Dabigatran

Conversion to its active form results in complete thrombin inhibition.

Trade name Pradaxa.

Dabigatran etexilate is a pro-drug orally administered, with rapid absorption.

Conversion to active metabolite carried out by serum esterase that is independent of cytochrome P-450 making this agent less susceptible to dietary and drug interactions and to genetic polymorphisms that affect warfarin.

Converted to active compound by nonspecific esterases in the plasma and liver.

Is an inactive prodrug absorbed in the stomach and proximal small bowel, and then metabolized to the active agent by serum and hatic esterases.

Becomes active via hydrolysis.

Requires no monitoring or dose modifications.

Half-life 12 to 17 hours and in the elderly 14 to 17 hours.

Metabolism is by hepatic mechanisms.

Renal elimination 80%, and time to peak levels is at one hour.

Eliminated predominately the in the kidneys.

Selectively targets thrombin in a dose dependent and reversible manner.

Absorption of dabigatran is delayed by approximately 2 hours if taken with a fatty meal.

The active compound competitively and reversibly binds to the active site of free and clot- bound thrombin, blocking its procoagulant activity.

Also inhibits thrombin induced platelet aggregation.

Mainly eliminated by renal excretion, 85%.

Area under the curve of dabigatran is, respectively 2.7 fold or six fold higher in patients with moderate creatinine clearance of less than50 mL/per minute or severe renal insufficiency with creatinine clearance of less than 30 mL per minute, with a two times longer half-life compared with patients with normal renal function.

AUC is increased by 40 to 60% in elderly patients.

Approved for the use in the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and for the primary prevention of venous thromboembolic events in adult patients following elective total hip or knee arthroplasty.

Increased bleeding associated with advanced stage, renal impairment, low body weight, recurrence of left ventricular thrombus formation, and skin exanthema.

Risk factors for bleeding include medications that increase the risk of bleeding such as anti-platelet agents, heparin, fibrinolytic therapy, and chronic use of NSAIDs.

Reversal agent for dabigatran is not available.

Dabigatran can be dialyzed.

Discontinuance for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of stroke.

Lapses in therapy should be minimized.

The concomitant use with P-gp inducers reduces exposure to dabigatran and should generally be avoided.

P-gp inhibition and impaired renal function are major independent factors in increased exposure to drug.

Concomitant use of P-gp inhibitors in patients with renal impairment is expected to increase exposure of dabigatran compared to either factor alone.

Medications with antiplatelet and antithrombotic effects can potentiate dabigatran anticoagulation.

In the pivotal trial comparing It to warfarin, the most frequent adverse reactions leading to discontinuation of the drug were bleeding and gastrointestinal (GI) events.

Dosage of 150 mg resulted in a higher rate of major GI bleeds and any GI bleeds compared to warfarin.

Patients on 150 mg had an increased incidence of GI adverse reactions:dyspepsia, abdominal and gastritis.

A higher rate of clinical myocardial infarction was reported in patients who received PRADAXA (0.7 per 100 patient-years for 150 mg dose) than in those who received warfarin (0.6).

Not affected by the P450 system.

AUC is increased by approximately 60% when co-administered with amiodarone, a strong inhibitor of p-glycoprotein of which dagbatran is a substrate.

Age and gender do not affect pharmacodynamics or pharmacokinetics.

A potent oral direct inhibitor administered in fixed dose, is excreted by the kidney and has a half-life of 12 to 17 hours.

Acts as a substrate of P-glycoprotein and therefore potent P-gp inhibitors or inducers can affect its bioavailability.

Requires twice daily dosing in contrast to warfarin.

Lacks an antidote.

Dyspepsia is a significant side effect.

As similar efficacy and safety compared to enoxaparin in the prevention of venous thromboembolism in patients with elective hip or knee arthroplasty.

In the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study 18,113 patients with atrial fibrillation at risk for stroke received two doses of this drug twice daily at 110mg and 150 mg compared to warfarin: the rate of primary outcome stroke or systemic embolism was signficantly lower with 150 mg dabigatran dose than the 110 mg dose of dabigatran or warfarin.

In the RE-LY study to prevent one hemorrhagic stroke, the number of patients that need to be treated with this agent at a dose of 150 mg twice a day, rather than warfarin is 357.

