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THERAPEUTIC CONTROVERSIES

Aspirin, Clopidogrel, and Warfarin: Is the Combination Appropriate and Effective or Inappropriate and Too Dangerous?

Pharmacy Practice Resident, Instructor in Clinical Pharmacy, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, Philadelphia, PA

Sarah A Spinler, PharmD FCCP BCPS (AQ Cardiology)

Professor of Clinical Pharmacy, Residency and Fellowship Program Coordinator, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia

Reprints: Dr. Spinler, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 S. 43rd St., Philadelphia, PA 19104, fax 215/596-8586, s.spinler{at}usp.edu

	Abstract

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OBJECTIVE: To review the rationale, clinical practice guideline recommendations, and clinical trial data describing bleeding and clinical outcomes associated with the use of the combination of aspirin, a thienopyridine, and warfarin.

DATA SOURCES: An English-language literature search was conducted using MEDLINE (1966–March 2008) and the search terms aspirin, clopidogrel, ticlopidine, thienopyridine, warfarin, antiplatelet, anticoagulant, myocardial infarction, atrial fibrillation, and percutaneous coronary intervention (PCI). Additional references were identified by reviewing reference citations of articles retrieved.

STUDY SELECTION AND DATA EXTRACTION: Applicable data were extracted from published reports and studies that included either clinical outcomes or adverse events.

DATA SYNTHESIS: Clinical guidelines recommend the combination of antiplatelets and anticoagulants based largely on writing committee consensus. To date, only one randomized clinical trial has evaluated the safety and efficacy of adding warfarin to dual antiplatelet therapy (ie, triple antithrombotic therapy). Other published data are from case series, observational studies, and case-controlled studies primarily of patients undergoing PCI with intracoronary stent placement. Four of 12 studies reported no increased risk of major bleeding events. In the other 8 studies, a 3- to 6-fold increase in bleeding events was reported with triple antithrombotic therapy. Ischemic events were reported in only 6 of the studies. Only 2 studies observed an additional benefit in the reduction of ischemic events, and 1 study reported worsened ischemic outcomes with the triple antithrombotic regimen compared with dual antithrombotic therapy.

CONCLUSIONS: Available guidelines pertaining to the concomitant administration of aspirin, a thienopyridine, and warfarin are based on limited trial data and consensus judgment. Overall, selection of triple antithrombotic therapy for patients with vascular disease is considered a matter of clinical judgment for an individual patient based on the prescriber's perceived balance between the patient's risk for recurrent ischemic events, expected duration of treatment, and patient's risk for bleeding.

Key Words: acute coronary syndrome, anticoagulation, antiplatelet, aspirin, clopidogrel, percutaneous coronary intervention, warfarin

Published Online, May 13, 2008. www.theannals.com, DOI 10.1345/aph.1K591

	Rationale for Dual Antiplatelet Therapy: Aspirin plus a Thienopyridine

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Aspirin and thienopyridines inhibit platelet aggregation in different manners and thereby may exert a complementary effect in prevention of vascular ischemic events. Dual antiplatelet therapy with aspirin and clopidogrel has been proven to be beneficial in patients with either non–ST-segment elevation (NSTE) ACS,⁴ ST-segment elevation MI (STEMI),⁵ and in patients undergoing PCI.^6,7 Evidence for an increased risk of major bleeding with combined use of aspirin and clopidogrel has been noted in the CURE trial.⁴ In CURE, the rate of major bleeding in patients with NSTE ACS taking clopidogrel plus aspirin for up to a year was 3.7% compared with 2.7% in patients taking aspirin alone (RR 1.4 [95% CI 1.1 to 1.7]). In contrast, no increased risk of major bleeding was found in COMMIT,⁵ the CREDO study,⁷ and the CHARISMA study.⁸ In COMMIT, clopidogrel plus aspirin administered for a mean of about 15 days in patients with STEMI showed no increased risk of major bleeding (0.58% vs 0.55%; p = 0.59).⁵ In the CREDO study, major bleeding rates did not differ significantly between monotherapy with aspirin and the combination of aspirin and clopidogrel after 9–12 months following PCI (8.8% vs 6.7%; p = 0.07).⁷ In CHARISMA, long-term administration of clopidogrel plus aspirin for a median of 28 months in patients with atherosclerotic vascular disease showed no significant increase in severe bleeding (1.7% vs 1.3%, RR 1.25 [95% CI 0.97 to 1.61]).⁸ Overall, current data support the administration of dual antithrombotic therapy in ACS and PCI.

