New Therapeutic Options for Chronic Stable Angina

1
New Therapeutic Options for Chronic Stable Angina
2
New mechanistic approaches to chronic stable
angina
Rho kinase inhibition (fasudil)
Metabolic modulation (trimetazidine)
Sinus node inhibition (ivabradine)
Preconditioning (nicorandil)
O
NO2
O
H3C O
H
O CH3
N
N
N
H3C O
N
CH3
O CH3
O
Late INa inhibition (ranolazine)
3
Evaluation of fasudil in stable angina Trial
design
N 84
80 mg tid
2 weeks
ET
60 mg tid
2 weeks
40 mg tid
ET
Fasudil20 mg tid(n 41)
2 weeks
ET
Run-in(Class II or III angina)
2 weeks
ET
3 weeks
Placebo (n 43)
ET
ET exercise test (treadmill) ET at trough and
1 and 4 hours post-dose
Vicari RM et al. J Am Coll Cardiol.
2005461803-11.
4
Results Fasudil improves exercise duration
N 84
2
4
6
8
Weeks
(20 mg)
(40 mg)
(60 mg)
(80 mg)
Visit (fasudil dose tid)
Placebo
Fasudil
Vicari RM et al. J Am Coll Cardiol.
2005461803-11.
5
Results Fasudil improves exercise time to 1 mm
ST depression
N 84

2
4
6
8
Weeks
(20 mg)
(40 mg)
(60 mg)
(80 mg)
Visit (fasudil dose tid)
Placebo
Fasudil
Vicari RM et al. J Am Coll Cardiol.
2005461803-11.
P 0.001
6
TACT Study design
Trimetazidine in Angina Combination Therapy
Trimetazidine 20 mg tid (n 90)
Primary outcomes

• ET duration
• Time to 1 mm ST ?
• Time to angina onset
• Mean no. angina attacks
• Mean short-acting nitrate use
• Change in rate-pressure product
• Change in CCS angina class

Run-in(CCS class IIII)
2 weeks
2 x ET (weeks -1, 0)
Placebo (n 87)
12 weeks
ET
ET
N 166 menET exercise test (treadmill/bicycle)
Chazov EI et al. Am J Ther. 20051235-42.
7
TACT Trimetazidine reduces angina episodes
N 166 men with CCS class IIII angina
P lt 0.05
Months
Placebo
Trimetazidine 20 mg tid
Chazov EI et al. Am J Ther. 20051235-42.
8
IONA Study design
Impact Of Nicorandil in Angina
Stable angina on optimum antianginal therapyN
5126
Nicorandil 20 mg bidn 2565
Placebon 2561
RandomizedDouble-blind
1.6 years mean follow-up
Primary outcomeCHD death, nonfatal MI,
hospitalization for chest pain
IONA Study Group. Lancet. 20023591269-75.
9
IONA Reduction in primary outcome
CHD death, nonfatal MI, hospitalization for chest
pain
1.0
0.9
Nicorandil
RRR 17 HR 0.83 (0.720.97)P 0.014
Proportionevent-free
0.8
Placebo
0.7
0
0
1.5
3.0
0.5
1.0
2.0
2.5
Follow-up (years)
IONA Study Group. Lancet. 20023591269-75.
10
INITIATIVE Study design
International Trial on the Treatment of Angina
with Ivabradine vs. Atenolol
ET exercise test (treadmill) ET at trough and
4 hours post-dose
Tardif J-C et al. Eur Heart J. 2005262529-36.
11
INITIATIVE Effects of ivabradine vs ß-blockade
on primary outcome
P lt 0.001 for noninferiority vs atenolol (both
ivabradine doses)
100 mg(n 286)
7.5 mg bid(n 300)
10 mg bid(n 298)
Tardif J-C et al. Eur Heart J. 2005262529-36.
Patients completing trial
12
INITIATIVE Summary

• Ivabradine 7.5 mg bid and 10 mg bid were
  noninferior to atenolol 100 mg as measured by
• Total exercise duration
• Time to limiting angina, angina onset, and 1 mm
  ST?
• Most common adverse events were transient visual
  symptoms, mainly increased brightness in limited
  areas
• Sinus bradycardia occurred in 2.2 (ivabradine
  7.5 mg),5.4 (ivabradine 10 mg), and 4.3
  (atenolol) of patients

If current inhibition may be as effective as
ß-blockade in treatment of stable angina
Tardif J-C et al. Eur Heart J. 2005262529-36.
13
Ranolazine Late Na current inhibitor

• First new class of antianginals to be approved in
  the US since 1960s
• Antianginal and anti-ischemic effects with no
  change in HR or BP
• May be used in patients with slow HR, low BP,
  prolonged AV conduction, CHF, diabetes, or asthma
• Modest prolongation of QTc interval with no known
  clinical sequelae

14
Ranolazine Pathophysiologic effects vs older
antianginals
O2 Demand
O2 Supply
Myocardial contractility
Venous return
Arterial pressure
Heart rate
Coronary blood flow
Drug class
?

