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Novel anticoagulants will likely replace need for vitamin K antagonists
BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.
The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.1 It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.2 Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.
Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.
Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.
Pharmacologic design
The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.3 These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.
NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.4 As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.
Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.5 Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.
Patient selection
The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.6
Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.6
Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.6 Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.
Overcoming challenges
Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.
Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.8 Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.9
Given these promising findings, it likely will not be long until reversal agents for NOACs become clinically available. Until that time, it is encouraging that the bleeding profile of these drugs has been found to be favorable compared to VKAs and their short half-life allows for a relatively expeditious natural reversal of their anticoagulant effect as the drug is eliminated.
Conclusion
Unlike the serendipitous path leading to the discovery of the first class of oral anticoagulants (VKAs), NOACs have been specifically designed to provide targeted anticoagulation and to address the shortcomings of VKAs. To this end, NOACs are becoming increasingly important in the management of patients with specific clinical conditions such as nonvalvular atrial fibrillation and venous thromboembolism, where they have been shown to provide a larger net clinical benefit relative to the available alternatives. Furthermore, with economic analyses providing evidence that NOACs are cost-effective for the healthcare system and clinical trial results suggesting progress in the development of antidotes for reversal, it is likely that with growing experience, these agents will replace VKAs as the mainstay for prophylactic and therapeutic oral anticoagulation in targeted patient populations.
Dr. Patel is a research fellow and Dr. Chaikof is surgeon-in-chief, both at the department of surgery, Beth Israel Deaconess Medical Center, Boston. They reported no conflicts of interest.
References
1. J Am Vet Med Assoc. 1924;64:553-75 (See Br J Haematol 2008 Mar 18;141[6]:757-63).
2. J Biol Chem. 1941;138:21-33 (See Nutr Rev. 1974 Aug;32[8]:244-6).
3. Am Soc Hematol Educ Program. 2013;2013:464-70.
4. Eur Heart J. 2013 Jul;34(27):2094-2106.
5. Stroke. 2013 Jun;44(6):1676-81.
6. Nat Rev Cardiol. 2014 Dec;11(12):693-703.
7. Lancet. 2014 Mar 15;383(9921):955-62.
8. N Engl J Med. 2015;373(6):511-20.
9. N Engl J Med. 2014;371(22):2141-2.
What the doctor didn’t order: unintended consequences and pitfalls of NOACs
BY THOMAS WAKEFIELD, M.D., ANDREA OBI, M.D., AND DAWN COLEMAN, M.D.
Recently, several new oral anticoagulants have gained FDA approval to replace warfarin, capturing the attention of popular media. These include dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Easy to take with a once- or twice-daily pill, with no cumbersome monitoring, they represent a seemingly ideal treatment for the chronically anticoagulated patient. All agents are currently FDA approved in the United States for treatment of acute venous thromboembolism (VTE) and atrial fibrillation (AF).
Dabigatran and edoxaban
As with warfarin, dabigatran and edoxaban require the use of a low-molecular-weight heparin (LMWH) or unfractionated heparin “bridge” when therapy is beginning, while rivaroxaban and apixaban are instituted as monotherapy without such a bridge. Dabigatran etexilate (PradaxaR, Boehringer Ingelheim) has the longest half-life of all of the NOACs at 12-17 hours, and this half-life is prolonged with increasing age and decreasing renal function.1 It is the only new agent that can be at least partially reversed with dialysis.2 Edoxaban (SavaysaR, Daiichi Sankyo) carries a boxed warning stating that this agent is less effective in AF patients with a creatinine clearance greater than 95 mL/min, and that kidney function should be assessed prior to starting treatment: Such patients have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at significantly increased risk of bleeding complications (low body weight and/or decreased creatinine clearance).3
Rivaroxaban and apixaban
Rivaroxaban (XareltoR, Bayer and Janssen), and apixaban (EliquisR, Bristol Myers-Squibb), unique among the NOACs, have been tested for extended therapy of acute DVT after treatment of 6-12 months. They were found to result in a significant decrease in recurrent VTE without an increase in major bleeding compared to placebo.4,5 Rivaroxaban has once-daily dosing and apixaban has twice-daily dosing; both are immediate monotherapy, making them quite convenient for patients. Apixaban is the only agent among the NOACs to have a slight decrease in gastrointestinal bleeding compared to warfarin.6
Consequences and pitfalls with NOACs
Problems with these new drugs, which may diminish our current level of enthusiasm for these agents to totally replace warfarin, include the inability to reliably follow their levels and to reverse their anticoagulant effects, the lack of data available on bridging when other procedures need to be performed, their short half-lives, and the lack of data on their anti-inflammatory effects.
