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Thrombembolism and atrial fibrillation treatment

Prof Job Harenberg

Professor of medicine and haemostaseology, 
Department of clinical pharmacology, 
University of Heidelberg, Germany

The current standard treatment for acute venous thromboembolism is to administer rapidly acting parenteral anticoagulants for five to seven days followed by at least three months of treatment with a vitamin K antagonist.1 Vitamin K antagonists are cumbersome to use, because of their multiple interactions with food and drugs, and they require frequent laboratory monitoring.

Therefore, they are often not used, and when they are, rates of discontinuation are high.2 Many patients receiving warfarin still have inadequate anticoagulation,3 so there is a need for new anticoagulant agents that are effective, safe and convenient to use.

Various oral thrombin- and factor Xa inhibitors are currently in development to overcome the disadvantages of vitamin K antagonists. Rivaroxaban and apixaban are potent selective reversible inhibitor of factor Xa with a high oral bioavailability, rapid onset of action and a half-life of about 12 to 17 hours. Food does not affect rivaroxaban or apixaban absorption. Both compounds are excreted to 25%–60% renally.

Cytochrome P450 3A4 (CYP3A4) and sulfotransferase 1A1 appear to be the major enzymes involved on the metabolism of rivaroxaban and apixaban. Both inhibitors increase the activated partial thromboplastin time and prothrombin time (PT) in a concentration-dependent fashion. PT is currently being investigated regarding the link between the quantity of rivaroxaban in plasma in relation to the prolongation of the coagulation time.4

Dabigatran etexilate is an oral prodrug that is rapidly converted by a serum esterase to dabigatran, a potent, direct, competitive inhibitor of thrombin. It has an absolute bioavailability of 6.5%, 80% of the given dose is excreted by the kidneys, its serum half-life is 12 to 17 hours, and it does not require regular monitoring.5

In trials of the only previously available oral direct thrombin-inhibitor, ximelagatran, it was found to be as effective as warfarin in treating recurrent venous thromboembolism, and rates of major bleeding were similar in both treatment groups.6 However, toxic effects to the liver occurred with prolonged exposure to ximelagatran,7 so it was subsequently withdrawn from the market.

Treatment of deep vein thrombosis and pulmonary embolism
Patients with acute deep vein thrombosis (DVT) and pulmonary embolism would benefit from a single antithrombotic drug such as dabigatran compared to the dual therapy using immediate-acting low molecular weight heparin followed by the slow-acting vitamin K antagonist.

In a randomised, double-blind, non-inferiority trial, patients with acute venous thromboembolism received 150mg twice daily oral dabigatran or enoxaparin/dose-adjusted warfarin to achieve an international normalised ratio (INR) of 2.0 to 3.0. Thirty of the 1,274 patients assigned to dabigatran (2.4%), as compared with 27 of the 1,265 patients assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 (95% confidence interval −0.8 to 1.5; P<0.001 for non-inferiority).

Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85).

The numbers of deaths, acute coronary syndromes and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (p=0.05).

For the treatment of acute venous thromboembolism (VTE), a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring.

Rivaroxaban was compared to Enoxaparin/INR-adjusted warfarin in a prospective randomised open-label study to investigate the incidence of recurrent events in patients with acute DVT (Einstein DVT-study). One thousand, seven hundred and thirty-one patients were randomised to receive 2x15mg rivaroxaban for three weeks followed by 20g once daily for three to 12 months according to the decision of the local principal investigator. One thousand, seven hundred and eighteen patients were randomly allocated to enoxaparin twice daily followed by INR-adjusted warfarin or phenindione for three to 12 months.

Recurrent VTE was documented in 2.1% of patients randomised to rivarxoaban and 3.0% of patients randomised to warfarin (p<0.001 for non-inferiority, hazard ratio 0.68, 95% confidence interval 0.44 to 1.04). Major clinical bleeding occurred in 0.8% and 1.2% of patients, respectively. Major and clinically relevant bleedings were observed in 8.1% of patients in both groups (p=0.77, hazard ratio 0.97, CI 0.76-1.22).

