Effects of Ranolazine:
from Angina to Cardiac Performance
Iacopo Olivotto, MD
Referral Center for Cardiomyopathies
Careggi University Hospital
Florence, Italy
olivottoi@aou-careggi.toscana.it
Referral Center for Cardiomyopathies
Careggi University Hospital - Florence
Angina Symptoms Predict
Total Mortality in Patients with CAD
• Prospective study 8900 VA
patients with CAD
– Primary endpoint all-cause
mortality
– Seattle Angina Questionnaire
(SAQ)
– Over 2 years mean follow up
Years
• Results
–
–
–
–
–
Avg age 67 years
98% male
~66% white
~25% diabetic
896 deaths
Mozaffarian D, et al. Am Heart J. 2003.
Greater physical limitation due to angina
“strongly associated with higher mortality”
Referral Center for Cardiomyopathies
Careggi University Hospital - Florence
Antianginal Drugs
O2 Supply
Drug class
Coronary
blood flow
O2 Demand
Heart
rate
Arterial
pressure
Venous
return
Myocardial
contractility
β-blockers
*
DHP CCBs
Non-DHP CCBs
Long-acting nitrates
/
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.
Mechanisms of action potential
prolongation in chronic angina: late INa
Remodeling
0
Sodium
Current
Late
0
Sodium
Current
Na+
Peak
Late
Peak
Impaired
Inactivation
Blocker:
Ranolazine
Na+
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.
Referral Center for Cardiomyopathies
University Hospital of Careggi - Florence
Ranolazine: Mechanism of Action
Ischemia
Late INa
Ranolazine:
Inhibits the late inward
Na+ current
Na+ Overload
Ca++ Overload
Diastolic relaxation failure
(Increased diastolic tension)
Extravascular compression
The Cycle of Ischemia
Ischaemia “begets” Ischaemia
Ischemia
 LV
Diastolic
Tension
 Na+i
Ca2+i
Overload
Ju YK, et al. J Physiol. 1996.
Murphy E, et al. Circ Res. 1991.
Jansen MA, et al. Circulation. 2004.
CARISA: Is Ranolazine effective on top of
atenolol/amlodipine?
Trough
* *
Change from baseline, sec
150
Placebo
Ranolazine 750 mg bid
Ranolazine 1000 mg bid
Pea
k
** **
*
*
***
***
**
*
100
50
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
Chaitman BR, et al. JAMA. 2004;291:309-316.
Effects of Ranolazine on Stress MPI
Rest
Exercise
Baseline
Peak HR = 142 bpm
25%
Reversible
Perfusion
Defect Size
After RAN (3-4 wks)
Peak HR = 142 bpm
MPI Variables (n=21)
10%
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
VenkataramanJ. A C C : C ardiovascular Imaging, V O L . 2 , N O . 1 1 , 2 0 0 9
Clinical efficacy
MERLIN: components of the primary efficacy end-point
Placebo
Recurrent ischaemia
20
Placebo 10.5%
15
10
Ranolazine 10.4%
5
HR 0.99 (95% CI 0.85 to 1.15)
P=0.87
0
Cumulative percentage*
Cumulative percentage*
CV death or MI
Placebo 16.1%
(n=3,281)
20
15
Ranolazine 13.9%
(n=3,279)
10
5
HR 0.87 (95% CI 0.76 to 0.99)
P=0.030
0
0
180
Ranolazine
360
Days from randomisation
540
0
180
Days from randomisation
*Kaplan-Meier cumulative incidence at 12 months
Morrow D, et al. JAMA 2007;297:1775-83
360
540
MERLIN: Reduction in VT Lasting ≥ 8
beats
10
8.3%
RR 0.65
P < .001
RR 0.67
P = .008
8
Incidence
(%)
6
4
Placebo
5.3%
Ranolazine
RR 0.63 (0.520.76)
P < .001
2
0
0
24
48
72
96
120
144
Hours from randomization
Scirica BM et al. Circulation 2007;116;1647-1652.
168
MERLIN: Reduction in VT Lasting ≥ 8 beats
10
8.3%
RR 0.65
P < .001
RR 0.67
P = .008
8
Incidence
(%)
6
Placebo
5.3%
4
Ranolazine
2
RR 0.63 (0.52-0.76)
P < .001
0
0
24
48
72
96
120
144
Hours from randomization
Scirica BM et al. Circulation 2007;116;1647-1652.
168
Referral Center for Cardiomyopathies
Careggi University Hospital - Florence
Baseline BNP and Effect of
Ranolazine on Primary Endpoint
CV Death, MI, or Recurrent Ischemia (%)
BNP POS
Placebo
30
25
BNP POS
Ranolazine
p = 0.009
BNP NEG
20
15
10
5
P-interaction = 0.05
0
0
180
360
Days from Randomization
*KM cumulative incidence (%) at 12 months
J Am Coll Cardiol 2010;55:1189–
Referral Center for Cardiomyopathies
Careggi University Hospital - Florence
Referral Center for Cardiomyopathies
Careggi University Hospital - Florence
Circulation, 2012
Referral Center for Cardiomyopathies
University Hospital of Careggi - Florence
3 Birds with 1 Stone
RANOLAZINE
Arrhythmias
Ischemia
Diastolic Dysfunction
Referral Center for Cardiomyopathies
Careggi University Hospital - Florence