Dabigatran

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Dabigatran etexilate
Dabigatran etexilate structure.svg
Dabigatran etexilate ball-and-stick.png
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 (Pradaxa in Australia, Europe, USA and Canada (previously was Pradax in Canada, name changed to Pradaxa as of January 2013), Prazaxa in Japan) is an oral anticoagulant drug that acts as a direct thrombin (factor IIa) inhibitor. It was developed by the pharmaceutical company Boehringer Ingelheim.

Dabigatran can be used for the prevention of stroke in patients with atrial fibrillation. The drug was developed as an alternative to warfarin, since it does not require maintenance of international normalized ratio or monitoring by frequent blood tests, while offering similar efficacy in preventing ischemic events. In early 2013, there is no way to reverse the anticoagulant effect of dabigatran in the event of clinically significant bleeding, unlike warfarin,[2] and there is still no routine coagulation test suitable for monitoring these patients; specific tests are only available in specialised laboratories.[3]

Medical uses[edit]

Dabigatran can be 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),[4] Patients already taking warfarin with excellent international normalized ratio (INR) control may have little to gain by switching to dabigatran in atrial fibrillation.[5] 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.[6] 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,[7] adverse events (bleeding), discontinuation[8] and drug interactions.[9]

Dabigatran can also be used to prevent the formation of blood clots in the veins (deep venous thrombosis) in adults who have had an operation to replace a hip or knee.[10] LMWH (low molecular weight heparin) and warfarin are the standard drugs for prevention of recurrences of deep venous thrombosis . LMWH and warfarin have similar harm-benefit balances. There is no evidence that rivaroxaban or dabigatran has a better harm-benefit balance than warfarin for long-term treatment.[11]

Dabigatran is not indicated for prosthetic heart valves [12] or for severe mitral stenosis.

Dabigatran is not indicated as add-on treatment for dual antiplatelet therapy in secondary prevention of coronary incidents. (Triple therapy).[13][14]

Non-valvular atrial fibrillation[edit]

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. There were no head-to-head comparisons of novel anticoagulants and limited data on harms.[8] The new oral anticoagulants seem no more effective than warfarin in preventing non haemorrhagic stroke and systemic embolism in non-valvular atrial fibrillation. However, they are generally associated with a lower risk of intra cranial bleeding than warfarin. The net benefit of the NOAC seems better than that of warfarin in situations in which quality of warfarin treatment is poor, given that thromboembolic complications, major bleeding, and mortality may be decreased. The netto benefit is better as well in people with prior stroke or transient ischemic attack, as the absolute risk reduction in intra cranial bleeding may be particularly significant. However,the absolute benefit of the NOAC tends to be of a lesser magnitude in Europe than in other regions, which might be due to regional differences in quality of oral anticoagulation and overall management of associated risk factors for thrombosis. These findings would deserve further investigation.[15]

NOACs are recommended as preferable to warfarin in the majority of AF patients by the European Society of Cardiology and the Canadian Cardiovascular Society in 2012, while the American College of Chest Physicians (ACCP) suggested dabigatran 150 mg twice a day over warfarin (Evidence Grade 2B).[16][17] In contrast, in their 2012 guideline update, the American Heart Association/American Stroke Association took a more cautionary individualised approach and suggested that the approved NOACs are on par with warfarin rather than preferable to warfarin because of concerns about their use in renal failure, safety in the absence of antidotes, and cost issues that could affect affordability and patient compliance.[18] According NICE warfarin should no longer automatically prescribed as the first line treatment for atrial fibrillation but its risks and benefits should be weighted up against those of the newer anticoagulants.[19]

Independent pharmacotherapeutic and general medicine associations as Préscrire, The Dutch College of General Practitioners, The Australian Guidelines, The Canadian Agency for Drugs and Technologies in Health recommend that the new oral anticoagulant agents should only be used in patients who are unable to achieve adequate anticoagulation with warfarin [3][20][21][9] and maybe only to consider a NOAC if all following conditions are fulfilled: age under 80 (arbitrary), not too much co morbidity, good renal function (GFR > 50 ml/min), good adherence and not having prosthetic heart valves or rheumatic mitral stenosis.[20]

Venous thromboembolism: perioperative[edit]

Direct thrombin inhibitors are as effective in the prevention of major venous thromboembolism in total hip replacement or total knee replacement as LMWH and vitamin K antagonists. However, they show higher mortality and cause more bleeding than LMWH.[22] New oral anticoagulants are effective for thromboprophylaxis after total hip repair and total knee repair. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding. There is no evidence that new anticoagulants have a better harm-benefit balance than LMWH. They have not been compared with warfarin in hip and knee operations.[23] The use of once-daily enoxaparin regimen as control in clinical trials will lead to more favorable estimates of relative efficacy for the new oral anticoagulants than if enoxaparin is used twice a day, the U.S.-approved dosage, had been chosen as a comparator.[24]

