Safety and Efficacy of Aspirin, Clopidogrel, and Warfarin After Coronary

Stent Placement in Patients With an Indication for Anticoagulation

James L. Orford, MBChB, MPH; Panayotis Fasseas, MD; Steven Melby,
RN; Kelli Burger, BSc; Steven R. Steinhubl, MD; David R. Holmes, MD;
Peter B. Berger, MD
American Heart Journal. 2004;147(3)

Abstract and Introduction

Background: Dual antiplatelet therapy with aspirin and clopidogrel has replaced aspirin and systemic
anticoagulation with warfarin as the preferred antithrombotic therapy after percutaneous coronary
intervention (PCI) with stent placement. However, a number of patients have indications for all 3 drugs.
We sought to determine the frequency and type of hemorrhagic complications in patients who undergo
systemic anticoagulation with warfarin while receiving aspirin and clopidogrel after a PCI with stent
placement.

Methods: We performed a retrospective analysis of the Mayo Clinic PCI database and identified 66
consecutive patients who were discharged from hospital after PCI between January 2000 and August
2002 (inclusive) receiving a combination of dual antiplatelet therapy (aspirin and clopidogrel) and
systemic anticoagulation (warfarin) to determine the incidence of bleeding and other clinical events during
the treatment period.
Results: Six patients (9.2%; 95% CI, 3.519.0) reported a bleeding event; 2 patients required a blood
transfusion.

No

patient

died

or

sustained

myocardial

infarction

or

stent

thrombosis.

Conclusions: The risk of bleeding may be increased in patients treated with aspirin, a thienopyridine,
and warfarin early after PCI with stent placement.

Dual antiplatelet therapy with aspirin and clopidogrel has replaced aspirin and systemic anticoagulation
with warfarin as the preferred antithrombotic therapy after percutaneous coronary intervention (PCI) with
stent placement.[1] However, a number of patients have indications for all 3 drugs (aspirin, clopidogrel,
and warfarin) because of atrial fibrillation, prosthetic heart valve, left ventricular mural thrombus, venous
thromboembolism, or other conditions. However, there has been concern that bleeding risks associated
with administration of all 3 drugs may be prohibitively high. In this study, we sought to determine the
incidence of hemorrhagic complications and characterize such complications in patients who undergo

systemic anticoagulation with warfarin while also receiving aspirin and clopidogrel after PCI with stent
placement.
Methods
We performed a retrospective analysis of the Mayo Clinic PCI database and identified all patients who
were discharged from hospital after PCI between January 2000 and August 2002 (inclusive) receiving a
combination of dual antiplatelet therapy (aspirin and clopidogrel) and systemic anticoagulation (warfarin)
to determine the incidence of bleeding, stent thrombosis, and other clinical events during the treatment
period. This computerized database includes prospectively collected baseline, procedural, and
angiographic data on all patients undergoing PCI at the Mayo Clinic (Rochester, Minn). The indications
for PCI included stable angina (elective procedures), unstable angina, and acute myocardial infarction
(urgent and emergency procedures). Angiographic, procedural, and clinical outcomes were recorded
prospectively. All patients were contacted at 6 months, 12 months, and yearly after the PCI procedure by
a clinical research coordinator according to a protocol approved by the Mayo Foundation Institutional
Review Board. Medical records of all patients requiring hospitalization at the Mayo Clinic and elsewhere
were reviewed to further characterize any clinical events during the study period. For the purposes of this
study, a detailed telephone interview was conducted by a trained research nurse with experience in postPCI patient care. Patients were asked: whether any bleeding problems had occurred, and if so, whether
they required discontinuation of any of the 3 medications; whether they were compliant with the
prescribed drug regimen and if not, why not; whether they were evaluated by any physicians or other
health care providers during this treatment period; and whether they were admitted to a hospital during
the period in which they were treated with all 3 drugs. The records of all patients requiring hospitalization
were reviewed.
All patients were included in this analysis when they had undergone successful deployment of at least 1
coronary stent and were discharged receiving aspirin, clopidogrel, and warfarin. Patients were excluded
when they were in cardiogenic shock before the procedure, when brachytherapy was administered, when
an experimental fibrin-coated stent was used, or when the patient refused permission for their records to
be used for research (as required by Minnesota state law).
Unstable angina was defined as new onset of chest pain at rest or progression of stable angina to an
increased class (Canadian Heart Classification) within 2 months of coronary intervention, with the last
episode of pain occurring within 1 week of the procedure. Any ischemic pain after myocardial infarction
was also considered to represent unstable angina.
Acute myocardial infarction was defined as prolonged chest pain with creatine kinase or creatine kinasemyocardial band enzyme level elevation more than twice the reference value, any elevation of troponin T
or I level, new Q waves on an electrocardiogram, or unexplained sudden death. Procedural success was
defined as a 20% decrease in luminal diameter stenosis to <50% in at least 1 treated lesion without

