- Email: [email protected]
Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation
Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation James L. Orford, MBChB, MPH,a Panayotis Fasseas, MD,a Steven Melby, RN,a Kelli Burger, BSc,a Steven R. Steinhubl, MD,b David R. Holmes, MD,a and Peter B. Berger, MDa Rochester, Minn, and San Antonio, Tex
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, 3.5–19.0) reported a bleeding event; 2 patients required a blood transfusion. No patient died or sustained a 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. (Am Heart J 2004;147:463–7.)
See related Editorial on page 395.
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 inci-
From the aDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn, and b Division of Cardiovascular Diseases, Wilford Hall Medical Center, San Antonio, Tex. Conflict of interest financial disclosure: Dr Berger has received grant support from, and served on a Scientific Advisory Board for, Sanofi Synthelabo and Bristol-Myers Squibb, who make and co-market clopidogrel. Submitted July 9, 2002; accepted June 13, 2003. Reprint requests: Peter Berger, MD, FACC, Division of Cardiovascular Diseases, Mayo Clinic, W16, 200 First St SW, Rochester, MN 55905. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.06.004
dence 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 Patient population 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
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or when the patient refused permission for their records to be used for research (as required by Minnesota state law).
Table I. Baseline characteristics of the study population
Male Age Weight (kg) Unstable angina Acute MI ⬍12 h Thrombolysis within 24 hours Max sheath size 5 6 7 8 9 Femoral sheath Radial sheath Brachial sheath Femoral venous sheath Glycoprotein IIb/IIIa use Stent placement Sheath dwell time (hours) Intra-aortic balloon pump Periprocedural complications Sheath-related hematoma (ⱖ5 cm) Bleeding requiring compression Thrombotic occlusion Pseudoaneurysm AV fistula Retroperitoneal hematoma Hematemesis/melena Intracranial hemorrhage Other bleeding Transfusion Groin complication Other
Bleed (n ⴝ 6)
No Bleed (n ⴝ 59)
5 (83) 75 ⫾ 7 92 ⫾ 15 3 (50) 0 (0) 0 (0)
37 (63) 73 ⫾ 10 84 ⫾ 18 15 (25) 8 (14) 2 (3)
1 (17) 4 (67) 0 (0) 1 (17) 0 (0) 5 (83) 1 (17) 0 (0) 0 (0) 3 (50) 6 (100) 5.0 ⫾ 2.5 0 (0)
6 (10) 42 (71) 5 (8) 5 (8) 1 (2) 52 (88) 8 (14) 2 (3) 2 (3) 28 (47) 58 (98) 7.4 ⫾ 7.4 2 (3)
.56 1.00 1.00 1.00 1.00 1.00 .44 1.00
1 (17) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
4 (7) 2 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (5)
.39 1.00 – – – – – – 1.00
0 (0) 0 (0)
1 (2) 0 (0)
1.00 –
P .41 .66 .28 .34 1.00 1.00 .97
MI, Myocardial infarction; IIb/IIIa, glycoprotein IIb/IIIa receptor inhibitor.
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 post-PCI 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.
Inclusion and exclusion criteria 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,
Definitions 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 kinase-myocardial 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 ⱖ20% 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.
Statistical analysis 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 Study population 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%).
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Bleeding events
Patient 2
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.
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 moderatesized 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.
Stent thrombosis 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.
Patient 1 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.
Patient 3 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.
Patient 4 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.
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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 smallbore 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.
Patient 5 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.
Patient 6 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 anti-
platelet 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.
Treatment options 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 ⱖ2.5%.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 antiplatelet therapy and warfarin.8 One might recommend
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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 clopidogrel (2.55% vs 4.86%).10 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.
Limitations 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
Orford et al 467
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).
Conclusions 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.
References 1. Popma JJ, Ohman EM, Weitz J, et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention. Chest 2001;119:321–36S. 2. Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial After Intracoronary Stenting (MATTIS). Circulation 1998;98:2126 –32. 3. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084 –9. 4. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–71. 5. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The Full Anticoagulation versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation 1998;98:1597– 603. 6. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002;39:9 –14. 7. Berger PB. Results of the Ticlid or Plavix Post-Stents (TOPPS) trial: do they justify the switch from ticlopidine to clopidogrel after coronary stent placement? Curr Control Trials Cardiovasc Med 2000;1: 83–7. 8. CAPRIE Steering Committee. A randomised, blinded, trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996;348:1329 –39. 9. Batchelor WB, Mahaffey KW, Berger PB, et al. A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: the ATLAST trial. J Am Coll Cardiol 2001;38:1608 –13. 10. Plavix (clopidogrel bisulfate tablets) product insert. Princeton, NJ: Bristol-Myers Squibb Company; 2002. 11. Berger PB, Bell MR, Hasdai D, et al. Safety and efficacy of ticlopidine for only 2 weeks after successful intracoronary stent placement. Circulation 1999;99:248 –53.
