1. Antiplatelet / Anticoagulant Therapy Evidence and Guidelines
Ty J. Gluckman, Andrew P. DeFilippis, James Mudd, Catherine Campbell, Gregg Fonarow, & Roger S. Blumenthal

2. Antiplatelet Therapy Evidence and Guidelines

3. Antiplatelet Therapy: Targets
dipyridamole
clopidogrel bisulfate
ticlopidine hydrochloride
phosphodiesterase
ADP
ADP
Gp 2b/3a Inhibitors
Collagen Thrombin TXA2
Gp IIb/IIIa
Activation
(Fibrinogen
Receptor)
COX
TXA2
Platelet activation leads to platelet aggregation. As illustrated above, various classes of antiplatelet therapies act by disparate mechanisms to reduce platelet activation and clot formation. Aspirin inhibits platelet aggregation by inhibiting the production of thromboxane A2. The thienopyridines, clopidogrel and ticlopidine, bind and inhibit adenosine diphosphate (ADP) receptors on platelets thereby inhibiting glycoprotein IIb/IIIa-receptor activation and preventing platelet aggregation. Dipyridamole interferes with platelet stimulating factors like collagen through various mechanisms including the inhibition of phosphodiesterase and inhibition of cellular uptake of adenosine. Glycoprotein IIb/IIa inhibitors directly interfere with platelet binding of fibrinogen, the final step in platelet aggregation.
aspirin
ADP=Adenosine diphosphate, COX=Cyclooxygenase, TXA2=Thromboxane A2
Schafer AI. Am J Med 1996;101:199–209

4. Antiplatelet Therapy: Common Oral Agents
Acetylsalicylic acid (ASA)
Clopidogrel bisulfate*
Ticlopidine hydrochloride*
Trade Name
Aspirin
Plavix®
Ticlid®
Class
Salicylate
Thienopyridine
Formulation
Active Drug
Pro-Drug
Maintenance Dose
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:
2Diener HC et al. Lancet 2004;364;331-7
3Plavix® package insert.
4Peters RJ et al. Circulation 2003;108:1682-7
5Hass WK. NEJM 1989;321:501-7
6Urban P. Circulation 1998;98:
7Ticlid® package insert.
*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

5. Aspirin: Mechanism of Action
Membrane Phospholipids
Arachadonic Acid
Aspirin
COX-1
Prostaglandin H2
Aspirin inhibits the production of thromboxane A2, thereby inhibiting platelet aggregation. Thromboxane promotes platelet aggregation and vasoconstriction. During platelet activation, the hydrolysis of membrane phospholipids yields arachidonic acid, which is converted to prostaglandin H2 by the catalytic activity of the cyclooxygenase enzyme prostaglandin G/H synthase. By the selective and irreversible acetylation of a single serine residue within prostaglandin G/H synthase, aspirin causes the inactivation of cyclooxygenase activity. Aspirin also inhibits the production of endothelial-produced prostacyclin, a vasodilator and inhibitor of platelet aggregation. Unlike platelets, endothelial cells recover their ability to synthesize prostacyclin within a couple of hours.
References:
1. Husain S, Andrews NP, Mulcahy D, Et al. Aspirin improves endothelial dysfunction in atherosclerosis. Circulation. 1998;97:
2. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231:235-5.
3. Patrono C. Aspirin as an antiplatelet drug. NEJM 1994;330:
Thromboxane A2
 Platelet Aggregation
Vasoconstriction
Prostacyclin
 Platelet Aggregation
Vasodilation

6. Physicians’ Health Study (PHS)
Aspirin 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
The Physicians' Health Study was a randomized, double-blind, placebo-controlled primary prevention trial designed to determine whether aspirin (325 mg every other day) was associated with a reduction in cardiovascular disease mortality. The trial included 22,071 participants, with an average follow-up of 60 months.
Aspirin use was associated with a 44% reduction in the risk of MI, however, this effect was mainly present in men >50 years of age and no reduction in total cardiovascular mortality (RR 0.96; 95% CI 0.60 to 1.54) was observed. A slightly increased risk of stroke was observed among those taking aspirin (p=NS). This trend was noted primarily in the subgroup with hemorrhagic stroke (RR 2.14; 95% CI [0.96 to 4.77]; p=0.06). The was a non-significant increased risk of gastrointestinal ulcers in the aspirin group (RR 1.22, CI [0.98 to 1.53]; p=0.08).
Overall: In men (especially >50 years of age), aspirin is associated with a reduced risk of a first MI.
CI=Confidence interval, MI=Myocardial infarction
Physicians’ Health Study Research Group. NEJM 1989;321:129-35

