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Oral and parenteral anticoagulants: New kids on the block S AdityaDepartment of Pharmacology, Dr. Harvansh Singh Judge Institute of Dental Sciences, Panjab University, Sector 25, Chandigarh, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.105448
Well-documented drawbacks of traditional anticoagulants have lead to the quest for an ideal anticoagulant resulting in a surge of novel anticoagulant molecules. These newer agents directly target specific steps in coagulation cascade and include newer low molecular weight heparins (adomiparin), ultra low molecular weight heparins (semuloparin, RO-14), inhibitors of activated factor II (dabigatran, AZD0837), X (rivaroxaban, apixaban, edoxaban, betrixaban), IX (REG1,2), XI (antisense oligonucleotides, BMS 262084, clavatadine A), VII/tissue factor (tifacogin, PCI 274836, and BMS 593214), V (recomodulin, solulin), VIII (TB402), dual thrombin/factor X inhibitors (EP21709, tanogitran), and newer vitamin K antagonists (tecarfarin). Direct thrombin inhibitors and Factor X inhibitors are the most clinically advanced. This article discusses the recent advances in the development of novel targets of anticoagulants. Medline, EMBASE, cochrane database, medscape, SCOPUS, and clinicaltrials.gov were searched using terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "'antithrombins." Journal articles published from 2007 to 2012 discussing pharmacology and/or clinical trials were screened. Keywords: Apixaban, dabigatran, novel anticoagulants, rivaroxaban
Venous thromboembolism (VTE) is a major health care problem with an incidence of 1 per 1000 person years. Sudden death is the initial clinical presentation for nearly one-quarter of patients with pulmonary embolism (PE). [1],[2] Thromboembolism is the most feared and devastating complication of atrial fibrillation (AF)-a common cardiac rhythm disorder and the risk of stroke in the setting of AF is as high as 23.5% in patients aged 80-90 years. [3] Risk of bleeding due to excessive anticoagulation and risk of recurrent thrombotic event due to subtherapeutic concentration are pertinent and constant threats in the management of patients on traditional anticoagulants. [4],[5] Even with frequent international normalized ratio (INR) monitoring, time in the therapeutic range of vitamin K antagonists (VKAs) is less than 60%. [4] Moreover, fear of adverse events and complexity of dose management have lead to a widespread underuse of warfarin for patients with AF who are qualified candidates for therapy. [3],[6] Numerous food drug interactions further complicate their long-term use. Besides showing an unpredictability of response, unfractionated heparin (UFH) fails to bind to fibrin bound thrombin-an important trigger of thrombin growth. Serious adverse effects of osteoporosis and heparin-induced thrombocytopenia (HIT) are other limitations of its use. [7],[8] Subcutaneous administration and potential for accumulation in renal impairment limit the long-term use of low molecular weight heparins (LMWH) and fondaparinux. The absence of antidote for fondaparinux remains a problem. [9] This has led to a quest for an ideal anticoagulant with high efficacy and safety, fixed dose, ability to bind clot bound coagulation factors, ease of administration, no requirement for therapeutic monitoring, emergent reversibility (antidote), minimal food drug interactions, and cost efficacy. Dabigatran etexilate, rivaroxaban, and apixaban have undergone phase III evaluations for prevention and treatment of deep vein thrombosis (DVT) and PE, stroke prevention in AF, and prevention of recurrent ischemic events in acute coronary syndrome (ACS) patients. Both oral and parenteral novel anticoagulants under development block initiation of coagulation in the extrinsic pathway (activated factor VII (FVIIa)/tissue factor (TF) inhibitors, activated factor XI (XIa), activated factor IX (FIXa), and activated factor VIII (FVIIIa) inhibitors) or inhibit the propagation of coagulation {activated factor X (FXa) and activated factor V (FVa) inhibitors) and/or fibrin generation (activated factor II (Flla (thrombin) inhibitors)) in the common pathway [Figure 1], and [Table 1]. [1]
Medline, EMBASE, cochrane database, medscape, SCOPUS databases, and clinicaltrials.gov were searched for published studies using MeSH terms "anticoagulants", "blood coagulation inhibitors", "anticoagulants and venous thromboembolism", "anticoagulants and atrial fibrillation", and "antithrombins". Journal articles published in English language from 2007 to 2012 discussing pharmacology and/or clinical trials of newer oral or parenteral coagulation factor inhibitors were screened. This review focuses on pharmacology and relevant clinical studies of new anticoagulants and ends with a perspective on their advantages and disadvantages.
