Combination Therapy with Aspirin, Clopidogrel and Warfarin Following Coronary Stenting is Associated with a Significant Risk of

Dual antiplatelet therapy of aspirin and a thienopyridine has been established as the standard of care in patients undergoing coronary stent implantation.^1–4 Those patients who require chronic anticoagulation for prosthetic cardiac valves, atrial fibrillation, venous or systemic thromboembolism will need warfarin therapy as well as dual antiplatelet therapy following coronary stenting. However, the bleeding risk of this triple therapy is unknown. In the era of drug-eluting stents, which necessitate a longer duration of dual antiplatelet therapy,⁵ this unresolved issue is especially important. Thus, we retrospectively studied the bleeding risk of patients requiring triple therapy and compared it with that of patients receiving dual antiplatelet therapy following coronary stenting. Methods Study Population. We performed a retrospective study of 107 consecutive patients on chronic warfarin therapy, who underwent stent implantation at our institution and were discharged on aspirin, clopidogrel and warfarin (triple therapy group) to a contemporary cohort of 107 randomly selected patients who were treated with dual antiplatelet therapy after stent implantation (dual therapy). The indications for warfarin therapy were chronic atrial fibrillation in approximately 80%, prophylactic anticoagulation to prevent left ventricular thrombus after a large anterior myocardial infarction in 13%, prosthetic valve in 5%, pulmonary embolism in 2%, and lost fractured guidewire in the coronary artery in 1 patient. A 300 mg loading dose of clopidogrel was given at the time of stent implantation, followed by a 75 mg daily dose for at least 1 year for all patients if they could tolerate it. Warfarin was usually started at the maintenance dose the day after the stent procedure without a loading dose. We evaluated their baseline bleeding history before and following coronary stenting. The bleeding histories were obtained by interviews with patients and their referring cardiologists. Any bleeding episode was confirmed by source documentation, usually from hospitalization records. Clinical follow up was performed by the research staff and was available for all patients. This study was approved by our Institutional Review Board and all patients provided written informed consent. Definitions. Major bleeding was defined as bleeding that was significantly disabling, intraocular or required greater than 2 units of blood transfusion.⁶ Minor bleeding was defined as other bleeding that led to an interruption of the antiplatelet or anticoagulant medication.⁶Statistical analysis. SPSS version 10.1 software was used for statistical analysis. Continuous variables are reported as the mean value ± standard deviation. The Student’s t-test was used to compare the differences between mean values. Categorical variables are presented as percentages and compared using the Fisher’s Exact test. Multivariate binary logistic regression was performed to determine the independent effect of triple therapy on bleeding complications. All variables from Table 1 were entered stepwise into the model. All probability tests are two-tailed. Probability values Results Baseline demographics. The baseline demographics of both groups are listed in Table 1. Patients on triple therapy were younger (average age 69 ± 11 vs. 72 ± 6; p Bleeding complications. The mean duration of follow up was 211 ± 114 days in the triple therapy group, and 250 ± 137 days in the dual antiplatelet group. Following stenting, patients on triple therapy had more major (6.6% vs. 0.0%; p = 0.014) and minor bleeding (14.9% vs. 3.8; p = 0.01) as compared to patients on dual antiplatelet therapy alone. After adjusting for confounding variables using multivariate analysis, triple therapy (versus dual therapy) was found to be an independent predictor of bleeding (hazard ratio = 5.44; p = 0.001; CI = 2.03, 14.53). Among patients on triple therapy, clopidogrel was discontinued prematurely in 8%, while coumadin was stopped in 6% due to bleeding. Among patients on triple therapy, mean international normalized ratio levels were not different between patients with or without major bleeding (2.3 ± 1.1 vs. 2.6 ± 1.4; p = ns), or between patients with or without minor bleeding (2.9 ± 1.5 vs. 2.6 ± 1.4; p = ns). Additionally, there was no difference in the frequency of major or minor bleeding with respect to 81 mg vs. 325 mg aspirin dosing in patients on chronic warfarin therapy. Details on 7 patients with major bleeding are listed in Table 2. It is interesting to note that none of the major bleeding episodes occurred within the first 30 days, the usual period of dual antiplatelet therapy for bare metal stents. There was 1 fatal death from intracranial hemorrhage which occurred in a patient with a prior history of major bleeding (intracranial hemorrhage on warfarin therapy alone). Of the other 6 cases, there were 2 patients with gastrointestinal bleeding requiring more than a 4-unit transfusion, and 4 patients with nose bleeding requiring either surgical cauterization and/or significant blood transfusion. No patient on the dual therapy experienced major bleeding. Among patients on triple therapy who experienced minor bleeding, 2 were gastrointestinal-related, 13 were mucosal and 1 was genitourinary. In the dual therapy group, all bleeding episodes were minor (mucosal, gastrointestinal or genitourinary). Discussion This study shows that warfarin, aspirin and clopidogrel therapy following coronary stenting results in a significantly increased bleeding risk compared with dual antiplatelet therapy. Whether any modification of this traditional triple therapy would result in similar efficacy, but improved safety, needs further studies. Previous studies of anticoagulation and concomitant antiplatelet therapy. Orford et al.⁷ performed a retrospective study of 65 patients requiring triple therapy. They found a 9.2% incidence of bleeding events, with 3.1% major bleeding episodes. Treatment consisted mainly of stopping either warfarin or antiplatelet therapy. Rubboli et al.