7. Womens’ Health Study (WHS)
Aspirin Evidence: Primary Prevention in Women
Womens’ Health Study (WHS)
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
Aspirin
Placebo
The Women's Health Study was a double-blind, placebo-controlled trial that randomized 39,876 healthy women >45 years of age to low dose aspirin (100 mg every other day) versus placebo for a mean follow up of 10 years. There was no reduction in the primary composite endpoint of nonfatal MI, nonfatal stroke, or death from a cardiovascular cause. Aspirin use was associated with a 17% reduction in the risk of stroke (RR 0.83; ; P=0.04), a 24% reduction in the risk of ischemic stroke (RR 0.76; ; P=0.009), and a non-significant increase in the risk of hemorrhagic stroke (RR 1.24; ; P=0.31). Aspirin had no effect on the risk of fatal or nonfatal myocardial infarction (RR 1.02; ; P=0.83).
Among women >65 years of age, aspirin use was associated with a reduction of major cardiovascular events (RR 0.74; ; P=0.008) and risk of ischemic stroke (RR 0.70; ; P=0.05). GI bleeding requiring transfusion was more frequent in the aspirin group (RR 1.40; ; P=0.02).
Overall: The routine use of aspirin in low risk women (<10% 10 year risk of a CHD event) is not recommended. Aspirin use in women >65 can reduce the risk of cardiovascular events.
MI=Myocardial infarction
Ridker P et al. NEJM 2005;352:

8. Aspirin Evidence: Primary Prevention
BDT, 1988
RR of MI in Men
RR of CVA in Men
PHS, 1989
TPT, 1998
HOT, 1998
PPP, 2001
RR = 0.68 ( ) P=0.001
RR = 1.13 ( ) P=0.15
Combined
0.2
0.5
1.0
2.0
5.0
0.2
0.5
1.0
2.0
5.0
RR of MI in Women
RR of CVA in Women
HOT, 1998
PPP, 2001
WHS, 2005
This slide demonstrates a reduction in the incidence in MI among men but not women and a reduction of CVA in women but not men in the major aspirin primary prevention trials. These differences may be due to a proportionally higher incidence of CVA versus MI in women as compared to men as well as differences in total CVD risk among the men and women in these trials. However, ultimately the reasons for any sex-based differences in the efficacy of aspirin for primary prevention of CVD are unclear and require further exploration.
Overall: Aspirin is recommended for men and women whose 10-year risks for a coronary-heart-disease event is > 10 percent over 10 years.
Pearson TA, Blair SN, Daniels SR, et al. AHA guidelines for primary prevention of cardiovascular disease and stroke: 2002 update: consensus panel guide to comprehensive risk reduction for adult patients without coronary or other atherosclerotic vasculardiseases. Circulation 2002;106:
Combined
RR = 0.99 ( ) P=0.95
RR = 0.81 ( ) P=0.01
0.2
0.5
1.0
2.0
5.0
0.2
0.5
1.0
2.0
5.0
Aspirin Better
Placebo Better
Aspirin Better
Placebo Better
CVA=Cerebrovascular accident, MI=Myocardial infarction, RR=Relative risk
Ridker P et al. NEJM 2005;352:

9. Aspirin Evidence: Secondary Prevention
Effect of antiplatelet treatment* on vascular events**
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
1.0
0.5
0.0
1.5
2.0
This data was taken from the collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, MI, and stroke in high risk patients. Absolute reductions in the risk of having a serious vascular event were 36 ± 5 per 1,000 treated for 2 years among patients with previous MI; 38 ± 5 per 1,000 patients treated for 1 month among patients with acute MI; 36 ± 6 per 1000 treated for 2 years among those with previous stroke or TIA; 9 ± 3 per 1000 treated for 3 weeks among those with acute stroke; and 22 ± 3 per 1000 treated for 2 years among other high risk patients (with separately significant results for those with stable angina (P=0.0005), peripheral arterial disease (P=0.004), and atrial fibrillation (P=0.01).
In each of these high risk categories, the absolute benefits substantially outweighed the absolute risks of major extra cranial bleeding.
Overall: Aspirin is recommended for the secondary prevention of CVD.
Antiplatelet better
Control better
*Aspirin was the predominant antiplatelet agent studied
**Include MI, stroke, or death
Antithrombotic Trialist Collaboration. BMJ 2002;324:71–86