Procoagulant activities of thrombin include conversion of soluble fibrinogen into clottable fibrin, activation of the fibrin cross linking factor XIII, activation of cofactors V and VIII, leading to autoamplification, and the downregulation of fibrinolysis by generating thrombin-activable fibrinolysis inhibitor (TAFI). [10] It also coordinates platelet activation and aggregation with coagulation. Parenteral direct thrombin inhibitors (DTIs) are lepirudin, argatroban, bivalirudin, and desirudin. Dabigatran etexilate and AZD 0837 are oral DTIs. In contrast to heparins, DTIs act independent of antithrombin III and inhibit both free (soluble) and fibrin-bound thrombin which is an important trigger of thrombus expansion. DTIs show more predictable anticoagulant effect as they do not bind to plasma proteins. Moreover, risk of HIT is absent as they are unaffected by platelet factor 4. Direct thrombin inhibitors Study in AF In 2010, FDA approved Dabigatran etexilate (150 mg twice daily (bd)) for prevention of stroke and systemic embolism in patients with AF [Table 2]. [11],[12] Dosage reduction to 75 mg bd is recommended for patients with renal impairment. The landmark trial-RELY (randomized evaluation of long-term anticoagulation therapy) in patients with AF demonstrated that dabigatran 150 mg bd was associated with lower incidence of stroke and thromboembolism compared with warfarin while major bleeding events were similar, whereas dabigatran 110 mg bd was associated with a similar rate of stroke and embolic occurrence and reduced incidence of major bleeding [Table 3]. [15]
Studies in DVT and PE REMODEL (dabigatran etexilate 150 or 220 mg once daily (od) vs. enoxaparin 40 mg od for prevention of thrombosis after knee surgery) and RENOVATE (dabigatran etexilate compared with enoxaparin in prevention of VTE following total hip arthroplasty) studies found noninferiority and similar bleeding rates of dabigatran 150 mg or 220 mg od compared with enoxaparin in prevention of VTE in the setting of total knee or hip replacement [Table 4]. [2],[18],[20],[21],[31] The REMOBILIZE (dabigatran etexilate vs. enoxaparin in the prevention of VTE post-total knee replacement) trial showed efficacy of dabigatran to be inferior compared to the twice daily North American enoxaparin regimen, likely due to more intense and prolonged dosing of enoxaparin. [20] In the RECOVER trial (a phase III, randomized, double-blind, parallel-group study of the efficacy and safety of oral dabigatran etexilate (150 mg bd) compared to warfarin (INR 2.0-3.0) for 6 months treatment of acute symptomatic venous thromboembolism, following initial treatment (5-10 days) with a parenteral anticoagulant in treatment of acute VTE), dabigatran was as effective as warfarin in acute VTE with similar bleeding rates [Table 4]. [19]
Study in ACS Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction (REDEEM (dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: A randomized, double-blind, phase II trial)) [Table 5]. [32]
The most common adverse events reported with dabigatran are dyspepsia, dizziness, headache, dyspnea, peripheral edema, diarrhea, and bone pain. [11],[12] AZD0837 is another oral DTI with a half-life of 9 h and eliminated through both renal and hepatic routes. Phase II trials conducted with 150 mg twice daily immediate release formulation found it to be noninferior to warfarin. Its further development has been stopped. [11],[34] Aptamers Aptamer (aptus-to fit) is a structured oligonucleotide that folds into unique specific conformations enabling it to bind to a specifically chosen target and act as a protein inhibitor. Aptamers achieve selectivity by adopting unique three-dimensional folds as a result of internal Watson-Crick base pairing. A complementary nucleotide sequence that competes effectively for critical base pair is used to design an antidote. Due to 1:1 binding, level of aptamer reversal by an active control agent can be fine-tuned. Aptamers have low inherent toxicity because of their small size and target specificity and no apparent immunogenic potential. Aptamers have been generated for a number of antithrombotic targets such as thrombin and FIXa. [35],[36],[37]