Myocardial infarction[edit]

In people with a recent acute coronary syndrome, the addition of a new oral anticoagulant to antiplatelet therapy results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy. The use of anti-Xa or direct thrombin inhibitors is associated with a dramatic increase in major bleeding events (2- to 3-fold higher odds), which might offset all ischemic benefits in patients receiving antiplatelet therapy after an ACS. There is no net clinical benefit, calculated as the sum of composite ischemic events and major bleeding events for different doses of new anticoagulants.[13][14]

Advantages and disadvantages[edit]

Novel anticoagulants have some advantages. They have a more predictable anticoagulant response, absence of food interactions, and limited drug interactions compared with warfarin. As a result, monitoring of anticoagulant effect seems to be unnecessary. The half-life periods of these agents are also shorter than that of warfarin, a potential benefit if major bleeding was to occur. They have either renal or mixed renal/liver elimination/metabolism, allowing a clinician to choose a particular drug to meet the patients' comorbid conditions. They have a reduced risk of intra cranial haemorrhage when used for stroke prevention in atrial fibrillation trials.

They have also some drawbacks, whose impact on real-world outcomes is not known. Because of their short half-life periods in combination with the fact that they do not require routine coagulation monitoring, the issue of medication adherence can become problematic. This can lead in real life to increased strokes and health costs. The lack of a simple coagulation assay to accurately measure the biological effect of new agents is another concern, in case of stroke, bleedings or urgent surgery. Moreover, there is no antidote or well-established procedure for reversing anticoagulation in emergent situations. Also, cost can be a major disadvantage, leading to lower adherence.[25] Reports of thrombotic and hemorrhagic complications after the introduction of dabigatran etexilate in New Zealand and Denmark sound a cautionary note regarding the many nuances related to safely prescribing NOACs, particularly in frail elderly patients with renal dysfunction and patients transitioning from warfarin.[26]

Adverse effects[edit]

There are limited data on harms in trials of NOAC.

According to a systematic review, adverse effects of new anticoagulants (dabigatran, rivaroxaban and apixaban) compared with warfarin were lower for fatal bleeding and haemorrhagic 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. The review was limited by absence of head-to-head comparisons of NOACs (new oral anticoagulants) and by limited data on harms.[8]

In the Re-Ly trial, dabigatran had a lower risk of intracranial bleeding absolute risk reduction (ARR 1%) and hospitalizations (ARR 1.6%), and 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%).[27] The most frequent adverse reactions leading to discontinuation of Pradaxa were bleeding and gastrointestinal events.[28] But comparing risks of warfarin to dabigatran if INR control is adequate (as in Northern and West-Europe), the total bleeding risks (major bleeding) are equal and for the elderly ≥ 75 years there was a trend for higher major bleeding risk of dabigatran.[10]

Considerable uncertainties still persist about the safety of the new anticoagulants. For example, the population that will be treated in everyday practice differs from the population taking part in the clinical trials.[29] Thrombotic and haemorrhagic events in the real-world anticoagulated atrial fibrillation population are higher than those reported in clinical trials, probably due to the strict selection of population and close follow up applied in clinical trials. In particular, patients aged 75 years or older were under represented in clinical trials (range: 31% to 43% of patients) compared with real-world atrial fibrillation cohorts (range: 47% to 64% of patients). This issue may have important implications in bleeding risk, as renal function declines with age and all NOAC undergo renal elimination to a greater or lesser extent. Post marketing reports of serious bleedings have frequently involved patients generally not qualified for the NOAC (i.e., severe renal insufficiency)[15] In direct rapports to the FDA in 2011 adverse events as bleedings, acute renal failure, strokes and deaths occurred more often in elderly patients (median age 80 years).[8]

Bleeding and gastrointestinal bleeding[edit]

The most common side effect of dabigatran, seen in more than one patient in 10, is bleeding.[10] There is a 58% higher risk of gastrointestinal bleeding for dabigatran compared to standard care; but it is also a problem for rivaroxaban (48% higher). Combined in all studies of new anticoagulants there was a 45% higher risk; the lowest numerical risk increase was for apixaban and edoxaban.[30] There is an increased risk for gastrointestinal bleeding in treatment of deep venous thrombosis or pulmonary embolism, or the acute coronary syndrome for new anticoagulants compared with standard care.[31]