10. Aspirin Evidence: Dose and Efficacy
Indirect comparisons of aspirin doses on vascular events in high-risk patients
Odds Ratio for Vascular Events
Aspirin Dose No. of Trials (%) mg mg mg
<75 mg
75 mg of aspirin per day results in almost complete inhibition of cyclooxygenase activity in platelets. This slide demonstrates that high doses of aspirin are no more effective than medium or low doses in reducing the odds of vascular events. Trials using doses of <75mg are less conclusive and, therefore, the available evidence supports daily doses of aspirin in the  mg range.
Overall: For secondary prevention of CVD an aspirin dose of  mg/d is recommended.
Any aspirin
P<.0001
0.5
1.0
1.5
2.0
Antiplatelet Better
Antiplatelet Worse
Antithrombotic Trialist Collaboration. BMJ 2002;324:71-86

11. Aspirin Recommendations
Primary Prevention (Women) I
IIa
IIb
III B
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
ACC/AHA primary prevention guidelines for aspirin include a Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) recommendation for the use of aspirin in women with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of > 10% over the next 10 years and over the age of 65 years. A Level B, Class IIb (conflicting evidence based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) for the use of aspirin in women with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of > 10% over the next 10 years and less than 65 years old. A Level B, Class III (certainty based on single large RCT trial or several non-RCT’s suggests risk is greater than benefit) for the use of aspirin in women with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of < 10% over the next 10 years and less than 65 years old.
CHD=Coronary heart disease

12. Aspirin Recommendations
Primary Prevention (Men*)
Aspirin ( mg daily) in those at intermediate risk (10 year risk of CHD >10%)
ACC/AHA primary prevention guidelines for aspirin include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation for the use of aspirin (75-162mg/d) in men with an estimated cardiovascular risk score (as calculated in NCEP ATPIII) of > 10% over the next 10 years.
*Specific guideline recommendations for men do not exist, but these guidelines are based on previous general (not gender specific) primary prevention guidelines
CHD=Coronary heart disease

13. Aspirin Recommendations (Continued)
Secondary Prevention
Aspirin ( mg daily) if known CHD/ASVD
Aspirin ( 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 ( mg daily) should be continued indefinitely
ACC/AHA secondary prevention guidelines for aspirin include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation for the use of aspirin (75-162mg/d) in men and women with known coronary heart disease/atherosclerotic vascular disease. A Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation for the use of aspirin following coronary artery bypass grafting.
ASVD=Atherosclerotic vascular disease, CABG=Coronary artery bypass graft, CHD=Coronary heart disease

14. Aspirin Recommendations (Continued)
Secondary Prevention I
IIa
IIb
III C
Aspirin ( mg daily) as the initial dose after stent implantation in those at higher bleeding risk
Aspirin ( mg daily) following CABG surgery*
ACC/AHA secondary prevention guidelines for aspirin include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation for the use of aspirin (75-162mg/d) in men and women with known coronary heart disease/atherosclerotic vascular disease. A Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation for the use of aspirin following coronary artery bypass grafting.
*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 Action
Clopidogrel or Ticlopidine
ADP / ATP
P2Y1
P2X1
P2Y12
Gq coupled
Calcium mobilization
Cation influx
Gi2 coupled
Ca2+
Ca2+
cAMP
The thienopyridines, clopidogrel and ticlopidine, selectively and irreversibly bind P2Y12, one of the adenosine diphosphate (ADP) receptors on platelets. This binding inhibits ADP-induced platelet glycoprotein IIb/IIIa-receptor activation and prevents platelet aggregation.
No effect on
fibrinogen
receptor
Platelet shape change Transient aggregation
Fibrinogen receptor activation
Thromboxane A2 generation
Sustained Aggregation Response
Savi 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