Factor Xa occupies a critical juncture in the coagulation cascade. One molecule of FXa catalyses the formation of approximately 1000 molecules of thrombin. Selective inhibition of FXa inhibits thrombin generation while allowing existing thrombin to continue its vital functions in normal hemostasis. [5] In contrast to thrombin inhibition, blocking FXa is less likely to have pleiotropic effects as it has fewer functions outside of coagulation. Direct factor Xa inhibitors Rivaroxaban, apixaban, betrixaban, and edoxaban are direct factor Xa inhibitors. They antagonize the active site of both the free-form and prothrombinase-bound forms of FXa. Rivaroxaban is a highly selective oral FXa inhibitor [Table 2]. [25] Study in AF In ROCKET AF (rivaroxaban once daily oral direct factor Xa prevention of stroke and embolism trial in atrial fibrillation) trial, rivaroxaban was found to be noninferior to warfarin in "intention to treat" analysis. Nonetheless, "on treatment" analysis showed a 21% risk reduction with rivaroxaban in comparison to warfarin [Table 3]. [16] Studies in DVT and PE Convincing results from RECORD (regulation of coagulation in major orthopedic surgery reducing the risk of deep vein thrombosis and pulmonary embolism) trials lead to FDA approval of rivaroxaban in 2011 for prevention of VTE in adult patients undergoing elective hip or knee replacement surgery [Table 4]. [22],[24],[26],[27] The EINSTEIN trials in DVT (oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis without symptomatic pulmonary embolism) and PE (oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic pulmonary embolism with or without symptomatic deep-vein thrombosis) showed rivaroxaban to be noninferior to VKA, but superior to combined enoxaparin and VKA regimen with potentially improved benefit-risk profile [Table 4]. [23],[25] Studies in ACS Rivaroxaban (2.5 mg bd) reduced overall and cardiovascular mortality vs. placebo, despite an increased rate of major bleeding and intracranial hemorrhage but without a significant increase in fatal bleeding in the Atlas More Details ACS TIMI 51 trial (anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome 2-thrombolyis in myocardial infarction) [Table 5]. [33] The most common adverse events reported are constipation, nausea, vomiting, pyrexia, anemia, wound secretion, decreased hemoglobin, dizziness, and insomnia. It should be used cautiously in patients with impaired renal or hepatic function. [5],[9] Apixaban is an oral FXa inhibitor [Table 2]. Studies in AF The ARISTOTLE (apixaban for reduction of stroke and other thromboembolic events in atrial fibrillation) trial compared apixaban (5 mg bd) with warfarin (target INR 2-3) in 18,201 patients with AF and ≥1 additional factor for stroke. It demonstrated apixaban to be superior to warfarin in preventing stroke and thromboembolism, reducing major bleeding and mortality in patients with AF. Although this was the first trial to show statistically significant improvement in mortality, overall stroke reduction was due to a marked reduction in the hemorrhagic stroke rate rather than reduction in the incidence of ischemic stroke [Table 3]. [17] The AVERROES trial (apixaban vs. acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment) was stopped early due to evidence of clear benefits of apixaban compared with aspirin among patients with AF who either failed or were unsuitable for warfarin. [11] Studies in DVT and PE In ADVANCE-2 and 3 studies (apixaban dosed orally vs. anticoagulation with enoxaparin), apixaban was found to be superior to enoxaparin without an increase in bleeding in prevention of VTE [Table 4]. [28],[29],[30] This drug is currently being evaluated in treatment of VTE in the AMPLIFY trials (efficacy and safety study of apixaban for treatment of deep vein thrombosis or pulmonary embolism). It has been approved in the European Union (EU) for prevention of VTE in major orthopedic surgery and approval in EU and by FDA for prevention of stroke in patients with AF is awaited. Study in ACS Development of apixaban for use in patients who had experienced recent ACS was discontinued due to a clinically relevant increase in bleeding in the global phase III APPRAISE-2 trial (safety of the factor Xa inhibitor, apixaban, in combination with antiplatelet therapy after acute coronary syndromes: A dose-guiding trial) [Table 5]. [13] Edoxaban, an oral FXa inhibitor [Table 2], is currently available only in Japan, licensed for prevention of VTE in patients undergoing total knee arthroplasty, total hip arthroplasty, and hip fracture surgery; it is not being developed for prevention of VTE in other parts of the world. Studies in DVT and PE Two phase III trials-STARS J-V (a phase 3, randomized, double-blind, double-dummy efficacy and safety study of the oral factor Xa inhibitor DU-176b compared with enoxaparin sodium for prevention of venous thromboembolism in patients after total hip arthroplasty) and STARS E-III (a phase 3, randomized, double-blind, double-dummy efficacy and safety study of the oral factor Xa inhibitor DU-176b compared with enoxaparin sodium for prevention of venous thromboembolism in patients after total knee arthroplasty) demonstrated superiority of edoxaban over enoxaparin in terms of both efficacy and safety. In a pooled analysis of these two trials, the incidence of symptomatic and asymptomatic DVT and PE was significantly reduced in the edoxaban-treated patients compared with the enoxaparin-treated patients (5.1% vs. 10.7%, P < 0.001). Overall, the rates of major and