In RE-LY when compared to warfarin, patients taking dabigatran had fewer life-threatening bleeds and fewer minor and major bleeds, including intra cranial bleeds, but the rate of GI bleeding was higher, mostly in older patients over 75 years. In patients over 75 years, extra cranial major bleeding risk was higher for high-dose dabigatran compared to warfarin.[32]

A randomised trial comparing dabigatran with warfarin, and 5 studies of several hundred serious bleeding events, identified factors that increased the risk of bleeding. They included even mild renal failure, age over 75 years, body weight less than 60 kg, switching between anticoagulants, opening the dabigatran capsules before ingestion, and concomitant use of drugs that interact with dabigatran. A dabigatran dose below 220 mg per day does not protect the person from the risk of haemorrhage.[33]

Concomitant use of anti-platelet agents, as aspirin and clopidogrel increases the risk of major bleeding with dabigatran approximately two-fold, an absolute increase of > 2% per year. Therefore a careful benefit-risk assessment should be made prior to initiation of treatment. This effect was similar for both doses of dabigatran and for warfarin.[27][34] In the RE-LY trial concomitant use of a single anti-platelet seemed to increase the risk of major bleeding 60% (HR, 1.60; 95% CI, 1.42–1.82); dual anti-platelet seemed to increase this even more 131% (HR, 2.31; 95% CI, 1.79–2.98).[35] SSRIs and SNRIs, both antidepressants, increased the risk of bleeding in RE-LY in all treatment groups.[36]

A favourable risk–benefit ratio for the use of aspirin (in terms of reduction in vascular events, including stroke) with warfarin has been reported only for patients with mechanical heart valves,[37] not for nonvalvular atrial fibrillation.[38] In the new anticoagulant trials between 29% and 40% of people took aspirin at inclusion. The baseline prevalence of prior myocardial infarction was between 12 and 17%, raising questions regarding the indication for aspirin.[39] In the real world pan-European PREFER in AF registry only 10% took combined anticoagulant anti-platelets therapy, and only 0,5% needed them, not being given because of recent stenting or acute coronary syndrome event. Only 1,3% of the PREFER cohort received triple combined therapy, of wich only 0,6% had an appropriate indication . The authors concluded there was massive over treatment of double and triple therapy with anti-aggregants in atrial fibrillation.[40][41]

For estimation of bleeding risk the HAS-BLED score [42] can be used. If the HAS-BLED score is higher than the CHADS2 score people have to be monitored closely.[43]

Gastrointestinal upset[edit]

The most commonly reported side effect of dabigatran was gastrointestinal upset (indigestion, upset stomach, burning and stomach pain) . Dabigatran capsules contain tartaric acid, which lowers the gastric pH and is required for adequate absorption. This has previously been associated with dyspepsia; this may play a role in the increased risk of gastrointestinal bleeding,[44] and in the high rate of discontinuation, which can lead to stroke.

Overdose[edit]

Accidental overdose may lead to hemorrhagic complications. There is currently no way to reverse the anticoagulant effect of dabigatran in the event of clinically significant bleeding.[3] [45] Clinical data about possible non-specific prohemostatic therapies (prothrombin complex concentrate [PCC], activated prothrombin complex concentrate [aPCC], recombinant factor VIIa) are lacking.[46] Administration of fresh frozen plasma or vitamin K would not be expected to have an effect on NOAC-related haemorrhage and are not recommended.[47]

The lack of a reliable blood test to monitor dabigatran makes it difficult to determine if a given patient is experiencing a drug interaction. Testing of anticoagulant activity may be required in specific circumstances, such as surgery, overdose and bleeding. In patients treated with dabigatran, rivaroxaban or apixaban, changes in the INR test (international normalised ratio) and activated partial thromboplastin time (aPTT) do not correlate with the dose and should not be performed. In early 2013, there is still no routine coagulation test suitable for monitoring these patients; specific tests are only available in specialised laboratories.[3] Measurement of aPTT may provide only a qualitative indication of the anticoagulant activity, it is not suitable for the precise quantification of anticoagulant effect, especially at high plasma concentrations of dabigatran. A dilute thrombin time assay (Hemoclot test, Hyphen Biomed, France) has been certified in several European countries for the determination of dabigatran plasma levels. Unfortunately, no results about the validity of this test are published yet. Concerns about the lack of laboratory monitoring of emergency situations after trauma have been raised recently by American traumatologists.[48]

Heart attacks[edit]

