1 antiplatelet / anticoagulant therapy evidence and guidelines ty j. gluckman, andrew p. defilippis,...

1

Antiplatelet / AnticoagulantAntiplatelet / AnticoagulantTherapy Evidence and GuidelinesTherapy Evidence and Guidelines

Ty J. Gluckman, Andrew P. DeFilippis, James Mudd, Catherine Campbell, Gregg Fonarow, &

Roger S. Blumenthal

2

Antiplatelet Therapy Evidence and Antiplatelet Therapy Evidence and GuidelinesGuidelines

3

Antiplatelet Therapy: TargetsAntiplatelet Therapy: Targets

CollagenThrombin

TXA2

ADP

(FibrinogenReceptor)

ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2

clopidogrel bisulfate

TXA2

phosphodiesterase

ADP

Gp IIb/IIIa Activation

COX

ticlopidine hydrochloride

aspirin

Gp 2b/3a Inhibitors

dipyridamole

Schafer AI. Am J Med 1996;101:199–209

4

Antiplatelet Therapy: Common Oral AgentsAntiplatelet Therapy: Common Oral Agents

Acetylsalicylic acid (ASA)

Clopidogrel bisulfate*

Ticlopidine hydrochloride*

Trade Name Aspirin Plavix® Ticlid®

Class Salicylate Thienopyridine Thienopyridine

Formulation Active Drug Pro-Drug Active Drug

Maintenance Dose 75-325 mg daily 75 mg daily 250 mg twice daily

Major Bleeding Risk (%)

2-3%1 1-4% alone2,3

3-5% w/ ASA4

1% alone5

2-6% w/ ASA6,7

1Topol EJ et al. Circulation 2003;108:399-4062Diener HC et al. Lancet 2004;364;331-73Plavix® package insert. www.sanofi-synthelabo.us4Peters RJ et al. Circulation 2003;108:1682-7 5Hass WK. NEJM 1989;321:501-7 6Urban P. Circulation 1998;98:2126-327Ticlid® package insert. www.rocheusa.com

*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

5

Aspirin: Mechanism of ActionAspirin: Mechanism of Action

Membrane Phospholipids

Arachadonic Acid

Prostaglandin H2

COX-1

Thromboxane A2

Platelet AggregationVasoconstriction

Prostacyclin Platelet Aggregation

Vasodilation

Aspirin

6

Aspirin Evidence: Primary Prevention in MenAspirin Evidence: Primary Prevention in Men

Physicians’ Health Study (PHS)22,071 men randomized to aspirin (325mg every other day) followed for an

average of 5 years

Aspirin significantly reduces the risk of MI in men

End point Relative Risk (95% CI) P value Myocardial infarction Fatal 0.34 (0.15-0.75) 0.007 Nonfatal 0.59 (0.47-0.74) <0.00001 Total 0.56 (0.45-0.70) <0.00001 Stroke Fatal 1.51 (0.54-4.28) 0.43 Nonfatal 1.20 (0.91-1.59) 0.20 Total 1.22 (0.93-1.60) 0.15

Physicians’ Health Study Research Group. NEJM 1989;321:129-35

CI=Confidence interval, MI=Myocardial infarction

7

Aspirin Evidence: Primary Prevention in WomenAspirin Evidence: Primary Prevention in Women

Womens’ Health Study (WHS)

Placebo

Aspirin

Ridker P et al. NEJM 2005;352:1293-304

MI=Myocardial infarction

39,876 women randomized to aspirin (100 mg every other day) or placebo for an average of 10 years

Aspirin did not reduce the risk of MI, CVA & CV death

8

Aspirin Evidence: Primary PreventionAspirin Evidence: Primary PreventionBDT, 1988

Combined

PPP, 2001

HOT, 1998

TPT, 1998

PHS, 1989

RR of MI in Men

1.0 2.0 5.00.50.2

RR = 0.68 (0.54-0.86)P=0.001

1.0 2.0 5.00.50.2

RR = 1.13 (0.96-1.33)P=0.15

HOT, 1998

Combined

WHS, 2005

PPP, 2001

1.0 2.0 5.00.50.2

Aspirin Better Placebo Better

RR = 0.99 (0.83-1.19)P=0.95

1.0 2.0 5.00.50.2

Aspirin Better Placebo Better

RR = 0.81 (0.69-0.96)P=0.01

RR of CVA in Men

RR of MI in Women

RR of CVA in Women

Ridker P et al. NEJM 2005;352:1293-304

CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk

9

Aspirin Evidence: Secondary PreventionAspirin Evidence: Secondary Prevention

Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86

Category % Odds Reduction

Acute MI

Acute CVA

Prior MI

Prior CVA/TIA

Other high risk

CVD(e.g. unstable angina, heart failure)