16. Clopidogrel Evidence: Secondary Prevention
Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) Trial
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 5
Aspirin 4
Event Rate for MI (%)
(fatal or nonfatal) 3
Clopidogrel 2 1
P = 0.008
CAPRIE was a randomized, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg daily) versus aspirin (325 mg daily) in reducing the risk of a composite outcome of ischemic stroke, MI, or vascular death in patients with atherosclerotic vascular disease manifested as either recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease.
An intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5% risk of ischemic stroke, myocardial infarction, or vascular death compared to 6% with aspirin, resulting in a statistically significant relative risk reduction of 9% (95% Cl , P= 0.043).
There were no major differences between the treatments comparing the incidence of rash, diarrhea, upper gastrointestinal discomfort, intracranial hemorrhage, and gastrointestinal hemorrhage.
Overall: Clopidogrel is slightly more efficacious than aspirin for the prevention of CVD events in patients with recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease but its cost is much higher. 3 6 9 12 15 18 21 24 27 30 33 36
Months Treated
CVA=Cerebrovascular accident, MI=Myocardial infarction, PAD=Peripheral arterial disease
CAPRIE Steering Committee. Lancet 1996;348:

17. Clopidogrel Evidence: Secondary Prevention
Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial
12,562 patients with a NSTE-ACS randomized to daily aspirin ( mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin ( mg) for 9 months
Dual antiplatelet therapy is more efficacious in NSTE-ACS
Aspirin + Clopidogrel
Aspirin + Placebo
Rate of death, myocardial infarction, or stroke
P<0.001
The CURE trial evaluated the efficacy and safety of clopidogrel and aspirin in patients with a non-ST-segment elevation acute coronary syndrome. Patients that presented within 24 hours after the onset of symptoms were randomly assigned to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients), in addition to aspirin for 3 to 12 months.
A composite of death from cardiovascular causes, nonfatal MI, or stroke, occurred in 9.3% of the patients in the clopidogrel + aspirin group and 11.4% in the aspirin alone group, corresponding to a significant 20% RRR.
The co- primary outcome (a composite of the first primary outcome along with refractory ischemia) occurred in 16.5% of patients in the clopidogrel + aspirin group vs. 19% of patients in the aspirin alone group, resulting in a significant 14% RR reduction. The percentage of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures was also significantly lower in the clopidogrel + aspirin group.
Patients on clopidogrel + aspirin had a significantly increased risk of major bleeding as compared to patients on aspirin alone (4% vs. 3%; relative risk, 1.38; P=0.001), but no greater incidence of life-threatening bleeding (2% vs. 2%, P=0.13) or hemorrhagic strokes.
Overall: The combination of aspirin + clopidogrel (for 3-12 months) is more efficacious than aspirin alone for the prevention of subsequent CVD events in patients presenting with non-ST-segment elevation acute coronary syndrome. 3 6 9 12
Months of Follow Up
NSTE-ACS=Non ST-segment elevation acute coronary syndrome
The CURE Trial Investigators. NEJM 2001;345:

18. Clopidogrel Evidence: Secondary Prevention
Clopidogrel for the Reduction of Events during Observation (CREDO) Trial
2,116 patients undergoing PCI randomized to 4 weeks of DAP* followed by aspirin ( mg) monotherapy vs persistent DAP* for 1 year
DAP* produces continued benefit when used for 1 year 15
4 weeks of DAP
1 year of DAP 10
Risk of MI, Stroke, or Death (%) 5
27% RRR, P=0.02 3 6 9 12
In the Clopidogrel for the Reduction of Events during Observation (CREDO) trial, 2116 patients scheduled to undergo percutaneous coronary intervention (PCI) or thought to be at high likelihood of undergoing PCI were randomized to a 300mg loading dose of clopidogrel vs. placebo 3-24 hrs prior to PCI. Following PCI, all patients received 75mg daily clopidogrel through day 28.
From day 28 through 1 yr, patients in the loading dose group received 75mg of clopidogrel daily. Clopidogrel reduced the 1-year risk of MI, CVA, or death by 27% (P=.02; absolute reduction 3%). No significant difference was seen in the 28 day combined risk of MI, death, or urgent target vessel revascularization (risk reduction 19%;p=0.23).
Months from Randomization
DAP=Dual antiplatelet therapy, PCI=Percutaneous coronary intervention, RRR=Relative risk reduction
*Dual antiplatelet therapy=Aspirin ( mg daily) plus Clopidogrel (300 mg load followed by 75 mg daily).
Steinhubl S et al. JAMA 2002;288:

