European Heart Journal Supplements

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Disclaimer Request Permissions Google Scholar Articles by Schulman, S. Articles by Beyth, R. J. Search for Related Content PubMed Articles by Schulman, S. Articles by Beyth, R. J. Social Bookmarking          What's this?

© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Risk of bleeding with long-term antithrombotic therapy in atrial fibrillation

Sam Schulman^1,2,* and Rebecca J. Beyth^3,4

¹McMaster Clinic, HHS—General Hospital, 237 Barton Street East, Hamilton, Ontario L8L 2X2, Canada
²Coagulation Unit, Karolinska University Hospital, Stockholm, Sweden
³Geriatrics Division, Department of Medicine, University of Florida, Gainesville, FL, USA
⁴Malcolm Randall VA Medical Center and Rehabilitation Outcomes Research Center, Gainesville, FL, USA

^* Corresponding author. Tel: +1 905 528 9946; fax: +1 905 5211551. E-mail address: schulms{at}mcmaster.ca

	Abstract

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
The fear of bleeding complications is a common reason for withholding effective prophylaxis with vitamin K antagonists (VKAs) against thromboembolism. This article reviews the epidemiology of bleeding complications with VKAs, with particular emphasis on studies in patients with atrial fibrillation. Risk factors for bleeding, which can be divided into those related to excessive anticoagulant effect and/or those related to increased patient susceptibility, are discussed. The strongest risk factors can be built into models for predicting bleeding during anticoagulant therapy, and two such models that have been published are described. Finally, effective corrective treatment of excessive anticoagulation and bleeding episodes, that are crucial for the outcome and different modalities, are also reviewed.

Key Words: Anticoagulation • Bleeding • Atrial fibrillation • Reversal • Prediction

	Introduction

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
Prophylaxis against ischaemic stroke with vitamin K antagonists (VKAs), such as warfarin, is highly effective in patients with atrial fibrillation (AF). However, many patients remain untreated. Inconvenience of monitoring and frequent dose adjustments, together with a fear of major haemorrhage associated with VKAs, contribute to this underuse.^1,2

	Epidemiological data

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
Meta-analyses of twelve randomized clinical trials investigating the efficacy and tolerability of VKAs in the prevention of stroke in patients with AF have demonstrated an increased risk of major haemorrhage. This risk corresponds to a relative risk of 2.4 or an odds ratio of 1.9 and an estimated annual absolute increase in risk of 0.3%.^3,4

It is often suggested that clinical trials of anticoagulation therapy recruit patients who are unrepresentative of those encountered in typical clinical care, who might be considered to be at a higher risk of haemorrhage than those in clinical trials. However, in the large prospective ATRIA study that included a cohort of 13 559 adults with non-valvular AF over a duration of follow-up of 31 119 person-years, warfarin was not associated with any such increase in the adjusted rate of all major haemorrhage [hazard ratio (HR), 1.11; 95% confidence interval (CI), 0.84–1.48].⁵ There was, however, a statistically significant increase in the risk of intracranial haemorrhage with warfarin in this study (HR, 1.59; 95% CI, 1.12–2.25).⁵ In two meta-analyses of clinical trials, the annual rate of intracranial haemorrhage was 0.3% per year with VKA vs. 0.1% among controls.^3,4 Difference in the incidence of intracranial haemorrhage between patients treated with VKA or aspirin (ASA) did not reach statistical significance in a meta-analysis of pooled individual data from all published trials (HR, 1.84; and absolute increase per 100 patient-years 0.2; P=0.19).⁶ The types of major haemorrhage reported in five studies with VKA in patients with AF^7–11 were pre-dominantly gastrointestinal (n=37), followed by a similar number of intracranial (n=9), respiratory tract (n=8), and urogenital (n=7) bleedings. Haemarthrosis, retroperitoneal haemorrhage, or pericardial haemorrhage was only reported in single cases.

