Dr Stavros Apostolakis (left) and Professor Paulus Kirchhof discuss the latest evidence on the use of novel oral anticoagulants for stroke prevention in non-valvular AF
People with atrial fibrillation (AF) are at increased risk of stroke, transient ischemic attack, and non-central nervous system systemic embolism. About two-thirds of incidences of stroke in patients with AF can be prevented by oral anticoagulation (antiplatelet agents such as aspirin or clopidogrel cannot prevent stroke in these individuals).1 In the UK, the Newcastle survey screened 4843 people aged 65 years or over in general practices and found a prevalence of AF of 4.7%.2 More recent data from the UK Clinical Practice Research Datalink showed 55,847 new AF diagnoses between 2000 and 2012. Fifty-four percent of men and 45% of women were initiated on anticoagulation therapy in the first year following diagnosis of AF.3
Initially, only patients at high risk of stroke were selected for trials on stroke prevention in AF. We now know that most patients with AF are at increased risk of stroke and will benefit from oral anticoagulation, except for those without any risk factors for stroke, and possibly also those with one risk factor.4-7
Until recently, vitamin K antagonists (VKAs) were the only type of oral anticoagulants that could reduce the risk of thromboembolism in patients with AF. They act by blocking the synthesis of vitamin K-dependent coagulation factors II, VII, IX, and X.8 Even though VKAs are highly effective for a variety of clinical indications, their use has been limited because of numerous disadvantages, which include:8
- significant inter- and intrapatient variability in dose response
- narrow therapeutic window
- slow pharmacodynamic response
- food and drug interactions
- the requirement for laboratory monitoring.
In recent years, three new oral anticoagulants have been approved for stroke prevention in AF:
- the direct thrombin inhibitor dabigatran
- the factor Xa inhibitors rivaroxaban and apixaban.
These novel oral anticoagulants (NOACs) are at least as effective as well-controlled VKA therapy and seem to carry a lower risk of intracranial haemorrhage.9-16 The purpose of this article is to summarise clinical trial data, international guidelines, and expert opinion on the optimal use of novel oral anticoagulants.
Novel oral anticoagulants: key clinical trials
See Box 1 for a summary of the findings from clinical trials of four NOACs (in chronological order of approval): dabigatran, rivaroxaban, apixaban, and edoxaban (it should be noted that edoxaban has not yet received marketing authorisation for stroke prevention in patients with AF).
Box 1: Novel oral anticoagulants—key clinical trials
- Dabigatran is a direct thrombin inhibitor with a rapid onset of action (1–2 hours), short half-life (12–17 hours), and is predominantly excreted renally.9 The RE-LY trial was a randomised, open-label, multicentre, non-inferiority study comparing the efficacy and safety of two fixed doses of dabigatran etexilate (150 mg twice daily and 110 mg twice daily) with dose-adjusted warfarin in 18,113 patients with non-valvular AF (average age of 71 years). The primary endpoint was the incidence of stroke (including haemorrhagic stroke) and systemic embolism at the median 2-year follow-up period10
- The RE-LY study demonstrated that treatment with 150 mg dabigatran twice daily significantly reduced the risk of stroke and systemic embolism (relative risk 0.66; 95% CI, 0.53 to 0.82; p< 0.001), with the overall risk for major bleeding being similar to that with warfarin. Of note, the rate of haemorrhagic stroke was 0.38% per year in the warfarin group compared with 0.10% per year with dabigatran 150 mg twice daily (p<0.001). A 110 mg twice daily dose of dabigatran resulted in a similar risk for stroke as with warfarin, but carried a 20% reduction in the rate of major bleeding events (2.71% per year with dabigatran vs. 3.36% per year in the warfarin group; p=0.003). The annual mortality rate was 4.13% in the group taking warfarin compared with:10
- 3.75% in the group taking dabigatran 110 mg twice daily (p=0.13)
- 3.64% in the group taking dabigatran 150 mg twice daily (p=0.051).
