Transcript Newer anti anginals

Dr Julian Johny Thottian
INTRODUCTION
Chronic angina is a condition that impairs quality of life
and is associated with decreased life expectancy
Cardiac metabolism- LCFAs are the major source of
energy (80%) and Glucose (20%) in aerobic
conditions.
In fetus , the main source of energy is glucose and shift
to FFA is in the early post natal period.
Cardiac metabolism
 Current therapies that reduce angina frequency and
increase the threshold at which demand-induced
myocardial ischemic symptoms become evident
include :
Drugs :Nitrates, β-blockers, Calcium antagonist
Exercise conditioning
Enhanced External Counterpulsation
Coronary revascularization
Current antianginal strategies
TMR
EECP
Exercise
training
Non
pharmacologic
Chelation
therapy
SCS
Current anti-anginal strategies
Fasudil
Pharmacologic
Trimetazidine
Nicorandil
Ivabradine
Ranolazine
Consequences associated with
dysfunction of late sodium current
• Diseases
(eg, ischemia, heart
failure)
Na+ channel
• Pathological milieu
(Gating
(reactive O2 species,
mechanism
ischemic metabolites)
malfunction)
• Toxins and drugs
(eg, ATX-II, etc.)
Mechanical
dysfunction
• Abnormal
contraction and
relaxation
• ↑ diastolic tension
(↑LV wall stiffness)
Oxygen supply
and demand
• Increase ATP
consumption
• Decrease ATP
formation
Electrical
instability
• Early after potentials
• Beat-to-beat ΔAPD
• Arrhythmias (VT)
Diastolic relaxation failure increases oxygen
consumption and reduces oxygen supply
Increased myocardial tension
during diastole:
Increases myocardial O2
consumption
 Compresses intramural small vessels


Reduces myocardial blood flow
 Worsens ischemia and
angina
Advances
 Ischemic heart disease is a prevalent clinical condition
 Improved understanding of ischemia has prompted new
therapeutic approaches
 Rho kinase inhibition
 Metabolic modulation
 Preconditioning
 Inhibition of If and late INa currents
Ranolazine
(N-(2,6-dimethyphenyl)-4-[2-hydroxy-3(2-methoxyphenoxy)-propyl]-1-piperazineacetamide)
is a substituted piperazine compound.
 pFOX inhibitor -that ranolazine only inhibits fattyacid oxidation during the periods of elevated plasma
FFA levels associated with myocardial ischaemia
 Late sodium current blocker
Understanding Angina at the
Cellular Level

Ischemia

↑ Late INa
Ranolazine
Na+ Overload

Ca++ Overload
Diastolic relaxation failure
Extravascular compression
Chaitman BR. Circulation. 2006;113:2462-2472
Ischemia impairs cardiomyocyte
sodium channel function
Impaired sodium channel function
leads to:
 Pathologic increased late sodium
current
 Sodium overload
 Sodium-induced calcium overload
Calcium overload causes diastolic
relaxation failure, which:
 Increases myocardial oxygen
consumption
 Reduces myocardial blood flow
and oxygen supply
 Worsens ischemia and angina
Na+/Ca2+ overload and ischemia
Myocardial
ischemia
Intramural small vessel compression
( O2 supply)
 Late Na+ current
 O2 demand
Na+ overload
 Diastolic wall tension (stiffness)
Ca2+ overload
Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.
Myocardial ischemia causes
enhanced late INa
0
Sodium
Current
Ischemia
Late
0
Sodium
Current
Late
Na+
Peak
Peak
Impaired
Inactivation
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.
Ranolazine – hemodynamic affects

No affect of Blood Pressure or Heart Rate
Can be added to Conventional Medical therapy,
especially when BP and HR do not allow further
increase in dose of BetaBlockers, Ca Channel
blockers, and Long Acting Nitrates.
Ranolazine has twin pronged action.