A significantly increased risk (33%-46%) of myocardial infarction (heart attacks) and acute coronary syndrome has been noted when combining the safety outcome data from multiple trials.[49][50] In another meta analysis the oral direct thrombin inhibitors were associated with significantly higher rates (RR 32-35%) for myocardial infarction as compared to warfarin.[51][52] In a systematic review of all new anticoagulants, subgroup analyses suggested a higher risk for myocardial infarction for direct thrombin inhibitors like dabigatran compared to FXa inhibitors like rivaroxaban and apixaban.[8] This may be explained by a potential platelet-activating activity of dabigatran . A further explanation for the lower rate of myocardial infarction in VKA-treated patients might be that VKA are protective against myocardial infarction.[48]

Long term safety[edit]

The safety (and efficacy) of dabigatran and other thrombin inhibitors in the longer term (beyond two years) are uncertain.[53]

Switching and stopping[edit]

People already taking warfarin with excellent international normalized ratio (INR) control may have little to gain by switching to dabigatran in atrial fibrillation, because of high risk of discontinuation and little clinical benefit.[5][54] The bleeding risk may be increased for those people switching from good controlled warfarin to dabigatran or other NOACS.[8] When switching from warfarin thromboembolic risk associated with dabigatran was 250% to 470% higher for low and high dose dabigatran than with warfarin during the first 4 months in a Danish nationwide study. This was unexpected and could reflect patient selection and ‘drug switching’ practices. No such risk was reported in the Re-Ly trial, in which 50% of patients switched from long-term warfarin treatment to dabigatran. There was also an increased risk of bleeding when switching from warfarin to a 110 mg dose of dabigatran.[55]

The rates of adverse reactions leading to stopping of treatment were 21% for dabigatran 150 mg and 16% for warfarin. The most frequent adverse reactions leading to discontinuation of dabigatran were bleeding and gastrointestinal events (i.e., dyspepsia, nausea, upper abdominal pain, gastrointestinal haemorrhage, and diarrhoea). People with atrial fibrillation should not stop taking dabigatran, except in case of bleeding, because it can increase their risk of stroke.[56] For this reason the pradaxa label now carries a boxed warning in the US, similar to the labels of other new oral anticoagulants,[57] not like warfarin that has a boxed warning because of serious bleeding risk. Albeit major bleeding risk is not significantly different between warfarin and new oral anticoagulants.[8]

In a meta analysis of 3 new oral anticoagulants stopping due to adverse events was significantly increased by 23% against warfarin.[8] Although people with poor adherence were excluded in the RE-LY trial, the discontinuation rate was high (21% for dabigatran, 17% for warfarin) during two years of follow-up.[48]

Drug interactions and contraindications[edit]

Drug interactions[edit]

For many potential interactions with drugs that are often used in atrial fibrillation no detailed information is available yet.[58]

Concomitant administration of a P-gp inducer, such as rifampicin, St Johns wort (Hypericum perforatum), carbamazepine (Tegretol), or phenytoin is expected to result in decreased dabigatran concentrations and should be avoided.[10]

Drug excretion through P-glycoprotein pumps is slowed when taking strong p-glycoprotein pump inhibitors, such as quinidine, verapamil (Isoptin), clarithromycin (Zitromax) and amiodarone (Cordarone), thus raising plasma levels of dabigatran.[59] Dosing should be reduced.

Taking long term anti-platelet drugs as aspirin or clopidogrel (Plavix) doubled the incidence of major bleeding events. This effect is similar for both doses of dabigatran and for warfarin.[60] Taking long term NSAIDs can cause more bleeding episodes;[61][62] also antidepressants such as SSRIs and SNRIs.[36]

Contraindications[edit]

  • Dabigatran is contraindicated in people with severe renal impairment (creatinine clearance <30 ml/min), to minimise the risk of bleeding. But the FDA allows dabigatran for patients with CrCl 15-30 mL/min.
  • Dabigatran is contraindicated in people with active pathological bleeding and must not be used in people who have lesions or conditions at significant risk of major bleeding such as current or recent gastrointestinal ulceration, recent brain or spinal injury or surgery, recent ophthalmic surgery, recent intra-cranial haemorrhage, etc.Also in uncontrolled hypertension due to heightened risk for intracerebral haemorrhage.[63]
  • Dabigatran is contraindicated in hepatic impairment or liver disease expected to have any impact on survival.[64]
  • Dabigatran is contraindicated in people with prosthetic heart valve requiring anticoagulant treatment, after studies found increased rate of strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of the anticoagulant warfarin.[12] Pradaxa is not indicated for valvular heart disease as mitral stenosis, because there is minimal data available.[65]
  • Dabigatran is contraindicated in people with a known serious hypersensitivity reaction (e.g., anaphylactic reaction or anaphylactic shock).