Aspirin plus clopidogrel treatment has not been found to be beneficial in patients with recent ischemic stroke or atrial fibrillation.^9,10 In the MATCH trial, a nonsignificant reduction in major vascular events was observed when clopidogrel was added to aspirin (15.7%) versus clopidogrel alone (16.7%), with absolute risk reduction of 1% (95% CI –0.6 to 2.7) in patients with ischemic stroke or transient ischemic attack.⁹ Conversely, the risk of major bleeding was increased in the dual antiplatelet group versus clopidogrel alone when administered for a mean of 18 months (2% vs 1%; p < 0.0001, respectively). In the ACTIVE-W trial, the combination of aspirin 75–100 mg daily plus clopidogrel 75 mg daily demonstrated inferiority against warfarin (target international normalized ratio [INR] 2.0–3.0) for stroke prevention in patients with atrial fibrillation and one or more risk factors for stroke.¹⁰ The study was stopped on the recommendation of the Data Safety and Monitoring Board before the planned follow-up was completed because of the clear evidence of superiority of oral anticoagulation. A significant reduction in the number of a first occurrence of stroke, non–central nervous system systemic embolus, MI, or vascular death with warfarin compared with dual antiplatelet therapy was observed (annual risk 3.93% vs 5.60%, respectively; RR 1.44 [95% CI 1.18 to 1.76]). However, the risk of major hemorrhage was not significantly different between the groups (aspirin plus clopidogrel 2.42% vs warfarin 2.21%; RR 1.10 [95% CI 0.83 to 1.5]). Warfarin demonstrated superiority to dual antiplatelet therapy in clinical outcomes without an increased risk of major bleeding.

	Clinical Practice Guidelines: Dual Antiplatelet Therapy

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Practice guideline recommendations from the American College of Cardiology (ACC) and the American Heart Association (AHA) for using dual antiplatelet therapy with aspirin and clopidogrel in patients with NSTE ACS, STEMI, and PCI are shown in Table 1.^11-17 The ACC/AHA recommend clopidogrel for prevention of recurrent myocardial ischemic events and stroke in patients with NSTE ACS or STEMI and in those undergoing elective PCI or PCI in the setting of NSTE ACS or STEMI.^11,12,14 In patients not undergoing intracoronary stenting, treatment with clopidogrel should be given for at least 2 weeks for patients with STEMI¹² and up to 1 year in patients with NSTE ACS.¹⁴ In patients undergoing elective PCI or PCI in the setting of ACS, the duration of clopidogrel treatment should be at least 30 days in patients receiving a bare metal intracoronary stent (ideally 1 y) and for at least 12 months in patients receiving a drug-eluting intracoronary stent if the patient is not at high risk of bleeding.¹¹ For patients at high risk of bleeding, clopidogrel should be administered for a minimum of 2 weeks.¹¹

	Rationale for Combining Antiplatelets and Anticoagulants

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Warfarin monotherapy has been proven beneficial for stroke prevention in patients with valvular heart disease, atrial fibrillation, atrial flutter, and patients with reduced left-ventricular function or left-ventricular thrombus following MI.^11-17 Current recommendations, dosing, and duration for combining warfarin and antiplatelet therapy are included in Table 1.