1.
2.
pFOX
Late Na inward entry blockade
Metabolic modulation (pFOX) and
ranolazine
 Clinical trials showed ranolazine SR 500–1000 mg bid
(~2–6 µmol/L) reduced angina
 Experimental studies demonstrated that ranolazine 100
µmol/L achieved only 12% pFOX inhibition
 Ranolazine does not inhibit pFOX substantially at clinically
relevant doses
 Fatty acid oxidation Inhibition is not a major antianginal
mechanism for ranolazine
pFOX = partial fatty acid oxidation
MacInnes A et al. Circ Res. 2003;93:e26-32.
Antzelevitch C et al. J Cardiovasc Pharmacol Therapeut.
2004;9(suppl 1):S65-83.
Antzelevitch C et al. Circulation. 2004;110:904-10.
Pharmacologic Classes for
Treatment of Angina
Medication
Class
Beta
Blockers
Calc
Channel
Blockers
Nitrates
Ranolazine
Impact Impact Physiologic
on HR on BP Mechanism
Decrease pump
function
Decrease Pump
function + Vasodilitation
Vaso-dilitation
O
O
Reduced Cardiac
Stiffness
Myocardial ischemia: Sites of action of
anti-ischemic medication
Development of ischemia
↑ O2 Demand
Heart rate
Blood pressure
Preload
Contractility
↓ O2 Supply
Traditional
anti-ischemic
medications:
β-blockers
Nitrates
Ca2+ blockers
Consequences of ischemia
Ischemia
Ca2+ overload
Electrical instability
Myocardial dysfunction
(↓systolic function/
↑diastolic stiffness)
Ranolazine
Courtesy of PH Stone, MD and BR Chaitman, MD. 2006.
3 ranolazine trials
Baseline characterstics
NO MUCH BENEFIT IN ACS
Contraindications
 Ranolazine is known to increase the QT interval on the
electrocardiogram.
Mean increase in the corrected QT interval (QTc) is
approximately 6 msec, about 5% of individuals may have
QTc prolongations of 15 msec or longer. (MARISA)
 It blocks Ikr and hence prolongs the QT interval.
 Clinical experience in coronary syndrome population did
not show an increased risk of proarrhythmia or sudden
death
 Strong CYP3A4 inhibitors and drug that interact with P
glycoprotein
Contd…
 Used with caution with other CYP3A4 inhibitors and
also drugs that prolong QT.
 INTERACTS with
Digoxin , simvastatin ,cyclosporine, diltiazem,
verapamil, ketoconazole, macrolides , grape fruit juice
Other beneficial effects
 US FDA has granted permission for-
HbA1c reduction in coronary artery disease patients
with diabetes and antiarrhythmic benefits according
to the results of MERLIN TIMI 36 trial.
 Uses in heart failure and neuropathic pain are being
studied extensively.
Side effects
 The most common adverse events that led to
discontinuation placebo were
Dizziness (1.3% versus 0.1%)
Nausea (1% versus 0%)
Asthenia, Constipation
Headache (each about 0.5% versus 0%).
Doses above 1000 mg twice daily are poorly tolerated.
Conclusions from CARISA MARISA & ERICA
Sinus node inhibition: Ivabradine
SA node
AV node
Common bundle
Bundle branches
Purkinje fibers
IVABRADINE
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
Sinus node inhibition: Ivabradine
Control
Ivabradine 0.3 µM
40
20
0
–20
–40
–60
Potential (mV)
0.5
 If current is an inward
Na+/K+ current that
activates pacemaker
Time
cells of the SA node
(seconds)
 Ivabradine
 Selectively blocks If in a
current-dependent
fashion
 Reduces slope of
depolarization, slowing
HR
DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
Trials associated
 It produces similar effects to those of atenolol, as
measured in the randomized double-blind
INITIATIVE trial, which compared ivabradine (5, 7.5
and 10 mg bid) with atenolol at doses of 50 and 100 mg
per day and found to be non inferior.
 It is safe agent and no changes in QT interval.
 ASSOCIATE Trial is double blind RCT done on 889
patients which found that ivabradine was better than
placebo in anti anginal and anti ischaemic efficacy.
Combination of this drug and betablockers was
definitely effective without untoward effects.
BEAUTifUL TRIAL-post hoc analysis
 The BEAUTIFUL investigators sought to analyze, post hoc, the
effect of ivabradine on patients with limiting angina at baseline
within the BEAUTIFUL trial.
Patients with limiting angina -13.8% of the trial population.
24% reduction in the primary endpoint [cardiovascular mortality
or hospitalization for fatal and non-fatal myocardial infarction
(MI) or heart failure HR, 0.76; 95% CI, 0.58–1.00] and a 42%
reduction in hospitalization for MI (HR, 0.58; 95% CI, 0.37–
0.92).
In patients with heart rate ≥70 bpm, there was a 73% reduction
in hospitalization for MI (HR, 0.27; 95% CI, 0.11–0.66) and a 59%
reduction in coronary revascularization (HR, 0.41; 95% CI, 0.17–
0.99). These results indicate that ivabradine is most helpful to
reduce adverse cardiac events in patients with limiting angina
and that in this population, its benefit may extend well beyond
symptom control.
Side effect /effects
 Blurring of vision
 No QT prolongation
 No negative inotropic properties
 Improvements in exercise tolerance and prevention of
exercise-induced ischaemia
Metabolic modulation (pFOX):
Trimetazidine
Myocytes
Glucose
FFA
Acyl-CoA
Pyruvate
β-oxidation
Trimetazidine
Acetyl-CoA
 O2 requirement of
glucose pathway is lower
than FFA pathway
 During ischemia,
oxidized FFA levels rise,
blunting the glucose
pathway
Energy for contraction
pFOX = partial fatty acid oxidation
FFA = free fatty acid
MacInnes A et al. Circ Res. 2003;93:e26-32.
Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45.
 It is piperazine derivative (1-[2,3,4-trimethoxibenzyl)]-
piperazine). Launched as a cytoprotective agent.
 No significant negative inotropic or vasodilator
properties either at rest or during dynamic exercise
 TRIMPOL II –RCT of 426 patients with CSA who were
randomised to either trimetazidine 20 mg three times
a day or placebo in addition to metoprolol 50mg.
This study demonstrated an improvement in time to
STsegment depression on exercise tolerance testing
(ETT), total exercise workload, mean nitrate
consumption, and angina frequency in patients
randomised to receive trimetazidine
 Large multicentric trial of 19000 patients post MI by
EMIP-FR group showed no benefit of iv infusion of
trimetazidine immediately post MI over 48hrs
 MOA – CPT -1 inhibitor and also acts in inhibition of
the enzyme long-chain 3-ketoacyl coenzyme A
thiolase (LC 3- KAT)[Kantor et al]
 VASCO ,largest RCT , showed no benefit as an add on
in angina
 Safety issues and adverse effects ?????
Side effects
 Extrapyramidal and parkinsonian symptoms recently
published by EMA 2012
 Restless leg syndrome.
 Use is limited in severe renal impairment.
Perhexilene
 Earlier designed as a CCB but doesnot act like a CCB
 It doesnot affect the heart rate or SVR
 Multiple randomised trials show that it has anti
anginal effect as monotherapy or as combination.
 Inhibition of CPT-1 and, to a lesser extent, CPT-2,
resulting in increased glucose and lactate utilisation
 S/E hepatotoxicity and peripheral neuropathy due to
phospholipid accumulation as a result of CPT ½
inhibition.
 Cole et al confirmed the safety of perhexiline in a
randomised, double-blind, crossover study following
initiation of 100 mg of perhexiline BD with subsequent
plasma-guided dose titration; none of the developed
the dreaded side effects.
Other s/e nausea ,dizziness and hypoglycaemia
Other uses – symptomatic aortic stenosis
Circulation 1990;81(4):1260–70
Etomoxir/ Oxfenicine
 Potential anti anginal agent
 Launched as an anti diabetic agent due to




