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Keywords:

  • Anticoagulant;
  • Antithrombotic;
  • Atrial fibrillation;
  • Direct thrombin inhibitor;
  • Factor Xa inhibitor;
  • Stroke

SUMMARY

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

Atrial fibrillation (AF) is the most commonly occurring arrhythmia, and is a condition of both significant clinical and economic importance. An antithrombotic agent is considered mandatory as part of the management in most patients with AF. It has been conclusively demonstrated that long-term anticoagulation therapy can significantly reduce the risk of stroke in patients with nonvalvular AF. While vitamin K antagonists (VKAs) such as warfarin are highly effective, they possess numerous limitations that curtail their use, or make their use challenging for clinicians and patients. A new generation of anticoagulants are being investigated in phase III clinical trials in patients with AF. One or more of these agents have the potential to either replace or act as alternatives to VKA therapy in AF. This group includes the direct thrombin inhibitor, dabigatran, the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, and finally, the vitamin K analogue, tecarfarin. Additional agents are being developed in phase I or II clinical trials. The direct thrombin and factor Xa inhibitors are generally small, synthetic molecules with predictable pharmacokinetics, a predictable pharmacodynamic effect, few drug interactions and do not require routine therapeutic drug monitoring. These new anticoagulants may well represent a new era in anticoagulation. However, they do possess their own limitations and will present new challenges for clinicians.


Introduction

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

Atrial fibrillation (AF) is a condition of both clinical and economic importance and is the most commonly occurring arrhythmia. It has a prevalence of approximately 2% in the general population, 5% in people over 60 years of age, and 10% in people over 75 years of age [1–3]. It is a growing public health problem associated with significant morbidity and mortality [4–7]. A recent epidemiological study found that the age-adjusted incidence of AF has increased significantly over time, with a 12.6% relative increase between 1980 and 2000 [8]. The significance of this finding is underlined by the fact that predictions for the number of Americans with AF by 2050 has increased from 5.6 to 12.1 million if the age-adjusted incidence of AF does not change [3], and 15.9 million if the increase in incidence continues [8].

The presence of AF has been confirmed as an important risk factor for ischaemic stroke and other thromboembolic events [6,9,10]. Compared with a control population matched for age and blood pressure, people with AF without underlying valvular heart disease are at least five times more likely to have a stroke; in those with valvular AF, the risk is 17 times greater than control [9–11]. The absolute annual risk of stroke in patients with AF of all causes is around 5%, but varies with age and the presence of other risk factors [12]. Approximately 15% of all strokes are associated with AF, and the association increases steadily with age, from 1.5% of all strokes for patients aged 50–59 years, to 23.5% of all strokes for patients aged 80–89 years [9,11,13]. The mortality rate of patients with stroke is also higher (1.5–3 times greater) in patients with AF compared to patients with sinus rhythm [14].

A number of models exist to aid in the stratification of patients with AF to determine their need for anticoagulation, mainly based on the well-validated CHADS2 index (see Table 1) [15–19]. In general, it is suggested that the benefits of oral anticoagulation outweigh the risks in those with a CHADS2 score of 2 or greater [20]. When the CHADS2 score is 1, vitamin K antagonists (VKAs) or antiplatelet agents are recommended, with VKAs generally preferred if the risk of bleeding is low [20]. For those with AF but no risk factors, antiplatelet therapy is recommended. In patients with lone AF, the risk of stroke is low and the effectiveness of antiplatelet therapy for the primary prevention of stroke is questionable, and consequently, antiplatelet therapy is not considered to be mandatory in these patients [21].

Table 1.  Stroke risk in patients with nonvalvular AF not treated with anticoagulation according to the CHADS2 score. Modified from Schomig et al. [71]
CHADS2 ScoreStroke rate (% per year) without treatmentRecommended antithrombotic treatment
  1. The CHADS2 score is calculated by giving 1 point for cardiac failure, arterial hypertension, age > 75 years or diabetes mellitus, respectively, and 2 points for prior stroke or transient ischaemic attack.

