- ACRONYMS AND DEFINITIONS
- ACCP - American College of Chest Physicians
- AHA - American Heart Association
- A fib - Atrial fibrillation
- DVT - Deep vein thrombosis
- EF - Ejection Fraction
- HR - Hazard Ratio
- INR - International Normalized Ratio
- MI - Myocardial Infarction
- NYHA - New York Heart Association heart failure classifications
- PCI - Percutaneous coronary intervention
- PE - Pulmonary embolism
- P-gp - P-glycoprotein
- PI - Manufacturer's package insert
- TIA - Transient ischemic attack
- ULN - Upper limits of normal
- VTE - Venous Thromboembolism (DVT and PE)
- DRUGS IN CLASS
- Direct Thrombin Inhibitors
- Dabigatran (Pradaxa®)
- MECHANISM OF ACTION
- Thrombin (Factor IIa)
- Thrombin enables the conversion of fibrinogen to fibrin
- Fibrin cross-links to form a mesh where activated platelets are trapped and a blood clot is formed
- Thrombin also stimulates platelets to become active
- Direct thrombin inhibitors block the action of thrombin on fibrinogen and platelets
- FDA-APPROVED INDICATIONS
- Dabigatran (Pradaxa®)
- Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation
- Treatment of Deep Venous Thrombosis and Pulmonary Embolism - in patients who have been treated with a parenteral anticoagulant for 5 - 10 days
- Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
- Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery
- EFFECTIVENESS
Atrial fibrillation (nonvalvular)
- Atrial fibrillation (A fib) is a common heart arrhythmia that increases a person's risk of stroke
- Dabigatran is currently approved for the treatment of nonvalvular atrial fibrillation
- "Nonvalvular" means atrial fibrillation that occurs in the absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair [1]
- The majority of atrial fibrillation is "nonvalvular"
- One large, randomized controlled trial has evaluated dabigatran in atrial fibrillation
- The RE-LY study enrolled 18,113 patients with atrial fibrillation and other risk factors for stroke
- Main inclusion criteria: A fib and one of the following - previous stroke or TIA, EF < 40%, NYHA class II - IV heart failure, age ≥ 75 years or age 65 - 74 with diabetes, hypertension, or coronary artery disease
- Main exclusion criteria: severe heart-valve disorder; stroke within 6 months; high risk for bleeding; CrCl < 30 ml/min
- Baseline characteristics: average age 72 years; A fib type, persistent - 32%, paroxysmal - 33%, permanent - 35%; average CHADS₂ score - 2.1; prior stroke or TIA - 20%
- Patients were randomized to 1 of 3 groups:
- Group 1 (6015 patients) - Dabigatran 110 mg twice a day
- Group 2 (6076 patients) - Dabigatran 150 mg twice a day
- Group 3 (6022 patients) - Warfarin (target INR 2.0 - 3.0)
- Warfarin therapy was open-label. Dabigatran was open-label but dose was blinded.