- Rivaroxaban is an oral direct factor Xa inhibitor that achieves peak concentration in plasma within 2–4 hours.12 Rivaroxaban has a half-life of 6–10 hours and two-thirds of it is excreted renally.15,16 The ROCKET-AF trial investigated the efficacy of rivaroxaban in preventing AF-related thromboembolism. ROCKET-AF was a double-blind, randomised trial of 14,264 patients comparing rivaroxaban 20 mg daily with dose-adjusted warfarin. The study recruited patients with non-valvular AF who were at moderate to high risk of stroke. The mean age was 73 years and 87% of participants had a CHADS2 score &#ge;3. The proportion of patients with previous stroke was 55%, which was much higher compared with participants in the RE-LY and ARISTOTLE trials (approximately 20% of people had previous stroke).10,11 The median follow up was 707 days
- In the per-protocol, as-treated analysis, rivaroxaban was found to be superior to warfarin, but this was not confirmed in the intention-to-treat analysis (p=0.12). The rates of major bleeding were similar; however, fatal bleeding was lower with rivaroxaban (0.2% vs. 0.5%, p=0.003).16 The intracranial bleeding rates were also significantly lower with rivaroxaban (0.5% vs. 0.7%, p=0.02).16
- Apixaban is an oral direct factor Xa inhibitor with a half-life of 8–12 hours and 25% renal excretion.11,12 The ARISTOTLE trial compared apixaban with warfarin in 18,201 patients with AF and &#ge;1 additional risk factor for stroke11
- In the ARISTOTLE trial, apixaban reduced the risk of stroke or systemic embolism by 21% compared with warfarin (1.27% vs. 1.60% per year). The reduction was significant and supported the superiority of apixaban over warfarin for the primary outcome of stroke or systemic embolism (p=0.01 for superiority). Apixaban also reduced all-cause mortality by 11% (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; p=0.047) and major bleeding by 31% (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; p<0.001), compared with warfarin.11
Edoxaban (NB edoxaban has not yet received marketing authorisation for stroke prevention in patients with AF)
- Edoxaban is an oral, rapidly absorbed factor Xa inhibitor with a half-life of 9–11 hours and a dual mechanism of elimination: approximately one-third is eliminated via the kidneys, and the remainder is excreted in the faeces.13 In the phase III ENGAGE AF-TIMI 48 trial, once-daily therapy with edoxaban at a dose of 30 mg or 60 mg was non-inferior to warfarin for preventing stroke or systemic embolism. Both dose levels of edoxaban were associated with significantly fewer incidences of major bleeding than with warfarin.13
- RE-LY=Randomized Evaluation of Long-Term Anticoagulation Therapy ; AF=atrial fibrillation; ROCKET-AF=Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; CHADS2=Congestive heart failure, Hypertension, Age &#ge;75, Diabetes, Stroke (doubled); ARISTOTLE=Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE AF-TIMI 48=Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48
Novel oral anticoagulants in clinical practice
In a recent document, the European Heart Rhythm Association (EHRA)acknowledges the impact of NOACs on the daily management of patients with AF.17 Although NOACs are very promising in many respects, the use of NOACs will require different approaches and safety considerations than with VKAs, and these different approaches and considerations could not be addressed in the summary of product characteristics or the European Society of Cardiology (ESC) practice guidelines.18 Thus the EHRA Practical guide on the use of new oral anticoagulants in patients with non-valvular AF 17 aimed to provide practical information on how to use NOACs in a safe and effective manner. The document explores the potential use of NOACs in different clinical scenarios and clinical settings from the perspective of the cardiologist, neurologist, geriatrician, and GP.
Step 1: when to start oral anticoagulation
Before prescribing a NOAC to a patient with AF, a decision should already have been made that anticoagulation therapy is justified.