Mortality rate was 2.2% and 2.9% in patients initially randomised to rivaroxaban or warfarin, respectively (hazard ratio 0.67, CI 0.44-1.02, ns). 55.7% of local INRs were within the therapeutic range. Rivaroxaban was non-inferior and as safe compared to standard therapy in patients with acute DVT for prevention of recurrent VTE.8

The prolonged prevention of acute VTE after an initial six months’ therapy was compared for 20mg rivaroxaban once daily (n=602) compared to placebo (n=594) in a double-blind prospective randomised trial over 12 months (Einstein-Extension study). About 2% of recurrent VTE was observed in patients randomised to rivaroxaban compared to about 9% of patients randomised to placebo (hazard ratio 0.184, p<0.0001).9 Major and minor bleeding events occurred only slightly more frequently in patients.

The Recover study adopted a double-blind and double-dummy design. The Einstein DVT-study was open and INR values were obtained locally and were not blinded. The endpoint committee of both studies was unaware of the treatment patients received when they developed recurrent thrombotic events. Nevertheless, suspicion of recurrent events may be influenced by an open design. Accordingly, differences in the absolute number of recurrent events are observed in those patients initially randomised to warfarin in the two studies.

Three per cent of patients developed recurrent events in the Einstein study using rivaroxaban and 2.1% of patients in the Recover Study using dabigatran. The incidence of recurrent events in patients treated with dabigatran (2.4%) and rivaroxaban (2.1%) was similar. Such differences remain to be analysed.

Prevention of cerebral and non-cerebral embolism in atrial fibrillation
Atrial fibrillation (AF) increases the risks of stroke and death. Vitamin K antagonists, such as warfarin, reduce the risks of stroke and death but increase the risk of hemorrhage as compared with control therapy.10 Therefore, warfarin is recommended for patients who have AF and are at risk for stroke.11

Dabigatran has been evaluated in a pilot trial involving patients with AF and in a study for the prevention of venous thromboembolism, in which doses of 150mg twice daily and 220mg once daily, respectively, showed promise.12 A randomised trial comparing 110mg twice daily and 150mg twice daily dabigatran with warfarin was performed.

Eighteen thousand, one hundred and thirteen patients who had AF and a risk of stroke received, in a blinded fashion, fixed doses of dabigatran –110mg or 150mg twice daily – or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years.

The primary outcome was stroke or systemic embolism. Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110mg of dabigatran (relative risk with dabigatran, 0.91; 95% CI, 0.74 to 1.11; P<0.001 for non-inferiority) and 1.11% per year in the group that received 150mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority).

The rate of major bleeding was 3.36% per year in patients receiving warfarin, as compared with 2.71% per year in patients receiving 110mg dabigatran (p=0.003) and 3.11% per year in patients receiving 150mg dabigatran (p= 0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110mg of dabigatran (P<0.001) and 0.10% per year with 150mg of dabigatran (P<0.001).

The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110mg of dabigatran (p=0.13) and 3.64% per year with 150mg of dabigatran (p=0.051).

In patients with AF, dabigatran given at a dose of 110mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage.13

Rivaroxaban and Apixaban
Double-blind and double-dummy studies are performed in patients with AF comparing the oral factor Xa inhibitors rivaroxaban 20mg once daily orally (Rocket study),14 and apixaban 5mg bid orally (Aristotle study)15 versus INR-adjusted warfarin in more than 15,000 patients in each study. Both studies have stopped admitting patients and results will be reported this year (Rocket) or next year (Aristotle).

Despite guideline recommendations, contemporary surveys of practice patterns in developed countries demonstrate that 40% to 50% of patients with AF who are at moderate or high risk for stroke do not receive a vitamin K antagonist.16 Of patients for whom a vitamin K antagonist is initially prescribed, nearly one-third, are no longer receiving it after 30 months.

The single most common reason for not treating AF patients with a vitamin K antagonist appears to be concern about the risk of bleeding.17 Other reasons include:

Expected poor compliance with dosing or monitoring requirements
  • Poor INR control
Need for other drugs that interfere with warfarin therapy
Lack of adherence to restrictions on alcohol, diet or non-prescription medications
  • Unwillingness to take warfarin.18

Thus, apixaban is an alternative to aspirin for prevention of stroke in patients with AF who are not receiving a vitamin K antagonist.

