Dabigatran

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"Pradax" redirects here. For the analgesic trade-named Paradex, see dextropropoxyphene. For the antiseptic trade-named Peridex, see chlorhexidine.
Dabigatran etexilate
Systematic (IUPAC) name
Ethyl 3-{[(2-{[(4-{N'-hexyloxycarbonyl carbamimidoyl}phenyl)amino]methyl}-1-

methyl-1H-benzimidazol-5-yl)carbonyl] (pyridin-2-yl-amino)propanoate
Clinical data
Trade names Pradaxa,Prazaxa
MedlinePlus a610024
Licence data EMA:Link, US FDA:link
Pregnancy cat. C (US)
Legal status Schedule VI (CA) POM (UK) ℞-only (US)
Routes oral
Pharmacokinetic data
Bioavailability 3–7%[1]
Protein binding 35%[1]
Half-life 12–17 hours[1]
Identifiers
CAS number 211915-06-9
ATC code B01AE07
PubChem CID 6445226
DrugBank DB06695
ChemSpider 4948999 YesY
ChEMBL CHEMBL539697 YesY
Chemical data
Formula C34H41N7O5 
Mol. mass 627.734 g/mol
 YesY (what is this?)  (verify)
Dabigatran
Systematic (IUPAC) name
3-({2-[(4-Carbamimidoyl-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
CAS number 211914-51-1 N
ATC code  ?
PubChem CID 216210
ChemSpider 187412 YesY
UNII I0VM4M70GC YesY
KEGG D09707 N
ChEMBL CHEMBL48361 YesY
Chemical data
Formula C25H25N7O3 
Mol. mass 471.511 g/mol
 N (what is this?)  (verify)

Dabigatran (Pradaxa in Australia, Europe, USA and Canada (previously was Pradax in Canada, name change to Pradaxa as of January 2013), Prazaxa in Japan) is an oral anticoagulant from the class of the direct thrombin inhibitors. It is used for various clinical indications, and in some cases it offers an alternative to warfarin as the preferred orally administered anticoagulant ("blood thinner"), since it does not require frequent blood tests for international normalized ratio monitoring, while offering similar results in terms of efficacy. No specific way exists to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event,[2][3] unlike warfarin.[4] It was developed by the pharmaceutical company Boehringer Ingelheim.

Contents

Medical uses[edit]

Dabigatran is used to prevent strokes in those with atrial fibrillation due to causes other than heart valve disease, and at least one additional risk factor for stroke (congestive heart failure, hypertension, age, diabetes, and prior stroke),[5] and to prevent the formation of blood clots in the veins in adults who have had an operation to replace a hip or knee.[6] Patients already taking warfarin with excellent international normalized ratio (INR) control may have little to gain by switching to dabigatran in atrial fibrillation.[7] In practice, warfarin remains the standard drug for patients with atrial fibrillation and a moderate or high risk of thrombosis. Aspirin is an alternative for low-moderate-risk patients. When the risk is significant and the INR cannot be maintained within the target range despite close monitoring, dabigatran is the alternative to warfarin, provided the patient is closely monitored, especially for changes in renal function,[8] adverse events (bleeding) and discontinuation.[9]

Mechanism of action[edit]

Dabigatran is a competitive, direct thrombin inhibitor.[10]

Adverse effects[edit]

The most common side effect of dabigatran, seen in more than one patient in 10, is bleeding.[6] When compared to people treated with warfarin, patients taking dabigatran had fewer life-threatening bleeds and fewer minor and major bleeds, including intracranial bleeds, but the rate of GI bleeding was higher, mostly in older patients over 75 years. In the RE-LY trial, the most commonly reported side effect of dabigatran was gastrointestinal upset. Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. The lower pH has previously been associated with dyspepsia; this may play a role in the increased risk of gastrointestinal bleeding.[11] In patients over 75 years, extracranial major bleeding risk was higher for high-dose dabigatran compared to warfarin.[12]

Concomitant use of antiplatelet agents increases the risk of major bleeding with dabigatran approximately two-fold, therefore a careful benefit-risk assessment should be made prior to initiation of treatment.[13] SSRIs and SNRIs, both antidepressants, increased the risk of bleeding in RE-LY in all treatment groups.[14]

A significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials.[15] In a systematic review of all new anticoagulants, subgroup analyses suggested a higher risk for myocardial infarction for direct thrombin inhibitors compared to FXa inhibitors.[9]

Comparing risks of warfarin to dabigatran, the total bleeding risks are equal if INR control is adequate, but in the Re-Ly trial, warfarin had more risk of intracranial bleeding [absolute risk reduction (ARR) 1% for dabigatran] and hospitalizations (ARR 1.6% for dabigatran), and dabigatran had more risk of heart attack [absolute risk increase (ARI) 0.4%], gastrointestinal bleeding (ARI 0.6%) and withdrawal because of serious adverse effect (ARI 1%) or withdrawal because of any adverse effect (ARI 4.1%).[16] The most frequent adverse reactions leading to discontinuation of Pradaxa were bleeding and gastrointestinal events.[17]

The lack of a reliable blood test to monitor dabigatran makes it difficult to determine if a given patient is experiencing a drug interaction.[18] Testing of anticoagulant activity may be required in specific circumstances, such as surgery, overdose and bleeding. The INR test should not be performed, as it is unreliable in patients on dabigatran. This can be done through thrombin time (TT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) tests. If ECT or TT is not available, the aPTT test provides an approximation of dabigatran's anticoagulant activity. An aPTT of >80 seconds at trough was associated with an increased risk of bleeding when dabigatran was used in atrial fibrillation patients in a clinical study.[19]

The safety (and efficacy) of dabigatran and other thrombin inhibitors in the longer term (beyond two years) are uncertain.[20]

Contraindications[edit]

Dabigatran is contraindicated in patients with severe renal impairment (creatinine clearance <30 ml/min), to minimise the risk of bleeding. A dose reduction and close clinical surveillance should be considered in patients with moderate renal impairment (creatinine clearance 30–50 ml/min), particularly in those at increased risk of bleeding. Similar precautions are recommended for patients older than 75 years.[21] Dabigatran is contraindicated in patients with active pathological bleeding and patients with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock) to dabigatran. Dabigatran must not be used in patients who have lesions or conditions at significant risk of major bleeding such as current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. It is contraindicated in hepatic impairment or liver disease expected to have any impact on survival.[22]

Pradaxa is contraindicated in patients with prosthetic heart valve requiring anticoagulant treatment, after studies found increased rate of thromboembolic events and bleeding events in those on dabigatran vs those on warfarin.[citation needed]

Pradaxa must not be used in patients taking medicines against fungal infections, either by mouth or injection, ketoconazole and itraconazole, or the immunosuppressant medicines cyclosporine and tacrolimus.[23] Concomitant administration of a P-gp inducer (such as rifampicin, St Johns wort (Hypericum perforatum), carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be avoided.[6] Use of dabigatran is contraindicated with dronedarone, and with other anticoagulants, except when switching treatment to or from dabigatran, or with the use of unfractionated heparin for maintenance of venous or arterial catheter patency. The use of dabigatran during pregnancy or lactation is not recommended.

Development[edit]

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 ethyl ester and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed prodrug, BIBR 1048 (dabigatran etexilate).[24]

Dosing[edit]

For patients who have had a hip or knee replacement, treatment with Dabigatran should start with one 110-mg capsule taken one to four hours after the end of the operation. Treatment then continues with 220 mg (as two 110-mg capsules) once a day for 28 to 35 days after hip replacement and for 10 days after knee replacement. A lower dose is used in patients with moderate kidney problems, in patients over 75 years of age, and in patients also taking amiodarone, quinidine or verapamil (medicines used to treat heart problems).

For the prevention of strokes and blood clots in patients with nonvalvular atrial fibrillation, Dabigatran is taken at a dose of 300 mg (as one 150 mg capsule twice a day) and should be taken long term. A lower dose is used in patients with moderate kidney problems who are at high risk of bleeding, patients aged over 80 years, and patients also taking verapamil. A lower dose may also be used in patients aged 75 to 80 years who are at high risk of bleeding. All patients considered to be at risk of bleeding should be monitored closely and the dose of Dabigatran lowered at the discretion of the doctor.[6]

In the US, a dose of 150 mg twice daily was approved for patients with a creatinine clearance >30 ml/min, whereas in patients with severe renal insufficiency (creatinine clearance 15 to 30 ml/min) the approved dose is 75 mg twice daily, a dose currently marketed in the European Union, but not evaluated in the RE-LY trial. The 110-mg, twice–daily dose used in the trial did not receive approval from the U.S. Food and Drug Administration (FDA).[7]