PAD(e.g. intermittent claudication)

High risk of embolism (e.g. Afib)

Other (e.g. DM)

All trials

1.00.50.0 1.5 2.0 Control better Antiplatelet better

Effect of antiplatelet treatment* on vascular events**

*Aspirin was the predominant antiplatelet agent studied**Include MI, stroke, or death

10

Aspirin Evidence: Dose and EfficacyAspirin Evidence: Dose and Efficacy

0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose No. of Trials (%)Odds Ratio for

Vascular Events

0

P<.0001

Indirect comparisons of aspirin doses on vascular events in high-risk patients

Antithrombotic Trialist Collaboration. BMJ 2002;324:71-86

11

Aspirin (81 mg daily or 100 mg every other day) in at risk women >65 years of age

Aspirin in at risk women <65 years of age for ischemic stroke prevention

Aspirin in optimal risk women <65 years of age

Primary Prevention (Women)

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

CHD=Coronary heart disease



Aspirin RecommendationsAspirin Recommendations

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Aspirin RecommendationsAspirin Recommendations

Aspirin (75-162 mg daily) in those at intermediate risk (10 year risk of CHD >10%)

Primary Prevention (Men*)


CHD=Coronary heart disease

*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines

13

Aspirin Recommendations (Continued)Aspirin Recommendations (Continued)


Aspirin (75-162 mg daily) if known CHD/ASVD

Aspirin (162-325 mg daily) for at least 3 months after sirolimus-eluting stent implantation and at least 6 months after paclitaxel-eluting stent implantation after which aspirin (75-162 mg daily) should be continued indefinitely

Secondary Prevention

ASVD=Atherosclerotic vascular disease, CABG=Coronary artery bypass graft, CHD=Coronary heart disease


14

Aspirin Recommendations (Continued)Aspirin Recommendations (Continued)

Aspirin (75-162 mg daily) as the initial dose after stent implantation in those at higher bleeding risk

Aspirin (100-325 mg daily) following CABG surgery*



*To be administered within the first 48 hours after surgery in order to reduce the risk of saphenous vein graft failure. Doses >162 mg/day may be continued for up to one year


15

Thienopyridine: Mechanism of ActionThienopyridine: Mechanism of Action

ADP / ATP

P2Y1P2X1 P2Y12

Gi2 coupled

Gq coupled

Ca2+ Ca2+ cAMP

Platelet shape change Transient aggregation

No effect on fibrinogen receptor

Cation influx Calcium mobilization

Fibrinogen receptor activation

Thromboxane A2 generation

Sustained Aggregation ResponseSavi P et al. Biochem Biophys Res Commun 2001; 283:379–83 and Ferguson JJ. The Physiology of Normal Platelet Function. In: Ferguson JJ, Chronos N, Harrington RA (Eds). Antiplatelet Therapy in Clinical Practice. London: Martin Dunitz; 2000: pp.15–35

Clopidogrel or Ticlopidine

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Clopidogrel Evidence: Secondary PreventionClopidogrel Evidence: Secondary Prevention

Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial

Months Treated

Eve

nt R

ate

for

MI (

%)

(fat

al o

r no

nfat

al)

0

1

2

3

5

3 6 9 12 15 18 21 24 27 30 33 36

Aspirin

Clopidogrel

4

P = 0.008

CAPRIE Steering Committee. Lancet 1996;348:1329-39

CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease

19,185 patients with ischemic CVA, MI, or PAD randomized to daily aspirin (325 mg) or clopidogrel (75 mg) for 2 years

Clopidogrel provides slightly greater risk reduction

17


Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

3 6 90 12

Rat

e of

dea

th,

myo

card

ial i

nfar

ctio

n,

or s

trok

e

P<0.001

Months of Follow Up

The CURE Trial Investigators. NEJM 2001;345:494-502

NSTE-ACS=Non ST-segment elevation acute coronary syndrome

Aspirin + Clopidogrel

Aspirin + Placebo

12,562 patients with a NSTE-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg)

for 9 months

Dual antiplatelet therapy is more efficacious in NSTE-ACS

18Steinhubl S et al. JAMA 2002;288:2411-20

Clopidogrel for the Reduction of Events during Observation (CREDO) Trial


DAP=Dual antiplatelet therapy, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction

*Dual antiplatelet therapy=Aspirin (75-325 mg daily) plus Clopidogrel (300 mg load followed by 75 mg daily).