?
?

ß-blockers
?

?
?
?
DHP CCBs
?

?
?
?
Non-DHP CCBs

?
?
? /
?
Long-acting nitrates





Late Na current inhibitors(ranolazine)
Boden WE et al. Clin Cardiol. 20012473-9.
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
Kerins DM et al. In Goodman and Gilmans The
Pharmacological Basis of Therapeutics. 10th ed.
Except amlodipineRanolazine No direct effect
butmay prevent ischemia-related decline
15
MARISA Study overview
Monotherapy Assessment of Ranolazine In Stable
Angina
Objective Assess the antianginal effects of
ranolazine as monotherapy in stable
angina Design Randomized, double-blind,
placebo-controlled, crossover Population N
191 with stable angina Treatment Ranolazine
SR 500 mg, 1000 mg, or 1500 mg bid Placebo Prima
ry outcome Total exercise duration at
trough Follow-up 3 active treatment periods,
each lasting 1 week 1-week placebo period
1-year open-label follow-up
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
16
MARISA Study design
Single-blind placebo qualifying phase
Double-blind phase
Post-study follow-up
1 week
2 weeks
4 weeks
Pre-visit 1
Visit 1
Visit 7
Randomized, 1-week periods, crossover, placebo,
ranolazine SR 5001500 mg bid
Qualifying ET
ET each week at trough and 4 hours post-dose
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
ET exercise test (treadmill)
17
MARISA Dose-related increase in exercise
duration with ranolazine
N 175 evaluable patients with stable angina



Ranolazine SR bid
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
P 0.003 vs placebo P lt 0.001 vs placebo
18
MARISA Tolerability of treatments
Dose-related adverse events
Occurring in 3 of patientsExceeds
recommended dose
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
19
MARISA Summary

• Compared with placebo, ranolazine SR 5001500 mg
  bid significantly improved
• Total exercise duration
• Time to angina onset
• Time to 1 mm ST ?
• No clinically significant ? in HR or BP at rest
  or during exercise
• 7 (13/191) of ranolazine patients discontinued
  due to adverse events, mostly (11/13) at the
  highest dose
• No effect on QT dispersion
• No patient discontinued because of QTc
  prolongation

Ranolazine monotherapy is associated with
increased exercise performance in the absence of
any clinically meaningful pathophysiologic effects
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
? gt30 from baseline
20
Antianginals Effects on exercise duration
1. Chaitman BR et al. J Am Coll Cardiol.
2004431375-82. 2. Davies RF et al. J Am Coll
Cardiol. 199525619-25. 3. Go M et al. Am J
Cardiol. 198453669-73. 4. Stone PH et al.
Circulation. 1990821962-72.
bid
21
CARISA Study overview
Combination Assessment of Ranolazine In Stable
Angina
Objective Assess the antianginal effects of
ranolazine when added to standard antianginal
therapy Design Randomized, double-blind,
placebo-controlled, parallel-group Population
N 823 with angina/ischemia despite standard qd
doses of amlodipine 5 mg, atenolol 50 mg, or
diltiazem 180 mg Treatment Ranolazine SR 750
mg or 1000 mg bid Placebo Primary outcome
Total exercise duration at trough Follow up 12
weeks
Chaitman BR et al. JAMA. 2004291309-16.
22
CARISA Study design
Background CCB or ?-blocker plus nitrates prn
Ranolazine SR 1000 mg bid (n 275)
Single-blind placeboqualifying phase
Ranolazine SR 750 mg bid (n 279)
1 week
ET
Placebo (n 269)
2 weeks
4 weeks
6 weeks
ET
ET
ET
ET
ET Exercise test (treadmill)ET at trough and
4 hours post-dose
Chaitman BR et al. JAMA. 2004291309-16.
23
CARISA Ranolazine increases exercise duration

