Using Dabigatran in Patients With Stroke
A Practical Guide for Clinicians
Atrial fibrillation (AF) is 1 of the most common causes of cardioembolic strokes accounting for at least 100 000 strokes each year in the United States. Strokes due to AF tend to be larger and more severe than other types of ischemic strokes with a 30-day mortality rate up to 24%.1 Anticoagulation with warfarin can reduce the risk of stroke in patients with moderate- and high-risk AF by ≥65%,2 yet the use of warfarin is limited by a number of factors, including concerns about bleeding, the need for frequent international normalized ratio (INR) monitoring as well as significant and common food and drug interactions.3–6
In October 2010, the Food and Drug Administration (FDA) approved the direct thrombin inhibitor dabigatran for primary and secondary stroke prevention (and systemic emboli prevention) in patients with AF.7 It is used as a fixed dose medication in most circumstances (150 mg twice a day if creatinine clearance is >30 mL/min or 75 mg twice a day if creatinine clearance is 15–30 mL/min) and does not require routine blood testing nor does it have any important interactions with most foods and medications. Dabigatran is not a substrate, inducer, or inhibitor of the cytochrome P450 enzymes.8 It has the potential to greatly expand clinicians' and patients' willingness to use anticoagulation in patients with high-risk AF.
Often there is a gap between a new medication being approved and its widespread use. This is still true when one considers the underuse of warfarin in patients with AF, although there are a number of reasons for this finding. Patients with AF are often cared for by various physicians and other healthcare professionals in a variety of specialty and primary care areas and settings. For example, 25% of patients with AF first present with a stroke or transient ischemic attack and are diagnosed and perhaps cared for by a neurologist.9 Therefore, educational efforts about treatment for AF must be targeted at a multidisciplinary audience.
The purpose of this article is to address a number of practical issues related to the use of dabigatran in patients with stroke or cerebrovascular disease. Some of these issues have been addressed in the clinical development program for dabigatran. In other cases, we have used available data and expert opinion to formulate reasonable answers to common clinical issues.10
In some cases, our recommendations are not based on data from large clinical trials, whereas in others, they are drawn from the inclusion and exclusion criteria and methodologies of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study.11 This is not a review of the overall use of all antithrombotic therapy in AF nor is it a review of the treatment of AF in terms of cardiac issues. These topics have been well covered in recent guidelines.2,12,13
Pharmacology of Dabigatran
Dabigatran etexilate is the orally administered prodrug and is rapidly converted by tissue esterases to dabigatran, a direct thrombin inhibitor. When taken by mouth, the bioavailability of dabigatran is approximately 7%. Dabigatran is predominantly excreted (80%) by the kidneys with the remainder excreted in the bile. In healthy volunteers, peak plasma concentrations are reached approximately 2 to 3 hours after oral ingestion. The anticoagulant effects begin minutes after oral ingestion and usually peak in 2 to 3 hours. Once at steady-state, dabigatran has a half-life of 13 to 17 hours in patients with normal renal function.8,14,15
Although part of the bioconversion from prodrug to active metabolite occurs in the liver through glucoronidation and esterification, the cytochrome P450 system is not involved. Plasma concentrations of dabigatran can be increased or decreased by inhibitors or inducers of the p-glycoprotein transporter. Rifampin, an inducer of p-glycoprotein transport, results in lowering of dabigatran concentration and is the only medication for which concomitant administration must be avoided. Multiple drugs including amiodarone, dronedarone, and verapamil are p-glycoprotein inhibitors and this interaction has the potential to increase the plasma level of dabigatran. One study indicates that dronaderaone has the potential to increase the plasma concentrations of dabigatran, but the FDA has not (as of April 2011) mandated any dose adjustment or advice to avoid concomitant dronedarone therapy (see http://www.pradaxa.com; accessed April 1, 2011, for further detailed information). Table 1 lists some medications that could alter the anticoagulant effects of dabigatran.
