Transcript 슬라이드 1

Cardiovascular Medications
Soon Jun Hong
Korea University Anam Hospital
• Antiplatelet Therapy
–1. Aspirin
–2. Clopidogrel, ticlopidine
–3. GP IIb/IIIa inhibitor (Abciximab, Eptifibatide, Tirofiban)
• Anticoagulants
–1. Bivalirudin
–2. Dalteparin
–3. Enoxaparin
–4. Fondaparinux
–5. Unfractionated heparin
The 3 Most Important Advances in
Antiplatelet Therapy for ACS
•
Aspirin
•
ADP antagonists
•
Platelet GP IIb/IIIa receptor antagonists
Antiplatelet Agents
Different Mechanisms of Action
Ticlopidine
Clopidogrel
Prasugrel ADP
Cangrelor
(P2Y receptor)
Epinephri
ne
Collage
n
Thrombin
Heparin
LMWH
Hirudin
Arachadonic
Acid
PGG
TxA2
2
Cyclooxygenase
PGI2
Aspirin
GPIIb/IIIa
Receptor
GP 2b/3a
antagonists
Platelet Aggregation
Central Role of Platelets in ACS and PCI
PCI
Plaque Rupture
TF
Adhesion/
Initial
Activation
Thrombin
Granule
Secretion
ADP
Sustained Activation
Membrane
PL’s
TxA2
(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)
Central Role of Platelets in ACS and PCI
PCI
Plaque Rupture
Procoagulant
State
TF
PLT-WBC
Aggregation/
Microparticles
Adhesion/
Initial
Activation
Thrombin
P-selectin
CD-40L
Granule
Secretion
ADP
Sustained Activation
Membrane
PL’s
TF
TxA2
(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)
Central Role of Platelets in ACS and PCI
Hypercoagulability
PCI
Plaque Rupture
Procoagulant
State
TF
Inflammation
Cytokine
Release
TF
PLT-WBC
Aggregation/
Microparticles
Adhesion/
Initial
Activation
Thrombin
Stent
Thrombosis
P-selectin
CD-40L
Granule
Secretion
ADP
GPIIb/IIIa
Activation
Platelet
Aggregation
Sustained Activation
Membrane
PL’s
TxA2
(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)
Myocardial Infarction
Central Role of Platelets in ACS and PCI
Hypercoagulability
PCI
Plaque Rupture
Inflammation
Procoagulant
State
TF
Cytokine
Release
TF
PLT-WBC
Aggregation/
Microparticles
Adhesion/
Initial
Activation
Thrombin
Clopidogrel
(modest variable)
Granule
Secretion
ADP
X
Stent
Thrombosis
P-selectin
CD-40L
GPIIb/IIIa
Activation
X
Platelet
Aggregation
Sustained Activation
Membrane
PL’s
X
TxA2
Myocardial Infarction
GP IIb/IIIa Inhibitor
(potent uniform)
Aspirin (modest uniform)
(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)
Long-Term Antiplatelet Therapy –
The Clopidogrel Continuum
Acute STEMI
CLARITY PCI-CLARITY
2005
Occluded
infarct –
related
artery or
D/MI by
time of
angio
2005
Death, MI, or
stroke
following PCI
NSTEMI / ACS
PCI
Post MI High Risk of Event
COMMIT
CURE
CREDO
CAPRIE
CHARISMA
2005
2001
2002
1996
2006
D/MI/Stroke
Up to 1 yr
Vasc
D/MI/Stroke
Up to 3 yrs
Vasc
D/MI/Stroke
For almost
3 yrs
Mortality
28 days
D/MI/Stroke
Up to 1 yr
D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia.
Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther. 2006;4:7-15.
Long-Term Antiplatelet Therapy –
The Clopidogrel Continuum
Acute STEMI
CLARITY PCI-CLARITY
2005
2007
Occluded
artery
36%
D/MI/UR/
RI 20%
NSTEMI / ACS
PCI
Post MI High Risk of Event
COMMIT
CURE
CREDO
CAPRIE
CHARISMA
2005
2001
2002
1996
2006
Mortality
Mortality
D/MI/Stroke
D/MI/Stroke
46 %
7%
20%
27%
Vasc
D/MI/Stroke
9%
Vasc
D/MI/Stroke
Benefit in
symptomatic
patients
D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia.
Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther. 2006;4:7-15.
CURE Protocol
Clopidogrel
Aspirin 75-325mg
Patients with
Acute Coronary
Syndrome
(UA or MI Without ST
elevation)
R
(6,259 patients)
3 months  double-blind treatment  12 months
Aspirin 75-325mg
Placebo
(6,303 patients)
R=Randomization
The CURE Trial Investigators
.N Engl J Med.2001;345:494-502.