Dabigatran has a half-life of about 12-14 h, and exerts a maximum anticoagulation effect within 2-3 h after ingestion.[25] The capsule should NOT be opened before taking the dose (such as sprinkling the contents of the capsule on food) because the amount of drug absorbed is substantially increased.[18] One study showed absorption may be moderately decreased if taken with a proton pump inhibitor,[26] but this decreased absorption is not thought to be clinically important.[18] Drug excretion through P-glycoprotein pumps is slowed in patients taking strong p-glycoprotein pump inhibitors, such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran.[27] Dosing should be reduced to 150 mg taken once daily in patients who receive concomitantly dabigatran etexilate and those P-gp inhibitors.[28]

Major trials[edit]

RE-LY study[edit]

A manufacturer-sponsored, phase III study, RE-LY, evaluated the efficacy and safety of two different doses of dabigatran relative to warfarin in over 18,000 patients with atrial fibrillation. They were randomized to one of three arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg twice daily, or (3) dabigatran 150 mg twice daily. The warfarin arm was open label, but adverse events were adjudicated by reviewers blinded to treatment.

Dabigatran 110 mg was not inferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.11% per year in the group who received 150 mg of dabigatran.[29] Analyses by EMA demonstrated the benefits observed in the comparison of dabigatran to warfarin diminished if INR control was good, with time in therapeutic range TTR >70%.[6] In Re-ly INR values were within the target range 64.4% of the time.[30] A systematic review of new anticoagulants states the treatment benefits of dabigatran and other new anticoagulants compared with warfarin are small and vary depending on the control achieved by warfarin treatment.[9]

Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg showed similar bleeding to warfarin.[29][31] The global INR control in RE-LY, although being comparable to contemporary trials in this indication, was not optimal from a Northern/Western European standard. When major bleeding events were analysed by time in therapeutic range (TTR), the outcome of warfarin treatment for the overall population improved with increasing TTR. For centres with TTR ≥ 70% (such as Western Europe) the major bleeding event rates were marginally higher for dabigatran 150 twice a day vs. warfarin, and for the elderly ≥ 75 years the risk was significantly higher.[6] During the trial approximately 40% of patients took aspirin and 7% took clopidogrel at some time. Taking either antiplatelet drug doubled the incidence of major bleeding events, an absolute increase of > 2% per year. This effect was similar for both doses of dabigatran and for warfarin.[16] A favorable risk–benefit ratio for the use of aspirin with warfarin has been reported only for patients with mechanical heart valves,[32] not for nonvalvular atrial fibrillation. In RE-LY, high rates of major bleeds occurred in warfarin-treated patients, despite being a low-risk population, and the rates of major bleeds did not match historic warfarin trials. The risk of major hemorrhage with warfarin was 3.45% a year in ROCKET (rivaroxaban study), 3.36% in RE-LY (dabigatran study ) and 3.09% in ARISTOTLE (apixaban study). These rates are clearly higher than in other warfarin studies: the BAFTA-study 1.6%,[33] the ACTIVE-W-study 2.21% [34] or in the meta-analyzes with RCTs about atrium fibrillation 1.3%.[35][36] In a new meta analysis of warfarin studies in atrial fibrillation major bleeding varied from 1.40% to 3.40% per year across the studies.[37] The rate of major bleeding in RE-LY is much higher than previously reported by the same author (1.78 to 2.92%) and than reported for warfarin groups in clinical trials of anticoagulants such as ximelagatran (1.8%) and idraparinux (1.4%).[29]