The AVERROES study
AVERROES was a double-blind, double-dummy superiority trial of apixaban 5mg twice daily (or 2.5mg twice daily in selected patients with impaired renal creatinine clearance) compared with apirin 81mg–324mg once daily for the prevention of stroke or systemic embolism in patients with AF and at least one factor for stroke who have failed or are unsuitable for vitamin K antagonist therapy.19 Two thousand, eight hundred and nine patients were randomised to apixaban and 2,791 patients were randomised to aspirin.

The annual rate of systemic arterial embolism including stroke was 1.6 in the apixaban group and 3.6 in the aspirin group (risk reduction 0.46, 95% CI 0.33 to 0.64, P<0.0001). Strokes severity as determined by the modified Rankin score was higher in patients treated with aspirin compared to apixaban (P<0.001). Cerebral haemorrhagic strokes were not different between the groups, with 0.2 per year (RR 1.01, CI 0.38-2.68, p=0.99).

Major bleeding was observed in 1.4% of patients randomised to apixaban and in 1.2% of patients randomised to aspirin (RR1.14, CI 0.74-1.75, p=0.56). Minor bleeding was more frequent in apixaban patients (5.1%) than in aspirin patients (4.1%, RR 1.27, CI 1.01-1.61, p=0.04). Death rates were 3.4 per year in patients randomised to apixaban and 4.4 per year randomised to aspirin (p=0.07). Other relevant side-effects were not observed.20

The Rely study demonstrates for the first time that a more effective anticoagulation can be achieved using twice daily 150mg dabigatran to prevent cerebral and non-cerebral embolism in patients with atrial fibrillation compared to warfarin. On the other hand, a lower dose of dabigatran (2 x 110mg/day) is as effective as warfarin and has a lower risk for bleeding complications.

In October 2010, the Unitd States Food and Drug Administration (FDA) approved the oral thrombin inhibitor dabigatran (Pradaxa) for the prevention of stroke or systemic embolism21. The approval was based on the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which found that dabigatran, an agent that does not require monitoring of the INR, was as safe and effective, and at the 150mg twice daily dose, actually superior to warfarin. It was surprising that only the 150mg twice daily doses of the two doses tested in the RE-LY was approved. 
With the FDA’s key focus on safety, how could they not approve this safer dose of the drug? For now we don’t know why. The agency could say that the 150mg dose is better, so there is no need to approve a dose that is not as efficacious, but I would counter that this is true for a lot of 

For clinical practice, patients with higher risk for thromboembolism can be treated with the higher dose of dabigatran and patients with a higher risk of bleeding complications can be treated with a lower dose of dabigatran in the presence of atrial fibrillation.

Apixaban demonstrated to be more effective compared to aspirin in patients with AF if practitioners or patients do not agree with warfarin therapy. Minor complications were only borderline significantly more frequent as compared to aspirin.

Comparing studies of aspirin against clopidogrel/aspirin or warfarin vs aspirin, the present risk reduction was higher than in the other comparative clinical trials. Furthermore, the study was terminated prematurely due to higher efficacy of apixaban.

Promising future
In addition to postoperative care, dabigatran, rivaroxaban and apixaban demonstrate in large clinical studies the effective and safe use for treating thromboembolic events, as well as prevention of cerebral and non-cerebral embolism.

In addition, dabigatran demonstrates a higher efficacy compared to warfarin when given at a higher dose without increasing bleeding complications. Lower doses of dabigatran are as effective and safer as INR-adjusted warfarin.

Apixaban is almost as effective and safe as enoxaparin/warfarin for prophylaxis of recurrent events after acute DVT. Apixaban demonstrates a higher efficacy and identical safety with regard to severe bleeding complications as aspirin for prevention of embolism in AF. In November,22 additional information will be generated from clinical studies in these indications with these oral new anticoagulants.


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Dabigatran: Good news (and Odd News from FDA)
  22. Bayer Aktiengesellschaft: Phase III ROCKET AF Study of Rivaroxaban meets its primary efficacy endpoint with Comparable Safety vs. Warfarin.…