death, occurrence of Q-wave myocardial infarction, or coronary artery bypass graft surgery during
hospitalization. Stent thrombosis was considered to have occurred when confirmed angiographically
(intraluminal filling defect within the stent resulting in Thrombolysis in Myocarcial Infarction grade 0 or 1
anterograde blood flow), when death was sudden and unexplained, or when a myocardial infarction
occurred in the territory of the treated vessel and stent thrombosis could not be excluded definitively.
Continuous variables are presented as means plus or minus 1 SD. Discrete variables are presented as
frequencies and percentages. Clinical and angiographic variables were compared with the 2 test for
discrete variables and the Student t test for continuous variables.
Results
We identified 66 patients who were discharged receiving dual antiplatelet therapy and systemic
anticoagulation with warfarin (January 2000 August 2002, inclusive). Complete follow-up data were
available for 65 patients (98.5%). The baseline clinical characteristics of the patients are displayed
in Table I . No statistically or clinically significant differences in the 2 groups were identified. Specifically,
there was no difference in patient sex, age, or weight, the maximum size of the sheath used to maintain
vascular access, the use of glycoprotein IIb/IIIa inhibitors, or periprocedural complications. The
indications for warfarin anticoagulation included atrial fibrillation (25 patients, 38.5%), mechanical aortic
valve prosthesis (16 patients, 24.6%), markedly depressed left ventricular ejection fraction (5 patients,
7.7%), left ventricular aneurysm (5 patients, 7.7%), left ventricular mural thrombus (3 patients, 4.6%),
cerebrovascular accident or transient ischemic accident (4 patients, 6.2%), pulmonary embolus (2
patients, 3.1%), and protein S deficiency (1 patient, 1.5%).

Table I. Baseline Characteristics of the Study Population

Bleed (n = 6) No Bleed (n = 59)

Male

5 (83)

37 (63)

.41

Age

75 7

73 10

.66

Weight (kg)

92 15

84 18

.28

Unstable angina

3 (50)

15 (25)

.34

Acute MI <12 h

0 (0)

8 (14)

1.00

Thrombolysis within 24 hours

0 (0)

2 (3)

1.00

Max sheath size

.97

1 (17)

6 (10)

4 (67)

42 (71)

0 (0)

5 (8)

1 (17)

5 (8)

0 (0)

1 (2)

Femoral sheath

5 (83)

52 (88)

.56

Radial sheath

1 (17)

8 (14)

1.00

Brachial sheath

0 (0)

2 (3)

1.00

Femoral venous sheath

0 (0)

2 (3)

1.00

Glycoprotein IIb/IIIa use

3 (50)

28 (47)

1.00

Stent placement

6 (100)

58 (98)

1.00

Sheath dwell time (hours)

5.0 2.5

7.4 7.4

.44

Intra-aortic balloon pump

0 (0)

2 (3)

1.00

Sheath-related hematoma (5 cm)

1 (17)

4 (7)

.39

Bleeding requiring compression

0 (0)

2 (3)

1.00

Thrombotic occlusion

0 (0)

0 (0)

Pseudoaneurysm

0 (0)

0 (0)

AV fistula

0 (0)

0 (0)

Retroperitoneal hematoma

0 (0)

0 (0)

Hematemesis/melena

0 (0)

0 (0)

Intracranial hemorrhage

0 (0)

0 (0)

Other bleeding

0 (0)

3 (5)

Periprocedural complications

1.00

Transfusion
Groin complication

0 (0)

1 (2)

Other

0 (0)

0 (0)

1.00

MI, Myocardial infarction; IIb/IIIa, glycoprotein IIb/IIIa receptor inhibitor.

Six patients (9.2%; 95% CI, 3.5 19.0) reported a bleeding event. Two of these patients required a blood
transfusion (each received 2 units of packed red blood cells). No episodes of intracranial, intraspinal,
intracerebral, subarachnoid, subdural, or epidural hemorrhage were reported. Two of the bleeding events
were of minimal clinical significance and resolved spontaneously, requiring no additional clinical
investigation or therapeutic intervention except the withdrawal of the offending agents (warfarin in 1 case
and clopidogrel in the other). One of the bleeding events occurred within 24 hours of discharge from the
hospital (vascular access site hematoma), and no effect of warfarin on the clotting profile was yet evident
(international normalized ratio [INR] = 1.0); strictly speaking, this bleeding event was a complication of
aspirin, clopidogrel and enoxaparin administration.
No events consistent with stent thrombosis were identified. Similarly, no patients died, sustained a
myocardial infarction, or required a repeat target vessel procedure within the study period (30 days).
The case histories of the 6 patients who required medical attention during the 4 weeks of combination
dual antiplatelet therapy and warfarin are summarized.
The patient was a 77-year-old woman with coronary, peripheral, and cerebrovascular disease who
underwent PCI for an acute coronary syndrome. A stent was placed in the first obtuse marginal branch,
and the patient was discharged receiving 325 mg of aspirin once a day, 75 mg of clopidogrel once a day,
and her routine dose of 2.5 mg of warfarin once a day. Warfarin was administered for multiple prior
embolic strokes. She was readmitted to the hospital approximately 2 weeks after the index PCI after a
syncopal episode. Emergency department evaluation identified melanotic stools and a hemoglobin count
of 6.9 gm/dL. Her prothrombin time was markedly prolonged (>130 seconds, INR = 12.4). She received 2
units of packed red blood cells, fresh frozen plasma, and oral vitamin K. She underwent both upper and
lower gastrointestinal endoscopy. No bleeding diathesis was identified, but multiple polyps were noted in
the transverse and sigmoid colon, and there was severe sigmoid diverticulosis. She was discharged 6
days later without evidence of any further gastrointestinal bleeding and after an otherwise uneventful
hospital stay. The use of warfarin (2.5 mg/day) was continued, but the use of aspirin and clopidogrel was
stopped.
The second patient was a 76-year-old man with coronary artery disease who had undergone aortic valve
replacement with a Bjork-Shiley mechanical prosthetic aortic valve for aortic stenosis. He also had

metastatic prostate cancer. He was referred for elective PCI for the treatment of chronic stable angina
pectoris refractory to medical therapy. He underwent successful stenting of the mid-right coronary artery,
the proximal left anterior descending coronary artery, and second obtuse marginal branch. He was
discharged receiving 81 mg of aspirin once a day, 75 mg of clopidogrel once a day, and 100 mg of
enoxaparin subcutaneously twice a day, and the use of warfarin was reinitiated at his routine dose of 2.5
mg once a day. He was readmitted within 24 hours of discharge with a moderate-sized groin hematoma
(approximately 10 cm in diameter). There was also concern that superficial cellulitis was present, and
intravenous antibiotics were administered. The INR was 1.0. No pseudoaneurysm or arteriovenous fistula
formation was revealed with an ultrasound scan. Both dual antiplatelet therapy and warfarin use were
continued, and the patient was discharged after 5 days in the hospital without further complication.
The third patient was an 83-year-old man with coronary artery disease, chronic atrial fibrillation, and
chronic obstructive pulmonary disease who had an acute coronary syndrome at presentation. He
underwent successful balloon angioplasty and stenting of the distal circumflex coronary artery. He was
discharged receiving 81 mg of aspirin once a day, 75 mg of clopidogrel once a day, 100 mg of enoxaparin
twice a day, and his routine dose of 5 mg of warfarin once a day. The indication for warfarin was atrial
fibrillation. Approximately 2 weeks later, he came to the emergency department with gross hematuria. At
this time, he had an INR of 9.6. The warfarin use was discontinued, and vitamin K was administered;
aspirin and clopidogrel use was continued. Urolithiasis and a hemorrhagic renal cyst were diagnosed with
abdominal computed tomography. The hemoglobin concentration remained stable throughout the 2-day
hospital observation, and the patient was discharged receiving aspirin, clopidogrel, and warfarin, which
was restarted once the INR was within an acceptable range.
The fourth patient was a 62-year-old man with coronary artery disease and atrial fibrillation who had an
acute ST elevation inferior myocardial infarction at presentation. He underwent successful balloon
angioplasty and stenting of the distal right coronary artery. He was discharged receiving 325 mg of aspirin
once a day, 75 mg of clopidogrel once a day, and his routine dose of 5 mg of warfarin once a day. He
came to the emergency department 9 days later with melanotic stools and anemia. His hemoglobin level
was 11.2 gm/dL, and the prothrombin time was 36.5 seconds (INR = 3.7). Aspirin and warfarin use was
discontinued, and 2 units of fresh frozen plasma and vitamin K were administered. A duodenal ulcer was
identified with esophagogastroduodenoscopy and treated with a small-bore heater probe. He required 2
units of packed red blood cells, and the remainder of his hospitalization was unremarkable. He was
discharged receiving clopidogrel alone, with coumadin use to be reinitiated after completion of a 28-day
course of clopidogrel.
The fifth patient was a 75-year-old man with coronary artery disease and prior coronary artery bypass
graft surgery and aortic valve replacement, who was referred for elective angiography because of
refractory angina pectoris that was limiting his daily activities. He underwent angioplasty and stenting of
the proximal right coronary artery. He was discharged receiving 81 mg of aspirin once a day, 75 mg of

