Dabigatran, sold under the brand name Pradaxa among others, is an

anticoagulant Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where t ...

used to treat and prevent

blood clots A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...

and to prevent

stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...

in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or

knee replacement Knee replacement, also known as knee arthroplasty, is a surgical procedure to replace the weight-bearing surfaces of the knee joint to relieve pain and disability, most commonly offered when joint pain is not diminished by conservative sources ...

and in those with a history of prior clots. It is used as an alternative to

warfarin Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...

and does not require monitoring by blood tests. It is taken by mouth. Common side effects include bleeding and

gastritis Gastritis is inflammation of the lining of the stomach. It may occur as a short episode or may be of a long duration. There may be no symptoms but, when symptoms are present, the most common is upper abdominal pain (see dyspepsia). Other possi ...

. Other side effects may include bleeding around the spine and allergic reactions such as

anaphylaxis Anaphylaxis is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of use of emergency medication on site. It typically causes more than one of the follo ...

. In cases of severe bleeding, it can be reversed with the antidote, idarucizumab. Use is not recommended during

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

. Compared to warfarin it has fewer interactions with other medications. It is a direct thrombin inhibitor. Dabigatran was approved for medical use in the United States in 2010. It is on the World Health Organization's List of Essential Medicines. In 2020, it was the 306th most commonly prescribed medication in the United States, with more than 1million prescriptions. Dabigatran etexilate was approved as a generic medication in the United States in 2020.

Medical uses

Dabigatran is used to prevent

s in those with atrial fibrillation not caused by

heart valve A heart valve is a one-way valve that allows blood to flow in one direction through the chambers of the heart. Four valves are usually present in a mammalian heart and together they determine the pathway of blood flow through the heart. A heart ...

issues, as well as

deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...

and

pulmonary embolism Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream ( embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathin ...

in persons who have been treated for 5–10 days with parenteral anticoagulant (usually

low molecular weight heparin Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism (deep vein thrombosis and pulmonary embolism) and in the treatment of myocardial in ...

), and to prevent deep vein thrombosis and pulmonary embolism in some circumstances. It appears to be as effective as

in preventing non-hemorrhagic strokes and embolic events in those with atrial fibrillation not due to valve problems.

Contraindications

Dabigatran is contraindicated in patients who have active pathological bleeding, since dabigatran can increase bleeding risk and can also cause serious and potentially life-threatening bleeds. Dabigatran is also contraindicated in patients who have a history of serious hypersensitivity reaction to dabigatran (e.g.

or anaphylactic shock). The use of dabigatran should also be avoided in patients with mechanical prosthetic heart valves due to the increased risk of thromboembolic events (e.g. valve thrombosis, stroke, and

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...

) and major bleeding associated with dabigatran in this population.

Adverse effects

The most commonly reported side effect of dabigatran is gastrointestinal upset. When compared with people anticoagulated with warfarin, patients taking dabigatran had fewer life-threatening bleeds, fewer minor and major bleeds, including intracranial bleeds, but the rate of gastrointestinal bleeding was significantly higher. 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 Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

; some hypothesize that this plays a role in the increased risk of gastrointestinal bleeding. A small but significantly increased risk of myocardial infarctions (heart attacks) has been noted when combining the safety outcome data from multiple trials. Reduced doses should be used in those with poor kidney function.

Pharmacology

Mechanism of action

Dabigatran reversibly binds to the active site on the thrombin molecule, preventing thrombin-mediated activation of coagulation factors. Furthermore, dabigatran can inactivate thrombin even when thrombin is

fibrin Fibrin (also called Factor Ia) is a fibrous, non-globular protein involved in the clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerize. The polymerized fibrin, together with pl ...

-bound; it reduces thrombin-mediated inhibition of fibrinolysis and, therefore, may enhance fibrinolysis.

Pharmacokinetics

Dabigatran has a half-life of approximately 12–14 h and exerts a maximum anticoagulation effect within 2–3 hours after ingestion. Fatty foods delay the intestinal absorption of dabigatran, although the

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of the drug is unaffected.Pradaxa Full Prescribing Information
.

Boehringer Ingelheim C.H. Boehringer Sohn AG & Co. is the parent company of the Boehringer Ingelheim group, which was founded in 1885 by Albert Boehringer in Ingelheim am Rhein, Germany. As of 2018, Boehringer Ingelheim is one of the world's largest pharmaceutical ...

. October 2010. One study showed that absorption may be moderately decreased if taken with a

proton pump inhibitor Proton-pump inhibitors (PPIs) are a class of medications that cause a profound and prolonged reduction of stomach acid production. They do so by irreversibly inhibiting the stomach's H+/K+ ATPase proton pump. They are the most potent inhibitor ...

