• both dabigatran and its metabolites are competitive, direct thrombin inhibitors. 
• because thrombin enables the conversion of fibrinogen ino fibrin during the coagulation cascade, its inhibition prevents the development of a thrombus
• both free and clot bound thrombin and thrombin induced platelet aggregation are inhibited by dab and its metabolites.

At recommended therapeutic doses, which coagulation markers are prolonged?

• activated partial thromboplastin time (aPTT)
• ecarin clotting time ECT
• thrombin Time (TT)
• INR is relatively insensitive to dab and cannot be interpreted the same way as used for warfarin monitoring

• the aPTT test provides an approximation of the anticoagulant effect of PRad
• PI states that advice cannot be provided on the level of recovery of aPTT needed in any particular clinical setting.
• PI notes that the curves can be used to estimate the time to get to a particular level of recovery, even when the time since the last dose of prad is not known.

what is ECT?

• a more specific measure of the effect of dab than aPTT
• in re-ly the mdian (10th to 90th percentile) trough in patients receiving the 150mg dose was 63 (44 to 103) seconds

Pharmacokinetics

Absorption?

• bioavailability is 3 to 7 %.
• dabigatran etexilate is asubstrate of teh p-glycoprotein efflux transporter
• Maximum plasma concentration (cmax) occurs at 1 hour post administration in the fasted state
• coadministraition with high-fat meaal delays time to cmax by ~2 hours, but does not effect bioavailability.
• the oral bioavailability of dab etexilate increases by 75% when the pellets are taken without the capsule shell compared to the intact capsule formulation

PK

Distribution?

• dab etex is converted to dab after oral admin
• this cleavage is the predominant metabolic reaction 
• dabi is metabolized to 4 glucuronides, dab and the glucuronides have similar pharmacologic activity
• dab is not a substrate, inhibitor, or inducer of cytochrome p-450 (CYP450) enzymes

• half life is 12-17 hours
• eliminated primarily in the urine

• exposure to dab increased with the severity of renal function impairment.
• this was shown in an open parallel group single center study comparing healthy patients and renally impaired patients.
• similar findings were observed in the RELY trial

Dosing Considerations:

How is it taken?

• taken BID with or without food
• dose dependant on renal function
• CrCl > 30 ml/min: 150 mg orally twice daily
• severe renal impairment (CRCL 15 to 30 ml/min): 75 mg BID
• CrCL <15 ml/min or on dialysis: the package insert states that recommendations cannot be provided

Dosing Adjustments:

How often should renal function be assessed?

• renal function should be assessed prior to initiation of treatment with Pradaxa. While on treatment, renal function should be assessed periodically as clinically indicated (that is, more frequently in clinical situations that may be associated with a decline in renal function) and then adjusted accordingly.
• prad should be discontinued in patients who develop acute renal failure while on Pradaxa and alternative anticoagulant therapy should be considered.

Instructions for patients:

What if a dose of pradaxa is missed?

• patients should swallow the capsules whole; breaking, chewing, or emptying the contents of the capsule can result in increased exposure.
• if a dose of prad is not taken at the scheduled time, it should be taken as soon as possible on the same day. If it cannot be taken at least 6 hours before the next scheduled dose the missed dose should be skipped. The dose should not be doubled to make  up for a missed dose.

Converting to Warfarin?

• based on creatinine clearance.
• crcl ≥50 ml/min: start warf 3 days beefore discontinuing prad
• crcl 30 to 50 ml/min; start warf 2 days before discontinuing prad.
• crcl 15 to 30 ml/min: start warf 1 day before discontinuing prad
• crcl < 15 the PI states that no recommendations can be made.
• Prad can contribute to an elevated INR; the INR will better reflect the effect of warfarin after prad has been stopped for at least 2 days.

• patients currently receiving a parenteral anticoagulant should start prad 0 to 2 hours before the time that the next dose of the parenteral drug was to have been administered or at the time of discontinuation of a continuously administered parenteral drug (eg, intravenous unfractionated heparin).
• patients currently taking prad whould wait 12 hours (crcl ≥ 30 or 24 hours crcl <30 after the last dose of Prad before initiating treatment with a parenteral anticoagulant.

• Due to the increased risk of bleeding, if possible, prad whould be discontinued 1 to 2 days (CRCL ≥50 or 3 to 5 days crcl <50 before invasive or surgical procedures.
• Longer time should be considered for patients undergoing major surgery, spinal puncure or placement of a spinal or epidural catheter or port, in whom complete hemostasis may be required. 

• 75 mg capsules
• 150 mg capsules
• NOTE that once a bottle of capsules has been opened, the capsules must be used within 4 months. The bottle should be tightly closed and the product stored in the original package to protect from moisture

• active pathological bleeding
• history of serious hypersensitivity reaction to Pradaxa

Warnings and Precautions:

Risk of Bleeding?

