management of Chronic stable angina

1. Management of
Chronic Stable Angina
&
Role of Trimetazidine
Dr. Mohammad Ali
MBBS, MD (Cardiology)
FCPS part I, MRCP part II
Associate Consultant
Cardiology Department
Bangladesh Specialized Hospital

2. Definition
 Angina pectoris – characterized by
pain or discomfort , typically occurring
in front of the chest (but may radiate
to the neck, shoulders, jaw or arms)
Brought on by physical exertion or
emotional stress
 Occurs when myocardial O2 demand
exceeds O2 supply- leading to
Myocardial ischemia

3. Nature of Chest Pain
Typical angina (definite)
1) Sub sternal chest discomfort with a characteristic
quality and duration that is ...
2) provoked by exertion or emotional stress and
3) relieved by rest or nitroglycerin
Atypical angina (probable)
meets 2 of the of characteristics
Non cardiac chest pain
meets  1 of the typical angina characteristics

4. Grading of Angina
Class Description
I Ordinary physical activity does not cause angina, it occurs
with strenuous, rapid or prolonged exertion
II Slight limitation of ordinary activity. Angina
occurs on rapid walking or climbing stairs,
emotional stress, walking uphill or after meals.
III Marked limitations of ordinary physical activity. Angina
occurs on walking one to two blocks on the level and
climbing one flight of stairs
IV Inability to carry on any physical activity without
Discomfort, anginal symptoms may be present at rest.

5. Pathophysiology of Angina

6. Key points of different angina
Stable Angina Occurs on exercise, emotion or eating
Relieved by rest, Nitroglycerine or both
Unstable Angina pain that occurs at rest and
with increase in severity, frequency & duration
Variant Angina Occurs at rest , generally during sleep
Caused by large coronary artery spasm
Angina Equivalent
Syndrome
Patients with exertional dyspnoea rather than exertional
chest pain
Syndrome- X Typical exertional angina with
positive exercise stress test
Anatomically normal coronary arteries
Silent Ischemia Very Common. More episodes of Silent than Painful angina
in the same patient

7. Aims of drug treatment for stable Angina
Relieve symptoms
Minimize the frequency, duration & intensity of attacks
Improve patient’s functional capacity with as few side effects as
possible
Stop and regression of the disease process
Prevent or delay the worst possible outcome, MI & death

8. Therapeutic goal
To reduce the cardiac workload and
metabolic demand
To increase the perfusion of the heart
muscle
To prevent myocardial infarction

9. Treatment options
Treatment Options
Non
Pharmacological
Pharmacological
Vesculoprotective
Conventional anti
anginal
Newer
Anti Anginal
interventional PCI
surgery CABG

10. Non Pharmacologic Therapy
1. Lifestyle Modification
• Regular aerobic activity
• Weight reduction and maintenance Diet
• Tobacco abstinence and avoidance of passive smoking
2. Control other risk factors-DM,HTN,DL

11. 23-Dec-20

12. Conventional Anti Anginal
Drugs
Nitrates
Beta blockers
Calcium channel blockers

13. Classification of Conventional Drugs
Classification of
conventional drugs
Organic nitrates
Nitroglycerin
, Glyceryl
Trinitrate:
Calcium
channel
blockers
Dihydropyridi
nes:
Nifedipine
Benzothiazepi
nes
Diltiazem
Phenylalkylam
ines:
Verapamil
Beta-blockers
(a)Non-
selective Beta
Blocker
Propranolol(I
nderal)
(b)Beta1-
Selective
Blockers
Atenolol
Metoprolol
bisoprolol

14. Limitations of conventional Anti
anginal Drugs
Beta
blockers
• Bradycardia - AV block
• Hypotension - Bronchospasm
• Fatigue and/or depression - Impotence
• Altered glucose metabolism - Lipid abnormalities
Calcium
channel
blockers
• Bradycardia - Peripheral oedema
• Hypotension - Constipation
• LV dysfunction
Short-
acting
nitrates
• Headache
• flushing
• Syncope and postural Hypotension
• Need for drug free interval

15. Newer Anti Anginal Drugs
• FasudilRho Kinase inhibitor
• TrimetazidineMetabolic Modulation
• NicorandilK + channel activator
• IvabradineSinus Node Inhibition
• RanolazineLater Na+ Inhibition

16. Reference: Marzilli M et al. J Am Coll Cardiol . 2012;60:951-6.
Effective strategy to treat
chronic stable angina
Trimetazidine
Ranolazine
Nicornadil
Beta-blocker
Nitrate
Calcium Channel Blocker
Ivabradine