. Dabigatran excretion through

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

pumps is slowed in patients taking strong p-glycoprotein pump inhibitors such as quinidine, verapamil, and amiodarone, thus raising plasma levels of dabigatran."Pradaxa Summary of Product Characteristics" (2018)
.

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Eur ...

. Dabigatran is formulated as the

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...

dabigatran etexilate.

History

Dabigatran (then compound BIBR 953) was discovered from a panel of chemicals with similar structure to

benzamidine Benzamidine is the organic compound with the formula C6H5C(NH)NH2. It is the simplest aryl amidine. The compound is a white solid that is slightly soluble in water. It is usually handled as the hydrochloride salt, a white, water-soluble solid. ...

-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 protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Seri ...

s, specifically thrombin, but also

trypsin Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...

. Addition of ethyl

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

and hexyloxycarbonyl carbamide hydrophobic side chains led to the orally absorbed

, BIBR 1048 (dabigatran etexilate). On 18 March 2008, the

(EMA) granted marketing authorization for Pradaxa for the prevention of thromboembolic disease following hip or knee replacement surgery and for non-valvular atrial fibrillation. The

National Health Service The National Health Service (NHS) is the umbrella term for the publicly funded healthcare systems of the United Kingdom (UK). Since 1948, they have been funded out of general taxation. There are three systems which are referred to using the " ...

(NHS) in Britain authorized dabigatran for use in preventing blood clots in hip and knee replacement surgery patients. According to a BBC article in 2008, Dabigatran was expected to cost the NHS £4.20 per day, which was similar to several other

s. Initially, there was no specific way to reverse the anticoagulant effect of dabigatran in the event of a major bleeding event, unlike for warfarin. Since then, the dabigatran-specific antidote idarucizumab, a humanized

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ...

for intravenous administration, was developed, and received

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) approval in 2015. Pradaxa received a Notice of Compliance (NOC) from

Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the department of the Government of Canada responsible for national health poli ...

on 10 June 2008, 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. The U.S.

(FDA) approved Pradaxa on 19 October 2010, for prevention of stroke in patients with non-valvular atrial fibrillation. The approval came after an advisory committee recommended the drug for approval on 20 September 2010 although caution is still urged by some outside experts. On 14 February 2011, the American College of Cardiology Foundation and the American Heart Association added dabigatran to their guidelines for management of non-valvular atrial fibrillation with a class I recommendation. In May 2014, the FDA reported the results of a large study comparing dabigatran with warfarin in 134,000 Medicare patients. The agency concluded that dabigatran is associated with a lower risk of overall mortality, ischemic stroke, and bleeding in the brain than warfarin. Gastrointestinal bleeding was more common in those treated with dabigatran than in those treated with warfarin. The risk of heart attack was similar between the two drugs. The FDA reiterated its opinion that dabigatran's overall risk/benefit ratio is favorable. On 26 July 2014, the ''

British Medical Journal ''The BMJ'' is a weekly peer-reviewed medical trade journal, published by the trade union the British Medical Association (BMA). ''The BMJ'' has editorial freedom from the BMA. It is one of the world's oldest general medical journals. Origi ...

'' (BMJ) published a series of investigations that accused the privately held

pharmaceutical group of withholding critical information about the need for monitoring to protect patients from severe bleeding, particularly in the elderly. Review of internal communications between Boehringer researchers and employees by the FDA and the EMA revealed that Boehringer researchers had found evidence that serum levels of dabigatran vary widely. The BMJ investigation suggested that Boehringer had a financial motive to withhold this concern from regulatory health agencies because the data conflicted with their extensive marketing of dabigatran as an anticoagulant that does not require monitoring. In August 2012, Pradaxa claims filed in U.S. federal courts were consolidated into a multi-district litigation in the Southern District of Illinois before Chief Judge David R. Herndon. On 28 May 2014, a $650 million settlement was announced on behalf of approximately 3,900 claimants who were injured by the drug Pradaxa made by Boehringer Ingelheim Pharmaceuticals, Inc. The drug was alleged to cause severe bleeding events and/or hemorrhaging to those who were taking the drug.

References

External links

* * * {{Portal bar, Medicine Amidines Anilines Aromatic amines Benzimidazoles Boehringer Ingelheim Carbamates Carboxamides Direct thrombin inhibitors Ethyl esters Propionate esters 2-Pyridyl compounds Wikipedia medicine articles ready to translate World Health Organization essential medicines