- Concomitant aspirin (< 100 mg/day) and other antiplatelet drugs were permitted
- PRIMARY OUTCOME: Stroke or systemic embolism
- After a median follow-up of 2 years, the following was seen:
- Primary outcome: Group 1 - 1.53%/year, Group 2 - 1.11%/year, Group 3 - 1.69%/year (1 vs 3, p=0.34; 2 vs 3, p<0.001; 1 vs 2, p=0.005)
- Stroke: Group 1 - 1.44%/year, Group 2 - 1.01%/year, Group 3 - 1.57%/year (1 vs 3, p=0.41; 2 vs 3, p<0.001; 1 vs 2, p=0.003)
- Overall mortality: Group 1 - 3.75%/year, Group 2 - 3.64%/year, Group 3 - 4.13%/year (1 vs 3, p=0.13; 2 vs 3, p=0.051; 1 vs 2, p=0.66)
- Hemorrhagic stroke: Group 1 - 0.12%/year, Group 2 - 0.10%/year, Group 3 - 0.38%/year (1 vs 3, p<0.001; 2 vs 3, p<0.001; 1 vs 2, p=0.67)
- Major bleeding: Group 1 - 2.71%/year, Group 2 - 3.11%/year, Group 3 - 3.36%/year (1 vs 3, p=0.003; 2 vs 3, p=0.31; 1 vs 2, p=0.052)
- Dyspepsia: Group 1 - 11.8%, Group 2 - 11.3%, Group 3 - 5.8% ( 1 and 2 vs 3, p<0.001)
- Drug discontinuation: Group 1 - 20.7%, Group 2 - 21.2%, Group 3 - 16.6% (1 and 2 vs 3, p<0.001)
- In the warfarin group, the INR was in the therapeutic range 64% of the time [2]
- Findings: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage
- Professional guidelines:
- The AHA 2014 atrial fibrillation guidelines state that warfarin, dabigatran, rivaroxaban, and apixaban are all appropriate as first-line agents in the prevention of stroke in atrial fibrillation
- Dabigatran or Factor Xa inhibitors are recommended in patients who have trouble maintaining a therapeutic INR
- Dabigatran and rivaroxaban are not recommended in patients with end-stage kidney disease [12]
- StraightHealthcare analysis:
- Dabigatran is an effective alternative to warfarin in preventing stroke in atrial fibrillation
- In the right patients, it may confer a small, but significant benefit over warfarin
- Dabigatran is much more expensive than warfarin, but it does not require continuous monitoring and therapy adjustments that are common with warfarin
Treatment of VTE
- Venous thromboembolism (VTE) includes deep vein thrombosis and pulmonary embolism
- Dabigatran is approved for the treatment of VTE after 5 - 10 days of initial parenteral anticoagulation
- Dabigatran was compared to warfarin for the treatment of VTE in the RE-COVER study detailed below
- The RE-COVER study enrolled 2539 patients with acute venous thromboembolism (DVT or PE)
- Main inclusion criteria: acute, symptomatic, objectively verified proximal DVT or PE
- Main exclusion criteria: duration of symptoms > 14 days; hemodynamic instability; high risk for bleeding; CrCl < 30 ml/min
- Baseline characteristics: average age 55 years; qualifying event, DVT - 69%, PE - 21%, both - 9.6%; previous VTE - 26%; active cancer - 4.7%
- Patients were randomized to 1 of 2 groups:
- Group 1 (1274 patients) - Dabigatran 150 mg twice a day for 6 months
- Group 2 (1265 patients) - Warfarin (target INR 2.0 - 3.0) for 6 months
- All patients were given parenteral anticoagulation for at least 5 days
- Warfarin was started at randomization and parenteral anticoagulation was continued until the INR was at least 2.0
- Dabigatran was started when parenteral anticoagulation was stopped. The first dose was given within 2 hours of the time that the next dose of parenteral therapy would have been due.
- Parenteral anticoagulation was given for an average of 10 days in both groups
- PRIMARY OUTCOME: Composite of symptomatic venous thromboembolism or death associated with venous thromboembolism in the
6 months after random assignment
- After 6 months, the following was seen:
- Primary outcome: Group 1 - 2.4%, Group 2 - 2.1% (HR 1.10, 95%CI [0.65 - 1.84])
- Symptomatic DVT: Group 1 - 1.3%, Group 2 - 1.4% (HR 0.87, 95%CI [0.44 - 1.71])
- Symptomatic nonfatal PE: Group 1 - 1.0%, Group 2 - 0.6% (HR 1.85, 95%CI [0.74 - 4.64])
- Overall mortality: Group 1 - 1.6%, Group 2 - 1.7% (HR 0.98, 95%CI [0.53 - 1.79])
- Major bleeding: Group 1 - 1.6%, Group 2 - 1.9% (HR 0.82, 95%CI [0.45 - 1.48])
- Major or clinically relevant nonmajor bleeding: Group 1 - 5.6%, Group 2 - 8.8% (HR 0.63, 95%CI [0.47 - 0.84])
- Early drug discontinuation: Group 1 - 16%, Group 2 - 14.5%
- In subgroup analysis, there was no significant difference between treatments in patients who presented with a DVT or a PE
