J Thromb Thrombolysis DOI 10.1007/s11239-015-1194-6
Anticoagulation therapy in 2015: where we are and where we are going Jeffrey I. Weitz
Ó Springer Science+Business Media New York 2015
Abstract Oral anticoagulants are a mainstay for the prevention and treatment of venous and arterial thrombosis. In 2015, the non-vitamin K oral anticoagulants (NOACs) are already replacing warfarin for many indications. Ongoing studies are focused on development of antidotes and specific reversal agents for the NOACs, and assessing their utility for prevention of cardiovascular events in patients with heart failure, coronary or peripheral artery disease, or embolic stroke of unknown source. This paper (a) lists the current indications for the NOACs; (b) reviews the current impact of the NOACs in each of these indications; (c) outlines future opportunities for the NOACs, and (e) provides perspective on new anticoagulant strategies that may be safer than the NOACs. Keywords Anticoagulants Dabigatran Rivaroxaban Apixaban Antidotes Non-vitamin K oral anticoagulants
Introduction The three major causes of death and disability worldwide are ischemic heart disease, stroke and venous thromboembolism (VTE). Thrombosis is the underlying pathology in acute coronary syndrome (ACS), ischemic stroke and VTE. Therefore, thrombosis is a major contributor to the global burden of disease and its prevention and
J. I. Weitz (&) Departments of Medicine and Biochemistry and Biomedical Sciences, The Thrombosis and Atherosclerosis Research Institute, McMaster University, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada e-mail: [email protected]
treatment are essential to prevent premature death and disability . Anticoagulation therapy is a cornerstone for prevention and treatment of thrombosis. Although parenteral and oral anticoagulants are available, oral agents are preferred for long term indications. The landscape of oral anticoagulant therapy has changed with the recent introduction of the non-vitamin K oral anticoagulants (NOACs). In contrast to warfarin, which requires frequent assessment of the international normalized ratio (INR) and dose adjustments, the NOACs can be given in fixed doses without routine monitoring. Nonetheless, there are circumstances where measuring the anticoagulant effects or levels of the NOACs is helpful, such as prior to surgery, or in patients who present with an ischemic or serious bleeding event. The potential advantages of the NOACs over warfarin are summarized in Table 1, as are the clinical implications of these features. Most importantly, however, in phase III clinical trials that enrolled over 150,000 patients, the NOACs have been shown to be at least as effective as warfarin and to be associated with less serious bleeding; in particular, the risk of intracranial bleeding is significantly lower with the NOACs than with warfarin . Because they are more convenient to administer than warfarin, the NOACs have the potential to increase the uptake of anticoagulation therapy for prevention of stroke in eligible patients with atrial fibrillation (AF), and to streamline the treatment of patients with established thrombosis. Therefore, despite some potential disadvantages, which are listed in Table 2, the NOACs are well positioned to reduce the burden of disease related to thrombosis. This paper (a) lists the current indications for the NOACs; (b) reviews the current impact of the NOACs in each of these indications; (c) outlines future opportunities
J. I. Weitz Table 1 Potential advantages of non-vitamin K oral anticoagulants over warfarin and their consequences Advantage
Faster onset of action
Obviates bridging in most situations
More predictable anticoagulant response
Enables fixed dosing without routine coagulation monitoring
No influence of dietary vitamin K
No dietary restrictions; therapeutic doses of rivaroxaban should be given with meals to enhance absorption More predictable anticoagulant response
Few drug–drug interactions Less intracranial bleeding
Safer therapy, particularly in older patients at higher risk for intracranial bleeding
Shorter offset of action
Simplifies periprocedural management and reduces need for antidotes or reversal agents
Table 2 Potential disadvantages of non-vitamin K antagonist oral anticoagulants (NOACs) relative to warfarin
Once or twice daily
Renal clearance of 25–80 %
Vitamin K, fresh frozen
No specific antidotes
plasma, prothrombin complex concentrate Cost
for the NOACs, and (e) provides perspective on emerging anticoagulant strategies.
