Abstract: Vitamin K antagonists (VKA), such as warfarin, have been the only available oral anticoagulants despite their many limitations. The greatest medical need is to find a replacement for warfarin for long-term therapy, particularly for stroke prevention in atrial fibrillation (AF) patients. Emerging oral anticoagulants are free from many of warfarin's drawbacks and may offer a convenient alternative. Drugs in advanced development target factor Xa (rivaroxaban, apixaban) or thrombin (dabigatran etexilate). Recently, the RE-LY phase III study found dabigatran etexilate was an effective and convenient alternative to warfarin in stroke prevention for AF patients. Within the next two years, similar studies comparing rivaroxaban and apixaban versus warfarin in AF patients will become available. This paper reviews warfarin's limitations, discusses the pharmacokinetics of emerging anticoagulants in advanced development, and summarizes trials with an emphasis on head-to-head studies comparing novel anticoagulants to warfarin.
Oral anticoagulants are the mainstay of therapy in the prevention and treatment of both venous and selected arterial thrombotic disorders. For over 60 years, warfarin has been the only available oral anticoagulant despite its many limitations. Warfarin’s drawbacks include a narrow therapeutic index, slow onset of therapeutic effect, numerous dietary and drug interactions, and a need for monitoring. New oral anticoagulants in development are free from many of warfarin’s drawbacks and may offer a convenient alternative to warfarin.
Drugs in advanced development target factor Xa or thrombin, and due to their central locations in the common coagulation pathway they block both intrinsic and extrinsic pathways (see Figure 1). These small molecules directly block specific coagulation enzymes at their catalytic pocket. Novel agents promise to be more convenient and possibly safer than warfarin because they are given in fixed dosages, do not require monitoring, have few or minimal interactions with drugs or diet, and have a rapid onset of action that eliminates the need for parenteral anticoagulation. Several landmark studies are now available on the direct thrombin inhibitor, dabigatran etexilate, and the two factor Xa inhibitors, rivaroxaban and apixaban leading to rivaroxaban’s and dabigatran’s European and Canadian approval for VTE prevention in patients undergoing orthopedic surgery.
Warfarin is a safe and effective oral anticoagulant if a therapeutic international normalized ratio (INR) is properly maintained. In practice, however, it is difficult to manage because its therapeutic level is affected by many factors including diet, medications, illnesses, and genetics. Whereas warfarin prevents 64% of strokes in a controlled research setting (Hart et al., 2007) , its clinical effectiveness averages 35% (Birman-Deych et al., 2006), and only 50% of patients maintain a therapeutic INR during therapy (Hirsch et al., 2001). Warfarin’s narrow therapeutic range predisposes to many adverse effects from both under anticoagulation (resulting in thrombus formation) and over anticoagulation (leading to hemorrhage). To ensure that a therapeutic INR is achieved, frequent monitoring is required that is inconvenient for patients and physicians and costly for the healthcare system. Specialized anticoagulation management clinics are needed to address the complexity in managing warfarin. Additional warfarin drawbacks include its slow onset and offset of action. It takes 72-96 hours to become effective and requires overlap with a rapidly acting parenteral anticoagulant or “bridging” until a therapeutic INR is achieved. Its slow offset, with an effective half-life of approximately 40 hours, makes it difficult to manage before procedures. Safety concerns and therapy complexity lead many physicians to underuse warfarin, prescribing it to only two thirds of appropriate candidates (Birman-Deych et al., 2006).
Emerging Oral Anticoagulants for Primary and Secondary Prevention
New oral anticoagulants promise effective anticoagulation with safer and more convenient therapies. See Table 1 (Zikria and Ansell, 2009) for a summary comparing warfarin with novel agents in advanced development. Emerging oral agents have a predictable effect allowing a fixed dose, thereby eliminating the need for drug monitoring. New drugs are unaffected by multiple factors (such as diet and genetics) and have minimal drug interactions compared to warfarin. They achieve an anticoagulant effect quickly, eliminating the need for a parenteral, rapidly acting anticoagulant such as heparin. Peak plasma dabigatran etexilate concentrations are attained after 2 hours, apixaban in 3 hours, and rivaroxaban in <4 hours compared to warfarin’s 72 hours. These drugs have a short half-life with rivaroxaban’s being 5-13 hours, apixaban 8-15 hours, and dabigatran etexilate 14-17 hours. Despite their advantages, the short-half lives of these new agents in the absence of a simple monitoring test makes medication adherence extremely important, especially for AF patients who may lack symptoms and may not understand the importance of taking preventative medications.
