Canadian Journal of General Internal Medicine

10 Volume 13, Special Issue 1, 2018

About the Authors

Jason Andrade and Laurent Macle are with the Electrophysiology Service at the Montreal Heart Institute and the Department of Medicine,

Université de Montréal, Montreal, Canada. Jason Andrade and Marc Deyell are is with the Heart Rhythm Services, Department of

Medicine, The University of British Columbia, British Columbia, Canada.

Correspondence may be directed to: Jason.andrade@vch.ca

Atrial Fibrillation and Coronary Artery Disease:

Deciding on The Best Antithrombotic Regimen

Jason G. Andrade MD, Marc W. Deyell MD MSc, Laurent Macle MD

DOI: 10.22374/cjgim.v13iSP1.309

ABSTRACT

Atrial fibrillation (AF) is a chronic progressive disease characterized by exacerbations and

remissions. Up to 20–30% of patients with AF also have coronary artery disease (CAD).

In patients with concomitant AF and CAD, the management of antithrombotic therapy is

challenging. Oral anticoagulation (OAC) is indicated for the prevention of AF-related stroke

and systemic embolism, whereas antiplatelet therapy is indicated for the prevention of coronary

events. Each of these therapeutic avenues offers a relative efficacy benefit (e.g., dual antiplatelet

therapy [DAPT] is more effective than OAC alone in reducing cardiovascular death, myocardial

infarction, stent thrombosis, and ischemic coronary events in an ACS population), but with a

relative compromise (e.g., DAPT is significantly inferior to OAC for the prevention of stroke/

systemic embolism in an AF population at increased risk of AF-related stroke). The purpose

of this review is to explore the current evidence and rationale for antithrombotic treatment

strategies in patients with both AF and CAD.

Atrial Fibrillation Special Issue

Atrial fibrillation (AF) is the most common sustained arrhythmia,

and represents a major burden to our healthcare system. Current

evidence indicates that the prevalence of AF is in the range of

2% of the general population.

1,2

Of those with AF, up to 20–30%

have concomitant coronary artery disease (CAD), and 5–15%

will require percutaneous coronary intervention (PCI).

3,4

In patients with both AF and CAD the management of

antithrombotic therapy can be challenging. Oral anticoagulation

(OAC) is indicated for the prevention of AF-related stroke and

systemic embolism, whereas antiplatelet therapy is indicated for

the prevention of coronary events. Each offers a relative efficacy

benefit with either a relative efficacy compromise or a relative

safety compromise (e.g., dual antiplatelet therapy [DAPT] is

more effective than OAC alone in reducing ischemic coronary

events in an ACS population but is significantly inferior to OAC

alone for the prevention of stroke/systemic embolism in an AF

population).

As such clinicians have perceived an obligation

to treat patients with concomitant AF and CAD using both

OAC with and antiplatelet therapy in spite of the potential for

increased risk of fatal and nonfatal bleeding events, including

intracranial hemorrhage.

6–8

The purpose of this review is to explore the current evidence

and rationale for antithrombotic treatment strategies in AF

patients at risk for AF-associated stroke (i.e., those aged ≥ 65

years or CHADS2 score ≥ 1) with concomitant CAD. Specifically,

with a focus on the key clinical questions of: (1) What is the

Canadian Journal of General Internal Medicine

Volume 13, Special Issue 1, 2018 11

preferred antithrombotic therapeutic regimen for AF patients

with ACS or undergoing PCI? (2) Should we use NOACs as part

of the dual or triple therapy regimen? (3) What is the preferred

P2Y12 inhibitor as part of the combination therapy regimen?

(4)What is the optimal duration of triple antithrombotic therapy?

(5)What is the optimal antithrombotic therapy for AF patients

with stable CAD?

Question 1 – What Is the Preferred Antithrombotic

Therapeutic Regimen for af Patients With Acs or

Undergoing Pci?

The most complicated scenario for management of AF and CAD

is the patient with a strong indication for OAC therapy for stroke

prevention (aged ≥ 65 years or CHADS2 score ≥ 1), in whom

an acute coronary event has occurred. In this circumstance the

patient is at risk for both AF-related stroke/systemic embolism as

well as adverse ischemic coronary events (e.g., stent thrombosis

and recurrent myocardial infarction). There are three key

clinical trials that have been performed in an effort to address

the therapeutic dilemma associated with patients requiring oral

anticoagulation and dual antiplatelet therapy (Table 1).