Pradaxa must not be used by people with poor warfarin treatment due to poor compliance. Patients with low compliance seem no good candidates for dabigatran since it has to be taken twice daily whereas warfarin has to be taken only once daily.[48]

Pradaxa must not be used in those taking medicines against mycosis, ketoconazole (Nizoral) and itraconazole (Sporanox), the immunosuppressant medicines cyclosporine and tacrolimus or the anti-arrhytmic quinidine or dronedarone (Multaq).[66]

Concomitant administration of a P-gp inducer, such as the tuberculosis medication rifampicin, St Johns wort (Hypericum perforatum), and the anti epileptics carbamazepine (Tegretol), phenobarbital, and phenytoin are expected to result in decreased dabigatran concentrations and should be avoided.[10]

The use of dabigatran during pregnancy or lactation is not recommended. There is currently no experience of new oral anticoagulants (rivaroxaban, apixaban, betrixaban or dabigatran) use in pregnancy.[67]

Mechanism of action[edit]

Ingested orally, dabigatran is a competitive and reversible direct thrombin inhibitor.[68]

Thrombin plays a role in the last step of blood coagulation, being composed of one active site and two secondary binding exosites. The first exosite aids active site binding through docking substrates such as fibrin, whilst the second binds heparin. Dabigatran thus inactivates both fibrin-bound and free thrombin through binding to the active site; proving more effective than indirect thrombin inhibitors such as unfractionated heparin (which cannot inhibit fibrin-bound thrombin).[69]

Pharmacokinetics[edit]

Dabigatran etexilate is the prodrug of dabigatran. Dabigatran-absorption is dependent on the intestinal P-glycoprotein (P-gp)-system. P-gp activity is influenced by several drugs and herbal components.[48] Dabigatran etexilate is split in the liver and the blood plasma by hydrolysis by cytochrome P 450-independent esterases to the active dabigatran. The absolute bioavailability is 6.5%. Dabigatran has a half-life of about 12-14 h, and exerts a maximum anticoagulation effect within 2-3 h after ingestion. Dabigatran is excreted by the kidneys for 85%. Half-life is prolonged if renal function is impaired. The oral bioavailability may be increased by 75% compared to the reference capsule formulation when the capsule is cut, chewed or opened prior to ingestion. There is a relatively low binding (34-35%) to plasma proteins, making dialysis possible.[70] Both doses of dabigatran are associated with a more than five-fold variation of plasma concentrations. A range of concentration between 35 and 300 ng/ml optimises the benefit-risk ratio. People above 75 year have a 68% increased concentration against people under 65.[71] After oral administration of a single dose of 150 mg dabigatran etexilate, compared with the values in healthy people, the area under the curve (AUC) values for the plasma concentration-time were 1.5-, 3.2- and 6.3-fold higher in people with a creatinine clearance of 50–80 mL/min, 30–50 mL/min, and <30 mL/min respectively. Pharmacokinetics and metabolism studies published so far come exclusively from laboratories of the manufacturer of the drug, and no independent studies, so far, have confirmed their findings.[48]

Society and culture[edit]

Controversies[edit]

Controversy: first- or second-line[edit]

Based on differing risk/benefit estimates, there are divergent opinions on whether dabigatran and the new oral anticoagulants should be a first- or a second-line treatment for non-valvular atrial fibrillation.[25] Cardiologic societies as The European Society of Cardiology and the Canadian Cardiovascular Society adhere the first line approach for new oral anticoagulants (NOACS).[16] The British NICE and the American Heart Association/American Stroke Association consider both warfarin and the NOACS as first line treatments.[72] Independent pharmacotherapeutic and general medicine associations as Préscrire, The Dutch College of General Practitioners, The Australian Guidelines, The Canadian Agency for Drugs and Technologies in Health still adhere a first line approach for warfarin.[3][9][20]

In an editorial The Cochrane Library advises caution in implementing these drugs into clinical practice. First, because of warfarin may be equally effective and as safe as NOACs in settings with well-organised anticoagulation clinics. Second, because in the absence of the need to visit anticoagulation clinics compliance with NOACs may be compromised. Such non-compliance may put patients at risk of thromboembolic events. Third, because there is currently no antidote against factor Xa inhibitors. This may be life-threatening in trauma patients or may pose difficulties in patients who need emergency surgery. Fourth, because cost-effectiveness analyses show that compared with warfarin new oral anticoagulants have high incremental cost effectiveness ratios (ICERs). In countries with high-quality anticoagulation clinics ICERs are likely to be higher. Whether factor Xa inhibitors with such ICERs are affordable outside high-income countries is debatable.[73] The Health Council of the Netherlands advised that the introduction of the new oral anticoagulants must be accompanied by more detailed research into their safety, effectiveness, and cost-effectiveness. They declared that considerable uncertainties still persist about the safety of these drugs. For example, the population that will be treated in everyday practice differs from the population taking part in the clinical trials. Also there is (still) no antidote with which the anticoagulant effect can be stopped in emergency situations. And due to the absence of frequent checks, the risk of poor compliance with the treatment in some of the patients is considerable, directly leading to serious consequences. They plead for a well-dosed introduction.[29] An Australian government commissioned report by prof Samson about atrial fibrillation concluded that the Pharmaceutical Benefits Scheme listing of NOACs should be a restricted benefit for patients unable to tolerate warfarin therapy and/or who are unable to obtain satisfactory INR control despite specific measures. Also that the cost-effectiveness and safety of the medications were still in doubt following fresh data on how dabigatran works in real life settings, compared with clinical trial evidence.[74]

