Friday, January 4, 2013

Resident Journal Review: Anticoagulation

Originally Published: Common Sense, Jan/Fab 2013

Original Authors: Authors: Susan Cheng, MD MPH; Jonathan Yeo, MD; Allison Regan, MD; Eli Brown, MD

Edited by: Michael C. Bond, MD; Jay Khadpe, MD

This Resident Journal Review focuses on the new oral anticoagulants and their use for stroke prophylaxis in patients with atrial fibrillation, venous thromboembolism (VTE), and acute coronary syndrome (ACS). Vitamin K antagonists such as
warfarin have historically been used to reduce the risk of stroke in patients with atrial fibrillation. Atrial Fibrillation is responsible for 15% of strokes in people of all ages and 30% in people over 80. Traditionally, warfarin has been the anticoagulant of choice in these patients and has been shown to significantly reduce the risk of stroke. Warfarin, however, is difficult to manage as it requires frequent laboratory monitoring and has multiple interactions with common foods and drugs. Furthermore, many people receiving warfarin therapy still have inadequate anticoagulation. Therefore, there is a significant need for new oral anticoagulants that are safe, effective, and convenient to use. As medical providers, it is important to be familiar with the pharmacology of these new oral anticoagulants, indications for their use, and reversal therapy in the setting of major hemorrhage.

Pollack CV, Jr. New oral anticoagulants in the ED setting: A Review. American Journal of Emergency Medicine. 2012.

This review by Pollack focuses on the three new oral anticoagulants being discussed in our review: dabigatran, rivaroxaban, and apixaban. Dabigatran is a direct thrombin inhibitor, which prevents the conversion of fibrinogen to fibrin. Rivaroxaban and apixaban are selective factor Xa inhibitors, which work on the preceding step in the coagulation cascade to prevent the conversion of prothrombin to thrombin. To date, the US Food and Drug administration (FDA) has approved dabigatran and rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation. Rivaroxaban has also been approved for deep vein thrombosis (DVT) prophylaxis in patients undergoing knee or hip replacement surgery. None of the three drugs have been approved for the treatment of VTE or ACS.

One of the most attractive features of these novel drugs is that routine laboratory monitoring is not necessary. All three drugs are administered orally and are partially excreted by the kidneys; therefore, they need dose adjustments in patients with renal insufficiency. They also have a rapid onset and offset of action compared to warfarin, and do not require overlap with low molecular weight heparins (LMWH) or unfractionated heparin (UFH).

One potential problem with these new oral anticoagulants is the inability to monitor their activity or drug levels, especially in emergency situations such as overdose or overt bleeding. In addition, no antidote exists for these three drugs if reversal is indicated. Therefore, it is important to be able to quickly and reliably assess coagulation function in patients with overt bleeding. Although not widely available, Ecarin clotting time may be a reliable assay to assess coagulation with dabigatran. For rivaroxaban and apixaban, anti-factor Xa assays may be useful in the future to monitor activity.

In the EINSTEIN trials published in the New England Journal of Medicine (NEJM) in 2010 — 3,449 patients with proximal DVT without pulmonary embolism (PE) were randomized to receive either rivaroxaban, or enoxaparin plus an oral vitamin K antagonist (VKA).(1) Symptomatic recurrent VTE occurred in 2.1% of the rivaroxaban group and 3% of the enoxaparin/VKA group. The rates of bleeding were similar between the groups. A study published in 2012, enrolled 4,832 patients
with PE and randomized them to the same treatment groups as the DVT study.(2) This study showed similar efficacy in both groups with rivaroxaban having fewer major bleeding events. In the RE-VOLUTION trials, dabigatran was evaluated against warfarin in the treatment of acute VTE.(3) All 2,539 patients were initially treated with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) and then randomized to receive either warfarin or dabigatran. The primary outcome of recurrent VTE occurred in 2.4% of patients receiving dabigatran compared to 2.1% in the warfarin group. Combined major and clinically relevant non-major bleeding rates were higher in the warfarin
group (8.8%) compared to the dabigatran group (5.6%). Apixaban was studied in the Botticelli DVT trial, which included 520 patients with DVT who were randomized to apixaban or LMWH/VKA combination.(4) Both groups had similar rates of recurrent VTE as well as bleeding.