Current indications for NOACs The NOACs include dabigatran, which inhibits thrombin, and rivaroxaban, apixaban and edoxaban, which inhibit factor Xa. Dabigatran, rivaroxaban and apixaban are licensed for various indications in the United States. Edoxaban was recently licensed in Japan and the United States for stroke prevention in AF and for treatment of VTE. Rivaroxaban and apixaban are licensed for prevention of postoperative deep-vein thrombosis (DVT), which can lead to pulmonary embolism (PE), in patients undergoing elective hip or knee replacement surgery. Dabigatran is approved for this indication in Canada and Europe, but not in the United States. Dabigatran, rivaroxaban and apixaban are licensed for treatment of acute VTE, which includes DVT and PE. In addition, they are approved for secondary prevention of VTE in patients who have received at least 3–6 months of anticoagulation therapy for their initial VTE event. All three agents also are licensed as alternatives to warfarin for reduction of the risk of stroke in patients with AF. With at least 2.5 million patients in the United States with AF ,
and with the number of AF patients increasing each year because of the aging population, AF represents the largest unmet need for oral anticoagulants that are more convenient and safer than warfarin. In Europe, rivaroxaban is licensed for prevention of recurrent ischemic events in patients with stabilized ACS. Although there is a need for more effective therapy in such patients, rivaroxaban is not approved for this indication in the United States or Canada. Focusing on where we are with anticoagulation in 2015, the next section reviews the impact of the NOACs in each of the approved indications.
Where we are with anticoagulation in 2015 The NOACs have had an impact in each of the licensed indications. Their impact is discussed in an indication-byindication fashion. VTE prevention Elective hip and knee arthroplasty are being performed with increasing frequency. Results of a nationwide inpatient survey in the United States identified a 37 % increase in the number of patients undergoing hip arthroplasty from 2000 to 2004, and a 54 % increase in those undergoing
Anticoagulation therapy in 2015
knee arthroplasty . In the United States, it is estimated that by 2015, elective hip and knee arthroplasty will be performed in 600,000 and 1.4 million patients, respectively . Therefore, more and more patients are undergoing arthroplasty each year. Patients having elective hip or knee arthroplasty are at risk for postoperative VTE. On average, the rate of symptomatic VTE 3 months after surgery is about 3.6 %, and the rate of fatal PE is approximately 0.13 % [6, 7]. Results from a global registry indicate that the median length of stay for patients undergoing such surgery is about 3–4 days . In contrast, the mean times to presentation with symptomatic VTE after hip or knee arthroplasty are 22 and 10 days, respectively . Therefore, symptomatic VTE in these patients is primarily an outpatient problem. This observation highlights the need for extended out-ofhospital thromboprophylaxis after surgery. Current guidelines recommended post-operative thromboprophylaxis with low-molecular-weight heparin (LMWH), fondaparinux, or warfarin (dose-adjusted to an INR of 2–3) for at least 10 days after elective hip or knee arthroplasty and for up to 35 days . The problem with these agents is that LMWH and fondaparinux require daily subcutaneous injection, which can be difficult for patients to manage after hospital discharge, whereas warfarin requires frequent monitoring and dose adjustment at a time when limited mobility complicates visits to the laboratory and may necessitate home visits for INR testing. Consequently, adherence to extended thromboprophylaxis is often suboptimal. Dabigatran, rivaroxaban, and apixaban have been compared with enoxaparin for post-operative thromboprophylaxis in patients