardial blood flow (subendocardium)

Worsens ischemia and angina

16

A new and complementary mechanism

Na+-inducedCa2+ overload

Ischemia

O2

demandO2

supply

• Mechanical dysfunction

• Electrical instability

• Decreased ATP formation

Ranolazine

Nitrates

Beta-blockers

CaCBs

SNI

Heart rate

Contractility

Preload

Afterload

Coronary supply

M

VO

2

Anti-ischaemic and Anti-anginal Effects of Ranolazine: A Comparison with Atenolol

Exercise duration

p < 0.04

Placebo Ranolazine IR 400 mg tid

(1741 ± 1026 ng base/mL)Atenolol 100 mg qd

All patients analysis, N = 154.Rousseau MF, et al. Am J Cardiol 2005;95(3):311-6

0 3 6 9 12 15 18

10,000

20,000

30,000

40,000

Rate

-Pre

ssu

re P

rod

uct

(mm

Hg

·min

-1 ±

SE

)

Minutes on treadmill

placebo

ranolazine

* p <0.001 vs placebo**

* * *atenolol (100mg)

p < 0.001 p = 0.006

Anti-anginal effect of ranolazine

Study Design

*Additional Peak ETTs

Trough

ETTsWeeks

Eligible patients

stratified by

background anti-

anginal therapy:

• atenolol 50 mg od

• amlodipine 5 mg od

• diltiazem 180 mg od

Placebo bid

Ranolazine 750 mg bid

Ranolazine 1000 mg bid

2* 6 12*-2 0*

Randomization

Chaitman et al. JAMA

2004; 291:309-316

Increased Exercise TimesWith Ranolazine added to a

Beta- or Calcium Blocker

Change fro

m b

aselin

e, sec

N = 791, ITT/LOCF; LS mean ± SE.

*p < 0.05; **p ≤ 0.01; ***p ≤ 0.001 vs placebo.

50

100

150

Exerciseduration

Time to angina

Time to 1-mmST depression

Exerciseduration

Timeto angina

Time to 1-mmST depression

PeakTrough

***

** **

*****

* *

**

Placebo 750 mg bid 1000 mg bid

*

Decreased Angina Attacksand Nitroglycerin Consumption

Angina attacks Nitroglycerin consumption

***

N = 791, ITT/LOCF; LS mean ± SE.

*p < 0.05, **p ≤ 0.01, ***p ≤ 0.001 vs placebo

******

Sustained Antianginal Effect

Chaitman BR, et al. JAMA 2004;291:309-16.

Ranolazine versus placebo:

*P0.02, **P<0.01 and ***P<0.001

40

60

80

100

120

140

0 2 4 6 8 10 12

Ranolazine

750 mg b.i.d.

Placebo

Ch

an

ge f

rom

baselin

e a

t tr

ou

gh

(sec

s.e

.m.)

***

***

Weeks on treatment

Anti-ischemic effect of ranolazine

UA/NSTEMI

CP < 48h, ST-Dep or +cTn, or DM, or TRS 3

Ranolazine

IV to PO(1000 mg BID)

RANDOMIZE (1:1)

Double-blind

Holter at enrollment x 7d

Follow-up Visits:

Q4 Months

ETT at M8 or Final

Primary End Point

Cardiovascular death, MI

or recurrent ischaemia

Standard Therapy

Final Visit

(Median 348 Days)

Duration

Event-driven

N = 6560

440 sites

17 Countries

Morrow DA et al.

JAMA 2007;297:1775-1783

Placebo

Matched IV/PO

Metabolic Efficiency with

Ranolazine for Less Ischemia

in Non-ST Segment Acute

Coronary Syndromes

Primary Endpoint

CV Death, MI, or Recurrent Ischaemia (% at 12M)

0

10

20

30

0 180 360 540

Days from Randomization

HR 0.92 (95% CI 0.83 to 1.02)

P=0.11

Ranolazine 21.8%(N=3,279)

Placebo 23.5%(N=3,281)

Components of 10 Endpoint

CV Death or MI (%) Recurrent Ischaemia (%)

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 monthsMorrow DA et al. JAMA 2007;297:1775-1783

RESULTS - Primary End Point(CV death, MI or Recurrent Ischaemia)

Wilson S.R. et al.: J Am Coll Cardiol 2009; 53 (17): 1510-1516

Perc

en

tag

e (

%)

P = 0.017

Among patient with prior angina

i.v. 1,000 mg b.i.d. p.o.