A risk/benefit analysis should always be undertaken before starting anyone on oral anticoagulation. Clinical scoring tools are available to assist the decision-making process.18 The latest guideline from the ESC promotes the use of a risk-assessment score with a factor-based approach for patients with non-valvular AF.18 The CHA2DS2VASc score quantifies a patient’s stroke risk per year and guides a decision on whether or not to use anticoagulant therapy: see Table 1.23
Oral anticoagulation (OAC) therapy is recommended for patients with AF and a CHA2DS2VASc score >1. In patients with a CHA2DS2VASc score of 1, the need for oral anticoagulation is less stringent.18 For low-risk patients (CHA2DS2VASc score of 0), it is recommended that no antithrombotic treatment is given. In recent registries, over 80% of patients with AF are eligible for OAC. Oral anticoagulation should be the default therapy in patients with AF.19-21
|Risk factor||Score (points)|
|Congestive heart failure/left ventricular dysfunction||1|
|Age > 75 years||2|
|Stroke/transient ischaemic attack thromboembolism||2|
|Age 65–74 years||1|
|Sex category (i.e. female sex)||1|
Step 2: which anticoagulant
Valvular atrial fibrillation
Vitamin K antagonists are currently the only option for patients with valvular AF, historically defined as AF in a background of at least moderate (and haemodynamically significant) mitral stenosis. These patients usually require surgical therapy for their valvular heart disease, and were not included in the NOAC phase III trials.9-16 The recently published RE-ALIGN study suggests that patients with mechanical heart valves should be given a VKA rather than a NOAC.
The ESC has defined valvular AF as the presence of severe or moderate mitral stenosis, or severe aortic stenosis.18 Patients with moderate mitral regurgitation were enrolled in some of the trials on NOACs, and subanalyses of the effectiveness of these drugs in these patients are awaited.11,13,16
Non-valvular atrial fibrillation
All patients with AF who are at risk of stroke need to take oral anticoagulation. The choice between NOAC and VKA allows patients to be given treatment with an effective anticoagulant where historically no therapeutic options were available. The opportunity for more patients to receive effective stroke prevention therapy is arguably the most important advantage of NOACs in clinical practice. Furthermore, NOACs appear to cause less intracranial bleeding, although they do result in slightly more gastrointestinal bleeds, than VKAs.9-16
The choice of anticoagulant should be made on the basis of approved indications as set out by regulatory authorities, national and international guidance, and local formulary committees, and following discussion of the available options with the patient.17 In choosing an agent, it is helpful to consider:
- individual patient characteristics (e.g. chronic kidney disease, prior gastrointestinal problems)
- patient preference
- considerations around therapy compliance and adherence
- the individual’s ability to access the anticoagulation checks required for VKA therapy.
The availability of different dosing regimens allows oral anticoagulation to be adapted to the patient’s own preferences and lifestyle. If one anticoagulant is not acceptable or tolerated, another agent should be chosen. There is reasonable evidence that patients with suboptimal international normalised ratio control (e.g. those who are out of the therapeutic range for more than 33% of the time) have less bleeding and fewer thromboembolic events when treated with a NOAC than with a VKA. On the basis of clinical experience (as there are no controlled trial data to support their use in these patients), VKAs are currently the only option for patients with creatinine clearance (CrCl) <15 ml/min. There are no outcome data for NOACs in patients with CrCl <30 ml/min.17
The use of VKAs is limited by multiple food and drug interactions (particularly important, in view of their narrow therapeutic range). However, the latter can be counteracted by dose adjustment of VKAs and intensified INR monitoring. The absence of a widely accessible monitoring method for NOACs makes the fewer interactions of these drugs and good therapy adherence clinically important. Because monitoring of NOACs is not routinely possible, potential interactions with other drugs need to be borne in mind by health practitioners before they prescribe the drugs, and it is important that patients adhere closely to the prescribed therapy. There are, however, very few concomitant drugs that constitute an absolute contraindication for NOACs (see Table 2).17
|Mechanism of action||Dabigatran||Rivaroxaban||Apixaban||Edoxaban*|
|Dronedarone||P-gp and CYP3A4 inhibitor||Not recommended||No data yet||No data yet||Dose reduction|
|Ketoconazole, itraconazole, voriconazole, posaconazole||P-gp and BRCP competition
|Not recommended||Not recommended||Not recommended||No data yet|
|HIV protease inhibitors||P-gp and BCRP competition or inducers; CYP3A4 inhibitors||Not recommended||Not recommended||Not recommended||Not recommended|
|Rifampicin, St John’s wort, carbamazepine, phenytoin, phenobarbital||P-gp, BCRP and CYP3A4, CYP2J2 inducers||Not recommended||Dose reduction if another 'caution factor'||Not recommended||Dose reduction if another 'caution factor'|
Step 3: which dose?