18. Trimetazidine

19. Glucose
Fatty acids
Energy (ATP)
Pyruvate
-oxidation
• Consumes more 02
than glucose pathway.
• ATP/02 = 5.6
(5.6 ATP molecules are produced
from one O2 molecule)
Glucose oxidation
• More 02-efficient
pathway.
• ATP/02 = 6.4
(6.4 ATP molecules are produced
from one O2 molecule)
Lactate
Reference: Rosano GM, Fini M, et al. Curr Pharm Des. 2008;14(25):2551-62.
Cardiac energy production
in normal condition

20. Glucose
Fatty acid
oxidation
Pyruvate
Anaerobic
glycolysis
Energy (ATP)
• Increase in FA oxidation
inhibits glucose oxidation.
• Uncoupling between
glycolysis and glucose
oxidation.
Cell acidosis
Calcium overload
• Increased need of ATP
for homeostasis.
Cell damage
Myocardial energy crisis
Angina pain
Contractile dysfunction
Fatty acids
Lactate
The consequences of myocardial
ischemia in cardiac energy production
Reference: Rosano GM, Fini M, et al. Curr Pharm Des. 2008;14(25):2551-62.

21. Role of Trimetazidine in ischemia
 Decreased fatty acid
oxidation
 Increased glucose
oxidation
 Prevent cell damage
Trimetazidine

22. Side effect and contraindications
Side effects
 Nausea , vomiting
 Rash
 Palpitation
 Exacerbation of chronic atopic
gastritis
contraindications
 Pregnancy and lactation
 Children
 Impaired renal and hepatic function
 Hypersensitivity reactions

23. Trimetazidine is included in
treatment algorithm.
Trimetazidine is recommended in
2nd line.
Depending on cases, Trimetazidine
is also recommended in 1st line.
Page#
2983
Page#
2981
Ref. 2013 ESC Clinical Practice Guidelines for Stable Coronary Artery Disease. Eur Heart J. 2013;34(38):2949-3003.
ESC Stable CAD
Guidelines 2013

24. 800+
PUBLICATIONS
Trimetazidine has an
unbeatable scientific track record

25. Trimetazidine has a proven efficacy
in a wide range of cardiac patients

26. Ref. Prof. Elena Nesukay et. al. Ukrainian Cardiology Journal. Sept. 2014;2:43-47. Also
Presented at ESC Congress 2013 BB: Beta Blockers, VMR: VASTAREL MR, LAN: Long-acting
Nitrates, CCB: Calcium Channel Blockers . Number of Patients: 1,213
The SOONER Trimetazidine is initiated,
the greater is angina attacks reduction!

27. CHOICE
NESUKAY
PIVOTAL
TRIMPOL
VASCO
METRO
EL-KADY
DI-NAPOLI
FRAGASSO
Only Trimetazidine
can achieve both the aims!
Page#2977
ESC Stable CAD
Guidelines 2013
Ref. 2013 ESC Clinical Practice Guidelines for Stable Coronary Artery Disease. Eur Heart J. 2013;34(38):2949-3003.

28. Meanweeklynumberofanginaattacks
-31%
p < 0.00001
-80%
p < 0.00001
Reference: Glezer M et. al. Adv Ther. 2017 ;34(4):915-924. [CHOICE-2 Study]. Patients: 896 Stable angina patients. Medication: VASTAREL MR
was added to background antianginal therapy. In half of the patients (405), VASTAREL MR was added to beta-blocker. Treatment duration: 6
months; data recorded at baseline, followed-up after 2 weeks, 2 months, 4 months and 6 months.
Published
APRIL
2017
Trimetazidine ensures QUICK, STRONG &
SUSTAINED relief from angina

30. Ref. Lopatin YM et al. Presented in European Society of Cardiology Congress 2012 held at Munich, Germany. Abstract-2052.
Trimetazidine significantly
improves survival

31. Ref. Gunez Y, et al. Heart Vessels. 2009;24:277-282.
significantly increases LVEF by over 9% in only 3 months.
Placebo
Trimatazidine
Trimetazidine provides rapid
improvement of left ventricular function

32. Refernce: Shamanna S. Iyengar, et al. Am J Cardiovasc Drugs 2009; 9 (5): 293-297.

33. long-acting nitrates: lack of clinical
proofs in favor of survival benefits
!!
Right
from the
diagnosis
Refernce: Shamanna S. Iyengar, et al. Am J Cardiovasc Drugs 2009; 9 (5): 293-297.
Trimetazidine significantly reduces
mortality risk and improves survival

34. Trimetaidine significantly reduces the total ischemic duration
and the episodes per day of silent myocardial ischemia
Placebo
trimetazidine Reference: Marazzi G et al. Int J Cardiol. 2007;120:79-84.
Trimetazidine significantly reduces
silent ischemia in diabetic IHD patients