Background CCB or ?-blocker plus nitrates prn


(n 258)
(n 272)
(n 261)
Ranolazine SR bid
Chaitman BR et al. JAMA. 2004291309-16.
P 0.03 vs placebo
24
CARISA Ranolazine reduces angina frequency

Background CCB or ?-blocker plus nitrates prn
P lt 0.001
P 0.006
Anginal episodes per week
Placebo
Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Chaitman BR et al. JAMA. 2004291309-16.
25
CARISA Ranolazine reduces nitrate consumption

Background CCB or ?-blocker plus nitrates prn
P lt 0.001
Number per week
Nitroglycerin use
Placebo
Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Chaitman BR et al. JAMA. 2004291309-16.
26
CARISA Summary

• Ranolazine SR added to standard therapy
  significantly improved
• Total exercise duration, time to angina onset,
  time to 1 mm ST ?
• Anginal frequency and nitroglycerin consumption
• No clinically significant changes in HR or BP at
  rest or during exercise
• Small QTc increases with no effect on QT
  dispersion

Ranolazine provides additional antianginal and
anti-ischemic efficacy in patients who remain
symptomatic on standard therapies
Chaitman BR et al. JAMA. 2004291309-16.
27
ERICA Study design
Evaluation of Ranolazine in Chronic Angina
Stable angina on amlodipine 10 mgN 565
Ranolazine SR 1000 mg bid
Placebo
RandomizedDouble-blind
7 weeks
Primary outcomeAngina frequency
Stone PH et al. Circulation. 2005112(suppl
II)II-748-9.
28
ERICA Ranolazine reduces angina frequency and
nitrate consumption
N 565
6
5
P 0.028
4
Mean
P 0.014
number
3
per
week
2
1
0
Baseline
Week 7
Baseline
Week 7
Anginal attacks
Nitroglycerin use
Placebo
Ranolazine SR 1000 mg bid
Stone PH et al. Circulation. 2005112(suppl
II)II-748-9.
29
ERICA Summary

• Added to maximum-dose amlodipine, ranolazine SR
  1000 mg bid significantly reduced anginal
  frequency and nitroglycerin use
• No change in HR or BP
• Early withdrawal rate due to adverse events was
  comparably low in both groups
• 1.1 ranolazine
• 1.4 placebo

Ranolazine provides additional, well-tolerated
antianginal efficacy in patients who remain
symptomatic despite maximal CCB therapy
Stone PH et al. Circulation. 2005112(suppl
II)II-748-9.
30
Ranolazine Long-term use
Exercise-induced chronic angina Successfully
completed 1 of 2 treadmill studiesN 746
Open label Ranolazine titrated to 1000 mg
bid 2.96 years mean follow-up
Results Overall mortality 2.8 per
patient year (PPY) SCD mortality 0.6 PPY QTc
gt500msec 10 patients Torsade de Pointes 0
patients Ranolazine discontinuation due to AEs
9.7 in first 2 years Age gt64 years and prior Hx
of HF were significant predictors of
AE-associated discontinuation
Koren MJ et al. J Am Coll Cardiol. 200647(suppl
A)Abstract 999-253.
SCD sudden cardiac death
31
Ranolazine extended-release tabletsApproved Jan
31, 2006

• Ranolazine is indicated for the treatment of
  chronic angina
• Because ranolazine prolongs the QT interval, it
  should be reserved for patients who have not
  achieved an adequate response with other
  antianginal drugs
• Ranolazine should be used in combination with
  amlodipine, ß-blockers or nitrates
• Effects on angina rate and exercise tolerance
  appear to be smaller in women

FDA. http//www.fda.gov/bbs/topics/news/2006/NEW01
306.html.Ranolazine extended-release tablets
prescribing information.
32
Ranolazine Drug interactions
Inhibitors of CYP3A increase ranolazine plasma
levels and QTc prolongation and should not be
coadministered with ranolazine

• Ketoconazole and other azole antifungals
• Diltiazem
• Verapamil
• Macrolide antibiotics
• HIV protease inhibitors
• Grapefruit juice or grapefruit-containing products

Ranolazine extended-release tablets prescribing
information.
33
Ranolazine extended-release tablets Dosing

• Dosing should be initiated at 500 mg bid and
  increased to 1000 mg bid, as needed, based on
  clinical symptoms
• The maximum recommended daily dose of ranolazine
  is 1000 mg bid

