Critical Review Practical aspects of the oral new anticoagulants

Thomas G. DeLoughery1,2*
After years of only oral vitamin K antagonists, there are new many new antithrombotic agents in development and on entering the marketplace. This review will analyze clinical trial results for these new agents especially dibigatran, rivaroxaban, and apixiban. Also to be discussed are practical aspects of use of these new agents such monitoring, reversal, and use before procedures. Am. J. Hematol. 86:586590, C 2011. V 2011 Wiley-Liss, Inc.

Introduction Antithrombotic agents have been in clinical use since World War II. Although in many other elds there has been tremendous progress (antibiotics, etc.) until very recently, the mainstay of antithrombotic therapy has been agents developed for use during the 1940sheparin and its derivatives (low molecular weight heparins, fondaparinux) and warfarin (derived from coumarin). Currently many new antithrombotic agents are in development, clinical trials, or even released on the market. This review will focus on agents with the most clinical data and try to put these new drugs into perspective. Table I reviews the properties of the major new agents and Tables IIV review the results of clinical trials. Advantages and Disadvantages of Traditional Antithrombotics For heparin, the major disadvantage is the need for parental administrationsubcutaneous or intravenously. The main problem with unfractionated heparin is its variable dosing, but this was lessened by the advent of low molecular weight heparins. LMWHs have the advantage of minimal monitoring, but many patients do not like once or twice a day injections, and the use of needles (and their safe disposal) is a chore. Heparin-induced thrombocytopenia also remains a concern. Although very effective, warfarin is notorious for its difcult dosingindividual patient doses can range from 1 to 25 mg/day, and there are a bewildering number of drug interactions. Patients on warfarin need constant monitoring; there are numerous drug interactions, and even dietary restrictions. However, it is important to remember that these traditional anticoagulants have some advantages. Given the long time these agents have been on the market their side effect proles are very well known. With unfractionated heparin there is experience with their use in a variety of clinical situations ranging from dialysis to cardiac bypass. Most clinicians and patients are very familiar with these drugs and there are decades of clinic trial ndings welldening the role of these agents in numerous clinical situations. Dabigatran Generation of thrombin is a pivotal step in hemostasis. Thrombin not only cleaves brinogen into brin to form a thrombosis, but it also activates platelets and many procoagulant factors including V, VIII, XI, and XIII. Thus, it represents a potent target for antithrombotic agents. Clinical studies of the direct thrombin inhibitor ximelagatran provided proof that novel oral anticoagulants could replace warfarin in therapy of thrombosis, but a high incidence of liver toxicity shut down development of this agent. Dabigatran is a direct thrombin inhibitor that has been tested
C V 2011 Wiley-Liss, Inc.

in phase III trials for stroke prevention in atrial brillation, and for venous disease prophylaxis and prevention. It is approved for use in the United States for stroke prevention in atrial brillation and many other countries for prevention of venous thrombosis after orthopedic surgery. Dabigatran reaches a peak activity after 23 hr after ingestion [1]. The half-life is 1214 hr [1,2]. It does not require activation by cytochromes, so there is no concern about these types of drug interactions. It is a substrate for the p-glycoprotein transporter, so there is the potential for drug interactions with agents using this transporter. Studies have shown only minor interactions with verapamil and digitalis. However, rifampin should not be given with dabigatran. Since it is 80% renally excreted, caution needs to be used in prescribing to patients with kidney disease. In the United States, the FDA recommends a lower therapeutic dose (75-mg bid) in patients with creatine clearances between 15 and 30 ml/min and no use with patients with clearances under 15 ml/min. However, no dose adjustment is needed for moderate liver disease [2]. In counties where it is approved for deep venous thrombosis prophylaxis, the dosing is 220 mg daily (110 mg the rst dose after surgery) with 150 mg (75 mg rst dose after surgery) daily for patients with renal impairment. Prevention of deep venous thrombosis Dabigatran has been studied in three phase III trials of deep venous thrombosis prophylaxis in lower extremity orthopedic surgery. In a study in total knee arthroplasty (TKA), when compared to enoxaparin 30-mg bid, dabigatran at 150 and 220 mg daily was inferior due to a greater number of distal thromboses (22027.6%, 15030.5%, and enoxaparin 23.0%) [3]. In studies comparing dabigatran to 40 mg of enoxaparin, equivalence was shown as far as both thrombosis prevention and bleeding in total hip arthroplasty (THA) and TKA with no increase in bleeding [4,5]. Therapy of deep venous thrombosis In the Schulman study, patients with established deep venous thrombosis or pulmonary embolism (21% of study group) were randomized to standard warfarin INR 2-3 vs.
1 Division of Hematology/Medical Oncology, Department of Medicine, Oregon Health Sciences University, Portland, Oregon; 2Division of Laboratory Medicine, Department of Pathology, Oregon Health Sciences University, Portland, Oregon *Correspondence to: Thomas DeLoughery, Hematology L586, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098. E-mail: [email protected] Conict of interest: Nothing to report