With regard to monitoring of anticoagulation, the International Society of Thrombosis and Hemostasis (ISTH) has published a recommendation7 that lists these scenarios:
• When a patient is bleeding.
• Before surgery or an invasive procedure when the patient has taken the drug in the previous 24 hours, or longer if creatinine clearance (CrCl) is less than 50 mL/min.
• Identification of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to affect pharmacokinetics.
• Identification of subtherapeutic or supratherapeutic levels in patients at body weight extremes.
• Patients with deteriorating renal function.
• During perioperative management.
• During reversal of anticoagulation.
• When there is suspicion of overdose.
• Assessment of compliance in patients suffering thrombotic events while on treatment.
Currently, there exists no commercially available reversal agent for any of the NOACs and existing reversal agents for traditional anticoagulants are of limited, if any, use. Drugs under development include agents for the factor Xa inhibitors and for the thrombin inhibitor. Until the time that specific reversal agents exist, supportive care is the mainstay of therapy. In cases of trauma or severe or life-threatening bleeding, administration of concentrated clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) may be utilized. However, data from large clinical trials is lacking. A recent study of 90 patients receiving an antibody directed against dabigatran has revealed that the anticoagulant effects of dabigatran were reversed safely within minutes of administration; however, drug levels were not consistently suppressed at 24 hours in 20% of the cohort.8
There are no national guidelines nor large scale studies to guide bridging NOACs for procedures. The relatively short half-life for these agents makes it likely that traditional bridging as is practiced for warfarin is not necessary.9 However, this represents a double edged sword; withholding anticoagulation for two doses (such as if a patient becomes ill or a clinician is overly cautious around the time of a procedure) may leave the patient unprotected.
The final question with the new agents is their anti-inflammatory effects. We know that heparin and LMWH have significant pleiotropic effects that are not necessarily related to their anticoagulant effects. These effects are important to decrease the inflammatory nature of the thrombus and its effect on the vein wall. We do not know if the new oral agents have similar effects, as this has never fully been tested. In view of the fact that two of the agents are being used as monotherapy agents without any heparin/LMWH bridge, the anti-inflammatory properties of these new agents should be defined to make sure that such a bridge is not necessary.
Conclusion
So, in summary, although these agents have much to offer, there are many questions that remain to be addressed and answered before they totally replace traditional approaches to anticoagulation, in the realm of VTE. It must not be overlooked that for all the benefits, they each carry a risk of bleeding as they all target portions of the coagulation mechanism. We believe, that as with any “gift horse,” physicians should perhaps examine the data more closely and proceed with caution.
Dr. Wakefield is director of the Samuel and Jean Frankel Cardiovascular Center, Dr. Obi is a vascular surgery fellow, and Dr. Coleman is program director, section of vascular surgery, at the University of Michigan, Ann Arbor. They reported no conflicts of interest.
References
1. N Engl J Med. 2009;361:2342-52.
2. J Vasc Surg: Venous Lymphat Disord. 2013;1:418-26.
3. N Engl J Med. 2013;369:1406-15.
4. N Engl J Med. 2010;363:2499-2510.
5. N Engl J Med. 2013;368:699-708.
6. Arterioscler Thromb Vasc Biol. 2015;35:1056-65.
7. J Thromb Haemost. 2013;11:756-60.
Novel anticoagulants will likely replace need for vitamin K antagonists
BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.
The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.1 It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.2 Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.
Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.
Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.
