Recent progress in anticoagulant therapy: oral direct inhibitors of thrombin and factor Xa

Authors


Kenneth A. Bauer, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.
Tel.: +617 667 2174; fax: +617 667 1030.
E-mail: kbauer@bidmc.harvard.edu

Abstract

Summary.  While parenteral anticoagulants such as unfractionated and low molecular weight heparins and the oral vitamin K antagonists are effective for the prevention and treatment of thrombosis, they have a number of limitations. Up until recently, vitamin K antagonists (e.g. warfarin) have been the only available oral anticoagulants. These drugs have a delayed onset of action, food and drug interactions, and variable pharmacokinetics/pharmacodynamics such that regular laboratory monitoring and dose adjustments are required to maintain the International Normalized Ratio (INR) in the therapeutic range. New oral anticoagulants that selectively inhibit either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban, apixaban) have now gained approval in many countries for some clinical indications. Unlike warfarin, these drugs have a rapid onset of action and a relatively wide therapeutic range such that coagulation monitoring is not required. These agents are more convenient for patients and health care providers, but also have potential for improving clinical outcomes and being more cost-effective than existing agents. This will result in major changes in the way that thrombosis is managed, both with respect to prevention and treatment. The new oral inhibitors of thrombin and factor Xa, however, have limitations and the absence of a need for regular laboratory monitoring makes medication compliance extremely important for maintaining efficacy given their relatively short half-lives. Furthermore there will be challenges in managing patients on these agents who develop recurrent thrombosis or major bleeding until methods to monitor and assess the levels of the new agents are readily available and specific antidotes are developed.

Introduction

The coagulation pathway is centrally involved in the formation of both venous and arterial thrombi and the development of molecules that inhibit its function is a major strategy for the design of new antithrombotic drugs. Until relatively recently, pharmacologic prophylaxis and treatment of venous thromboembolism (VTE) were based on two types of anticoagulants, parenteral agents working indirectly by potentiating plasma antithrombin activity (unfractionated heparin, low-molecular-weight heparins, and fondaparinux) and vitamin K antagonists (e.g. warfarin). These antithrombotic agents are multi-targeted, that is act on a number of coagulation factors.

For more than 50 years, vitamin K antagonists (e.g. warfarin) were the only available oral anticoagulants. However, the use of warfarin is associated with > 10-fold inter-individual variation in dose to achieve therapeutic anticoagulation; genetic polymorphisms (CYP 2C9 and VKORC1) account for a portion of the variability in dose-response. The pharmacokinetics of warfarin are also influenced by dietary vitamin K intake, other medications, alcohol use, patient age, body weight, and various diseases states, necessitating regular coagulation monitoring to ensure that patient’s international normalized ratio (INR) remains within the target range.

New oral anticoagulants that are selective for one specific coagulation factor, either thrombin or factor Xa, have been taken through clinical development and have recently become available for the prevention and treatment of thrombosis. Thrombin plays a central role as a procoagulant by converting fibrinogen to fibrin as well as by activating its other substrates including factor factor V, factor VIII, factor XI, factor XIII, and the platelet protease activated receptors (PAR-1 and PAR-4). The substrate specificity of thrombin derives from specific surface binding sites (e.g. exosite 1 for fibrin) for its substrates. Direct thrombin inhibition is therefore an attractive antithrombotic strategy. Oral direct thrombin inhibitors inhibit thrombin by directly binding to the active site of thrombin. Factor Xa is also an attractive target for the design of new anticoagulants as factor Xa is positioned at the start of the common pathway of coagulation. As the amount of serine protease is amplified at each step of the cascade, it has been hypothesized that the selective inhibition of coagulation factors above thrombin might also be a highly effective antithrombotic strategy. Furthermore by not inhibiting thrombin activity directly, such agents might allow traces of thrombin to escape neutralization, thereby facilitating hemostasis and leading to a favorable safety profile with respect to bleeding.

