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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
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
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
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
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
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
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
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.
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
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
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
Recommended