Direct Thrombin Inhibitors
Oral direct thrombin inhibitors (DTIs) bind to the active site of both free and clot-bound thrombin and block its fibrin interaction. Limiting thrombin activity is critical since it amplifies its own generation by activating factors VIII and V. Thrombin also activates factor XI, factor XIII, and platelet protease activated receptors (PAR-1 and PAR-4) (Nutescu et al., 2008). Ximelagatran, the first oral DTI, was studied extensively in the early 2000s and found effective in arterial and venous thrombotic disorders, including stroke prevention in AF patients in phase III trials. However, it was removed from the market in 2006 because of hepatotoxicity associated with long-term use. Although ximelagatran failed to provide an alterative to warfarin, it proved that thrombin was an effective anticoagulation target.
Numerous oral DTIs are being developed, including dabigatran etexilate (Boehringer Ingelheim), AZD0837 (AstraZeneca), MCC-977 (Mitsubishi Pharma), and aptamer ARC183 (Archemix-Nuvelo).
Dabigatran etexilate (Rendix, Pradaxa, BIBR 1048) is a DTI administered once or twice daily. It is an oral prodrug that is rapidly converted by a serum esterase to dabigatran, a potent, direct, competitive thrombin inhibitor. Dabigatran etexilate has a 2-hour onset and 14-17-hour half-life, and a 6.5% bioavailability (Gross and Weitz, 2008). Because 80% of the drug is renally metabolized, patients with a creatinine clearance <30 ml/hr have been excluded from clinical trials. Dabigatran etexilate’s dose must be reduced if given with proton pump inhibitors or a p-glycoprotein transporter inhibitor, like amiodarone, verapamil, or quinidine. Table 1 reviews dabigatran etexilate’s properties.
Dabigatran etexilate received European and Canadian regulators’ approval for VTE prevention following orthopedic surgery based on the RE-MODEL (Eriksson et al., 2007a) and RE-NOVATE (Eriksson et al., 2007b) trials. Dabigatran etexilate (150 mg and 220 mg) and enoxaparin (40 mg daily initiated pre-operatively) were equally effective in VTE prevention with no increased bleeding risk. The North American enoxaparin regimen (30 mg bid beginning post-operatively) used in the RE-MOBILIZE trial (RE-MOBILIZE Writing Committee et al., 2009), however, showed that dabigatran was inferior to enoxaparin based on the criteria use for non-inferiority, as the upper limit of the 95% CI for the absolute risk difference vs. enoxaparin was higher than the pre-specified non-inferiority margin of 9.2%. For 220 mg, the risk difference was 5.8% (95% CI, 0.8-10.8; P=0.0234) and for 150 mg, the risk difference was 8.4% (95% CI, 3.4-13.3; P=0.0009) compared to enoxaparin (Table 2). Consequently, dabigatran etexilate 220 mg dose is recommended for a majority of patients, and 150 mg dose is reserved for patients >75 years (Dahl et al., 2008) old for VTE prevention following orthopedic surgery in Europe and Canada.