19. Clopidogrel Evidence: Secondary Prevention
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 ( mg) or aspirin ( mg) & clopidogrel (75 mg) for a mean of 30 months
Routine DAP therapy offers little long-term benefit 8
Placebo
Clopidogrel 6
Incidence of CV Death, MI, or CVA (%) 4 2
The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin ( mg) or aspirin ( mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint of stroke, myocardial infarction, or death from cardiovascular causes occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend for increased total events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend for benefit in those subjects with a history of prior atherothrombotic event (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046).
Overall: The combination of aspirin + clopidogrel provided no benefit over aspirin alone for the prevention of CVD events in patients with multiple CV risk factors.
P = 0.22 6 12 18 24 30
Months
CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction
Bhatt DL et al. NEJM 2006;354:

20. Clopidogrel Evidence: Secondary Prevention
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 ( mg) or aspirin ( 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 (0.77, 0.998)
Multiple Risk Factors (0.91, 1.59)
Overall Population (0.83, 1.05)
The CHARISMA trial randomized 15,603 patients with multiple CV risk factors or known CVD to aspirin ( mg) or aspirin ( mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint of stroke, myocardial infarction, or death from cardiovascular causes occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (RR 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend for increased total events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend for benefit in those subjects with a history of prior atherothrombotic event (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046).
Overall: The combination of aspirin + clopidogrel provided no benefit over aspirin alone for the prevention of CVD events in patients with multiple CV risk factors.
0.4
0.6
0.8
1.2
1.4
1.6
CV=Cardiovascular, CVA=Cerebrovascular accident, CVD=Cardiovascular disease, DAP=Dual antiplatelet MI=Myocardial infarction
Bhatt DL et al. NEJM 2006;354:

21. Thienopyridine Recommendations
Primary Prevention
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)
Secondary Prevention I
IIa
IIb
III B
There are no ACC/AHA primary prevention guidelines for thienopyridines. ACC/AHA secondary prevention guidelines for clopidogrel (75 mg/d), in patients intolerant of aspirin, include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation after a NSTE-ACS; Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) following a STEMI; Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) in patients with unstable angina.
NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI

22. Thienopyridine Recommendations (Continued)
Secondary Prevention
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
ACC/AHA secondary prevention guidelines for ticlopidine (75 mg/d), in patients intolerant of aspirin, include a Level A, Class I (highest level of certainty, greatest risk benefit ratio) recommendation after a NSTE-ACS; Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) following a STEMI.
ACC/AHA secondary prevention guidelines for clopidogrel (75 mg/d for 1y), in addition to aspirin, include a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation after a NSTE-ACS.
NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI
*Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

23. Thienopyridine Recommendations (Continued)
Secondary Prevention
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 I
IIa
IIb
III C
ACC/AHA guidelines for clopidogrel (75 mg/d for 1y), in addition to aspirin, include a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) recommendation for a minimum of: 1 month after a bare metal, 3 months for sirolimus or 6 months for paclitaxel stents. In addition the AHA released a statement in 2006 encouraging strong consideration to extending clopidogrel in addition to aspirin for 12 months after PCI if patient is a low risk for bleeding (especially with drug eluting stent implantation).
STEMI=ST-segment elevation myocardial infarction

24. Anticoagulant Therapy Evidence and Guidelines

25. Warfarin: Mechanism of Action
Vitamin K
Antagonism of
Vitamin K
VII
Synthesis of Non- Functional Coagulation Factors IX X II
Warfarin is a vitamin K antagonist. Vitamin K is required for the carboxylation of clotting proteins II, VII,IX, and X. Without adequate vitamin K, the liver produces partially carboxylated and decarboxylated clotting proteins, which have reduced procoagulant activity. Warfarin interferes with vitamin K dependent production of clotting proteins.
Warfarin
Ansell J et al. Council on Clinical Cardiology.