Pharmacologic design
The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.3 These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.
NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.4 As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.
Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.5 Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.
Patient selection
The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.6
Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.6
Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.6 Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.
Overcoming challenges
Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.
Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.8 Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.9
Given these promising findings, it likely will not be long until reversal agents for NOACs become clinically available. Until that time, it is encouraging that the bleeding profile of these drugs has been found to be favorable compared to VKAs and their short half-life allows for a relatively expeditious natural reversal of their anticoagulant effect as the drug is eliminated.
Conclusion
Unlike the serendipitous path leading to the discovery of the first class of oral anticoagulants (VKAs), NOACs have been specifically designed to provide targeted anticoagulation and to address the shortcomings of VKAs. To this end, NOACs are becoming increasingly important in the management of patients with specific clinical conditions such as nonvalvular atrial fibrillation and venous thromboembolism, where they have been shown to provide a larger net clinical benefit relative to the available alternatives. Furthermore, with economic analyses providing evidence that NOACs are cost-effective for the healthcare system and clinical trial results suggesting progress in the development of antidotes for reversal, it is likely that with growing experience, these agents will replace VKAs as the mainstay for prophylactic and therapeutic oral anticoagulation in targeted patient populations.
Dr. Patel is a research fellow and Dr. Chaikof is surgeon-in-chief, both at the department of surgery, Beth Israel Deaconess Medical Center, Boston. They reported no conflicts of interest.
References
1. J Am Vet Med Assoc. 1924;64:553-75 (See Br J Haematol 2008 Mar 18;141[6]:757-63).
2. J Biol Chem. 1941;138:21-33 (See Nutr Rev. 1974 Aug;32[8]:244-6).
3. Am Soc Hematol Educ Program. 2013;2013:464-70.
4. Eur Heart J. 2013 Jul;34(27):2094-2106.
5. Stroke. 2013 Jun;44(6):1676-81.
6. Nat Rev Cardiol. 2014 Dec;11(12):693-703.
7. Lancet. 2014 Mar 15;383(9921):955-62.
8. N Engl J Med. 2015;373(6):511-20.
9. N Engl J Med. 2014;371(22):2141-2.
What the doctor didn’t order: unintended consequences and pitfalls of NOACs
BY THOMAS WAKEFIELD, M.D., ANDREA OBI, M.D., AND DAWN COLEMAN, M.D.
Recently, several new oral anticoagulants have gained FDA approval to replace warfarin, capturing the attention of popular media. These include dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Easy to take with a once- or twice-daily pill, with no cumbersome monitoring, they represent a seemingly ideal treatment for the chronically anticoagulated patient. All agents are currently FDA approved in the United States for treatment of acute venous thromboembolism (VTE) and atrial fibrillation (AF).
Dabigatran and edoxaban
As with warfarin, dabigatran and edoxaban require the use of a low-molecular-weight heparin (LMWH) or unfractionated heparin “bridge” when therapy is beginning, while rivaroxaban and apixaban are instituted as monotherapy without such a bridge. Dabigatran etexilate (PradaxaR, Boehringer Ingelheim) has the longest half-life of all of the NOACs at 12-17 hours, and this half-life is prolonged with increasing age and decreasing renal function.1 It is the only new agent that can be at least partially reversed with dialysis.2 Edoxaban (SavaysaR, Daiichi Sankyo) carries a boxed warning stating that this agent is less effective in AF patients with a creatinine clearance greater than 95 mL/min, and that kidney function should be assessed prior to starting treatment: Such patients have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at significantly increased risk of bleeding complications (low body weight and/or decreased creatinine clearance).3
Rivaroxaban and apixaban
Rivaroxaban (XareltoR, Bayer and Janssen), and apixaban (EliquisR, Bristol Myers-Squibb), unique among the NOACs, have been tested for extended therapy of acute DVT after treatment of 6-12 months. They were found to result in a significant decrease in recurrent VTE without an increase in major bleeding compared to placebo.4,5 Rivaroxaban has once-daily dosing and apixaban has twice-daily dosing; both are immediate monotherapy, making them quite convenient for patients. Apixaban is the only agent among the NOACs to have a slight decrease in gastrointestinal bleeding compared to warfarin.6
Consequences and pitfalls with NOACs
Problems with these new drugs, which may diminish our current level of enthusiasm for these agents to totally replace warfarin, include the inability to reliably follow their levels and to reverse their anticoagulant effects, the lack of data available on bridging when other procedures need to be performed, their short half-lives, and the lack of data on their anti-inflammatory effects.