01.9Aspirin (75–300 mg daily)
12.8Warfarin (INR 2–3) or aspirin (75–300 mg daily)
24.0Warfarin (INR 2–3)
35.9 
48.5 
512.5 
618.2 

It has been conclusively demonstrated that long-term anticoagulation therapy with VKAs can reduce the risk of stroke by approximately 60% in patients with nonvalvular AF [15,22–25]. This is an overall reduction from 4.5% to 1.4% per year, with acceptable rates of major bleeding or intracranial hemorrhage in trial populations [22,26,27]. This means that VKAs, such as warfarin, will prevent approximately 30 strokes per 1000 patients treated for 1 year at a cost of at least two serious bleeding episodes per 1000 patient-years of treatment [28]. The benefit of warfarin as a secondary prevention in AF patients with a previous history of stroke or transient ischaemic attack has also been well established [23,29,30]. Treatment with an antiplatelet medication therapy represents an inferior alternative for patients who are either not suitable for anticoagulation or whose risk of bleeding with warfarin exceeds the risk of ischaemic stroke.

The optimal INR for patients on warfarin for AF is between 2.0 and 3.0 (target 2.5) [20]. At INRs below 2.0 and above 3.0, the risk of thromboembolism and hemorrhage, respectively, increase [20]. The benefit of warfarin therapy in AF is strongly linked to the proportion of time that patients spend in the target INR range (time in therapeutic range, TTR) [31,32]. The risk of death, myocardial infarction (MI), major bleeding and stroke or systemic embolism are all related to INR control [33]. It is worth noting that improvements in TTR of even 5–10% are clinically important [33,34].

In community-based practice, the TTR is usually only 50–60%[35], with some studies estimating that patients on warfarin may be in the therapeutic range as little as one-third of the time [36]. INR control in prospective randomized controlled trials is typically higher than that achieved in community practice. This creates issues when interpreting clinical trials comparing new antithrombotics to warfarin. In the ACTIVE-W study, for example, the benefit of warfarin over the combination of aspirin and clopidogrel was not present unless the TTR was more than 58–65%, a level that may not be achieved by many people taking warfarin. On the other hand, patients who self-monitor their INR typically spend a greater proportion of time in range than patients managed by usual care [35].

While warfarin is a widely prescribed oral anticoagulant, the optimal use of the drug has been hampered by its greater than 10-fold interpatient variability in the doses required to maintain therapeutic responses [37]. Recently, it was demonstrated that being a carrier of a combination of polymorphisms of VKORC1 and CYP2C9, rather than carrying either one of these polymorphisms, is associated with increased risk of severe over anticoagulation (INR greater than 6.0) [38]. Approximately 40% of a person's variability to warfarin dose can be explained by CYP2C9 and VKORC1 genotype [39]. The anticoagulant effect of warfarin is also subject to multiple drug and dietary interactions [40]. These include the dietary content or extent of absorption of vitamin K, the absorption and metabolism of warfarin (which are increased or decreased by many drugs), and the clearance of blood clotting factors. Intercurrent illness, starting or stopping therapy with other drugs and changes in diet or bowel function can all influence the INR. These limitations help to explain why many high-risk patients with AF and no contraindications to warfarin are not prescribed warfarin [4,41,42]. The bleeding risks and/or inconvenience of therapy with traditional anticoagulants have driven the development of new anticoagulants. This article focuses on a number of antithrombotics in development that may soon represent important new treatment options for AF.

New Antithrombotic Agents/Strategies in AF

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

The limitations of warfarin include a slow onset and offset of antithrombotic effect, a narrow therapeutic index, many pharmacokinetic and pharmacodynamic interactions, and a variable and unpredictable antithrombotic effect, all of which necessitate regular monitoring and dose adjustment. The ideal characteristics of an antithrombotic agent for AF might include the following: a rapid onset of action, a wide therapeutic index and low risk of bleeding, oral administration, a predictable antithrombotic response, freedom from drug and food interactions, a lack of significant adverse effects, no requirement for routine monitoring (although monitoring should be available if required), reversibility of antithrombotic effect and cost-effectiveness.