- In Group 2, the INR was in the therapeutic range 60% of the time [7]
- Findings: For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring
- Professional guidelines:
- The ACCP 2016 VTE guidelines recommend dabigatran, rivaroxaban, apixaban, or edoxaban as first-line therapies for the treatment of VTE in patients without cancer. If these therapies are not used, then warfarin is recommended. [13]
- StraightHealthcare analysis:
- In 2014, the FDA approved dabigatran for the treatment of venous thromboembolism in patients have been treated with a parenteral anticoagulant for 5 - 10 days
- It was also approved for the long-term prevention of recurrent thromboembolism in patients who have been previously treated
Prevention of recurrent VTE
- Dabigatran is approved for the prevention of recurrent DVT and PE in patients who have experienced a previous episode
- Dabigatran was compared to warfarin for the extended treatment of VTE in the RE-MEDY study detailed below
- The RE-MEDY study enrolled 2856 patients who had been treated for 3 - 12 months with anticoagulation for a VTE
- Main inclusion criteria: symptomatic, objectively confirmed DVT or PE that had been treated for 3 - 12 months with approved anticoagulation; increased risk for recurrent VTE based on site investigator's assessment
- Main exclusion criteria: interruption of anticoagulant therapy for ≥ 2 weeks during initial 3 - 6 months; high risk for bleeding; CrCl < 30 ml/min; significant liver disease
- Baseline characteristics: average age 55 years; qualifying event, DVT - 65%, PE - 23%, both - 12%; active cancer - 4%; known thrombophilia - 18%
- Patients were randomized to 1 of 2 groups:
- Group 1 (1430 patients) - Dabigatran 150 mg twice a day
- Group 2 (1426 patients) - Warfarin (target INR 2 - 3)
- Average treatment before study enrollment was 199 days
- PRIMARY OUTCOME: Composite of recurrent symptomatic and objectively verified venous thromboembolism or death associated with venous thromboembolism
- During follow-up in which patients received study drugs an average of 473 days, the following was seen:
- Primary outcome: Group 1 - 1.8%, Group 2 - 1.3% (HR 1.44, 95%CI [0.78 - 2.64])
- Symptomatic DVT: Group 1 - 1.2%, Group 2 - 0.9% (HR 1.32, 95%CI [0.64 - 2.71], p=0.46)
- Symptomatic nonfatal PE: Group 1 - 0.7%, Group 2 - 0.4% (HR 2.04, 95%CI [0.70 - 5.98], p=0.19)
- Overall mortality: Group 1 - 1.2%, Group 2 - 1.3% (HR 0.90, 95%CI [0.47 - 1.72], p=0.74)
- Major bleeding: Group 1 - 0.9%, Group 2 - 1.8% (HR 0.52, 95%CI [0.27 - 1.02], p=0.06)
- Major or clinically relevant bleeding: Group 1 - 5.6%, Group 2 - 10.2% (HR 0.54, 95%CI [0.41 - 0.71], p<0.001)
- Acute coronary syndrome: Group 1 - 0.9%, Group 2 - 0.2% (p=0.02) [11]
- Findings: Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo
- StraightHealthcare analysis:
- The RE-MEDY study showed that dabigatran was comparable to warfarin for VTE prevention
- Because of a lower than expected event rate, the study follow-up was extended for patients who consented to the extension. This could have potentially introduced bias into the study by selecting for positive responders.
VTE prophylaxis after surgery
- One large study has looked at the use of dabigatran for prophylaxis against VTE after hip surgery
- The RE-NOVATE study enrolled 3494 patients undergoing total hip replacement
- Main inclusion criteria: scheduled to undergo unilateral total hip replacement
- Main exclusion criteria: bleeding disorder; history of acute intracranial disease or hemorrhagic stroke; GI bleed or ulcer disease within 6 months; use of long-acting NSAIDs; significant liver disease; CrCl < 30 ml/min
- Baseline characteristics: average age 64 years; history of VTE - 3%; average duration of surgery - 86 minutes; median duration of hospital stay - 9 days
- Patients were randomized to 1 of 3 groups:
- Group 1 (1146 patients) - Dabigatran 220 mg once daily for 28 - 35 days
- Group 2 (1163 patients) - Dabigatran 150 mg once daily for 28 - 35 days
- Group 3 (1154 patients) - Enoxaparin 40 mg subq daily for 28 - 35 days
- Enoxaparin was started the evening before surgery
- Dabigatran was started 1 - 4 hours after surgery. First dose was halved.