Controversy: under- and overtreatment[edit]

A 2009 prospective study concluded the net clinical benefit of warfarin was essentially zero in CHADS(2) stroke risk categories 0 and 1 (low and moderate risk), leading to potential overuse of warfarin in low and moderate risk categories (at least half of patients with atrial fibrillation).[75][76]

A 2010 Bayer healthcare UK sponsored systematic review concluded that there was under use of anticoagulants in high risk people with atrial fibrillation. In 7 of 9 studies in people with a CHADS2 score ≥2 treatment levels with anticoagulants were reported below 70% (range 39%-92.3%) and were "suboptimally treated".[77]

In the Danish Stroke Registry 17.1% of ischaemic stroke patients (7.482) had atrial fibrillation. Oral anticoagulation prescription rates were increasing, and in 2011 46.6% were prescribed oral anticoagulants, 42.5% had a contraindication, and 3.7% were not prescribed OAC without a stated contraindication. Contraindications were generally present in people not in therapy, and the assumed under use of oral anticoagulants may be overestimated. This raises the question if alleged under-use of oral anticoagulants really is of the previously assumed size or could for a majority be explained by contraindications and risk/benefit ratios made by clinicians on an individual patient level. Advanced age, severe stroke, female gender, institutionalization, smoking, and excessive alcohol consumption were associated with lower oral anticoagulation rates.[78]

Stroke risk prediction tools including the CHADS2 and CHA2DS2VASC models are helpful in clinical practice. However, these are limited within the context of complex cardiogeriatric syndromes. Expanding such models to consider frailty, cognitive and functional decline, or non-adherence to anticoagulant therapy is warranted. Although avoiding stroke is an important consideration, the potential adverse effects of treatment needs to be balanced within the context of best available evidence.[79]

With the CHADS2 scoring system anticoagulation is generally not recommended for people with atrial fibrillation who are at low risk for thromboembolism (CHADS2 score of 0; about 20% of people with atrial fibrillation, who face an average stroke risk of 1% per year), but it is favoured for people at high risk (CHADS2 score ≥2; about 45% of people with atrial fibrillation, whose stroke risk averages 4% to 5% per year) who can tolerate warfarin. For those at moderate risk (CHADS2 score of 1; about 35% of people with atrial fibrillation, with an average stroke risk of 2% per year), either warfarin or aspirin is recommended.[17][75] With the new ESC 2012 guidelines update, using Chadsvasc score for stroke risk calculation, much more people have to take anticoagulants. The reason is that broad risk categories were included (woman, age above 65, age above 75 double points, vascular disease) and that the cut-of risk value for treatment was lower than in the CHADS2 score. For instance in CHA2DS2VASC al 75 aged people and al woman above 65 with atrial fibrillation are at high risk for ischaemic stroke. With CHA2DS2VASC the overall numbers recategorised as high risk for anticoagulant drugs in atrial fibrillation have risen from 18% to 79% of all atrial fibrillation patients in general practice.[80] Moreover the ESC 2012 guidelines update advises to anti-coagulate at CHA2DS2VASC risk score 1 at annual risk of 1,3% and only not to anti-coagulate in "really low risk" people (approximately 5% of atrial fibrillation people at annual risk of 0.5%).[16] The 2012 ACCP guidelines advise anticoagulation for CHADS2 score ≥1 at annual risk of 2,8% (Grade 1B)[17] NICE 2014 offers anticoagulation to people with a CHA2DS2-VASc score of ≥2 and can be considered for men with a score of ≥1.[19]

Controversy: netto clinical effect[edit]

Although net clinical benefit was defined differently in the three studies (RE-LY, ARISTOTLE, and ENGAGE-AF) all three analyses suggested improved net clinical benefit against warfarin. But the net clinical benefit was exaggerated because of double counting of intracerebral haemorrhage (haemorrhagic stroke) by including these events as strokes (efficacy outcome) and major bleeds (safety outcome) in all four trials. Hence it reveals that only dabigatran 150 mg bid is more effective than warfarin in reducing the risk of ischaemic stroke and it shows that the perceived superiority of apixaban over warfarin in both stroke reduction and intracranial bleeding is explained by including haemorrhagic stroke in both outcomes.[18]