Rather than affecting multiple factors within the coagulation process, the new anticoagulants are generally small, synthetic molecules, which target specific factors. The exception to this is tecarfarin, a novel VKA. The tissue factor pathway and its control mechanisms present many possible targets for antithrombotic agents (see Figure 1). Thrombin and factor Xa represent central targets within the tissue factor pathway for new anticoagulants and recent data suggests that direct thrombin inhibitors (DTIs) and direct (and indirect) factor Xa inhibitors are effective anticoagulants. At present, it is unclear whether inhibition of thrombosis at the level of factor Xa (upstream) or thrombin (downstream) is more effective. Recently, new anticoagulants such as fondaparinux, dabigatran, and rivaroxaban have emerged and are indicated in various countries for the prevention and/or treatment of venous thromboembolism (VTE). Many others are currently involved in phase II or III clinical trials for stroke prevention in AF. Characteristics of selected new anticoagulants are shown in Table 2.

image

Figure 1. The role of thrombin in hemostasis. Taken from Adams [72]. Thrombin plays a central role in hemostasis through its multiple roles: (1) catalyzing the conversion of fibrinogen to fibrin, (2) amplification of blood coagulation by the activation of factors V, VIII:C, and XI, (3) activation of FXIII to FXIIIa to covalently cross-link and stabilize adjacent fibrin monomers, (4) activation of platelets by binding and cleaving protease-activated receptor molecules and proteolysis of glycoprotein V, (5) thrombomodulin-dependent activation of protein C (PC) to activated protein C, and (6) thrombomodulin-dependent activation of thrombin-activated fibrinolysis inhibitor (TAFI) to TAFIa, which helps to stabilize fibrin clots by disrupting binding sites for the fibrinolytic proteins plasminogen and tissue plasminogen activator. TF, tissue factor.

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Table 2.  Overview of selected characteristics of antithrombotics currently available for or in advanced stages of clinical development in atrial fibrillation. Modified from Harenberg [73]
 TecarfarinDabigatran etexilateApixabanRivaroxabanEdoxaban
Mechanism of actionInhibits synthesis of vitamin-K dependent clotting factorsDirect thrombin inhibitorDirect factor Xa inhibitorDirect factor Xa inhibitorDirect factor Xa inhibitor
Bioavailability%N/A6.58050>60
Administration routeOralOralOralOralOral
Dosing frequency in atrial fibrillationOnce dailyTwice dailyTwice dailyOnce dailyOnce daily
Half-life119 h14–17 h12 h9 h (12 h in elderly)9–11 h
Metabolism/excretionHepatic (noncytochrome P450 medicated)80% renal, fecalRenal, fecalRenalRenal
ReversibilityYes, vitamin KNoNoNoNo
MonitoringRegular INR monitoring requiredNo routine monitoring requiredNo routine monitoring requiredNo routine monitoring requiredNo routine monitoring required
Recent studies involving patients with atrial fibrillation (phase)EmbraceAC (II/III)RE-LY (III), RELY-ABLE (IIIb)ARISTOTLE (III), AVERROES (III)ROCKET-AF (III)ENGAGE TIMI-48 (III)

Dual Antiplatelet Therapy

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

In addition to new anticoagulant agents, dual antiplatelet therapy has also recently been compared to warfarin for the prevention of stroke in AF. In the ACTIVE-W study, patients received warfarin or aspirin and clopidogrel for the prevention of thromboembolic stroke associated with AF [43]. This study demonstrated that clopidogrel plus aspirin was less effective than warfarin and the trial was stopped early. Additionally, the rate of major bleeding with clopidogrel and aspirin was not significantly lower than for warfarin treatment (2.4% per annum for clopidogrel and aspirin vs. 2.2% per annum for warfarin). In the aspirin arm of the ACTIVE study (ACTIVE-A), the combination of aspirin and clopidogrel was compared to aspirin alone for the prevention of stroke in people with AF, who had an increased risk of stroke, but were deemed ineligible for warfarin therapy [44]. After a 3.6-year follow-up period, the risk of stroke was reduced from 3.3% per year with aspirin to 2.4% per year with aspirin and clopidogrel. This 28% relative risk reduction in stroke came at a cost of a 57% relative risk increase in major bleeding (from 1.3% per year to 2.0% per year). The authors concluded that more intensive antiplatelet therapy was superior to aspirin alone for stroke prevention in AF in those people who are ineligible for warfarin therapy.

