Dabigatran

{{drugbox | | IUPAC_name = Ethyl 3-{[(2-{[(4-{N'-[(hexyloxy)carbonyl] carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H- benzimidazol-5-yl)carbonyl] (2-pyridinyl)amino}propanoate | image = Dabigatran etexilate.png | width = 135px | CAS_number = 211915-06-9 | CAS_supplemental = 211914-51-1 | ATC_prefix = | ATC_suffix = | ATC_supplemental= | PubChem = 6445226 | DrugBank = | chemical_formula = | C=34 | H=41 | N=7 | I= | Br= | Cl= | F= | O=5 | P= | S= | Se= | Na= | charge= | molecular_weight = 627.734 (471.511 without etexilate) | specific_rotation = | sec_combustion = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_UK = | legal_US = | legal_status = | dependency_liability = unknown | routes_of_administration = oral }} Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications, for some of which it may replace warfarin as the preferred anticoagulant. It is orally administered as the prodrug dabigatran etexilate (planned trade names Rendix and Pradaxa). It was developed by pharmaceutical company Boehringer-Ingelheim.

Development

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to benzamidine-based thrombin inhibitor α-NAPAP (N-alpha-(2-naphthylsulfonylglycyl)-4-amidinophenylalanine piperidide), which had been known since the 1980s as a powerful inhibitor of various serine proteases, specifically thrombin but also trypsin. Addition of a hydrophobic side chain led to the orally absorbed prodrug BIBR 1048 (dabigatran etexilate).
Phase 3 clinical trials are ongoing in treatment and prevention of secondary venous thromboembolism (VTE) in post-operative orthopedic patients (expected results by Oct 2007); long-term prophylaxis in acute coronary syndrome and stroke patients and symptomatic VTE because of various causes (expected results by 2009-2010).

Dosing

Unlike coumadin, there is no monitoring required (an INR is not required).

FDA Review of Atrial Fibrillation Data From RELY on September 20th, 2010

Design

RELY was a randomized, unblinded, non-inferiority trial. The primary endpoint was a composite of stroke and systemic embolism. RELY patients included those patients with non-valvular atrial fibrillation. Both patients who were warfarin naive and non-naive were enrolled.

Efficacy

Both doses of dabigatran were non-inferior to warfarin and were within the pre-specified hazard ratio margin of 1.38. The 150 mg dose of dabigatran was actually superior to warfarin in the prevention of the primary endpoint. The FDA reviewer was not clear that dabigatran achieved superiority given the 1) open label nature of the study; 2) given the adequate but moderate time in a therapeutic range for warfarin use; and 3) given that this is a single study without replication. A p-value of 0.00125 is often required to establish superiority in a single trial.

There was an increased risk of clinically manifest MI associated with Dabigatran dosing. There was no increased risk of revascularization associated with dabigatran. There was no data available regarding study drug discontinuation in the day or days before an MI that might link rebound associated with drug discontinuation to an increased risk of MI. There was numerically a higher risk of major bleeds the week before an MI in the dabigatran group, although this number did not reach statistical significance. The excess number of MIs in the dabigatran group was observed months after drug discontinuation, raising questions as to the biologic plausability of the relationship to study drug.

Bleeding

There was a dose response curve for bleeding associated with dabigatran such that the 150 mg dose was associated with a higher rate of bleeding compared with 110 mg. 150 mg of dabigatran was associated with similar to increased risks of bleeding compared to warfarin (depending upon the definition used) while the 110 mg dose was associated with less bleeding than warfarin. While dyspepsia was increased with dabigatran, this was not associated with an increased risk of bleeding. A greater time in TTR was associated with no excess risk of bleeding for warfarin. The FDA stated that if a patient is well-controlled on warfarin, then there is no reason to switch to dabigatran.

Net Clinical Benefit (NCB)

The 150 mg dose of dabigatran was associated with a greater reduction in stroke events than an increase in major bleeding events. While the clinical impact of efficacy and safety events must be carefully weighed, there was a net benefit observed for the 150 mg dose of dabigatran. This was true in those patients over the age of 75 as well. The patients over the age of 75 had a higher risk of bleeding, but an even higher risk of efficacy events as well. There was not a benefit of the 110 mg dose in those over the age of 75 and the net benefit of the 110 mg dose was less clear.