A net clinical benefit of the new oral anticoagulants dabigatran, rivaroxaban and apixaban compared with VKA was calculated in a modelling analysis, using data from the Danish National Patient registry and from clinical trials investigating the new anticoagulants. The analysis showed that when the risk of bleeding and stroke are both high, the new anticoagulants appear to have a greater net clinical benefit compared with VKA. The future will show if this beneficial effect, found in the model, will also occur in clinical practice.[48]

Approval[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.[81] It was approved for use in patients with non-valvular atrial fibrillation in the EU in August 2011.[82]

Pradax received a Notice of Compliance (NOC) from Health Canada on June 10, 2008,[83] 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.[84][85]

The U.S. Food and Drug Administration (FDA) approved Pradaxa on October 19, 2010, for prevention of stroke in patients with nonvalvular atrial fibrillation.[86] On April 7, 2014 the FDA approved Pradaxa for treatment and reduction in the risk of recurrence of deep vein thrombosis and pulmonary embolism.[87]

Uptake[edit]

An analysis of NHS primary care prescribing data for the past three years in England shows that the total number of NHS prescriptions for warfarin rose from 9,4 million in 2011 to 10.2 million prescriptions dispensed in 2012. The total prescriptions for dabigatran, including those prescribed in patients with atrial fibrillation and venous thromboembolism, went up from around 3,200 in 2011, to 48,300 in 2012. Prescriptions for rivaroxaban and apixaban also rose, but their use remains much lower than that of dabigatran.[88]

In the US among atrial fibrillation visits, warfarin use decreased from 55.8% visits (2010Q4) to 44.4% (2011Q4), whereas dabigatran use increased from 4.0% to 16.9%. Of atrial fibrillation visits, the fraction not treated with any oral anticoagulants has remained unchanged at ≈ 40%.[89]

In the US ORBIT AF registry in community-based outpatient practices, 76 percent of patients received oral anticoagulants (71 percent warfarin and 5 percent dabigatran).[90]

In the pan-European PREFER in AF registry (recruiting from January 2012 to January 2013) 66% of patients were taking vitamin K antagonists and 6% one of the new oral anticoagulants.[40]

Off-label[edit]

In the US only 63% of all dabigatran treatment visits in the last quarter of 2011 were for atrial fibrillation. The rest was for off-label uses. The most common off-label uses of dabigatran in the last quarter of 2011 were coronary artery disease (7% vs 6% in the last quarter of 2010), hypertensive heart disease (9% vs 7% in 2010), and venous thromboembolism (18% vs 15% in 2010).[91]

The addition of the new oral anticoagulants to single or dual antiplatelet therapy after an acute coronary syndrome results in a modest reduction in cardiovascular events but a substantial increase in bleeding, most pronounced when new oral anticoagulants are combined with dual antiplatelet therapy (triple therapy).[13][14] For acute treatment of venous thromboembolism Dabigatran is not indicated. It requires 5–7 days of initial heparin treatment.[92] There is no proof of benefit for dabigatran in hypertensive heart disease without atrial fibrillation.

Cost[edit]

The costs of new anticoagulants ($3000/year) are substantially higher than those of warfarin ($48/year), even after addition of the extra cost of INR testing and provider visits for warfarin dose adjustment.[93] This is 60 times higher. In the fourt quarter of 2011 costs of dabigatran exceeded costs of warfarin in the US: US$ 166 million (€ 129 million) against US$ 144 million (€112 million) for warfarin.[89]

Cost effectiveness[edit]

The cost effectiveness of Dabigatran is extreme variable with incremental cost-effectiveness ratios (ICERSs) from € 7468 per quality-adjusted life year QALY in Canada to € 49 030 in UK, depending from input in modelling. In countries with high-quality anticoagulation clinics ICERs are likely to be higher. Whether new oral anticoagulants with such ICERs are affordable outside high-income countries is debatable.[73] All those studies are based on the RE-LY (open label) trial data.