With regard to monitoring of anticoagulation, the International Society of Thrombosis and Hemostasis (ISTH) has published a recommendation7 that lists these scenarios:
• When a patient is bleeding.
• Before surgery or an invasive procedure when the patient has taken the drug in the previous 24 hours, or longer if creatinine clearance (CrCl) is less than 50 mL/min.
• Identification of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to affect pharmacokinetics.
• Identification of subtherapeutic or supratherapeutic levels in patients at body weight extremes.
• Patients with deteriorating renal function.
• During perioperative management.
• During reversal of anticoagulation.
• When there is suspicion of overdose.
• Assessment of compliance in patients suffering thrombotic events while on treatment.
Currently, there exists no commercially available reversal agent for any of the NOACs and existing reversal agents for traditional anticoagulants are of limited, if any, use. Drugs under development include agents for the factor Xa inhibitors and for the thrombin inhibitor. Until the time that specific reversal agents exist, supportive care is the mainstay of therapy. In cases of trauma or severe or life-threatening bleeding, administration of concentrated clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) may be utilized. However, data from large clinical trials is lacking. A recent study of 90 patients receiving an antibody directed against dabigatran has revealed that the anticoagulant effects of dabigatran were reversed safely within minutes of administration; however, drug levels were not consistently suppressed at 24 hours in 20% of the cohort.8
There are no national guidelines nor large scale studies to guide bridging NOACs for procedures. The relatively short half-life for these agents makes it likely that traditional bridging as is practiced for warfarin is not necessary.9 However, this represents a double edged sword; withholding anticoagulation for two doses (such as if a patient becomes ill or a clinician is overly cautious around the time of a procedure) may leave the patient unprotected.
The final question with the new agents is their anti-inflammatory effects. We know that heparin and LMWH have significant pleiotropic effects that are not necessarily related to their anticoagulant effects. These effects are important to decrease the inflammatory nature of the thrombus and its effect on the vein wall. We do not know if the new oral agents have similar effects, as this has never fully been tested. In view of the fact that two of the agents are being used as monotherapy agents without any heparin/LMWH bridge, the anti-inflammatory properties of these new agents should be defined to make sure that such a bridge is not necessary.
Conclusion
So, in summary, although these agents have much to offer, there are many questions that remain to be addressed and answered before they totally replace traditional approaches to anticoagulation, in the realm of VTE. It must not be overlooked that for all the benefits, they each carry a risk of bleeding as they all target portions of the coagulation mechanism. We believe, that as with any “gift horse,” physicians should perhaps examine the data more closely and proceed with caution.
Dr. Wakefield is director of the Samuel and Jean Frankel Cardiovascular Center, Dr. Obi is a vascular surgery fellow, and Dr. Coleman is program director, section of vascular surgery, at the University of Michigan, Ann Arbor. They reported no conflicts of interest.
References
1. N Engl J Med. 2009;361:2342-52.
2. J Vasc Surg: Venous Lymphat Disord. 2013;1:418-26.
3. N Engl J Med. 2013;369:1406-15.
4. N Engl J Med. 2010;363:2499-2510.
5. N Engl J Med. 2013;368:699-708.
6. Arterioscler Thromb Vasc Biol. 2015;35:1056-65.
7. J Thromb Haemost. 2013;11:756-60.
Novel anticoagulants will likely replace need for vitamin K antagonists
BY MADHUKAR S. PATEL, M.D., AND ELLIOT L. CHAIKOF, M.D.
