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Original Research: ANTITHROMBOTIC THERAPY |

Anticoagulant and Antiplatelet Therapy Use in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention*: The Need for Consensus and a Management Guideline FREE TO VIEW

Gregory Y. H. Lip, MD; Manas Karpha, MB
Author and Funding Information

*From the Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, UK.

Correspondence to: Gregory Y. H. Lip, MD; City Hospital, Dudley Rd, Birmingham, B18 7QH, UK; e-mail: g.y.h.lip@bham.ac.uk



Chest. 2006;130(6):1823-1827. doi:10.1378/chest.130.6.1823
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Published online

Background: There is a lack of published evidence on what is the optimal management strategy in anticoagulated patients with nonvalvular atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) and, hence, need antiplatelet therapy.

Aims: Review of cases of patients with nonvalvular AF undergoing PCI in our hospital, either as an elective case or following acute coronary syndrome (ACS).

Methods: By means of our local West Midlands Regional Health Authority computerized Hospital Activity Analysis register, we obtained a list of all patients seen at our hospital with a diagnosis of AF in association with ACS or PCI between 2000 and 2005. Patient clinical details and antithrombotic therapy management during PCI were recorded.

Results: Of the drugs prescribed on discharge, aspirin and clopidogrel were prescribed to 25 patients (71.4%), while 6 patients (17.1%) were discharged receiving triple therapy, 2 patients (5.7%) receiving clopidogrel alone, and 2 patients (5.7%) receiving warfarin plus one antiplatelet drug (either aspirin or clopidogrel). There was wide variability in the antithrombotic regime and duration of treatment used by the four interventionists in our unit.

Conclusion: This case series reveals the lack of any coordinated strategy in the prevention of thrombotic or thromboembolic events in patients with AF and a recent PCI. Further large studies are required to assess the bleeding and thrombotic risk with various post-PCI strategies in order to facilitate the development of guidelines. Suggested management guidelines are made in this article.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its association with cardiovascular disease or its risk factors is well recognized. In high-risk patients with nonvalvular AF, anticoagulation with warfarin is recommended to reduce the risk of stroke and thromboembolic events.1In patients with coronary artery disease, treatment with aspirin and/or clopidogrel is recommended for cardiovascular prevention2; following presentation with an acute coronary syndrome (ACS), or with coronary stent insertion, combination aspirin-clopidogrel therapy is recommended.34 The duration of dual antiplatelet therapy also varies, ranging from 4 weeks following bare metal stent implantation during elective angioplasty, to 6 to 12 months with drug-eluting stents, in view of the risk of late stent thrombosis.4Warfarin monotherapy is a poor therapeutic choice after bare metal stenting, with a high rate of adverse cardiac complications after stent implantation.5However, in patients with coronary artery disease, anticoagulation with warfarin may provide a similar degree of “vascular protection” to antiplatelet therapy, at least in post-ACS or post-myocardial infarction settings.67

Many patients with AF have associated coronary artery disease. Common clinical practice is to coprescribe low-dose aspirin (eg, 75 mg/d) with warfarin, when it is used, on the assumption that aspirin and warfarin act on differing aspects of the thrombotic pathway. Many contemporary clinical trials of anticoagulation in AF have even allowed concomitant use of aspirin to doses ≤ 100 mg/d.8 However, the use of “aspirin plus warfarin” or “triple therapy” (aspirin, clopidogrel, plus warfarin) is recognized to be associated with more bleeding complications.67

There is a lack of published evidence on what is the optimal management strategy in anticoagulated AF patients who undergo percutaneous coronary intervention (PCI) and hence need antiplatelet therapy. Current clinical guidelines on antithrombotic therapy use in AF do not adequately address this issue. The recent UK National Institute for Health and Clinical Excellence clinical guidelines9 on AF management noted that the addition of aspirin to oral anticoagulation produced “no extra benefit for stroke prevention but increased bleeding risk” and recommended that for stroke prevention in AF, aspirin should not be administered as adjunctive therapy to warfarin. It was considered a matter for clinical judgement on the appropriateness, duration, and safety (eg, risk of bleeding) of the concomitant administration of warfarin with aspirin, for example, in the setting of vascular disease.