Marketing[edit]

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.[94] EvaluatePharma's new World Preview report predicts that the market for anticoagulant drugs will soar by 11.5% annually through 2018, hitting $15.3 billion in sales. Overall anticoagulant sales were $8 billion in 2012.[95]

Boehringer spent $464 million in 2011 to promote Pradaxa, including direct-to-consumer advertising. During the same period, the company's sales topped $1 billion.[96]

In Australia Patient Familiarisation programs to become familiar with the product were launched to specialists and extensively to general practitioners with free treatment for 10 patients, and without warning of the increased risks of myocardial infarction and gastrointestinal bleeding in the marketing summary.[97] Boehringer Ingelheim launched a web campaign and website called “vote against stroke”, which encouraged people to write to their member of parliament to protest the delay in approving dabigatran. This was heavily criticised by the media and public, forcing the company to shut down the website.[98] The company organised almost 300 “educational events” around the country for GPs, cardiologists and other health professionals, mostly with dinner and drinks laid on, at upmarket restaurants. It spent almost $800,000 on these events, according to the company’s public declarations to Medicines Australia all between April 2011 and September 2012.[99]

In 2013, the company will extend Pradaxa-focussed educational events on stroke prevention to more than 4,000 cardiologists in China, the world’s biggest market, with support from the American College of Cardiology and in collaboration with the Chinese Society of Cardiology.[99][100]

Lawsuits[edit]

On February 2014 Boehringer says it's fighting more than 2,000 lawsuits in the US over Pradaxa safety.[101] Patients and their families contend in lawsuits that Boehringer executives knew Pradaxa posed a deadly risk to consumers when it won FDA approval in October 2010. And indeed Boehringer Ingelheim GmbH didn’t disclose a data analysis to U.S. regulators that indicated the blood-thinner Pradaxa may have caused more fatal bleeding after it was cleared for sale than the drug did in the Re-ly study used to win approval, unsealed court filings show. Marjorie Moeling, a company spokeswoman, said Boehringer gave the FDA the underlying data and provided an analysis using what the drugmaker considered to be the most appropriate comparison. District Judge David Herndon in East St. Louis, Illinois set the first case for trial among the consolidated federal suits for August 2014. He also ordered Boehringer to pay almost $1 million in fines for withholding or failing to preserve files about the drug’s development and marketing. [102] Begin february 2014 the same judge unsealed documents revealing that Boehringer Ingelheim tried to quash an internal study for fear it would damage Pradaxa sales. The study findings suggested that some Pradaxa users do in fact need blood testing because metabolic differences, especially in older patients. This could result in the individual having too little or too much of the drug in his bloodstream, meaning that he could be inadequately protected or face increased bleeding risks. This conclusion alarmed Boehringer executives and led to pressure to revise the paper or suppress it.[103][104] After this discovery the company said the change between the draft and final version represented an evolution in the scientists' thinking on the topic, and was not motivated by marketing concerns.[105]

History[edit]

Ximelagatran, Exanta from AstraZeneca, a direct thrombin inhibitor, was the first member of this class that could be taken orally. It was also the first oral Direct Thrombin Inhibitor within this class to show potential for treatment of Atrial Fibrillation, and the first in the United States for which FDA approval was applied. 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 THRIVE.[52][106] In an earlier study, ESTEEM, administration of ximelagatran in combination with aspirin helped to prevent a recurrence of myocardial infarction, despite a double risk of major bleedings against placebo.[107] 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%.[108] The results of the SPORTIF 3[109][110] and 5[111] 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.[112] There was a big difference in outcome between open-label and double blinded trials. In the unsuccessfully double blinded SPORTIF 5 trial ( North American multicenter) the relative risk of stroke for dabigatran was numerically 24% higher than for warfarin, but in the earlier open label trial SPORTIF 3 (International multicenter) the relative risk of stroke was numerically 33% lower. In SPORTIF 5 (18,5% aspirin use) risk of cardial events was numerically lower, in SPORTIF 3 (10,5% aspirin use) risk was numerically higher [113] The SPORTIF 3 trial was the predecessor of the RE-LY, the ROCKET-AF, the ARISTOTLE and ENGAGE AF-TIMI trials for the new oral anticoagulants and their design was influenced by it. In those big trials 30 to 40% of patients were exposed initially to combined treatment of aspirin with anticoagulants, possibly resulting in doubling of incidence of major bleeding events and an increase of >2% a year in the 3 arms of the RE-LY trial,[27] and possibly similar increases in ROCKET-AF and ARISTOTLE. Also those trials proceeded with international multicenter trials including centers with worse warfarin controle, advancing the benefits of NOACS. Contrary to the SPORTIF trials in later NOAC trials patiënts with previous coronary disease were not specifically included; this reversed the ratio of previous stroke to previous coronary disease at entry. This ratio was 18,5% against 41,5% in the unsuccessful SPORTIF 5 trial and inverse in the NOAC trials.[110] Reversing this ratio and adding aspirin was meant for diminishing risk of heart infarction.

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, dabigatran etexilate.[114]

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