Dabigatran: Difference between revisions
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==FDA Review of Atrial Fibrillation Data From RELY on September 20th, 2010== | ==FDA Review of Atrial Fibrillation Data From RELY on September 20th, 2010== | ||
RELY was a 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 [[ | ===Design=== | ||
There was an increased risk of clinically manifest MI associated with Dabigatran dosing. There was no increased risk of revascularization. There was no data available regarding study drug discontinuation in the day or days before an MI to link rebound 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. | 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 with a hazard ratio margin of 1.38. The 150 mg dose of dabigatran was superior in the prevention of the primary endpoint. | |||
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 to 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. | |||
===Bleeding=== | ===Bleeding=== | ||
There was a | 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 (it depends 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. | |||
===Drug Induced Liver Injury (DILI)=== | |||
Dabigatran was not associated with an excess riks 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 as well. | |||
===Follow-up=== | ===Follow-up=== | ||
Patients who dropped out could be followed up by telephone contact. Being seen in clinic may yield different ascertainment of endpoints than when being followed up by phone. Similar rates were observed for | 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=== | ===Drop outs and Drug Discontinuation=== | ||
96% of subjects completed the trial. 19% of dabigatran patients and 15% of | 96% of subjects completed the trial. 19% of dabigatran patients and 15% of warfarin patients discontinued therapy. | ||
===Event Rates for Warfarin=== | ===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 are consistent with prior RCTs. | 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=== | ||
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. | 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 Adjudciation=== | ===Quality of Data and Adjudciation=== | ||
The rate of concordance between investigator and CEC reported events was 50% to 85%. | 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. | ||
==References== | ==References== | ||
<references/> | <references/> | ||
Revision as of 15:38, 20 September 2010
{{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).[1]
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).[2]
Dosing
Unlike coumadin, there is no monitoring required (an INR is not required).
A 2004 study showed a good safety profile at doses between 12.5 and 300 mg twice daily.[3]
In a phase II study comparing dabigatran with enoxaparin showed increased efficacy in preventing thrombosis in patients undergoing orthopedic surgery, but a possible increased bleeding risk in patients receiving higher doses of dabigatran.[4]
Absorption is unrelated to food but may be decreased with co-administration of proton pump inhibitors.[5]
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 with a hazard ratio margin of 1.38. The 150 mg dose of dabigatran was superior in the prevention of the primary endpoint.
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 to 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.
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 (it depends 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.
Drug Induced Liver Injury (DILI)
Dabigatran was not associated with an excess riks 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 as well.
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 Adjudciation
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.
References
- ↑ Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 2002;45:1757-66. PMID 11960487.
- ↑ Currently active clinical trials of Dabigatran at ClinicalTrials.gov http://www.clinicaltrials.gov/ct/search?term=Dabigatran&submit=Search
- ↑ Eriksson BI, Dahl OE, Ahnfelt L, Kalebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004;2:1573-80. PMID 15333033.
- ↑ Eriksson BI, Dahl OE, Buller HR, Hettiarachchi R, Rosencher N, Bravo ML, Ahnfelt L, Piovella F, Stangier J, Kalebo P, Reilly P; BISTRO II Study Group. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005;3:103-11. PMID 15634273.
- ↑ Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stahle H, Rathgen K, Svard R. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005;45:555-63. PMID 15831779.
External links
- Official site ("under construction")
- Warfarinfo page on dabigatran