- Compression stockings were permitted, but intermittent pneumatic compression devices were not.
- PRIMARY OUTCOME: Composite of symptomatic thromboembolism (DVT and PE), thromboembolism detected on venography performed within 24 hours of last dose, and death from any cause
- After a median treatment of 33 days, the following was seen:
- Primary outcome: Group 1 - 6%; Group 2 - 8.6%, Group 3 - 6.7% (1 vs 3, p>0.05, 2 vs 3, p>0.05)
- Asymptomatic DVT: Group 1 - 4.6%; Group 2 - 7.2%, Group 3 - 6.3%
- Symptomatic PE: Group 1 - 0.4%; Group 2 - 0.1%, Group 3 - 0.3%
- Overall mortality: Group 1 - 0.3%; Group 2 - 0.3%, Group 3 - 0%
- Major bleeding: Group 1 - 2%, Group 2 - 1.3%, Group 3 - 1.6% (1 vs 3, p=0.44, 2 vs 3, p=0.60)
- Dabigatran was started an average of 3.4 hours after surgery and continued for a median of 33 days after surgery
- About 24% of randomized patients were not included in the final efficacy analysis, primarily because they did not undergo proper venography at study end [10]
- Findings: Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile
- Professional guidelines:
- The ACCP guidelines from 2012 state that low molecular weight heparins (e.g. enoxaparin) are the preferred agents for thromboembolism prophylaxis after major orthopedic surgeries
- Dabigatran, apixaban, and rivaroxaban are acceptable alternatives for patients unwilling to inject themselves daily with low molecular weight heparins, but they lack long-term safety data [9]
- StraightHealthcare analysis:
- In the RE-NOVATE study, dabigatran was as effective as enoxaparin for preventing VTE after hip surgery
- Joint replacements are common in older patients so it is important to assess kidney function before using dabigatran
- EXPLORATORY STUDIES
A fib ablation
- Atrial fibrillation is often treated with catheter ablation
- Patients must be anticoagulated before, during, and after ablation to prevent cardiovascular events. Warfarin has traditionally been the anticoagulant of choice.
- The study detailed below compared dabigatran to warfarin in patients undergoing catheter ablation for A fib
- Design: Randomized, controlled trial (N=704, length - 8 weeks) in patients with paroxysmal or persistent A fib undergoing ablation
- Baseline characteristics: Average age - 59 years | Mean CHA₂DS₂-VASc score - 2.1 | CHF - 10.2% | CAD - 12.5% | Paroxysmal A fib - 68%, Persistent A fib - 32%
- Treatment:
- Group 1 (317 patients): Dabigatran 150 mg twice daily
- Group 2 (318 patients): Warfarin target INR 2 - 3
- The trial had a 4 - 8 week pre-ablation phase where patients were stabilized on their anticoagulants
- Primary outcome: Incidence of adjudicated major bleeding events during and up to 8 weeks after ablation
- Results:
- Primary outcome: Group 1 - 1.6%, Group 2 - 6.9% (Diff 5.3%, 95%CI [8.4 - 2.2] p<0.001)
- Dabigatran was associated with fewer periprocedural pericardial tamponades (1 vs 6) and groin hematomas (0 vs 8) than warfarin
- One thromboembolic event occurred in the warfarin group
- Findings: In patients undergoing ablation for atrial fibrillation, anticoagulation with uninterrupted dabigatran was associated with fewer bleeding complications than uninterrupted warfarin
- StraightHealthcare analysis:
- Dabigatran conferred a lower risk of serious bleeding when compared to warfarin in patients undergoing catheter ablation for A fib. A prior, smaller study also found rivaroxaban to be comparable to warfarin in the same scenario [PMID 25975659].