Oral direct thrombin inhibitors

Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, was the first targeted oral anticoagulant to be taken through clinical development. Preclinical studies indicated that ximelagatran had a relatively wide therapeutic window compared to the vitamin K antagonist warfarin, and pharmacologic studies in humans showed that ximelagatran produced a predictable anticoagulant response with little in the way of food or drug interactions. In randomized phase III clinical trials, ximelagatran was as efficacious as warfarin in the prophylaxis and treatment of venous thromboembolism (VTE) as well as stroke prevention in atrial fibrillation [1–6]. However due to hepatotoxicity, ximelagatran did not receive FDA approval in the U.S. in 2004. While a regimen of ximelagatran along with the parenteral agent melagatran in the perioperative period was approved in Europe for the short-term prophylaxis of deep venous thrombosis (DVT) following major orthopedic surgery, the drugs were removed from the market in 2006 and its development was discontinued. Serious liver injury was observed in patients in a clinical trial receiving ximelagatran as thromboprophylaxis for up to 35 days following major orthopedic surgery. The phase III clinical trials of ximelagatran, nevertheless, provided ‘proof of principle’ by demonstrating that fixed doses of an oral anticoagulant without routine coagulation monitoring is as efficacious as warfarin in preventing and treating thrombosis in adults with adequate renal function (i.e. creatinine clearance > 30 mL min−1). Ximelagatran also had a safety profile similar to warfarin with respect to major bleeding complications. Fixed dosing using either once or twice daily drug administration without coagulation monitoring is a central feature of the oral direct thrombin and factor Xa inhibitors in clinical development; similar to ximelagatran, these agents have a relatively wide therapeutic window compared to vitamin K antagonists. The pattern of hepatotoxicity observed with ximelagatran was specific to this drug or drug class, and has not been observed with the other oral anticoagulants that have gone through advanced phases of clinical development.

Dabigatran etexilate is an oral prodrug that is converted to dabigatran (Fig. 1), a competitive direct thrombin inhibitor (Ki 4.5 nmol L−1), by hydrolytic cleavage mediated by plasma esterases in vivo [7]. The properties of dabigatran etexilate are shown in Table 1 in comparison with warfarin and several oral factor Xa inhibitors in clinical development. Dabigatran is not metabolized by the cytochrome P450 enzymes or oxidoreductases. Dabigatran etexilate has 6%–7% oral bioavailability and is encapsulated with tartaric acid to facilitate absorption in the gastrointestinal tract. Peak plasma concentrations are reached 1–2 h after administration, and its mean terminal half-life is ∼9 and 13 h in younger and older healthy individuals, respectively. About 80% of the drug is cleared renally. Despite the need for a localized acidic environment for consistent absorption of dabigatran etexilate, it is not dependent on overall gastrointestinal acidity and dose modifications are not required with the use of proton pump inhibitors. Dabigatran etexilate has relatively few drug interactions, but p-glycoprotein transporter inhibitors, like amiodarone, verapamil, or quinidine increase drug exposure; use of the drug with rifampin, a p-glycoprotein inducer, should be avoided as it reduces the drug’s anticoagulant effect. There is no specific antidote to reverse the anticoagulant effect of dabigatran; approaches for managing serious bleeding and monitoring the drug’s anticoagulant activity in such situations have been published [8]. Hemodialysis is effective in removing ∼60% of the dabigatran in the blood over 2–3 h and can be used to treat dabigatran toxicity.

Figure 1.

 Chemical structures of the dabigatran [7], and the direct oral factor Xa inhibitors, rivaroxaban [9], and apixaban [10]. Dabigatran etexilate is an oral prodrug that is converted to dabigatran, a direct thrombin inhibitor, by hydrolytic cleavage.

Table 1.   Properties of warfarin and oral inhibitors of thrombin and factor Xa inhibitors approved for use or in advanced stages of development
DrugWarfarinDabigatran etexilateRivaroxabanApixabanEdoxaban
TargetApixaban Vitamin K epoxide reductase (VKORC1) (reducing the functional levels of vitamin K dependent coagulation factors)ThrombinFactor XaFactor XaFactor Xa
  1. T (max), peak plasma levels; h, hours; INR, international normalized ratio; PT, prothrombin time; CYP, Cytochrome P; p-gp transporters, p-glycoprotein transporters. Adapted from [13] and [14].