The extent to which the lack of evidence or guidelines is problematic in the UK setting is unknown. We are aware of one retrospective US case series10 that reported safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in 66 patients with an indication for anticoagulation, where 6 patients (9.2%) sustained a bleeding event. In this article, we present a case series of patients with nonvalvular AF undergoing PCI in our hospital, either as an elective case or following ACS. More importantly, we also try to make some suggestions on the rational management of this clinical scenario, based on the perceived risk of bleeding and the clinical setting (ACS/non-ACS), drawing on the limited data available from different clinical studies in diverse patient groups.

City Hospital, Birmingham is a city-center teaching hospital serving a catchment population of 350,000. There are five cardiologists based in this hospital, four of whom perform PCI. By means of our local West Midlands Regional Health Authority computerized Hospital Activity Analysis register, we obtained a list of all patients seen at our hospital with a diagnosis of AF (International Classification of Diseases, Tenth Revision [ICD-10] code I48), in association with ACS (ICD-10 codes I20/I21/I22) or PCI (ICD-10 codes K498/Y022) from 2000 to 2005. This coding system has been proved free of errors for definitive diagnoses,11 although errors are found in the coding of nonspecific diagnoses such as “viral infections” or “gastroenteritis.” To minimize any inaccuracies in coding, we also inspected the case notes and cross-referenced with our computerized PCI database that records our PCI activity for annual returns to the British Coronary Intervention Society.

Patient clinical details and antithrombotic therapy management during PCI were recorded. For inclusion in this case series, patients could have a preexisting diagnosis of AF, or new-onset AF could have developed in the setting of the current acute admission (usually with an ACS). There is a proactive revascularization strategy in place in our unit, in which the majority of patients presenting with an ACS undergo diagnostic cardiac catheterization with a view to PCI within 48 to 72 h of admission. Individual patient management decisions were left to the discretion of the responsible cardiologist.

From 2000 to 2005, 1,234 PCIs were performed at our hospital. A total of 35 patients (2.8%) with AF were identified. (Full details of individual patients are provided in a Web-only supplementary Table.) Nineteen patients had preexisting AF, while new-onset AF developed in 16 patients following admission. The mean age of our population was 71 years (range, 50 to 91 years). Of the whole cohort, 22 patients (62.9%) had a previous history of ischemic heart disease, 12 patients (34.3%) were diabetic, and 23 patients (65.7%) were hypertensive.

Drug therapy at the time of hospital admission consisted of warfarin in 11 patients (31.4%), aspirin in 13 patients (37.1%), and clopidogrel in 5 patients (14.3%), while 6 patients (17.1%) were receiving no anticoagulants/antiplatelets. Of those with previously known AF (n = 19), 11 patients were receiving warfarin, 5 were receiving aspirin, 2 were receiving clopidogrel, and 1 patient was receiving no antithrombotic therapy. The majority of patients (65.7%) were treated with a low-molecular-weight heparin in addition to aspirin-clopidogrel therapy on admission. All patients receiving warfarin had this discontinued on admission prior to PCI.

At the time of hospital discharge, aspirin and clopidogrel were prescribed to 25 patients (71.4%), while 6 patients (17.1%) were discharged receiving triple therapy, 2 patients (5.7%) receiving clopidogrel alone, and 2 patients (5.7%) receiving warfarin plus one antiplatelet drug (either aspirin or clopidogrel). The majority of our patients had their duration of treatment documented in the notes, but there was wide variability in the antithrombotic therapy regime and duration of treatment used by the four interventionists in our unit. A total of 10 patients were administered 1 year of clopidogrel with lifelong aspirin, and 4 patients were treated with aspirin and clopidogrel lifelong. In the whole cohort, eight patients were told to stop one of their antiplatelet drugs after either 1, 3, 4, or 12 months, replacing it with warfarin. In two patients, it was not possible to determine their duration of therapy from the notes.

Management of Patients Receiving Warfarin Before PCI

Of the 11 patients admitted who were receiving warfarin, 6 patients had their warfarin restarted at some point in their follow-up when an antiplatelet was stopped (patients 7, 8, 10, 13, 16, and 18) [Web-only supplementary Table]. Two patients had their warfarin stopped (patients 5 and 6), and one other patient had warfarin stopped following PCI in 2000 but was seen in clinic and had warfarin restarted in 2006 (patient 11). One patient was planned to receive warfarin for 3 months but died after PCI (patient 17). One patient was discharged receiving warfarin and clopidogrel with no duration documented in the notes; unfortunately, she died 2 months later with acute renal failure and sepsis (patient 19).