undergoing elective hip or knee arthroplasty. The pooled data  show that rivaroxaban significantly reduces the rate of VTE compared with enoxaparin (relative risk [RR] 0.56, 95 % confidence interval [CI] 0.43–0.73; P \ 0.0001) but is associated with a potential for an increased risk of major bleeding (RR 1.26, 95 % CI 0.94–1.69; P = 0.13), whereas dabigatran provides no significant advantage over enoxaparin for reduction of VTE (RR 1.10, 95 % CI 0.90–1.35; P = 0.34) and is associated with a similar rate of major bleeding. The results with apixaban are mixed; when compared with enoxaparin 40 mg once daily in patients undergoing hip or knee arthroplasty, apixaban reduced the risk of major VTE from 1.5 to 6.7 %; an absolute risk difference of -0.8 % (95 % CI -1.2 to -0.3; P \ 0.001) without increasing the risk of major bleeding . In contrast, when compared with 30 mg twice-daily enoxaparin in patients undergoing knee arthroplasty , apixaban was not more effective for VTE prevention (RR 1.02, 95 % CI 0.78–1.32; P = 0.06 for non-inferiority). Overall, the NOACs are at least as effective as enoxaparin and have similar safety. The major advantage of the NOACs is that they can be given orally in fixed doses once-
or twice-daily, thereby streamlining out-of-hospital thromboprophylaxis by obviating the need for daily subcutaneous injections or coagulation monitoring. Although more expensive than warfarin, the NOACs are more convenient and they are less expensive than LMWH or fondaparinux. Therefore, the NOACs represent a more costeffective option than enoxaparin for extended thromboprophylaxis after elective hip or knee arthroplasty . Because of these benefits, the NOACs are being used more frequently than both warfarin and enoxaparin for this indication, at least in Canada. VTE treatment Anticoagulants are the cornerstone of VTE treatment. Traditionally, treatment starts with a rapidly acting parenteral anticoagulant, usually LMWH, which is overlapped with warfarin for at least 5 days. The parenteral anticoagulant is stopped when the INR reaches 2 or higher, and then warfarin is continued long-term for a minimum of 3 months. At this point, the decision to stop or continue treatment depends on the balance between the risk of recurrence if warfarin is stopped and the risk of bleeding if it is continued . Patients with VTE in the setting of transient and reversible risk factors, such as surgery, have a low risk of recurrence if anticoagulant therapy is stopped at 3 months, whereas those with ongoing risk factors, such as active cancer, and patients with unprovoked VTE are often prescribed extended anticoagulation therapy provided that the bleeding risk is not excessive . Therefore, conventional anticoagulant treatment of VTE has been divided into three stages: (a) initial therapy for 5–10 days, the goal of which is to prevent thrombus extension and fatal PE; (b) long-term therapy for 3 months, which is given to prevent recurrent VTE and to reduce the risk of complications, such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension; and (c) extended therapy beyond 3 months, which is administered when the risk of recurrent VTE is high and exceeds the risk of major bleeding with continued anticoagulant treatment. Though effective, traditional treatment of VTE is cumbersome because initial therapy with LMWH requires daily subcutaneous injection, whereas warfarin requires frequent INR monitoring and dose adjustments. Because of the complexity of initial therapy, many VTE patients are hospitalized, which increases healthcare costs . This is problematic because there is increasing evidence that the majority of patients with DVT and low-risk patients with PE can safely be treated at home . By simplifying VTE treatment, NOACs facilitate transition of care from the emergency department or the hospital to home, thereby reducing healthcare costs  and enhancing patient satisfaction .
