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Peter Collins Professor of Clinical Cardiology, Faculty of Medicine,
Imperial College London
& Royal Brompton Hospital,
London, UK
Update on the Management of Chronic Stable Angina
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Cardiovascular Disease in China
• “Report on Cardiovascular Disease in China 2011”
• 230 million patients with CVD
• 3 million cases of death of CVD each year accounting for 41% in total.
• 23 million Chinese will develop angina which is difficult to control
Cardiovascular diseases in China: Current status and future perspectives
Li and Ge IJC Heart & Vasculature 6 (2015) 25–31
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Question
A 72 year old fisherman has a DES 3 months ago and returns complaining of angina. This occurs in:
1) Less than 5% of patients per year
2) In 10% of patients per year
3) In 15% of patients per year
4) In over 25% of patients per year
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Question
A 72 year old fisherman has a DES 3 months ago and returns complaining of angina. This occurs in:
1) Less than 5% of patients per year
2) In 10% of patients per year
3) In 15% of patients per year
4) In over 25% of patients per year
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Is this common?
Ben-Yehuda et al Catheter Cardiovasc Interv. 2016 Jan 17. doi: 10.1002/ccd.26365
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Freedom from angina over time as assessed with the seattle
angina questionnaire
COURAGE N Engl J Med 2008;359:677-87
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Elements of OMT for stable CAD
1. SIGN. Management of stable angina, February 2007
2. Coylewright et al. Mayo Clin Proc 2008; 83: 799–805
OMT
Anti-platelet
therapy
Anti-ischaemic
agents
Lipid-lowering
therapy
Nicotinic acid,
fibrates ACE inhibitors
Lifestyle
measures
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Two Primary Goals of Treatment in Stable CAD
These goals should govern
the decision to revascularize
1. To Improve Survival
2. To Improve Angina and Quality of Life (QOL)
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Sedlis et al N Engl J Med 2015;373:1937-46
COURAGE
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OMT vs OMT plus stenting in patients with stable angina
and documented myocardial ischaemia (n = 5286)
Stergiopoulos et al JAMA Intern Med. 2014;174(2):232-240
Death Non-fatal MI
Persistent angina Unplanned revascularisation
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PCI:
• reduces the incidence of angina.
• has not been demonstrated to improve survival in stable patients.
• may increase the short-term risk of MI.
• does not lower the long-term risk of MI.
Angina guidelines – AHA/ACC 2014 – Revasc and survival
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Optimising medical therapy for stable angina1: Other therapies?
a LAN = a long-acting nitrate, BB = beta blocker, CCB = calcium channel blocker.
* When using ivabradine with a calcium channel blocker, use a dihydropyridine calcium channel blocker.
† Nicorandil is not licensed for this indication. Informed consent should be obtained and documented.
Adapted from NICE stable angina: Full guideline (July 2011).
Revascularisation should only
be considered if symptoms are
not satisfactorily controlled with
optimal medical therapy.