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, 3.5–19.0) reported a bleeding event; 2 patients required a blood transfusion. No patient died or sustained a 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. (Am Heart J 2004;147:463–7.)
See related Editorial on page 395.
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 inci-
From the aDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn, and b Division of Cardiovascular Diseases, Wilford Hall Medical Center, San Antonio, Tex. Conflict of interest financial disclosure: Dr Berger has received grant support from, and served on a Scientific Advisory Board for, Sanofi Synthelabo and Bristol-Myers Squibb, who make and co-market clopidogrel. Submitted July 9, 2002; accepted June 13, 2003. Reprint requests: Peter Berger, MD, FACC, Division of Cardiovascular Diseases, Mayo Clinic, W16, 200 First St SW, Rochester, MN 55905. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.06.004
dence 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 Patient population 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
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or when the patient refused permission for their records to be used for research (as required by Minnesota state law).
Table I. Baseline characteristics of the study population
Male Age Weight (kg) Unstable angina Acute MI ⬍12 h Thrombolysis within 24 hours Max sheath size 5 6 7 8 9 Femoral sheath Radial sheath Brachial sheath Femoral venous sheath Glycoprotein IIb/IIIa use Stent placement Sheath dwell time (hours) Intra-aortic balloon pump Periprocedural complications Sheath-related hematoma (ⱖ5 cm) Bleeding requiring compression Thrombotic occlusion Pseudoaneurysm AV fistula Retroperitoneal hematoma Hematemesis/melena Intracranial hemorrhage Other bleeding Transfusion Groin complication Other
Bleed (n ⴝ 6)
No Bleed (n ⴝ 59)
5 (83) 75 ⫾ 7 92 ⫾ 15 3 (50) 0 (0) 0 (0)
37 (63) 73 ⫾ 10 84 ⫾ 18 15 (25) 8 (14) 2 (3)
1 (17) 4 (67) 0 (0) 1 (17) 0 (0) 5 (83) 1 (17) 0 (0) 0 (0) 3 (50) 6 (100) 5.0 ⫾ 2.5 0 (0)
6 (10) 42 (71) 5 (8) 5 (8) 1 (2) 52 (88) 8 (14) 2 (3) 2 (3) 28 (47) 58 (98) 7.4 ⫾ 7.4 2 (3)
.56 1.00 1.00 1.00 1.00 1.00 .44 1.00
1 (17) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
4 (7) 2 (3) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (5)
.39 1.00 – – – – – – 1.00
0 (0) 0 (0)
1 (2) 0 (0)
1.00 –
P .41 .66 .28 .34 1.00 1.00 .97
MI, Myocardial infarction; IIb/IIIa, glycoprotein IIb/IIIa receptor inhibitor.
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 post-PCI 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.
Inclusion and exclusion criteria 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,
Definitions 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 kinase-myocardial 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 ⱖ20% 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.
Statistical analysis 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 Study population 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%).
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Bleeding events
Patient 2
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.
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 moderatesized 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.
Stent thrombosis 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.
Patient 1 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.
Patient 3 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.
Patient 4 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.
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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 smallbore 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.
Patient 5 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.
Patient 6 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 anti-
platelet 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.
Treatment options 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 ⱖ2.5%.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 antiplatelet therapy and warfarin.8 One might recommend
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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 clopidogrel (2.55% vs 4.86%).10 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.
Limitations 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
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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).
Conclusions 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.
References 1. Popma JJ, Ohman EM, Weitz J, et al. Antithrombotic therapy in patients undergoing percutaneous coronary intervention. Chest 2001;119:321–36S. 2. Urban P, Macaya C, Rupprecht HJ, et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial After Intracoronary Stenting (MATTIS). Circulation 1998;98:2126 –32. 3. Schomig A, Neumann FJ, Kastrati A, et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:1084 –9. 4. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998;339:1665–71. 5. Bertrand ME, Legrand V, Boland J, et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The Full Anticoagulation versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation 1998;98:1597– 603. 6. Bhatt DL, Bertrand ME, Berger PB, et al. Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting. J Am Coll Cardiol 2002;39:9 –14. 7. Berger PB. Results of the Ticlid or Plavix Post-Stents (TOPPS) trial: do they justify the switch from ticlopidine to clopidogrel after coronary stent placement? Curr Control Trials Cardiovasc Med 2000;1: 83–7. 8. CAPRIE Steering Committee. A randomised, blinded, trial of Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996;348:1329 –39. 9. Batchelor WB, Mahaffey KW, Berger PB, et al. A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: the ATLAST trial. J Am Coll Cardiol 2001;38:1608 –13. 10. Plavix (clopidogrel bisulfate tablets) product insert. Princeton, NJ: Bristol-Myers Squibb Company; 2002. 11. Berger PB, Bell MR, Hasdai D, et al. Safety and efficacy of ticlopidine for only 2 weeks after successful intracoronary stent placement. Circulation 1999;99:248 –53.