The “What Is the Optimal Antiplatelet and Anticoagulation

Therapy in Patients With Oral Anticoagulation and Coronary

Stenting” (WOEST) study randomized 573 patients with a need

for anticoagulation undergoing PCI to dual pathway therapy

(OAC and clopidogrel 75mg/day) or to triple antithrombotic

therapy (OAC, clopidogrel, and aspirin 80 mg/day).

19,20

Treatment was continued for 1 month after BMS placement

(35% of patients) and for 1 year after DES placement (65% of

patients). The primary outcome of this open-label trial was any

Woest Pioneer AF-PCI Re-Dual PCI

Design Multicenter RCT Multicenter RCT Multicenter RCT

Population 573 2124 2725

Groups W+A+C (284)

W+C (279)

W+A+C (697)

R15+C (696)

R2.5+A+C (706)

W+A+C (981)

D110+C (981)

D150+C (763)

Follow-up 12 months 12 months 14 months

Age in years 68.7 70.1 70.8

Male 74.4% 74.4% 80.0%

% AF 69% 100% 100%

Outcomes

•

Any Bleeding HR 0.36

95%CI 0.26–0.50

R15+C - HR 0.59

95%CI 0.47–0.76

R2.5+A+C - HR 0.63

95%CI 0.50-0.80

D110 HR 0.52**

95%CI 0.42-0.63

D150 HR 0.72**

95%CI 0.58-0.88

•

Major TMI bleeding HR 0.56

95%CI 0.25-1.27

R15+C - HR 0.66

95% CI 0.33-1.31

R2.5+A+C - HR 0.57

95%CI 0.28-1.16

D110 HR 0.37*

95%CI 0.20-0.68

D150 HR 0.51

95%CI 0.28-0.93

• MACE HR 0.6

95%CI 0.38-0.94

R15+C - HR 1.08

95%CI 0.69-1.68

R2.5+A+C - HR 0.93

95%CI 0.59-1.48

D110 HR 1.13

95%CI 0.90-1.43

D150 HR 0.89

95%CI 0.67-1.19

W = warfarin; A = ASA 81 mg daily; C = clopidogrel 75 mg daily; R15 = rivaroxaban 15 mg daily; R2.5 = rivaroxaban 2.5 mg bid; D110 = dabigatran 110 mg bid; D150 = dabigatran 150 mg bid.

**ISTH and clinically relevant non-major bleeding.

WOEST = death, myocardial infarction, stroke, target vessel revascularization, stent thrombosis.

PIONEER AF-PCI = cardiovascular death, myocardial infarction, stroke.

RE-DUAL PCI = Death, revascularization, myocardial infarction, stroke, systemic thromboembolism.

Table 1. Relative Comparison of the WOEST, PIONEER AF-PCI, RE-DUAL Trials

Andrade et al.

Canadian Journal of General Internal Medicine

12 Volume 13, Special Issue 1, 2018

bleeding event within 1 year of follow-up (e.g., TIMI major plus

minor). Dual pathway therapy was associated with a significant

reduction in overall bleeding complications (19.4% with DT vs.

44.4% with TT), without significant differences in major bleeds

(3.2% vs. 5.6%). Though not powered to detect differences in

major thrombotic outcomes, the combined endpoint of major

adverse cardiac and cerebrovascular events (MACCE – death,

myocardial infarction, stroke, target vessel revascularization,

stent thrombosis) was significantly reduced with dual pathway

therapy (11.1% vs. 17.6) as was all-cause mortality (2.5% vs.

6.4%; P = 0.027).

The “Prevention of bleeding in patients with AF undergoing

PCI” (PIONEER AF-PCI) study randomized 2,124 patients

with non-valvular AF undergoing PCI for ACS (51%) or for

stable CAD to receive, in a 1:1:1 ratio: (1) P2Y12 inhibitor (94%

clopidogrel) plus rivaroxaban 15 mg daily (dual pathway) for 12

months (709 patients), (2) DAPT plus rivaroxaban 2.5 mg twice

daily (reduced dose triple antithrombotic therapy) for 1, 6 or 12

months (709 patients), or (3) traditional triple antithrombotic

therapy with warfarin (target INR 2-3) plus DAPT for 1, 6,

or 12 months (706 patients).