The RE-LY Study
The RE-LY study randomly assigned 18 113 patients who had non-valvular AF and ≥1 stroke risk factors to either open-label warfarin or dabigatran; 2 doses of dabigatran were tested, and patients and investigators were blinded to the dose. The primary outcome was stroke or systemic embolism, and the median duration of follow-up was 2.0 years.11 The adjudication of end points was done in a blinded manner with respect to therapy. Detailed inclusion and exclusion criteria are not reviewed here.
In the warfarin group, the mean percentage of the study period during which the INR was within the therapeutic range was 64%. Half of the patients had received long-term therapy with vitamin K antagonists before enrollment. The mean CHADS2 (Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack) score was 2.1. Rates of the primary outcome were 1.69% per year in the warfarin group compared with 1.53% per year in the group that received 110 mg twice a day of dabigatran (relative risk with dabigatran, 0.91; 95% CI, 0.74–1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg twice a day of dabigatran (relative risk, 0.66; 95% CI, 0.53–0.82; P<0.001 for superiority).11
The rate of major bleeding was 3.36% per year in the warfarin group as compared with 2.71% per year in the group receiving 110 mg twice a day of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg twice a day of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group as compared with 0.12% per year with 110 mg twice a day of dabigatran (P<0.001) and 0.10% per year with 150 mg twice a day of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group as compared with 3.75% per year with 110 mg dabigatran (P=0.13) and 3.64% per year with 150 mg dabigatran (P=0.051). The only adverse effect that was significantly more common with dabigatran than with warfarin was major gastrointestinal bleeding; there was also a higher risk of dyspepsia. There was a trend for more major extracranial bleeding in elderly patients (≥75 years) treated with dabigatran compared with warfarin.16 There was a small increase in the occurrence of myocardial infarction in the dabigatran- versus warfarin-treated patients.11 A further analysis found additional myocardial infarctions in both treatment groups based on the strict diagnostic criteria (0.81%/year dabigatran 150 mg twice a day versus 0.64%/year warfarin, P=0.12).17 The benefits of dabigatran versus warfarin were equivalent regardless of whether or not patients were “warfarin-naïve” and regardless of whether patients did or did not have a history of prior stroke or transient ischemic attack.18,19
Based on these results, the US FDA approved dabigatran at 150 mg twice a day (if the creatine clearance is >30 mL/min) for the following indication: “To reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.” Based on pharmacological modeling (but no clinical data), 75 mg twice a day was approved for patients with a creatine clearance 15 to 30 mL/min. The 110-mg dose was not approved because the 150-mg dose was superior to both warfarin and the 110-mg dose in reducing stroke or systemic embolism.20 However, the 110-mg dose is available outside of the United States.
Based on these data, the American College of Cardiology Foundation/American Heart Association/Heart Association Task Force recommended that “dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance ≤15 mL/min) or advanced liver disease (impaired baseline clotting function) with a Level of Evidence of B.”21
Use in Nonvalvular Versus Valvular AF
The RE-LY study specifically enrolled patients with nonvalvular AF; however, the definition of “nonvalvular” AF is somewhat open to interpretation. Most cardiologists agree that a patient with a mechanical heart valve would not qualify as having “nonvalvular” AF and indeed such patients were not enrolled in RE-LY. Patients with end-stage or severe (hemodynamically significant) valvular disease were also excluded from RE-LY. Patients with less severe valvular disease and those with tissue valves were enrolled in RE-LY.
Based on these considerations, it seems reasonable to use dabigatran in most patients with AF and minor or moderate valvular dysfunction as determined by clinical factors and echocardiographic findings. In patients with severe valvular dysfunction (ie, hemodynamically significant to warrant consideration of valve replacement), we lack clear data on which to make a recommendation.
When and How to Check for Compliance With Therapy
In general, routine monitoring of the anticoagulant effects of dabigatran is not needed in most cases. However, in certain clinical situations, a clinician may wish to determine the degree to which dabigatran is reducing the coagulant potential of the blood. For example, if a patient taking dabigatran requires emergency surgery, has an intracranial or major systemic bleed, or is being considered for thrombolysis due to an ischemic stroke, it would be very helpful to determine if (1) the patient was actually taking the medication; and (2) if the medication was having the desired anticoagulant effect.