• Pradaxa increases the risk of bleeding and can cause significant and sometimes fatal bleeding
• disc in patients with active pathological bleeding
• risk factors for bleeding include the use of other drugs that increase the risk of bleeding (anti-platelets, heparin fibrinolytic therapy, and chronic use of Nsaids.
• The anticoagulant activity and half-life of prad are increased in patients with renal impairment
• a specific reversal agent for dabigatran is not available; dab can be dialyzed; however, data supporting this approach are limited

1. risk of bleeding
2. temporary discontination
3. effect of P-glycoprotein (P-gp) inducers and inhibitors

• from rely 21% dab vs. 16% warf.
• usu bleeding and gi events (dyspepsia, nausea, upper abdominal pain, gi hemorrhage, and diarrhea.

• fatal
• symptomatic intracranial bleed
• reduction in hemoglobin of at least 5 g/dl
• transfusion of at least 4 units of blood
• associated with hypotension requiring the use of intravenous inotropic agents
• necessitating surgical intervention

• major bleeds met one or more of the following:
• bleeding associated with a reduction in hemoglobin of at least 2 g/dl or leading to a transfusion of at least 2 units of blood.
• symptomatic bleeding in a critical area or organ (intraocular, intracranial, intraspinal or intramuscular with compartment syndrome, retroperitoneal bleeding, intraarticular bleeding, or pericardial bleeding)

prad 150 = 6076 or 12,033 patient years

warf = 6022 or 11794 patient years

• risk of major bleeds was similar with the exception of age where there was a tendency towards a higher incidence of major bleeding on prad vs warf for patients ≥75 years of age
• there was a higher rate of major gi bleeds in patients receiving prad 150 mg than in patients receiving warf (1.6% vs. 1.1%) and a higher rate of any gi bleed (6.1% vs. 4.0%)

• patients on prad 150 mg had an increased incidence of GI adverse reactions 35% vs 24% on warf:
• dyspepsia, including abdominal pain upper abdominal pain, abdominal discomfort and epigastric discomfort
• gastritis like symptoms, including gastroesophageal reflux disease, esophagitis, erosive gastritis, gastric hemorrhage, hemorrhagic gastritis, hemorrhagic erosive gastritis, and gi ulcer

• pregnancy category C
• safety and effectiveness during labor and delviery have not been studied in clinical trials (consider risks)
• Nursing Mothers - it is not known if prad is excreted in human milk (exercise caution)
• Pediatric use - safety and effectiveness not been established
• geriatric use - in the re-ly trial, 82% of patients were 65 and older while 40% were 75 and older
• the risk fo stroke and bleeding increases with age, but the risk benefit profile is favorable in all age groups
• Renal Impairment you know the drill

• accidental overdose of pradaxa may lead to hemorrhagic complications. There is no reversal agent for dab. In the event of hemorrhagic complications:
• initiate appropriate clinical support
• discontinue treatment with prad
• investigate the source f bleeding
• dab can be dialyzed (protein binding is low, with removal of about 60% drug over 2-3 hours however, the amount of data supporting this approach is limited
• Measurement of aPTT or ECT may help guide therapy

• multicenter, multinational, randomized parallel group trial comparing 2 blinded doses of prad (150 BID and 110 BID) vs warf open label dosed to target INR of 2 to 3
• Patients had nonvalvular, persistent, paroxysmal, or permanent AF and one or more of the following additional risk factors:
• previous stroke, TIA or systemic embolism
• left ventricular ejection fraction <40%
• symptomatic heart failure, ≥ NY Heart association class 2
• age ≥ 75
• age ≥ 65 and one of the following: diabetes mellitus, CAD or hypertension

• determine if prad was noninferior to warf in reducing the occurrence of the composite endpoint: stroke (ischemic and hemorrhagic and systemic embolism.
• study designed to ensure that prad perserved more than 50% of the effect of warf as established by previous randomized, placebo controlled trials of warf in NVAF. Statistical superiority was also analyzed.

• 18113 patients for median 2 years
• age = 71.5
• mean chads = 2.1
• 64% male, 70% caucasian, 16% asian, 1%black
• 20% history of stroke or tia
• 50% were vitamin k antagonist naive, 32% never been exposed to vka
• 79% of patients had hypertension, 23% had DBT2, 28% CAD.
• 40% of patients were on asa and 6% on plvx
• for patients randomized to warfarin, the mean percentage of time in the therapeutic range was 64%

• Prad 150: N = 6076. event rate 134 (2.2%)
• Warfarin: n 6022. event rate 202 (3.4%)
• RR REDUCTION = 35% HR 0.65 P=.0001
• treatment effect was primarily a reduction in stroke. Prad 150 bid was superior in reducing ischemic and hemorrhagic strokes relative to warf
• results were generally consistent across subgroups
• a higher rate of MI was reported in patients who received prad than in those who received warfarin 0.7 vs 0.6.