hypoglycaemic effects
CPT 1 INHIBITOR
Improvement in LV function in rats- Turcani & Rupp
Single study available on humans (15 patients) with
NYHA II – III Etomoxir 80mg was administered.\
Only animal studies on oxfenicine.
Preconditioning: Nicorandil
Activation of ATP-sensitive K+ channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles
N
O
HN
O NO2
Nitrate-associated effects
• Vasodilation of coronary epicardial arteries
IONA Study Group. Lancet. 2002;359:1269-75.
Rahman N et al. AAPS J. 2004;6:e34.
 DOSAGE- 20mg bid
 Tolerance is seen with chronic dosage
 No cross tolerance with nitrates
 The Impact Of Nicorandil in Angina (IONA) trial showed a
significant reduction of major coronary events in stable
angina patients treated with nicorandil compared with
placebo as add-on to conventional therapy
 Also used in unstable angina. It also reduces the number of
further attacks
 Additive effects with nitrates
Rho kinase inhibition: Fasudil
 Rho kinase triggers vasoconstriction through
accumulation of phosphorylated myosin
Ca2+
Ca2+
Agonist
PLC
VOC
ROC
Receptor
PIP2
Fasudil
IP3
Rho
Rho kinase
SR Ca2+
Myosin
Myosin phosphatase
MLCK
Ca2+
Calmodulin
Myosin-P
Adapted from Seasholtz TM. Am J Physiol Cell Physiol. 2003;284:C596-8.
 Fasudil up to 80 mg three times daily significantly
increased the ischemic threshold of angina patients during
exercise with a trend toward increased exercise duration.
Double-Blind, Placebo-Controlled, Phase 2 Trial on 84
patients
J Am Coll Cardiol. 2005;46(10):1803-1811
Molsodomine & linsodomine
 Anti anginal and anti ischaemic
 Acts like nitrates
 Metabolises in liver to form linsodomine
 Orally active
 Metabolised in liver
TMLR
 Surgical
 surgeons use the laser to make holes between 20 and
40 tiny (one-millimeter-wide)
 Surgical incision made
 Done along with CABG sometimes
Percutaneous TMR
Rationale
 Improved perfusion by stimulation of angiogenesis
 Potential placebo effect
 Anesthetic effect mediated by the destruction of
sympathetic nerves carrying pain-sensitive afferent
fibers
 Peri-procedural infarction.
TMLR - Transmyocardial Laser
Revascularization
 High power CO2 YAG and
excimer laser conduits in
myocardial to create new
channels for blood flow
 Possible explanations for
effect
 Myocardial angiogenesis
 Myocardial denervation
 Myocardial fibrosis with
secondary favorable
remodelling
TMLR
–
Direct
Trial
 Only major blinded study
High Surgical Risk