Received for publication 23 February 2011; Accepted 25 February 2011 Am. J. Hematol. 86:586590, 2011. Published online 14 March 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.22021

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TABLE I. New Anticoagulants in Development Apixaban Action Bioavailability Onset to peak action (hours) Half-life (hours) Renal excretion (%) Dose-Prophylaxis Therapeutic Drug Interaction Refs. [612]. TABLE II. Novel Anticoagulants in Prevention of Thrombosis in Total Knee Arthroplasty Total thrombosis and death Ref [3] [4] [13] [14] [15] [16]
a

Betrixaban Anti-Xa 47% 19 0

Dabigatran Anti-IIa 6.5% 23 1214 80 150 mg qD 220 mg qD 150 mg BID P-glycoprotein

Edoxaban Anti-Xa 45% 11.5 911 33

Rivaroxaban Anti-Xa 80100% 2.54 59 66 10 mg qD 20 mg qD CYP 3A4

Anti-Xa 66% 13 815 25 2.5 mg BID 5 mg BID CYP 3A4

None

30 mg, 60 mg qD CYP 3A4

Major bleeding Enoxaparin 25.3 37.7 Enox 18.9 10.1 Enox 8.8a 24
a

Number 1,896 2,076 2,531 3,148 3,195 3,057 Signicant.

Comparator Enoxaparin 30 mg BID Enoxaparin 40 mg qD Enoxaparin 40 mg/day Enoxaparin 30 mg BID Enoxaparin 30 mg BID Enoxaparin 40 mg/day