Novel oral anticoagulants are administered in a fixed dose, with a dose adjustment (reduced dose) in defined patient groups.17 Detailed guidance on dose adjustment is given in the summary of product characteristics. Lower doses of NOACs are generally recommended for:
- elderly patients (above 80 years)
- people with a low body weight (less than 50 kg)
- people with impaired renal function (e.g. CrCl of 30–50 ml/min).
There are a few clinically relevant drug-to-drug interactions that necessitate alteration of the dose of NOACs, as summarised in Table 3.
All patients taking anticoagulants, whether VKAs or NOACs, will have a higher bleeding risk when the anticoagulant is combined with antiplatelet agents (aspirin, clopidogrel, prasugrel, or ticagrelor). Such combination therapy should be limited to the approved indications and prescribed for a short time only.17,18
|Mechanism of interaction||Dabigatran||Rivaroxaban||Apixaban||Edoxaban*|
|Verapamil||P-gp competition||Dose reduction||No data||Dose reduction|
|Diltiazem||P-gp competition||Dose reduction if another 'caution factor'||No data|
|Quinidine||P-gp competition||Dose reduction if another 'caution factor'||Dose reduction if another 'caution factor'||No data||Dose reduction|
|Amiodarone||P-gp competition||Dose reduction if another 'caution factor'||No data|
|Clarithromycin, erythromycin||P-gp competition; CYP3A4 inhibitors||Dose reduction if another 'caution factor'||Dose reduction if another 'caution factor'||No data||No data|
Step 4: follow up and the role of primary care
There is no need to assess the anticoagulant effect in patients on NOAC therapy. However, follow up is required to assess the clinical profile, especially with regard to kidney function, and to ensure adherence to therapy. The following points should be noted:
- therapy with NOACs should be initiated by specialist physicians
- effective communication should be established between caregivers delivering different levels of care17
- patients should return to the specialist clinic regularly, preferably every
3 months, for ongoing review of their treatment.17
Review may be undertaken by GPs with experience in this field and/or by appropriate secondary care physicians; nurse-coordinated AF clinics may be also very helpful.17 Regular review should involve assessment of:
- the patient’s adherence to therapy
- any event that might signal thromboembolism in the cerebral, systemic, or pulmonary circulations
- any adverse effects, particularly bleeding events
- co-medications, whether prescribed or over-the-counter
- blood sampling for haemoglobin, renal (and hepatic) function.17
When to stop oral anticoagulation
Stroke prevention in AF is an indication for lifelong oral anticoagulation.17,18 Vitamin K antagonists or NOACs should be prescribed on the understanding that treatment will be interrupted only in the case of bleeding, or before any surgical interventions or invasive procedures that carry a bleeding risk.17
All NOACs have in common the fact that specific antidotes and clinically accessible (routine) quantitative measurements of their anticoagulant effect are not currently available.17,18 Strategies for reversal of the anticoagulant effects rely on: interruption of NOAC therapy, which will be effective in many cases due to the short half-life of NOACs; measures to increase plasma volume and achieve local haemostasis; and direct elimination by dialysis (dabigatran); or inhibition of absorption. Patients with life-threatening bleeding may be treated with prothrombin complex concentrates or activated factor VII, although the clinical effectiveness of such extreme measures has not been systematically studied. Establishing a defined protocol on how to manage patients who present with a life-threatening bleed is the responsibility of individual institutions, and this protocol should already be in place before the first patient presents.