clopidogrel once a day, and 5 mg of warfarin once a day. He experienced a minor nose bleed that
resolved spontaneously without treatment. The use of clopidogrel was discontinued, but aspirin and
warfarin use was continued without further bleeding events.
The sixth patient was an 81-year-old woman with coronary artery disease, coronary artery bypass graft
surgery, and aortic valve replacement who was admitted to the hospital with pulmonary edema.
Diagnostic angiography was performed as part of a comprehensive cardiac evaluation, and angioplasty
and stenting of a large diagonal branch was performed. She was discharged receiving 81 mg of aspirin
once a day, 75 mg of clopidogrel once a day, and 5 mg of warfarin once a day. After she was discharged
from the hospital, she noted a bloody discharge from the ear; this resolved spontaneously. Warfarin use
was withheld for 2 days, and no further bleeding episodes were reported.
Discussion
Dual antiplatelet therapy with aspirin and ticlopidine has been rigorously compared with warfarin use in
patients after PCI and has been demonstrated to be superior to systemic anticoagulation.[2

5]

Clopidogrel

has now largely replaced ticlopidine because of its improved tolerability, more favorable adverse-effect
profile, and more rapid onset of action.[6,7]However, a number of patients have indications for both dual
antiplatelet therapy (aspirin and clopidogrel) and systemic anticoagulation (warfarin).
This observational study of 65 patients who were treated with aspirin, a thienopyridine (ticlopidine or
clopidogrel), and warfarin identified 6 patients who required medical attention for bleeding events after
PCI (9.2%; 95% CI, 3.5 19.0). Two of the bleeding episodes (patients 5 and 6) were of minimal clinical
significance and resolved spontaneously, requiring no additional clinical investigation or therapeutic
intervention except the withdrawal of the offending agents (warfarin and clopidogrel, respectively). The
bleeding event reported by patient 2 was, strictly speaking, a complication of aspirin, clopidogrel, and
enoxaparin administration (INR = 1.0). However, this event is included because it represents a
complication of the strategy of dual antiplatelet therapy and systemic anticoagulation.
Although the confidence intervals around this point estimate are wide, these data suggest that the risk of
bleeding during treatment with aspirin, clopidogrel, and warfarin may be higher than the low bleeding
rates seen in studies in which aspirin and a thienopyridine (1.8%) or aspirin and coumadin (6.5%) were
administered after stent placement, although different definitions of bleeding events were applied.[2

5]

The

case histories aforementioned highlight the importance of careful attention to the monitoring of the INR
and strict adherence to recommended levels of systemic anticoagulation. It is quite possible that the
bleeding events in patients 1 and 3 would not have occurred if the recommended level of anticoagulation
had been maintained. Further study of larger numbers of patients is needed to identify more precisely the
true risk of bleeding when all 3 drugs are administered, but significant and careful consideration should be
given to the indications for this potentially morbid combination of drugs and the respective risk-benefit
ratios. No clinical episodes of stent thrombosis were identified.

