1. Anticoagulation Therapy: New Opportunities, New Challenges
Suraj Kapa, MD
Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION
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2. Indications for Oral Anticoagulation
Multiple clinical trials and guideline statements support the use of long-term oral anticoagulation for stroke prevention in high-risk patients with atrial fibrillation (AF).1–8
Long-term oral anticoagulation is also a mainstay in the management of patients with:
Mechanical heart valves
Deep venous thrombosis (DVT)
Pulmonary embolism
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3. Shortcomings of Warfarin
Warfarin therapy requires control of patients’ prothrombin time or international normalized ratio (INR) within a narrow therapeutic range.
Warfarin levels above the therapeutic range lead to an increased risk of life-threatening bleeding, and levels below the therapeutic range obviate any potential benefits from the drug.
Ensuring maintenance of therapeutic INRs requires frequent blood testing.
Multiple dietary and pharmacologic interactions may complicate the maintenance of a therapeutic INR.9,10
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4. Thrombus Formation
In AF, the tissue factor pathway is the primary target for preventing thrombus formation and stroke.12–15
Thrombus formation involves tissue factor-bearing cells that come into contact with circulating coagulation factors.
As factor VII comes into contact with tissue factor on these cells, an activated complex forms, which triggers factors IX and X.
Factor Xa and factor Va then form prothrombinase complexes that activate prothrombin to thrombin, which, in turn, then stimulates factor VII and other components of the coagulation cascade.
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5. Coagulation Cascade
Schematic diagram of the coagulation cascade along the tissue factor pathway and the targets of direct factor Xa and thrombin inhibitors. The vitamin K antagonist warfarin typically works on several calcium-dependent clotting factors, including factors II, VII, IX (not shown), and X.
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6. Targeting Specific Coagulation Factors
Newer oral anticoagulants target specific points in the coagulation cascade:
Factor Xa inhibitors (eg, rivaroxaban, apixaban) target factor Xa, preventing the conversion of prothrombin to thrombin.
Direct thrombin inhibitors (eg, dabigatran, ximelagatran) target thrombin (factor IIa), blocking the conversion of fibrinogen to fibrin.
The goal of novel oral anticoagulants is, in part, to offer more specific targeting and to afford more predictable responses than current anticoagulant therapies, such as warfarin, can offer.
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7. The Ideal Oral Anticoagulant
Ideally, an oral anticoagulant would:
Require no remote monitoring
Have little interaction with food or other drugs
Offer a good safety profile with regard to bleeding risk
Have similar efficacy to warfarin in reducing thromboembolic events
Reach therapeutic levels within several hours
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8. Warfarin
When warfarin therapy is started, its anticoagulant effects may not be apparent for several days.
The duration of action of a single dose is 2–5 days.
The therapeutic effect of warfarin exists within a narrow therapeutic window as dictated by the INR.
Considerable inter- and intraindividual dose variability may be affected by a wide range of physiologic (liver and thyroid function), genetic, and environmental (eg, diet, other drugs) factors.9,10
Regular monitoring is required to avoid excessive or insufficient anticoagulation.16
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9. Dabigatran
Dabigatran etexilate is a direct thrombin inhibitor that is given at a fixed oral dose without the need for INR monitoring.17,18
Because of potential P-glycoprotein (P-gp) interactions, its absorption may be decreased if dabigatran is taken with a proton pump inhibitor.19
Excretion may be slowed in patients taking P-gp pump inhibitors such as quinidine, verapamil, or amiodarone, raising plasma levels of dabigatran.19
The drug has a relatively short half-life (12–17 hours).
Patients with acute or chronic renal failure may require reduced doses.17,18
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10. Rivaroxaban and Apixaban
Rivaroxaban and apixaban are direct factor Xa inhibitors.20–23 The two drugs interact slightly differently with the S4 region of factor X.
Both rivaroxaban and apixaban bind to the catalytic/active site of factor X and directly interfere with the coagulation cascade.
They have predictable pharmacokinetics and allow for fixed oral dosing without the need for INR monitoring.
Similar to dabigatran, the half-lives of rivaroxaban and apixaban are under 12 hours.
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11. Models of Care: Warfarin Therapy
Routine medical care, wherein a physician or office staff manage warfarin dosing based on INRs obtained from blood draws in a laboratory or via a point-of-care device in the clinic.