Intracranial hemorrhages were significantly fewer with dabigatran compared to warfarin. But in RE-LY, an unusually high incidence of intracranial hemorrhages by warfarin occurred, 0.76% per year, which is much more than meta-analyses from cochrane 0.3% and 0.45% or individual trials 0.53% in SPORTIF III or 0.28% in SPORTIF V.[16] Already in 1999, a meta-analysis found the use of aspirin with oral anticoagulants was associated with more than double the frequency of intracranial hemorrhage (relative risk = 2.4, 95% CI = 1.2-4.8, p = 0.02).[38] In 2004, a retrospective cohort analysis found that major bleeding events during 90 days after discharge for ventricular fibrillation occurred in 1.3% of the warfarin-only users versus 1.9% on combined warfarin–antiplatelet therapy (OR, 1.46; 95% CI, 0.998 to 2.12). The major difference was seen in intracranial haemorrhage, which occurred three times more frequently in the combined group.[39] In RE-LY, independent predictors of intracranial hemorrhage were assignment to warfarin, aspirin use, age and previous stroke/transient ischemic attack. Concomitant aspirin use was the most important modifiable independent risk factor for intracranial hemorrhage.[40] The combined risk of aspirin with warfarin was not stated, although very relevant.

A post hoc analysis from RE-LY showed patients under 75 with atrial fibrillation at risk for stroke have lower risks of both intracranial and extracranial bleeding in both doses of dabigatran compared with warfarin. In patients over 75 years, intracranial bleeding risk is lower, but extracranial bleeding risk is higher with high-dose dabigatran when compared with warfarin.[12]

Dabigatran trended to decreased mortality compared to warfarin. The FDA clinical reviewer found the trend toward increased mortality with warfarin was entirely due to investigator sites where INR monitoring was inferior. At sites where INR was within therapeutic range ≥ 67% of the time, relative risk for mortality (RR 1.05) favoured warfarin over dabigatran.[16][41]

Significantly more patients withdrew from dabigatran, due to serious adverse events and to any adverse event, compared to warfarin. and significantly more adverse events occurred with dabigatran compared to warfarin. Absolute numbers of serious adverse events were not reported.[16]

Exclusion criteria included severe heart-valve disorder, stroke within 14 days or severe stroke within 6 months, conditions that increase risk for hemorrhage, creatinine clearance < 30 ml/min, active liver disease, and pregnancy.[42]

According to a systematic review, adverse effects of new anticoagulants (dabigatran, rivaroxaban and apixaban) compared with warfarin were lower for fatal bleeding and hemorrhagic stroke, numerically lower for major bleeding, numerically higher for gastrointestinal bleeding, and higher for discontinuation due to adverse events. Bleeding risks may be increased for persons older than 75 years or those receiving warfarin who have good control.[43]

Some reviewers argue, because of major flaws in RE-LY, a double-blinded trial should be performed testing dabigatran against warfarin to verify the results of the RE-LY trial.[16][36]

RE-COVER[edit]

A 2009 large (2539 patients), randomized, double-blind trial by the RE-COVER study group demonstrated no inferiority of dabigatran 150 mg twice daily compared to warfarin in the treatment of acute venous thromboembolism for prevention of recurrent venous thromboembolism, with a similar rate of major bleeding and a lower rate of combined major plus nonmajor bleeding. Patients randomized to dabigatran had fewer minor bleeds, but more dyspepsia and more drug discontinuation. Dabigatran-treated patients did not undergo coagulation testing.[44] In a systematic review of three trials, novel anticoagulants did not differ for mortality or venous thromboembolism related mortality from warfarin in prevention of venous thromboembolism. The following trials were included: Einstein-DVT and Einstein-PE for rivaroxaban and RE-COVER for dabigatran.[45]

Approval and indications[edit]

On March 18, 2008, the European Medicines Agency granted marketing authorisation for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery.[46] It was approved for use in patients with non-valvular atrial fibrillation in the EU in August 2011.[47]

Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[48] for the prevention of blood clots in patients who have undergone total hip or total knee replacement surgery. Approval for atrial fibrillation patients at risk of stroke came in October 2010.[49][50]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with nonvalvular atrial fibrillation.[29][51][52][53] The approval came after an advisory committee recommended the drug for approval on September 20, 2010,[54] although caution is still urged by reviewers.[55]

On February 14, 2011, the American College of Cardiology Foundation and American Heart Association added dabigatran to their guidelines for management of nonvalvular atrial fibrillation with a class I recommendation, level of evidence: B.[7]

Cost[edit]

The costs of new anticoagulants ($3000/year) are substantially higher than those of warfarin ($48/year), even after addition of the extra cost of INR testing and provider visits for warfarin dose adjustment.[56] This is 60 times higher.