The primary safety endpoint,

consisting of clinically significant bleeding (e.g., TIMI major

plus minor), was lower in the dual pathway and reduced dose

triple antithrombotic therapy groups when compared to the

group receiving traditional triple antithrombotic therapy with

warfarin (16.8% in patients treated with dual pathway therapy,

18% in patients treated with reduced dose triple antithrombotic

therapy, and 26.7% in patients treated with traditional triple

antithrombotic therapy). Similar to WOEST there was a non-

significant reduction in major bleeding dual pathway and reduced

dose triple antithrombotic therapy groups when compared to

the group receiving traditional triple antithrombotic therapy

with warfarin.

The “Dual antithrombotic therapy with dabigatran after PCI

in atrial fibrillation” (RE-DUAL PCI) trial randomized 2,725

patients with non-valvular AF undergoing PCI for ACS (51%)

or stable CAD to: (1) dual pathway therapy with dabigatran

110mg bid plus P2Y12 inhibitor (D110 - 981 patients), (2) dual

pathway therapy with dabigatran 150mg bid plus P2Y12 inhibitor

(D150 - 763 patients), or (3) traditional triple antithrombotic

therapy with warfarin (target INR 2-3) plus a P2Y12 inhibitor

(clopidogrel or ticagrelor) plus ASA (981 patients).23 In the triple

antithrombotic therapy group aspirin was discontinued after 1

month (in patients with BMS) or after 3 months (in patients

with DES), however the P2Y12 inhibitor was continued for

12-months post-PCI. The primary outcome was ISTH major or

clinically relevant non-major bleeding, which was significantly

reduced in both dual pathway therapy groups when compared

to triple antithrombotic therapy (11.5% absolute reduction with

D110 and 5.5% absolute reduction with D150). In secondary

efficacy analyses both dual pathway therapy groups significant

reduced ISTH major bleeding (4.2% absolute reduction with

D110 and 2.8% absolute reduction with D150), and TIMI major

bleeding (2.4% absolute reduction with D110 and 1.8% absolute

reduction with D150). While the study was underpowered to

detect differences in thromboembolic events, the rates of death,

myocardial infarction, stroke, or stent thrombosis were similar

across the three groups, the use of dual pathway therapy was non-

inferior for the composite efficacy endpoint (thromboembolic

events).

There are several notable limitations to the above trials.

Firstly, a large proportion of patients were undergoing elective

PCI (72% in WOEST, 48% in PIONEER AF-PCI, and 44% in

RE-DUAL), meaning the rate relative risk of coronary outcomes

may be underestimated. Second, measures to decrease bleeding

risk were underutilized, suggesting that the observed bleeding

rate may be higher than contemporary practice. Third, it is

unknown whether the results of PIONEER AF-PCI and RE-

DUAL PCI would have been similar had the dual pathway

therapy groups utilized a VKA, or if the triple therapy group

utilized a standard-dose NOAC.

While each of the trials were individually underpowered

to detect meaningful differences in the incidence of ischemic

events a limited meta-analysis of these randomized trials

demonstrated that the use of dual pathway therapy was

associated with a significant reduction in major bleeding

events (2.22% vs 3.78%; OR 0.58, 95%CI 0.39-0.86), without

an excess in the occurrence of MI (3.58% vs. 3.21%; OR 0.96),

stent thrombosis (1.02% vs. 0.77%; OR 0.95), or stroke (1.35%

vs. 1.43%).

However, the meta-analysis focused only on the comparison

between dual pathway therapy and triple antithrombotic therapy.

We have performed a larger network meta-analysis of 114,887

ACS patients in 10 randomized and 38 non-randomized studies

to examine the relative risks/benefits of DAPT vs. dual pathway

therapy versus triple antithrombotic therapy. In comparison to

DAPT both dual pathway therapy and triple antithrombotic

therapy were associated with a significantly higher incidence

of major bleeding and with a significant reduction in stroke,

but no significant effect on myocardial infarction or all-cause

mortality (Figure 1). Compared to dual pathway therapy, triple

antithrombotic therapy demonstrated significantly more major

bleeding (OR 1.54; 95%CI 1.18-2.00), a trend towards less

myocardial infarction (OR 0.82; 95%CI 0.66-1.03) and stent

thrombosis (OR 0.66; 95%CI 0.42-1.03), with no differential

effect on stroke or all-cause mortality.