Although the thrombin time and ecarin clotting time are considered the most accurate measures of dabigatran's anticoagulant effect, these tests are not widely available and cannot be done on an emergent basis in many circumstances.14,22 Clinicians who use the thrombin time or ecarin clotting time to assess dabigatran-related anticoagulation should ensure that their laboratory is using an assay that reliably reflects the plasma concentration of dabigatran. The activated partial thromboplastin time (aPTT) correlates reasonably well with dabigatran plasma concentrations, especially at lower levels (see Figure 1 of Van Ryn).22 Practically speaking, a patient with an aPTT ≤1.0 times control can be assumed to have no meaningful anticoagulant effect present (Figure 1) and a low risk of serious bleeding events. Conversely, a prolonged aPTT is consistent with the presence of dabigatran, but the degree of prolongation does not correlate well with plasma concentrations.
Because the aPTT is widely available in all hospitals and can be performed on an emergency basis, we conclude that for most clinical settings, the aPTT is a reasonable semiquantitative method to determine if there is a dabigatran-induced anticoagulant effect. However, if a more precise determination of clotting function is needed, a thrombin time or ecarin clotting time should be performed.
Recommendations for Interruption of Dabigatran for Invasive Procedures
Because dabigatran is a direct thrombin inhibitor and has potent anticoagulant effects, it will have to be discontinued for some invasive and surgical procedures. The advantage of dabigatran therapy is that due to its short half-life, a patient's coagulation status will normalize more rapidly than that of a patient treated with warfarin in almost all cases. Dabigatran should be discontinued 1 to 2 days (creatine clearance ≥50 mL/min) or 3 to 5 days (creatine clearance <50 mL/min) before invasive or surgical procedures (Table 2). Clinicians may want to consider longer periods of discontinuation for patients undergoing major surgery in which bleeding could have serious consequences (ie, cardiac, neurosurgery, major abdominal or pelvic, spinal puncture, or placement of a spinal or epidural catheter or port). If surgery cannot be delayed, there is an increased risk of bleeding. Patients with a normal aPTT appear to have a low risk of serious bleeding (Figure 1).
The converse is true when restarting dabigatran therapy; anticoagulation occurs within a few hours of dabigatran initiation. Dabigatran should therefore be restarted only once it would be safe to initiate acute anticoagulation (eg, intravenous heparin). Importantly, this is different from reinitiating warfarin, where there is a much longer latency between reinitiation of therapy and full anticoagulation. Based on these factors, it might be reasonable to wait at least 24 to 36 hours after all serious or major bleeding has stopped before restarting dabigatran therapy after procedures with limited invasiveness and 2 to 5 days for major surgery and central nervous system procedures. This timeframe should be sufficient for the primary clot to stabilize and for secondary hemostasis to be well underway.
Use of Dabigatran With Mechanical Prosthetic Heart Valves
The rationale for long-term anticoagulation in patients with mechanical heart valves is based on their inherent thrombogenicity and high rates of thromboembolism in the absence of therapeutic anticoagulation. The rates of thromboembolism are higher for valves in the mitral compared with those in the aortic position. In addition, caged-ball valves are the most thrombogenic followed by tilting-disk and bileaflet valves.5,23
Patients were excluded from the RE-LY trial if they had a mechanical prosthetic cardiac valve. Preliminary in vitro and animal studies suggest that dabigatran may have some benefit for preventing clot formation on mechanical valves, but data are not available from humans.24,25 Until such data are available and demonstrate the safety and efficacy of dabigatran in patients with mechanical prosthetic valves, the drug should not be used routinely for this indication.
In cases in which standard warfarin therapy is not possible in the setting of a mechanical prosthetic valve, dabigatran might be a reasonable alternative. Several dozen patients in RE-LY had bioprosthetic valves and there was no signal of decreased efficacy in these patients (data on file with Boehringer-Ingelheim). However, the numbers were too small to make any firm conclusions.