29.4

25.2

23

24

25

26

27

28

29

30

Placebo (n = 1,776) Ranolazine (n = 1,789)

Ranolazine reduces Ca2+ overload and oxidative stress

and improves mitochondrial integrity to protect against

ischemia reperfusion injury in isolated hearts

M. Aldakkak et al. Pharmacological Research 2011;64:381–392

Anti-anginal effects of ranolazine in women

Women (n = 2291) vs men (n = 4269)

• Older, with higher rates of

– DM, HTN

– HF

– Prior angina

– ST↓

– ↑BNP

• However, lower rates of

– Stenosis > 50%

– ↑Troponin

• Greater burden of ischemia on Holter

monitoring and Seattle anginal

questionnaire

Mega, J. L. et al. Circulation 2010;121:1809-1817

11,3

18,2

25,8

1113

21,8

0

5

10

15

20

25

30

CV Death

or MI

Recurrent

Ischemia

Primary EP

Placebo

Ranolazine

1–Year

event

rate

(%)

RRR

P-value

3%

0.82

29%

0.002

17%

0.03

Outcomes in Women

Ranolazine is Effective in Women

Beneficial metabolic effect of ranolazine in diabetics

Ranolazine Significantly Reduced HbA1cin Patients With Diabetes and CAD

Placebo (n = 37)

Ranolazine 750 mg b.i.d. (n = 47)

-0.02%

-0.50%

Absolute Reduction in HbA1c From Baseline to Week 12*

Timmis AD, et al. Eur Heart J. 2006;27:42-48.

Me

an

Ch

an

ge

Fro

m B

as

eli

ne

in

Hb

A1

c (

%)

p = 0.008

0.48% reduction*

*At baseline, mean HbA1c was 7.9% in patients receiving ranolazine and 7.5% in patients receiving placebo.

Anti-anginal Effects of Ranolazine in Patients with T2DM

0

50

100

150 +40%

Ch

an

ge in

baselin

e e

xerc

ise

du

rati

on

at

tro

ug

h

(LS

Mean

SE

, sec)

Exercise

duration

Time to

angina onset

T2DM- Type 2 diabetes mellitus

SE- Standard error

Ranolazine HbA1c by 0.7%

0

50

100

150

200

+52%

Ch

ang

e in

bas

elin

e ti

me

to

on

set

of

ang

ina

at t

rou

gh

(LS

Mea

n

SE

, se

c)

0

1

2

3

4

-65%

An

gin

a e

pis

od

es

(LS

Mean

SE

, p

er

wk)

Angina

episodes

Nitroglycerin

use

0

2

4

6

-87%

Nit

rog

lyceri

n c

on

su

mp

tio

n

(LS

Mean

SE

, p

er

wk)

*No DM +23% *No DM +16% *No DM -27% *No DM -25%

Placebo

(n=57)

Ranolazine (1000 mg)

(n=64)

CARISA: Timmis, AD et al (2006). Eur Hrt J, 27, 42

Effect of Ranolazine on Glucose

Stimulated Insulin Secretion (GSIS) in

Pancreatic Islets

Glucose 0 100 nM 1 uM0

200

400

600 n = 4 - 6 *

**

20 mM Glucose

Ranolazine Concentration

Ins

ulin

Re

lea

se

(% o

f C

on

tro

l)

0

25

50

75

100

n = 4

Glucose Glucose 3mM 20 mM

Control

10 uM Ran

**

Insu

lin

(n

g/m

l/10 I

sle

ts)

Rat Islets

Mouse Islets

3mM

*) p<0.05, **) P <0.01

Human Islets

Glucose 0 100 nM 5 uM0

150

300

450 n = 3 - 7**

20 mM Glucose

Ranolazine Concentration

Ins

ulin

Re

lea

se

(% o

f C

on

tro

l)

3mM

Beneficial effect of ranolazine on diastolic function

LV end diastolic pressure

Baseline 15 30 45 600

10

20

30

40

50

60

70

Vehicle (n = 10)

Ranolazine 10 µM (n = 7)

*

*

Reperfusion time (minutes)

mm

Hg

LV -dP/dt (Relaxation)

Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

Gralinski MR et al. Cardiovasc Res. 1994;28:1231-7.*P < 0.05

Vehicle Ranolazine

Baseline 30 60 75 90

-1000

-800

-600

-400

-200

0**

*

*

mm

Hg

/sec

Reperfusion time (minutes)

Vehicle (n = 12)

Ranolazine 5.4 µM (n = 9)

Isolated rabbit hearts

Late INa blockade blunts experimental

ischemic LV damage

Baseline BNP and Effect

of Ranolazine on Primary Endpoint

CV Death, MI, or Recurrent Ischemia (%)

Days from Randomization

0

5

10

15

20

25

30

0 180 360

BNP NEG

p = 0.009

BNP POS

Placebo

BNP POS

Ranolazine

P-interaction = 0.05

Morrow DA et al. AHA 2007, Orlando, FL

Ranolazine for the treatment of heart failure withpreserved ejection fraction: RALI-DHF study.

Clin Cardiol 201134(7):426-32.

HYPOTHESIS:

RAnoLazIne for the Treatment of Diastolic Heart Failure (RALI-DHF) is a prospective, single-center, randomized, double-blind, placebo-controlled proof-of-concept study to determine if ranolazine compared with placebo will be more effective in improving diastolic function in patients with HFpEF.