Anticoagulation clinics managed by dedicated healthcare professionals that have systematic policies to manage and dose patients, using either point-of-care or laboratory-based INRs.25–27
Patients using a point-of-care monitor at home to measure their INRs and then reporting back to the personnel in a clinic to alter the dose.28,29
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12. Switching to Newer Oral Anticoagulants
Advantages:
Fixed oral dosing
No need to monitor prothrombin time or INR
Fewer drug interactions
No dietary restrictions
Disadvantages:
Lack of validated tests to assay their anticoagulant effect30
No antidote readily available to halt bleeding
More difficult to assess patient compliance
Lack of data on long-term adverse effects beyond bleeding
Absence of head-to-head comparisons between novel oral anticoagulants
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13. Other Issues with Newer Anticoagulants
Peaks and troughs in anticoagulation levels may result from their relatively shorter half-lives, compared with warfarin.
The dosing of these drugs is fixed, so there is no easy way to measure their therapeutic effects using specific blood tests.
Additional monitoring of liver and renal function may be needed to ensure that dose adjustments or switching of agents is not required.
There is little to educate patients about beyond compliance.
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14. Comparison of Oral Anticoagulants
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15. Anticoagulant Therapy and Stroke
Patients with AF-related stroke have a 1.8-fold increase in mortality when compared with those who experience a stroke unrelated to AF, possibly because AF-related strokes tend to be larger in size and more often lead to hemorrhagic transformation.2,31,32
Although patients with AF and at least two additional risk factors for stroke benefit from warfarin therapy, many patients and their physicians resist using warfarin because of concerns related to INR monitoring, the risk of falls, and the potential for bleeding and intracranial hemorrhage.
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16. INR Variability in AF Patients
Randomized clinical trials comparing dabigatran, apixaban, and rivaroxaban with warfarin have shown a strong trend toward the superiority of these novel oral anticoagulants in preventing stroke and in reducing the rate of intracranial hemorrhage.33–36
However, data from systematic overviews suggest that patients on warfarin maintain a therapeutic INR only 63% of the time at best, with even worse results being observed in community practices.37
The importance of maintaining a minimum INR of 2.0 to obtain effective stroke prevention during warfarin therapy has been well documented.38–41
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17. INR Variability in AF Patients
Analyses of data from the ROCKET AF, RE-LY, and ARISTOTLE studies have shown no significant difference in stroke outcomes between patients given a novel oral anticoagulant and those using warfarin.33–36,42
However, RE-LY data showed that 50% of patients using warfarin who had a therapeutic INR at least 67% of the time had a composite event rate of 5.48, which was lower than the event rates among patients using dabigatran, whereas patients who were in the therapeutic range less than 54% of the time had an event rate of 12.32, which was much worse than the event rate in patients taking dabigatran.42
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18. INR Variability in AF Patients
In the SPORTIF trial, 25% of patients who had the greatest percentage of time in the therapeutic INR range had the lowest event rates; however, patients who were in the therapeutic range less than 60% of the time had much higher event rates.43,44
In the ATRIA study, there was an 8-fold increase in ischemic events with any reduction in the INR < 1.3; if the INR was > 4.0, there was a 12-fold increase in intracranial hemorrhage.45
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19. Self-Monitoring of INR Levels
Self-testing may provide a better way to maintain INR levels within a narrow therapeutic window.
Results from the THINRS trial suggested beneficial trends in mortality, major bleeding, and stroke when patients performed self-testing, rather than relying on specific clinics for monitoring and managing their anticoagulation therapy.46–48
Similarly, in the STOARM2 trial, INR management improved with automated self-monitoring, with INR values < 1.5 or > 5 seen in only 0.47% of patients.49
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20. Self-Monitoring of INR Levels
Other studies have suggested that anticoagulation clinics run by clinical pharmacists may reduce major events, hospitalizations, and emergency visits by 60%–80%, when compared with usual clinic-based management of warfarin, and that weekly INR self-testing and self-management may reduce major events by as much as 70% and mortality by as much as 61%.28,29,46–51
Thus, some contend that the primary issue is to fix how we are managing patients using warfarin rather than to switch patients to another agent.
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21. Cost-Effectiveness
Cost-effectiveness analyses of newer anticoagulants in preventing stroke in patients with AF are limited.
At a cost of $7–$9/day (two capsules), dabigatran use may cost an estimated $10,000 per year of life saved.52–54
However, this analysis does not consider direct comparisons against the cost of maintaining patients on warfarin under current models of care.
Further studies are needed to better analyze the relative cost-effectiveness of warfarin versus that of any of the newer oral anticoagulants and also to consider the cost of improving INR management.