ProdrugNoYesNoNoNo
Bioavailability> 95%6.5%80%∼66%50%
T (max)72–96 h1–2 h2.5–4 h3 h1–3 h
Half-life40 h9–13 h7–11 h8–15 h9–11 h
Routine coagulaton monitoringYesNoNoNoNo
DosingOnce daily (INR-adusted)Fixed, once or twice dailyFixed, once or twice dailyFixed, twice dailyFixed, once daily
EliminationNone80%67% renal (half is inactive drug), 33% fecal25% renal, 75% fecal35% renal, 65% fecal
Potential drug interactionsCYP 2C9, 3A4, and 1A2Potent p-gp inhibitorsPotent CYP 3A4 and p-gp inhibitorsPotent CYP 3A4 inhibitorsPotent CYP 3A4 and p-gp inhibitors

Oral factor Xa inhibitors

Rivaroxaban is a synthetic small molecule that binds competitively to the active site of factor Xa (Ki 0.4 nmol L−1); it is a not a prodrug. It is rapidly absorbed after ingestion with ∼80% bioavailability and maximal plasma concentrations are achieved in 2.5–4 h [11]. Rivaroxaban has a half-life of 7–11 h and a dual mode of elimination; one-third is excreted unchanged by the kidney and two-thirds is converted by the liver (CYP 3A4) to inactive metabolites. Strong inhibitors of both CYP 3A4 and p-glycoprotein, such as ketoconazole or HIV protease inhibitors (e.g. ritonavir), are not recommended.

Like rivaroxaban, apixaban is not a pro-drug and binds to the active site of factor Xa (Ki 0.08 nmol L−1). It has > 50% oral bioavailability and maximal plasma concentrations are achieved within 3 h. It has a half-life of 8–15 h and is metabolized by the liver (partially by CYP 3A4); 75% is eliminated in the feces and 25% by the kidneys [12]. Strong inhibitors of both CYP 3A4 and p-glycoprotein can raise plasma levels of apixaban.

The discussion below will focus on the agents for which phase III trials for major indications have been completed, dabigatran etexilate, rivaroxaban, and apixaban. Edoxaban is currently in phase III trials for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and for the initial and long-term treatment of VTE. The properties of these agents are summarized in Table 1 [13,14]. Other oral factor Xa inhibitors in clinical development include betrixaban, darexaban, and TAK-442.

Prophylaxis of VTE

Adult patients who undergo major surgical procedures or who are hospitalized for major medical illness should receive pharmacologic thromboprophylaxis to prevent VTE in the absence of contraindications. Unfractionated and low molecular weight heparin, or fondaparinux require subcutaneous injection. Warfarin is widely used in some countries following major orthopedic surgery, but is relatively ineffective soon after surgery, due to its delayed onset of action, and requires dose adjustments to achieve an INR of 2–3. These limitations often lead to the duration of thromboprophylaxis being shorter than that used in clinical trials demonstrating its efficacy. It is estimated that nearly 50% cases of symptomatic VTE in the U.S. are associated with a hospitalization in the previous 90 days [15]. Administration of one of the new anticoagulants for a longer duration than is currently done in routine clinical practice could significantly reduce the incidence, morbidity, and mortality of VTE.

Dabigatran etexilate received approval in Europe and Canada for VTE prevention following orthopedic surgery. This was based on two studies that showed non-inferiority to enoxaparin at a dose of 40 mg daily beginning 12 h pre-operatively and daily post-operatively [16,17]; the doses of dabigatran etexilate were 75 or 110 mg starting 1–4 h postoperatively followed by 150 or 220 mg once daily. Patients undergoing total knee replacement and total hip replacement were treated for 6–10 and 28–35 days, respectively. Dabigatran did not achieve non-inferiority, however, in the RE-MOBILIZE trial [18], where enoxaparin was dosed at 30 mg twice daily beginning 12–24 h post-operatively in patients undergoing total knee replacement. In this trial, the initial dose of dabigatran etexilate was only administered 6–12 h post-operatively for 12–15 days.

Rivaroxaban starting 6–8 h post-operatively at a dose of 10 mg daily is approved in Europe and Canada for VTE prevention following major orthopedic surgery based on the four RECORD trials; two were in patients undergoing total hip replacement with one trial having different durations of therapy [19,20], and two were in total knee replacement using the two different enoxaparin prophylaxis regimens [21,22]. In all four RECORD trials, rivaroxaban was superior to enoxaparin in preventing VTE with similar risks of major bleeding. A pooled analysis of the four trials however indicated a small increase in bleeding [23], an issue of particular concern to orthopedic surgeons that carries a potential need for reoperation [24]. Using the Canadian Healthcare System, a model including both acute VTE and long-term complications indicates that rivaroxaban is a cost-effective alternative to enoxaparin for VTE prophylaxis in patients undergoing total hip or knee replacement [25].