- Dabigatran is a safer anticoagulant than warfarin for patients undergoing catheter ablation in A fib
PCI in patients with A fib
- In some cases, indications may arise in the same patient for dual antiplatelet therapy (P2Y12 inhibitors + aspirin) and anticoagulation (dabigatran, factor Xa inhibitors, etc.)
- A common scenario would be PCI with heart stent placement in someone with atrial fibrillation. The stent placement is an indication for dual antiplatelet therapy, and the atrial fibrillation is an indication for anticoagulation. Taking all three medications together greatly increases a person's risk of bleeding, and there are few studies to help guide treatment decisions in these scenarios. See triple therapy for more.
- In 2017, a study was published that compared two different doses of dabigatran + a P2Y12 inhibitor to triple therapy with warfarin, aspirin, and a P2Y12 inhibitor. The study is detailed below.
- ]
- The RE-DUAL study enrolled 2725 patients with atrial fibrillation who had undergone PCI
- Main inclusion criteria: nonvalvular atrial fibrillation; successful PCI with a BMS or DES within the previous 120 hours
- Main exclusion criteria: bioprosthetic or mechanical heart valve; CrCl < 30 ml/min; bleeding disorder; major bleeding episode within a month
- Baseline characteristics: average age 71 years; PCI indication, ACS - 51%, stable CAD - 43%; average CHA₂DS₂-VASc score ∼ 3.6; stent type, DES - 83%, BMS - 15%; average CrCl ∼ 78 ml/min; previous stroke ∼ 8.6%; previous myocardial infarction ∼ 26%
- Patients were randomized to one of three groups:
- Group 1 (981 patients): Dabigatran 110 mg twice daily + P2Y12 inhibitor (clopidogrel or ticagrelor)
- Group 2 (763 patients): Dabigatran 150 mg twice daily + P2Y12 inhibitor (clopidogrel or ticagrelor)
- Group 3 (981 patients): Warfarin + Aspirin (≤ 100 mg/day) + P2Y12 inhibitor (clopidogrel or ticagrelor)
- Aspirin was discontinued after 1 month in patients who received a BMS and after 3 months in patients with DES
- All patients were to receive the P2Y12 inhibitor for at least 12 months
- 88% of patients received clopidogrel
- The trial continued until all the patients had a minimum of 6 months of follow-up and the target number of end-point events was anticipated to be reached
- Outside of the United States, elderly patients were not randomized to Group 2 because the higher dabigatran dose was not approved in that age group. For the primary outcome, Group 2 was compared to a subgroup of Group 3 patients which did not include elderly patients outside the United States.
- PRIMARY OUTCOME: First major or clinically relevant nonmajor bleeding event, as defined by the International Society on Thrombosis and Hemostasis (ISTH), in a time-to-event analysis
- After an average follow-up of 14 months, the following was seen:
- Primary outcome (Group 1 vs Group 3): Group 1 - 15.4%, Group 3 - 26.9% (HR 0.52, 95%CI [0.42 – 0.63], p<0.001)
- Primary outcome (Group 2 vs Group 3): Group 2 - 20.2%, Group 3 - 25.7% (HR 0.72, 95%CI [0.58 – 0.88], p=0.002)
- Composite of thromboembolic events, death, or unplanned revascularization (Group 1 vs Group 3): Group 1 - 15.2%, Group 3 - 13.4% (HR 1.13, 95%CI [0.90 – 1.43], p=0.30)
- Composite of thromboembolic events, death, or unplanned revascularization (Group 2 vs Group 3): Group 2 - 11.8%, Group 3 - 12.8% (HR 0.89, 95%CI [0.67 – 1.19], p=0.44)
- Overall mortality (Group 1 vs Group 3): Group 1 - 5.6%, Group 3 - 4.9% (HR 1.12, 95%CI [0.76 – 1.65], p=0.56)
- Overall mortality (Group 2 vs Group 3): Group 2 - 3.9%, Group 3 - 4.6% (HR 0.83, 95%CI [0.51 – 1.34], p=0.44)
- In Group 3, patients had a therapeutic INR (2 - 3) 64% of the time
- The average duration of treatment with trial anticoagulant was 12.3 months
- Findings: Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events.