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Canadian Journal of General Internal Medicine

Volume 13, Special Issue 1, 2018 13

Question 2 – Should We Use Noacs As Part of the

Dual or Triple Therapy Regimen?

It has been postulated that the use of NOACs may be beneficial

given the increased risk of fatal and nonfatal bleeding events

(including intracranial hemorrhage) observed with dual pathway

or triple antithrombotic therapy. Collectively the phase 3 clinical

trials studies comparing NOAC therapy to warfarin demonstrated

a non-significant 14% reduction in major bleeding with NOAC

therapy when compared to warfarin (95%CI 0.73-1.00).

The

majority of this benefit was achieved through a significant

reduction in hemorrhagic stroke, and subdural, epidural, and

subarachnoid bleeding (RR 0.48; 95%CI 0.39-0.59), which was

counterbalanced by an increase in gastrointestinal bleeding (RR

1.25; 95%CI 1.01–1.55).

For the subset of subjects (24–38%; total 21,722 patients)

who received combination OAC and antiplatelet therapy the use

of a standard-dose NOAC was not associated with any significant

difference in outcomes, however non-significant trends were

observed in terms of reduction in major bleeding (OR 0.94; 95%CI

0.80-1.10), all-cause mortality (OR 0.91; 95%CI 0.79-1.04), and

stroke (OR 0.89; 95%CI 0.62-1.30); with a non-significant increase

in the rates of myocardial infarction with NOAC therapy (OR

1.24; 95%CI 0.98-1.57) when compared to warfarin.

Question 3 – What Is the Preferred P2Y12 Inhibitor

As Part of the Combination Therapy Regimen?

In patients without a need for OAC, the antiplatelet guidelines

recommend the use of prasugrel or ticagrelor in preference to

clopidogrel for the management of non-ST-segment elevation

ACS and ST-elevation myocardial infarction. This is because of

their greater efficacy at reducing recurrent MI (11% reduction

with prasugrel; 15% reduction with ticagrelor), and stent

thrombosis (52% reduction with prasugrel; 26% reduction for

ticagrelor).

10,11

However, these agents are not recommended as a

part of a combination therapy owing to their greater propensity of

bleeding.

As such, clopidogrel is the preferred P2Y12 inhibitor

when used in combination therapies with an OAC.

Questions 4 – What Is the Optimal Duration

ofTriple Antithrombotic Therapy?

The benefit of triple antithrombotic therapy in reducing ischemic

outcomes is established in selected subgroups (i.e., those undergoing

high-risk PCI), however this benefit must be balanced against the

increased bleeding risk with this therapeutic regimen (Figure 2).

The “Intracoronary Stenting and Antithrombotic Regimen-

Testing of a 6-Week Versus a 6-Month Clopidogrel Treatment

Regimen in Patients with Concomitant Aspirin and Oral

Anticoagulant Therapy Following Drug-Eluting Stenting”

(ISAR-TRIPLE) study randomized patients receiving OAC

to 6 weeks or 6 months of triple antithrombotic therapy (307

patients in each group).

All patients underwent PCI (33.2%

with ACS). The primary composite endpoint included death,

MI, stent thrombosis, stroke, or TIMI major bleeding. Although

underpowered, there was not difference in composite outcome

(cardiac death, MI, stent thrombosis, or ischemic stroke - 4.0%

vs. 4.3%; HR 0.93, 95%CI 0.43-2.05), TIMI major bleeding

Figure 1. Relative risk and benefits of antithrombotic therapies for each treatment phase.

Andrade et al.

Canadian Journal of General Internal Medicine

14 Volume 13, Special Issue 1, 2018

(5.3% vs. 4.0%; HR 1.35, 95%CI 0.64-2.84), or death (4.0% vs.

5.2%; HR 0.75, 95%CI 0.35-1.59). A post-hoc landmark analysis

from 6 weeks to 9 months (i.e. excluding the period where both

groups were on TT) demonstrated a significant reduction in

any bleeding in the 6 weeks group (20.5% vs. 27.9%; HR 0.68,

95%CI 0.47-0.98). In addition, the ischemic outcomes did not

differ between the 51% of patients in PIONEER AF-PCI used TT

durations shorter than 12 months, compared to those who were

on TT for a year. On balance, these findings suggest shortening

the triple antithrombotic therapy course to ≤ 6 months, and

thereafter continuing with OAC and clopidogrel, is reasonable

in patients at elevated bleeding risk.