0 123 6 90

Ris

k of

MI,

Str

oke,

or

Dea

th (

%)

27% RRR, P=0.02

10

5

15 4 weeks of DAP1 year of DAP

Months from Randomization

2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin (75-325 mg) monotherapy vs persistent DAP* for 1 year

DAP* produces continued benefit when used for 1 year

19Bhatt DL et al. NEJM 2006;354:1706-17

Months

8

6

4

2

00 6 12 18 24 30

PlaceboClopidogrel

Inci

den

ce

of

CV

D

eath

, M

I, o

r C

VA

(%

)

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial


P = 0.22

CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction

15,603 patients with multiple CV risk factors or known CVD randomized to aspirin (75-162 mg) or aspirin (75-162 mg) & clopidogrel (75 mg) for a

mean of 30 months

Routine DAP therapy offers little long-term benefit

20Bhatt DL et al. NEJM 2006;354:1706-17

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) Trial


15,603 patients with multiple CV risk factors or known CVD randomized to aspirin (75-162 mg) or aspirin (75-162 mg) & clopidogrel (75 mg) for a

mean of 30 months

Long-term DAP provides benefit to those with CV disease

Population RR (95% CI) p value Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.04

Multiple Risk Factors 1.20 (0.91, 1.59) 0.20

Overall Population 0.93 (0.83, 1.05) 0.22

0.6 0.8 1.41.2 1.60.4

CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction

21

Thienopyridine RecommendationsThienopyridine Recommendations


No data to support the use of thienopyridines in primary prevention

Clopidogrel (75 mg daily) if aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI; Class IIa, Level B in those with stable angina)



Primary PreventionIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII


NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI

22

Ticlopidine* (250 mg twice daily) for aspirin intolerance or a true aspirin allergy (Class I, Level A following a NSTE-ACS; Class I, Level C following a STEMI)

Clopidogrel* (75 mg daily) in addition to aspirin for a minimum of 1 month (Class I, Level A) and ideally 1 year (Class I, Level B) after a NSTE-ACS






Thienopyridine Recommendations (Continued)Thienopyridine Recommendations (Continued)

*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile


23

Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 14 days (Class I, Level A) and up to 1 year (Class IIa, Level C) in those treated with fibrinolytic therapy or no reperfusion therapy after a STEMI

Clopidogrel (75 mg daily) in addition to aspirin for a minimum of 1 month and ideally for 12 months after bare metal stent implantation and for at least 12 months after drug-eluting stent implantation in those at low bleeding risk


STEMI=ST-segment elevation myocardial infarction


Thienopyridine Recommendations (Continued)Thienopyridine Recommendations (Continued)



24

Anticoagulant Therapy Evidence and Anticoagulant Therapy Evidence and GuidelinesGuidelines

25

Warfarin

Synthesis of Non-

Functional Coagulation

Factors

Antagonismof

Vitamin K

Vitamin K

VII

IX

X

II

Warfarin: Mechanism of ActionWarfarin: Mechanism of Action

Ansell J et al. Council on Clinical Cardiology. www.americanheart.org

26

WA*

N=1277

W*

N=1268

A*

N=1268

P*

N=1272

MI and coronary death (primary end point)

71 (0.87%)

83 (1.03%)

83 (1.02%)

107 (1.33%)

Stroke 29 (0.36%)

22 (0.27%)

18 (0.22%)

26 (0.32%)

All cause mortality 103 (1.24%)

95 (1.14%)

113 (1.36%)

110 (13.1%)

RRR of primary end point compared to placebo

34% (p=0.006)

21% (p=0.02)

20% (p=0.04)

N/A

Warfarin Evidence: Primary PreventionWarfarin Evidence: Primary Prevention

Thrombosis Prevention Trial (TPT)