J. I. Weitz
In patients with acute VTE, dabigatran, rivaroxaban, apixaban, and edoxaban were compared with conventional treatment in the RE-COVER I and II, EINSTEIN-DVT and EINSTEIN-PE, AMPLIFY, and Hokusai-VTE trials, respectively [20–25]. The primary efficacy endpoint of these trials was recurrent VTE, and the principal safety outcome was either major bleeding or the composite of major and clinically relevant non-major bleeding. In a recent meta-analysis of these trials , which included 24,455 patients with acute VTE, rates of recurrent VTE, fatal PE, and all-cause mortality were not significantly lower with the NOACs than with conventional treatment (RR 0.88, 95 % CI 0.74–1.05; RR 1.02, 95 % CI 0.39–5.96; and RR 0.97, 95 % CI 0.83–1.14, respectively). In contrast, the rate of major bleeding was significantly lower with the NOACs than with warfarin (RR 0.60, 95 % CI 0.41–0.88), as was the rate of fatal bleeding (RR 0.36, 95 % CI 0.15–0.87). The numbers needed to treat with NOACs instead of warfarin to prevent one major bleed or one fatal bleed were 149 and 1111, respectively. A fixedeffect network analysis did not reveal significant differences between any one NOAC and rivaroxaban. Overall, therefore, NOACs are non-inferior to conventional therapy for VTE treatment and are associated with less bleeding. Importantly, NOACs are more convenient to administer. Rivaroxaban and apixaban can be given in all-oral regimens that obviate the need for a parenteral anticoagulant at the outset, and all of the NOACs are easier to administer than warfarin because they can be given in fixed doses without routine coagulation monitoring. Because of these advantages, NOACs are replacing conventional treatment for many VTE patients. For extended VTE treatment, rivaroxaban, apixaban, and dabigatran were compared with placebo in the EINSTEINExtension, AMPLIFY-Extension, and RE-SONATE trials, respectively [22, 27, 28]. Patients enrolled in these trials had completed at least 6 months of anticoagulation therapy for their index VTE event. Whereas single-dose regimens of rivaroxaban and dabigatran were evaluated in the EINSTEIN-Extension and RE-SONATE trials, two dosage regimens of apixaban were studied in the AMPLIFY-Extension trial. All of the trials were powered to demonstrate superiority of the NOACs over placebo, and the primary efficacy outcome was recurrent VTE or VTE-related mortality. Dabigatran is the only agent to be compared with warfarin for extended VTE treatment in the RE-MEDY trial . Patients enrolled in this trial had received 3–12 months of anticoagulant treatment for their index VTE event, and the study was designed to show non-inferiority of dabigatran compared with warfarin. Although edoxaban has yet to be evaluated in an extension study, the drug has been administered for up to 12 months because of the flexible treatment duration in the Hokusai-VTE trial.
Dabigatran, rivaroxaban, and apixaban were superior to placebo for prevention of recurrent VTE and were associated with low rates of major bleeding [22, 27, 28]. Compared with placebo, both the treatment and the prophylactic dose of apixaban (5 and 2.5 mg twice daily, respectively) significantly reduced the risk of recurrent VTE . Although both dose regimens were associated with low rates of major bleeding, there was a trend for less clinically relevant non-major bleeding with the lower-dose apixaban regimen. This finding raises the possibility that for extended VTE treatment, the intensity of treatment with NOACs can be lowered to reduce the risk of bleeding without compromising efficacy. In contrast, attempts to lower the intensity of warfarin therapy for extended VTE treatment resulted in reduced efficacy without evidence of decreased bleeding. Therefore, NOACs are effective and safe for extended secondary prevention of VTE. Dabigatran was non-inferior to warfarin for extended VTE treatment in the RE-MEDY trial , and was associated with less major and clinically relevant non-major bleeding (5.6 and 10.2 %, respectively; P \ 0.001). Although the number of events was small, myocardial infarction was more common with dabigatran than with warfarin, a phenomenon observed in other studies that compared dabigatran with warfarin . The clinical relevance of this finding is uncertain, however, because the rates of all-cause mortality and cardiovascular mortality tend to be lower with dabigatran than with warfarin, and a large observational study based on Medicare claims data in 134,414 patients with AF failed to show a higher risk of myocardial infarction with dabigatran than with warfarin . Overall, therefore, NOACs are effective and safe for initial, long-term, and extended VTE treatment. Atrial fibrillation One in four persons over the age of 40 years will develop AF during their lifetime, and it is estimated that, by the year 2050, up to 16 million persons in the United States will have AF . AF is a major healthcare problem because it is associated with a fivefold increase in the risk of ischemic stroke, and strokes in patients with AF are more likely to be fatal or disabling than those in patients without AF. For this reason, most patients with AF should receive anticoagulant therapy to reduce the risk of stroke. Traditionally, warfarin has been used for stroke prevention in patients with AF. Compared with control, warfarin reduces the risk of stroke and systemic embolism by about 64 % and reduces mortality by about 25 % . However, because of the complexity of warfarin management, it is estimated that at least half of eligible AF patients are not receiving anticoagulant therapy, and in those who are taking warfarin, the INR is frequently outside the
Anticoagulation therapy in 2015
therapeutic range . Because of the increased risk of stroke in AF patients, underuse of and poor adherence to warfarin therapy are costly to the health-care system. The problems with warfarin in AF patients prompted trials with the NOACs. Dabigatran, rivaroxaban, apixaban, and edoxaban were compared with warfarin in 71,683 patients with AF in four phase III trials, which were powered to demonstrate noninferiority of the NOACs. The primary efficacy endpoint in these trials was the composite of stroke (both ischemic and hemorrhagic) and systemic embolism, whereas the principal safety outcome was major bleeding. A meta-analysis of the trials  reveals that the NOACs significantly reduced the rate of stroke and systemic embolism by 19 % (RR 0.81, 95 % CI 0.73–0.91) mainly driven by a reduction in hemorrhagic stroke (RR 0.49, 95 % CI 0.38–0.64). Compared with warfarin, NOACs also significantly reduced allcause mortality by 10 % (RR 0.90, 95 % CI 0.85–0.95) and intracranial hemorrhage by 52 % (RR 0.48, 95 % CI 0.39–0.59). With the exception of apixaban, however, the NOACs were associated with a 25 % increase in the risk of gastrointestinal bleeding (RR 1.25, 95 % CI 1.01–1.55). Therefore, the NOACs are at least as effective as warfarin for prevention of stroke and systemic embolism in patients with AF, and are associated with less intracranial hemorrhage and reduced all-cause mortality. Based on these observations, several recent guidelines give preference to the NOACs over warfarin for most patients with AF [34– 36]. Certainly, the NOACs are more convenient to administer than warfarin and appear to be more cost-effective . Consequently, they have the potential to increase the uptake of anticoagulation therapy for eligible AF patients, thereby reducing the burden of disease from stroke.
Anticoagulation beyond 2015 Although the NOACs represent an advance in oral anticoagulation, their future penetration into the marketplace depends on several factors. Most important among these are development of specific antidotes or reversal agents for the NOACs, and provision of evidence that the NOACs are efficacious for new indications, such as prevention of cardiovascular death, myocardial infarction and stroke in patients with heart failure, coronary artery or peripheral artery disease, or ischemic stroke of unknown source. Even if the NOACs prove effective for these new indications, however, there still are situations where they cannot be used. These include patients with mechanical heart valves and end-stage renal disease. To address these gaps, new targets are emerging that enable development of anticoagulant strategies that may not only be effective for these indications, but may also be safer than the NOACs in other
patient populations. Each of these potential advances will briefly be discussed in turn. Specific antidotes and reversal strategies for the NOACs Many physicians are reluctant to prescribe NOACs because they lack specific antidotes. They fear that without antidotes, the outcome of patients with serious bleeds or of those requiring urgent surgery or intervention will be worse with the NOACs than with warfarin. These concerns are not supported by the clinical trial evidence. First, the rate of intracranial bleeding, the most serious form of bleeding, is reduced by over 50 % with the NOACs compared with warfarin  and the outcome of patients with intracranial bleeds is no worse with the NOACs than with warfarin . Fatal bleeding also is