The efficacy of apixaban in VTE prevention following major orthopedic surgery was compared to enoxaparin in the ADVANCE trials. The ADVANCE 1 trial in patients undergoing total knee replacement failed to show that apixaban at a dose of 2.5 mg twice daily was non-inferior based on pre-specified criterion to enoxaparin 30 mg twice daily starting post-operatively; both drugs were started ∼12 h after surgery. Apixaban however was associated with significantly less major bleeding than enoxaparin (0.7% vs. 1.4%, P = 0.05). The ADVANCE 2 and 3 trials in total knee and hip replacement, respectively [26,27], found apixaban to be significantly more efficacious (all VTE and death) than the 40 mg regimen of enoxaparin with similar rates of major bleeding.

It is important to note that absolute rates of DVT after major orthopedic surgery can differ between trials based upon the criteria for adjudicating leg thrombi on venograms. In patients undergoing total knee replacement, this may account, in part, for the markedly different DVT rates that were ∼20% higher for the 40 mg enoxaparin regimen in the dabigatran trials than in the RECORD trials.

In acutely ill medical patients, the efficacy and safety 10 mg of rivaroxaban once daily for 35 days (http://www.clinicaltrials.gov; identifier NCT00571649) or apixaban 5 mg twice daily (http://www.clinicaltrials.gov; identifier NCT00457002) are separately being studied in phase III trials vs. 10 days of enoxaparin administered at a dose of 40 mg once daily. The preliminary results of the MAGELLAN trial demonstrated non-inferiority of rivaroxaban at 10 days for the primary efficacy endpoint (a composite of asymptomatic proximal DVT detected by ultrasonography, symptomatic DVT, symptomatic nonfatal pulmonary emboli, and VTE-related death), which occurred in 2.7% of patients in each group. Continuation of rivaroxaban for 35 days resulted in significantly fewer events at day 35 as compared to placebo (4.4% vs 5.7%; RR = 0.77, 95% CI 0.62–0.96). However the primary safety endpoint, a composite of major bleeding and clinically relevant non-major bleeding was significantly increased at both day 10 and day 35 (RR = 2.3, P ≤ 0.0001 and RR = 3.0, P ≤ 0.0001). In a previous randomized trial in acutely ill medical patients, extended-duration enoxaparin at a dose of 40 mg for 28 ± 4 vs. 10 ± 4 days significantly reduced the incidence of VTE to 2.5% from 4% [28]. Extended duration enoxaparin, however, also significantly increased major bleeding events from 0.3% to 0.8% at 28 days. The benefits of extended-duration enoxaparin seemed to be restricted to women, patients older than 75 years, and those with level 1 immobility (bedrest or sedentary without bathroom privileges).

Treatment of VTE

The RE-COVER [29] and RE-MEDY trials (http://www.clinicaltrials.gov; identifier NCT NCT00329238) are comparing dabigatran etexilate to warfarin for the treatment and secondary prevention of symptomatic VTE, respectively. The RE-COVER trial was a blinded, non-inferiority trial comparing the efficacy and safety of dabigatran etexilate at a dose of 150 mg twice daily with warfarin at a target INR of 2–3) for 6 months in patients with acute VTE; all were initially treated with a 5- to 10-day course of standard parenteral LMWH or heparin therapy. Pre-specified criteria for non-inferiority were met; recurrent VTE occurred in 2.4% of dabigatran-treated patients vs. 2.1% of warfarin patients (hazard ratio, 1.10; 95% CI, 0.65–1.84). Major bleeding occurred in 1.6% and 1.9% of dabigatran- and warfarin-treated patients, respectively. Additional trials of dabigatran etexilate for the treatment and secondary prevention of VTE are ongoing. The drug has not yet been approved by regulatory agencies for the treatment of VTE, though the dose is the same as that approved for stroke prevention in atrial fibrillation.

In the EINSTEIN study of patients presenting with acute DVT, rivaroxaban alone was compared with enoxaparin followed by a vitamin K-antagonist for 3, 6, or 12 months; the rivaroxaban dose was 15 mg twice daily for 3 weeks followed by 20 mg once daily [30]. Rivaroxaban alone had non-inferior efficacy with respect to the primary outcome (2.1%) vs. enoxaparin/vitamin K antagonist (3.0%); (hazard ratio, 0.68; 95% confidence interval [CI], 0.44–1.04). The principal safety outcome of major and clinically-relevant non-major bleeding occurred in 8.1% of the patients in each group. In the continued-treatment study, rivaroxaban had superior efficacy with a recurrence rate of 1.3%, vs. 7.1% in patients on placebo (hazard ratio, 0.18; 95% CI, 0.09–0.39; P < 0.001). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), vs. none in the placebo group (P = 0.11).

