Effects of Ranolazine: from Angina to Cardiac Performance

Iacopo Olivotto, MDReferral Center for CardiomyopathiesCareggi University HospitalFlorence, Italy olivottoi@aou-careggi.toscana.it

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

• Prospective study 8900 VA patients with CAD– Primary endpoint all-cause

mortality– Seattle Angina Questionnaire

(SAQ)– Over 2 years mean follow up

• Results– Avg age 67 years– 98% male– ~66% white– ~25% diabetic– 896 deaths

Mozaffarian D, et al. Am Heart J. 2003.

Years

Greater physical limitation due to angina “strongly associated with higher mortality”

Angina Symptoms Predict Total Mortality in Patients with CAD

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

β-blockers

DHP CCBs

Non-DHP CCBs

Long-acting nitrates

Drug class

Coronaryblood flow

Arterialpressure

Venousreturn

Myocardialcontractility

Heartrate

CCB = calcium channel blocker, DHP = dihydropyridine *Except amlodipine

Boden WE et al. Clin Cardiol. 2001;24:73-9. Gibbons RJ et al. ACC/AHA 2002 Chronic Angina Guidelines. Kerins DM et al. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed.

O2 DemandO2 Supply

/

*

Antianginal Drugs

SodiumCurrent

0Late

Peak

0

Late

Peak

SodiumCurrent

Na+

ImpairedImpairedInactivationInactivation

ImpairedImpairedInactivationInactivation

Na+

Remodeling Remodeling

Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

Blocker: Blocker: RanolazineRanolazine

Mechanisms of action potential prolongation in chronic angina: late INa

Referral Center for Cardiomyopathies University Hospital of Careggi - Florence

Ranolazine: Mechanism of Action

Ischemia

Late INa

Na+ Overload

Diastolic relaxation failure(Increased diastolic tension)Extravascular compression

Ca++ Overload

Ranolazine:Inhibits the late inward

Na+ current

Ju YK, et al. J Physiol. 1996. Murphy E, et al. Circ Res. 1991. Jansen MA, et al. Circulation. 2004.

LV Diastolic

Tension

Ca2+i

Overload

Na+i

Ischemia

The Cycle of Ischemia

Ischaemia “begets” IschaemiaIschaemia “begets” IschaemiaIschaemia “begets” IschaemiaIschaemia “begets” Ischaemia

Cha

nge

from

bas

elin

e, s

ec

Peak

Trough

***

** **

*****

* *

**

*

50

100

150

Exercise

duration

Time

to angina

Time to 1-mm

ST depression

Exercise

duration

Time

to angina

Time to 1-mm

ST depression

N = 791, ITT/LOCF; LS mean ± SE. *P < .05; **P ≤ .01; ***P ≤ .001 vs placebo

PlaceboRanolazine 750 mg bidRanolazine 1000 mg bid

CARISA: Is Ranolazine effective on top of atenolol/amlodipine?

Chaitman BR, et al. JAMA. 2004;291:309-316.

BaselinePeak HR = 142 bpm

After RAN (3-4 wks)Peak HR = 142 bpm

25%

10%

Effects of Ranolazine on Stress MPI

RestRest ExerciseExercise

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 PDSIschaemia PDS 16 16 ++ 11 11 8 8 ++ 5 5 0.0050.005

Reversible Perfusion

Defect Size

VenkataramanJ. A C C : C ardiovascular Imaging, V O L . 2 , N O . 1 1 , 2 0 0 9

MERLIN: components of the primary efficacy end-point

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

Recurrent ischaemia

Days from randomisation

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

CV death or MI

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 randomisation

Clinical efficacy

Placebo Ranolazine

Cu

mu

lati

ve p

erce

nta

ge*

Cu

mu

lati

ve p

erce

nta

ge*

*Kaplan-Meier cumulative incidence at 12 months

0

2

4

6

8

10

0 24 48 72 96 120 144 168Hours from randomization

Incidence

(%) Ranolazine

Placebo

RR 0.63 (0.52-0.76)P < .001

RR 0.67P = .008

RR 0.65P < .001

8.3%

5.3%

MERLIN: Reduction in VT Lasting ≥ 8 beats

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

0

2

4

6

8

10

0 24 48 72 96 120 144 168Hours from randomization

Incidence

(%) Ranolazine

Placebo

RR 0.63 (0.52-0.76)P < .001

RR 0.67P = .008

RR 0.65P < .001

8.3%

5.3%

MERLIN: Reduction in VT Lasting ≥ 8 beats

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

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Baseline BNP and Effect ofRanolazine on Primary Endpoint

CV Death, MI, or Recurrent Ischemia (%)

Days from Randomization

*KM cumulative incidence (%) at 12 months

0

5

10

15

20

25

30

0 180 360

BNP NEG

p = 0.009

BNP POS Placebo

BNP POSRanolazine

P-interaction = 0.05

J Am Coll Cardiol 2010;55:1189–96J Am Coll Cardiol 2010;55:1189–96

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

Referral Center for Cardiomyopathies University Hospital of Careggi - Florence

Circulation, 2012

Referral Center for Cardiomyopathies Careggi University Hospital - Florence

3 Birds with 1 Stone

Ischemia

Arrhythmias

Diastolic Dysfunction

RANOLAZINERANOLAZINE