	Clinical trials vs. usual clinical care

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
Why is the risk of haemorrhage not greater among the patients in usual clinical care? It could be speculated that the anticoagulant treatment was less intensive in usual clinical care. In the cohort study, international normalized ratio (INR) values were reported from occasions when the patients were admitted because of a stroke, and the median was 1.7 on admission with the antecedent value being 2.2.¹² In the AFASAK study,⁷ 73% of the INR values were within the range 2.4–4.2; in the EAFT trial,¹⁰ the mean INR was 2.9; and in the CAFA study,¹³ the mean INR was 2.4. This probably reflects a certain selection bias, with more compliant patients being included in the studies, resulting in improved INR values. The average age of the patients in the respective warfarin groups was comparable. Another reason for a seemingly low incidence of major haemorrhage, in the typical clinical care cohort of the ATRIA study, is that some events may have been overlooked in the review of hospital databases.

	Risk factors for bleeding complications

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
The two major determinants of bleeding are excessive anticoagulation and increased patient susceptibility. Although sometimes being perceived as independent, these are associated with other factors such as duration of anticoagulant therapy and interactions with other drugs. With increasing duration of therapy, there is an increased chance that situations with excessive anticoagulation or changes in patient susceptibility will occur, and the interactions usually cause bleeding by generating excessive anticoagulation.

High target INR range
The mechanisms for excessive anticoagulant effect are summarized in Table 1. The recommended target for anticoagulation in patients with AF is an INR of 2.5 (range 2.0–3.0).¹⁴ At the Leiden Anticoagulation Clinic, a reduction in anticoagulation intensity in patients with AF, targeted originally at INR 3.0–4.5 until 1996, and then lowered to 2.5–3.5, led to a reduction of major haemorrhage from 3.6 to 2.7 per 100 patient-years, without an increase in the incidence of major thromboembolic events.¹⁵

View this table: [in this window] [in a new window]   Table 1 Causes of excessive anticoagulant effect

 
A similar effect of reduced anticoagulation intensity has been observed in randomized clinical trials. For example, in a Japanese trial with 115 patients who were followed for almost 2 years, no major haemorrhages were reported in patients with a target INR of 1.5–2.1, whereas major haemorrhages occurred in six patients in the group with an INR targeted at 2.2–3.5.⁸ Similarly in the AFASAK-II trial,¹⁶ there were 1.1% haemorrhages per year in the group, with an INR targeted at 2.0–3.0 vs. 0.8% among those receiving a fixed low dose of 1.25 mg warfarin per day. However, in the SPAF-III trial,¹⁷ addition of ASA 325 mg daily to warfarin with a target INR of 1.2–1.5 did not result in any reduction of major haemorrhage compared with the group receiving warfarin alone at a target INR of 2.0–3.0. Overall, randomized clinical trials, independent of the indication for VKA, have demonstrated that the frequency of major bleeding is reduced by >50% in patients assigned to an INR of 2.0–3.0 compared with those allocated to a target INR of >3.0.^18–21

Poor anticoagulation control
Laboratory error in the use of the INR system can be reduced by using thromboplastin reagents with a high sensitivity and calibration of the reagent and instrument. These procedures are now routine in major hospitals and laboratories. Unfortunately, however, inexperience with dose adjustments according to the INR results is still relatively common. Randomized clinical trials using surrogate markers, such as time within the therapeutic range or number of dose adjustments, have shown better results when nomograms or computer software are used to support the decision-making process.^22–24 For highly motivated patients, self-testing and self-adjustments seem to result not only in more stable INR values but also in a reduction in clinical complications.²⁵

Early phase of anticoagulant therapy
The initial period of VKA treatment, for example during the first 90 days, is associated with a particularly high risk for major bleeding.^26–28 It is well known that it may take several weeks to reach a stable INR, and thus, the risk of reaching too high an INR value is higher in the early phase of treatment.

Patient compliance
Patients with poor compliance, which can be expected in cases of alcohol abuse for example, are not usually included in clinical trials. In usual clinical care, such patients are often given platelet function inhibitors instead of a VKA or may receive no antithrombotic therapy at all. There is, therefore, only limited data on haemorrhagic complications in these patients. In a retrospective cohort study, however, the risk of bleeding was greatest among those in whom anticoagulant control had been difficult from the outset.²⁹