Rivaroxaban offers a simple and convenient single-drug oral approach to the initial treatment of venous thrombosis; this approach is also being tested with apixaban (http://www.clinicaltrials.gov; identifier NCT00643201). Regulatory agency approval of this new pharmacologic strategy for treating VTE by regulatory agencies may await completion of the EINSTEIN pulmonary embolism study (http://www.clinicaltrials.gov; identifier NCT00439777); this trial has a similar design to the EINSTEIN-DVT study and is still ongoing. A single drug oral approach will likely improve the benefit-to-risk profile of anticoagulation for VTE and eliminate the need for a two anticoagulant approach (heparin followed by warfarin); it also will be highly cost-effective by reducing the need for hospitalization and INR monitoring, which is particularly cumbersome during the initial phase of treatment with a vitamin K-antagonist. It should be emphasized however that the patients enrolled in these trials are standard or low risk patients, most of whom are sustaining their first episode of DVT or pulmonary embolism. At this time, we have little information regarding the efficacy and safety of the targeted oral anticoagulants in high-risk patients such as those with active malignancy, who are known to have a high recurrence rate on warfarin or patients who develop a recurrence while on warfarin with an INR of 2–3. Currently such patients are often managed by administering low molecular weight heparin at therapeutic doses on a chronic basis [31].

Prevention of stroke and systemic embolism in atrial fibrillation

Warfarin prevents more than 60% of strokes in patients with atrial fibrillation and has been the recommended treatment for those with this rhythm abnormality and one additional risk factor [32]. Failure to maintain the INR in the therapeutic range can either reduce its benefit or increase the risk of major hemorrhage. As a result, many patients with atrial fibrillation at risk for stroke are either not started on warfarin or discontinue therapy after it is started. Thus many patients with atrial fibrillation at risk of stroke could benefit from the approval of oral direct thrombin or factor Xa inhibitors in this indication.

The RE-LY trial compared dabigatran etexilate to warfarin in 18 113 patients with non-valvular atrial fibrillation [33]. Two doses of dabigatran etexilate, 110 or 150 mg twice daily administered in a blinded fashion, were compared with adjusted-dose warfarin administered in an unblinded manner. The median CHADS2 score of the population was 2.1. The primary efficacy outcome was systemic embolism or stroke (including hemorrhagic stroke); the major safety endpoint was hemorrhage, which was defined as a drop in the hemoglobin level of at least 2 g dL−1, transfusion of at least 2 units of blood, or symptomatic bleeding in a critical organ. The stroke or systemic embolism rate was significantly lower with dabigatran etexilate at a dose of 150 mg twice daily (1.11%, RR 0.66; 95% CI 0.53–0.82; P < 0.001 for superiority) compared to warfarin, and the 110 mg BID dose was non-inferior (1.53%; RR 0.91; 95% CI 0.74–1.11 P < 0.001 for noninferiority) compared to warfarin (1.69%). The rate of major bleeding with the 150 mg dose was not different to that with warfarin (3.11% vs. 3.36%; RR 0.93; 95% CI 0.81–1.07 P = 0.31), while it was significantly lower with the 110 mg dosed compared with warfarin (2.71% vs. 3.36%; RR 0.80; 95% CI 0.69–0.93; P = 0.003). The rates of hemorrhagic stroke with the 110 and 150 mg dabigatran etexilate doses (0.12% and 0.10%) were both significantly lower than with warfarin (0.38%).

The achievement of therapeutic INRs was 64% in the warfarin arm of the RE-LY trial. A sub-group analysis of the warfarin arm according to INR control (based on time on therapeutic range) showed that the advantages of dabigatran were greater at sites with poorer INR control; this data indicates that patients on warfarin with excellent INR control (> 72.6% time in therapeutic range) have less to gain by switching to dabigatran from warfarin [34].

A side effect of dabigatran etexilate was dyspepsia, which occurred significantly more commonly with dabigatran etexilate (11.8% and 11.3% in 110 and 150 mg dabigatran group) than with warfarin (5.8%) (P < 0.001 for both). Myocardial infarction (MI) also occurred more commonly with dabigatran (0.72% and 0.74% with 110 and 150 mg of dabigatran etexilate, respectively), compared to 0.53% with warfarin (P = 0.07 and 0.048, respectively); the latter was no longer statistically significant with the inclusion of newly identified events that were indentified after the database was originally locked (P = 0.12) [35].