 298 pts with low dose, high
dose, or no laser channels
 No benefit to TMLR vs
Med therapy to
 Patient survival
 Angina class
 Quality of life assessment
 Exercise duration
 Nuclear perfusion imaging
Leon MB, et al. JACC 2005; 46:1812

(Mortality 5%)
Mainly used as adjunct
therapy during CABG to
treat myocardial that
cannot be bypassed.
EECP
EECP
 Increases arterial blood pressure and retrograde aortic
blood flow during diastole (diastolic augmentation).
 Cuffs are wrapped around the patients legs and
sequential pressure (300mmHg) is applied in early
diastole.
 3 pairs of cuffs
Patient selection
 Angina class III/IV
 Refractory to medical therapy
 Reversible ischemia of the free wall
 not amenable for revascularization
 Excluded if LVEF<20% or had current major illness
EECP - Enhanced External
CounterPulsation
 External, pneumatic compression of lower extremities
in diastole.
EECP - Enhanced External CounterPulsation
EECP - Enhanced External CounterPulsation
Sequential
inflation of cuffs
Simultaneous
deflation of
cuffs in late
Diastole
 Retrograde aortic




pressure wave
Increased Coronary
perfusion pressure
Increased Venous
Return
Increased Preload
Increased Cardiac
Output




Lowers Systemic
Vascular Resistance
Reduced afterload
Decreased Cardiac
workload
Decreased Oxygen
Consumption
EECP - Enhanced External CounterPulsation
 35 total treatments
 5 days per week x 7 weeks
 1 hour per day
 Appears to reduce severity of Angina
 Not shown to improve survival or reduce
myocardial infarctions
 Indicated for CAD not amenable to
revascularization
 Anatomy not amenable to procedures
 High risk co-morbidities with excessive risk
 May be beneficial in treatment of refractory CHF
too, but generally this is not an approved
indication.
EECP – Contraindications & Precautions
 Arrhythmias that interfere with machine triggering
 Bleeding diathesis
 Active thrombophlebitis & severe lower extremity vaso-
occlusive disease
 Presence of significant AAA
 Pregnancy
MUST EECP
 Blinded RCT on 139 patients to check the safety and
efficacy of EECP
 Patients with CSA were given 35hrs of EECP/WK
 Exercise duration increased . Time to ≥1-mm STsegment depression increased significantly .
Patients saw a decrease in angina episodes (p < 0.05).
Nitroglycerin usage decreased.
Chelation
Therapy
 IV EDTA infusions

 30 treatments over about 3
months
 Cost – about $3,000
 Aggressive marketing by 500
to 1000 physicians offering
this treatment
 PLACEBO effect only
Claimed
pathophysiologic effects
Liberation of Calcium
in plaque
 Lower LDL, VLDL, and
Iron stores
 Inhibit platelet
aggregation
 Relax vasomotor tone
 Scavenge “free radicals”