Interactions with other drugs or food
VKAs are associated with a large number of drug interactions and also some food interactions, mostly described with warfarin.³⁰ The list of interactions is expanding and these can be looked up in any pharmacopoeia. The more common and important ones are shown in Table 2. The majority of identified interactions leads to an increased effect of the anticoagulation activity of VKA. Paracetamol (acetaminophen) used to be on this type of list, but recent studies have shown that the evidence for an interaction is confounded by indication, i.e. the effects on the INR were predominantly caused by the complaint or symptom that necessitated the use of paracetamol. One of the most difficult drug interactions to manage is that between amiodarone and warfarin because of the slow onset of action of amiodarone (2 weeks with oral administration) and its very long half-life (20–100 days). Although food interactions, usually due to high vitamin K content, may lead to a decreased anticoagulant effect, a high number of concomitant, prescribed medications have been reported as an independent risk factor for bleeding at any site.³¹ Furthermore, one alternative medicine, ginkgo biloba, has also been demonstrated as a risk factor for increased risk of bleeding.³² Oral and written instructions to patients concerning risks of interactions and how to avoid them should contribute to a reduction of bleeding complications.

View this table: [in this window] [in a new window]   Table 2 Major drug interactions with warfarin causing an increased anticoagulant effect

 
Multiple impairment of the haemostatic system
Inhibitors of platelet function, such as ASA and non-steroid anti-inflammatory agents, not only affect the pharmacokinetics of VKAs, but they also contribute to additional haemostatic defects that are likely to increase the risk of bleeding complications. All of the serotonin re-uptake inhibitors (citalopram, fluoxetine, paroxetine, sertraline, etc.) have a mild inhibitory effect on platelet function that can result in subcutaneous haematoma and bleeding from mucous membranes. This, however, is a rare problem unless one or more other haemostatic defects are present concomitantly.

Increased patient susceptibility
A relatively rare genetic cause of increased bleeding tendency on treatment with VKAs is due to mutations in the factor IX gene,³³ where missense mutations in the propeptide region (Ala–10 Val and Ala–10 Thr) generate a selective drastic decrease of factor IX without any remarkable change of the INR. Polymorphisms in the cytochrome P450 CYP2C9 gene occur in almost 40% of the population with one or more of the alleles CYP2C9*2 and CYP2C9*3.³⁴ In a recent study, the contribution of these polymorphisms and mutations in seven vitamin K-dependent proteins to the sensitivity to warfarin was investigated. In addition to the cytochrome variants, 402GA mutation of the factor VII gene and 165ThrMet of the factor II gene were independently associated with increased sensitivity to warfarin, the three of them accounting for 50% of the variance.³⁵

In some patients, there is an increased risk of bleeding in spite of INR levels within the therapeutic range. The most typical cause is cancer. The risk of bleeding during anticoagulant therapy is greater in patients with cancer than those without cancer as observed in several studies (Table 3).^36–38 Although bleeding in patients without cancer often occurs at time-points of excessive anticoagulation, this is not always the case among patients with cancer.^37,38 In contrast, patients with extensive cancer disease have a higher risk of bleeding than those with limited disease,³⁸ which is probably related to the degree of vascular lesions.

View this table: [in this window] [in a new window]   Table 3 Risk of major bleeding (haemorrhages per 100 patient-years) during anticoagulant therapy in patients with or without cancer in cohort studies

 
Comorbid conditions that have been associated with an increased risk of bleeding include hypertension, cerebrovascular disease, ischaemic stroke, renal insufficiency, and serious heart disease.³⁹ A history of peptic ulcers with bleeding also appears to confer an increased risk of new bleeding events.⁴⁰ Whether this is due to an increased risk of drug interactions, periods of excessive anticoagulation, or increased vascular fragility is currently unknown. It is also difficult to determine from available studies whether or not a history of previous major bleeding is a risk factor. In many such cases, anticoagulant treatment is altered after a bleeding event, either by adjusting intensity or by switching to platelet function inhibitors.

Several studies have reported old age as a risk factor for bleeding,^{17,26,28,41,42} although a few studies suggest that this risk is dependent on the intensity of anticoagulant therapy⁴³ or on the number of comorbid conditions.²⁷ There may, however, have been limitations in the latter studies due to non-inception cohorts or other biases, and therefore, age can be considered as an independent predictor of bleeding.