Use of Dabigatran Related to Cardioversion of AF
Although dabigatran has not been studied in a prospective randomized trial to assess the drug's safety and efficacy related to cardioversion procedures, cardioversion on the study drug was permitted during the RE-LY trial. Precardioversion transesophageal echocardiography was encouraged. A recent publication reported on the available data from before, during, and 30 days after cardioversion for patients in RE-LY.26 A total of 1983 cardioversions were performed in 1270 patients: 647 (dabigatran at 110 mg twice a day), 672 (dabigatran at 150 mg twice a day), and 664 (warfarin). Transesophageal echocardiography was performed before 25.5% (dabigatran at 110 mg), 24.1% (dabigatran at 150 mg), and 13.3% (warfarin) of cardioversions, of which 1.8%, 1.2%, and 1.1%, respectively, were positive for left atrial thrombi. Continuous treatment with the study drug for ≥3 weeks before cardioversion was less frequent in low-dose (76.4%) and high-dose dabigatran groups (79.2%) compared with warfarin (85.5%; P≤0.01 for both).
Stroke and systemic embolism rates at 30 days were 0.8%, 0.3%, and 0.6%, respectively (dabigatgran at 100 mg versus warfarin, P=0.71; dabigatran at 150 mg versus warfarin, P=0.40) and similar in patients with and without transesophageal echocardiography. Major bleeding rates were 1.7%, 0.6%, and 0.6% (dabigatran at 110 mg versus warfarin, P=0.06; dabigatgran at 150 mg versus warfarin, P=0.99). This study is the largest published cardioversion experience to date and the first to evaluate dabigatran in this setting. The frequencies of stroke and major bleeding within 30 days of cardioversion on the 2 doses of dabigatran were low and comparable to those on warfarin with or without transesophageal echocardiography guidance.26
Although not FDA-approved for this indication, the data from RE-LY indicate that dabigatran is a reasonable alternative to warfarin in patients requiring cardioversion. Some clinicians are considering using dabigatran instead of warfarin for 3 weeks before cardioversion of persistent AF of >48 hours or unknown duration given the fact that therapeutic anticoagulation can be maintained throughout that period without the problems of trying to maintain a therapeutic INR for 3 weeks. Although this approach is reasonable and supported by some data, it is important to note that RE-LY was not designed to test the efficacy or safety of dabigatran before cardioversion.
Use of Dabigatran in Patients With Severe Renal Dysfunction
As noted previously, dabigatran is primarily excreted through the kidneys, and the dose is adjusted based on renal function. The RE-LY study excluded patients if their creatinine clearance was <30 mL/min. Although the FDA approved a dose of 75 mg twice a day for patients with creatinine clearances in the 15- to 30-mL/min range, they made no recommendations if the creatinine clearance was <15 mL/min or if the patient was getting dialysis. Many clinicians are reluctant to use warfarin in patients with renal failure due to concerns about bleeding and the risk of valvular calcification.27,28
Starting Dabigatran After an Ischemic Stroke
The large clinical trials of oral direct thrombin inhibitors and new oral antifactor Xa medications for stroke prevention in patients with AF have waited 7 days to 4 weeks after an ischemic stroke before initiating therapy, likely in an effort to avoid early cerebral bleeding complications. This study design has 2 potential limitations when applied to a routine clinical setting: (1) some patients may have a recurrent ischemic stroke in the intervening weeks; and (2) clinicians might begin therapy with warfarin or aspirin in the intervening timeframe and then switch to dabigatran in a few weeks.
Several clinical factors (besides antithrombotic medications) have been identified as being associated with an increased risk of hemorrhagic transformation of ischemic strokes; these include (1) the size of the stroke; (2) patient age; (3) other medical factors such as hypertension, diabetes, and prior strokes; (4) early petechial hemorrhage within the area of ischemia; and (5) cardioembolic source. In the vast majority of cases, symptomatic hemorrhagic transformation occurs within 7 to 10 days after the initial stroke.29
In general, patients with a large embolic stroke should not be treated acutely with anticoagulants because they already have a devastating deficit, are at high bleeding risk, and such treatment is unlikely to benefit their overall disability in terms of preventing another stroke.29 The converse may be true for patients with a small stroke. Such patients are unlikely to have hemorrhagic transformation, have a large amount of “at-risk” brain, and may benefit greatly by preventing another stroke. However, this strategy has not been proven in large clinical trials.