clinically relevant nonmajor bleeding were similar in both treatment arms (4.6% in the edoxaban patients vs. 3.7% in the enoxaparin patients, P = 0.427). [38] HOKUSAI VTE study (comparative investigation of low molecular weight (LMW) heparin/edoxaban tosylate (DU 176b) versus (LMW) heparin/warfarin in the treatment of symptomatic deep-vein blood clots and/or lung blood clots) is currently evaluating edoxaban in VTE. [39] Study in AF Edoxaban is being evaluated in ENGAGE AF TIMI (effective anti coagulation with factor xA next generation in atrial fibrillation-thrombolysis in myocardial infarction study 48). [39] Betrixaban is an oral direct FXa inhibitor with unique properties such as half-life suitable for once-daily dosing, a low level of clearance through the kidney-thus needing no dose adjustment in renally compromised patients and lack of metabolism through the CYP pathway [Table 2]. An added advantage is that its antidote is being codeveloped (PRT064445). Study in AF In a dose comparative trial, EXPLORE Xa (phase 2 study of the safety, tolerability, and pilot efficacy of oral factor Xa inhibitor betrixaban compared to warfarin), it showed fewer bleeding incidences with a dose of 40 mg daily when compared with warfarin in patients with AF and one additional risk factor for stroke. However, comparison with higher doses of betrixaban showed bleeding rates to be similar to warfarin. [40] Studies in prevention of VTE: In the phase II EXPERT trial (a randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement), though VTE incidence with betrixaban was comparable to enoxaparin, clinically significant bleeds were markedly reduced. The phase III APEX trial (acute medically ill VTE prevention with extended duration betrixaban study) will compare extended-duration betrixaban (35-42 days) with standard of care enoxaparin for hospital and postdischarge prevention of VTE in high-risk acute medically ill patients. [41] Otamixaban is a parenteral FXa inhibitor with rapid on-off anticoagulant activity. Like betrixaban, it needs no dose modification in renal insufficiency. Intermediate dose (bolus of 0.08 mg/kg/h followed by infusion of 0.10-0.14 mg/kg/h) of this drug showed a greater reduction of ischemic complications or death when compared with heparin plus eptifibatide. [42] A trial studying its effects in unstable angina or non-ST elevation myocardial infarction is currently recruiting participants. [1] Indirect FXa inhibitors They require antithrombin as a cofactor and do not inhibit FXa bound to prothrombinase complex. Clinical development of idraparinux, a hypermethylated derivative of fondaparinux, was stopped when trials showed excessive risk of major hemorrhage as a consequence of its long half-life. [43],[44] Biotinylated idraparinux (idrabiotaparinux) is a long-acting synthetic pentasaccharide and differs from idraparinux in being bound to biotin so that avidin can neutralize its effects. Although it demonstrated lesser incidence of recurrent VTE and reduced bleeding compared to the enoxaparin-warfarin group in PE, its further development has been stopped. [34],[45],[46]
Semuloparin sodium is a ULMWH with higher ratio of anti-FXa/FIIa activity (>30) synthesized from UFH by selective and controlled depolymerization. It is not neutralized by protamine. A meta-analysis of three studies involving patients undergoing knee and hip replacement surgery suggested superior efficacy of semuloparin vs. enoxaparin in total VTE plus total death, with similar rates of clinically relevant bleeding. However, after excluding asymptomatic distal DVT, the results of the meta-analysis were inconclusive. [47],[48] It is under evaluation for prevention of cancer-associated thrombosis. [49] RO-14 is a new ULMWH with predominant anti-Xa activity and virtually devoid of anti-FIIa activity. [1],[50]
Adomiparin (M118) is a new LMWH (anti-Xa/anti-IIa activity, 1.4) rationally designed to capture, in a single therapy, the positive attributes of both UFH (reversibility, monitorability, and broad inhibition of the coagulation cascade) and LMWH (adequate bioavailability and predictable pharmacokinetics to allow for subcutaneous administration). Phase IIb trials in percutaneous coronary intervention (PCI) have shown it to be well tolerated. [1],[34],[51]
They are chemoenzymatically prepared, and constitute a library of diverse, nonsugar aromatic molecules with structure radically different from heparin that mimic biological activities of heparin and heparin sulfate. Mechanistically, they represent the first example of an exclusive exosite II-dependent inactivation of catalytic function of thrombin. These sulfated dehydropolymers are better than heparin as they are less polyanionic and more hydrophobic. Presently, they are in preclinical phase. [1],[52]