In the ACTIVE-A trial, patients who were not suitable for warfarin therapy received aspirin or dual antiplatelet therapy. The reasons for enrolment into the study were the presence of specific risk factors for bleeding (23% of patients; inability to comply with monitoring requirements, predisposition to falls, persistent blood pressure above 160/100 mmHg, previous serious bleeding on warfarin, severe alcohol abuse for more than 2 years, peptic ulcer disease, or the need for chronic use of nonsteroidal antiinflammatory drugs), physician's judgment that warfarin therapy was inappropriate (50% of patients) or patient preference not to take warfarin (27%). One intriguing aspect of the ACTIVE-W and ACTIVE-A trials was that the risk of major bleeding was very similar in the two groups of patients treated with aspirin and clopidogrel (2.4% per year in ACTIVE-W and 2.0% per year in ACTIVE-A). In comparison, the major bleeding rate for warfarin in ACTIVE-W was 2.2% per year. Hence, while the combination of aspirin and clopidogrel may be seen as an attractive alternative for patients who are deemed ineligible for warfarin therapy, it does not seem to confer any reduction in the risk of major bleeding. Therefore, the role of aspirin and clopidogrel therapy in people with AF and an elevated risk of stroke is somewhat unclear—inferior to well-controlled warfarin, superior to aspirin but with a similar risk of major bleeding as warfarin. Double antiplatelet therapy should only be considered for patients who are definitely ineligible for warfarin (e.g., the presence of contraindications such as refusal to undergo monitoring or mental incapacity to take the dose of warfarin mandated by monitoring) [45]. Perceived high bleeding risk by prescribes should not make patients ineligible for warfarin, because the bleeding risk with dual antiplatelet therapy in both ACTIVE studies was very similar to the bleeding risk with warfarin [45].

Factor Xa Inhibitors

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

A number of direct and indirect factor Xa (FXa) inhibitors are in various stages of clinical development. The orally administered direct FXa inhibitors currently in development for the management of AF include rivaroxaban, apixaban, betrixaban, YM150, and edoxaban. Of these, rivaroxaban is the most advanced, with the phase-III ROCKET-AF study expected to finish mid-2010. The phase III ARISTOTLE study involving apixaban is also currently underway.

Factor Xa Inhibitors

Indirect antithrombotics acting via antithrombin include UFH, LMWH, heparinoids, and the pentasaccharides, fondaparinux, idraparinux, and idrabiotaparinux (biotinylated idraparinux). The structure of fondaparinux and idraparinux is based on the pentasaccharide region of UFH and LMWH molecules that is required to bind to antithrombin. The pentasaccharides exclusively inhibit factor Xa, as they do not possess the longer saccharide chains required to bind to thrombin [46]. The absence of longer saccharide chains also carries the advantage of an absence of binding to other proteins. The pentasaccharides have predictable pharmacokinetics and are administered subcutaneously, with almost 100% bioavailability. Fondaparinux has a half-life of approximately 17 h, permitting once-daily injection [47]. Fondaparinux has been evaluated in the setting of prevention and treatment of VTE and the management of acute coronary syndrome (ACS), but its need for daily administration by the subcutaneous route has precluded its evaluation in the context of chronic AF. The pentasaccharides with an extended duration of action, idraparinux and idrabiotaparinux, were compared to adjusted-dose warfarin in phase III studies involving patients with AF [48,49], but in each case further development has been ceased. The AMADEUS study comparing warfarin to idraparinux was ceased early due to an excess of bleeding in the idraparinux group (19.7% vs. 11.3%, P < 0.01), although the drug was not inferior to warfarin from an efficacy standpoint [48]. Bleeding events were more common in the elderly and in patients with renal impairment, which is perhaps not surprising given its extensive half-life and route of elimination. The development of the biotinylated derivative of idraparinux, idrabiotaparinux, was recently halted by the manufacturer.

Direct Factor Xa (FXa) Inhibitors

Direct FXa inhibitors are able to reversibly inhibit FXa when it is present in the prothrombinase complex, as well as when it is “free,” while indirect FXa inhibitors are only able to inactivate free FXa via antithrombin. The advantages of this distinction are not clear at present. The most advanced direct FXa inhibitors in clinical development are rivaroxaban, apixaban, and edoxaban, which are currently involved in phase III studies in AF. Betrixaban, YM-150, and LY-517717 are other direct factor Xa inhibitors currently in various stages of development.