Days

220 mg/dabigatran

150 mg/day

220 mg/dabigatran

150 mg/day

Enoxaparin 1.4 1.3 Enoxaparin 0.5 0.3 Enoxaparin 1.4 0.9

1014 1115 1014 1014

31.1 33.7 36.4 40.5 Rivaroxaban 10 mg/day a 9.6 6.9a Apixaban 2.5 mg BID 9.0 15a

0.6 0.6 1.5 1.3 Rivaroxaban 10 mg/day 0.6 0.7 Apixaban 2.5 mg BID 0.7 0.6

dabigatran 150 mg twice daily [17]. All patients received heparin or low molecular weight heparin for a median of 9 days. The recurrent thrombosis endpoints were identical and the bleeding endpoints showed less minor bleeding and equivalent major bleeding. (Table IV). Currently there is an extension study underway for longer duration of dabigatran therapy in secondary prevention of deep venous thrombosis. Stroke prevention in atrial brillation In the pivotal study, 18,234 patients with atrial brillation and at least one risk factor for stroke were randomized between warfarin INR 2-3, 110 mg of dabigatran twice daily, or 150 mg of dabigatran twice daily [18]. The patients randomized to 150-mg arm showed a reduced rate of stroke compared to warfarin (RR 5 0.66) and reduced serious bleeding, including intracranial hemorrhage (RR 5 0.40). The only bleeding endpoint that increased in the 150-mg arm was gastrointestinal bleeding (RR 5 1.5). The 110-mg arm was equivalent in stroke prevention but did show decreased rates of major bleeding (RR 5 0.80). Further analysis showed that results were similar in patients with a previous history of stroke or transient ischemic attack [19], or patients previously taking warfarin or new to anticoagulation [20]. There is an ongoing extension safety study currently underway to look at long-term use of dabigatran. Summary Dabigatran has been shown in three studies to be just as effective as enoxaparin in the prevention of major venous thrombosis after lower extremity orthopedic surgery, and is just as effective as warfarin in therapy of acute thrombosis with no increase risk of bleeding. In stroke prevention in atrial brillation, the 150-mg dose was more effective than warfarin with a lesser risk of intracranial hemorrhage. To date, except for a slight increase in the rate of dyspepsia, there appears to be no novel side effects of dabigatran beyond the bleeding risk. Liver toxicity appears not to be a concern. Rivaroxaban The majority of new antithrombotic drugs in developments mechanism of action is blocking factor Xa. Stopping

hemostasis at this point halts the generation of potent procoagulant thrombin and is another proven method of anticoagulation. Rivaroxaban is the rst and the most studied of these agents but many other factor Xa inhibitors are in clinical trials or development. Rivaroxaban is readily absorbed, being 80100% bioavailable, and has a half-life of 59 hr. It is metabolized by cytochrome CYP 3A4, and there are signicant interactions with ketoconazole and ritonavir. It is recommended that patients on these drugs not use rivaroxaban. Since carbamazepine, rifampin, and phenytoin induce CYP 3A4, these are another group of patients where caution should be used. Rivaroxaban is only 33% renally excreted and a lower dose (15 mg/day) was used in the atrial brillation study for patients with renal insufciency. Prevention of deep venous thrombosis Rivaroxabans effectiveness in prevention of venous thrombosis in lower extremity orthopedic surgery was studied in four phase III clinical trialstwo in THA and two in TKA [13,14,21,22]. The standard dose of rivaroxaban was 10 mg daily started 68 hr after wound closure. In THA, rivaroxaban compared to 40 mg of enoxaparin for 35 days was more effective in preventing thrombosisincluding proximal thrombosiswith no increase in bleeding [21]. In RECORD 2 THA trial, the comparator was a short course of enoxaparin 40 mg daily for 1014 days compared to 42 days of rivaroxaban 10 mg daily [22]. The rationale for this trial was that many patients receive only a short course of prophylaxis currently with enoxaparin. As would be expected, in this trial there was a decrease in total, proximal, and symptomatic thrombosis with no increase in bleeding. Two trials in TKA used either 30 mg twice a day or 40 mg daily of enoxaparin for 1014 days as the comparator drug [14,22]. In both trials rivaroxaban was superior in prevention of total deep venous thrombosis, and in the 40-mg trial rivaroxaban showed decreased symptomatic thrombosis. An increase in bleeding was not seen in any trial. Therapy of deep venous thrombosis This trial for rivaroxaban for therapy of venous thrombosis was different from the dabigatran trial in several aspects

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TABLE III. Novel Anticoagulants in Prevention of Thrombosis in Total Hip Arthroplasty Total thrombosis and death Ref [5] [21] [22] Number 3,494 4,541 3,148 Comparator Enoxaparin 40 mg/day Enoxaparin 40 mg/day Enoxaparin 40 mg/day 35 E-1014 R-3139 35 Days 220 mg/dabigatran 150 mg/day Enoxaparin 6.7 Enoxaparin 3.7 9.3 Enoxaparin 3.9a Major bleeding 220 mg/dabigatran 150 mg/day Enoxaparin 1.6 Enoxaparin 0.1 <0.1 Enoxaparin 0.7

6.0 8.6 Rivaroxaban 10 mg/day a 1.1 2.0a Apixaban 2.5 mg BID 1.4a

2.0 1.3 Rivaroxaban 10 mg/day 0.3 <0.1 Apixaban 2.5 mg BID 0.8

[16]
a

5,407 Signicant.