Question 5 – What Is the Optimal Antithrombotic

Therapy for AF Patients With Stable CAD?

For patients with both AF and CAD the question that dominates

is whether OAC therapy alone is an adequate substitute for

ASA, or whether ASA should be added to OAC therapy on the

rationale that the anticoagulant effect of a VKA combined with the

antiplatelet effect of ASA may enhance antithrombotic efficacy.

Historically several studies have evaluated this question.

These studies randomized post myocardial infarction patients

to ASA alone vs. combined warfarin and aspirin therapy,

14–17

or ASA alone versus warfarin alone versus combined warfarin

and aspirin therapy.

18,19

Collectively these studies demonstrated

that combination therapy was associated with a reduction in the

combined endpoint of death/non-fatal MI/non-fatal stroke (OR

0.73; 95%CI 0.63-0.84) with a reduction in the rate of myocardial

infarction (OR 0.70; 95%CI 0.52-0.95) and stroke (RR 0.43;

95%CI 0.27-0.70), but an increase in the risk of bleeding (OR

2.32; 95%CI 1.63-3.29), when compared to ASA monotherapy.

Interestingly, OAC monotherapy was associated with similar

rates of death, MI, and stroke (e.g. 16.7% in warfarin group vs.

15.0% in Warfarin plus ASA group; P = 0.18) but lower rates of

bleeding compared to combined OAC and aspirin therapy (e.g.,

overall bleeding 2.82% vs. 3.27%).

18,19

When these studies are put together in a network meta-analysis

(132,657 CAD patients in 13 randomized and 7 non-randomized

studies) OAC monotherapy was associated with significantly

less major bleeding (OR 0.76; 95%CI 0.65-0.90), and a lower

all-cause mortality (OR 0.82; 95%CI 0.72-0.94), with a trend

towards reduced MI (OR 0.84; 95%CI 0.70-1.00) vs. combination

therapy. Therefore, for patients at risk of AF-associated stroke/

systemic embolism the cumulative evidence base supports the

use of OAC alone as it provides protection against both stroke

and coronary events. The addition of antiplatelet therapy to

OAC confers an increased risk of adverse bleeding outcomes

while providing only limited benefit on coronary outcomes.

Summary

General recommendations for antithrombotic therapy include

the following (see Figure 1):

1. For patients at low risk of AF-associated stroke

(age<65years and CHADS2 Score = 0) OAC therapy

ofthe coronary generally not recommended. The disease

should follow the recommendations found in the 2018

CCS/CAIC Focused Update of the Guidelines for the Use

of Antiplatelet Therapy.

2. For patients at high risk of AF-associated stroke

(age≥65years or CHADS

Score ≥ 1) and stable CAD we

recommend OAC alone.

Figure 2. Risk factors for bleeding, stroke, and coronary ischemic events.

Atrial Fibrillation and Coronary Artery Disease

Canadian Journal of General Internal Medicine

Volume 13, Special Issue 1, 2018 15

3. For patients at high risk of AF-associated stroke

(age ≥ 65 years or CHADS

Score ≥ 1) undergoing elective

or low-risk PCI, OAC combined with clopidogrel (dual

therapy) for one year should be employed.

4. For patients at high risk of AF-associated stroke

(age ≥ 65 years or CHADS

Score ≥ 1) undergoing high-

risk PCI, OAC combined with ASA and clopidogrel (triple

therapy) should be employed for up to 6 months post PCI,

followed by dual therapy with OAC plus clopidogrel until

one-year post PCI.

5. When OAC is used a NOAC is preferred.

Clopidogrel is the preferred antiplatelet agent in dual

pathway or triple therapy.

Conclusion

The management of patients with concomitant AF and CAD

is challenging and requires a comprehensive assessment of the

competing risks of the therapeutic options. For most patients

OAC alone can be used for stable CAD, with triple therapy

used for a short period (<6 months) after ACS or high-risk PCI,

followed by dual therapy until 12 months post event.

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