Rivaroxaban

Rivaroxaban is currently indicated in some countries for the prevention of VTE following major orthopaedic surgery of the lower limbs. Rivaroxaban is well absorbed orally and can be given once daily, due to a prolonged effect on factor Xa activity. It is cleared hepatically and renally, and is contraindicated in patients with significant hepatic or severe renal impairment (CrCl < 15 mL/min), and should be used with caution in patients with significant renal impairment (CrCl 15–30 mL/min). Rivaroxaban is partly metabolized by CYP3A4 and is also a substrate for P-glycoprotein (P-GP). Coadministration of drugs that are strong inhibitors of both CYP3A4 and P-GP with rivaroxaban is contraindicated (e.g., protease inhibitors such as ritonavir, and ketoconazole). These medications may increase the plasma levels of rivaroxaban and increase the risk of bleeding. Less potent CYP3A4 and P-GP inhibitors, such as fluconazole and diltiazem, may be used with caution. Combination of rivaroxaban and other anticoagulants is not recommended [50]. Rivaroxaban should be used with caution with antiplatelet medication and nonsteroidal antiinflammatory drugs, as additive antithrombotic effects have been noted [50]. The effectiveness of rivaroxaban as thromboprophylaxis for major orthopaedic surgery has been established in the phase III RECORD studies [52–54]. Each study compared rivaroxaban 10 mg once daily to subcutaneous enoxaparin (40 mg once daily or the North American dose of 30 mg twice daily). These studies essentially found that rivaroxaban was superior to enoxaparin in thrombosis prevention. In RECORD-3 (total knee replacement), for example, rivaroxaban treatment was associated with a 49% reduction in the primary outcome (deep vein thrombosis, nonfatal pulmonary embolism and all-cause mortality) compared to enoxaparin. Major VTE (proximal deep vein thrombosis, nonfatal pulmonary embolism and VTE-related mortality) was reduced by more than 50% compared with enoxaparin [53]. The increased efficacy did not appear to come at a cost of increased bleeding, with major and minor bleeding rates being similar between treatment groups in all of the trials.

Phase III studies investigating rivaroxaban at a dose of 20 mg once daily compared to conventional treatment are underway for treatment of VTE, stroke prevention in AF and management of ACS. The ROCKET-AF study is a randomized, double-blind study comparing rivaroxaban and adjusted-dose warfarin in the prevention of stroke associated with AF. A fixed dose of 20 mg once daily is being investigated; however, patients with reduced renal function (CrCl 30 to 49 mL/min) receive 15 mg once daily.

Apixaban

Apixaban is an orally administered, selective inhibitor of free and clot-bound FXa. It has high oral bioavailability, is eliminated by multiple pathways (renal and fecal) and a low potential for drug interactions [55]. Apixaban is currently under evaluation for the prevention of thromboembolic events associated with AF in two-phase III studies: the ARISTOTLE and AVERROES studies. In ARISTOTLE, apixaban (5 mg twice daily) is being compared to adjusted-dose warfarin in patients with nonvalvular AF. A lower dose (2.5 mg twice daily) is being used for people with impaired renal function (CrCL < 30 mL/min) and for those >80 years of age or with body weight <60 kg. AVERROES includes patients who are unsuitable for warfarin. Participants are randomized to receive either apixaban (5 mg twice daily) or aspirin (81–325 mg daily). A lower dose of apixaban (2.5 mg twice daily) will be used for people >80 years and those with impaired renal function or low bodyweight.

Edoxaban

Edoxaban is a highly specific inhibitor of FXa. It is well absorbed orally, suitable for once-daily dosing, and is cleared predominantly by the kidneys. The results of a phase II study suggest that doses of 30 and 60 mg once daily are safe and effective in patients with AF. A phase III study, ENGAGE-AF TIMI-48) comparing edoxaban to warfarin for the prevention of thromboembolism associated with nonvalvular AF is currently underway.

Direct Thrombin Inhibitors

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

DTIs are a class of anticoagulants that bind directly to thrombin and block its effect on various substrates. DTIs are able to inactivate both soluble and clot-bound thrombin, which is potentially advantageous, as clot-bound thrombin can further trigger thrombus growth [56]. DTIs do not bind to plasma proteins, and so produce a predictable therapeutic effect. Ximelagatran was the first new antithrombotic to undergo phase III head-to-head comparison with warfarin in AF. The results of the RE-LY trial, comparing dabigatran and warfarin in AF, were recently published and are discussed below.