CURE: Results
Primary End-Point
CV Death, MI, Stroke
Number of events
1000
RRR = 20%; p=0.00005
800
600
723
581
ARR = 2.19
NNT = 46
400
200
0
9.28
%
11.47%
Clopidogrel + ASA
(n=6259)
Aspirin
(n=6303)
The CURE Trial Investigators
.N Engl J Med.2001;345:494-502.
Lipid lowering drug therapy
• 60s and 70s
- nicotinic acid
- resins
• 70s to 90s
- fibrates
• the 90s
- statins
• 21st century
- ezetimibe
Metabolic Pathways Blocked By
Statins
Acetyl-CoA + Acetoacetyl-CoA
HMG-CoA
Statins
Block
Mevalonate
Slower
Late Benefit
Isopentanyl PP
Related to Hepatic
LDL Reduction
Geranyl PP
Early/Rapid and Later Benefit
(pleiotropic effect)
Important in
Vascular Cellular Responses
Prenylation
Farnesyl PP
Geranyl Geranyl PP
Squalene
Cholesterol
Translocates to the
Cell Membrane
PP = pyrophosphate.
Reproduced from Ray and Cannon. Curr Opin Lipidol. 2004;15:637, with permission.
Ray and Cannon. Am J Cardiol. 2005;96(suppl):54F.
Rho
The Pleiotropic Effects of Statins
• Increased plaque stability
• Decreased inflammation
• Improved endothelial function
• Reduced oxidative stress
• Antithrombotic properties
• Effects on bone marrow
Atherosclerosis progression varies directly with
LDL-cholesterol
y = 0.0004 x – 0.0267
0.05
PLAC1-P
MLD Decrease (mm/year )
R² = 0.6116
REGRESS-P
CCAIT-P
LCAS-P
p = 0.001
0.04
PLAC1-S
0.03
REVERSAL-PR
0.02
MARS-P
MAAS-P
CCAIT-S
MARS-S
0.01
REGRESS-S
LCAS-S
0
MAAS-S
P
Placebo
S
Statin
PR Pravastatin
REVERSAL-AT
AT Atorvastatin
-0.01
70
80
90
100
110
120
130
140
150
160
170
180
LDL cholesterol (mg/dL)
O’Keefe et al. JACC 2004; 43: 2142-6
How Low is Low Enough?
LDL-C Levels vs. Events in Landmark Statin Trials
4S-PBO
Secondary prevention
Primary prevention
With CHD event (%)
25
20
LIPID-PBO
4S-Rx
15
CARE-Rx
10
CARE-PBO
LIPID-Rx
5
WOS-PBO
WOS-Rx
AFCAPS-Rx
AFCAPS-PBO
0
50
70
90
110
130
150
LDL-C (mg/dL)
170
190
210
Early Statin Therapy in ACS
Human Being Has the Highest Serum
Cholesterol Levels
• ACE inhibitors: Ramipril, Acertil, Captopril
• Angiotensin Receptor Blockers: Telmisartan,
Valsartan, Candesartan, Losartan, Olmesartan,
Eprosartan
• Beta blockers: Carvedilol, Bisoprolol,
Propranolol
• Calcium channel blockers: Amlodipine,
Nifedipine, Verapamil, Diltiazem
• Diuretics: Furosemide, Dichlozid, Indapamide
Renin-Angiotensin
Aldosterone System
Non-ACE Pathways




(e.g., chymase)
Vasoconstriction
Cell growth
Na/H2O retention
Sympathetic activation
Angiotensinogen
renin
AT1
Angiotensin I
Angiotensin II
ACE
Cough,
Angioedema
Benefits?