Recently, dabigatran etexilate was compared to warfarin in the RE-LY phase III trial for stroke prevention in AF patients (Connolly et al., 2009). RE-LY compared dabigatran etexilate to warfarin in 18,113 patients with AF and an additional stroke risk factor. Two doses of dabigatran etexilate (110 mg twice daily and 150 mg twice daily), administered in a blinded fashion, were compared with adjusted-dose warfarin administered in an unblinded manner. The primary outcome was systemic embolism or stroke (including hemorrhagic stroke); the safety outcome was major hemorrhage. The rate of stroke was significantly lower with dabigatran etexilate at a dose of 150 mg twice daily (1.11%, p<0.001 for superiority) than with either dabigatran etexilate at a dose of 110 mg twice daily (1.53%, p<0.001 for noninferiority) or warfarin (1.69%). To satisfy the non-inferiority hypothesis, the upper bound of the one-sided 97.5% confidence interval for the relative risk of an outcome with dabigatran as compared with warfarin needed to fall below 1.46. The rate of major bleeding with the 150 mg dose was not different to that with warfarin (3.11% vs. 3.36%; p=0.31), while it was significantly lower compared with warfarin (2.71% vs. 3.36%; p=0.003) with the 110 mg dose. The rates of hemorrhagic stroke with the 110- mg and 150-mg dabigatran etexilate doses (0.12% and 0.10%) were both significantly lower than with warfarin (0.38%). Dyspepsia was significantly more common with dabigatran etexilate than warfarin, occurring in 5.8% in warfarin patients but 11.8% and 11.3% in 110-mg and 150-mg dabigatran groups respectively (p<0.001 for both). Gastrointestinal adverse effects are thought to be due to dabigatran’s tartaric acid core needed to create a low-pH essential for the drug’s absorption. Myocardial infarction (MI) was also significantly more common with dabigatran 150-mg than with warfarin with rates of 0.72% (p=0.07) and 0.74% (p=0.048) with 110 mg and 150 mg of dabigatran etexilate, respectively, and 0.53% with warfarin. There was no evidence of hepatotoxicity with dabigatran, as was seen with ximelagatran, during the two-year median duration of the study. In conclusion, dabigatran 150 mg twice daily was superior to warfarin in preventing stroke, whereas dabigatran 110 mg twice daily resulted in significantly less major bleeding than warfarin. However, there were significantly more myocardial infarctions with dabigatran, 150 mg, than with warfarin.
Ongoing studies are comparing dabigatran etexilate to warfarin. Patients in the RE-LY trial are extending their anticoagulation (with dabigatran or warfarin) for an additional 28 months in the RELY-ABLE study. Other trials comparing dabigatran etexilate to warfarin include the RE-COVER and RE-MEDY trials for the acute and chronic treatment of VTE. RE-COVER will include more than 2,550 patients for 6 months; RE-MEDY is evaluating 2,000 patients who completed 6 months of anticoagulation, and extending their treatment with 18 months of dabigatran etexilate or warfarin.
Direct Factor Xa Inhibitors
Oral factor Xa inhibitors (FXaIs) bind to the active site of Xa, both the free form and within the prothrombinase complex, and block its thrombin interaction. Numerous FXaIs are in clinical development, including rivaroxaban (Bayer and Scios), apixaban (Bristol-Myers Squibb), betrixaban (PRT054021, MLN-1021; Portola Pharmaceuticals), edoxaban (DU-176b, Daiichi), YM150 (Astellas), LY517717 (Lilly), TAK-442 (Takeda), and PD0348292 (Pfizer). Rivaroxaban and apixaban are in the most advanced stages of development.
Rivaroxaban (Bay 59-7939) is a selective FXaI administered once or twice daily. It has a 2.5-4 hour onset and 5-9 hour half-life (Piccini et al., 2008). Rivaroxaban is metabolized partially by cytochrome P450 (CYP) 3A4 and its elimination is impaired if given with strong CYP3A4 inhibitors (e.g., ketoconazole and ritonavir). Table 1 lists rivaroxaban’s properties.
Rivaroxaban was approved in Europe and Canada for VTE prevention following orthopedic surgery based on the RECORD (Eriksson et al., 2008; Kakkar et al., 2008; Lassen et al., 2008a; Turpie et al., 2009) trials (Regulation of Coagulation in major Orthopedic surgery Reducing the risk of DVT). The RECORD studies included four phase III trials with differing durations of treatment, enoxaparin dosings, and orthopedic procedures (Table 3). RECORD trials found rivaroxaban to be superior to enoxaparin in preventing VTE for both short- and long-term treatment regardless of enoxaparin regimen with similar safety profiles. RECORD-2 found an excess of cardiovascular events (0.4 vs. 0% with enoxaparin) after discontinuing rivaroxaban; however, the low number of events prevented meaningful conclusions and no trend was evident in pooled RECORD analysis (Fisher et al., 2007). Food and Drug Administration review is currently in progress.