less common with the NOACs than with warfarin [2, 26], and in patients with major bleeding from extracranial sites, including the gastrointestinal tract, mortality is similar or lower with the NOACs than with warfarin [39, 40]. The clinical trial data with dabigatran in AF are supported by a recent analysis of the Medicare database by the United States Food and Drug Agency . Based on data from 134,414 new users of dabigatran or warfarin for AF who were 65 years of age or older, rates of intracranial bleeding were lower with dabigatran than with warfarin (3.3 and 9.6 %, respectively) as were rates of ischemic stroke (11.3 and 13.9 %, respectively) after matching for confounding variables. Although the rate of gastrointestinal bleeding was higher with dabigatran than with warfarin (34.2 and 26.5 %, respectively), major hemorrhage rates were similar (42.7 and 43.9 %, respectively), and mortality rates were lower with dabigatran than with warfarin (32.6 and 37.8 %, respectively). Consequently, the fear of uncontrollable bleeding is not a valid reason to withhold NOACs. The outcomes of patients requiring surgery or interventions are similar with the NOACs and warfarin . Furthermore, patients undergoing surgery within 24 h may do better with NOACs than with warfarin because the NOACs have shorter half-lives . Therefore, the fear of urgent surgery or intervention also is not a valid reason to withhold NOACs. Antidotes and reversal agents for the NOACs are under development (Table 3). These include idarucizumab, a humanized monoclonal antibody fragment directed against dabigatran ; andexanet alfa, a recombinant factor Xa variant that serves as a decoy for factor Xa inhibitors ; and aripazine (PER977), a cationic small molecule that is purported to bind heparin, dabigatran, rivaroxaban, apixaban and edoxaban . These agents reverse the anticoagulant effect of NOACs in volunteers given the drugs. An ongoing study is evaluating the utility of idarucizumab in
J. I. Weitz Table 3 Features of antidotes and reversal agents for non-vitamin K oral anticoagulants Features
Humanized Fab fragment
Recombinant factor Xa variant with the active site Ser residue replaced with Ala and the Gla-domain absent
Synthetic anionic small molecule
Mechanism of action
Binds dabigatran with high affinity
Serves as a decoy for rivaroxaban or apixaban; competes with factor Xa for binding to the LMWH- or fondaparinuxantithrombin complex
Binds dabigatran, rivaroxaban, apixaban or edoxaban via hydrogen bond formation, and binds LMWH or fondaparinux in a chargedependent manner
Specific antidote for dabigatran
Reverses rivaroxaban, apixaban, edoxaban, LMWH and fondaparinux
Reverses dabigatran, rivaroxaban, apixaban, edoxaban, LMWH and fondaparinux
Competes with factor Xa for binding to tissue factor pathway inhibitor and induces a procoagulant effect
Binds calcium chelators, which negates assays of activity in citrated plasma; activity must be determined in whole blood
Ala alanine, Gla c-carboxyglutamic acid, LMWH low-molecular-weight heparin, Ser serine
dabigatran-treated patients who present with serious bleeding or require urgent surgery, and similar studies are planned with andexanet alfa in patients taking rivaroxaban or apixaban. With promising data in volunteers and in patients, it is likely that these agents will be available in the near future. Once specific antidotes and reversal agents are on the market, the fear of uncontrollable bleeding will no longer be a valid reason to withhold NOACs, and their uptake is likely to increase. New indications NOACs are under investigation in several new indications, including heart failure, coronary or peripheral artery disease, and embolic stroke of unknown source. The rationale for each of these will briefly be discussed. Heart failure Almost 6 million people in the United States suffer from heart failure and despite recent advances in treatment, about 50 % die within four years of diagnosis. Patients with heart failure require frequent hospitalization, which renders this disease costly for the healthcare system. Most patients with heart failure have underlying coronary artery disease. Compared with placebo, the addition of low-dose rivaroxaban to antiplatelet therapy reduced the risk of cardiovascular death, myocardial infarction and stroke in ACS patients . Consequently, it is possible that rivaroxaban may also be of benefit in heart failure patients. To address this, the placebo-controlled COMMANDER HF trial (NCT01877915) will determine whether low-dose rivaroxaban reduces cardiovascular events in heart failure patients.