In atrial fibrillation patients with a history of stroke/TIA who are vitamin K antagonist naïve, dabigatran provides similar protection to warfarin against the current stroke/TIA.

Warfarin experienced patients with AF and a history of stroke or transient ischemic attack who are switched to dabgatran therapy may have an increased rate of recurrent stroke compared to patients persisting with vitamin K antagonist treatment: caution required when switching prior warfarin experienced atrial fibrillation patients to dabigatran.

VA study in patients with atrial fibrillation switched from warfarin to dabigatran

there was an increased likelihood of gastrointestinal bleeding (Vaughan Sarrazin MS et al).

Hemorrhagic stroke with dabigatran at the 110 or 150 mg doses was significantly lower than that with warfarin, and the number of individuals that would have to be treated with this drug rather than warfarin to prevent one hemorrhagic stroke is approximately 370.

In randomized trials, patients with atrial fibrillation (AF) receiving dabigatran, a direct oral anticoagulant, had lower risk of intracranial bleeding (ICB) than those on warfarin.

In-hospital mortality in AF patients with ICB being treated with dabigatran versus warfarin in a real-world population in the United States showed no difference, so lack of a reversal medication is not a concern in this setting.

RE-LY study dabigatran treated subgroup of patients older than 75 years patients in the lowest dose group 110 mg BID did not benefit as they have an increased risk of major bleeding.

Rate of external hemorrhage in the RE-LY study was similar in the 110mg, 150 mg, and the warfarin groups (2.51-2.84%).

In the RE-LY trial both doses of dabigatran associated with a non significant increased risk of myocardial infarction compared with warfarin.

May provide less protection against myocardial infarction then warfarin in patients with atrial fibrillation,

In a randomized, double-blind, noninferiority trial of patients with acute venous thromboembolism initially treated with parenteral anti-coagulation therapy for a median of nine days and then randomized to oral dabigatran at 150 mg TID compared with warfarin at a dose adjusted INR of 2.0-3.0: a fixed dose of dabigatran was as effective as warfarin, had of safety profile similar to that of warfarin, and does not require laboratory monitoring(RE-COVER study group).

RE-NOVATE trial enrolled 3494 patients undergoing hip arthroplasty: 220 mg and 150 mg doses of this agent was compared to enoxaparin No statistically significant differences between dabigatran and enoxaparin for venous thromboembolism or all cause mortality, and rates of bleeding were similar as were clinical relevant non-major bleeding events.

In a pooled analysis of the total knee replacement (RE-MODEL and RBe-MOBILIZE) trials and total hip replacement (RE-NOVATE) trial including a total of 8210 patients showed no statistical differences between dabigatran and enoxaparin for total VTE and all-cause mortality, pulmonary embolism, and no differences were found in safety outcomes including relevant bleeding and major bleeding.

RE-COVER study, a double-blind trial, randomizing 2539 patients with acute, symptomatic, proximal lower extremity DVT or pulmonary embolism to receive either oral dabigatran 150 mg B. I D., or dose adjusted warfarin to achieve INR of 2-3 for six months:Dabigatran was non inferior to warfarin and preventing recurrent VTE (2.4% versus 2.1%), And major bleeding was comparable (1.6% versus 1.9%).

In the RE-COVER trial the use of dabigatran as monotherapy for acute symptomatic DVT was not substantiated since the drug was started only after initial parenteral anticoagulants and had been administered for a median of nine days( Schulman S et al).

Meta-analysis of 3 studies RE-Model, RE-Mobilize and Re-Novate concluded noninferiority of this agent compared to enoxaparin as thromboembolism prophylaxis in orthopedic surgery setting.

In the RE-LY Phase 3 study (Prevention of Embolic and Thrombotic Events in Patients with Persistent Atrial Fibrillation) which included 18,113 patients with atrial fibrillation and risk factors for stroke: the patients were randomized to receive dabigatran 110 mg or 150 mg BID, or warfarin: the primary outcome of stroke and systemic embolism was 1.69% per year for the warfarin group, 1.53% per year in the 110 mg dabigatran group and 1.11% in the 150 mg dabigatran group.

RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial followed more than 18,000 patients with AF and compared safety and efficacy of dabigatran with that of warfarin in preventing stroke and systemic embolism for a median observation time of two years: reported a decrease in stroke and systemic embolism of 34% in the group receiving dabigatran, hundred and 50 mg BID compared with adjusted dose warfarin but reported relative increase in myocardial infarction of 38%.

In the RE-LY Phase 3 study (Prevention of Embolic and Thrombotic Events in Patients with Persistent Atrial Fibrillation) the rate of major bleeding was 3.3% in the warfarin group compared to 2.71% in the 110 mg dabigatran group and 3.11% in the 150 mg dabigatran group, And the rates of life-threatening bleeding events, intracranial bleeding events, and major or minor bleeding events or higher in the warfarin group compared to the other groups.

The RE-DEEM (Randomized Dabigatran Etexilate Dose Finding Study In Patients With Acute Coronary Syndromes Post Index Event With Additional At Risk Factors For Cardiovascular Complications Also Receiving Aspirin And Clopidogrel) trial, a phase II randomized, double-blind, placebo-controlled, dose escalation study to evaluate the safety of four doses of dabigatran: 1878 subjects and with major and clinically relevant minor bleeding events seen in 2.4% of patients in the placebo group compared to 3.5%, 4.3%, 7.9%, and 7.8% in the 50, 75, 110, and 150 mg twice daily groups, respectively, and rates of cardiovascular death, nonfatal M,I or stroke were 3.8% in the placebo group, compared 4.6%, 4.9%, 3%, and 3.5% in the 50, 75, 110, and 150 mg twice daily groups, respectively.

Slight increase in myocardial infarction and acute coronary syndrome rates compared to warfarin.

Meta-analysis suggest increase in acute coronary events, and a 27-33% higher relative risk of myocardial infarction.

In a veterans affairs study of 85,344 patients with atrial fibrillation switched from warfarin to dabigatran resulted in a 54% high risk of gastrointestinal bleeding (Vaughan Sarrazin MS et al)

Seven trials, including studies of stroke prophylaxis in AF, acute venous thromboembolism, acute coronary syndrome, and in short-term prophylaxis of deep vein thrombosis revealed increased risk of MI or acute coronary syndrome when tested against different controls (Uchino K, Hernandez AV).

Should be discontinued one to 2 days in patients with a creatinine clearance of greater than 50 mL per minute, or 3-5 days in patients with a creatinine clearance of less than 50 cc a minute before invasive surgical procedures.

Longer periods of time for discontinuation of therapy should be considered for patients undergoing major surgical procedures, spinal puncture, placement of spinal or epidural catheters, ports or in patients who need complete hemostasis.

Dabigatran (Pradaxa) has an elimination half life of 14-10 hours with normal or mildly impaired renal function.

Premature discontinuation may lead to stroke.

In patients undergoing a surgical procedure with a high risk of bleeding, the last dose of dabigatran should be given 3 days before surgery.

In patients with moderate renal impairment, dabigatran has a half-life of 16-18 hours in the last those should be given 5 days before surgery.

In an analysis of patients with bleeding events two thirds of patients were older than 80 years and nearly 60% ha moderate to severe renal impairment (Harper P et al).

Bleeding risk is best assessed by the ecarin clotting time, and this is a better marker of anticoagulant activity of this drug then the activated partial thromboplastin time, prothrombin time, or thrombin time.

If the ecarin clotting time is not available the a PTT provides an approximation anticoagulant activity.

Can be dialyzed with removal of about 60% of the drug over 2-3 hours.

In the presence of hemorrhage fresh frozen plasma, activated prothrombin complex concentrates recombinant factor VIIa, or concentrates offactors II, IX, or X are to be considered.

In a large Danish study of AF patients switching to dabigatran from warfarin increased the risk of myocardial infarction compared to continued warfarin usage in the early period after switching (Larsen TB et al).

Dosage​ reduction in Risk of Stroke and Systemic Embolism in Non-valvular AF​

CrCl >30 mL/min: ​150 mg twice daily

​CrCl 15 to 30 mL/min: ​75 mg twice daily

CrCl <15 mL/min or on dialysis: Dosing recommendations cannot be provided

Idarucizumab,a humanized antibody fragment is a reversal agent.

Hemodialysis can also partially reverse the anticoagulant effect.

Higher incidence of G.I. bleeding than with warfarin (1.6 versus 1.1 per 100 patient-years).