26. Warfarin Evidence: Primary Prevention
Thrombosis Prevention Trial (TPT)
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
WA*
N=1277 W*
N=1268 A* 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
The Thrombosis Prevention Trial evaluated the effect of low dose oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischemic heart disease (IHD).
The primary end point was an IHD composite, defined by the sum of coronary death and fatal and non-fatal myocardial infarction (MI). Warfarin reduced the primary end point by 21% (95% CI 4-35, P=0.02) due to a 39% reduction (95% CI 15-57, P=0.003) in fatal events and reduced all-cause mortality by 17% (95% CI 1-30, P=0.04).
The main effect of aspirin was a reduction in the primary end point by 20% (95% CI 1-35, P=0.04), almost entirely due to a 32% reduction (95% CI 12-48, P=0.004) in non-fatal events. Absolute reductions in the primary end point due to warfarin or aspirin were 2.6 and 2.3 per 1,000 person years, respectively.
Combination therapy with warfarin and aspirin reduced the primary end point by 34% (95% CI 11-51%, P=0.006) compared with placebo, but increased hemorrhagic and fatal strokes.
Overall: Aspirin and warfarin to INR of 1.5 are equally efficacious in the reduction of first time MI, stoke and mortality. Warfarin + aspirin was more effective at reducing primary IHD events, but with a higher risk of hemorrhagic and ischemic strokes.
*WA=Warfarin and aspirin, W=Warfarin, A=Aspirin, P=Placebo
TPT Investigators. Lancet 1998;351:233-41

27. Warfarin Evidence: Secondary Prevention
Meta-analysis of 31 trials comparing the effects of oral anticoagulation with and without aspirin on CV outcomes
Events prevented per 1000 patients treated (95% CI)
Major bleeds per 1000 patients treated (95% CI)
High intensity OA vs. control
98 (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)
This meta-analysis was designed to analyze the effects of long-term oral anticoagulation (OA) therapy, stratified by the intensity of anticoagulation and aspirin therapy, on outcomes in patients with CAD.
Compared to placebo, high-intensity (INR ) OA produced significant reductions in mortality, MI, and thromboembolic complications (including stroke), but with a 6-fold increased risk of major bleeding (including hemorrhagic stroke). Compared to placebo, moderate (INR 2-3) OA produced significant reductions in MI, stroke, but not death and had an 8-fold increased risk of major bleeding.
Compared to aspirin therapy, moderate or high-intensity OA (INR>2) produced no reduction in death, MI, or stroke, and was associated with a 2.4 fold increased risk of major bleeding. Compared to aspirin therapy, low-intensity OA (INR, <2) + aspirin produced no significant reduction in death, MI, or stroke, nor a significant increased risk of major bleeding. Compared to aspirin therapy alone, moderate or high-intensity OA (INR>2) + aspirin produced a 56% reduction in death, MI, or stroke, and was associated with a 1.6 fold increased risk of major bleeding that did not reach statistical significance.
Overall: High intensity OA (INR ) is an option for reducing CVD risk. In patients with an indication for moderate to high intensity OA (INR>2), the addition of aspirin is associated with more CVD events prevented and greater increase in bleeding risk than OA alone.
Overall: High intensity OA (INR ) is associated with more CVD events prevented than major bleeds caused as compared to placebo alone. Moderate to high intensity OA (INR>2) + aspirin is associated with more CVD events prevented than major bleeds caused as compared to aspirin alone.
ASA=Aspirin, CI=Confidence interval,
CV=Cardiovascular, OA=Oral anticoagulation
Anand SS et al. JAMA 1999;282:

28. Warfarin Evidence: Secondary Prevention
Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Trial
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
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
The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) prospectively randomized symptomatic heart failure patients in sinus rhythm and an ejection fraction <35% to treatment with open-label warfarin (target INR ) or double-blind antiplatelet therapy with aspirin (162 mg) or clopidogrel (75 mg).
Although the trial was designed to enter 4500 patients, it was terminated 18 months prematurely in June 2003 by the VA Cooperative Study Program because of poor enrollment, resulting in a reduction in power to achieve the original objective. Nonetheless, the results demonstrated no significant benefit to warfarin or clopidogrel over aspirin for the specified end points in patients with sinus rhythm and left ventricular dysfunction.
Overall: Anti-platelet / anticoagulation recommendations are not impacted by left ventricular systolic dysfunction.
EF=Ejection fraction, HF=Heart failure, LVSD=Left ventricular systolic dysfunction, MI=Myocardial infarction
Massie BM. American College of Cardiology 2004 Scientific Sessions; Mar 7-10, 2004; New Orleans, LA