The data on the three new anticoagulants roles in ACS was also discussed by Pollack. A phase II trial was published where 1,861 patients with ST and non-ST elevation myocardial infarction (NSTEMI) were randomized to receive four different doses of dabigatran versus placebo along with dual antiplatelet therapy.(5) They found that the dabigatran groups had significantly higher rates of bleeding with no significant improvement in cardiovascular death, nonfatal MI, and hemorrhagic
stroke compared to the placebo. Rivaroxaban was also studied and became the first of the new anticoagulants to successfully complete a phase III trial for ACS. This trial enrolled 15,526 patients stabilized after an ACS event.(6) They were randomized to receive either two different doses of rivaroxaban or placebo in addition to standard medical therapy in all groups. The risk of cardiovascular death, MI and stroke occurred at a rate of 8.9% in the rivaroxaban groups and 10.7% in the placebo group. The lower dose of rivaroxaban also reduced the rate of all-cause mortality when compared to placebo (2.9% vs. 4.5%). The rivaroxaban group did have a higher rate of bleeding events compared to placebo (2.1% vs. 0.6%) but there was no significant difference in fatal bleeding between the groups. Apixaban also had a phase III trial for ACS that was terminated early due to higher rates of major bleeding events in the apixaban group. Over 7,000 patients were assigned to receive either apixaban or placebo and no significant difference in rates of recurrent ischemic events was found.(7)

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2011 Sep 15; 365:981-982.

This randomized, double-blind trial compared apixaban, a direct oral factor Xa inhibitor, with warfarin in patients with non-valvular atrial fibrillation. The primary outcome was rate of stroke (ischemic or hemorrhagic) or systemic embolism in patients receiving warfarin versus those receiving apixaban. Patients were eligible if they had atrial fibrillation or flutter at time of enrollment or at least two episodes of atrial fibrillation or flutter on ECG at least two weeks apart in the twelve months prior to enrollment. Eligible patients also required one or more of the following risk factors for stroke: age greater than or equal to 75 years; prior stroke, transient ischemic attack, or systemic embolism; symptomatic heart failure within the last three month or ejection fraction less than or equal to 40%; diabetes mellitus; or hypertension requiring medication.

Patients were randomized to receive warfarin, apixaban, or placebo. The standard dose of apixaban administered was 5mg twice daily. Patients received a reduced dose of 2.5mg daily if they met two or more of the following criteria: age over 80, serum creatinine greater than 1.5, or body weight less than or equal to 60 kg. Warfarin doses were adjusted to achieve a goal INR of 2.0 to 3.0. The primary efficacy outcome of interest was stroke or systemic embolism and the key secondary outcome was death from any cause. The authors also monitored for major and non-major bleeding as well as other adverse events and liver function abnormalities.

The study recruited 18,201 patients, 9120 of whom were assigned to the apixaban group and 9,081 to the warfarin group. Enrolled patents had similar baseline characteristics (demographics, medical history, etc.) and the mean CHADS2 score was 2.1. Patients assigned to the warfarin group had a goal INR (2.0 to 3.0) for a median of 66.0% of the time and a mean of 62.2% of the time. Stroke or systemic embolism occurred in 212 patients in the apixaban group (1.27% per year) and in 265 patients in the warfarin group (1.6% per year). Ischemic stroke occurred in 149 patients in the apixaban group and in 155 patients in the warfarin group. In patients with ischemic stroke, hemorrhagic transformation occurred in 12 patients who received apixaban and in 20 patients who received warfarin. The rate of death from any cause was 3.52% per year for patients in the apixaban group, compared with 3.94% per year for patients in the warfarin group. Major bleeding occurred in 327 patients in the apixaban group (2.13% per year) and 462 patients in the warfarin group (3.09% per year). The rate of intracranial hemorrhage was 0.33% per year in the apixaban group and 0.8% per year in the warfarin group, while the rate of any bleeding was 18.1% per year in the apixaban group and 25.8% per year in the warfarin group.

The authors concluded that in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke, apixaban was superior to warfarin for prevention of stroke or systemic embolism. The most notable reduction found was risk of hemorrhagic stroke. They also found that patients randomized to the apixaban group had fewer episodes of major bleeding and lower risk of death from any cause than those patients in the warfarin group.

One of the main limitations to this study is that the patients randomized to receive warfarin had INRs in the therapeutic range only 62% of the time. While this is a fairly common occurrence in clinical practice, sub-therapeutic INRs may alter the efficacy of warfarin in prevention of ischemic strokes and systemic emboli, while supra-therapeutic INRs can contribute to the relative increase in risk of hemorrhagic stroke seen in the warfarin group compared to those who received apixaban. This may have been remedied had the authors included a subgroup analysis of patients with INRs in the goal range.

In addition to the superior efficacy and reduced risk of bleeding found by this trial, apixaban offers additional benefits over warfarin such as the lack of need for monitoring and few, if any, drug or food interactions. However, in the setting of major bleeding, an effective reversal agent for apixaban is yet to be determined. In addition, the cost of apixaban far exceeds that of warfarin. These concerns must be addressed and further studied before apixaban is able to replace warfarin as the preferred agent for stroke prevention in patients with non-valvular atrial fibrillation.

Connolly SJ, Ezekowitz MD. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009; 361: 1139-1151.

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) is a randomized non-inferiority trial comparing fixed doses of dabigatran to adjusted-dose warfarin in patients with atrial fibrillation and a risk of stroke. The primary outcome of the study was either stroke or systemic embolism, and the primary safety outcome was major hemorrhage. Inclusion criteria consisted of a documented history of atrial fibrillation on electrocardiogram (ECG) within 6 months of screening plus at least one of the following: a previous stroke or transient ischemic attack, congestive heart failure with an ejection fraction of less than 40%, an age of at least 75 years, or 65-74 years with either diabetes mellitus, hypertension, or coronary artery disease. Patients were excluded if they had: a severe heart-valve disorder, stroke within 14 days or a severe stroke within six months, a condition the increased the risk of hemorrhage, a creatinine clearance < 30mL per minute, active liver disease, or pregnancy.

This study recruited patients from 951 clinical centers in 44 countries in order to obtain 18,133 participants. Participants were randomly assignedto receive one of two doses of dabigatran, or anticoagulation therapy with warfarin. The dabigatran dosage was blinded, as participants received either 110mg or 150mg twice daily. The warfarin was administered in an unblinded fashion and adjusted to an INR of 2.0 to 3.0.

Final follow-up visits were recorded with a median follow-up period of 2.0 years. Stroke or systemic embolism occurred in 182 patients receiving 110mg of dabigatran (1.53% per year), 134 patients receiving 150mg of dabigatran (1.11% per year), and 199 patients receiving warfarin (1.69% per year). The relative risk for 110mg of dabigatran was 0.91 (95% CI 0.74-1.11; p<0.001) for non-inferiority. The relative risk for 150mg of dabigatran was 0.66 (95% 0.53-0.82; p<0.001) for superiority.

Major hemorrhage occurred at a rate of 3.36% per year in patients within the warfarin group. It occurred relatively less in those receiving dabigatran at 2.71% per year in the 110mg dosed group (relative risk 0.93; 95% CI 0.81-1.07; p =0.003) and 3.11% per year in the group that received 150mg of dabigatran (relative risk 0.93; 95% CI 0.81-1.07; p=0.31). The only adverse effect found to be significantly more common with dabigatran was dyspepsia.

This study found both dabigatran doses to be non-inferior to warfarin with respect to prevention of stroke or systemic embolism. Furthermore, the 150mg dose of dabigatran twice daily was superior
to warfarin in stroke or systemic embolism prevention, and the 110mg dose of dabigatran was superior in regards to major bleeding. Therefore, dabigatran should be considered as an alternative to warfarin therapy for the prevention of strokes in patients with atrial fibrillation in the setting of normal kidney and liver function and no severe heartvalve disorder.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-91.

This randomized, double-blind, trial that included patients with non-valvular atrial fibrillation compared rivaroxaban and warfarin in the prevention of stroke and systemic embolism. Inclusion criteria were patients with non-valvular atrial fibrillation documented on ECG with elevated risk of stroke based on presence of at least two of the following criteria: heart failure or ejection fraction of 35% or less, hypertension, age ≥ 75, or diabetes mellitus.

Patients were randomized to receive rivaroxaban 20mg daily or adjusted-dose warfarin with goal INR of 2.0 to 3.0 in addition to a placebo tablet. Patients with reduced GFR who were assigned to the rivaroxaban group received a reduced dose of 15mg daily. The study generated sham INR values for patients in the rivaroxaban group. The primary efficacy outcome was rate of hemorrhagic or ischemic stroke and systemic embolism. Secondary end points included death from cardiovascular causes. The primary safety outcomes were major and non-major bleeding events.

The trial enrolled 14,264 patients, with 7,131 randomized to the rivaroxaban group and 7,133 randomized to the warfarin group. Age, coexisting illnesses and other demographics were similar between the two groups. Mean and median CHADS2 scores were 3.5 and 3.0, respectively. For patients assigned to the warfarin group, INR was within the goal range (2.0 to 3.0) a mean of 55% of the time.

Stroke or systemic embolism occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 patients in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% CI 0.66-0.96; p<0.001 for non-inferiority). Major and/or clinically relevant non-major bleeding occurred in 1,475 patients in the rivaroxaban group (14.9% per year) and in 1,449 patients in the warfarin group (14.5% per year) (hazard ratio in the rivaroxaban group, 1.03; 95% CI 0.96-1.03;
p=0.44). Rates of major bleeding were 3.6% in the rivaroxaban group and 3.4% in the warfarin group. Rates of intracranial hemorrhage were 0.5% in the rivaroxaban group versus 0.7% in the warfarin group, while rates of major gastrointestinal bleeding were higher in the rivaroxaban group (3.2% versus 2.2% in the warfarin group).