	Prediction rules for anticoagulant-related bleeding

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
The clinical decision of administering long-term anticoagulants for patients with AF involves weighing the benefits of stroke prevention against the risk of potential bleeding. Two prediction models have been developed and validated in out-patients treated with warfarin for assessing the risks of anticoagulant-related bleeding. In one study, four independent risk factors for bleeding were identified: age 65 years; history of gastrointestinal bleeding; history of stroke; and one or more of four specific comorbid conditions, that is; recent myocardial infarction, renal insufficiency, severe anaemia, or diabetes (Table 4).⁴⁴ In the validation cohort, the cumulative risk of major bleeding at 12 months was 3, 8, and 30% in the low-, intermediate-, and high-risk patients, respectively. Another prediction model has been developed on the basis of age, gender, and the presence of malignancy (Table 4).⁴⁵ In this model, the frequency of major bleeding in the validation cohort was 1, 4, and 7% in patients classified at low-, middle-, and high-risk, respectively, after 3 months of therapy. Although these models are useful in assessing the risk of anticoagulant-related bleeding at the start of therapy, they should not be the sole criterion for deciding to initiate anticoagulation therapy. Ideally, they should be used in conjunction with other assessments such as the patient's risk of thrombosis, functional and cognitive status, likelihood of adherence to therapy, and personal preferences.⁴⁶

View this table: [in this window] [in a new window]   Table 4 Scoring systems for prediction of the risk of bleeding on treatment with VKAs

 
Applying these prediction rules directly to the primary prevention trials of AF is not possible with the available published data. A more relevant issue when deciding whether or not patients with AF should receive anticoagulants is their risk of stroke. Using the available stroke risk schemes, approximately one-third of patients with AF are at a low risk of stroke and can safely be treated with ASA, one-third are at high risk and should be treated with warfarin if it can be given safely, and one-third are at moderate risk.⁴⁷ It is in these patients with a moderate risk of stroke where bleeding risk assessment along with assessment of patient preferences would be most helpful.

	Treatment of bleeding complications

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
Vitamin K antagonists
In addition to attempts to minimize the risk factors for bleeding mentioned previously, prompt reversal of excessive anticoagulation appears beneficial. Thus, instead of only eliminating one dose of VKA when the INR value is >4, administration of a small dose of vitamin K₁ (1 mg orally), effectively reduces the risk of bleeding.⁴⁸ Given intravenously, 0.5 mg is considered optimal because 1 or 2 mg of vitamin K₁ results in overcorrection in an unacceptable number of cases.⁴⁹ In cases of INR values >10, 2 mg of vitamin K₁ given orally is advisable.⁵⁰

In patients who are already bleeding, reversal with vitamin K₁ is usually not sufficient because of a slow onset of action, with the full effect occurring only after 12–24 h. A more rapid reversal can be obtained with plasma or with prothrombin complex concentrate. The former, however, is difficult to use because prohibitively large volumes of plasma are often required.⁵¹ The dose of prothrombin complex concentrate required to achieve the desired INR value can be calculated as previously described,⁵² and it may be combined with a small dose of vitamin K₁ to avoid rebound and the need to repeat infusion of concentrates.

Heparin
It is often sufficient to simply discontinue unfractionated heparin (UFH) to arrest bleeding if administered by intravenous infusion as its half-life is only 1–2 h. In cases of bleeding due to overdosing, protamine sulphate reverses the effect of UFH but only partly that of low-molecular-weight heparin. Further, excessive dosing of protamine sulphate may cause platelet aggregation with a pronounced drop in platelet count, and it may even act as an anticoagulant itself. Desmopressin reverses the prolonged bleeding time generated by heparin and can be used to reduce or counteract bleeding without annihilating the antithrombotic effect of heparin.⁵³

New anticoagulant drugs
Two novel anticoagulants may soon enter the market for prophylaxis of stroke in patients with AF. Phase III clinical trials with the oral direct thrombin inhibitor ximelagatran have been completed recently,⁵⁴ and trials of the long-acting pentasaccharide, idraparinux, are ongoing. Oral ximelagatran exhibits a low potential for interaction with other medications^55–59 and dosing requirements do not vary with age, gender,⁶⁰ ethnicity,⁶¹ obesity,⁶² or food⁶³ or alcohol⁶⁴ intake and, therefore, ximelagatran can be given in fixed doses to most patients.