Ximelagatran, a pro-drug of melagatran, has an elimination half life of 4–5 h and is administered orally twice daily [57]. Ximelagatran does not interact with food, has a low potential for drug interactions and produces a predictable anticoagulant effect. The drug underwent extensive evaluation for prevention and treatment of VTE, prevention of thrombosis associated with AF and prevention of myocardial ischaemic events in patients with recent MI. It was initially licensed in Europe for the prevention of VTE for patients undergoing major orthopaedic surgery. Ximelagatran was compared to warfarin for the prevention of thromboembolism associated with nonvalvular AF in the two phase-III SPORTIF trials [58,59]. The rates of stroke and systemic emboli were the same for warfarin and ximelagatran, but the pooled data showed a significant reduction in major bleeds associated with ximelagatran compared to warfarin (2.5% vs. 3.4%). The pooled analysis also showed that ximelagatran increased the risk of having an elevated alanine transaminase to above three times the upper limit of normal (6.1% vs. 0.8% for warfarin). Ximelagatran was voluntarily withdrawn from the global market by the manufacturer following concerns regarding the long-term safety of the drug, after 3 deaths due to hepatic failure occurred in patients receiving the medication.

Dabigatran

Dabigatran etexilate, another oral DTI, has recently become available in some countries for the prevention of VTE associated with major orthopaedic surgery. Dabigatran etexilate is a double pro-drug which is poorly absorbed from the GI tract (5 to 6% bioavailability) [60]. Absorption requires an acidic environment and is reduced by potent acid suppressive therapy [57]. The area under the plasma concentration-time curve for dabigatran was reduced by 30% when co-administered with pantoprazole, although no clinical adverse effects were noted in early clinical trials. Ranitidine does not have a significant effect on absorption. Given the requirement for low pH to enhance absorption, dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core. This acidity is thought to be partly responsible for an increase in dyspeptic symptoms associated with dabigatran therapy [61].

Dabigatran etexilate is a substrate for P-GP, and co-administration with other medications that induce or inhibit P-GP will affect its oral absorption. Quinidine (a P-GP inhibitor) is contraindicated as it resulted in a number of adverse effects when administered with dabigatran. Close surveillance is recommended with moderately strong P-GP inhibitors, such as amiodarone, clarithromycin, cyclosporin, itraconazole, ketoconazole, nelfinavir, ritonavir, saquinavir, tacrolimus and verapamil, as co-administration would be expected to increase plasma dabigatran levels and increase the risk of bleeding. Concomitant use of additional antithrombotic agents would be expected to increase the risk of bleeding, and the results of trials involving combination antithrombotic therapy in patients with ACS will be informative. Nonsteroidal antiinflammatory drugs, particularly those with long half-lives, may also increase the risk of bleeding. Routine monitoring of the anticoagulant effect of dabigatran is not required, although the aPTT or plasma dabigatran level can be measured. Hepatic impairment is listed as a precaution for dabigatran therapy, but hepatotoxicity has not yet emerged as a significant problem.

Dabigatran has a half-life of 8 h after a single dose and up to 17 h after continuous dosing; it is therefore be suitable for once-daily dosing for some indications [57]. Dabigatran is predominantly excreted unchanged (∼80%) via the kidneys; it is contraindicated in significant renal impairment (CrCl < 30 mL/min). Dosage reduction is recommended in moderate renal impairment (CrCl 30 to 50 mL/min).