Planned surgical intervention
Interruption of anticoagulation before an invasive procedure should take into account surgical factors and patient characteristics, for example:17
- kidney function
- age of the patient
- history of bleeding complications
- concomitant medication.
Bridging with parenteral anticoagulation has traditionally been used in patients treated with VKAs who are at high thromboembolic risk. The rapid onset and offset of action of NOACs makes such ‘bridging’ unnecessary in patients receiving anticoagulation with NOACs.
For interventions without clinically important bleeding risk, the procedure can be performed at trough concentration of the NOAC, depending on the frequency of dosing (i.e. 12 hours or 24 hours after the last intake). Invasive procedures should not be performed at times of peak concentrations of NOACs. For procedures with a low bleeding risk, it is recommended that NOACs are discontinued 24 hours before the elective procedure in patients with a normal kidney function. In the case of procedures that carry a higher bleeding risk,17,24 slightly longer durations of interruption to the therapy may be needed (see Table 3 in the ESC guidance, reference 23).
Restarting anticoagulation therapy
Restarting NOAC therapy will result in full anticoagulation a few hours after the patient has taken the first tablet or capsule. Therefore, treatment can be resumed once haemostasis has been achieved, often as soon as 6–8 hours after a minor procedure. For many surgical interventions, however, resuming anticoagulation within the first 48–72 hours may carry a bleeding risk that could outweigh the risk of thromboembolism.
For procedures associated with immobilisation, it is considered appropriate to administer a reduced dose of a venous thromboprophylactic, or intermediate dose of a low molecular weight heparin, 6–8 hours after surgery if haemostasis has been achieved; restarting NOACs for therapeutic anticoagulation should be deferred until 48–72 hours after the invasive procedure.17
Recent clinical trials have demonstrated that NOACs are safe and effective alternatives to VKAs for the prevention of stroke in patients with AF. NOACs allow adequate stroke prevention therapy to be offered to patients who are unwilling to undergo, or unsuitable for, VKA therapy, and so fill a therapeutic gap. While use of NOACs is in many respects easier than VKA therapy, there are specific challenges for healthcare professionals who see patients treated with NOACs. At present, NOACs should be initiated in a specialist setting, and patients on NOACs should be followed up by physicians who know about these medications, in appropriate clinical settings. Therapy adherence is of paramount importance for effective stroke prevention. Good communication between different levels of care providers is necessary to prevent prescribing errors and inappropriate peri-procedural handling of NOACs.
- The availability of NOACs as an option for the prevention of stroke in non-valvular AF presents many therapeutic and commissioning challenges for CCGs and prescribers
- NOACs are not currently recommended over VKAs for this indication but there are likely to be individual circumstances in which they are preferable over traditional VKA therapy
- NOACs are considerably more expensive than VKAs but do not require monitoring as frequently. CCGs bear the cost of VKA monitoring and the cost of reagents and pathology tests, which are considerable
- CCGs could (with local cardiology, stroke, primary care, and pharmacology advisers) produce guidelines for prescribers to support the sometimes difficult therapeutic decisions about individual patients. These guidelines could be published alongside:
- risk-profiling tools in local joint primary and secondary care formularies
- an education programme on the identification of AF and on effective thrombo-prophylaxis
- CCGs should be aware that the QOF currently still promotes the use of CHADS2 as a risk-profiling score and the use of anti-platelet agents (indicator AF003) that are no longer the recommended approaches; they could consider working with NHS England to produce local variations to the QOF, to support the use of CHA2DS22VASc and HAS-BLED and oral anti-coagulants where indicated
- An increased investment in prescribing budgets for NOACs is likely to be necessary. It may be possible to recoup some of this from other budgets for VKA monitoring services (but recognising that NOACs will also need regular review of their use).