- StraightHealthcare analysis:
- The RE-DUAL PCI study found that dabigatran/P2Y12 inhibitor therapy was superior to triple therapy for bleeding events and noninferior for a composite of thromboembolic events, death, or unplanned revascularization
- The study was underpowered to determine a mortality benefit, and there was no obvious trend in the data
- See triple therapy for more
- SIDE EFFECTS
- Bleeding
- The therapeutic effect of dabigatran is to inhibit clot formation, therefore it will inherently increase the risk of unwanted bleeding
- In the RE-LY study, the risk of major bleeding was not significantly different from warfarin for the 150 mg dose (Warfarin - 3.36%/yr, dabigatran - 3.11%/yr)
- One of the concerns with bleeding from dabigatran is the ability to reverse its effect in emergency situations (see reversing dabigatran below)
- StraightHealthcare analysis:
- Post-marketing reports of bleeding from dabigatran received much press after its release
- These reports were logged in the FDA's Adverse Event Reporting System (AERS). The AERS is helpful for identifying trends but has no statistical value.
- The RE-LY study was a very large, randomized trial and it found no increased risk of bleeding from dabigatran when compared to warfarin
- After a review of dabigatran, the FDA issued a statement in November 2012 (FDA statement on dabigatran) in which they said they found no increased risk of bleeding when compared to warfarin. The review did discuss proper dosing in patients with decreased kidney function.
- The ability to reverse the effect of dabigatran in emergency situations is an ongoing concern and discussed below (reversing dabigatran below)
- Upset stomach (dyspepsia)
- In the RE-LY study, patients on dabigatran had significantly more complaints of upset stomach (dyspepsia) than patients on warfarin
| Side Effect | Dabigatran (% of patients) |
Warfarin (% of patients) |
|---|---|---|
| Upset stomach | 11 - 12% | 5.8% |
- COAGULATION STUDIES
- Dilute thrombin time (dTT)
- The dTT is a clotting assay that correlates closely with dabigatran levels. It is one of the preferred tests for measuring dabigatran activity.
- Unfortunately, the dTT is not widely available.
- Ecarin clotting time (ECT) and ecarin chromogenic assay (ECA)
- The ECT and ECA are clotting assays that correlate closely with dabigatran levels. They are preferred tests for measuring dabigatran activity.
- These tests may not be widely available, especially in emergency situations. [4,5,16]
- Thrombin time (TT)
- Dabigatran prolongs the thrombin time, but the effect is nonlinear
- A normal TT typically excludes clinically relevant dabigatran levels, but a prolonged TT does not discriminate between clinically important and insignificant levels [16]
- Partial thromboplastin time (aPTT)
- Dabigatran prolongs the aPTT, but the effect is nonlinear
- A normal aPTT typically excludes clinically relevant dabigatran levels if a sensitive reagent is used
- A prolonged aPTT does not discriminate between clinically important and insignificant levels [16]
- Prothrombin time (PT) and INR
- Dabigatran may prolong the PT and INR
- The effect is linear, but small
- The PT/INR is not a sensitive measure of the effect of dabigatran [4,5]
- CONTRAINDICATIONS
- Active pathological bleeding
- History of a serious hypersensitivity reaction
- Mechanical prosthetic heart valve
- Kidney disease with certain medications - See kidney disease below
- PRECAUTIONS
- Kidney disease
- Atrial fibrillation
- Mild-moderate kidney disease (CrCl > 30 ml/min): No dose adjustment necessary
- Severe kidney disease (CrCl 15 - 30 ml/min): 75 mg twice a day
- End-stage kidney disease (CrCl < 15 ml/min): No recommendation can be made