Patients Discharged Receiving Triple Therapy

Of the patients discharged receiving triple therapy, again there was no consistency in the duration of treatment, with either warfarin or one antiplatelet agent being stopped from 1 to 3 months following PCI, which was performed using bare metal stents. There were no bleeding complications requiring hospitalization at 30-day follow-up. At follow-up (up to 1 year), one patient who was discharged receiving aspirin and clopidogrel only was admitted to hospital with rectal bleeding and anemia.

Our case series highlights the variability in the use of anticoagulant/antiplatelet therapy in patients undergoing PCI who have AF. Although the combination of aspirin and clopidogrel accounted for the majority of patients (71.4%), the duration of their use still varied widely among patients. The use of triple therapy was relatively low among these patients due to the concerns of life-threatening bleeding.

This variability of post-PCI prescription is understandable in light of the lack of guidelines available. It has been suggested that the post-PCI strategy should be tailored to the individual patient and their risk of thromboembolism and stent thrombosis against their risk of bleeding while receiving triple therapy.12 For example, in patients with lone AF (who would not normally be prescribed warfarin, especially if aged < 65 years), dual antiplatelet therapy after PCI should be used, with a view to stopping clopidogrel after 4 weeks for bare metal stents or 6 to 12 months for drug-eluting stents, in view of the risk of late stent thrombosis with the latter.4 If other stroke risk factors have been identified, notably hypertension or diabetes, then the clopidogrel should be continued indefinitely or changed to warfarin after 4 weeks. Another strategy suggested the continuous use of triple therapy (warfarin, aspirin plus clopidogrel)—since aspirin-clopidogrel therapy is recommended after ACS for up to 12 months—but keeping the international normalized ratio (INR) target value in the “lower therapeutic range.”13 However, these “suggestions” are, as described, just suggestions and not evidence-based guidelines.

Our own suggestions for management guidelines in this setting are summarized in Table 1 . These make certain assumptions, and are (very) limited by extrapolation of evidence from diverse observations from different clinical studies, in different settings. Firstly, anticoagulation is a reasonable strategy in ACS6,14 and may be an alternative to aspirin, as evident by some clinical trials, such as the Warfarin, Aspirin, Reinfarction Study (WARIS-II).67 Secondly, the main benefit of aspirin after myocardial infarction is seen in the first 35 days, with little further mortality benefit or loss during subsequent years.15In ACS patients, there is evidence of a benefit of aspirin-clopidogrel use for up to 9 months, as shown in the Clopidogrel in Unstable Angina To Prevent Recurrent Events study16(and the Clopidogrel in Unstable Angina To Prevent Recurrent Events-PCI study17), but the benefit seen (death from cardiovascular causes, nonfatal myocardial infarction, or stroke occurred in 9.3% of the clopidogrel group vs 11.4% in the placebo group) needs to be put in context with the increased risk of bleeding (3.7% in the clopidogrel group vs 2.7% in the placebo group) with combination aspirin-clopidogrel therapy.1618 In the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial,19 clopidogrel (75 mg/d) plus aspirin (75 to 162 mg/d) was not significantly more effective than aspirin alone in reducing the rate of myocardial infarction, stroke, or death from cardiovascular causes in 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors, with an increase in moderate-to-severe bleeding. There is also a very well-argued analysis that clopidogrel therapy beyond a few months after PCI does not influence mortality, has a questionable effect on the incidence of myocardial infarction, and is not cost-effective, but results in a significant increase in major bleeding.18 In contrast to clopidogrel, aspirin may have more direct effects on the gastric mucosa, leading to erosions and bleeding; however, one recent analysis20 among patients with a history of aspirin-induced ulcer bleeding whose ulcers had healed, aspirin plus esomeprazole (a proton-pump inhibitor) was superior to clopidogrel in the prevention of recurrent ulcer bleeding.