The RE-LY trial compared dabigatran etexilate 110 or 150 mg twice daily versus warfarin for stroke prevention in 18,000 patients with AF [61]. The primary outcome was a composite of stroke (hemorrhagic or ischaemic) or systemic embolism. The primary outcome occurred at a rate of 1.69% per year in the warfarin group, 1.53% per year in the dabigatran 110 mg group and 1.11% per year in the dabigatran 150 mg group. The difference in the primary outcome between the warfarin group and the dabigatran 150 mg group was statistically significant (P < 0.001). The rate of major bleeding was 3.36% per year in the warfarin group, 2.71% per year in the dabigatran 110 mg group (P= 0.003) and 3.11% per year in the dabigatran 150 mg group (P= 0.31). Warfarin therapy was well controlled in the trial (TTR was 64%). In summary, dabigatran at a dose of 110 mg twice daily was safer than warfarin, while 150 mg twice daily was slightly more effective. People with severe renal impairment (<30 mL/min), hepatic impairment or who were known to be noncompliant with medication were excluded from the trial, so the role of dabigatran in these patients is unclear [62]. Dabigatran was associated with a greater incidence of nonhemorrhagic adverse effects (mainly GI in nature), which is probably due to the formulation characteristics of dabigatran capsules, which contain an acidic core to assist absorption. The rate of myocardial infarction was also higher in patients who received dabigatran. The rates of myocardial infarction for patients receiving dabigatran 110 mg twice daily, 150 mg twice daily and warfarin were 0.72%, 0.74%, and 0.53%, respectively. Given that approximately 30% of people with AF have ischaemic heart disease [20], it will be important to determine whether or not selective thrombin inhibition contributes to myocardial infarction and how concomitant antiplatelet therapy influences this risk. Potential disadvantages with dabigatran include the need for twice-daily dosing and the increased risk of nonhemorrhagic complications. For people already well controlled on warfarin, these issues would need to be considered against the potential benefits of switching to dabigatran. For other patients with AF and an increased risk of stroke, dabigatran may represent a useful alternative to warfarin.

The RELY-ABLE study is an extension of RE-LY, and will include patients who took dabigatran and successfully completed RE-LY. Participants will remain on dabigatran (110 mg twice daily or 150 mg twice daily) for 12–36 months. This study will provide important longer-term safety information regarding dabigatran.

Novel Vitamin K Antagonist

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

Tecarfarin is a novel VKA which, like warfarin, inhibits vitamin K epoxide reductase [63]. It is a structural analogue of warfarin and has a half-life of approximately 119 h and is highly plasma protein bound. The key difference between tecarfarin and warfarin is that tecarfarin is not metabolized by cytochrome P450 enzymes in the liver. Instead it undergoes metabolism by carboxylesterases found in hepatic microsomes, yielding an inactive metabolite [63]. This agent, therefore, is expected to be largely free of metabolic drug interactions and the genetic differences in CYP450 enzyme activity that make other VKAs problematic to initiate and manage. Compared to the other new anticoagulants, tecarfarin, because of its identical mode of action to warfarin, would retain its advantages, which include the availability of routine testing, validated target ranges for a range of indications and reversibility with vitamin K. Freedom from a vast array of drug interactions and a major source of dose variation should result in improved INR control, and consequently, improved clinical outcomes. An open-label phase II study compared warfarin and tecarfarin in 66 patients with AF. The majority of these patients were switched from warfarin to tecarfarin (64/66). The time in range during the 6–12 week exposure to tecarfarin was 71%, a value comparing favorably to the average TTR for the previous 12 months on warfarin, which was 59% (P < 0.001) [64].

EmbraceAC was a phase II/III randomized, double-blind trial comparing tecarfarin and warfarin in patients requiring long-term anticoagulation (AF, prosthetic heart valve, VTE or a history of myocardial infarction or cardiomyopathy). The primary outcome was INR control, measured by the TTR. Six hundred twelve patients were enrolled and treated for a minimum of 6 months with tecarfarin or warfarin. A central dose control center comprised of clinicians experienced in managing anticoagulation therapy independently controlled the dosing of patients and monitoring of patients’ anticoagulation status. Excluding the initial 4-week initiation and stabilisation phase, the TTR in the tecarfarin and warfarin groups was 74.0% and 73.2%, respectively (P= 0.506). The impressive performance of warfarin in EmbraceAC is likely to have been due to the skill of the dose control center clinicians managing the INRs, including anticipatory dose adjustments and increased follow-up when interacting medications were used. It remains to be seen whether tecarfarin will result in improved INR control compared to warfarin when managed in conventional primary care settings.