Other Phase III clinical trials comparing rivaroxaban to warfarin are ongoing. Rivaroxaban’s efficacy in acute and chronic VTE treatment is being studied in the EINSTEIN trials. The study compares rivaroxaban 20 mg twice daily for 3 weeks followed by 20 mg once daily to enoxaparin (LMWH) followed by warfarin for efficacy in treating DVT or PE, respectively, for 3 months. Another study comparing rivaroxaban to warfarin is the ROCKET AF trial (Rivaroxaban Once daily oral direct factor Xa inhibition Compared with vitamin K antagonism for the prevention of stroke and Embolism Trial in Atrial Fibrillation) that includes 14,000 patients. The ROCKET AF trial outcomes will likely be available in 2010.
Apixaban (BMS-562247) is a selective direct FXaI administered twice daily. It has a 3-hour onset and 8-15-hour half-life (Carreiro and Ansell, 2008). It is well tolerated by renal and liver disease patients. Apixaban is metabolized partially by CYP3A4 and its elimination is impaired if given with strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir). Table 1 reviews apixaban’s properties.
Apixaban’s efficacy in VTE prevention following orthopedic surgery was compared to enoxaparin in the ADVANCE (Apixaban Dosed orally Versus ANtiCoagulation with Enoxaparin) trials, including three studies with differing treatment duration and enoxaparin dosage. ADVANCE-1 (Lassen et al., 2008b) (knee arthroplasty) failed to show that apixaban was non- inferior to enoxaparin when the latter was dosed according to the North American regimen, although it was associated with significantly less bleeding than enoxaparin (0.7 vs. 1.4%, p=0.05). However, ADVANCE 2 (knee arthroplasty) (Lassen et al., 2009) found that apixaban was superior to enoxaparin when dosed according to a European regimen (Table 4).
The phase II BOTTICELLI (Buller et al., 2008) trial compared apixaban to enoxaparin (LMWH) followed by warfarin for VTE treatment. Apixaban and LMWH followed by VKA had similar efficacy in both the initial and long-term (3 month) VTE treatment without increasing bleeding. The study recommends apixaban 10 mg twice daily for acute VTE treatment and 5 mg twice daily for chronic uses in phase III AMPLIFY trials (Apixaban after the initial Management of PuLmonary embolism and deep vein thrombosis with First-line therapy) comparing apixaban to warfarin for VTE treatment for 6 months.
The ARISTOLTLE phase III study compares apixaban to warfarin for stroke prevention in AF patients. This randomized, double-blind study will enroll 18,000 patients (see www.clinicaltrials.gov; identifier NCT00412984) and be completed in 2011.
Novel oral anticoagulants promise more convenience and safety than warfarin for the prevention and treatment of venous and selected arterial thrombotic disease. Recent studies with dabigatran etexilate and rivaroxaban versus enoxaparin for patients undergoing orthopedic procedures demonstrated effectiveness in short-term VTE prevention. However, the greater medical need is to find a replacement for warfarin for long-term therapy, particularly for stroke prevention in atrial fibrillation (AF) patients and VTE treatment. The RE-LY trial is the first study establishing dabigatran etexilate as equally efficacious to warfarin in preventing stroke in AF patients without increasing bleeding. Similar trials with rivaroxaban and apixaban will soon be complete. Warfarin will likely remain the mainstay for venous and arterial thrombotic disease until more results in AF patients become available. Whether or not these novel agents will provide a convenient alternative to warfarin will be determined within the next few years. It is uncertain whether long-term, non-hematological side effects exist. This is an exciting period for the treatment of thrombosis since a new era in anticoagulation therapy may be beginning.
(Disclosures: J.A. has acted as a consultant to Bayer/Scios and BMS. J.Z. reports no financial interests.)
