angina management with metabolic agents
DESCRIPTION
Dr. Dendi Puji Wahyudi, SpJP, FIHA. 3rd Pekanbaru Cardiology Update, August 24th 2013. Pangeran Hotel, Pekanbaru. Learn more at PerkiPekanbaru.comTRANSCRIPT
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