35. Difference between
Ranolazine and Trimetazidine
Trimetazidine Ranolazine
Shift of APT formation from fatty acid to
glucose
Shift of APT formation from fatty acid to
glucose
No effect on hemodynamic No effect on hemodynamic
Reduce blood sugar in diabetic patients
with ACS
Lower fasting blood sugar and HbA1c in
diabetic patients
No effect on QT interval Avoid in those with prior QT prolongation
Increased survival in post MI patients No effect on post MI survival

36. ESC Heart Failure
Guidelines 2016
Trimetazidine may be
considered when angina
persists despite treatment
with a beta-blocker (or
alternative) to relieve
angina (effective anti-
anginal treatment, safe in
HF).
Recommended Class: IIB,
Level of evidence: A
Page#
2164
Ref. 2016 ESC Clinical Practice Guidelines for Acute and Chronic Heart Failure. Eur Heart J. 2016;37(27):2129-2200.
Ranolazine level of evidence: C
Safety in HF uncertain!!!

37. Ref. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J. 2013;34(38):2949-3003.
ESC CAD Guideline 2013
What is written for Ranolazine?
Page#2981

38. Reference: 1. Chaitman BR et al. JAMA. 2004;291(3):309-16. 2. Morrow DA et al. JAMA. 2007;297(16):1775-83.
Tolerability is also a big concern
for Ranolazine
CARISA TRIAL1
31%
Patients in Ranolazine
group faced adverse events
MERLIN TIMI TRIAL2
28%
Patients discontinued Ranolazine
due to adverse events

39. Take home message
 Angina is like an iceberg should be treated with proper
medication
 2nd line anti-angina drugs can be used in combination with
1st line anti angina drugs or as mono therapy
 Trimetazidine acts as Metabolic Modulator in ischemic
heart disease.
 Trimetazidine has no effect on hemodynamics and
Reduced silent ischemic attack in diabetic patient
 Trimetazidine Reduced angina attacks, increased exercised
capacity and increased survival in post MI patient.
 And trimetazidine doesn’t cause QT prolongation like
renolazine and cost effective.

40. Thanks for patience hearing..

43. Newer anti-anginal drugs:
Trimetazidine
43
Shift of APT formation from free fatty acid to glucose oxidation
Treatment option for patients in sinus rhythm if 1st line therapy inadequate or
contraindicated or can use as add on therapy with conventional drugs
Increase exercise time and reduces frequency of angina attacks
Reduce blood sugar in diabetic patients with ACS
Use in patients with erectile dysfunction in place of nitrate for free use of sildenafil
Avoid in patients with parkinson disease

44. Newer anti-anginal drugs: Ranolazine44
Shift of APT formation from fatty acid to glucose and
Prevent diastolic stiffness by inhibiting late Na+ entry
Treatment option for patients in sinus rhythm if 1st line therapy inadequate or
contraindicated or can use as add on therapy with conventional drugs
Increase exercise time and reduces frequency of angina attacks
Lower fasting blood sugar and HbA1c in diabetic patients
Suppressing atrial fibrilation
Avoid in those with prior QT prolongation
No effect on hemodynamic

45. Potassium channel activator with nitrate component
Treatment option if 1st line therapy inadequate or contraindicated
Headache is a common side effect
Dilated large coronary artery as well as reduced pre and after load
Widely used as an anti anginal agent in japan
Newer anti-anginal drugs: Nicorandil45

46. Newer anti-anginal drugs: Ivabradine46
Blocker of pacemaker current If, effect similar to beta blocker and amioderone
Treatment option for patients in sinus rhythm if 1st line therapy inadequate or
contraindicated
Lower heart rate during exercise
If combination with CCB use dihydropyridine
Disturbance of nocturnal vision with flashing lights
Data on long time safety and efficacy are limited

48. All that glitters
is not gold

50. NEW
Study!
US FDA analyzed the modified-release formulations
approved by them to find out how bioequivalence,
efficacy and safety of copy modified release products
differ compare to their respective brand name drugs.

51. • In case of modified
release formulation,
US FDA found that
copies show reduced
efficacy, lack of
bioequivalence and
more adverse events
than original research
brand.
• So, copies and
original research
brand are not same in
case of modified
release formulation.

52. Official journal of
Cardiovascular Therapy and Prevention

53. 7.4
VASTAREL MR ensures 63% more anti-anginal
efficacy compared to other TMZ brands

54. Reference: 1. Gunes Y et. al. Heart Vessels. 2009;24:277-282. 2. Momen A et. al. Indian Heart Journal. 2016;68(6):809-815.
VASTAREL MR1
COPY TRIMETAZIDINE2
9.1%
3.7%
VASTAREL MR is 3 times better and 2 times faster
Similar Study! Same Protocol!!
Different Results!!!

55. • Only the research brand
VASTAREL MR –
 Ensures +33% more
energy to each cardiac
cell.
 Reduces angina attacks,
increases exercise
capacity, improves cardiac
function & survival.
 Confirms a better life.
Take home message