The CHADS2 score can be used to assess a patient's risk for subsequent stroke, and the HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) score can be used to assess the risk of cerebral and systemic bleeding.30,31 (The applicability of these scores in the setting of an acute stroke is unclear.) A brain MRI with gradient echo sequences can be used to determine if petechial hemorrhage already exists within the area of ischemia.32
Studies of heparin for secondary stroke prevention in the acute period showed that although this treatment prevented early recurrent ischemic strokes, it also caused more cerebral hemorrhages (than aspirin); thus, there was no net benefit.33–36 We also weigh the results of cardiac imaging and might be more likely to use early anticoagulation in patients with a visualized clot in the left atrium or left ventricle.37–40 Based on these data and concerns, we believe it may be justified to use dabigatran soon after stroke onset (ie, within a few days to 2 weeks) in some patients at high risk for recurrent stroke and low risk of cerebral bleeding (Figure 2).
Use of Intravenous Tissue Plasminogen Activator in a Patient Taking Dabigatran
Recombinant tissue plasminogen activator (rtPA, also known as tPA) is the only FDA-approved medication proven to reduce neurological deficits in the setting of an acute ischemic stroke. tPA is a potent thrombolytic agent that can cause serious cerebral and systemic hemorrhages. In some studies, up to 50% of cerebral hemorrhages related to intravenous tPA use in patients with an acute stroke are fatal.41 Because dabigatran is a potent and fast-acting oral anticoagulant, there is a reasonable concern that intravenous tPA administration to a patient being treated with dabigatran might increase the risk of bleeding. This is certainly true when intravenous lytic therapy has been used in patients receiving other anticoagulants or antiplatelet therapy in the acute setting.42
The American Heart Association/American Stroke Association guidelines for the use of intravenous tPA use within 3 hours specifically state “not taking an oral anticoagulant or, if anticoagulation being taken, INR ≤1.7.”43 A recent American Heart Association/American Stroke Association scientific advisory on the use of intravenous tPA in the 3- to 4.5-hour time window states, “all patients receiving an oral anticoagulant are excluded regardless of their international normalized ratio.”44
Based on these considerations, we suggest that intravenous tPA not be used in patients known to be taking dabigatran. However, if there is clear evidence that the patient had normal renal function (creatine clearance >50 mL/min), has not taken any dabigatran for at least the past 48 hours, and their coagulation testing is entirely normal (aPTT, INR, platelet count), then treatment with intravenous tPA is reasonable assuming all other inclusion/exclusion criteria for the use of intravenous tPA are addressed. There are isolated case reports of patients taking dabigatran who had an acute ischemic stroke and were treated with intravenous tPA. Although no bleeding complications were reported, the overall clinical experience is too limited to recommend such therapy.45–47
There are no data about endovascular cerebral interventions in acute stroke for patients actively taking dabigatran. Such procedures are sometimes performed after the administration of intravenous tPA. Recent large studies have shown such procedures are associated with cerebral hemorrhage rates of 15% to 20%.48 Acute cerebral endovascular interventions in the setting of full anticoagulation due to dabigatran might have similar rates of hemorrhage, although there are no data on this point. The situation might be analogous to performing such procedures in patients taking warfarin with a therapeutic INR. We recommend that the risks versus benefits of such endovascular therapies in this setting be carefully considered and discussed by the treating physicians as well as patients and family members.
Although this might be a setting where checking the thrombin time and/or ecarin clotting time would be beneficial, in many institutions, it is unlikely these tests could be completed within a 3- or 4.5-hour treatment time window. Also, these time recommendations assume normal renal function. If renal function is impaired, one can assume the serum half-life of dabigatran would be prolonged. In that setting, perhaps the exclusionary time period for prior exposure (before using tPA) should be at least 5 half-lives.