Based on the results of the RE-LY trial, dabigatran etexilate has been approved in many countries for the prevention of stroke and systemic embolism as an alternative to warfarin. While both the 110 and 150 mg dosing schedules have been approved in some countries, only the higher dose was approved in the U.S. [36]; a dose of 75 mg twice daily was however approved for patients with renal dysfunction (creatinine clearance 15–30 mL min−1). The cost-effectiveness of dabigatran etexilate for stroke prevention in atrial fibrillation has been estimated compared to INR-adjusted warfarin over patient’s lifetime using clinical data from the RE-LY trial. Using Markov decision model, the analysis indicates that dabigatran is a cost-effective alternative to warfarin at its current price in the U.S. (wholesale acquisition cost of ∼$7 per day) [37].

In the double-blind ROCKET-AF trial containing over 14 000 patients, rivaroxaban at a dose of 20 mg once daily was noninferior to warfarin in reducing stroke and systemic embolism with a similar rate of major bleeding [38]. The median CHADS2 score of the population was just under 3.5. Though the ‘on-treatment’ analysis did show superiority, superiority was not achieved in the intention-to-treat analysis. Therapeutic INRs were achieved in 58% of patients in the warfarin arm, and the rate of intracranial hemorrhage was significantly lower in patients randomized to rivaroxaban.

The ARISTOTLE study is evaluating apixaban at a dose of 5 mg twice daily to warfarin, for stroke prevention in over 18 000 AF patients with a median CHADS2 score of 2 [39]. This randomized, event driven, double-blind, non-inferiority study is closed to patient entry and completing follow up. It will be reported in 2011 (see http://www.clinicaltrials.gov; identifier NCT00412984).

Apixaban at a dose of 5 mg twice daily was compared to aspirin (81–324 mg QD) for stroke prevention in atrial fibrillation (AVERROES trial) [40]. This study included 5599 patients, who had failed or were deemed unsuitable for warfarin, was stopped early because of a clear benefit in favor of apixaban The rates of stroke and systemic embolism were 1.6% and 3.7% per year in patients on apixaban and aspirin, respectively (hazard ratio with apixaban 0.45; 95% CI 0.32–0.62, P < 0.001). The annual rates of major bleeding were similar at 1.4% and 1.2% per year in the apixaban and aspirin arms, respectively, as were the number of cases of intracranial bleeding (11 with apixaban and 13 with aspirin). The mean CHADS2 score of patients in this trial was 2.0. Based on the results of the intention-to-treat analysis, treatment of 1000 patients for 1 year with apixaban as opposed to aspirin would prevent 21 strokes or systemic emboli, nine deaths, and 33 hospitalizations for cardiovascular causes, at the cost of only two major bleeding events.

Acute coronary syndromes

Phase II studies have been performed to evaluate whether the oral factor Xa inhibitors, rivaroxaban or apixaban, can reduce the risk of recurrent coronary ischemic events in conjunction with antiplatelet agents [41,42] Though a trend toward a reduction in ischemic events was observed, there was a dose-related increase in bleeding that is accentuated in the presence of dual anti-platelet therapy (i.e. aspirin and a thienopyridine). Indeed APPRAISE-2 (http://www.clinicaltrials.gov; identifier NCT00831441), a phase III trial of apixaban in acute coronary syndrome used the same dose and schedule (5 mg twice daily) that is being investigated for stroke prevention in atrial fibrillation, and it was stopped in late 2010 because of an excessive bleeding risk. A phase III trial of rivaroxaban for this indication (http://www.clinicaltrials.gov; identifier NCT00809965) is still ongoing; however the total daily dose of rivaroxaban being tested is substantially lower that that used in ROCKET-AF trial (either 2.5 or 5 mg twice daily in addition to standard antiplatelet therapy).

Conclusion

Oral direct thrombin and factor Xa inhibitors offer many advantages over vitamin K-antagonists and parenteral anticoagulants for several common clinical indications (Table 2). The availability of an immediately acting oral anticoagulant that does not require laboratory monitoring will greatly facilitate prophylaxis against VTE and likely lead to a more extended duration of primary prophylaxis for patients with major transient thrombotic risk factors than is the case today, thereby reducing the burden of symptomatic VTE. For the therapy of symptomatic VTE, the oral agents are likely to eliminate the need for two-drug regimens for many acute thromboembolic conditions (i.e. heparin or LMWH followed by warfarin). This will simplify care for the patient and physician, lead to improved quality of life for the patient, and likely be highly cost-effective. The new agents may also lead to greater use of anticoagulants in patients with atrial fibrillation, which is widely undertreated with vitamin K-antagonists, as well as better outcomes.

