Dabgatran – Wikipedia

The Dabigatran etexilato It is an anticoagulant drug belonging to the new category of direct trombin inhibitors, which are part of the group said: new oral anticoagulants (Nao).

The drug, available in Europe since 2008 and marketed by Boehringer Ingelheim with the name of Pradaxa , is approved by the EMA for the primary prevention of thromboembolic episodes in adult patients undergoing total elective replacement surgery of the hip or knee. On August 4, 2011, the European Commission of AMA approved Dabigatran for the prevention of stroke and systemic embolism in patients with non -valve atrial fibrillation. Dabigatren had already received approval as an indication for the reduction of the risk of brain stroke in patients with atrial fibrillation not valve On the part of several regulatory agencies of the drug, including the Food and Drug Administration of the USA and others in Canada, Japan, South Korea, New Zealand and Indonesia. Since summer 2013, the European Medicines Agency has also approved the molecule for the same indication. The drug is prepared in the form of capsules containing an inactive protharmaco, the Dabigatran Etexilate. After oral administration, Dabigatran Etexilate is quickly absorbed and, through hydrolysis, is converted into Dabigatran.

Dabigatran exercises anticoagulant activity as a powerful direct, competitive, reversible inhibitor of trombin and is the active ingredient that is found in the plasma. ^[first] It acts by inhibiting both the circulating free trumpet and the one linked to the fibrine clot and is also able to reduce the platelet aggregation stimulated by trombin.
For this reason it is more effective than the indirect inhibitors of the thrombin, such as unpaid heparin, which cannot inhibit the trumpet linked to the fibrin. ^[2] The anticoagulant effect that is obtained is less variable than that produced by Warfarin and the other antagonists of vitamin K, therefore it does not require periodic monitoring of the protrombin time nor of possession adjustments. ^[3] A specific antidote has recently been tested and approved by EMA, the hydarucizumab for hospital use only.

It is recalled that for Warfarin the specific antidote is vitamin K whose effect can be evaluated in the following 24/48 hours. Experimental studies with prodrombin complex concentrates have highlighted the possibility of significantly reducing the time necessary to reverse the effects of oral anticoagulants (the action is expressed in the order of a few minutes). ^{[4] [5] [6]}

Following oral administration, Dabigatran Etexilate is absorbed by the gastrointestinal tract and quickly and completely metabolized in Dabigatren, the active form dosed in the plasma. Dabigatran Etexilate can therefore be considered a protharmaco intended for hydrolysis in Dabigatran, conversion catalyzed by a specific outset.
The absolute bioavailability of the molecule after OS administration is quite low, wandering around 6.5%.
After oral administration, the plasma concentrations of the molecule increase rapidly and the peak concentration is reached within 30 minutes – 2 hours after taking. ^{[7] [8]} The simultaneous administration of a meal does not seem to alter the bioavailability of Dabigatran Etexilate, but involves a delay of about 2 hours over the time necessary to achieve the peak plasma concentration. The link with human plasma proteins is quite low, equal to 34-35%, and independent of concentration.

The terminal half -life after multiple doses was about 12 – 14 hours, and appears independent of the dose. The same half -life tends to be prolonged in subjects where renal function is compromised: from the studies it should be noted that after an intravenous dose of Dabigatran Radiomercato, radioactivity was largely eliminated by renal route (about 85%), while the elimination Facal via was estimated at about 6% of the dose administered. In the human body Dabigatran is combined with the formation of acilglucuronid compounds, pharmacologically active. However, the molecule is mainly eliminated with the urine in unchanged form.

The drug was initially approved for adults in the primary prevention of thromboembolic events in subjects subjected to total elective replacement surgery of hip or knee. ^{[9] [ten]}

Starting from summer 2013, the Italian drug agency (AIFA) has granted the reimbursement to the Dabigatran ^[11] Also for the prevention of cerebral stroke and systemic embolism in adult patients with non -valve atrial fibrillation and one or more risk factors (including previous stroke or transient ischemic attack or systemic embolism, fraction of ejection of the left ventricle of less than 40% , symptomatic heart failure (NYHA class ≥ 2), age of over 65 years associated with diabetes mellitus, coronary artery or hypertension). ^[twelfth] , or unstable in the last six months with time spent in the range (TTR) <70%.