Antiplatelet Therapy and Dabigatran
Forty percent of patients in the RE-LY study were taking aspirin at the time of enrollment. In all 3 arms of the trial, the use of aspirin was associated with an increase in the risk of major bleeding. The increase in bleeding risk did not differ based on treatment assignment; in other words, concomitant aspirin use was associated with similar rates of additional bleeding in the dabigatran-treated and warfarin-treated patients (FDA Advisory Committee briefing document; September 20, 2010). Physicians should weigh this increased bleeding risk against any potential benefit when contemplating the use of aspirin in any patient taking an anticoagulant (such as warfarin or dabigatran). Based on these concerns, if a patient with AF and receiving dabigatran therapy required a coronary stent, the use of a bare metal stent might be reasonable to avoid long-term triple therapy (ie, dabigatran, aspirin, and clopidogrel).
If an anticoagulated patient receiving concomitant antiplatelet therapy presents with serious bleeding, reversal of the anticoagulant effect as well as platelet transfusion may be appropriate (this is discussed subsequently in more detail).
The use of dabigatran in RE-LY was associated with a nonsignificant increase in the occurrence of myocardial infarction. The use of antiplatelet therapy (mostly aspirin) did not appear to affect this end point, although further analyses are needed. At this time, the potential benefits of adding antiplatelet therapy to dabigatran may be outweighed by the risks, unless there is a compelling indication for short-term antiplatelet therapy (eg, drug-eluting coronary stent).
Use in Patients With a Known Cardiac Thrombus
In the process of evaluating patients with a known or suspected cardioembolic stroke or systemic emboli, neurologists and cardiologists sometimes discover an intracardiac clot using transthoracic echocardiography, transesophageal echocardiography, or cardiac MRI. In some cases, we might choose to use acute anticoagulation to prevent recurrent embolic events.5,12,43 There are no data about the safety and efficacy of dabigatran in such patients nor are there data to recommend the use of dabigatran in patients with left ventricular thrombi or patients with wall motion abnormalities from a myocardial infarction or a dilated cardiomyopathy. This is not a FDA-approved indication for dabigatran.
However, in the RE-LY study, patients who had left atrial appendage thrombi (diagnosed by transesophageal echocardiography) were treated for 3 weeks with dabigatran before direct current cardioversion. There was no evidence of an increased risk of stroke or systemic emboli in these patients compared with similar patients treated with warfarin.11 The potential risks include cerebral or systemic hemorrhage, although in RE-LY, dabigatran caused fewer cerebral bleeding events than warfarin (but more gastrointestinal bleeding). The potential benefits include rapid anticoagulation and the potential to prevent recurrent embolic events.
Based on the limited available data, it seems reasonable to consider dabigatran therapy in patients with an intracardiac thrombus and a stroke if they are otherwise good candidates for acute anticoagulation (see previously). Alternative therapies include antiplatelet agents, warfarin, unfractionated intravenous heparin, and low-molecular-weight heparins.
Switching Among Warfarin, Parenteral Anticoagulants, and Dabigatran
Both dabigatran and warfarin are powerful anticoagulants, and there is concern that taking both medications together might produce a significant coagulopathy. Therefore, if a patient is taking warfarin with a therapeutic INR, it is recommended that the warfarin be discontinued and that dabigatran be started once the INR is <2.0.
If the patient is currently taking dabigatran, its anticoagulant effects will be gone within a few hours after the cessation of therapy. Therefore, warfarin should be started several days before dabigatran is stopped; otherwise, the patient will be “uncovered” until the INR becomes therapeutic. Because the longevity of the anticoagulant effect of dabigatran depends on the creatinine clearance, the timeline for the initiation of warfarin therapy is dependent on renal function (Table 3).
Some patients will be receiving a parenteral anticoagulant such as intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin before dabigatran is started. In such cases, it is recommended that dabigatran be started either at the time that an intravenous heparin infusion is stopped or 2 hours before the next dose of a parenteral heparinoid agent is to be administered. This approach will reduce the time that a dual anticoagulant effect is present.
Use of Dabigatran in Patients With Stroke, AF, and Coexisting Venous Thromboembolic Disease
No trial with dabigatran has addressed this population directly, and these patients would have been excluded from RE-LY. However, dabigatran at 150 mg twice a day has been compared with dose-adjusted warfarin in 1274 patients with acute venous thromboembolism in the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER) trial.49 This randomized, double-blind, noninferiority trial allocated patients with acute deep venous thrombosis or pulmonary embolism to either dabigatran at 150 mg twice a day or dose-adjusted warfarin with a goal INR 2 to 3. All patients were treated initially with parenteral anticoagulation. The primary outcome was recurrent symptomatic, objectively confirmed venous thromboembolism, or death related to venous thromboembolis. The primary safety end point was major bleeding.