Drug Induced Liver Injury (DILI)

Dabigatran was not associated with an excess risks of DILI including Hy's law.

Blinding

The trial was unblinded. The FDA found that in 20% of patients, there was data in the source documents that could have unblinded the CEC.

Follow-up

Patients who dropped out could be followed up by telephone contact or in clinic. Being seen in clinic may yield a different ascertainment of endpoints than when being followed up by phone. Similar rates of phone follow-up were observed for the different strategies (8%).

Drop outs and Drug Discontinuation

96% of subjects completed the trial. 19% of dabigatran patients and 15% of warfarin patients discontinued therapy.

Event Rates for Warfarin

One question is always whether Warfarin was administered in the right way. When you look at other RCTs, historical rates for Warfarin in RELY are consistent with prior RCTs.

Time in Therapeutic Range

Time in therapeutic range (TTR) of 64% is not too dissimilar to other RCTs. TTR in RELY is similar to that in SPORTIF III and V. Rate may depend upon frequency of TTR monitoring. High TTR may reflect a low frequency of INR monitoring.

Quality of Data and Adjudication

The rate of concordance between investigator and CEC reported events was 50% to 85%. In 20% of cases, the CEC could have been unblinded by the source documents.

Questions posed by the FDA

Question 1: Was RELY adequately designed?

Unblindinded design was adequate but not optimal. Some argued that an unblinded trial actually parallels the real world practice better. Mortality was still favorable.

Question 2: Were the drug doses appropriate?

Yes.

Question 3: Were events after drug discontinuation handled appropriately?

An ITT analysis for efficacy is the appropriate method with mITT analyses providing supportive information. For safety analyses, mITT may be more informative.

Question 4: Was the trial adequately conducted?

The time in therapeutic range of 65% parallels clinical practice and is adequate for comparison. This rate is similar to other trials. Would not want to compare to unrealistic medical care.

Question 5: Was the follow-up of endpoints adequate?

Yes. Implausible that patients who were missing would have changed the results. Hepatotoxicity data good.

Was dabigatran effective in reducing the primary endpoint?

For stroke yes, non CNS embolism was not sufficiently powered.

Was dabigatran effective at both doses?

Yes was the majority view of the panel, but not by some of the FDA reviewers.

Is the 150 mg dose of dabigatran superior to warfarin?

Yes was the majority view of the panel (with a dissenting view by Dr. Steven Nissen). FDA reviewers were not convinced.

Is 150 mg superior to 110 mg?

Less compelling than the data showing superiority to warfarin. Majority view was yes.

Is there any evidence of hepatic injury

No, although idiosyncratic reactions may take years to appear.

Is there any evidence of less bleeding for the 110 mg dose vs warfarin?

Yes. Mixed reviews as to whether the data split by TTR is of relevance (criticized as a post-randomization event).

Is the risk of bleeding with 150 mg of dabigatran similar to warfarin?

150 mg dabigatran bleeding risk was slightly better but did not reach statistical significance.

Voting Question: Should dabigatran be approved for the reduction of stroke and non CNS embolization for non-valvular atrial fibrillation?

The panel voted 9 to 0 yes.

Should both 110 mg and 150 mg doses be approved?

Mixed views were expressed. 150 mg appears to be the preferred dose. 110 mg may also be appropriate in patients at high risk of bleeding, where the risk of bleeding may outweigh the potential benefit, but it should be realized that this 110 dose is not superior to warfarin with respect to efficacy.

What dose of dabigatran should be approved

There was mixed views on this. Steve Nissen and others recommended approval of both doses. While the primary benefit over warfarin is in the 150 mg dose, people at risk of bleeding may be getting nothing at all and could benefit from the 110 mg dose. Sanjay Kaul, Michael Lincoff and others would approve only the 150 mg dose.