Oral anticoagulants are routinely indicated as monotherapy for prophylaxis and/or treatment of venous thromboembolism and stroke prevention in atrial fibrillation or in patients with mechanical or certain bioprosthetic heart valves.^15,16 Warfarin, in combination with low-dose aspirin, has also been proven beneficial in patients with ACS. The WARIS II trial showed a reduction in death, nonfatal reinfarction, or thromboembolic stroke in patients receiving aspirin 75 mg daily plus warfarin (target INR 2–2.5) compared with aspirin 160 mg daily alone (15% vs 20%; p = 0.001).¹⁸ The APRICOT II trial (aspirin 80 mg daily and median INR 2.6; target INR 2.0–3.0) demonstrated a significant reduction in coronary artery reocclusions, defined as the presence of Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow or less at angiographic follow-up (28% aspirin alone vs 15% dual antithrombotic therapy; p < 0.02), revascularization (31% vs 13%, respectively; p < 0.01), reinfarction (8% vs 2%, respectively; p < 0.05), and event-free survival rate (65% vs 86%, respectively; p < 0.01) at 3 months following STEMI.¹⁹ In the ASPECT-2 open-label trial, moderate-intensity (INR 2.0–2.5) oral anticoagulation in combination with low-dose aspirin was compared with either a low dose of aspirin (80 mg daily) alone or high-intensity (INR 3.0–4.0) oral anticoagulation.²⁰ Results indicated a reduction in the composite endpoint of MI, stroke, or death for both warfarin monotherapy (HR 0.55 [95% CI 0.3 to 1.0]) and aspirin plus warfarin (HR 0.5 [95% CI 0.27 to 0.92]) compared with aspirin monotherapy. Major bleeding rates in all of these studies were higher in the warfarin plus aspirin-treated patients compared with aspirin alone.^18,19,21,22 While efficacious, the combination of aspirin plus warfarin is less commonly recommended, secondary to an increased risk of bleeding. A recent meta-analysis of the aforementioned studies found a higher incidence of major bleeding in patients receiving aspirin and warfarin compared with the incidence in patients receiving warfarin alone (OR 1.43 [95% CI 1.00 to 2.02]).²³

In patients with mechanical heart valves, the addition of antiplatelet therapy, with low-dose aspirin (75–100 mg daily), to warfarin anticoagulation has been found useful for stroke prevention. A meta-analysis of 5 randomized controlled trials was conducted to address the efficacy and safety of oral anticoagulation alone compared with oral anticoagulation plus antiplatelet therapy after prosthetic heart valve replacement.²⁴ The combined therapy decreased thromboembolism by 67% (OR 0.33 [95% CI 0.16 to 0.69]) and overall mortality by 40% (OR 0.60 [95% CI 0.32 to 1.12]). However, a significant increase in risk of hemorrhage was observed (OR 1.65 [95% CI 1.15 to 2.39]).

Warfarin added to aspirin is relatively ineffective in preventing stent thrombosis and other clinical events following PCI. In the Stent Anticoagulation Restenosis Study, aspirin plus ticlopidine was more effective than aspirin plus warfarin in reducing the risk of angiographically evident thrombosis (RR 0.20 [95% CI 0.07 to 0.61]) as well as the primary endpoint of death, stent thrombosis, target lesion revascularization, or MI (RR 0.20 [95% CI 0.07 to 0.61]).²⁵

	Clinical Practice Guidelines: Warfarin plus Antiplatelet Therapy

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Recommendations from contemporary clinical practice guidelines for ACS, PCI, atrial fibrillation, stroke, and valvular heart disease describing the indications for combining warfarin and antiplatelet agents are described in Table 1.^11-17 The current American Stroke Association guidelines for management of ischemic stroke list selected indications for combining aspirin and warfarin.²⁶ More recently, the addition of warfarin at a narrow INR range of 2.0–2.5 with low-dose aspirin and clopidogrel is recommended for older patients and for those with other risk factors for bleeding who also have a firm indication for anticoagulation (eg, atrial fibrillation, left-ventricular thrombus, cerebral embolism, venous embolism, or pulmonary embolism) in the 2007 ACC/AHA NSTE ACS guidelines,¹⁴ PCI guidelines,¹¹ and STEMI guidelines.¹² The lower INR target is recommended especially in geriatric patients as well as in patients with other risk factors for bleeding.

In patients with atrial fibrillation, the ACC/AHA guidelines from 2006 recommended aspirin alone for patients with no risk factors for stroke and warfarin alone for patients with any high-risk for stroke factor or more than one moderate-risk factor for stroke.¹³ When anticoagulated patients with chronic atrial fibrillation have an indication for antiplatelet therapy, ACC/AHA consensus recommendations for atrial fibrillation are to administer clopidogrel and warfarin, while omitting aspirin.¹⁵

The ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease recommend that the combination of aspirin (75–100 mg daily) and warfarin be considered in patients with prosthetic heart valves.¹⁶ For patients with a mechanical prosthetic valve, the recommendation is to add low-dose aspirin to warfarin therapy in patients who have experienced a thromboembolic event while receiving adequate warfarin anticoagulation. The risk of thromboembolism while taking warfarin is 1–2% per year. With the addition of aspirin to therapy with warfarin, a further 77% risk reduction in the risk of thromboembolism is achieved.^27,28 For patients who have a biological prosthetic valve and are at high risk for stroke, low-dose aspirin plus warfarin treatment for 3 months should be considered due to an increased risk of thromboemboli, especially when the valve is in the mitral position. Lastly, pregnant women with a mechanical prosthetic mitral valve should receive low-dose aspirin in their second and third trimesters plus either warfarin or heparin; several weeks prior to delivery, warfarin must be switched to heparin or a low-molecular-weight heparin.¹⁶ Therefore, the only current ACC/AHA recommendations for using triple antithrombotic therapy are for patients with either ACS or PCI with indications for chronic anticoagulant therapy and for patients with atrial fibrillation who require anticoagulation and also have an indication for clopidogrel plus aspirin.

	Clinical Studies Evaluating the Combination of Aspirin, Thienopyridines, and Anticoagulants

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A total of 12 studies (1 case–control, 2 case series, 8 retrospective cohorts, 1 randomized open-label) have been published describing outcomes in patients receiving dual antiplatelet therapy in combination with warfarin.^29-40 Study design, patient population, reasons for warfarin use, doses and duration of antithrombotic therapy, as well as ischemic and bleeding outcomes are described in Table 2. Logically, these studies have been performed most often in patients following ACS or PCI who have additional indications for chronic anticoagulation. Doses of aspirin used in the studies ranged from 81 mg/day to 325 mg/day, while the target INR varied by indication and was reported in only 2 of the studies.^35,36

Data from the Mayo Clinic PCI database were analyzed by Orford et al.²⁹ for all patients who were discharged between January 2000 and August 2002 following PCI. The incidence and characteristics of hemorrhagic complications were assessed in patients after a PCI with stent placement while receiving aspirin, clopidogrel, and warfarin. Sixty-six patients were included in the case series and followed for up to 12 months. Of the 6 patients who experienced a bleeding event, 2 required a blood transfusion, and 2 were determined to have minor bleeding events requiring no additional clinical or therapeutic intervention except discontinuation of offending agents. No events consistent with stent thrombosis were reported. The authors concluded that the risk of the triple antithrombotic therapy is associated with a high risk of bleeding in patients who have undergone PCI with stent placement; thus, careful monitoring of the INR is essential in this population. Some limitations of the study include small sample size, wide confidence intervals, and all limitations associated with a case series, but the findings are useful to encourage further study evaluations.

A case–control study evaluated the risk of hospitalization for bleeding in elderly patients who were receiving the combination of aspirin, a thienopyridine, and/or warfarin following hospitalization for an MI.³⁰ Using a national hospital database, all patients in Quebec, Canada, were included in the study if they were 65 years of age or older and admitted to the hospital with a diagnosis of MI between January 1996 and March 2000. Investigators followed patients after discharge monthly over a mean of 654 days. Random matching using 5 controls (not experiencing a bleeding event per case) to aspirin monotherapy group, warfarin monotherapy group, aspirin plus a thienopyridine group, aspirin plus warfarin group, and aspirin plus a thienopyridine and warfarin group was done based on duration of time since MI hospitalization. Controls included had no bleeding episodes, nor were they at risk of future bleeding episodes. The risk of bleeding associated with the 5 different regimens was assessed by calculating a per month crude incidence rate of bleeding. The crude incidence of events was 656 for 20,176 patient-years of exposure (incidence rate 0.032 [95% credible interval 0.030 to 0.035]) in the aspirin monotherapy group, 195 events per 3314 patient-years of exposure (incidence rate 0.059 [95% credible interval 0.050 to 0.067]) in the warfarin monotherapy group, 289 events per 3314 patient-years of exposure (incidence rate 0.068 [95% credible interval 0.042 to 0.102]) in the aspirin and thienopyridine group, 34 events per 407 patient-years of exposure (incidence rate 0.083 [95% credible interval 0.058 to 0.144]) for the aspirin and warfarin group, and 1 event per 12 patient-years of exposure (0.085) for the 3-drug combination group. Among the patients in the triple antithrombotic therapy group, only 1 patient out of 141 experienced a bleeding event; thus, the incidence rate ratio could not be obtained due to the small sample size.