The discovery of oral anticoagulants began in 1924, when Schofield linked the death of grazing cattle from internal hemorrhage to the consumption of spoiled sweet clover hay.1 It was not until 1941, however, while trying to understand this observation, that Campbell & Link were able to identify the dicoumarol anticoagulant, which formed as a result of the spoiling process.2 Ultimately, after noting that vitamin K led to reversal of the dicoumarol effect, synthesis of the first class of oral anticoagulants, known as vitamin K antagonists (VKAs), began.
Despite the numerous challenges associated with managing patients using this class of anticoagulants, VKAs have become the mainstay of oral anticoagulation therapy for the past 70 years. Over the past 5 years, however, new oral anticoagulants (NOACs) have emerged and are changing clinical practice.
Mechanistically, these medications are targeted therapies and work as either direct thrombin inhibitors (dabigatran etexilate) or direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban). Given their favorable pharmacologic design, NOACs have the potential to replace VKAs as they not only have an encouraging safety profile, but also are therapeutically equivalent or even superior to VKAs when used in certain patient populations.
Pharmacologic design
The targeted drug design of NOACs provides many pharmacologic advantages. Compared to VKAs, NOACs have a notably more predictable pharmacologic profile and relatively wide therapeutic window, which allows for fixed dosing, a rapid onset and offset, and fewer drug interactions.3 These characteristics eliminate the need for the routine dose monitoring and serial dose adjustments frequently associated with VKAs.
NOACs less commonly require bridging therapy with parenteral unfractionated heparin or low-molecular-weight heparins (LMWH) while awaiting therapeutic drug levels, as these levels are reached sooner and more predictably than with VKAs.4 As with any medication, however, appropriate consideration should to be given to specific patient populations such as those who are older or have significant comorbidities that may influence drug effect and clearance. Lastly, it should be mentioned that the pharmacologic benefits of NOACs apply not only from a patient perspective, but also from a health care systems standpoint, as their use may provide an opportunity to deliver more cost-effective care.
Specifically, economic models using available clinical trial data for stroke prevention in nonvalvular atrial fibrillation have shown that NOACs (apixaban, dabigatran, and rivaroxaban) are cost-effective alternatives when compared to warfarin.5 Although the results from such economic analyses are limited by the modeling assumptions they rely upon, these findings suggest that at least initially, cost should not be used as a prohibitive reason for adopting these new therapeutics.
Patient selection
The decision to institute oral anticoagulation therapy depends on each patient’s individualized bleeding risk to benefit of ischemia prevention ratio. A major determinant of this ratio is the clinical indication for which anticoagulation is begun. Numerous phase III clinical trials have been conducted comparing the use of NOACs to VKAs or placebos for the management of nonvalvular atrial fibrillation and venous thromboembolism, and as adjunctive therapy for patients with acute coronary syndrome.6
Meta-analyses of randomized trials have shown the most significant benefit to be in patients with nonvalvular atrial fibrillation, where NOACs yield significant reductions in stroke, intracranial hemorrhage, and all-cause mortality compared to warfarin, while displaying variable effects with regard to gastrointestinal bleeding.6,7 In patients with VTE, NOACs have been found to have efficacy similar to that of VKAs with regard to the prevention of VTE or VTE-related death, and have been noted to have a better safety profile.6
Lastly, when studied as an adjunctive agent to dual antiplatelet therapy in patients with acute coronary syndrome, NOACs have been associated with an increased bleeding risk without a significant decrease in thrombosis risk.6 Taken together, these data suggest that the primary indication for instituting NOAC therapy should be considered strongly when deciding upon which class of anticoagulant to use.
Overcoming challenges
Since the introduction of NOACs, there has been concern over the lack of specific antidotes to therapy, especially when administered in patients with impaired clearance, a high likelihood of need for an urgent or emergent procedure, or those presenting with life threatening bleeding complications.
