angina management with metabolic agents

Dendi Puji Wahyudi

Angina pectoris is a syndrome characterized by sudden severe pressing substernal chest pain or heaviness radiating to the neck, jaw, back and arms

The primary cause is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels, due to:◦ a decrease in myocardial oxygen delivery◦ an increase in myocardial oxygen demand◦ or both

Coronary artery blood flow is the primary determinant of oxygen delivery to the myocardium◦ Myocardial oxygen extraction from the blood is nearly

complete, even at rest

Coronary blood flow is essentially negligible during systole and is therefore determined by: ◦ Perfusion pressure during diastole (aortic diastolic

pressure)◦ Duration of diastole◦ Coronary vascular resistance

The major determinants of myocardial oxygen consumption include:◦ Ventricular wall stress

Both preload (end-diastolic pressure) and afterload (end-systolic pressure) affect ventricular wall stress

◦ Heart rate◦ Inotropic state (contractility)◦ Myocardial metabolism (glucose vs fatty acids)

Stable angina: clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arms◦ Elicited by exertion or emotional stress◦ Relieved by rest or nitroglycerin

Term is usually confined to cases in which the syndrome can be attributed to myocardial ischemia

Purpose of diagnosis & assessment :◦ Confirmation of the presence of ischemia in

patients with suspected stable angina◦ Identification or exclusion of associated conditions

or precipitating factors◦ Risk stratification◦ To plan treatment options ◦ Evaluation of the efficacy of treatment

Diagnosis and Assessment

Pharmacological management

Interventional cardiology and cardiac surgery

Patient issues and follow up

Presentation

Chest pain evaluation service

Drug intervention to prevent new vascular events

Stable angina and non-cardiac surgery

Psychological and cognitive issues

Journey of Angina Patient

Patient presents with chest pain likely to be due to stable angina

Consider characteristics of pain and associated features

Detailed clinical examination

Consider need for early referral

Refer for confirmation of diagnosis to chest pain service

Coronary angiography

Exercise tolerance test or Myocardial perfusion scintigraphy if unable to exercise or pre existing ECG abnormalities

12 Lead ECG Measure Hb, TSH, TC, RBS

Confirm diagnosis and assess severity of CHD

Use chest pain evaluation service with earliest appointment

Early access to angiography and coronary artery bypass surgery may reduce the risk of adverse cardiac events

and impaired quality of life

Improve prognosis Decrease symptoms

◦ Medical treatments Hemodynamics If inhibitor Metabolic agents

◦ Revascularization PCI, CABG

Average angina patients

4.9 drugsNitrates 72%

Beta blockers 69%

CCBs 44%

Anti-thrombotics 89%

ACEi 62%

Statins 47%

Angina attack per week 5.2

Nitroglycerin use per week 5.1

Angina at rest 27%

Angina during exercise 93%

Angina attack nearly

every day!

TIBET, Dargie et al. IMAGE, Savonitto et al. CESAR, Knight et al.

Eur Heart J, 1996;17:96–103 JACC, 1996;27:311–316 Am J Cardiol, 1998;81:133–136

Atenolol, nifedipine SR & its combination

Metoprolol, nifedipine SR & its combination

Amlo + atenolol vs diltiazem + atenolol

No additive benefit from combination purported benefit of 2 drugs is due to addition of new drug in resistant patients

Exercise test parameters don’t improve when adding second hemodynamic

drug

Akhras et al. Meyer et al. Madjlessi-Simon et al.

Lancet, 1991;338:1036–1039 Cardiovasc drugs ther, 1993;7:909–913 Eur Heart J, 1995;16:1780–1788

Atenolol, nifedipine SR, ISMN & its combination

Atenolol, nifedipine SR & its combination Beta blockers, amlodipine & its combination

No substantial benefit to any combination over beta blocker

monotherapy

Combination therapy is no betterthan atenolol alone

Combination provides no additional benefits in patients resistant to beta

blockers

All of these studies agree:Combination of hemodynamic

agents is

NOT ENOUGH

ONE patients out of THREE remains symptomatic despite hemodynamic therapy

Boden et al. COURAGE STUDY. N Engl J Med 2007: 365: 1503-1516

Most patients with typical angina do not have coronary atherosclerotic

obstruction

Sambuceti G, Eur J Nucl Mol Imaging 2005; 32: 385-388. Chang VY et al., Circulation 2001; 124: 2423-2432

Many patients with coronary lesions do not have ischemic heart disease

Everyday …Beats 100,000 timesPumps 7,000 liters of blood through the bodyNeeds 6 kg of ATP to function