Conclusions

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References

There is a clear need for antithrombotics which are as effective or superior to warfarin, but do not share its limitations such as a need for regular monitoring and dosage adjustment. Because of these limitations, warfarin is underused in AF, and in those who are taking it, control of the INR is often suboptimal [65]. A number of new anticoagulants may soon be available for use in AF as alternatives to warfarin. While they possess potential advantages to warfarin, clinicians should also consider the potential limitations (see Table 3). It is interesting to note that a lack of routine monitoring can be considered as an advantage or as a critical limitation. The newer agents do not requiring routine monitoring of their anticoagulant effect because they have a more predictable pharmacokinetics, so this is not likely to be an issue for many patients. Some people for whom monitoring might prove useful include those with renal and/or hepatic failure, advanced age and those taking certain interacting medications. At present it is unclear how these new agents should be monitored. The activated prothrombin time, anti-FXa activity, INR or drug level are possibilities but to be used in a meaningful way these need to be validated to establish target parameters for each new anticoagulant. This will be important considering that these medications may be used widely in an elderly population a long-term basis.

Table 3.  Potential limitations of the new anticoagulants
Potential limitationNotes
  1. INR, international normalised ratio.

Lack of validated tests to monitor anticoagulant effectCan monitor the INR with tecarfarin as for warfarin
No established therapeutic rangeEstablished INR ranges can be used for tecarfarin
No antidoteVitamin K can be used for tecarfarin
Assessment of compliance difficultTecarfarin can be monitored
Unknown potential for long-term adverse effectsXimelagatran was withdrawn due to serious hepatic adverse events
Unknown cost-effectiveness compared to established therapiesEstablished vitamin K antagonists are cheap and effective, although the cost and difficulty of routine monitoring must be considered
Lack of head-to-head studies comparing new anticoagulantsPotentially, multiple new anticoagulants will become available in a relatively short period of time without comparative studies
New agents are being tested for some, but not all indicationsNo phase III studies of new anticoagulants have involved patients with mechanical heart valves
Lack of evidence surrounding the risks and benefits of combination antithrombotic therapy for people with multiple conditions requiring antithrombotic treatmentMany patients with AF have ischaemic heart disease and may be treated with antiplatelet medications in addition to their anticoagulant

Nonadherence to the treatment regimen may also be an issue with new oral antithrombotics, as it is with other medications used to treat chronic diseases [66]. For example, more than half of elderly patients receiving statin therapy discontinue their treatment within the first 6 months [67]. Medication adherence also declines as the dosing frequency increases [68]. Interestingly, regular monitoring is one strategy to improve adherence [69]. It is well known that adherence to medication is higher in the clinical trial setting, so in the real-world there will be a balance between the ability of new antithrombotics to potentially increase the prescribing of antithrombotics in people with AF at high risk of stroke against the proportion of people who continue to actually take their medication on a regular basis. This may be preferable to the current situation with warfarin, where underuse is prevalent, but it is relatively easy to identify people who are nonadherent or nonpersistent with treatment, but this remains to be seen.

Experience with other unmonitored medications (e.g., clopidogrel) suggests that, in real-world conditions, resistance (either acquired or genetic) to the pharmacological effects of some anticoagulants may become an issue. Finally, the new anticoagulants do not currently have antidotes, so the management of bleeding will therefore be challenging [70].

Notwithstanding these potential issues, the days of VKAs remaining the only choice for long-term anticoagulation are short. New anticoagulants possess many advantages to established treatment options and may result in more high-risk patients with AF receiving appropriate antithrombotic therapy. Clinicians will need to come to terms with the availability of several new anticoagulants and their associated clinical issues. It is too early to establish the comparative effectiveness of the new anticoagulants in AF, but this will become clear as additional trial results become available and the relative effectiveness of these agents to warfarin can be assessed. Only the long-term use of the new outside of the clinical trial environment will conclusively demonstrate how these agents compare to established agents in terms of efficacy, safety, and cost, but the new anticoagulants certainly carry significant potential to improve the management of AF.

References

  1. Top of page
  2. SUMMARY
  3. Introduction
  4. New Antithrombotic Agents/Strategies in AF
  5. Dual Antiplatelet Therapy
  6. Factor Xa Inhibitors
  7. Direct Thrombin Inhibitors
  8. Novel Vitamin K Antagonist
  9. Conclusions
  10. Conflict of Interests
  11. References