Targeting coagulation factors upstream from the common pathway reduces thrombin just enough to impede occlusive thrombosis yet support hemostasis. [53] FXIa inhibitors indirectly enhance clot dissolution as FXIa also leads to activation of TAFI, which makes clot less sensitive to fibrinolysis. BMS 262084 is an irreversible inhibitor of FXIa presently in preclinical evaluation. [54] Antisense oligonucleotides (ASO) are novel therapeutic agents that inhibit gene by cleaving specific mRNA sequences leading to the corresponding reduction in target protein. ISIS 404071, a FXIa ASO, leads to dose-dependent reductions in plasma FXIa protein levels and activity. [55] Hybrid analogs of Clavatadine A, a marine sponge natural product with improved bioavailability and selectivity, are being synthesized. [56]
An RNA aptamer system termed REG 1 consists of pegnivacogin, the therapeutic aptamer, and anivamersen (its neutral antidote helping in safe reversal). This approach allows clinicians with the flexibility to provide enough anticoagulant effect to prevent or treat thrombosis while also controlling the risk of bleeding. [57],[58] Evaluation of pegnivacogin in ACS in the RADAR trial (a randomized, partially blinded, multicenter, active-controlled, dose-ranging study assessing the safety, efficacy, and pharmacodynamics of the REG1 anticoagulation system in patients with acute coronary syndromes) reported reduced rate of ischemic events (3.0% vs. 5.7% with heparin). [59] REG 2 is a once or twice weekly subcutaneous formulation having benefits of improved administration, faster onset of action, and virtually instantaneous reversal. It has the potential to be an alternative to heparin/protamine in cardio surgery.
Factor VIIIa is a cofactor for FIXa that further activates factor X and is associated with intrinsic and propagation phase of coagulation. TB402, a human monoclonal antibody (IgG4), is a novel, long-acting agent being developed as a single injection for prevention of VTE following orthopedic surgery. [14],[60]
FVIIA/TF (thromboplastin) plays a crucial role in the initiation of coagulation cascade. The caveat is that FVIIa/TF is essential for hemostasis and inhibition of this complex may result in extensive bleeding. Drugs targeting FVIIa/TF are tifacogin, rNAPc2 (recombinant nematode anticoagulant protein), PCI 274836, and BMS 593214. Tifacogin is recombinant tissue factor pathway inhibitor (TFPI) that inhibits FXa directly as well as FVIIa/TF catalytic complex leading to inhibition of thrombin generation. However, trials with tifacogin have failed to show benefit in patients with sepsis due to severe community acquired pneumonia. [61] Development of rNAPc2 isolated from hematophagous hookworm has been recently suspended and potential in cancer is being explored owing to positive correlation between TF and tumor progression. [62] Dual mode of action involving inhibition of thromboembolism and intracellular signaling in tumor growth has prompted evaluation of PCI 27483 in patients undergoing pancreatic cancer treatment with gemcitabine. [63] BMS 593214 is a potent direct FVIIa inhibitor in preclinical evaluation studies. [64]
Factor Va acts as a cofactor of FXa (both form the prothrombinase complex) in thrombin generation. It is inhibited by activated protein C (APC). Drotrecogin alpha (recombinant APC) is licensed for treatment of adult patients with severe sepsis and multiple organ failure due to disseminated intravascular coagulation (DIC). ART-123 (recomodulin) is recombinant thrombomodulin alpha. The thrombin-recomodulin complex activates protein C-produces APC, which inactivates factors VIIIa and Va, thereby inhibiting thrombin formation. It has been licensed for treatment of DIC in Japan. [65] Solulin is modified thrombomodulin with reduced affinity for thrombus and enhanced TAFI activation. Low dose solulin has recently shown potential in hemophilia, where it acts by virtue of antifibrinolytic property and improved clot stability. [66]
EP 217609 is a combination of an indirect FXa inhibitor (antithrombin-binding pentasaccharide), a direct thrombin active site inhibitor and biotin, which allows its neutralization by avidin. Phase II trials are planned in extracorporeal circulation in cardiac surgery and PCI in ACS. [67] Tanogitran is a reversible dual inhibitor evaluated in phase I studies in human endotoxemia models. [68]
Tecarfarin, a vitamin K epoxide reductase inhibitor, is an oral, nonchiral, novel synthetic VKA differing from warfarin with regard to pharmacokinetics. Not being metabolized by CYP450 system, it avoids drug-drug interactions and genetic variations that occur with warfarin and is nonteratogenic. A comparative trial with warfarin failed to meet its goals of superiority as time in the therapeutic range was high in both tecarfarin and warfarin groups (74% vs. 73.2%, respectively). Its further development has been halted. [34],[69],[70]