 Bradykinin
Aldosterone
Inactive
Fragments
AT2
 Vasodilation
 Antiproliferation
(kinins)
SAVE
AIRE
Radionuclide
EF  40%
TRACE
Clinical and/or
radiographic
signs of HF
Echocardiographic
EF  35%
All-Cause Mortality
0.4
Probability of Event
0.35
0.3
Placebo
0.25
ACE-I
0.2
0.15
Placebo: 866/2971 (29.1%)
0.1
ACE-I: 702/2995 (23.4%)
0.05
Years
0
OR: 0.74 (0.66–0.83)
0
1
2
3
4
ACE-I
2995
2250
1617
892
223
Placebo
2971
2184
1521
853
138
Flather MD, et al. Lancet. 2000;355:1575–1581
SAVE
Radionuclide
EF  40%
AIRE
TRACE
Clinical and/or
radiographic
signs of HF
Echocardiographic
EF  35%
Death and Major CV Events
ACE-I (n = 2995)
Placebo (n = 2971)
0.75*
(0.67 – 0.83)
Events (%)
40
30
0.73*
20
(0.63 – 0.85)
0.80*
(0.69 – 0.95)
10
n=
355
0
n=
460
Readmission
for HF
*odds ratio (95% CI)
n=
324
n=
391
Reinfarction
n=
1049
n=
1244
Death/MI or
Readmission for HF
Flather MD, et al. Lancet. 2000;355:1575–1581
Commonly used AT1-antagonists
Schieffer et al., J Med Chem 2003
Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible
(either clinical/radiologic signs of HF or LV systolic dysfunction)
Major Exclusion Criteria:
— Serum creatinine > 2.5 mg/dL
— BP < 100 mm Hg
— Prior intolerance of an ARB
or ACE-I
— Nonconsent
double-blind active-controlled
Captopril 50 mg tid
(n = 4909)
Valsartan 160 mg bid
(n = 4909)
Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)
median duration: 24.7 months
event-driven
Primary Endpoint:
All-Cause Mortality
Secondary Endpoints: CV Death, MI, or HF
Other Endpoints:
Safety and Tolerability
Mortality by Treatment
0.3
Captopril
Valsartan
Probability of Event
0.25
Valsartan + Captopril
0.2
0.15
0.1
0.05
Valsartan vs. Captopril: HR = 1.00; P = 0.982
Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726
0
Months
0
Captopril 4909
Valsartan 4909
Valsartan + Cap 4885
6
12
18
24
30
36
4428
4464
4414
4241
4272
4265
4018
4007
3994
2635
2648
2648
1432
1437
1435
364
357
382
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Conclusion
In patients with MI complicated by heart failure, left
ventricular dysfunction or both:
• Valsartan is as effective as a proven dose of
captopril in reducing the risk of:
– Death
– CV death or nonfatal MI or heart failure admission
• Combining valsartan with a proven dose of captopril
produced no further reduction in mortality—and more
adverse drug events.
Implications:
In these patients, valsartan is a clinically effective
alternative to an ACE inhibitor.
ONTARGET: The ONgoing Telmisartan Alone
and in Combination with Ramipril Global
Endpoint Trial
Eligibility Criteria
• Inclusion:
– 55 years or older with
one of following
– Coronary artery disease
– Peripheral artery disease
– Cerebrovascular disease
– High risk diabetes with
evidence of end-organ
damage
• Exclusion:
– Inability to discontinue,
hypersensitivity or intolerance to,
ACE inhibitors or ARB
– Symptomatic CHF; significant
primary valvular or outflow tract
obstruction; constricitive
pericarditis; syncope unknown
etiology, CABG or PCI < 3 mths;
uncontrolled hypertension
– Significant renal artery stenosis;
hepatic dysfunction
– Other medical conditions or social
reasons
Non-inferiority Margin
ONTARGET Non-Inferiority
ONTARGET
Comparison
Primary Composite
(p = 0.0033)
CV Death / MI / Stroke
(HOPE Composite)
(p = 0.0008)
Telmisartan better
Ramipril better
0.8
0.9
1.0
1.1
1.2
RR (95% CI)
Note that the outcomes are presented as point estimates with confidence intervals. The solid line
is the 95% CI representing 1.96 SD and the dashed line is the 97.5% CI representing the adjusted CI for each outcome
Efficacy Comparison
ONTARGET
Composite
(p = 0.8522)
CV Death
MI
Stroke
CHF Hosp
Ramipril + Telmisartan better
0.4
0.6
0.8
Ramipril better
1.0
1.2
1.4
1.6
RR (95% CI)
Note that the outcomes are presented as point estimates with confidence intervals. The solid line
is the 95% CI for each outcome
Conclusions: Telmisartan
vs. Ramipril
1. Telmisartan is clearly “non-inferior” to ramipril
• Primary composite outcome (p=0.0045)
• HOPE primary outcome (p=0.001)
Most (>90%) of the benefits of ramipril are
preserved
2. Combination therapy does not reduce the
primary outcome to a greater extent compared
to ramipril alone
Beta Blockade
 Heart rate
 After load
 Heart size
diastolic
perfusion
Wall
stress
O2
vs O2
demand supply
Subendocardial
ischemia
 Contractility
Less exercise
vasoconstriction
More spasm?
 O2 wastage
Anti-arrhythmic
DEMAND
O2 deficit
anaerobic metabolism
SUPPLY
LH Opie, 33
2001
Effect of beta blockade on mortality rate in
AMI
34
Benefit of propranolol after
myocardial infarction
Results of the Beta Blocker Heart Attack Trial which randomized 3837
patients with an AMI to propranolol or placebo. At an average follow-up of 25
months, propranolol significantly reduced total, cardiovascular, and sudden
death mortality and reduced the incidence of nonfatal infarction and all
coronary events. Benefit occurred in all patient groups, but was more
marked in those with heart failure (HF). Data from Chadda, K, Goldstein, S,
Byington, R, et al, Circulation 1986; 73:503.
Beta blocker reduces mortality in
patients with CHF after MI
he AIRE trial randomized 2006 patients with congestive heart failure after a
myocardial infarction to ramipril or placebo. Cumulative mortality in the 22
percent who were also receiving a beta blocker was significantly lower than in
those not receiving a beta blocker (12 versus 22 percent, p = 0.008). Data from
Spargias, KS, Hall, AJ, Greenwood, DC, et al, Heart 1999; 81:25
Calcium Channel Blocker
Amlodipine Besylate
Cl
O
•H3
C
CH3
O
O
H3C
O
NH
O
Amino group
side chain
NH2
Mechanism of Action
Slow Calcium
Channel Receptors
2
Amlodipine besylate
1
Muscle Cell
1
2
•일반적으로 칼슘(
) 은 칼슘채널의 수용체에 부착하여 수
축을 일으키는 세포 속으로 유입된다.
•NORVASC® 는 칼슘채널 수용체를 억제하여 Ca2+ 의 부착
및 세포 내로의 유입을 억제한다.
Median Angina Attack Rate
(Episodes per Week)
Efficacy in Chronic Stable Angina
* P = 0.0225 versus placebo
=
P = 0.0001 versus
placebo
5.0
5
4.0
4
3.0
2.8
Week 4
Week 8
2.5*
3
1.5=
2
1
0
Baseline
Week 4
Week 8
NORVASC (n = 180)
Adapted from Deanfield et al, 1994
Baseline
Placebo (n = 91)
Mean Change in Angina Episodes/Day
Safety in Patients With Vasospastic Angina
0.0
-0.1
-0.2
-0.3
-0.4
Placebo
(n = 28)
-0.5
-0.6
-0.7
NORVASC®
(n = 24)
-0.8
-0.9
-1.0
Adapted from Chahine et al, 1993
P = 0.009
Calcium channel blockers do not
change mortality after AMI
A meta-analysis of controlled trials of calcium channel blockers in
postinfarction patients failed to show any effect on mortality, although
the agents that reduce heart rate, particularly verapamil, showed a
trend toward an improved survival while nifedipine, which increases
heart rate, showed a trend toward an increased mortality.
Data from Held, PH, Yusuf, S. In: Cardiovascular Pharmacology and
Therapeutics, Singh, BN, Dzau, V, Vanhoutte, PM, Woosley, RL Eds,
Churchill Livingstone, New York, 1993, p. 525.
PHARMACOLOGICAL ACTIONS OF
ANTI-ANGINAL DRUGS
Coronary
Blood Flow
ß-Blockers
Heart
Rate
Arterial
Pressure
Cardiac
Contractility
No Effect
Ca 2+ Channel
Antagonists
Long-acting
Nitrates
No Effect
From Stanley, European Heart Journal, 2002.
Myocardial Energy Metabolism Under Aerobic Conditions
Glycolysis
Fatty
Acids
60-90%
Lactate
Pyruvate
10-40%
ATP
Pyruvate
Dehydrogenase
O2
Mitochondrion
CO2
Contractile Work,
Ca2+ uptake,
Ion Homeostasis
ADP
+ Pi
Glycolysis
Pyruvate
X
Pyruvate
Dehydrogenase
-
Lactate
X
NADH
Acetyl CoA
-
Fatty Acid
Oxidation
Trimetazidine, Ranolazine,
Etomoxir, Oxfenicine, Perhexiline
Lactate
Nonesterified Fatty Acids
Glucose
GLYCOLYSIS
Cytosol
Triglyceride
Lactate
Pyruvate
Fatty Acyl-CoA
Outer Membrane
CPT-I
Fatty Acyl-Carnitine
Inner Membrane
NAD+
+ CoA-SH
PDH
Mitochondrial
Matrix
NADH
Acetyl-CoA
CO2
CitricAcid
Cycle
CPT-II
CAT
Fatty Acyl-CoA
Fatty Acid
-Oxidation
Trimetazidine
NAD+ + CoA-SH