Ranolazine extended-release tablets prescribing
information.
34
Electrophysiologic effects of ranolazine
35
Late INa effect mitigates IKr effect
Antzelevitch C et al. J Cardiovasc Pharmacol
Therapeut. 20049(suppl 1)S65-83.Antzelevitch C
et al. Circulation. 2004110904-10.Cobbe S. Eur
Heart J Suppl. 20046(suppl I)I9-11.
At 5001000 mg bid,mean concentration range
26 µM
36
Overview of torsade de pointes
? Net repolarizing current (?IKr or ?INa)
?Action potential duration and QT interval
? Dispersion of ventricular repolarization (?APD)
Early afterdepolarizations (EADs)
Trigger
Substrate
Torsade de pointes
Antzelevitch C et al. J Cardiovasc Pharmacol
Therapeut. 20049(suppl 1)S65-83.
APD action potential duration
37
Ranolazine No apparent proarrhythmic
characteristics

• No potential for early afterdepolarizations
  (EADs)
• Did not cause EADs
• Suppressed EADs induced by proarrhythmic agents
• Does not cause ? dispersion of ventricular
  repolarization
• Concentration-dependent ? transmural dispersion
  of APD (cardiomyocytes)
• No effect on QT dispersion in humans
• No torsade de pointes reported in clinical trials

Antzelevitch C et al. Circulation.
2004110904-10. Cobbe S. Eur Heart J Suppl.
20046(suppl I)I9-11. Chaitman BR et al. J Am
Coll Cardiol. 2004431375-82.
38
Current nonpharmacologic antianginal strategies

• Exercise Training
• Enhanced external counterpulsation (EECP)
• ? Endothelial function
• Promotes coronary collateral formation
• ? Peripheral vascular resistance
• ? Ventricular function
• Placebo effect

• Transmyocardial revascularization (TMR)
• Sympathetic denervation
• Angiogenesis
• Spinal cord stimulation (SCS)
• ? Neurotransmission of painful stimuli
• ? Release of endogenous opiates
• Redistributes myocardial blood flow to ischemic
  areas

Allen KB et al. N Engl J Med. 19993411029-36. Bo
netti PO et al. J Am Coll Cardiol.
2003411918-25.Murray S et al. Heart.
200083217-20.
39
Potential cardioprotective benefits of exercise
NO production
ROS generation
ROS scavenging
Other mechanisms
Vasculature
Thrombosis
Myocardium
Domenech R. Circulation. 2006113e1-3. Kojda G
et al. Cardiovasc Res. 200567187-97. Shephard
RJ et al. Circulation. 199999963-72.
40
Exercise vs PCI in low-risk CAD
N 101 men with CCS class IIII angina
PCI
20 min bicycle ergometry daily
Assessed at 12 months
Exercise vs PCI
Lower resting HR (P lt 0.01) Greater improvement
in maximal O2 uptake (P lt 0.001)
Fewer rehospitalizations Lower cost
Hambrecht R et al. Circulation. 20041091371-8.
gt80 had 1- or 2-vessel disease
41
EECP improves angina class
N 2289 consecutive EECP Clinical Consortium
patients
Lawson WE et al. Cardiology. 20009431-5.
EECP enhanced external counterpulsation
42
Surgical laser TMR improves angina class
N 275 with CCS class IV angina
P lt 0.001 TMR vs medical (both time points)

Reduction of 2 CCS classes Due to treatment
failure TMR transmyocardial revascularization
Allen KB et al. N Engl J Med. 19993411029-36.
43
SCS vs CABG Equivalent symptom relief in
high-risk patients
N 104 with CCS class III or IV angina
18
16
14
12
Mean
10
?70
?73
?68
?77
number

per
8


week

6
4
2
0
Anginal attacks
Nitrate consumption
Anginal attacks
Nitrate consumption
SCS
CABG
Baseline
6 months
SCS spinal cord stimulationP lt 0.0001
Mannheimer C et al. Circulation. 1998971157-63.
44
Summary

• Many patients continue to experience angina
  despite medical therapy and/or revascularization
• Late Na blockade is a potentially effective new
  antianginal option with a mechanism of action
  complementary to traditional agents
• Potential clinical application in broad range of
  patients unresponsive to current treatment
  options
• Elderly
• Diabetes
• LV dysfunction or heart failure