METHODS:

Twenty patients with HFpEF (EF ≥ 50% and ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity [E/E'] >15 or N-terminal pro-type brain natriuretic peptide >220 pg/mL) will be randomized to receive ranolazine or placebo in a 1.5:1 ratio during their catheterization if the LV end-diastolic pressure is ≥18 mm Hg and the time constant of relaxation (τ) is ≥50 ms. Treatment will consist of intravenous infusion of study drug (or placebo) for 24 hours, followed by oral treatment for a total of 14 days.

ENDPOINTS:

(1) change from baseline to 30 minutes from initiation of intravenous study drug administration during cardiac catheterization hemodynamic parameters at both resting and paced (120 beats per minute) conditions: τ, LV end-diastolic pressure, and dP/dt(min) .

(2) change from baseline to day 14 in E/E', maximal oxygen consumption, and N-terminal pro-type brain natriuretic peptide.

Anti-arrhythmic effect of ranolazine

Major Safety Endpoints

Death - any cause (N)

Sudden Cardiac Death

Death or CV Hosp

Symptomatic Documented

Arrhythmia

Clinically significant

arrhythmia on Holter (%)

RANOLAZINE

(N=3,268)

175

65

1065

102

83.1

HR P-value

172

56

1037

99

73.7

0.99 p = 0.91

0.87 p = 0.43

0.98 p = 0.67

0.97 p=0.84

0.89 p<0.001

PLACEBO

(N=3,273)

Placebo Ranolazine0

50

100

75 (2.3%)

55 (1.7%)

=20, RR 0.74, p=0.08

Nu

mb

er

of p

atie

nts

Placebo Ranolazine0

1752 (53.5%)

1413 (43.2%)

=339, RR 0.81, p<0.001

1000

1500

2000

Nu

mb

er

of p

atie

nts

B. New-Onset Atrial FibrillationA. Supraventricular Tachycardia

Supraventricular Tachyarrhythmias in

the Merlin-TIMI 36 Trial

Scirica et al. Circulation. 2007;116:1449-1457.

MERLIN-TIMI 36: Reduction in VT lasting ≥8 beats

0

2

4

6

8

10

0 24 48 72 96 120 144 168

Hours from randomization

Incid

en

ce (

%)

Ranolazine

n = 3,162

Placebo

n = 3,189

RR 0.63 (0.52-0.76)

P < 0.001

RR 0.67

P = 0.008

RR 0.65

P < 0.001

8.3%

5.3%

Scirica BM et al. Circulation. 2007;116: 1647-1652

Use of ranolazine in clinical practice

Baseline

Peak HR =

142 bpm

After RAN

(3-4 wks)

Peak HR =

140 bpm

25%

10%

Effects of Ranolazine on Stress MPI

Rest Exercise

Venkataraman, Iskandrian et al, JACC Imaging 2010

MPI Variables (n=21) Baseline After RAN p Value

Summed difference score 7.2 + 5 4.7 + 4 0.006

Total perfusion defect size (PDS) 24 + 16 17 + 15 0.003

Ischaemia PDS 16 + 11 8 + 5 0.005

Reversible

Perfusion

Defect Size

Ischemia in a diabetic patient

Before Ranolazine 750 mg BID After Ranolazine 750 mg BID

Ischemia due to vascular micro-angiopathy in a diabetic patient with previous PTCA in

RCA and no other obstructive CAD – Optimizing treatment with new drugs

Th 201: Comparison of baseline and post-treatment ischemia

Before ranolazine treatment

After ranolazine treatment

Anti-ischemic effect of ranolazine in a patient with stable angina due to multi-vessel CAD no proper

for PCI or Revasc

6/10/2009 18/2/2010

J. Parissis courtesy

Effect of 5-month ranolazine therapy (500 mg x2) on the top of anti-anginal

treatment

The recommended initial dose of Ranolazine is 375 mg twice daily

After 2–4 weeks, the dose should be titrated to 500 mg twice daily

and, according to the patient’s response, further titrated to a

recommended maximum dose of 750 mg twice daily

If a patient experiences treatment-related adverse events (e.g.

dizziness, nausea, or vomiting), down titration of Ranolazine to

500 mg or 375 mg twice daily may be required. If symptoms do

not resolve after dose reduction, treatment should be discontinued

Dose Titration

Ranexa® Summary of Product Characteristics, July 2008

375mg 500mg 750mg

Myocardial ischemia: Novel therapeutic

approach

Consequences of ischemia

Ca2+ overload

Electrical instability

Myocardial dysfunction

(↓systolic function/

↑diastolic stiffness)Ischemia

↑ O2 Demand

Heart rate

Blood pressure

Preload

Contractility

↓ O2 Supply

Development of ischemia

Traditional

anti-ischemic

medications:

β-blockers

Nitrates

Ca2+ blockers

PH Stone, MD and BR Chaitman, MD. 2006.

Late sodium current

inhibition:

Ranolazine