A Canadian study, sponsored by the manufacturer of dabigatran and based on RE-LY patient level data, assessed its cost effectiveness according to the same age adjusted dosing schedule as approved in Europe. Dabigatran was cost effective compared with warfarin, at $C10 440 (£6466; €7468; $10 026) per quality-adjusted life year QALY gained.[57]

In another study from UK, dabigatran was unlikely to be cost effective in clinics, such as those in the UK, able to achieve good control of the international normalised ratio (INR) with warfarin. Dabigatran 150 mg twice daily, and an age-adjusted dosing regimen, should be cost effective only for patients at increased risk of stroke or for whom INR is likely to be less well controlled. High-dose dabigatran had an incremental cost effectiveness ratio of £23 082 (€26 700; $35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS2 score of 3 or above. However, at centres that achieved good control of INRs, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 (€49 030) per QALY gained. Differences between the Canadian and UK studies related largely to costs, which were proportionally much greater for the management of events and long-term care in the Canadian analysis. In the UK analysis, the cost of stroke was about five times higher than the cost of drugs, whereas in the Canadian study it was more than 15 times higher.[20] On the contrary, the Nice Committee (UK) concluded the most plausible incremental cost-effectiveness ratio ICERs for the whole population eligible for dabigatran were at £18 900 per QALY gained, considering average time in therapeutic range in UK was 67.9%. This was considered within the range of a cost-effective use of NHS resources, being less than £20 000 (€23 134) per QALY gained.[58]

In another US study in a hypothetical cohort of 70-year-old patients with AF using a cost-effectiveness threshold of $50 000/quality-adjusted life-year (€39 750) for patients with the lowest stroke rate (CHADS2 stroke score of 0), only aspirin was cost-effective. For patients with a moderate stroke rate (CHADS2 score of 1 or 2), warfarin was cost-effective unless the risk of hemorrhage was high or quality of INR control was poor (time in the therapeutic range <57.1%). For patients with a high stroke risk (CHADS(2) stroke score ≥3), dabigatran 150 mg (twice daily) was cost effective unless INR control was excellent (time in the therapeutic range >72.6%). Neither dabigatran 110 mg nor dual therapy (aspirin and clopidogrel) was cost effective.[59]

An analysis from Frost and Sullivan's "Analysis of the Anticoagulant Market research" found the market of anticoagulants earned revenues of $4.7 billion in 2010 and expects it to reach $11.8 billion in 2016.[60]

Pharmacovigilance[edit]

On August 12, 2011, the Ministry of Health, Labour and Welfare in Japan required Nippon Boehringer Ingelheim Co., Ltd. to include a new boxed warning and to revise precautions of the package insert, because several fatal cases resulting from severe haemorrhagic adverse effects, including gastrointestinal haemorrhages, had been reported in patients treated with Prazaxa.[61]

On December 7, 2011, the U.S. FDA initiated an investigation into serious bleeding events associated with dabigatran, stating, "[the] FDA is working to determine whether the reports of bleeding in patients taking Pradaxa are occurring more commonly than would be expected, based on observations in the large clinical trial that supported the approval of Pradaxa [RE-LY trial]." In November 2011, Boehringer Ingelheim confirmed 260 fatal bleeding events worldwide between March 2008 and October 2011[62] of which 20 in Europe.

The Therapeutic Goods Administration in Australia published a Safety Advisory on 3 November 2011 regarding the risk of bleeding in people using dabigatran. The analysis of these reports shows some of the bleeding adverse events occurred during the transition from warfarin to dabigatran; many of the adverse events are occurring in patients on the reduced dosage regimen; and the most common site of serious bleeding for dabigatran is the gastrointestinal tract, whereas for warfarin it is intracranial. Risk factors for bleeding are: age ≥ 75 years, moderate renal impairment (30-50 ml/min) - severe renal impairment is a contraindication, concomitant use of aspirin (approximately twice the risk), clopidogrel (approximately twice the risk), non-steroidal anti-inflammatory drugs including COX-2 inhibitors[63] (50% more risk).[64]

On 25 May 2012, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP)(Europe) found the frequency of occurrence of fatal bleedings with Pradaxa seen in postmarketing data was significantly lower than what was observed in the clinical trials that supported the authorisation of the medicine, but considered this issue should nonetheless be kept under close surveillance.[65]