NOAC=novel oral anticoagulant; AF=atrial fibrillation; CCG=clinical commissioning group; VKA=vitamin K antagonists; CHADS2=Congestive heart failure, Hypertension, Age ?75, Diabetes, Stroke (doubled)
- Hart R, Pearce L, Aguilar M. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146 (12): 857–867.
- Sudlow M, Thomson R, Thwaites B et al. Prevalence of atrial fibrillation and eligibility for anticoagulants in the community. Lancet 1998; 352 (9135): 1167–1171.
- Scowcroft A, Cowie M. Atrial fibrillation: improvement in identification and stroke preventive therapy—data from the UK Clinical Practice Research Datalink, 2000–2012. Int J Cardiol 2013 Dec 6. pii: S0167-5273(13)02129-3. doi: 10.1016/j.ijcard.2013.11.086 (epub ahead of print).
- Go A, Hylek E, Phillips K et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001; 285 (18): 2370–2375.
- Krahn A, Manfreda J, Tate R et al. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med 1995; 98 (5): 476–484.
- Healey J, Connolly S, Gold M et al; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 2012; 366 (2): 120–129.
- Kirchhof P, Curtis A, Skanes A et al. Atrial fibrillation guidelines across the Atlantic: a comparison of the current recommendations of the European Society of Cardiology/European Heart Rhythm Association/European Association of Cardiothoracic Surgeons, the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society, and the Canadian Cardiovascular Society. Eur Heart J 2013; 34 (20): 1471–1474.
- Holbrook A, Pereira J, Labiris R et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10): 1095–1106.
- Katsnelson M, Sacco R, Moscucci M. Progress for stroke prevention with atrial fibrillation: emergence of alternative OACs. Stroke 2012; 43 (4): 1179–1185.
- Connolly S, Ezekowitz M, Yusuf S et al;
RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361 (12): 1139–1151.
- Granger C, Alexander J, McMurray J et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365 (11): 981–992.
- Connolly S, Eikelboom J, Joyner C et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364 (9): 806–817.
- Giugliano R, Ruff C, Braunwald E et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22): 2093–2104.
- Ruff C, Giugliano R, Braunwald E et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2013; S0140-6736(13):62343-0 (e-pub ahead of print).
- Perzborn E, Roehrig S, Straub A et al. Rivaroxaban: a new oral factor Xa inhibitor. Arterioscler Thromb Vasc Biol 2010; 30 (3): 376–381.
- Patel M, Mahaffey K, Garg J et al; ROCKET AF investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10): 883–891.
- Heidbuchel H, Verhamme P, Alings M et al; European Heart Rhythm Association. European Heart Rhythm Association practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013; 15 (5): 625–651.
- Camm A, Lip G, De Caterina R et al; ESC Committee for Practice Guidelines-CPG; Document Reviewers. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation—developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14 (10): 1385–1413.
- Olesen J, Lip G, Hansen M et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ 2011; 342: d124.
- Lip G, Laroche C, Dan G et al. A prospective survey in European Society of Cardiology member countries of atrial fibrillation management: baseline results of EuroObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot General Registry. Europace 2013; Dec 17 (epub ahead of print).
- Kirchhof P, Ammentorp B, Darius H, de Caterina R, Le Heuzey J, Schilling RJ, Schmitt J, Zamorano P. Management of atrial fibrillation in seven European countries after the publication of the 2010 ESC guidelines on atrial fibrillation: primary results of the prevention of thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF). Europace. 2013; published online October 2013.
- Eikelboom J, Connolly S, Brueckmann M et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369 (13): 1206–1214.
- Camm A, Kirchhof P, Lip G et al. Guidelines for the management of atrial fibrillation: the Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429.
- Torn M, Rosendaal F. Oral anticoagulation in surgical procedures: risks and recommendations. Br J Haematol 2003; 123 (4): 676–682. G