In the WARIS-II trial,7 “warfarin plus aspirin” was not significant different to “warfarin alone” after myocardial infarction in reducing the composite end point of death, nonfatal reinfarction, or thromboembolic cerebral stroke, but a more recent metaanalysis21(which included the WARIS-II data) found that for patients recovering from ACS, a combined strategy of aspirin plus warfarin at INR values of 2 to 3 was superior to aspirin alone in preventing major adverse events (all-cause death, nonfatal myocardial infarction, and nonfatal thromboembolic stroke) but doubled the risk of major bleeds. Given the risk of bleeding of “warfarin plus aspirin,” we have made the recommendation of “warfarin plus clopidogrel” in Table 1, but whether this combined regimen is also superior to triple therapy (warfarin plus “double” antiplatelet strategy) or to newer evolving treatments, or safer in terms of bleeding risk (especially with the use of a proton-pump inhibitor), warrants further investigation. Of note, aspirin-clopidogrel was a poor strategy for stroke prevention in high-risk patients with AF, as shown in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events Trial.22

Clearly, a balance is needed between stroke and cardiac event prevention, as well as bleeding risks. Indeed, a recent metaanalysis23with estimates of risk and benefit of warfarin plus aspirin after myocardial infarction or ACS reviewed 10 trials involving a total of 5,938 patients (11,334 patient-years) concluded that for patients who are at low or intermediate risk for bleeding, the cardiovascular benefits of warfarin outweigh the bleeding risks. However, this metaanalysis reviewed studies that did not include coronary stenting, and results therefore may not be applicable to patients with stents. Nonetheless, the real-life bleeding complications associated with combinations of aspirin, thienopyridine derivatives (clopidogrel or ticlopidine) and warfarin in elderly patients following acute myocardial infarction is only modestly increased and the overall risk may be small,24as shown in our small cases series. The utility of bleeding risk stratification schemes for anticoagulated patients with AF also requires further prospective data.25

Although limited by the experience of a single center, this case series reveals the lack of any coordinated strategy in the prevention of thrombotic or thromboembolic events in patients with AF and a recent PCI. Further large studies are required to assess the bleeding and thrombotic risk with various post-PCI strategies in patients with AF, in order to facilitate the development of guidelines. As AF is common in patients with coronary artery disease, the need to make an informed decision in the long-term strategy of these patients is a commonplace clinical scenario affecting many physicians in today’s clinical practice.

Abbreviations: ACS = acute coronary syndrome; AF = atrial fibrillation; ICD-10 = International Classification of Diseases, Tenth Revision; INR = international normalized ratio; PCI = percutaneous coronary intervention; WARIS-II = Warfarin, Aspirin, Reinfarction Study

Dr. Lip has received funding for research, educational symposia, consultancy, and lecturing from different manufacturers of drugs used for the treatment of AF and thrombosis. He is Clinical Adviser to the Guideline Development Group writing the United Kingdom National Institute for Health and Clinical Excellence guidelines on AF management (www.nice.org.uk), and is a contributor to the American College of Chest Physicians Consensus Guidelines on Antithrombotic Therapy. Dr. Karpha has no conflicts of interest to disclose.

Table Graphic Jump Location
Table 1. Suggested Management Strategy for Patients With Nonvalvular AF Requiring Anticoagulation and PCI With Stenting*
* 

Doses: aspirin, 75 to 81 mg/d; clopidogrel, 75 mg/d. Warfarin is dose adjusted to target INR of 2.0 to 2.5.

 

Particular attention paid to the following risk factors: (1) patients who are > 75 yr old; (2) patients receiving nonsteroidal anti-inflammatory drugs; (3) patients receiving multiple other drug treatments (polypharmacy); (4) patients with uncontrolled hypertension; (5) patients with a history of bleeding (for example, peptic ulcer or cerebral hemorrhage); and (6) patients with a history of poorly controlled anticoagulation therapy.

Lip, GYH, Boos, CJ (2006) Antithrombotic treatment in atrial fibrillation.Heart92,155-161. [PubMed]
 
JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice Prepared by: British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association.Heart2005;91(Suppl 5),v1-v52. [PubMed]
 
Bertrand, ME, Simoons, ML, Fox, KA, et al Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.Eur Heart J2002;23,1809-1840. [CrossRef] [PubMed]
 
Task Force for Percutaneous Coronary Intervention of the European Society of Cardiology.. Guidelines for percutaneous coronary interventions.Eur Heart J2005;26,804-847. [CrossRef] [PubMed]
 
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 Med1998;339,1665-1671. [CrossRef] [PubMed]
 
Lip, GYH, Varma, C Anticoagulation plus aspirin following acute myocardial infarction: yes or no … and if the latter, why not?Thromb Res2006;118,429-432. [CrossRef] [PubMed]
 
Hurlen, M, Abdelnorr, M, Smith, P, et al Warfarin, aspirin or both after myocardial infarction.N Engl J Med2002;347,969-974. [CrossRef] [PubMed]
 
Halperin, JL, Executive Steering Committee, SPORTIF III and V Study Investigators.. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V).Am Heart J2003;146,431-438. [CrossRef] [PubMed]
 
National Collaborating Centre for Chronic Conditions... Atrial fibrillation: national clinical guideline for management in primary and secondary care. 2006; Royal College of Physicians. London, UK:.
 