Enoxaparin 40 mg/day

TABLE IV. Novel Anticoagulants in Therapy of Acute Thrombosis Recurrent thrombosis/death Ref [17] [23]
a

Major bleeding D150 BID 1.6 Rivaroxaban 20 mg/dayb 0.8 Warfarin 1.9 Warfarin 1.2

N 2,564 14,264

PE (%) 21 73

Initial heparin Yes No

% Cancer 4.6 6

Age (%) 64 58

D150 BID 2.4 Rivaroxaban 20 mg/daya 2.1

Warfarin 2.1 Warfarin 3.0

15 mg BID 3 3 weeks then 20 mg/day.

TABLE V. Novel Anticoagulants in Prevention of Stroke in Atrial Fibrillation Stroke and embolism Ref [18] [24] [6] N 18,113 14,264 5,599 Age 71 73 70 CHADS2 2.1 3.5 2.0 ASA (%) 20 ? 100 TRR (%) 64 58 D110 BID D150 BID Warfarin 1.69%/yr Warfarin 2.16%/yr Aspirin 3.7%/yr D110 BID Major bleeding D150 BID Warfarin 3.36%/yr Warfarin 3.45%/yr Aspirin 1.2%/yr

1.53%/yr 1.11%/yr Rivaroxaban 20 mg/day 1.71%/yr Apixaban 5 mg BID 1.6%/yr

2.71%/yr 3.11%/yr Rivaroxaban 20 mg/day 3.6%/yr Apixaban 5mg BID 1.4%/yr

[25]. One was that only patients with deep venous thrombosis and not pulmonary embolisms were randomized. Second, the patients randomized to rivaroxaban immediately started the agent without heparin overlap. Finally, patients received 15 mg twice daily for 3 weeks and then 20 mg daily for 36 months. The trial showed equivalence to enoxaparin followed by warfarin in thrombosis recurrence with no increased risk of bleeding. In a follow-up study, patients after a course of antithrombotic therapy were randomized to rivaroxaban 20 mg daily or no therapy. As expected, the rivaroxaban arm had markedly decreased rate of thrombosis (1.3% vs. 7% with placebo) with no increase in major bleeding, but an increase in minor bleeding (5.4% vs. 1.2%). Stroke prevention in atrial brillation The presented but not yet published trial of rivaroxaban randomized patients to warfarin INR 2-3 or rivaroxaban 20 mg daily. In patients with creatinine clearances of 3049 mm/ml a 15 mg dose was used daily [24]. The stroke rate was equivalent when analyzed by intention to treat (HR 5 0.88, 0.741.03) with superiority of rivaroxaban seen when only patients on study drug were evaluated (HR 5 0.79, 0.650.95). Bleeding rates were the same except for patients on rivaroxaban having lower rates of fatal or intracranial hemorrhage (HR 5 0.67). Of note the mean CHADS2 score in this trial was 3.5 compared to 2.1 in the dabigatran study, suggesting that patients at higher risk of stroke were enrolled in this study. Ongoing clinical trials Currently, trials are underway using a lower dose of rivaroxaban (2.5- or 5-mg bid) in acute coronary syndromes in addition to standard antiplatelet therapy. There is an ongoing trial for acute therapy of pulmonary embolism and