29. Warfarin Recommendations
Primary Prevention
Warfarin (INR ) if aspirin intolerance or a true aspirin allergy*
Warfarin either without (INR ) or with aspirin (75-81 mg; INR ) 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
Secondary Prevention
There are no ACC/AHA guidelines for warfarin in the primary prevention setting. ACC/AHA secondary prevention guidelines include a Level B, Class IIb (conflicting evidence based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) for the use of warfarin to INR <2 as an alternative to aspirin in NSTE-ACS patients or in addition to aspirin in patients with stable angina.
*No guideline recommendation exists
NSTE-ACS=Non ST-Segment Elevation Acute Coronary Syndrome; STEMI=ST-Segment Elevation MI

30. Warfarin Recommendations (Continued)
Secondary Prevention
Warfarin (INR ) following a STEMI without stent implantation in those with aspirin intolerance or aspirin allergy. Use clopidogrel preferentially if no indication for anticoagulation*
Warfarin (INR ) 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
ACC/AHA secondary prevention guidelines include a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) for the use of warfarin to INR in aspirin intolerant patients without a stent. Level C, Class I (generally agreed that benefit outweighs harm but only based on expert opinion or case series) for the use of warfarin to INR 2-3 in addition to clopidogrel in aspirin intolerant patients with a stent and an indication for anticoagulation.
*Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities

31. Warfarin Recommendations (Continued)
Secondary Prevention
Warfarin (INR ) 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 ) in addition to aspirin ( mg daily) following a STEMI without stent implantation in those with (Class I, Level A) and without (Class IIa, Level B) indication for anticoagulation* I
IIa
IIb
III B I
IIa
IIb
III B
ACC/AHA secondary prevention guidelines include a Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) for the use of warfarin to INR as an aspirin alternative in patients without a stent and an additional indication for anticoagulation. Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) for the use of warfarin to INR as an aspirin alternative in patiennts without a stent and no other indication for anticoagulation.
Level A, Class I (highest level of certainty, greatest risk benefit ratio) for the use of warfarin to INR 2-3 in addition to aspirin (75-162mg/d) in patients without a stent after a STEMI with an additional indication for anticoagulation. Level B, Class IIa (certainty based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) for the use of warfarin to INR 2-3 in addition to aspirin (75-162mg/d) in patients without a stent after a STEMI without an additional indication for anticoagulation.
*Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities

32. Warfarin Recommendations (Continued)
Secondary Prevention
Warfarin (INR ) in addition to aspirin ( mg daily) and clopidogrel (75 mg daily) following a STEMI with stent implantation in those with indication for anticoagulation*
Warfarin (INR ) in those with HF or LVSD with indication for anticoagulation*
ACC/AHA secondary prevention guidelines include a Level C, Class IIb (only conflicting expert opinion that benefit outweighs risk) for the use of warfarin to INR 2-3 in addition to aspirin (75-162mg/d) and clopidogrel (75mg/d) in patients with a stent after a STEMI with an additional indication for anticoagulation. Level A, Class I (highest level of certainty, greatest risk benefit ratio) for the use of warfarin to INR 2-3 in patients with heart failure of left ventricular systolic dysfunction and an additional indication for anticoagulation.
HF=Heart failure, LVSD=Left ventricular systolic dysfunction
*Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities

33. Warfarin Recommendations (Continued)
Secondary Prevention
Warfarin (INR ) 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
Level B, Class IIb (conflicting evidence based on single large RCT trial or several non-RCT’s suggests benefit is greater than risk) for the use of warfarin to INR 2-3 in patients with heart failure of left ventricular systolic dysfunction and no additional indication for anticoagulation. Level B, Class I (certainty based on single large RCT trial or several non-RCT’s, greatest risk benefit ratio) for close monitoring of anticoagulation in those receiving warfarin along with aspirin and/or clopidogrel because of an increased risk of bleeding.
HF=Heart failure, LVSD=Left ventricular systolic dysfunction
*Indications for anticoagulation include: atrial fibrillation, left ventricular thrombus, cerebral emboli, or extensive regional wall motion abnormalities