In patients who receive a coronary stent and have an indication for warfarin, there are several treatment
options. One can withhold a thienopyridine; in patients who are generally at low risk, such as the patients
enrolled in the randomized trials, withholding a thienopyridine would be expected to increase the risk of
death or myocardial infarction by at least 50% at 30 days, from approximately 1.5% to 2.5%.[2

5]

One

can withhold aspirin and administer a thienopyridine and warfarin; aspirin may cause more bleeding than
clopidogrel, although it is a weaker agent, because of aspirin's local effect on the stomach, but there are
no randomized controlled clinical trial data comparing this approach with aspirin and warfarin or with dual
[8]

antiplatelet therapy and warfarin. One might recommend aspirin, clopidogrel, and subcutaneous
injections of a low-molecular weight heparin for 2 to 4 weeks before reinitiating coumadin. This
combination (aspirin, clopidogrel, and enoxaparin) was associated with a trend toward an increase in the
risk of major bleeding (3.3% for enoxaparin, 1.6% for placebo, P = .08) in the Antiplatelet Therapy versus
Lovenox Plus Antiplatelet Therapy for Patients with an Increased Risk of Stent Thrombosis (ATLAST)
trial, in which enoxaparin was administered in an attempt to reduce the risk of stent thrombosis in patients
at high risk, but minor nuisance bleeding was significantly increased with enoxaparin (25% vs
5.1%, P <.001).[9] However, little is known about the safety or efficacy of low-molecular weight heparin
when it replaces warfarin for the conditions in which warfarin is commonly used. Other researchers have
proposed a discharge drug regimen that includes aspirin, clopidogrel, and low-dose enoxaparin (0.5
mg/kg) with a slow titration of warfarin (2 4 weeks) for most indications, including apical aneurysm, atrial
fibrillation, and valve prosthesis, but this strategy also remains unproven. A final option might be the
routine administration of low-dose aspirin (<100 mg) and regular dose clopidogrel (300 mg loading dose
and 75 mg/day) when there is an indication for warfarin therapy. The Clopidogrel in Unstable Angina to
Prevent Recurrent Events (CURE) investigators reported a lower incidence of major or life-threatening
bleeding with low-dose aspirin and clopidogrel when compared with high-dose aspirin (>200 mg) and
[10]

clopidogrel (2.55% vs 4.86%).

Because the risk of stent thrombosis is highest in the 2 weeks after stent placement and is less frequent
thereafter, it seems reasonable to recommend the discontinuation of either aspirin or clopidogrel 2 weeks
after stent placement and continuting treatment with a single antiplatelet agent thereafter in patients who
require systemic anticoagulation with warfarin.[11] This study is the first that we are aware of to track the
frequency of bleeding complications in patients treated with aspirin, clopidogrel, and warfarin, and these
results suggest that, as one would expect, the frequency of bleeding might be greater than has been
reported with aspirin and clopidogrel therapy alone or therapy with aspirin and warfarin.
This is a retrospective study, with all the limitations inherent to this methodology. The sample size is
small, and the 95% CIs are wide. However, because it is the first study to address this issue, we hope
that it will spur other researchers to analyze their data so more can be learned about the most appropriate
therapy to administer in this frequently encountered clinical situation. Another limitation of this study is 1
patient being lost to follow-up. This patient died of catastrophic trauma after the 30-day study period. We

were unable to ascertain with certainty whether he had sustained any bleeding event during the study
period, and therefore we elected to regard his data as incomplete (lost to follow-up).
We identified 6 of 65 patients (9.2%; 95% CI, 3.5 19.0) who required medical attention for bleeding
events while receiving dual antiplatelet therapy and warfarin after coronary stent placement. The risk of
bleeding may be increased in patients treated with aspirin, a thienopyridine, and warfarin early after PCI
with stent placement. Careful attention to monitoring of the INR and strict adherence to recommended
levels of systemic anticoagulation is important.

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2.

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Batchelor WB, Mahaffey KW, Berger PB, et al. A randomized, placebo-controlled trial of enoxaparin after high-risk
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