These results suggest that, compared with taking aspirin alone, the crude incidence of bleeding complications was almost twice as high in patients receiving warfarin alone, in patients receiving aspirin plus warfarin, and in patients receiving aspirin plus a thienopyridine. As individual patients were involved in multiple crossovers between regimens, the study did not report the total number of patients in each treatment group or the length of treatment. Doses (with the exception of aspirin) were not addressed in this study, nor was the rate of stent thrombosis.³⁰

Mattichak et al.³¹ evaluated the safety of dual versus triple antithrombotic therapy in 82 patients undergoing primary PCI with intracoronary stent placement and continued for up to 12 months in a retrospective, single center study. After 6 and 12 months, the rates of reinfarction, death, stroke, and gastrointestinal bleeding were not significantly different between the 2 groups. However, there was a significantly greater incidence of blood transfusions reported in the triple antithrombotic group after 12 months. Overall, triple antithrombotic therapy with the addition of warfarin to dual antiplatelet therapy did not reduce the risk of reinfarction in patients undergoing primary PCI and did increase the risk for transfusion.

Analyses of the incidence, baseline characteristics, and outcomes of patients with ACS receiving triple antithrombotic therapy versus dual antithrombotic therapy were conducted.³² This retrospective cohort study was performed in Israel from 2000 through 2004 and included 3 nationwide surveys, each over 2 months. A total of 5706 patients were discharged following ACS, with 1.3% on triple (aspirin, a thienopyridine, warfarin) and 46.7% on dual (aspirin, a thienopyridine) antithrombotic therapy. A logistic regression model was used to adjust for age, sex, history of CAD, congestive heart failure, past renal failure, primary PCI, and logarithmic transformation of creatine kinase to determine whether triple antithrombotic therapy was an independent predictor of 30-day and 6-month mortality. Interestingly, a trend toward a higher incidence of revascularization by PCI during the 30-day follow-up was noted in the dual antithrombotic therapy group compared with the triple antithrombotic therapy group. Complications during initial hospitalization (eg, heart failure, tachyarrhythmias, reinfarctions) occurred significantly more often in the triple antithrombotic therapy group compared with the dual antithrombotic therapy group. Also, the incidence of in-hospital major bleeding was 4-fold higher in the triple antithrombotic therapy group. When mortality was adjusted for different confounders, there was no significant difference in mortality between the 2 groups at 30 days or 6 months. However, there was no mention of actual numbers or percentage of events or study power to detect such events. Bleeding outcomes were not reported during follow-up. The authors concluded that triple antithrombotic therapy in high-risk ACS patients seems to be a reasonable option among those who require concomitant warfarin treatment. Unfortunately, there was no information on the doses, duration of treatments, nor type of bleeding complications in-hospital or out of hospital.

A case series by Porter et al.³³ evaluated triple antithrombotic therapy and its effects on long-term prognosis and incidence of bleeding complications in patients undergoing PCI with intracoronary stent placement (type not specified). Patients were retrospectively analyzed during 2000 through 2004. Patients were included if they were chronically treated with aspirin, ticlopidine or clopidogrel, plus warfarin dosed to a target INR based on indication. Eleven percent of patients developed bleeding complications (mean INR in pts. who bled was 2.1 at 7 days post-PCI). One had a major groin hematoma, and 18 had minor bleeding complications. The median survival rate was 89.4% after a median of 476 days of follow-up, with a median mortality interval of 60 days. The authors concluded that triple antithrombotic therapy for 30 days in patients undergoing PCI should be favorably considered for those in whom warfarin is indicated because of the lack of association with high bleeding complication rates. The authors also suggested that overlap of warfarin and heparin be avoided, if possible, with no specific mention of exceptions (eg, pts. with mechanical heart valves). Unfortunately, the study did not have a control group to help determine statistical significance of the outcomes, nor did the investigators look at the rate of stent thrombosis.

The risk of bleeding in patients requiring triple antithrombotic therapy with aspirin, clopidogrel, and warfarin compared with those taking dual antithrombotic therapy with aspirin and clopidogrel was assessed in a retrospective cohort of patients undergoing PCI with intracoronary stent placement.³⁴ Eight percent of patients on triple antithrombotic therapy prematurely discontinued clopidogrel and 6% discontinued warfarin secondary to bleeding. A significantly increased incidence of major and minor bleeding was noticed in the triple versus dual antithrombotic therapy groups. No bleeding events occurred within the first 30 days. With adjustment for confounding baseline variables using a multivariate analysis, the risk of bleeding with triple versus dual antithrombotic therapy was 5-fold higher when warfarin was added to the dual antithrombotic therapy. The authors concluded that a "significantly increased bleeding risk" exists with triple versus dual antithrombotic therapy in post-PCI patients and that it would be important to evaluate an alternative treatment regimen. The study did not evaluate the rate of stent thrombosis or recurrent myocardial ischemic events or the method by which patients were selected for inclusion in the study.