The incidence of recurrent venous thrombosis was 2.4% among the patients assigned to dabigatran and 2.1% among those assigned to warfarin with a hazard ratio of 1.10 (95% CI, 0.65–1.84; P<0.001 for noninferiority). Major bleeding occurred in 1.6% of those assigned dabigatran and 1.9% of those assigned warfarin (hazard ratio, 0.82; 95% CI, 0.45–1.48). Importantly, for the population with coexisting stroke and venous thromboembolism, there was no excess of intracranial bleeding with dabigatran, no difference in the occurrence of acute coronary syndrome, and no difference in hepatic toxicity.49 Based on RE-COVER, dabigatran is noninferior to warfarin in patients with venous thromboembolism, and the presence of venous thromboembolism in a patient with stroke and AF should not mitigate against long-term treatment with dabigatran.
Other Indications for Anticoagulation
Neurologists often use warfarin for indications besides AF in an attempt to reduce the risk of a new or recurrent stroke. Some clinical scenarios in which warfarin is commonly used include patients with a hypercoagulable state (lupus anticoagulant, anticardiolipin antibodies, protein C and S deficiency, others), cervical arterial dissection, cerebral venous thrombosis, and post-partum, among others.12 In some cases, this therapy is supported by guideline recommendations but is based on limited data.12 There are some cases in which the use of heparin and/or warfarin is particularly problematic. Examples include some patients with a hypercoagulable state (eg, antiphospholipid antibody syndrome) in which the partial thromboplastin time and/or prothrombin time/INR may be misleading or unstable due to the underlying coagulopathy. Other problems include patients who must take medications that interact with warfarin or if they cannot get INR monitoring due to logistical factors.
In such cases, alternative therapies might include antiplatelet agents or low-molecular-weight heparin. Even these therapies are based on limited data in terms of efficacy and safety. Although there are no data to recommend dabigatran in such cases, it is reasonable to consider such therapy based on the particular and unique clinical circumstances of each patient. These conditions are not FDA-approved indications for dabigatran therapy. However, neurologists and others often use many medications in an “off-label” situation. Indeed, many of the common uses of intravenous unfractionated heparin and warfarin in the setting of cerebrovascular disease are “off-label.”
Rapid Reversal of Direct Thrombin Inhibitors
In some clinical settings, it will be important and perhaps life-saving to be able to rapidly reverse the anticoagulant effects of dabigatran (ie, intracerebral hemorrhage, systolic/diastolic hypertension, epidural hematoma). Although the data are limited, the prothrombin complex concentrates have been proposed as a reasonable therapy for the rapid reversal of dabigatran's anticoagulant effects.22 The prothrombin complex concentrates generally contain all or most of the vitamin K-dependent clotting factors. Some of the prothrombin complex concentrate preparations contain inactivated clotting factors, whereas others (activated prothrombin complex concentrate) contain activated clotting factors.50 The latter preparations may be more potent but also have higher thrombogenic potential.
There are limited in vitro and in vivo studies showing that the activated prothrombin complex concentrate preparations (such as FEIBA) are effective in reversing the anticoagulant effects in dabigatran in various bleeding models. The optimal dose of FEIBA to reverse the anticoagulant effects of dabigatran in humans is unknown; animal studies suggest a dose of 50 to 100 U/kg may be needed.22 Limited preclinical and clinical data suggest that recombinant factor VIIa may also reverse the anticoagulant effects of dabigatran.51,52 More clinical data are needed on both of these potential reversal agents. Diuresis with intravenous fluids may enhance the renal excretion of dabigatran. Acute hemodialysis might also be useful if these measures do not stop the bleeding, although this can take hours to begin and complete.