- For patients with CrCl 30 - 50 ml/min who are also taking dronedarone or ketoconazole, consider a dose of 75 mg twice daily
- For patients with CrCl < 30 ml/min who are also taking a P-gp inhibitor, avoid co-administration
- See drug interactions below
- Treatment and prevention of DVT and PE
- CrCl > 30 ml/min: 150 mg twice daily
- CrCl ≤ 30 ml/min: dosing recommendations cannot be provided
- For patients with CrCl < 50 ml/min who are also taking a P-gp inhibitor, avoid co-administration
- Liver disease
- Dabigatran is not metabolized by the Cytochrome P450 system
- The manufacturer makes no specific dosage recommendations in liver disease
- NOTE: Patients with severe liver disease often have blood clotting disorders (see coagulopathy of liver disease). Use with caution in these patients [5]
- Prosthetic heart valve
- Dabigatran should not be used in patients with mechanical prosthetic heart valves
- The RE-ALIGN study compared dabigatran to warfarin in patients with mechanical heart valves. The study was stopped after 252 patients were enrolled because the dabigatran group had a significantly higher incidence of stroke and major bleeding. [PubMed abstract]
- Body weight
- A case report in the NEJM found that body weight may affect blood levels of dabigatran (see PubMed abstract for more)
- In the case report, the authors note that in the RE-LY study, trough levels of dabigatran in patients who weighed more than 220 pounds were 20% lower than trough levels in patients who weighed 110 - 220 pounds
- The package insert for dabigatran does not discuss the possible effects of body weight on dabigatran
- Physicians should be aware that dabigatran efficacy may be decreased in obese patients. Further studies of the effects of body weight on dabigatran pharmacokinetics are needed.
- REVERSING DABIGATRAN
- Idarucizumab
- In emergency situations, the effects of dabigatran may need to be reversed immediately
- An antibody fragment specific for dabigatran called idarucizumab has been developed. Idarucizumab binds dabigatran and inactivates it.
- In 2015, a study published in the NEJM found that idarucizumab completely reversed the anticoagulant effects of dabigatran within minutes in 88 - 98% of patients [PMID 26095746]. A phase 1 study published in the Lancet also found idarucizumab to be effect in reversing dabigatran [PMID 26088268]. A cohort study published in 2017 found idarucizumab to be effective in clinical practice [PMID 28693366].
- In 2015, the FDA approved idarucizumab (Praxbind®) for emergency reversal of dabigatran
- As far as using blood products to reverse dabigatran, prothrombin complex concentrate has been studied in one trial, and it had no effect [PMID 21900088]
- Professional guidelines:
- In 2017, the ACC issued recommendations for managing bleeding in patients taking oral anticoagulants. Those guidelines are available at the link below.
- STOPPING BEFORE PROCEDURES
- Professional guidelines
- Professional guidelines for stopping dabigatran before procedures are available at the link below
- Manufacturer recommendations
- CrCl ≥ 50 ml/min - discontinue 1 - 2 days before invasive or surgical procedures
- CrCl < 50 ml/min - discontinue 3 - 5 days before invasive or surgical procedures
- Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- HIGH ALERT INTERACTIONS
- P-glycoprotein (P-gp) inducers/inhibitors - dabigatran is a sensitive P-glycoprotein substrate. Recommendations for concomitant use of P-glycoprotein inhibitors/inducers with dabigatran depend on the indication, the patient's kidney function, and the specific drug. The recommendations below should not be used for other P-gp inhibitors.