1. NICE stable angina: Full guideline (July 2011).
Ranolazine
Ranolazine
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ESC Guidelines - European Heart Journal (2013) 34, 2949–
3003
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Class of recommendation I Level of evidence B
• 1. Beta blockers
• 2. Calcium channel blockers
• 3. Calcium channel blockers or long-acting nitrates, in combination with beta blockers
• 4. Sublingual nitroglycerin or nitroglycerin spray
Angina guidelines – AHA/ACC 2014 – Medical Therapy
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Angina guidelines – AHA/ACC 2014 – Medical Therapy
Class of recommendation IIa
• Non dihydropyridine CCB (verapamil or diltiazem) instead of a beta blocker (B)
• Ranolazine in place of BB if SE (B)
• Ranolazine in combination with beta blockers ( A)
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Anti-anginal drugs Heart rate Blood pressure Anti-anginal effect
Ranolazine
No significant effect 1,2
No significant effect 1,2
Improved diastolic tone 1,2
Improved coronary blood flow 1
Potential antiarrhythmic effects 1,2
Beta-blockers Decrease 4 Decrease 4 • Decrease O2 demand, primarily
slowing heart rate 3
Calcium channel blockers
• Dihydropyridine
• Verapamil/diltiazem
Increase 4
Decrease 4
Decrease 4
Decrease 4
• Reduction in myocardial O2 demand3
• Increase in O2 supply 3
• Relaxes systemic and coronary
vascular
smooth muscle 3
Long-acting nitrate No effect 4 Decrease 4
• Relax vascular smooth muscle 3
• Reduces myocardial wall tension
and O2 requirements 3
Trimetazidine No significant effect 5 No significant effect 5 • Decreases fatty acid oxidation,
stimulates glucose utilisation 3,5
Ivabradine Decrease 6 No significant effect 6 • Decrease O2 consumption 6
Table elaborated from:
1. Hasenfuss G, et al. Clin Res Cardiol 2008;67:222-6. 2. Ranolazine European SmPC. Revised April 2014. 3. Braunwald’s
Heart Disease - A Textbook of Cardiovascular Medicine. Eighth edition. 4. Stone PH. Cardiol Clin 2008;26:603-14. 5.
Bertomeu-Gonzalez V, et al. Am J Cardiol. 2006;98(5A):19J-24J. 6. Ivabradine European SmPC. Revised March 2014.
Ranolazine’s anti-anginal effect: comparison with other anti-anginal agents
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Approved indication for Ranexa in Hong Kong
Ranexa is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris who are inadequately controlled or intolerant to first-line antianginal therapies (such as beta-blockers and/ or calcium antagonists)
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Unmet needs:
• An increasing number of patients are unsuitable for
revascularisation because of complicating factors such as
age, medical co-morbities and unsuitable coronary
anatomy1
• Despite treatment with conventional agents or
revascularisation, or both, many patients remain
symptomatic one year after CABG or PCI2.3
• Some patients may not tolerate the upward titration of
currently available antianginal drugs because of their
depressive effects on blood pressure and heart rate4
1. Hamm Eur Heart J 2004 (Suppl 1): i2-i2
2. Serrys et al N Engl J Med 2001: 344; 1117
3. Holubkov et al Am Heart J 2002: 144; 826
4. Chaitman et al JAMA 2004: 291; 309
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Ranolazine
• Unique mode of action
• Clinical trial data in chronic stable
• Clinical trial data in chronic stable in patients with diabetes
• Clinical trial data in acute coronary syndromes
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The sodium current
• The sodium current peaks at the onset of the action potential and continues throughout systole, with a so-called late component of late INa, which decays gradually.
The cardiac sodium channel current.
Elaborated from:
Camm J. Br J Cardiol 2008;15(Suppl 1):S5-S7.
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APD: action potential duration; VT: ventricular tachycardia.
The sodium channel
Elaborated from:
1. Saint DA. Br J Pharmacol 2008;153(6):1133-42;
2. Belardinelli L, et al. Heart 2006;92(Suppl IV):iv6-14.
Na+ channel
(Gating mechanism malfunction)
Oxygen supply
and demand
• Abnormal contraction and relaxation
• ↑ Diastolic tension (↑LV wall stiffness)
Mechanical
dysfunction
• After potentials
• Beat-to-beat ΔAPD
• Arrhythmias (VT)
Electrical
instability
• Increased ATP consumption
• Decreased ATP formation
Diseases (e.g. ischaemia, heart failure) Pathological milieu (Reactive O2 species, ischaemic metabolites) Toxins and drugs (ATX-II, pyrethroid, DPI201-106, etc.)
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1. Saint DA. Br J Pharmacol 2008;153(6):1133-42 2. Hasenfuss G, et al. Clin Res Cardiol 2008;97:222-6. 3. Shryock JC, et al. Br J Pharmacol 2008:153;1128-32.
Na+ and Ca++ overload Increased diastolic wall tension:
– Increases MVO2 (myoc. O2 consumption) – Compresses intramural small vessels
– Reduces endocardial blood flow
Worsens ischaemia and angina
An increase in INa impairs diastolic relaxation, increases MVO2 and reduces coronary O2 supply
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Outline
• A review of clinical evidence on ranolazine’s efficacy and safety profile.
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ROLE
N=746
Chronic angina
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
MARISA
N=191
Chronic
angina
Ranexa vs placebo
Ranolazine: Main Clinical Studies
TERISA
N=949
CAD &
DM II
Ranexa vs placebo
on top of
standard care
Morrow DA, et al. JAMA. 2007;297:1775-1783
J Am Coll Cardiol 2004;43:1375– 82
Chaitman BR, et al. JAMA. 2004;291:309-316
Stone PH, et al. J Am Coll Cardiol 2006;48:566-575.
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n=175 pts who completed three of the four treatment periods.
**p≤0.005 vs. placebo ; ***p<0.001 vs. placebo
Tim
e, s
ec
Modified from:
Chaitman BR, et al. J Am Coll Cardiol 2004;43:1375-82 (from Tab II).
***
*** ***
***
*** ***
*** ***
***
** ***
***
**
*** *** ***
***
***
400
440
480
520
560
Exercise duration
Time to angina
Time to 1-mm ST-depression
Exercise duration
Time to angina
Time to 1-mm ST-depression
Peak Trough
Placebo for 1 wk
Ranolazine 500 mg bid for 1 wk
Ranolazine 1,000 mg bid for 1 wk
Ranolazine 1,500 mg bid for 1 wk
MARISA: efficacy on exercise parameters
Note: in the European Union ranolazine is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.
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ERICA: effect on angina frequency
Adapted from:
Stone PH, et al. J Am Coll Cardiol. 2006;48(3):566-75
0
1
2
3
4 3.3
2.9*
Weekly
an
gin
a f
req
uen
cy
Tri
mm
ed
mean
S
E
5
*p=0.028
Placebo +
amlodipine 10 mg od
(n=281)
Ranolazine 1,000 mg bid +
amlodipine 10 mg od
(n=277)
Note: in the European Union ranolazine is recommended, at a maximum dose of 750 mg bid, as add-on therapy for patients with stable angina.
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Objectives Study Design
MERLIN-TIMI 36
Three major aims
Acute Coronary Syndrome
major CV events?
1) ACUTE EFFICACY
Chronic Management
recurrent ischemia?
2) CHRONIC EFFICACY
3) SAFETY
Morrow DA et al. JAMA 2007; 297: 1775-83
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Pati
en
ts (
%)
p=0.048
p=0.005
p=0.002
8.1
16.4
21.1
5.6
12.5
16.5
0
5
10
15
20
25
Worsening
angina
New anti-anginal
therapy
Reccurrent
ischaemia
Placebo (n=1776)
Ranolazine i.v. followed by 1,000 mg bid orally
(n=1789)
Morrow D, et al. JAMA 2007;297:1775-83;.
Adapted from: Figure 1 in: Wilson SR, et al. Am Coll Cardiol 2009;53:1510-6.
Angina and recurrent ischaemia in patients with a history of chronic angina, with an acute coronary syndrome
HR 0.77 (0.59-1.00)
HR 0.77 (0.64-0.92)
HR 0.78 (0.67-0.91)
MERLIN-TIMI 36: anti-anginal effect of ranolazine
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Me
an
sc
ore
s S
AQ
* a
t 1
2 m
on
ths
p=0.018
p=0.019
60
70
80
90
QoL Treatment satisfaction
*SAQ=Seattle Angina Questionnaire; scores ranging from 0 to 100, with higher scores indicating less disease burden.