TPT Investigators. Lancet 1998;351:233-41

*WA=Warfarin and aspirin, W=Warfarin, A=Aspirin, P=Placebo

5,499 men at high risk for CHD randomized to aspirin (75 mg), warfarin (mean INR=1.5), warfarin and aspirin, or placebo for 6.4 years

Warfarin has similar efficacy to aspirin

27

Warfarin Evidence: Secondary PreventionWarfarin Evidence: Secondary Prevention

Meta-analysis of 31 trials comparing the effects of oral anticoagulation with and without aspirin on CV outcomes

Anand SS et al. JAMA 1999;282:2058-2067

Events prevented per 1000 patients treated

(95% CI)

Major bleeds per 1000 patients treated

(95% CI)High intensity OA vs.

control98 (73-123) 39 (35-43)

Moderate intensity OA vs. control

24 (22-26) 35 (21-49)

Moderate to high intensity OA and ASA vs. ASA

54 (43-65) 16 (10-22)

Moderate to high intensity OA vs. ASA

13 (11-14) 14 (12-16)

Low intensity OA and ASA vs. ASA

7 (6-8) 5 (4-6)

ASA=Aspirin, CI=Confidence interval, CV=Cardiovascular, OA=Oral anticoagulation

28

Outcome Aspirin

(n=523) Warfarin (n=540)

Clopidogrel(n=524)

Death, MI, or stroke (%) 20.5 19.8 21.8

HF hospitalizations (%) 22.2 16.1 18.3

Major bleeding (number of episodes)

19 30 13*

*p=0.012 vs warfarin

Massie BM. American College of Cardiology 2004 Scientific Sessions; Mar 7-10, 2004; New Orleans, LA

Warfarin Evidence: Secondary PreventionWarfarin Evidence: Secondary Prevention

Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Trial

EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction

1,587 patients with HF and LVSD (EF <0.35) randomized to aspirin (162 mg), clopidogrel (75 mg), or warfarin (mean INR=2.6) for 23 months

There is no significant benefit to clopidogrel or warfarin over aspirin in LVSD for reduction of hard end points

29

Warfarin RecommendationsWarfarin Recommendations

Warfarin (INR 1.3-1.8) if aspirin intolerance or a true aspirin allergy*

Warfarin either without (INR 2.5-3.5) or with aspirin (75-81 mg; INR 2.0-2.5) may be reasonable for patients at high CAD risk and low bleeding risk who are intolerant of clopidogrel following a NSTE-ACS

Warfarin (INR <2.0) in addition to aspirin in those with stable angina



Primary Prevention



*No guideline recommendation exists

30

Warfarin Recommendations (Continued)Warfarin Recommendations (Continued)

Warfarin (INR 2.5-3.5) following a STEMI without stent implantation in those with aspirin intolerance or aspirin allergy. Use clopidogrel preferentially if no indication for anticoagulation*

Warfarin (INR 2.0-3.0) in addition to clopidogrel (75 mg daily) following a STEMI with stent implantation in those with an indication for anticoagulation* and either aspirin intolerance or aspirin allergy




*Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities

31


Warfarin (INR 2.5-3.5) following a STEMI without stent implantation as an alternative to aspirin in those with (Class I, Level B) and without (Class IIa, Level B) indication for anticoagulation*

Warfarin (INR 2.0-3.0) in addition to aspirin (75-162 mg daily) following a STEMI without stent implantation in those with (Class I, Level A) and without (Class IIa, Level B) indication for anticoagulation*

Secondary PreventionIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII





32


Warfarin (INR 2.0-3.0) in addition to aspirin (75-162 mg daily) and clopidogrel (75 mg daily) following a STEMI with stent implantation in those with indication for anticoagulation*

Warfarin (INR 2.0-3.0) in those with HF or LVSD with indication for anticoagulation*





HF=Heart failure, LVSD=Left ventricular systolic dysfunction

33


Warfarin (INR 2.0-3.0) in those with HF or LVSD, but without indication for anticoagulation*

Close monitoring of anticoagulation in those receiving warfarin along with aspirin and/or clopidogrel because of increased risk of bleeding




HF=Heart failure, LVSD=Left ventricular systolic dysfunction


1 antiplatelet / anticoagulant therapy evidence and guidelines ty j. gluckman, andrew p. defilippis,...

Documents

aspirin evidence

years aspirin

men rr of mi

risk of mi

women rr of cva

antiplatelet therapy

relative risk slide

myocardial infarction