Most recently, however, interim analysis from clinical trial data has shown complete reversal of the direct thrombin inhibitor dabigatran with the humanized monoclonal antibody idarucizumab within minutes of administration in greater than 88% of patients studied.8 Similarly, agents such as a PER977 are currently under phase II clinical trials as they have been shown to form noncovalent hydrogen bonds and charge-charge interactions with oral factor Xa inhibitors as well as oral thrombin inhibitors leading to their reversal.9
Given these promising findings, it likely will not be long until reversal agents for NOACs become clinically available. Until that time, it is encouraging that the bleeding profile of these drugs has been found to be favorable compared to VKAs and their short half-life allows for a relatively expeditious natural reversal of their anticoagulant effect as the drug is eliminated.
Conclusion
Unlike the serendipitous path leading to the discovery of the first class of oral anticoagulants (VKAs), NOACs have been specifically designed to provide targeted anticoagulation and to address the shortcomings of VKAs. To this end, NOACs are becoming increasingly important in the management of patients with specific clinical conditions such as nonvalvular atrial fibrillation and venous thromboembolism, where they have been shown to provide a larger net clinical benefit relative to the available alternatives. Furthermore, with economic analyses providing evidence that NOACs are cost-effective for the healthcare system and clinical trial results suggesting progress in the development of antidotes for reversal, it is likely that with growing experience, these agents will replace VKAs as the mainstay for prophylactic and therapeutic oral anticoagulation in targeted patient populations.
Dr. Patel is a research fellow and Dr. Chaikof is surgeon-in-chief, both at the department of surgery, Beth Israel Deaconess Medical Center, Boston. They reported no conflicts of interest.
References
1. J Am Vet Med Assoc. 1924;64:553-75 (See Br J Haematol 2008 Mar 18;141[6]:757-63).
2. J Biol Chem. 1941;138:21-33 (See Nutr Rev. 1974 Aug;32[8]:244-6).
3. Am Soc Hematol Educ Program. 2013;2013:464-70.
4. Eur Heart J. 2013 Jul;34(27):2094-2106.
5. Stroke. 2013 Jun;44(6):1676-81.
6. Nat Rev Cardiol. 2014 Dec;11(12):693-703.
7. Lancet. 2014 Mar 15;383(9921):955-62.
8. N Engl J Med. 2015;373(6):511-20.
9. N Engl J Med. 2014;371(22):2141-2.
What the doctor didn’t order: unintended consequences and pitfalls of NOACs
BY THOMAS WAKEFIELD, M.D., ANDREA OBI, M.D., AND DAWN COLEMAN, M.D.
Recently, several new oral anticoagulants have gained FDA approval to replace warfarin, capturing the attention of popular media. These include dabigatran, rivaroxaban, apixaban, and edoxaban. Dabigatran targets activated factor II (factor IIa), while rivaroxaban, apixaban, and edoxaban target activated factor X (factor Xa). Easy to take with a once- or twice-daily pill, with no cumbersome monitoring, they represent a seemingly ideal treatment for the chronically anticoagulated patient. All agents are currently FDA approved in the United States for treatment of acute venous thromboembolism (VTE) and atrial fibrillation (AF).
Dabigatran and edoxaban
As with warfarin, dabigatran and edoxaban require the use of a low-molecular-weight heparin (LMWH) or unfractionated heparin “bridge” when therapy is beginning, while rivaroxaban and apixaban are instituted as monotherapy without such a bridge. Dabigatran etexilate (PradaxaR, Boehringer Ingelheim) has the longest half-life of all of the NOACs at 12-17 hours, and this half-life is prolonged with increasing age and decreasing renal function.1 It is the only new agent that can be at least partially reversed with dialysis.2 Edoxaban (SavaysaR, Daiichi Sankyo) carries a boxed warning stating that this agent is less effective in AF patients with a creatinine clearance greater than 95 mL/min, and that kidney function should be assessed prior to starting treatment: Such patients have a greater risk of stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specifically tested at a lower dose in patients at significantly increased risk of bleeding complications (low body weight and/or decreased creatinine clearance).3
Rivaroxaban and apixaban
Rivaroxaban (XareltoR, Bayer and Janssen), and apixaban (EliquisR, Bristol Myers-Squibb), unique among the NOACs, have been tested for extended therapy of acute DVT after treatment of 6-12 months. They were found to result in a significant decrease in recurrent VTE without an increase in major bleeding compared to placebo.4,5 Rivaroxaban has once-daily dosing and apixaban has twice-daily dosing; both are immediate monotherapy, making them quite convenient for patients. Apixaban is the only agent among the NOACs to have a slight decrease in gastrointestinal bleeding compared to warfarin.6
Consequences and pitfalls with NOACs
Problems with these new drugs, which may diminish our current level of enthusiasm for these agents to totally replace warfarin, include the inability to reliably follow their levels and to reverse their anticoagulant effects, the lack of data available on bridging when other procedures need to be performed, their short half-lives, and the lack of data on their anti-inflammatory effects.