In the only randomized trial reported to date, of patients with peripheral arterial disease (PAD) and either ACS or intracoronary stent placement, the WAVE trial investigators sought to determine whether triple antithrombotic therapy was superior to dual antithrombotic therapy.³⁵ Two coprimary composite outcomes were determined during the randomized, open-label, multicenter trial. Coprimary outcome 1 included MI, stroke, or death from cardiovascular disease causes and was not statistically significant among the triple versus dual antithrombotic therapy, nor was the coprimary outcome 2, which included MI, stroke, severe ischemia of the peripheral or coronary arteries leading to urgent intervention, or death from cardiovascular disease causes. Life-threatening bleeding was significantly higher with triple versus dual antithrombotic therapy in patients with PAD. The results of the study found no benefit for prevention of major cardiovascular disease complications with triple versus dual antithrombotic therapy and showed a significant increase in the risk of life-threatening bleeding in patients randomized to the triple antithrombotic arm. One strength of the study was the duration of follow-up (2.5–3.5 y). It is the longest triple versus dual antithrombotic therapy trial performed to date.

In a retrospective cohort study conducted by DeEugenio et al.,³⁶ bleeding risk and risk factors for bleeding were assessed in patients who underwent PCI, stent placement, or brachytherapy and received aspirin, clopidogrel, and warfarin. The 97 active patients receiving triple antithrombotic therapy were matched 1:1 to controls (aspirin plus clopidogrel therapy) not receiving warfarin. Major bleeding events were reported to be more common in the treatment versus the control group. Results of multivariate analysis revealed that the risk of major bleeding after PCI was 5 times higher for patients receiving triple antithrombotic therapy compared with dual antiplatelet therapy, while controlling for sex and stent type. The number needed to harm was 9 additional patients treated with triple antithrombotic therapy to cause one major bleed. The rate of stent thrombosis, myocardial ischemic events, and hospitalizations were not reported. The authors concluded that warfarin was an independent predictor of major bleeding after PCI; thus, it may be prudent for patients who are at low risk for a thromboembolic event to avoid taking warfarin until the combination of aspirin and clopidogrel is no longer required. Unfortunately, the study was underpowered to detect other independent predictors of major bleeding, and results for minor bleeding were collected but not reported.

A larger study of PCI patients compared the one-year results of a warfarin-containing antithrombotic therapy regimen (treatment group) versus a regimen that did not contain warfarin therapy (control group) in patients receiving antiplatelets, either clopidogrel plus aspirin or aspirin alone.³⁷ Patients were selected from a PCI database, and a total of 227 patients in the control group were matched (age ± 5 years, sex, and similar disease states) to 219 patients with an indication for long-term anticoagulation with warfarin who underwent PCI during the study period. Patients received a variety of antithrombotic agent combinations. The control group received either monotherapy with a single antiplatelet agent (either aspirin or clopidogrel) or dual antiplatelet therapy (aspirin plus clopidogrel), while the treatment group received a warfarin-containing regimen per the treating physician's discretion. The most commonly used regimen in the treatment group was warfarin plus aspirin and clopidogrel (48.4%), followed by warfarin plus clopidogrel (20.5%), warfarin plus aspirin (15.1%), and warfarin alone (0.5%). Patients in the control group received aspirin plus clopidogrel (94.3%), clopidogrel alone (4.4%), or aspirin alone (0.9%). The percentage of patients receiving a drug-eluting stent was similar between the treatment and control groups (41% and 42%, respectively) versus a bare metal stent (58% and 59%, respectively). On multivariate analyses, the rate of the primary efficacy endpoint (death, MI, target vessel revascularization, or stent thrombosis) was not higher in the patients receiving warfarin versus control patients at discharge, but was significantly higher at 12 months. Interestingly, there was no significant difference in the rate of stent thrombosis in either group. Major bleeding was 3-fold higher in warfarin-treated patients. No significant difference in the incidence of stroke was seen between the groups at 12 months. Overall, the conclusion of the authors was that the long-term prognosis of warfarin-treated patients was disappointing, irrespective of the drug combination used.