Orford, JL, Fasseas, P, Melby, S, et al Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation.Am Heart J.2004;147,463-467. [CrossRef] [PubMed]
 
George, LM, Maddock, K Accuracy of hospital activity notifications for infectious diseases.Br Med J1979;1,1332-339. [CrossRef] [PubMed]
 
Wong, EML, Wu, EB, Chan, WWM, et al A review of the management of patients after percutaneous coronary intervention.Int J Clin Pract2006;60,582-589. [CrossRef] [PubMed]
 
Schneider, H, Weber, F, Holzhausen, C, et al Dual antithrombotic therapy after implantation of coronary stents.Dtsch Med Wochenschr2006;131,1105-1110. [CrossRef] [PubMed]
 
Wallentin, L, Wilcox, RG, Weaver, WD, et al Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial.Lancet2003;362,789-797. [CrossRef] [PubMed]
 
Baigent, C, Collins, R, Appleby, P, et al ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomized comparison of IV streptokinase, oral aspirin, both, or neither; The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.BMJ1998;316,1337-1343. [CrossRef] [PubMed]
 
The Clopidogrel in Unstable Angina To Prevent Recurrent Events (CURE) Trial investigators.. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med2001;345,494-502. [CrossRef] [PubMed]
 
Mehta, SR, Yusuf, S, Peters, RJ, et al Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.Lancet2001;358,527-533. [CrossRef] [PubMed]
 
Eriksson, P Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDO: the “emperor’s new clothes” revisited.Eur Heart J2004;25,720-722. [CrossRef] [PubMed]
 
Bhatt, DL, Fox, KA, Hacke, W, et al Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.N Engl J Med2006;354,1706-1717. [CrossRef] [PubMed]
 
Chan, FK, Ching, JY, Hung, LC, et al Clopidogrel vs aspirin and esomeprazole to prevent recurrent ulcer bleeding.N Engl J Med.2005;352,238-244. [CrossRef] [PubMed]
 
Andreotti, F, Testa, L, Biondi-Zoccai, GG, et al Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients.Eur Heart J2006;27,519-526. [CrossRef] [PubMed]
 
Connolly, S, Pogue, J, Hart, R, et al Clopidogrel plus aspirin vs oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomized controlled trial.Lancet2006;367,1903-1912. [CrossRef] [PubMed]
 
Rothberg, MB, Celestin, C, Fiore, LD, et al Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit.Ann Intern Med2005;143,241-250. [PubMed]
 
Buresly, K, Eisenberg, MJ, Zhang, X, et al Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction.Arch Intern Med.2005;165,784-789. [CrossRef] [PubMed]
 
Kakar, P, Lane, D, Lip, GYH Bleeding risk stratification models in deciding on anticoagulation in patients with atrial fibrillation: a useful complement to stroke risk stratification schema.Chest2006;130,1296-1299. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Suggested Management Strategy for Patients With Nonvalvular AF Requiring Anticoagulation and PCI With Stenting*
* 

Doses: aspirin, 75 to 81 mg/d; clopidogrel, 75 mg/d. Warfarin is dose adjusted to target INR of 2.0 to 2.5.

 

Particular attention paid to the following risk factors: (1) patients who are > 75 yr old; (2) patients receiving nonsteroidal anti-inflammatory drugs; (3) patients receiving multiple other drug treatments (polypharmacy); (4) patients with uncontrolled hypertension; (5) patients with a history of bleeding (for example, peptic ulcer or cerebral hemorrhage); and (6) patients with a history of poorly controlled anticoagulation therapy.