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22. Potential of Newer Oral Anticoagulants
Newer anticoagulant agents have issues55 not shared with warfarin, including:
A shorter half-life with rapid offset and potential attendant clotting risk
The need for a reversal agent in cases of acute bleeding or at the time of emergent procedures
The lack of laboratory monitoring to evaluate patient adherence
These newer agents are easy to use, and AF patients can benefit from lower stroke risk without needing repeated blood tests for INR monitoring, so the potential benefits are obvious.
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23. Anticoagulant Therapy and DVT
The same concerns related to INR monitoring, the narrow therapeutic window of warfarin, and the wide variety of dietary and pharmacologic interactions with warfarin still exist in treating patients with DVT.
One key difference in these patients is that the goal is treating an existing problem rather than preventing a potential one.56,57
However, the decision to treat as an outpatient versus as an inpatient is more difficult, because the time to reach an effective therapeutic range on warfarin varies from 2 to 5 days.
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24. Rivaroxaban vs Warfarin in DVT
In both the EINSTEIN DVT trial, which compared rivaroxaban with warfarin, and in an extension of the EINSTEIN trial, which examined the prevention of recurrent venous thromboembolism with rivaroxaban, a nonsignificant decrease in mortality was noted with rivaroxaban therapy.58,59
The study population excluded use of interacting medications (strong CYP3A4 inhibitors and inducers) and patients with significantly elevated liver function tests or renal impairment.
Warfarin-treated patients were within the therapeutic INR range less than 60% of the time.
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25. Dabigatran vs Warfarin in DVT
In the RE-COVER trial, dabigatran was noninferior to warfarin in treating acute DVT.60
The study population excluded patients if they had recent unstable cardiovascular disease, baseline liver function test results that were more than twice the upper limit of normal, or significant renal impairment.
As in the EINSTEIN DVT trial and similar clinical trials in AF, warfarin-treated patients were within the therapeutic INR range less than 60% of the time.
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26. Choosing an Oral Anticoagulant for DVT
Considerations related to the choice of an initial oral anticoagulant for patients with acute DVT are similar to those used for patients with AF, namely, the:
Ability to keep the patient on warfarin within therapeutic INR levels
Costs of individual agents
Unknown long-term risks related to novel anticoagulants
Lack of clarity regarding efficacy in patients with significant liver or renal impairment
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27. Laboratory Monitoring
Although dabigatran can raise the INR, activated partial thromboplastin time (aPTT), and thrombin time, the degree of elevation has not been clearly associated with its therapeutic effect.61
The ecarin clotting time (ECT)—in which a known quantity of ecarin is added to the patient’s plasma and the time to clotting is evaluated—has been suggested for monitoring the anticoagulant activity of dabigatran.61
ECT is notably unaffected by heparin or warfarin.61
Recently developed chromogenic dabigatran assays may permit monitoring serum dabigatran levels.61
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28. Laboratory Monitoring
Similarly, an anti-factor Xa level may be used to evaluate the therapeutic effects of rivaroxaban or apixaban.61
These assays are not as quickly obtained or as widely available as is the INR.
Furthermore, therapeutic ranges for these laboratory tests remain to be determined.
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29. Managing Bleeding Complications
There is some evidence that the anticoagulant actions of dabigatran and rivaroxaban may be reversible.62–65
Preclinical studies suggest that both recombinant factor VIIa and prothrombin complex concentrate (PCC) can reverse the effects of dabigatran and rivaroxaban on bleeding time and aPTT.
Injection of PCC immediately reversed the anticoagulant activity of rivaroxaban in 12 healthy human volunteers but had no effect on dabigatran-induced increases in aPTT, ECT, or thrombin time.62
How these blood products might function in actual emergent clinical situations is unknown.
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30. Conclusions
Although the introduction of rivaroxaban, apixaban, and dabigatran has the potential to revolutionize the day-to-day care of patients who require oral anticoagulation therapy, the best use of these drugs ultimately may need to be determined on a patient-by-patient and center-by-center basis.
The efficacy of individual centers in managing INRs, the ability to safely maintain a therapeutic INR range in individual patients on warfarin, and the current lack of a clear methodology for monitoring or reversing the anticoagulant effects of these new agents all must be taken into account when a patient is switched from warfarin to them.
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31. Conclusions
The new era of anticoagulant therapy has resulted in a milieu of studies and evolving guidelines to help refine the optimum use of these novel agents as more convenient and possibly safer therapeutic alternatives to warfarin.
Future studies to examine the cost-effectiveness of these agents and their impact on individual patients and systems-based care, as well as head-to-head comparisons of novel oral anticoagulants, will be the key to understanding how these novel agents may enter the current lexicon of anticoagulation.
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