The authors concluded that rivaroxaban was non-inferior to warfarin in the prevention of stroke or systemic embolism in patients with non-valvular atrial fibrillation. In addition, there were no significant differences between rivaroxaban and warfarin in rates of major and non-major bleeding and a lower incidence of intracranial hemorrhage in the rivaroxaban group. While fatal or critical bleeding occurred at similar rates in the rivaroxaban and warfarin groups, bleeding from gastrointestinal sites occurred more frequently in the rivaroxaban group.

Once again the main limitation of this study is that patients assigned to the warfarin group had INRs within the therapeutic range at a mean of only 55%. However, the authors cite this lower rate as a possible consequence of including only North American sites. They also state that in other studies, rivaroxaban has been proven to be equally effective in cohorts with the best INR control as well as with the poorest control. One does have to wonder though if stroke rates would go down with the INR being ideal at all times, though the risk of bleeding may also increase.

Similar to other direct factor Xa inhibitors, rivaroxaban offers the benefit of not needing blood tests or any other monitoring; however, additional trials are needed to compare it with warfarin in patients with a greater percentage of INRs within the therapeutic range in order to accurately compare its efficacy.

Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate: A Randomized, Placebo-Controlled, Crossover Study in Healthy Subjects. Circulation. 2011; 124: 1573-1579.

This was a randomized, double-blind, placebo-controlled study with 12 healthy male volunteers to evaluate the potential of prothrombin complex concentrate (PCC) to reverse the anticoagulant effect ofrivaroxaban or dabigatran. Half of the volunteers were randomized to receive rivaroxaban 20 mg twice daily for 2.5 days, while the other half received dabigatran 150 mg twice daily for the same 2.5 days. Afterwards, the volunteers were randomized to receive either a single infusion bolus of 50 IU/kg of PCC or saline infusion as placebo. The brand name of PCC used was Cofact, which contains factor II, VII, IX, X, protein C, S and antithrombin. Volunteers were not blinded to type of anticoagulant, but were blinded to PCC or saline. Laboratory technicians were blinded to anticoagulant and type of infusion. Blood was collected from each volunteer at baseline, on the third day of anticoagulant use prior to infusion of PCC or saline, and at multiple time intervals post infusion (15 minutes, 30 minutes, one hour, two hours, four hours, six hours, and 24 hours). This was followed by an 11-day washout period and the volunteers repeated the process with the other oral anticoagulant.

Rivaroxaban increased prothrombin time (PT) that was immediately and completely reversed by PCC (p<0.001). Rivaroxaban also inhibited endogenous thrombin potential (ETP) that was normalized with PCC (p<0.001). Dabigatran increased activated partial thromboplastin time (aPTT), ecarin clotting time (ECT) and thrombin time; however, none of these coagulation tests were reversed by PCC. Dialysis is an alternative or reversal of dabigatran, but it has limited effectiveness because 1/3 of dabigatran is bound to plasma and therefore not dialyzable. Rivaroxaban is 95% bound to protein, and therefore cannot be dialyzed.

This is the first study conducted in humans that shows that nonactivated PCC immediately reverses the effect of full-dose rivarobaxan and is a promising option for reversal in the setting of bleeding or emergent pre-operative measures. The study used randomization and a crossover design to minimize bias, however, the study was limited. The test subjects were healthy males around 24 years old and there were only 12 subjects. It would be difficult to generalize to an older patient population and or those with medical co-morbidities. Coagulation profiles were analyzed as a surrogate marker for bleeding risk, and this may be difficult to translate directly into clinical practice. In addition, the dose of PCC was chosen from animal study data and further studies are needed to confirm the efficacy of a lower dose of PCC to reverse rivaroxaban. Future studies should also test alternative formulations of PCC for their possible reversal effects.

This Resident Journal Review includes recent studies concerning the use of new oral anticoagulants for stroke prophylaxis in atrial fibrillation, VTE, and ACS. Although the studies have not demonstrated efficacy in their use for ACS, they are encouraging that dabigatran, rivaroxaban, and apixaban can provide comparable if not superior efficacy and reduced risk of bleeding when compared to warfarin in the treatment of VTE and stroke prevention. However, effective reversal agents have yet to be identified and studied adequately for use in the setting of a major bleed. Regardless, we will continue to see patients taking new oral anticoagulants and must be familiar with the pharmacology of each and how to approach reversing the anticoagulation in the safest and most rapid manner possible. ■

1. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363: 2499-510.
2. Buller HR, Prins MH, Lensing AWA. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
3. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
4. Buller H, Deitchman D, Prins M, Segers A. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli
DVT dose-ranging study. J Thromb Haemost 2008;6:1313-8.
5. Oldgren J, Budaj A, Granger CB. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind,
phase II trial. Eur Heart J 2011;32:2781-9.
6. Mega JL, Braunwald E, Wiviott SD. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012;366:9-19.
7. Alexander JH, Lopes RD, James S. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011;365:699-708.

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