As ximelagatran has a relatively short half-life of 5 h, it may often be sufficient to simply discontinue the treatment if bleeding occurs, treat symptomatically with volume and red blood cell replacement and ensure adequate diuresis under close observation in the hospital. Haemodialysis may be useful in the event of an overdose—ximelagatran is eliminated efficiently by haemodialysis in animal models.⁶⁵ Further, according to the results from an experimental model, activated prothrombin complex concentrate is a promising alternative to reverse the effect of life-threatening haemorrhages.⁶⁶ Activated recombinant factor VII (rFVIIa) reduced bleeding time of high-dose melagatran administration (0.6 mg/kg bolus+0.6 mg/kg/h, 4 h, intravenous) without promoting thrombus propagation in a non-human primate model of progressive vascular graft thrombosis.⁶⁷ Other recent studies have also shown that rFVIIa reverses most of the in vitro or ex vivo haemostatic defects of the short-acting fondaparinux⁶⁸ and idraparinux injections.⁶⁹ However, rFVIIa does not appear to reverse the effect of thrombin inhibition with ximelagatran at the dose used for therapeutic indications (90 µg/kg)⁷⁰ and may not, therefore, be considered a ‘true’ antidote for ximelagatran-induced bleeding events.

	Conclusion

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
Anticoagulant therapies are used for the prevention or treatment of thromboembolic disorders in a wide range of patient populations and indications including the prevention of stroke in patients with AF. The VKAs (e.g. warfarin, acenocoumarol, and phenindione) are the only oral anticoagulants currently available. Although they have been in use for 60 years, their efficacy and safety are limited by a narrow therapeutic window and unpredictable anticoagulant activity. The latter is due to variable inter-patient pharmacokinetics and interactions with dietary vitamin K and numerous commonly used drugs. Hence, regular monitoring of coagulation and dose adjustments, supported by nomograms or specific computer software, are required to maintain an effective level of anticoagulation and to avoid serious bleeding during VKA therapy. VKAs also have a slow onset of anticoagulant effect. The difficulties of managing anticoagulant therapy with VKAs have contributed to their underuse in some populations, particularly elderly patients at risk of thromboembolic events.

Several factors influencing the incidence of bleeding events during VKA therapy include increase in the number of concomitant diseases and the use of concurrent medications, increasing intensity and duration of anticoagulation, genetic factors, age, and so forth. Applicability of bleeding rates obtained in clinical trials to clinical practice is another consideration. For example, monitoring and control of anticoagulation with VKAs to maintain a safe and effective INR may be improved in a clinical trial setting to that used in practice where INR control may be suboptimal, leading to increased risk of bleeding complications and/or reduced antithrombotic efficacy.

Treatment with any anticoagulant may result in increased risk of bleeding. In cases of severe bleeding, excessive dosing, or the need for acute surgery, urgent therapeutic intervention may be required. The first steps in the management of major bleeding events during anticoagulant therapy with heparins and VKAs include stopping treatment or omitting the next dose and, if necessary, administration of protamine or vitamin K for patients receiving heparin or VKAs, respectively.

Ximelagatran, an oral direct thrombin inhibitor, has shown promising efficacy and safety results in comparison with standard anticoagulant therapies in a range of clinical trials. Results of comparative trials demonstrate that oral ximelagatran twice daily can be used at a fixed dose without dose titration, dose adjustment, or coagulation monitoring, without compromising efficacy or safety. The rates of major bleeding events in clinical trials of ximelagatran were low and similar to those of other anticoagulant drugs.

	Acknowledgements

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 
Thrombosis quorum is supported by an educational grant from AstraZeneca. This Supplement has been developed as part of the Thrombosis Quorum initiative, under the direction of the Thrombosis Quorum Steering Group [G. Agnelli (Chairman), P. Bath, J. Emmerich, B. Gersh, M. Ögren, S. Schulman, and J. Weitz].