With regard to monitoring of anticoagulation, the International Society of Thrombosis and Hemostasis (ISTH) has published a recommendation7 that lists these scenarios:
• When a patient is bleeding.
• Before surgery or an invasive procedure when the patient has taken the drug in the previous 24 hours, or longer if creatinine clearance (CrCl) is less than 50 mL/min.
• Identification of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to affect pharmacokinetics.
• Identification of subtherapeutic or supratherapeutic levels in patients at body weight extremes.
• Patients with deteriorating renal function.
• During perioperative management.
• During reversal of anticoagulation.
• When there is suspicion of overdose.
• Assessment of compliance in patients suffering thrombotic events while on treatment.
Currently, there exists no commercially available reversal agent for any of the NOACs and existing reversal agents for traditional anticoagulants are of limited, if any, use. Drugs under development include agents for the factor Xa inhibitors and for the thrombin inhibitor. Until the time that specific reversal agents exist, supportive care is the mainstay of therapy. In cases of trauma or severe or life-threatening bleeding, administration of concentrated clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) may be utilized. However, data from large clinical trials is lacking. A recent study of 90 patients receiving an antibody directed against dabigatran has revealed that the anticoagulant effects of dabigatran were reversed safely within minutes of administration; however, drug levels were not consistently suppressed at 24 hours in 20% of the cohort.8
There are no national guidelines nor large scale studies to guide bridging NOACs for procedures. The relatively short half-life for these agents makes it likely that traditional bridging as is practiced for warfarin is not necessary.9 However, this represents a double edged sword; withholding anticoagulation for two doses (such as if a patient becomes ill or a clinician is overly cautious around the time of a procedure) may leave the patient unprotected.
The final question with the new agents is their anti-inflammatory effects. We know that heparin and LMWH have significant pleiotropic effects that are not necessarily related to their anticoagulant effects. These effects are important to decrease the inflammatory nature of the thrombus and its effect on the vein wall. We do not know if the new oral agents have similar effects, as this has never fully been tested. In view of the fact that two of the agents are being used as monotherapy agents without any heparin/LMWH bridge, the anti-inflammatory properties of these new agents should be defined to make sure that such a bridge is not necessary.
Conclusion
So, in summary, although these agents have much to offer, there are many questions that remain to be addressed and answered before they totally replace traditional approaches to anticoagulation, in the realm of VTE. It must not be overlooked that for all the benefits, they each carry a risk of bleeding as they all target portions of the coagulation mechanism. We believe, that as with any “gift horse,” physicians should perhaps examine the data more closely and proceed with caution.
Dr. Wakefield is director of the Samuel and Jean Frankel Cardiovascular Center, Dr. Obi is a vascular surgery fellow, and Dr. Coleman is program director, section of vascular surgery, at the University of Michigan, Ann Arbor. They reported no conflicts of interest.
References
1. N Engl J Med. 2009;361:2342-52.
2. J Vasc Surg: Venous Lymphat Disord. 2013;1:418-26.
3. N Engl J Med. 2013;369:1406-15.
4. N Engl J Med. 2010;363:2499-2510.
5. N Engl J Med. 2013;368:699-708.
6. Arterioscler Thromb Vasc Biol. 2015;35:1056-65.
7. J Thromb Haemost. 2013;11:756-60.