References

Lip, GYH, Boos, CJ (2006) Antithrombotic treatment in atrial fibrillation.Heart92,155-161. [PubMed]
 
JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice Prepared by: British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association.Heart2005;91(Suppl 5),v1-v52. [PubMed]
 
Bertrand, ME, Simoons, ML, Fox, KA, et al Task Force on the Management of Acute Coronary Syndromes of the European Society of Cardiology. Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.Eur Heart J2002;23,1809-1840. [CrossRef] [PubMed]
 
Task Force for Percutaneous Coronary Intervention of the European Society of Cardiology.. Guidelines for percutaneous coronary interventions.Eur Heart J2005;26,804-847. [CrossRef] [PubMed]
 
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 Med1998;339,1665-1671. [CrossRef] [PubMed]
 
Lip, GYH, Varma, C Anticoagulation plus aspirin following acute myocardial infarction: yes or no … and if the latter, why not?Thromb Res2006;118,429-432. [CrossRef] [PubMed]
 
Hurlen, M, Abdelnorr, M, Smith, P, et al Warfarin, aspirin or both after myocardial infarction.N Engl J Med2002;347,969-974. [CrossRef] [PubMed]
 
Halperin, JL, Executive Steering Committee, SPORTIF III and V Study Investigators.. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V).Am Heart J2003;146,431-438. [CrossRef] [PubMed]
 
National Collaborating Centre for Chronic Conditions... Atrial fibrillation: national clinical guideline for management in primary and secondary care. 2006; Royal College of Physicians. London, UK:.
 
Orford, JL, Fasseas, P, Melby, S, et al Safety and efficacy of aspirin, clopidogrel, and warfarin after coronary stent placement in patients with an indication for anticoagulation.Am Heart J.2004;147,463-467. [CrossRef] [PubMed]
 
George, LM, Maddock, K Accuracy of hospital activity notifications for infectious diseases.Br Med J1979;1,1332-339. [CrossRef] [PubMed]
 
Wong, EML, Wu, EB, Chan, WWM, et al A review of the management of patients after percutaneous coronary intervention.Int J Clin Pract2006;60,582-589. [CrossRef] [PubMed]
 
Schneider, H, Weber, F, Holzhausen, C, et al Dual antithrombotic therapy after implantation of coronary stents.Dtsch Med Wochenschr2006;131,1105-1110. [CrossRef] [PubMed]
 
Wallentin, L, Wilcox, RG, Weaver, WD, et al Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial.Lancet2003;362,789-797. [CrossRef] [PubMed]
 
Baigent, C, Collins, R, Appleby, P, et al ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomized comparison of IV streptokinase, oral aspirin, both, or neither; The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group.BMJ1998;316,1337-1343. [CrossRef] [PubMed]
 
The Clopidogrel in Unstable Angina To Prevent Recurrent Events (CURE) Trial investigators.. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med2001;345,494-502. [CrossRef] [PubMed]
 
Mehta, SR, Yusuf, S, Peters, RJ, et al Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.Lancet2001;358,527-533. [CrossRef] [PubMed]
 
Eriksson, P Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDO: the “emperor’s new clothes” revisited.Eur Heart J2004;25,720-722. [CrossRef] [PubMed]
 
Bhatt, DL, Fox, KA, Hacke, W, et al Clopidogrel and aspirin vs aspirin alone for the prevention of atherothrombotic events.N Engl J Med2006;354,1706-1717. [CrossRef] [PubMed]
 
Chan, FK, Ching, JY, Hung, LC, et al Clopidogrel vs aspirin and esomeprazole to prevent recurrent ulcer bleeding.N Engl J Med.2005;352,238-244. [CrossRef] [PubMed]
 
Andreotti, F, Testa, L, Biondi-Zoccai, GG, et al Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients.Eur Heart J2006;27,519-526. [CrossRef] [PubMed]
 
Connolly, S, Pogue, J, Hart, R, et al Clopidogrel plus aspirin vs oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomized controlled trial.Lancet2006;367,1903-1912. [CrossRef] [PubMed]
 
Rothberg, MB, Celestin, C, Fiore, LD, et al Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit.Ann Intern Med2005;143,241-250. [PubMed]
 
Buresly, K, Eisenberg, MJ, Zhang, X, et al Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction.Arch Intern Med.2005;165,784-789. [CrossRef] [PubMed]
 
Kakar, P, Lane, D, Lip, GYH Bleeding risk stratification models in deciding on anticoagulation in patients with atrial fibrillation: a useful complement to stroke risk stratification schema.Chest2006;130,1296-1299. [PubMed]
 
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