For a dabigatran-treated patient with life-threatening hemorrhage, we suggest, pending further evidence that unless the aPTT is normal (ie, ratio to control ≤1.0), the patient should receive FEIBA or another activated prothrombin complex concentrate or recombinant factor VIIa in high doses. These interventions involve a nontrivial risk of precipitating thromboembolism and should be reserved for patients with life-threatening bleeding. Enhanced diuresis with intravenous fluids is also reasonable if such hydration can be tolerated by the patient.
It might be useful for a medical group or company to organize a registry to track the occurrence, treatment, and outcomes of patients treated with dabigatran who develop serious hemorrhagic complications.
Other Practical Considerations
The dosing of dabigatran is based on renal function. Many institutions and clinics report renal function in terms of glomerular filtration rate, not creatinine clearance. It is important to realize that glomerular filtration rate is not equivalent to creatinine clearance. Age, gender, and weight are needed to make the conversion. There are various formulas online that can be used to calculate creatinine clearance (see www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation).
Many patients have dysphagia as a result of their stroke and receive nutrition and medications through a feeding tube for 1 to 2 weeks and then a percutaneous gastrostomy tube for weeks to months. Dabigatran is a capsule; opening or crushing it changes the absorption of the drug and may lead to exposure of the patient to an excessive dose. There are no currently available rectal or parenteral formulations of dabigatran. Therefore, in patients who require a feeding tube, dabigatran should not be used and alternative anticoagulation therapies are indicated.
The cost of dabigatran will vary in different parts of the world. In the United States, there are various discount programs that may be available to assist some patients who cannot afford this medication. It is important for practitioners to ensure that patients can afford dabigatran before prescribing it. For many patients, warfarin will remain a relatively inexpensive and effective alternative.
For patients taking dabigatran, it will be important that they get their prescription refilled regularly, because stopping therapy will result in the rapid reversal of its anticoagulant effect. Strategies should be used to ensure high patient compliance and reduce the risk of running out of medication.
Dabigatran has some significant advantages over warfarin as we now understand these 2 medications (Table 4). However, there are also some areas where we do not fully understand its risks, including its safety soon after an ischemic stroke and the ease/effectiveness of its reversal in case of a major hemorrhage. There are a host of related cerebrovascular diseases in which dabigatran might have a meaningful clinical role, yet the paucity of data precludes any firm recommendations. Either way, it is always good to have treatment options, and dabigatran appears to be a new and important option that may benefit many of our patients at risk of having a stroke in the setting of AF.
As this article is being revised and submitted, the results of 2 large Phase III trials of oral factor Xa inhibitors for the treatment of patients with AF have just been published.53,54 These medications, rivaroxaban and apixaban, are pharmacologically different from dabigatran, although both showed good efficacy and safety profiles when compared with warfarin. The recommendations we have made for dabigatran may not be applicable in all cases for these new agents due to differences in metabolism and other clinical factors. We urge caution in applying some of our recommendations to these new agents.
The FDA recently issued instructions about the storage of dabigatran. The medication should be stored in its original container and not be taken out and placed into a pill organizer or other secondary container. The contents of each bottle should be used within 4 months. See the following web site for further details: www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm249005.htm.
M.J.A. has received speaking honoraria from Boehringer-Ingelheim and is a consultant for Ortho-McNeil-Janssen, Merck, Bristol Myers Squibb, Sanofi-Aventis, and Pfizer. R.A.B. has received speaking and/or consulting honoraria from Boehringer-Ingleheim, Sanofi, and Ortho-McNeil-Janssen and research support from Bristol Myers Squibb, Pfizer, Lifewatch, and Medtronic. G.V.N. has received research support from Boehringer-Ingelheim and is a consultant for Pfizer, Bristol-Myers Squibb, Boehringer-Ingelheim, Portola, and Ortho-McNeil-Janssen. D.A.G. has received research funding from Bristol Myers and Boehringer Ingelheim and is a consultant for Bristol Myers, Boehringer-Ingleheim, OrthoMcNeil, and Daichii Sankyo.
- Received April 8, 2011.
- Revision received September 9, 2011.
- Accepted September 12, 2011.
- © 2012 American Heart Association, Inc.
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