◦ 20-30 times its own weight

Maximize the use of O2 to make more ATP available

“ Metabolically acting agents protect from ischaemia by increasing glucose metabolism

relative to that of fatty acids” 1

“may be used incombination therapy with haemodynamically

actingagents, as their primary effect is not through

reduction inheart rate or blood pressure” 1

1. Guidelines on the management of stable angina pectoris – ESC 2006

O2 + Glucose

Lactate Pyruvate

O2 + Fatty Acids

ATP

Glucose Oxidation•Provides 10-40% Energy•More O2 efficient•1 O2 yields 6.4 ATP

Fatty Acids Oxidation•Provides 60-90% Energy•Less O2 efficient•1 O2 yields 5.6 ATP

Glucose

Lactate Pyruvate

Fatty Acids

ReducedReduced ATPATP

productiproductionon

• Pyruvate to Lactate• Cell Acidosis• Calcium Overload

Increased Fatty Acid Oxidation Rate

Need more ATP

Glucose

Lactate Pyruvate

Fatty Acids

ReducedReduced ATPATP

productiproductionon

• Pyruvate to Lactate• Cell Acidosis• Calcium Overload

Increased Fatty Acid Oxidation Rate

Need more ATP

Trimetazidine MR partially

inhibits Fatty Acid pathway

IncreaseIncrease

d d ATP ATPproductiproducti

onon

More Effective

Lowers fatty acid oxidation, increase glucose & lactate oxidation

Selective KAT-3 inhibitor

Optimize use of oxygen, reduce acidity in tissue, improve cardiac function & contractility during ischemia while

maintaining cell membrane homeostasis

Does not interfere heart rate & blood

pressure

Partial inhibition of enzyme KAT-3 (last step of beta oxidation from Fatty Acid pathway)

Trimetazidine MR increases myocardial energy during ischemia More effective ATP synthesis

Management of stable angina pectoris. Recommendations from the Task Force of the ESC . Eur Heart J. 2006; 27:1341-81.

“The ischaemic cascade is characterized by a sequence of events, resulting in metabolic abnormalities, perfusion

mismatch, regional and then global diastolic and systolic dysfunction, electrocardiographic (ECG) changes, and

angina.”Angina

ECG Change

Cardiac Dysfunction

Metabolic Change

Perfusion

Prevents ischemic cascade Right from the start

Nesukay E. Circulation 2012

Trimetazidine MR

Less angina, less nitroglycerin consumption… no matter how you combine it

Less angina, less nitroglycerin consumption

Glezer MG. PARALLEL study. Eur Heart J. 2007;28(Abst Suppl):770.

Mean weekly nitroglycerin consumption

0

10

20

30

40

50

60

70

80

Mean weekly number of angina attacks

P<0.0001 P<0.0001

Mean e

volu

tion b

etw

een

base

line a

nd

week-1

2 (

%)

-76% -79%

Trimetazidine MRISDN

n=903

Preserves cardiac function as early as 3rd month

33.230.6

42.4

33.3

0

10

20

30

40

50

Baseline 3-months

LV

EF (

%) *

* P<0.05 vs baseline† P<0.01 vs baseline‡ P<0.05 vs placebon=87

†‡

+9,5%

Control Trimetazidine MR

Gunes Y, et al. Heart Vessels. 2009;24:277-282.

0

5

10

15

Without Trimetazidine MRInci

den

ce o

f M

AC

E (%

)Primary end point : MACE

JS KIM. Korean Circulation 2010 Autumn Poster 21

65%65%

Total mortality Hospitalization

Control Trimetazidine MR

Cum

ula

tive s

urv

ival

(%)

Pati

ents

fre

e o

f H

osp

italiz

ati

onl (%

)

Reduction of -56% of the total mortality rate

Reduction of -47% of the hospitalization

rate

n=63

Di Napoli P, et al. J Cardiovasc Pharmacol. 2007;50:585-589.

-70

-60

-50

-40

-30

-20

-10

0Nitrates CCB Nicorandil Trimetazidine

MR

6 month all cause mortality risk with different anti angina treatments

Iyengar & Rosano, Am J Cardiovasc Drugs. 2009 ; 9 (5): 293-297

-64%

Rosano G, et al. Int J Cardiol. 2007:79-84

Protects diabetic patients against silent myocardial ischemia

Many patients continue to experience angina despite medical therapy and/or revascularization

Metabolic agent are 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