SAQ quality of life and treatment satisfaction Placebo
(n=3,281)
Ranolazine
(n=3,279) i.v.
followed by
1,000 mg bid
orally
Morrow D, et al. JAMA 2007;297:1775-83.
Extrapolated from: Arnold SV, et al. Circ Cardiovasc Qual Outcomes.
2008;1(2):107-15.
MERLIN-TIMI 36: ranolazine increased QoL and treatment satisfaction
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Arrhythmias Ranolazine
(n) %
Placebo
(n) % p-value
New-onset atrial
fibrillation 55 (1.7) 75 (2.4) 0.08
Supraventricular
tachycardia* 1,413 (44.7) 1,752 (55) <0.001
Pauses ≥ 3 sec 97 (3.1) 136 (4.3) 0.01
VT ≥8 beats 166 (5.3) 265 (8.3) <0.001
Continuous ECG (Holter) recording was performed for the first 7 days after randomisation
* ≥120 bpm lasting at least 4 beats
Morrow D, et al. JAMA 2007;297:1775-83.
Elaborated from Scirica BM, et al. Circulation. 2007;116:1647-52.
MERLIN-TIMI 36: significant lower incidence of arrhythmias
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Ranolazine
(n=3,268)
Dizziness 13% 7%
Nausea 9% 6%
Constipation 9% 3%
Placebo
(n=3,273)
Adapted from:
Morrow D, et al. JAMA 2007;297:1775-83.
Tolerability of Ranolazine
Usually associated with higher doses in the studies
Note: in the European Union ranolazine is recommended, at a maximum dose of 750 mg bid, as add-on
therapy for patients with stable angina, but not for patients with acute coronary syndrome.
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TERISA – Type 2 diabetes Evaluation of Ranolazine In Subjects with Angina pectoris
Kosiborod et al J Am Coll Cardiol 2013;61:2038–45
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*Relative difference in the incidence rates
HbA1c >6
HbA1c ≤ 6
HbA1c >6.5
HbA1c ≤ 6.5
HbA1c >7
HbA1c ≤ 7
HbA1c >7.5
HbA1c ≤ 7.5
HbA1c >8
HbA1c ≤ 8
Incidence Density Ratio*
p for
interaction Ranolazine better Placebo better
0.7 0.8 0.9 1 1.1 1.2
0.046
0.047
0.022
0.041
0.038
Kosiborod M, et al. J Am Coll Cardiol. 2013;61:2038-45.
TERISA: Exploratory analysis among patients with diabetes – HbA1c
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Belsey et al European Journal of Preventive Cardiology 2015; 22(7) 837–848
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RIVER-PCI
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River-PCI
primary endpoint was time to first occurrence of ischaemia-driven
revascularisation or ischaemia-driven hospitalisation without revascularisation
Placebo (n=1,287)
Ranolazine 1,000 mg bid orally (n=1,287)
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• 40% of events driven by lesion targeted for original PCI – restenosis/plaque rupture
• No test for ischaemia after enrollment
• Now have results of FAME 1/2
• Caution in interpreting post-hoc analyses
• Different patient population studied from MERLIN-TIMI 36
• Does not challenge efficacy of ranolazine on treatment of myocardial ischaemia
• No CV harm except in >75 yrs on MACE
Possible reasons for null result
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Ranolazine European SmPC. Revised April
2014.
Ranolazine: contraindications
• Hypersensitivity to the active substance or to any of the excipients
• Severe renal impairment (creatinine clearance <30 ml/min)
• Moderate or severe hepatic impairment
• Concomitant administration of potent CYP3A4 inhibitors (e.g. itraconazole, ketoconazole, voriconazol, posaconazol, HIV protease inhibitors, clarithromycin, telithromycin, nefazodone)
• Concomitant administration of Class Ia (e.g. quinidine) or Class III (e.g. dofetilide, sotalol) antiarrhythmics other than amiodarone
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Thank You!
Royal Brompton Hospital, London