	References

Top Abstract Introduction Epidemiological data Clinical trials vs. usual... Risk factors for bleeding... Prediction rules for... Treatment of bleeding... Conclusion Acknowledgements References

 

1. Frykman V, Beermann B, Rydén L et al. Management of atrial fibrillation: discrepancy between guideline recommendations and actual practice exposes patients to risk for complications. Eur Heart J 2001;22:1954–1959.[Abstract/Free Full Text]
2. Bungard TJ, Ghali WA, Teo KK et al. Why do patients with atrial fibrillation not receive warfarin? Arch Intern Med 2000;160:41–46.[Abstract/Free Full Text]
3. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999;281:1830–1835.[Abstract/Free Full Text]
4. Segal JB, McNamara RL, Miller MR et al. Prevention of thromboembolism in atrial fibrillation. A meta-analysis of trials of anticoagulants and antiplatelet drugs. J Gen Intern Med 2000;15:56–67.[CrossRef][Web of Science][Medline]
5. Go AS, Hylek EM, Phillips KA et al. Effectiveness and safety of warfarin to prevent thromboembolism among 13 559 patients with atrial fibrillation: how well do results of randomized trials apply to clinical practice? The ATRIA Study. Circulation 2002;106:515.
6. van Walraven C, Hart RG, Singer DE. Oral anticoagulants versus aspirin in nonvalvular atrial fibrillation. An individual patient meta-analysis. JAMA 2002;288:2441–2448.[Abstract/Free Full Text]
7. Petersen P, Boysen G, Godtfredsen J et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989;1:175–179.[Web of Science][Medline]
8. Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation. A multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation–Embolism Secondary Prevention Cooperative Study Group. Stroke 2000;31:817–821.[Abstract/Free Full Text]
9. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–539.[Abstract/Free Full Text]
10. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255–1262.[Web of Science][Medline]
11. Ezekowitz MD, Bridgers SL, James KE et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992;327:1406–1412.[Abstract]
12. Hylek EM, Go AS, Chang Y et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med 2003;349:1019–1026.[Abstract/Free Full Text]
13. Connolly SJ, Laupacis A, Gent M et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349–355.[Abstract]
14. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(Suppl. 3):429S–456S.[Abstract/Free Full Text]
15. Torn M, van der Meer FJM, Rosendaal FR. Lowering the intensity of oral anticoagulant therapy. Arch Intern Med 2004;164:668–673.[Abstract/Free Full Text]
16. Gulløv AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Arch Intern Med 1999;159:1322–1328.[Abstract/Free Full Text]
17. Blackshear JL, Halperin JL, Hart RG et al. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996;348:633–638.[CrossRef][Web of Science][Medline]
18. Altman R, Rouvier J, Gurfinkel E. Comparison of two levels of anticoagulant therapy in patients with substitute heart valves. J Thorac Cardiovasc Surg 1991;101:427–431.[Abstract]
19. Saour JN, Sieck JO, Mamo LA et al. Trial of different intensities of anticoagulation in patients with prosthetic heart valves. (Comment). N Engl J Med 1990;322:428–432.[Abstract]
20. Turpie AG, Gent M, Laupacis A et al. A comparison of aspirin with placebo in patients treated with warfarin after heart-valve replacement. N Engl J Med 1993;329:524–529.[Abstract/Free Full Text]
21. Hull R, Hirsh J, Jay R et al. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982;307:1676–1681.[Abstract]
22. Ageno W, Turpie AG. A randomized comparison of a computer-based dosing program with a manual system to monitor oral anticoagulant therapy. Thromb Res 1998;91:237–240.[CrossRef][Web of Science][Medline]
23. Doecke CJ, Cosh DG, Gallus AS. Standardised initial warfarin treatment: evaluation of initial treatment response and maintenance dose prediction by randomised trial, and risk factors for an excessive warfarin response. Aust N Z J Med 1991;21:319–324.[Web of Science][Medline]
24. Poller L, Shiach CR, MacCallum PK et al. Multicentre randomised study of computerised anticoagulant dosage. European Concerted Action on Anticoagulation. Lancet 1998;352:1505–1509.[CrossRef][Web of Science][Medline]
25. Körtke H, Körfer R. International normalized ratio self-management after mechanical heart valve replacement: is an early start advantageous? Ann Thorac Surg 2001;72:44–48.[Abstract/Free Full Text]
26. Palareti G, Leali N, Coccheri S et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996;348:423–428.[CrossRef][Web of Science][Medline]
27. Fihn SD, McDonell M, Martin D et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993;118:511–520.[Abstract/Free Full Text]
28. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989;87:144–152.[Web of Science][Medline]
29. Forfar JC. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br Heart J 1979;42:128–132.[Free Full Text]
30. Schulman S. Oral anticoagulation. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds Williams Hematology. 6th ed. New York: McGraw-Hill; 2001. p1777–1792.
31. Bleeding during antithrombotic therapy in patients with atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators. Arch Intern Med 1996;156:409–416.[Abstract/Free Full Text]
32. Izzo AA, Ernst E. Interactions between herbal medicines and prescribed drugs: a systematic review. Drugs 2001;61:2163–2175.[CrossRef][Web of Science][Medline]
33. Oldenburg J, Kriz K, Wuillemin WA et al. Genetic predisposition to bleeding during oral anticoagulant therapy: evidence for common founder mutations (FIXVal-10 and FIXThr-10) and an independent CpG hotspot mutation (FIXThr-10). Thromb Haemost 2001;85:454–457.[Web of Science][Medline]
34. Aithal GP, Day CP, Kesteven PJL et al. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1998;353:717–719.
35. Shikata E, Ieiri I, Ishiguro S et al. Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and gamma-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 2004;103:2630–2635.[Abstract/Free Full Text]