study using a higher dose of rivaroxaban in patients taking strong CYP 3A4 inducer medication. Summary In trials for thrombosis prophylaxis, rivaroxaban was more effective than enoxaparin with no increased risk of bleeding. In therapy of deep venous thrombosis and stroke prevention in atrial brillation, rivaroxaban was equivalent to warfarin. Plus, it is the rst factor Xa inhibitor to be widely studied in phase III trials and provides a proof of concept for this class of antithrombotic agents. Apixaban Apixaban is the third new anticoagulant to have published phase III trial data. It is also a factor Xa inhibitor. It is 66% bioavailable and has a peak onset of action in 13 hr after ingestion with a half-life is 815 hr. It is only 25% renal excreted, but is metabolized by CYP 3A4. Prevention of deep venous thrombosis There are three studies of apixaban in thrombosis prevention in lower extremity orthopedic surgery. In a trial comparing apixaban to 30 mg twice daily of enoxaparin, apixaban showed inferiority in thrombosis prevention (by 0.2%) with decreased bleeding [26]. But when compared to enoxaparin 40 mg/day, apixaban was actually superior in thrombosis prevention, including a decrease seen in major thrombosis (proximal vein thrombosis and pulmonary embolism) with no increased risk of bleeding [15]. In the only trial in THA, apixaban was again superior to enoxaparin 40 mg/day given for 35 days in reducing major thrombosis [16]. Stroke prevention in atrial brillation The only published study of apixaban in stroke prevention is in comparison to aspirin in patients deemed