A 2012 Medco Health Solutions report found the actual stroke and bleeding rates found at four months for dabigatran were equivalent to or higher than the stroke and bleeding rates per year for warfarin from the RE-LY trial, partly by early discontinuing dabigatran. They conclude patients need to be monitored closely to prevent bleeds or blood clots.[66]

Until recently, the most often cited cause for drug-related mortality by the FDA was warfarin.[67] In October 2006, the FDA issued a black box warning for warfarin due to its hazards. According to new data compiled by QuarterWatch, in 2011, the FDA received more safety reports about dabigatran than any other drug. Dabigatran was the subject of 3,781 serious adverse events reported to the FDA in 2011, including 542 patient deaths, 2,367 hemorrhages, 291 acute renal failures and 644 strokes. Warfarin was the subject of 1,106 serious adverse events, including 72 deaths. Quarter Watch and other groups have raised concerns or made recommendations for adjusting dosage to age or renal function.[9] According to Dr. Robert Temple, FDA spokesman, few doctors notify the agency about incidents from warfarin because its risks are already well known. There were 33 million US prescriptions filled for warfarin for atrial fibrillation and other uses in 2011, and some 2.2 million prescriptions for Pradaxa according to IMS Health[68]

The company-based prospective RE-LY AF Registry study, found, worldwide, the proportion of patients presenting to the emergency department with AF, who were dead within a year, was quite high and somewhat higher than expected, at 11,7%. It was significantly lower in Western Europe than in North America (8.3% vs 11.4%). Differences across world regions between one-year mortality were attenuated after adjustment for heart failure, coronary disease, hypertension, diabetes, and rheumatic heart disease. Most important cause of death was problems of the heart 47% (heart failure 34%, sudden death 8%, myocardinfarct 5%) preceding stroke at 10%. Mortality was two to three times higher if atrial fibrillation was a secondary diagnosis.[69][70] In the RE-LY trial, the mortality rate was 4.13% per year in the warfarin group and 3.64% per year with high-dose dabigatran,[29] so the big difference (300% relative rate) between trial data and real world emergency unit data is large, despite the availability of modern medical therapy.

On Dec. 19, 2012, the FDA began requiring a contraindication (a warning against use) of Pradaxa (dabigatran) in patients with mechanical heart valves (also called mechanical prosthetic heart valves).[71]

Related drugs[edit]

Ximelagatran, a direct thrombin inhibitor, was the first member of this class that can be taken orally. In 2006, it was withdrawn after reports of hepatotoxicity (liver damage) during trials. Also the rate of serious coronary events was higher in one trial.[72] In another study, administration of ximelagatran in combination with aspirin helped to prevent a recurrence of myocardial infarction, despite a double risk of major bleedings against placebo.[73] In a post hoc analysis of the Sportif trials for atrial fibrillation, about 10% of patients took aspirin combined with warfarin or ximelegatran. The combination of aspirin plus warfarin was associated with a significantly increased annual risk for major bleeding, 3.9% versus 2.3% (P=0.01), whereas the combination of ximelegatran plus aspirin had no such effect on bleeding risk, 2.0% versus 1.9%.[74] The results of the sportif 3 and 5 trials for atrial fibrillation were not considered to fulfil the current US FDA requirements to prove non-inferiority in efficacy. So ximelagatran was inferior to warfarin in this indication. These findings, in combination with evidence of liver toxicity and higher risk of coronary events, prevented the registration at the first application in the USA in 2004.[75] The SPORTIF trials were the predecessors of the RE-LY trial. AZD 0837, another oral thrombine inhibitor, is under development.[76]

A new series of oral, direct-acting inhibitors of Factor Xa have entered clinical development, and are competitors of dabigatran. These include rivaroxaban, apixaban, betrixaban (LY517717), darexaban (YM150) and edoxaban (DU-176b).[77]

Expiration of capsules[edit]

Once a bottle of dabigatran is opened, the medication expires after four months. This unusually short period exists because the drug can be affected by humidity. The bottle cap contains a desiccant to reduce the humidity and prevent degradation of the drug. Blister packs do not have that same four-month expiration because a capsule is not exposed to humidity until its own blister is opened.[78]

See also[edit]

References[edit]

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External links[edit]
Antiplatelet drugs
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Anticoagulants
Factor Xa inhibitors
(with some II inhibition)
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Thrombolytic drugs/
fibrinolytics
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