Spinal Cord Stimulation
power source
conducting wires
electrodes at
stimulation site
Stimulation typically
administered for 1-2 hrs tid
Therapeutic mechanism appears to be alteration of anginal pain perception
Long-term Outcomes Following SCS
Prospective Italian Registry: 104 Patients, Follow-up 13.2 Months
20
Baseline
SCS
15
* p<0.0001
10
5
*
*
*
*
*
CCS
Class
# Hosp
Adms
*
*
0
Total
Angina
Angina
at Rest
Exert
Angina
NTG
Use/wk
Days in
Hosp
Episodes/wk
(DiPede, et al. AJC 2003;91:951)
Randomized Trial of SCS vs. CABG For Patients
with Refractory Angina
104 Patients with refractory angina, not suitable for PCI and
high risk for re-op (3.2% of patients accepted for CABG)
18
16
14
Mean 12
number 10
8
per
6
week
4
2
0
16.2
15.2
14.6
*
4.4
13.7
*
*
5.2
4.1
*
Baseline
6 months
3.1
*P < 0.0001
Anginal attacks
NTG
consumption
Anginal attacks
Spinal cord stimulation (n=53)
NTG
consumption
CABG (n=51)
No difference in symptom relief between SCS and CABG
(Mannheimer, et al. Circulation 1998;97:1157)
Potential cardioprotective benefits
of exercise
NO
production
ROS
generation
Vasculature
ROS
scavenging
Myocardium
Other
mechanisms
Thrombosis
Domenech R. Circulation. 2006;113:e1-3.
Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:963-72.
THANK YOU
BOOK REFERENCES
 Braunwald`s heart diseases -9th edition-Unit 7
Chapt-57
 Cardiovascular medicine 3rd edition –Brian GriffinSection-1 Chapt-5
 Hurst-The Heart -13th edition. Part 8 Chapt-54
 Harrisons Principles of internal medicine –18th edition
Part 10 Section 5 Chapt-243
 US FDA APPROVAL OF RANOLAZINE 2008
REFERENCES
Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular
myocytes. J Physiol. 1996;497 ( Pt 2):337-347.
Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13
PH Stone, MD and BR Chaitman, MD. 2006
DiPede, et al. AJC 2003;91:951
Domenech R. Circulation. 2006;113:e1-3.
Kojda G et al. Cardiovasc Res. 2005;67:187-97. Shephard RJ et al. Circulation. 1999;99:96372
Mannheimer, et al. Circulation 1998;97:1157
Leon MB, et al. JACC 2005; 46:1812
Circulation 1990;81(4):1260–70
MacInnes A et al. Circ Res. 2003;93:e26-32.
Lopaschuk GD et al. Circ Res. 2003;93:e33-7.
Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45
Chaitman et al JAMA 2004; 43: 1375
PH Stone Circulation 2005;11
Question 1
All are partial fatty acid oxidase inhibitors except?
a) Fasudil
b) Trimetazidine
c) Etomoxir
d) Oxfenicine
Question 2
a) IONA trial proves efficacy of nicorandil in ACS
b) Activation of ATP-sensitive K+ channels
c) Helps in Ischemic preconditioning
d) Dilation of coronary resistance arterioles
e) Vasodilation of coronary epicardial arteries
Question 3
 False statement regarding ischaemia at cellular level
a) Calcium overload
b) Sodium overload
c) Decreased late sodium current
d) Increased early after potentials
Question 4
 False regarding ranolazine trials
a) CARISA- ranolazine as an adjunct with other anti
anginals
b) MARISA- effect of various doses of ranolazine as
monotherapy compared with placebo
c) ERICA- effect of ranolazine with amlodipine
d) ASSOCIATE – ranolazine in ACS patients
Question 5
 True about ranolazine are all except
a) Does not affect double product
b) Decrease diastolic stiffness
c) Blockade of Late sodium current
d) Prolongs QT interval
e) Decrease Hb A1C levels
Question 6
 False regarding TMR
a) Improved perfusion by stimulation of angiogenesis
b) Potential placebo effect
c) Anesthetic effect mediated by the destruction of
sympathetic nerves carrying pain-sensitive afferent
fibers
d) Free radical scavenging
Question 7
 False regarding EECP
a) Sequential inflation and simultaneous deflation
b) MUST EECP shows definite benefit in decreasing
angina
c) Contraindicated in pregnancy
d) Can be done in those with EF < 20%
Question 8
 False about ivabradine
a) INITIATIVE trial compared ivabradine with
betablockers
b) ASSOCIATE trial compares ivabradine with placebo
and found it definitely better AND also found
beneficial when combined with beta blockers
c) Prolongs QT interval
d) Beautiful Trial proved the anti anginal efficacy of
ivabradine.
Question 9
 False about SCS
a) Stimulates spinal cord at level C7-T4
b) No added benefits when compared to CABG
c) Mechanism of action is pain modification by gate
control mechanism.
d) Eddicks et al proved it to be more beneficial than
TLR
Question 10
Which is a false match
a) IONA – NICORANDIL
b) TRIMPOL – MOLSODOMINE
c) MERLIN TIMI 36- RANOLAZINE
d) ASSOCIATE – IVABRADINE