In a retrospective cohort study, Nguyen et al.³⁸ reported 6-month outcomes and identified risk factors for bleeding in patients receiving single versus dual antithrombotic therapy (aspirin plus a thienopyridine) in combination with warfarin, using data from 800 patients with ACS enrolled in a multinational PCI registry between years 1999 and 2006. Approximately 25% of patients received a drug-eluting stent. Using multivariate logistic regression, major inhospital bleeding events were found to be similar between the dual and single antithrombotic therapy groups combined with warfarin. Additional results for in-hospital events and 6-month outcomes are detailed in Table 2. No information on 6-month bleeding episodes was reported. The authors concluded that mortality and MI were not significantly different between dual antiplatelet therapy plus warfarin compared with single antiplatelet therapy plus warfarin at 6 months, and single and dual antiplatelet therapies in combination with warfarin are common following stenting. Interestingly, the authors included data on the cohort with drug-eluting stents and also found no significant difference in death, stroke, unscheduled PCI, or MI between the dual and single antiplatelet therapy groups. This study would seem to support the use of either a single or dual antithrombotic therapy in patients with chronic conditions requiring warfarin therapy, with the additional benefit of the reduction in stroke after 6 months in patients with atrial fibrillation in the triple antithrombotic regimen. However, limitations of the study include no description on the method of follow-up, small sample size for individual groups, and no data reported for long-term bleeding events.

Nguyen et al.³⁹ also assessed the bleeding risks of dual versus triple antithrombotic therapy over 30 days in patients with STEMI who were also receiving fibrinolytic therapy in a post hoc analysis from the EXTRACT-TIMI 25 study. After 30 days, only 1 of 86 patients treated with triple antithrombotic therapy had a TIMI major bleed compared with 14 of 4497 patients treated with dual antiplatelet therapy. There were no major or minor bleeds in the subgroup of patients undergoing PCI during hospitalization. In this recent study, the authors suggested that a short course of triple antithrombotic therapy is safe in patients with STEMI. The study was limited to patients who survived to hospital discharge and it was unclear whether the reported bleeding events included in-hospital bleeding events.

Finally, Ruiz-Nodar et al.⁴⁰ reported the results of a large retrospective cohort study comparing long-term outcomes (median follow-up was 595 days) between patients with atrial fibrillation and undergoing PCI who received anticoagulation (most, triple antithrombotic therapy) at hospital discharge with those not receiving anticoagulation (most, dual antiplatelet therapy). Selection of anticoagulation at hospital discharge and other antithrombotic therapy was at the discretion of the physician. Because risks for ischemic outcomes, namely stroke, were higher in patients receiving anticoagulation, adjusted survival analyses were performed. Major bleeding was not significantly increased by adding anticoagulation to antiplatelet therapy. However, adding anticoagulation to antiplatelet therapy improved ischemic event-free survival (death, MI, or target vessel revascularization; p = 0.01), the primary endpoint, as well as all-cause mortality (p = 0.02). Not receiving anticoagulation at hospital discharge was an independent predictor of both the primary endpoint defined above (HR 4.9; 95% CI 2.17 to 11.09) as well as the composite endpoint of death, MI, target vessel revascularization, major bleeding, and stroke (HR 4.33; 95% CI 1.96 to 9.59). The authors concluded that triple antithrombotic therapy is preferred in patients with atrial fibrillation who are undergoing PCI and have a low bleeding risk. It is important to note that this population is older than most others studied (mean age 71.5 y), since the study was conducted in patients with atrial fibrillation. This is also the largest study reported to date of patients receiving triple antithrombotic therapy (n = 213) where clinical outcomes of both bleeding and ischemic events are reported.