36. Hutten BA, Prins MH, Gent M et al. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078–3083.[Abstract/Free Full Text]
37. Palareti G, Legnani C, Lee A et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000;84:805–810.[Web of Science][Medline]
38. Prandoni P, Lensing AW, Piccioli A et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484–3488.[Abstract/Free Full Text]
39. Levine MN, Raskob G, Beyth RJ et al. Hemorrhagic complications of anticoagulant treatment: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(Suppl. 3):237S–310S.
40. White RH, McKittrick T, Takakuwa J et al. Management and prognosis of life-threatening bleeding during warfarin therapy. Arch Intern Med 1996;156:1197–1201.[Abstract/Free Full Text]
41. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994;120:897–902.[Abstract/Free Full Text]
42. van der Meer FJM, Rosendaal FR, Vandenbroucke JP et al. Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 1996;76:12–16.[Web of Science][Medline]
43. Fihn SD, Callahan CM, Martin DC et al. The risk for and severity of bleeding in elderly patients treated with warfarin. The National Consortium of Anticoagulation Clinics. Ann Intern Med 1997;124:970–979.
44. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting risk of major bleeding in outpatients treated with warfarin. Am J Med 1998;105:91–99.[CrossRef][Web of Science][Medline]
45. Kuijer PMM, Hutten BA, Prins MH et al. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999;159:457–460.[Abstract/Free Full Text]
46. Man-Son-Hing M, Laupacis A. Anticoagulant-related bleeding in older persons with atrial fibrillation. Physicians' fears often unfounded. Arch Intern Med 2003;163:1580–1586.[Abstract/Free Full Text]
47. Hart RG, Halperin JL, Pearce LA et al. Lessons from the Stroke Prevention in Atrial Fibrillation trials. Ann Intern Med 2003;138:831–838.[Abstract/Free Full Text]
48. Crowther MA, Julian J, McCarty D. Treatment of warfarin-associated coagulopathy with oral vitamin K: a randomised controlled trial. Lancet 2000;356:1551–1553.[CrossRef][Web of Science][Medline]
49. Hung A, Singh S, Tait RC. A prospective randomized study to determine the optimal dose of intravenous vitamin K in reversal of over-warfarinization. Br J Haematol 2000;109:537–539.[CrossRef][Web of Science][Medline]
50. Gunther KE, Conway G, Leibach L et al. Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10. Thromb Res 2004;113:205–209.[CrossRef][Web of Science][Medline]
51. Makris M, Greaves M, Phillips WS et al. Emergency oral anticoagulant reversal: the relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemost 1997;77:477–480.[Web of Science][Medline]
52. Schulman S. Care of patients receiving long-term anticoagulant therapy. N Engl J Med 2003;349:675–683.[Free Full Text]
53. Schulman S, Johnsson H. Heparin, DDAVP and the bleeding time. Thromb Haemost 1991;65:242–244.[Web of Science][Medline]
54. Executive Steering Committee on behalf of the SPORTIF III Investigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691–1698.[CrossRef][Web of Science][Medline]
55. Teng R, Sarich TC, Eriksson UG et al. A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor. J Clin Pharmacol 2004;44:1063–1071.[Abstract/Free Full Text]
56. Bredberg E, Andersson TB, Frison L et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug–drug interactions. Clin Pharmacokinet 2003;42:765–777.[CrossRef][Web of Science][Medline]
57. Sarich TC, Schützer K-M, Dorani H et al. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran. J Clin Pharmacol 2004;44:928–934.[Abstract/Free Full Text]
58. Sarich TC, Schützer K-M, Wollbratt M et al. No pharmacokinetic or pharmacodynamic interaction between digoxin and the oral direct thrombin inhibitor ximelagatran in healthy volunteers. J Clin Pharm 2004;44:935–941.
59. Fager G, Cullberg M, Eriksson-Lepkowska M et al. Pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, are not influenced by acetylsalicylic acid. Eur J Clin Pharmacol 2003;59:283–289.[CrossRef][Web of Science][Medline]
60. Johansson LC, Frison L, Logren U et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003;42:381–392.[CrossRef][Web of Science][Medline]
61. Johansson LC, Andersson M, Fager G et al. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers. Clin Pharmacokinet 2003;42:475–484.[CrossRef][Web of Science][Medline]
62. Sarich TC, Teng R, Peters GR et al. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003;42:485–492.[CrossRef][Web of Science][Medline]
63. Eriksson UG, Bredberg U, Gislén K et al. Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003;59:35–43.[Web of Science][Medline]
64. Sarich TC, Johansson S, Schützer K-M et al. The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor, are unaffected by a single dose of alcohol. J Clin Pharmacol 2004;44:388–393.[Abstract/Free Full Text]
65. Carlsson SC, Attman P-O, Samuelsson O et al. Antithrombotic effects and pharmacokinetics of the direct thrombin inhibitor melagatran administered in dialysate in a porcine model of hemodialysis. (Abstract SU-PO474) J Am Soc Nephrol 2004;15:638A.
66. Elg M, Carlsson S, Gustafsson D. Effects of activated prothrombin complex concentrate or recombinant Factor VIIa on bleeding time and thrombus formation during anticoagulation with a direct thrombin inhibitor. Thromb Res 2001;101:145–157.[CrossRef][Web of Science][Medline]
67. Gruber A, Carlsson S, Kotzé H et al. Activated factor VII is hemostatic without promoting thrombus propagation. (Abstract 2998) Blood 2003;102:809a.
68. Bijsterveld NR, Moons AH, Boekholdt SM et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002;106:2550–2554.[Abstract/Free Full Text]
69. Bijsterveld NR, Vink R, van Aken BE et al. Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 2004;124:653–658.[CrossRef][Web of Science][Medline]
70. Wolzt M, Levi M, Sarich TC et al. Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. Thromb Haemost 2004;91:1090–1096.[Web of Science][Medline]