⁸ performed an international survey of the various antithrombotic regimens following stent implantation in patients requiring chronic anticoagulation therapy. They found a wide spectrum of different regimens ranging from the triple therapy to dual antiplatelet therapy to any permutations in-between, including the addition of one antiplatelet agent to coumadin or replacement of warfarin with low-molecular weight heparin. This study did not report on clinical consequences, such as the bleeding or stent thrombosis rates. The randomized trials to evaluate the optimal post-stent regimen^1–4 consistently reported that the dual antiplatelet therapy resulted in reduced stent thrombosis and adverse cardiac events, as well as reduced bleeding risk compared with warfarin and aspirin therapy. Studies of anticoagulation and concomitant antiplatelet therapy in patients with prosthetic heart valves⁹ suggest that antiplatelet therapy does increase the bleeding risk, with a lower dosage of aspirin resulting in less bleeding while providing benefit regarding systemic embolism or mortality. Buresly et al.¹⁰ studied elderly (> 65 years) Canadian patients, who were admitted to Québec hospitals with acute myocardial infarction and whose prescription medications, including aspirin, warfarin and either ticlopidine or clopidogrel, were available from another database. They found the overall risk of bleeding to be “small” in this population, although the addition of warfarin or thienopyridine to aspirin significantly increased the bleeding risk compared with aspirin alone. Clinical implication. The issue of triple therapy and its bleeding complication are especially topical, with the widespread use of drug-eluting stents and the need for prolonged antiplatelet therapy.⁵ Iakovou et al.⁵ showed that the “premature” discontinuation of antiplatelet therapy was the strongest predictor of stent thrombosis in patients receiving drug-eluting stents. In addition, stent thrombosis was associated with 45% mortality and nonfatal myocardial infarction in the remaining patients. Thus, faced with the decision regarding the anticoagulant and antiplatelet therapy, the practical approach would be to prevent stent thrombosis foremost and then to try to minimize bleeding complications. There are only certain variables that we can control regarding this balance to prevent bleeding complications while ensuring stent patency. The most important variable is the optimal stent implantation guided by intravascular ultrasound to minimize the risk of stent thrombosis attributable to the suboptimal stent deployment. In addition, other variables include: 1) types of drugs; 2) dosages of drugs; and 3) duration of therapy. Regarding the patients requiring chronic warfarin therapy, the physician providing the long-term care of the patient must decide whether warfarin could be withheld during the dual antiplatelet therapy period, especially if the patient has a history of bleeding complication on warfarin therapy alone. It is unclear if low-molecular weight heparin could replace warfarin during the antiplatelet therapy, but the bleeding risk of aspirin, clopidogrel and enoxaparin is higher compared with the dual antiplatelet therapy.¹¹ Furthermore, since multiple studies demonstrated the benefit of dual antiplatelet therapy over aspirin or aspirin/warfarin combination,^1–4 it would be difficult to withhold the dual antiplatelet therapy. It is untested whether clopidogrel alone could be an effective antiplatelet agent against stent thrombosis. Although novel antiplatelet agents, such as triflusal,¹² may reduce bleeding risk while ensuring equivalent antiplatelet efficacy compared with aspirin, this agent has not been tested in stent patients. On the other hand, dosages of drugs can be more easily controlled. For the dual antiplatelet therapy, the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial showed that the risk of bleeding could be minimized with low-dose aspirin.⁶ Thus, it would be important to minimize the aspirin dose. However, the fact that in our retrospective study, there were no correlations between the aspirin dosage or anticoagulation intensity and bleeding risk is disconcerting. Further studies are needed to confirm this alarming finding. Also, the major bleeding episodes occurred between 2 and 10 months, suggesting that shorter-term solutions, such as a different regimen within 30 days after stent implantation may not completely address the issue. Since longer duration of triple therapy, especially with drug-eluting stents, could increase the bleeding risk, it is possible that those patients with a documented bleeding history on warfarin therapy alone or at high risk for bleeding may need to get bare metal stents to reduce the duration of triple therapy and bleeding risk. None of the patients with major bleeding experienced this complication within 30 days of stenting. Another strategy would be the implantation of stents with a reduced thrombosis risk. Recently, stents with antibody coating for CD34 to capture circulating endothelial progenitor cells have been shown to facilitate rapid re-endothelialization.¹³Study limitations. The main limitation of the study is the retrospective nature. Thus, we cannot capture the strategies following stent implantation in those previously on warfarin therapy. There was no uniform pattern regarding the aspirin dosage or the international normalized ratio level. The comparison group was randomly selected from a contemporary cohort, but there were differences between the groups, such as different ages and hypertension prevalence. These differences pose a limitation in drawing conclusions about the potential bleeding risks. Finally, the lack of correlation of aspirin dosage or anticoagulation intensity with bleeding rates could have been due to the small sample size. Conclusions This study suggests that following stent implantation, the combination therapy of warfarin, aspirin and clopidogrel results in significantly increased bleeding risk compared with dual antiplatelet therapy alone. It is important to prospectively evaluate alternative regimens to reduce the bleeding risk while ensuring long-term stent patency.

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