Following the evidence that emerged from the RE-CEO studio, in the United States the FDA authorized the use of Dabigatran only in the high dose (300 mg/day) in patients with atrial fibrillation not valve ^[13] .

The clinical evidence of Dabigatran’s effectiveness was evaluated in the Re –ry study (Randomized Evaluation of Long -Term Anticaglant Therapy) ^[14] , a multi-centric, international, randomized study, in parallel groups that compared two doses of the drug administered blind (110 mg and 150 mg twice a day) compared to Warfarin in open.

18,113 patients were randomized in the Re –ry studio, with an average age of 71.5 years and an average Chads2 score of 2.1. For patients randomized in Warfarin, the average percentage of the time in the therapeutic interval (TTR) (INR 2–3) was 64.4% (67% median TTR).

The Re –ry has shown that the Dabigatren, at a dose of 110 mg/bid, is not less than Warfarin in the prevention of stroke and systemic abolia in subjects with atrial fibrillation, also highlighting a reduced risk of intracranial bleeding, of total bleeding and greater bleeding. The dose of 150 mg/bid was significantly more effective than Warfarin in reducing the risk of ischemic and hemorrhagic stroke, vascular death, intracranial bleeding and total bleeding. The incidence of greater bleeding with this dose was comparable to Warfarin.

However, patients with atrial fibrillation who already take Warfarin with an excellent value of INR, do not always come switchati Al Dabigatran. ^[15]

When the risk is significant and the INR cannot be maintained within the reference interval, the Dabigatren is an excellent alternative to Warfarin ^{[16] [17]}

Dabigatran was also studied in the field of antitrombotic therapy in patients with atrial fibrillation and ischemic heart disease, in the prevention and treatment of venous thromboembolism, and in other clinical scenarios. ^[18]

On 28.06.2012 the American Heart Journal published the design of the Re-Align study, the first clinical study that aims to evaluate the use of oral anticoagulant Dabigatran Etexilate as an alternative to Warfarin (current long-term treatment standard) for Patients with mechanical cardiac valves must undergo an anticoagulant therapy.

• Prevention of episodes of venous thromboembolism in subjects subjected to elective knee or hip surgery surgery

In the adult the recommended dosage of Dabigatran is 220 mg (equal to two 110 mg capsules), once a day. The treatment should start by OS within 4 hours of the end of the intervention with a capsule and continue, starting from the next day, with 2 capsules, always once a day. In knee surgery, the treatment continues for 10 days, while in the case of hip surgery it is recommended to continue the treatment for a period of 4-5 weeks.

In September 2013 AIFA issued an information note agreed with the European Medicines Agency (EMA) in which it is underlined that Dabigatren does not require routine monitoring of anticoagulant activity, but that, however, clinical studies and post- Marketing have shown that major bleeding events, and among these the same fatal events, are not limited to the use of vitamin K or low -shaped vitamin K vitamin (EBPM) but are also significant for Dabigatran and the new oral anticoagulants . ^[19] Based on these “evidence”, nothing prevents you from being controlled the INR with the intake of Dabigatran, but the blood test is paid and not paid by the health service.

• hypersensitivity to the active ingredient or to any of the excipients
• severe renal failure (cicr <30 ml/min)
• Clinically significant active bleeding
• organic lesion at risk of bleeding
• spontaneous or pharmacological alteration of the hemostasis
• Hepatic insufficiency or liver disease that may have any impact on survival
• concomitant treatment with systemic ketoconazole
• Concomitant treatment with Dronedarone (Multaq)

In the event of overdose or hemorrhagic complications, a suspension of the treatment with Dabigatren is recommended and the origin of bleeding must be studied. Since the drug is mainly excreted by renal way, adequate diuresis must be supported to facilitate the elimination of the drug. Appropriate treatments such as surgical hemostasis, or the administration of fresh frozen plasma or whole blood must be taken into consideration. Since the bond with proteins is low, Dabigatren can be dialyzed. The clinical experience that demonstrates the usefulness of this approach to clinical studies is limited.

Experimental studies on animals have highlighted a reproductive toxicity of Dabigatran whose administration can lead to a decrease in the systems and an increase in pre-system loss. In addition, a drop in body weight of the fetus, fetal vitality and an increase in fetal variations as well as of fetal mortality has been observed.
In pregnant women the drug has not been experienced, therefore the actual risks cannot be excluded.
It follows that women in fertile must avoid any pregnancy during treatment with Dabigatran Etexilate.