- Atrial fibrillation
- P-gp inducers: DO NOT COMBINE
- P-gp inhibitors and CrCl < 30 ml/min: DO NOT COMBINE
- P-gp inhibitors dronedarone or systemic ketoconazole and CrCl 30 - 50 ml/min: reduce dose of dabigatran to 75 mg twice daily
- P-gp inhibitors verapamil, amiodarone, quinidine, clarithromycin, and ticagrelor and CrCl 30 - 50 ml/min: no dose adjustment necessary
- Treatment and prevention of recurrent VTE
- P-gp inducers: DO NOT COMBINE
- P-gp inhibitors and CrCl < 50 ml/min: DO NOT COMBINE
- VTE prophylaxis after hip surgery
- P-gp inducers: DO NOT COMBINE
- P-gp inhibitors and CrCl < 50 ml/min: DO NOT COMBINE
- P-gp inhibitors dronedarone or systemic ketoconazole and CrCl ≥ 50 ml/min: give dabigatran several hours before or after P-gp inhibitor
- Drugs that increase the risk of bleeding
- Drugs that inhibit coagulation may increase the risk of bleeding when taken with direct thrombin inhibitors
- In some conditions, it may be appropriate to take direct thrombin inhibitors with these drugs
- Drugs that may increase the risk of bleeding include:
- Warfarin (Coumadin®)
- Aspirin
- Factor Xa inhibitors (rivaroxaban, Xarelto®, apixaban, Eliquis®)
- P2Y12 inhibitors (clopidogrel, Plavix®, ticagrelor, prasugrel)
- NSAIDs (ibuprofen, naproxen, Aleve®, Celebrex®, Motrin®, etc.)
- SSRIs and SNRIs (Prozac®, Cymbalta®, Paxil®, Effexor®, Zoloft®, etc.)
- Vorapaxar (Zontivity®)
- METABOLISM AND ELIMINATION
- NOTE: Drugs can be metabolized by more than one enzyme. Drugs may be metabolized by an enzyme and inhibit/induce the enzyme at the same time. Drug transporters (ex. p-glycoprotein) can play a role in drug metabolism. Not all drug interactions are clinically significant. Consult your physician or pharmacist if you are taking medications together and are concerned about a possible interaction.
- Dabigatran (Pradaxa®)
- P-glycoprotein - substrate
- Dabigatran undergoes glucuronidation
- Dabigatran does not undergo Cytochrome P450 metabolism
- LONG TERM SAFETY
- Dabigatran was approved for use in the U.S. in October 2010
- To date, no unusual long-term effects have been noted
- The overall long term safety of the drug is not well-defined
- SPECIAL STORAGE INSTRUCTIONS
- Dabigatran is sensitive to moisture which can cause breakdown of the active ingredient
- The FDA issued a warning that dabigatran should only be dispensed and stored in its original bottle (FDA dabigatran storage statement)
- Pharmacies should dispense dabigatran in its original bottle and not repackage it in amber bottles
- Patients should leave dabigatran in the original bottle and not place it in pill boxes, etc.
- The FDA statement says that the capsules are good for 30, possibly 60 days, once the bottle is opened. The manufacturer package insert states that capsules are good for 4 months once the bottle is opened.
- DOSING
- Direct thrombin inhibitor dosing chart
- See drug interactions and kidney disease for other dosing recommendations
- GENERIC AVAILABILITY
- Generic:
- None
- Possible generic:
- NOTE: Drug companies typically file multiple patents on their drugs in order to protect them from competition. The patent expiration listed here is the date that the earliest patent on the drug expires (accounting for pediatric exclusivity). Because drug companies use numerous techniques to extend the life of their patents, it does not necessarily mean a generic will become available around this date.
| DRUG | PATENT EXPIRES |
|---|---|
| Dabigatran (Pradaxa®) | FEB 2018 |
- BIBLIOGRAPHY
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
1 - 16908781
2 - 19717844 - RE-LY study
3 - 22858728 - AHA statement on Afib
4 - 17506785 - Clotting study
5 - Dabigatran PI
6 - 21900088
7 - 19966341 - RE-COVER study
8 - 21422387 - AHA GL on VTE
9 - 22315278 - ACCP GL on VTE
10 - 17869635 - RE-NOVATE study
11 - 23425163 - RE-MEDY AND RE-SONATE
12 - 24682348 - AHA 2014 A fib GL
13 - 26867832 - ACCP 2016 VTE update
14 - 23625942 - European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation
15 - 23147769 - Periprocedural Management and Approach to Bleeding in Patients Taking Dabigatran
16 - 29203195 - 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants