Cardiovascular Medications Soon Jun Hong Korea University Anam Hospital.

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

The 3 Most Important Advances in Antiplatelet Therapy for ACS

• Aspirin

• ADP antagonists

• Platelet GP IIb/IIIa receptor antagonists

Antiplatelet AgentsDifferent Mechanisms of Action

Antiplatelet AgentsDifferent Mechanisms of Action

TiclopidineClopidogrel

PrasugrelCangrelor

(P2Y receptor)

Platelet Aggregation

GPIIb/IIIa

Receptor

HeparinLMWHHirudin

ADP

Epinephrine

Collagen

Thrombin

ArachadonicAcid

TxA2PGI2

CyclooxygenasePGG

2 Aspirin

GP 2b/3a antagonists

Central Role of Platelets in ACS and PCICentral Role of Platelets in ACS and PCI

Membrane Membrane PL’sPL’sMembrane Membrane PL’sPL’s

PlateletPlateletPlateletPlateletADPADP

TxATxA22

Granule SecretionGranule Secretion

Sustained Activation

(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)(Gurbel PA et al. Rev Cardiovasc Med. 7: S20-S28, 2006)

PCI PCI Plaque RupturePlaque Rupture


ThrombinThrombin

PlateletPlateletPlateletPlatelet

Adhesion/Initial

Activation

Adhesion/Initial

Activation

TFTF

Co

llag

en,

vW

FC

ol l

agen

, v

WF




TxATxA22



P-selectin P-selectin CD-40LCD-40L

PLT-WBCPLT-WBCAggregation/Aggregation/

MicroparticlesMicroparticles

Procoagulant Procoagulant StateState

TFTF




ThrombinThrombin


Adhesion/Initial

Activation

Adhesion/Initial

Activation

TFTF

Co

llag

en,

vW

FC

ol l

agen

, v

WF




TxATxA22



Platelet Platelet AggregationAggregation

GPIIb/IIIaGPIIb/IIIa

ActivationActivation

CytokineCytokineReleaseRelease

Myocardial Infarction

Inflammation

Stent Thrombosis

Hypercoagulability





TFTF




ThrombinThrombin


Adhesion/Initial

Activation

Adhesion/Initial

Activation

TFTF

Co

llag

en,

vW

FC

ol l

agen

, v

WF




TxATxA22



Platelet Platelet AggregationAggregation

GPIIb/IIIaGPIIb/IIIa

ActivationActivation

CytokineCytokineReleaseRelease

Myocardial Infarction

Inflammation

Stent Thrombosis

Hypercoagulability

XX

Aspirin (modest uniform)Aspirin (modest uniform)

XX

GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor(potent uniform)(potent uniform)GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor(potent uniform)(potent uniform)

XX

Clopidogrel Clopidogrel (modest variable)(modest variable)Clopidogrel Clopidogrel (modest variable)(modest variable)





TFTF




ThrombinThrombin


Adhesion/Initial

Activation

Adhesion/Initial

Activation

TFTF

Co

llag

en,

vW

FC

ol l

agen

, v

WF

Long-Term Antiplatelet Therapy – Long-Term Antiplatelet Therapy – The Clopidogrel ContinuumThe Clopidogrel Continuum

Acute STEMIAcute STEMI NSTEMI / ACSNSTEMI / ACS PCIPCI Post MIPost MI High Risk of EventHigh Risk of Event

CLARITYCLARITY20052005

PCI-CLARITYPCI-CLARITY20052005

COMMITCOMMIT20052005

CURECURE20012001

CREDOCREDO20022002

CAPRIECAPRIE19961996

CHARISMACHARISMA20062006

Occluded Occluded infarct –infarct –related related

artery orartery orD/MI by D/MI by time of time of angioangio

Death, MI, or Death, MI, or stroke stroke

following PCI following PCI

MortalityMortality28 days28 days

D/MI/StrokeD/MI/StrokeUp to 1 yrUp to 1 yr

D/MI/StrokeD/MI/StrokeUp to 1 yrUp to 1 yr

Vasc Vasc D/MI/StrokeD/MI/StrokeUp to 3 yrsUp to 3 yrs

Vasc Vasc D/MI/StrokeD/MI/Stroke

For almost For almost

3 yrs3 yrs

D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia.D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia.

Baggish AL, Sabatine MS. Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther.Expert Rev Cardiovasc Ther. 2006;4:7-15. 2006;4:7-15.

Long-Term Antiplatelet Therapy – Long-Term Antiplatelet Therapy – The Clopidogrel ContinuumThe Clopidogrel Continuum

Acute STEMIAcute STEMI NSTEMI / ACSNSTEMI / ACS PCIPCI Post MIPost MI High Risk of EventHigh Risk of Event

D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia.D, cardiovascular death; MI, myocardial infarction; UR, urgent revascularization; RI, recurrent ischemia.

Baggish AL, Sabatine MS. Baggish AL, Sabatine MS. Expert Rev Cardiovasc Ther.Expert Rev Cardiovasc Ther. 2006;4:7-15. 2006;4:7-15.

CLARITYCLARITY20052005

PCI-CLARITYPCI-CLARITY20072007

COMMITCOMMIT20052005

CURECURE20012001

CREDOCREDO20022002

CAPRIECAPRIE19961996

CHARISMACHARISMA20062006

Occluded Occluded arteryartery36% 36%

D/MI/UR/D/MI/UR/RI 20%RI 20%

MortalityMortality

46 %46 %

MortalityMortality

7% 7%

D/MI/StrokeD/MI/Stroke

20% 20%

D/MI/StrokeD/MI/Stroke

27% 27%


9% 9%


Benefit in Benefit in symptomatic symptomatic

patientspatients

3 months double-blind treatment 12 months

Aspirin 75-325mg

Clopidogrel(6,259 patients)

Placebo(6,303 patients)

Aspirin 75-325mgD

ay 1

6 m

. Vis

it

9 m

. Vis

it

12 m

.

or F

inal

Vis

it

Clopidogrel 300mg loading +75mg qd dose

3 m

. Vis

it

Dis

char

ge V

isit

1 m

. Vis

it

Patients withAcute Coronary

Syndrome

(UA or MI Without STelevation)

R

Plac

ebo

load

ing

dose

R=Randomization

The CURE Trial InvestigatorsThe CURE Trial InvestigatorsThe CURE Trial InvestigatorsThe CURE Trial Investigators. . N Engl J Med.N Engl J Med.2001;345:4942001;345:494--502.502.

CURE ProtocolCURE Protocol

CURE: ResultsPrimary End-PointCURE: ResultsPrimary End-Point

581

723

0

200

400

600

800

1000

Nu

mb

er

of e

ven

ts RRR = 20%; p=0.00005

CV Death, MI, Stroke

9.28%

11.47%

Clopidogrel + ASA (n=6259)

Aspirin (n=6303)

ARR = 2.19NNT = 46

The CURE Trial InvestigatorsThe CURE Trial Investigators. N Engl J Med.2001;345:494-502.

Lipid lowering drug therapy

• 21st century

- ezetimibe

• the 90s

- statins

• 70s to 90s

- fibrates

• 60s and 70s

- nicotinic acid

- resins

Metabolic Pathways Blocked By Statins

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.

Statins

Prenylation

Translocates to theCell Membrane

SlowerLate Benefit

Related to Hepatic LDL Reduction

Block

Acetyl-CoA + Acetoacetyl-CoA

HMG-CoA

Mevalonate

Isopentanyl PP

Geranyl PP

Geranyl Geranyl PPFarnesyl PP

Squalene

Cholesterol

Early/Rapid and Later Benefit(pleiotropic effect)

Important inVascular Cellular Responses

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

O’Keefe et al. JACC 2004; 43: 2142-6

LDL cholesterol (mg/dL)

REVERSAL-AT

y = 0.0004 x – 0.0267

R² = 0.6116

p = 0.001

MARS-S

REVERSAL-PR

LCAS-SMAAS-S

REGRESS-S

CCAIT-SMAAS-P

MARS-P

PLAC1-S

LCAS-P

PLAC1-P

REGRESS-PCCAIT-P

P Placebo

S Statin

PR Pravastatin

AT Atorvastatin MLD

Dec

reas

e (m

m/y

ear

)

0

0.01

0.02

0.03

0.04

0.05

70 80

LDL cholesterol (mg/dL)

-0.0190 100 110 120 130 140 150 160 170 180

How Low is Low Enough? LDL-C Levels vs. Events in Landmark Statin Trials

Wit

h C

HD

ev

en

t (%

)

50 70 90 110 130 150 170 190 210

0

5

10

15

20

25

LIPID-Rx

CARE-PBOCARE-Rx

4S-RxLIPID-PBO

4S-PBO

AFCAPS-Rx

WOS-RxWOS-PBO

AFCAPS-PBO

LDL-C (mg/dL)

Secondary preventionSecondary preventionPrimary preventionPrimary prevention

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-AngiotensinAldosterone System

Angiotensinogen

Non-ACE Pathways(e.g., chymase)

Vasoconstriction Cell growth Na/H2O retention Sympathetic activation

renin Angiotensin I

Angiotensin II

ACE

Cough,Angioedema

Benefits? Bradykinin

InactiveFragments

Vasodilation Antiproliferation

(kinins)

Aldosterone AT2

AT1

All-Cause Mortality

Years

Pro

bab

ilit

y o

f Even

t

0

0.05

0.1

0.15

0.2

0.25

0.3

0 1 2 3

0.35

0.4

4

ACE-I

Placebo

ACE-I 2995 2250 1617 892 223

Placebo 2971 2184 1521 853 138

Flather MD, et al. Lancet. 2000;355:1575–1581

OR: 0.74 (0.66–0.83)OR: 0.74 (0.66–0.83)

ACE-I: 702/2995 (23.4%)ACE-I: 702/2995 (23.4%)

Placebo: 866/2971 (29.1%)Placebo: 866/2971 (29.1%)

TRACEEchocardiographicEF 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF 40%

Readmission for HF

n =460

n =355

(0.63 – 0.85)

0.73*

Reinfarction

n =324

n =391

(0.69 – 0.95)

0.80*

*odds ratio (95% CI)

Death and Major CV Events

Flather MD, et al. Lancet. 2000;355:1575–1581

Placebo (n = 2971)ACE-I (n = 2995)

Death/MI or Readmission for HF

Even

ts (

%)

0

10

20

30

40

n =1049

n =1244

(0.67 – 0.83)

0.75*

TRACEEchocardiographicEF 35%

AIREClinical and/or radiographic signs of HF

SAVERadionuclideEF 40%

Schieffer et al., J Med Chem 2003

Commonly used AT1-antagonists

Primary Endpoint: All-Cause MortalitySecondary Endpoints: CV Death, MI, or HFOther Endpoints: Safety and Tolerability

Captopril 50 mg tid(n = 4909)

Valsartan 160 mg bid

(n = 4909)

Captopril 50 mg tid + Valsartan 80 mg

bid(n = 4885)

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— Nonconsentdouble-blind active-controlled

median duration: 24.7 monthsevent-driven

Captopril

0

0.05

0.1

0.15

0.2

0.25

0.3

0 6 12 18 24 30 36

Pro

bab

ilit

y o

f Even

tMortality by Treatment

Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349

Valsartan 4909 4464 4272 4007 2648 1437 357

Months

Valsartan vs. Captopril: HR = 1.00; P = 0.982

Valsartan + Captopril vs. Captopril: HR = 0.98; P = 0.726

Captopril 4909 4428 4241 4018 2635 1432 364

Valsartan + Cap 4885 4414 4265 3994 2648 1435 382

Valsartan

Valsartan + Captopril

ConclusionIn patients with MI complicated by heart failure, leftventricular 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 effectivealternative 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

ONTARGET Non-Inferiority Comparison

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 lineis the 95% CI representing 1.96 SD and the dashed line is the 97.5% CI representing the adjusted CI for each outcome

Non

-infe

riorit

y M

argi

n

Primary Composite (p = 0.0033)

CV Death / MI / Stroke (HOPE Composite)

(p = 0.0008)

Telmisartan better Ramipril better

ONTARGET

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Composite (p = 0.8522)

CV Death

MI

Stroke

CHF Hosp

Ramipril + Telmisartan better Ramipril better

RR (95% CI)

Note that the outcomes are presented as point estimates with confidence intervals. The solid lineis the 95% CI for each outcome

Efficacy Comparison ONTARGET

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

33

Beta Blockade

diastolic perfusion

Less exercisevasoconstriction

More spasm?

Heart rate

After load

Heart size

Contractility

O2 wastage

Anti-arrhythmic

DEMAND SUPPLY

O2 deficit anaerobic metabolism

Subendocardialischemia

O2 vs O2

demand supply

Wallstress

Col

late

rals

LH Opie, 2001

34

Effect of beta blockade on mortality rate in AMI

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

Amlodipine BesylateAmlodipine Besylate

•H3C

Cl

H3C NH

CH3

O

O

O

O

O

NH2Amino group side chain

Calcium Channel Blocker

Mechanism of ActionMechanism of Action

•일반적으로 칼슘 ( ) 은 칼슘채널의 수용체에 부착하여 수축을 일으키는 세포 속으로 유입된다 . •NORVASC® 는 칼슘채널 수용체를 억제하여 Ca2+ 의 부착 및 세포 내로의 유입을 억제한다 .

Muscle Cell

Slow Calcium Channel Receptors

Amlodipine besylate

1

2

1

2

Efficacy in Chronic Stable AnginaEfficacy in Chronic Stable AnginaM

edia

n A

ng

ina

Att

ack

Rat

e (E

pis

od

es p

er

Wee

k) 5

4

3

2

1

0

Baseline Week 8 Baseline Week 4 Week 8

NORVASC (n = 180) Placebo (n = 91)

Week 4

5.0

2.5*

1.5

4.0

3.0 2.8

* P = 0.0225 versus placeboP =0.0001 versus placebo

Adapted from Deanfield et al, 1994

Safety in Patients With Vasospastic AnginaSafety in Patients With Vasospastic AnginaM

ean

Ch

ang

e in

An

gin

a E

pis

od

es/D

ay

-1.0

Placebo (n = 28)

NORVASC® (n = 24)

P = 0.009

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

-0.8

-0.9

Adapted from Chahine et al, 1993

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 OFPHARMACOLOGICAL ACTIONS OF

ANTI-ANGINAL DRUGSANTI-ANGINAL DRUGS

Coronary Coronary HeartHeart Arterial Arterial Cardiac CardiacBlood FlowBlood Flow Rate Rate PressurePressure ContractilityContractility

ß-Blockersß-Blockers

Ca Ca 2+2+ Channel Channel AntagonistsAntagonists

Long-actingLong-acting NitratesNitrates

No EffectNo Effect

No EffectNo Effect

From From Stanley, European Heart Journal, 2002. Stanley, European Heart Journal, 2002.

OO22

ATPATP

ADPADP+ Pi+ Pi

Contractile Work, Contractile Work, CaCa2+2+ uptake, uptake, Ion HomeostasisIon Homeostasis

Mitochondrion

LactateLactate FattyFattyAcidsAcids

10-40%10-40%

60-90%60-90%

GlycolysisGlycolysis

Myocardial Energy Metabolism Under Aerobic ConditionsMyocardial Energy Metabolism Under Aerobic Conditions

COCO22

PyruvatePyruvate

PyruvatePyruvateDehydrogenaseDehydrogenase

PyruvatePyruvate

PyruvatePyruvateDehydrogenaseDehydrogenase

LactateLactate

Fatty AcidFatty Acid OxidationOxidation

GlycolysisGlycolysis

----

XX

Trimetazidine, Ranolazine, Trimetazidine, Ranolazine, Etomoxir, Oxfenicine, Perhexiline Etomoxir, Oxfenicine, Perhexiline

--

NADHNADH

Acetyl CoAAcetyl CoA

NADHNADH

Acetyl CoAAcetyl CoA

XXXX

Fatty Acyl-Carnitine

Cytosol

Outer Membrane

Inner Membrane

NADH

Fatty Acyl-CoA

CPT-IINAD+ + CoA-SHCAT

Fatty Acyl-CoA

Nonesterified Fatty Acids

Fatty Acid-Oxidation

Mitochondrial Matrix

CPT-I

Acetyl-CoA

Pyruvate

CitricAcidCycle

PDH

NAD+ + CoA-SH

Lactate

Lactate

GLYCOLYSIS

Glucose

CO2

Triglyceride

Trimetazidine

Cardiovascular Medications Soon Jun Hong Korea University Anam Hospital.

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Transcript of Cardiovascular Medications Soon Jun Hong Korea University Anam Hospital.