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unsuitable for warfarin [6]. Unsuitability for warfarin was broadly dened and the average CHAD2 score was 2.0. In this study, apixaban showed benet with a HR of 0.45 for stroke or embolism and the trial was halted early. There was no increased risk of bleeding when compared to aspirin. Ongoing clinical trials Soon the results of apixaban compared with warfarin for stroke prevention in atrial brillation should be reported. There are also ongoing trials in acute and long-term therapy of deep venous thrombosis. A trial of apixaban 2.5-mg BID in acute coronary syndromes was halted early due to excess bleeding [27]. Edoxaban Edoxaban is another factor Xa inhibitor in clinical trials. It is 45% bioavailable and has a peak onset of action in 11.5 hr with a half-life of 911 hr. It is 33% renally excreted. Currently, the 30 and 60 mg daily dose is being compared to warfarin in an atrial brillation stroke prevention phase III trial [28,29]. Betrixaban This factor Xa inhibitor is 47% bioavailable with a peak onset in 23 hr. Its two unique features are a long half-life of 19 hr and a total lack of renal excretion. Another potential advantage is the lack of metabolism by CYP3A4. It is currently in phase III clinical trials. If effective, its lack of renal clearance may make it an appropriate agent for many older patients with renal insufciency. Practical issues With the advent of new antithrombotic drugs, the clinician will be faced with many practical issues. These would include who should be changed over, off-label use, use in cancer patients, mechanical heart valve patients, pregnancy, monitoring, and reversal. Which patients currently on warfarin should be changed to new agents? The rst group of patients are those who currently have difcult either obtaining an INR (distance to clinic, travel, etc.) or despite compliance continue to have an unstable INR. Patient who simply are not compliant with warfarin will most likely also not be compliant with newer agents. The more challenging question is when to change someone who is stable on warfarin over to the new agents. Arguments for maintaining on warfarin are its over 60-year record of use and familiarity of the drug. Arguments for changing is reducing the need for monitoring, potential for drug or food interactions, andat least for rivaroxaban and dabigatran in atrial brillationlower rates of intracranial hemorrhage. Use in cancer patients It is known from four randomized trials that use of LMWH in cancer patients is associated with reduced in the rates of recurrent thrombosis compared to warfare [30,31]. It is not known if the new anticoagulants will also show this benet. For patients who cannot afford or do not want to use LMWH, the new agents may be an option as they can be easier to stop in case of thrombocytopenia or bleeding and would have less potential for drug interactions in patients undergoing chemotherapy. Mechanical heart valves Warfarin is the standard therapy for mechanical heart valves. Early use of LMWH in these patients was plagued with problems of under dosing that has lead to continue concern about their use with valves. There will need to be well done studies in this patient population before any recommendations can be made with perhaps the low risk valves (aortic bileaet valve) being the rst studied. A major concern with any of these new agents would be compliance. One advantage of the long half-life of warfarin is that with one or two missed doses the patient still has some anticoagulant effect while with the new oral agents this anticoagulant effect would rapidly dissipate leading to potential thrombosis. These patients may be a group where the ability to monitor drug effect would be important. Pregnancy For any of these new agents there is limited data on pregnancy or breast feeding. Also unknown are if these agents are excreted in the breast milk and use should be excluded until more data is known. Given the abundance data on LMWH in pregnancy, these agents remain the anticoagulant of choice for treatment and prophylaxis. Monitoring The appeal of all these new agents is the lack of need for monitoring. However, there are several situations where monitoring may be of value. For patients who are at the extremes of weight to would be good to know if the patient is being over or under anticoagulated. For patients with renal insufciency, monitoring could help prevent bleeding complications. Finally for patients being seen for acute thrombotic or bleeding complications, knowledge of blood levels could help guide therapy. For example, a patient on dabigatran for stroke prevention who presents with a new strokedoes this represent failure of therapy or failure of the patient to be compliant? For dabigatran, aPTT appears to be most responsive of the commonly available coagulation tests [7]. In studies patients 2 hr after drug ingestion had an aPTT 2 times the control and this had decreased to 1.5 times control at the trough [2,7]. However, it is unknown if this is sufcient data to ne-tune therapy but obtaining an aPTT should provide information on if the patient has recently taken the drug or if drug effect is still present. There is little effect on the INR. The Ecarin timea snake venom-based assaymay provide better correlation for monitoring dabigatran but this test is not widely available [7]. For rivaroxaban, the prothrombin time is the common coagulation test that appears to correlate the best with serum levels [32,33]. Again it is unknown if the prothrombin times can be used to adjust therapy unless it is specically standardized for assaying rivaroxaban. One issue is many laboratories now just report their prothrombin times as INR. Since the INR is standardized for warfarin and not rivaroxaban, it has the potential to be very unreliable. Given that prothrombin time-based monitoring potentially needs to be standardized to each agent, this may not be practical for all laboratories to have a full set of reagents. The commonly used anti-Xa assayused in many laboratory for monitoring heparin and LMWH levelscan also be adjusted to measure Xa inhibitors and this may become more widely used in the future [34]. Procedures Many patients on anticoagulation will need procedures. For most procedures performed on patients taking dabigatran, the drug should be stopped 24 hr before the procedures except for high risk procedure such as brain surgery where 3648 more hours would be appropriate [7]. For patient with renal insufcient again a longer time should be allowed between drug cessation and procedures. For the Xa inhibitors, the timing will be dependent on the drugs half-life with the potential for some agents requiring 3648 hr off drug. Reversal Unlike warfarin and heparin, there are no standard antidotes for the new anticoagulants. For dabigatran use of prothrombin complex concentrates or activated prothrombin

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complex concentrates has been suggested because of in vivo data, suggesting that activated prothrombin concentrates doses at 50 units/kg may also be useful, perhaps because of transfused thrombin overwhelming the thrombin inhibition [7,3538]. For the factor Xa inhibitors these agents may also work by the similar principle of providing more factor X or Xa. In theory recombinant factor VIIa may also work in factor Xa bleeding given its benet with the indirect Xa inhibitor fondaparinux [39,40]. There is also in development a novel universal antidote to reversal all Xa inhibitors [41]. This involves using recombinant factor Xa that has been rendered inactive by removal of the gladomain and an active site modication. An agent that can reverse this entire class of anticoagulants would be very valuable and would encourage broader use of these agents. Conclusion The next few years will provide not only excitement, but also potential for confusion to clinicians caring for patients on anticoagulation. There will be many new agents to choose from but uncertainty on what agent is the best for what patient. However, once we are over this learning curve, the availability of easier to use anticoagulation will allow safer and perhaps more effective therapy for patients with thrombotic disease. References
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