Coronary and peripheral artery disease Patients with coronary or peripheral artery disease are at risk of cardiovascular events. Aspirin, the current standard of care in most such patients, reduces the risk by about 25 %. Therefore, there is an unmet need for more effective therapy. Antiplatelet drugs and anticoagulants have complementary mechanisms of action and there is increasing evidence that thrombin contributes to recurrent ischemic events in patients with ACS . The ongoing phase III trial with rivaroxaban (COMPASS trial; NCT01776424) is evaluating the role of rivaroxaban for secondary prevention of cardiovascular death, myocardial infarction and stroke in 19,500 patients with coronary artery or peripheral arterial disease. This three-arm study is comparing aspirin alone, rivaroxaban alone at a dose of 5 mg twice daily, and the combination of aspirin plus rivaroxaban at a dose of 2.5 mg twice daily. If rivaroxaban reduces the risk of recurrent ischemic events in this broad population of patients with atherosclerosis, the findings will provide further support for the role of thrombin in the pathogenesis of atherothrombosis. Embolic stroke of unknown source Strokes of unknown source represent about 25 % of all ischemic strokes. There is increasing evidence that most of these stokes are embolic in origin . Thrombi in such patients may originate from many sources, including the left atrial appendage in those with subclinical AF, deep veins of the leg via paradoxical embolism and atherosclerotic plaques in the aortic arch or carotid or cerebral arteries. The optimal management of patients with embolic stroke of unknown source is uncertain and most patients are given aspirin. The RE-SPECT ESUS and NAVIGATE
Anticoagulation therapy in 2015
ESUS trials will compare aspirin with dabigatran and rivaroxaban, respectively, on the risk of recurrent stroke in patients with embolic stroke of unknown source. New targets The intrinsic pathway is initiated by factor XII activation, which then activates factor XI. The subsequent activation of factor IX then culminates in thrombin generation. There is mounting evidence that the intrinsic pathway is important for thrombus stabilization and propagation; findings that render factor XII and factor XI attractive targets for new anticoagulants strategies because patients with congenital deficiency of factor XII do not bleed, and those with factor XI deficiency have only a mild bleeding diathesis. Studies in mice, rabbits and non-human primates have shown that strategies that target factor XII or XI attenuate arterial and venous thrombosis and decrease clotting on catheters, vascular grafts and extracorporeal circuits [49–51]. Nonetheless, questions remained as to whether inhibition of the intrinsic pathway in humans would attenuate thrombosis. Results of a recent phase II study in patients undergoing elective knee arthroplasty indicates that it does . Thus, using a factor XI antisense oligonucleotide to reduce the levels of factor XI during and after surgery, there was dosedependent reduction in the rate of postoperative VTE, and the rate of VTE with the higher dose of oligonucleotide was significantly lower than that with enoxaparin. This reduction was achieved without an increase in bleeding; suggesting that strategies that target factor XI can dissociate thrombosis from hemostasis. If these findings can be confirmed in other settings, they raise the possibility that factor XII- or factor XI-directed anticoagulant strategies may have a better benefit-to-risk profile than those that target downstream clotting enzymes, such as factor Xa or thrombin. In addition, because clotting on artificial surfaces is mediated by the intrinsic pathway, these strategies may also provide novel therapies for patients with mechanical heart valves, left ventricular assist devices or other blood-contacting devices.
Conclusions The introduction of the NOACs represents a tremendous advance in long-term anticoagulation. The NOACs streamline therapy because they can be given in fixed doses without routine coagulation monitoring. These agents are at least as effective as warfarin and are associated with less intracranial bleeding and less fatal bleeding. Although the uptake of the NOACs is steadily climbing [53, 54], the higher cost of these agents relative to warfarin remains a barrier to their widespread use in many countries. The development of specific antidotes and reversal agents may further increase uptake of
the NOACs by allaying concerns about uncontrollable bleeding. On this background, there will be even more use of the NOACs if ongoing studies indicate that they reduce cardiovascular events in patients with heart failure, coronary or peripheral artery disease and embolic stroke of unknown source. Therefore, in 2015, we are on the cusp of an evolution of new indications for the NOACs. What is the future of anticoagulation beyond 2015? The holy grail of anticoagulation treatment is to attenuate thrombosis without perturbing hemostasis. With emerging evidence for the role of the intrinsic pathway in thrombosis, factor XII and XI may be ideal targets to dissociate thrombosis from hemostasis. Although initial results in humans are promising, large randomized trials will be needed to determine whether the benefit-to-risk profiles of these new strategies are superior to those of the NOACs. Never has the future of anticoagulation been so promising. Acknowledgments Dr. Weitz holds the Canada Research Chair (Tier 1) in Thrombosis and the Heart and Stroke Foundation/J. Fraser Mustard Chair in Cardiovascular Research. Disclosures Dr. Weitz is a consultant for, and receives honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, DaiichiSankyo, Janssen, Merck, Pfizer, ISIS Pharmaceuticals, and Portola.
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