CiteULike    Connotea    Del.icio.us    What's this?

This article has been cited by other articles:

				D. E. Singer, Y. Chang, M. C. Fang, L. H. Borowsky, N. K. Pomernacki, N. Udaltsova, and A. S. Go Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation?: The ATRIA Study Circ Cardiovasc Qual Outcomes, July 1, 2009; 2(4): 297 - 304. [Abstract] [Full Text] [PDF]

This Article Abstract FREE Full Text (PDF) E-letters: Submit a response Alert me when this article is cited Alert me when E-letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My Personal Archive Download to citation manager Disclaimer Request Permissions Google Scholar Articles by Schulman, S. Articles by Beyth, R. J. Search for Related Content PubMed Articles by Schulman, S. Articles by Beyth, R. J. Social Bookmarking          What's this?

Online ISSN 1554-2815 - Print ISSN 1520-765X

Copyright © 2009 European Society of Cardiology

Oxford Journals Oxford University Press

• Site Map
• Privacy Policy
• Frequently Asked Questions

Other Oxford University Press sites: Oxford University Press Oxford Journals China Oxford Journals Japan American National Biography Booksellers' Information Service Children's Fiction and Poetry Children's Reference Corporate & Special Sales Dictionaries Dictionary of National Biography Digital Reference English Language Teaching Higher Education Textbooks Humanities International Education Unit Law Medicine Music Online Products Oxford English Dictionary Reference Rights and Permissions Science School Books Social Sciences Very Short Introductions World's Classics