	Discussion

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Limited data suggest that warfarin increases the risk of bleeding events when added to dual antiplatelet therapy with aspirin and clopidogrel. In most studies, major bleeding following hospital discharge for PCI or ACS is increased in patients receiving aspirin and a thienopyridine in combination with warfarin, with studies reporting a range of between 3.2- to 6.6-fold increased risk compared with dual antiplatelet therapy alone.^34,36,37 In-hospital bleeding risk with anticoagulation added to aspirin and a thienopyridine also appears to be increased, from 1.3- to 4.3-fold, compared with dual antiplatelet therapy alone.^32,37,38 Three studies reported similar bleeding events between dual and triple antithrombotic therapy: one study reported similar in-hospital bleeding rates,³⁸ one reported similar rates of 30-day bleeding events,³⁹ and the third reported similar long-term major and minor bleeding events.⁴⁰ Only one study was prospective and randomized.³⁵ Most studies were of short duration (30 days–6 months),^32,33,37-39 and longer-term follow-up ranged from 12 months³¹ to 3 years.³⁵ Ischemic events, either stroke, MI, or stent thrombosis, are less well studied than are bleeding events, with only 6 of the 12 trials reporting those outcomes.^{31,32,35,37,38,40} One study suggested that omission of 1 of the 2 antiplatelet agents does not increase cardiovascular disease events or decrease bleeding risk.³⁸ Three studies suggested no benefit in reducing cardiac outcomes, nor did they observe an increase in the risk of bleeding.^31,38,39 One study of patients with atrial fibrillation undergoing PCI suggested a reduction in ischemic events without an increased risk of bleeding.⁴⁰ However, limitations in most of these studies, namely small sample size and short duration of follow-up, prohibit clinicians from applying their results to individual patients in their practices. Lack of data on the target INR and INR reporting during bleeding events limits conclusions regarding safety of the triple antithrombotic therapy.

Based on case series, retrospective cohort studies, and one randomized prospective study reported to date, there is inconsistency in the indications for use of triple antithrombotic therapy. The most common indications, shown by evaluations of triple antithrombotic therapy when safety and efficacy data have been reported, are in patients undergoing PCI with stent implantation. It appears that bleeding events are more common when warfarin is added to clopidogrel and aspirin therapy. However, in all studies that analyzed baseline characteristics, the group receiving warfarin always had higher-risk characteristics for ischemic events and likely bleeding events. Few studies adjusted for any of the baseline differences in groups,^{31,32,34,35,37,38,40} and potential confounding by indication likely persists.

Current guidelines for ACS and PCI recommend selected use of the combination of low-dose aspirin, clopidogrel, and warfarin using a more narrow target INR of 2.0–2.5.^11,12,14 In contrast, the most recent ACC/AHA atrial fibrillation guidelines¹⁵ suggest no indications for using warfarin plus dual antiplatelet therapy and recommend that aspirin be omitted in patients undergoing PCI, despite the fact that no randomized trials of warfarin plus thienopyridine in PCI have been conducted. In our experience, triple antithrombotic therapy is used for patients at high risk of ischemic events, either stroke or MI, most commonly in the setting of recent PCI with stent placement. Warfarin is monitored more closely to maintain an INR within the more narrow range of 2.0–2.5. Dual antiplatelet therapy, using clopidogrel 75 mg and aspirin 81 mg daily, is typically continued for the minimum time recommended for the type of stent: either 30 days for a bare metal stent or 12 months for a drug-eluting stent. Clopidogrel is then discontinued, aspirin is continued indefinitely, and warfarin is continued for as long as clinically indicated.

	Summary

Top Abstract Rationale for Dual Antiplatelet... Clinical Practice Guidelines:... Rationale for Combining... Clinical Practice Guidelines:... Clinical Studies Evaluating the... Discussion Summary References

 
Overall, concomitant administration of aspirin, clopidogrel, and warfarin is considered a matter of clinical judgment on the appropriateness, duration, and safety (eg, risk of bleeding) in the setting of vascular disease. With such limited reported data comparing ischemic outcomes between dual antiplatelet therapy and triple antithrombotic therapy, it is premature to base any recommendation for an individual patient on such data. Therefore, the clinician is left with consensus statements from practice guidelines, often with mixed messages. Because of the known risks of anticoagulation, there is unlikely to be a randomized trial to determine the effect on patients of adding anticoagulation to standard dual antiplatelet therapy without a clear indication for anticoagulation. Therefore, we await the report of larger databases to more clearly identify when the risk of harm exceeds the benefit. The most likely patients to be included in such a study will be those with atrial fibrillation and ACS and/or PCI.

	Footnotes

 
Dr. Spinler is a member of the Bristol-Myers Squibb Speakers Bureau.

	References

Top Abstract Rationale for Dual Antiplatelet... Clinical Practice Guidelines:... Rationale for Combining... Clinical Practice Guidelines:... Clinical Studies Evaluating the... Discussion Summary References

 

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