Pharmacological inhibition of factor XII may offer anticoagulation therapy with minimal or no bleeding risk. [71],[72] FXIII inhibitors have the potential to increase the susceptibility of thrombus to lysis. Peptides isolated from leech (e.g. tridegin) have been identified as specific FXIII inhibitors. [9]
New agents represent important therapeutic advances and credible alternatives to warfarin as they possess benefits of predictable pharmacokinetics and pharmacodynamics, minimal food-drug interactions with no requirement for routine coagulation monitoring and repeated dose adjustments. In addition, newer parenteral anticoagulants also offer rapid onset and offset. The use of novel oral anticoagulants will lead to a decrease in burden of care for physicians, an increase in quality of life, and greater use of anticoagulants for under-treated conditions. They will most likely eliminate the need for perioperative treatment (bridge therapy) with parenteral agents. [73] They reflect a paradigm shift in stroke prevention from VKA to a direct factor inhibitor. Because these compounds block thrombin generation and indirectly inhibit platelet aggregation, they may be effective not only in fibrin dominant VTE, but also in platelet dominant arterial thrombosis settings. [1],[11] Warfarin marketed in the generic form is considerably cheaper than newer agents. However, the costs involved in coagulation monitoring, manpower involved in clinic visits, extra hospital admissions when bridging therapy is required for invasive procedures, and extra cost involved in managing warfarin dose may outweigh the increased cost of a new drug. In a cost analysis study, dabigatran yielded an additional 0.56 quality adjusted life years (QALY) when compared with warfarin. [74]
Novel anticoagulants are not supported by the depth of clinical evidence that is available for the currently recommended anticoagulants in terms of clinical experience and indications. Limited evaluations have been done in special populations. Additional trials are needed to establish the efficacy and safety of oral anticoagulants such as dabigatran etexilate for other antithrombotic indications such as acute transient ischemic attack and ischemic stroke, and mechanical heart valves. Long-term safety of these potentially new candidates is hitherto unknown. [75] Many agents lack an antidote that may be needed when anticoagulant treated patient requires urgent surgery or suffers from major blunt trauma. Although the prothrombin complex concentrate and recombinant FVIIa have been proposed to be useful antidote agents, data supporting these are scarce. [76] The therapeutic proteins (tifacogin, recomodulin, and avidin, an egg-derived protein) or monoclonal antibodies and derivatives of animal protein may have immunogenic potential. Results of the trials need careful critical evaluation. The RELY trial was an open label trial and reported a small but increased risk of myocardial infarction with dabigatran though this has been attributed to better efficacy of warfarin. The ROCKET AF assessed the effect of rivaroxaban on an older population with more comorbid conditions and higher risk for stroke, which could confound the results. Additionally, in the ROCKET AF trial, management of warfarin in the control arm was suboptimal (time in the therapeutic range was only 55%). Similarly, in the ARISTOTLE trial, time in the therapeutic range was only 62%. Therefore, both the studies were effectively comparing FXa inhibitors with poorly controlled warfarin therapy. [77],[78],[79],[80],[81] Another issue is whether a fixed dose regime can be universally applied to all patients. Currently, no routine standardized laboratory monitoring tests are established for these drugs. Lack of monitoring may deny the physician opportunity for individual tailoring of treatment and early detection of bleeding problem. Short half-lives make issue of adherence to treatment an important consideration. There is no way to objectively assess for nonadherence. [77],[78],[79],[80],[81] Thrombin plays an important role not only in coagulation, but also in immune response, infection, angiogenesis, endothelial function, and tumor growth. Therefore, unintended and unexpected off target effects may be disclosed in time to come. [80]
A new era dawns as several promising new anticoagulants are in the race to replace and outshine conventional anticoagulants. Oral DTIs and factor Xa inhibitors-dabigatran, rivaroxaban, and apixaban are at least as effective as dose-adjusted warfarin with similar bleeding profiles. Direct comparison between these new agents will help decide how these agents will impact prescribing and get integrated into routine clinical practice; the path to this slow transition has been paved.
[Figure 1]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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