(Correspondence should be addressed to Jack Ansell, M.D., Chairman, Department of Medicine, Lenox Hill Hospital, 6 Black Hall, 100 East 77th Street, New York, NY 10075, USA.)
Birman-Deych E, Radford MJ, Nilasena DS, Gage BF. Use and effectiveness of warfarin in Medicare beneficiaries with atrial fibrillation. Stroke 37:1070-4, 2006.
Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 6(8):1313-8, 2008.
Carreiro J, Ansell J. Apixaban, an oral direct Factor Xa inhibitor: awaiting the verdict. Expert Opin Investig Drugs 17(12):1937-45, 2008.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, et al.; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139-51, 2009.
Dahl O, Kurth A, Rosencher N, et al. Effficacy and safety profile of dabigatran etexilate compared with enoxaparin in primary venous thromboembolism prevention after total knee or hip replacement surgery in patients over 75 years. Blood 112:abstract #437, 2008.
Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Kälebo P, Christiansen AV, Hantel S, Hettiarachchi R, Schnee J, Büller HR; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 5(11):2178-85, 2007a.
Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk CN, Frostick SP, Prins MH, Hettiarachchi R, Hantel S, Schnee J, Büller HR; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 370(9591):949-56, 2007b.
Eriksson BI, Borris LC, Friedman RJ, Haas S, Huisman MV, Kakkar AK, Bandel TJ, Beckmann H, Muehlhofer E, Misselwitz F, Geerts W; RECORD1 Study Group. RECORD1 Study Group: Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 358(26):2765-75, 2008.
Fisher WD, Eriksson BI, Bauer KA, et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost 97:931-7, 2007.
Gross PL, Weitz JI. New anticoagulants for treatment of venous thromboembolism. Arterioscler Thromb Vasc Biol 28(3):380-6, 2008.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146:857-67, 2007.
Hirsch J, Dalen J, Anderson D, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimum therapeutic range. Chest 119(1191, suppl.):8S-21S, 2001.
Kakkar AK, Brenner B, Dahl OE, Eriksson BI, Mouret P, Muntz J, Soglian AG, Pap AF, Misselwitz F, Haas S; RECORD2 Investigators. RECORD2 Investigators: Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet 372(9632):31-9, 2008.
Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. RECORD3 Investigators: Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 358(26):2776-86, 2008a.
Lassen M, Gallus A, Pineo G, Raskob G. Randomized double-blind comparison of apixaban with enoxaparin for thromboprophylaxis after knee replacement: the ADVANCE-1 trial. Blood 112:abstract #31, 2008.
Lassen MR, Gallus AS, Pineo GF. The ADVANCE 2 study: A randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement. J Thromb Haemost 7:abstract #LB-MO-005, 2009.
Nutescu EA, Shapiro NL, Chevalier A. New anticoagulant agents: direct thrombin inhibitors. Cardiol Clin 26(2):169-87, 2008.
Piccini JP, Patel MR, Mahaffey KW, et al. Rivaroxaban, an oral direct factor Xa inhibitor. Expert Opin Investig Drugs 17(6):925-37, 2008.
RE-MOBILIZE Writing Committee, Ginsberg JS, Davidson BL, Comp PC, Francis CW, Friedman RJ, Huo MH, Lieberman JR, Muntz JE, Raskob GE, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 24(1):1-9, 2009.
Turpie AG, Lassen MR, Davidson BL, Bauer KA, Gent M, Kwong LM, Cushner FD, Lotke PA, Berkowitz SD, Bandel TJ, Benson A, Misselwitz F, Fisher WD; RECORD4 Investigators. RECORD4 Study Investigators. Rivaroxaban - an oral, direct Factor Xa inhibitor - versus enoxaparin for thromboprophylaxis after total knee replacement. Lancet 373(9676):1673-80, 2009.
Zikria JC, Ansell J. Oral anticoagulation with factor Xa and thrombin inhibitors: on the threshold of change. Curr Opin Hematol 16(5):347-56, 2009.
[Discovery Medicine, 8(43):196-203, December 2009]