Table 2.   Potential advantages and disadvantages of oral direct thrombin and factor Xa inhibitors
AdvantagesDisadvantages
Immediate onset of action potentially eliminates need for initially treating thrombosis or ‘bridging’ patients at high risk of thrombosis with a parenteral anticoagulantRenal elimination contraindicates use or necessitates dose reduction in patients with kidney dysfunction
Absence of food interactions, relatively wide therapeutic index, limited hepatic metabolism and few drug interactions enables fixed dosing in adults without need for laboratory monitoringLimited availability of assays for measuring drug levels and absence of validated monitoring strategies prevent dose titration or determination of failure of therapy vs. poor compliance
Greater convenience for patients and providers with potential for greater use than vitamin K-antagonists, particularly in atrial fibrillationPotential for overuse (e.g. long term treatment of VTE patients at low recurrence risk)
May be more cost-effective than vitamin K-antagonists (no routine monitoring, fewer serious adverse events requiring hospitalization)High acquisition cost of drug in comparison to vitamin K-antagonists
 Short half-life leads to rapid decline in anticoagulant/antithrombotic effect if doses are missed affecting efficacy
 No specific antidote in case of major bleeding

However, there are significant issues that must be recognized with the new oral agents. Patient education and medication compliance will be extremely important to attain good clinical outcomes, especially for patients with atrial fibrillation who have not experienced symptoms of cerebral ischemia. The lack of a requirement for regular coagulation monitoring may limit the initial and continuing education that is currently provided to patients on vitamin K-antagonists along with early detection of medication non-adherence. Warfarin’s long half-life of about 40 h may actually be an advantage for patients who occasionally miss doses of medication as compared to one of the new oral anticoagulants with a short half-life. Furthermore the twice daily dosing schedules of some of the new agents will be more difficult for some patients to adhere to than a once daily regimen.

Another challenge is difficulty in determining if one of the new anticoagulants has failed when patients develop an initial or recurrent thrombotic event. If a thromboembolic event occurs on warfarin, INR levels can be reviewed to determine if they were in the therapeutic range at the time of presentation as well as the weeks prior to the event; this helps determine whether it is actually a therapeutic failure or sub-therapeutic dosing of the medication. In the latter case, dosing can be adjusted to increase the INR and measures put in place to improve patient education and monitoring. With the use of non-monitored drugs such as the oral thrombin and factor Xa inhibitors, such determinations cannot readily be made at the present time. Other considerations for the new oral agents include contraindications in renal dysfunction and the absence of specific antidotes when patients develop major bleeds with significant amounts of medication in their blood stream. The availability of oral anticoagulants that are ‘simple-to-prescribe’, because they do not require regular laboratory monitoring, could lead to overuse in some patient populations for whom the hemorrhagic risk exceeds the risk of recurrent VTE (e.g. long-term anticoagulation for secondary prevention of VTE in a patient with a single provoked event).

Finally, warfarin is a generic medication and relatively inexpensive, though substantial cost is incurred in performing regular INR monitoring and caring for patients with treatment-related hemorrhagic complications. New agents will be more expensive and health authorities and insurers will need to develop guidelines and strategies to optimize outcomes with the new agents that are cost-effective. The vitamin K-antagonists will therefore remain an important option and are the anticoagulant of choice for patients with mechanical heart valves until trials of the new agents are completed for this indication. They will be a preferred option for patients who ‘fail’ or develop recurrent thrombotic while taking one of the new agents. It should also be noted that vitamin K antagonists have been widely prescribed for more than 50 years, and have minimal, if any, long-term effects on organ systems and physiologic processes, other than blood coagulation, when taken for decades; there is no such experience with the new agents. For the prevention and treatment of thrombosis in pregnancy, low-molecular-weight heparins remain the agents of choice due to the teratogenicity of warfarin in the latter half of the first trimester [43] and the the lack of safety data with the new oral agents.

Disclosure of Conflict of Interest

The author is a consultant for Johnson & Johnson, BMS.

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