Generic Name: Dabigatran
Brand Names: Various around the world
What is Dabigatran;
Dabigatran is an oral anticoagulant medication used to prevent blood clots. Dabigatran side effects will be extensively analysed later in the text. Popular brand names containing this generic medicine include Pradaxa, Pradaxar, Prazaxa, and Predaxa. Dabigatran was first discovered and synthesised in the early 2000s by researchers at the pharmaceutical company Boehringer Ingelheim in Germany. It was approved for medical use in the European Union in 2008 and in the United States in 2010. In this article, we will analyse information from key medical journals and research papers concerning the specific active ingredient dabigatran etexilate, rather than focusing on the various brand names.
An oral anticoagulant medication called dabigatran is used to stop blood clots. In the early 2000s, scientists at the German pharmaceutical company Boehringer Ingelheim made the first discovery and synthesis of it. In 2008, the European Union legalised its usage for medicinal purposes, and in 2010, the United States did too.
Dabigatran is a member of the group of medications known as direct thrombin inhibitors. It functions by preventing the action of thrombin, an enzyme essential to the process of blood clotting. Dabigatran helps people who are more susceptible to blood clots by blocking thrombin.In individuals with nonvalvular atrial fibrillation, the medication is often administered to prevent stroke and systemic embolism in addition to treating and preventing deep vein thrombosis and pulmonary embolism.
Without concentrating on the different brand names, we will examine data on the particular active ingredient dabigatran etexilate from scholarly articles and prestigious medical journals in this post. We will examine this significant anticoagulant’s chemical makeup, mode of action, dosage, indications, adverse effects, safety measures, and interactions in detail.
Chemical Structure and Mechanism of Action
Dabigatran, also known as β-alanine, is a chemical(hexyloxy)carbonyl]amino]-N-[[2-[[[4-[[[]phenyl]amino]methyl] iminomethyl]5-yl]carbonyl] -1-methyl-1H-benzimidazole-5A strong, low molecular weight direct inhibitor of thrombin is -N-2-pyridinyl-ethyl ester.
In the journal Arteriosclerosis, Thrombosis, and Vascular Biology, Eisert et al. noted in their article “Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin” that dabigatran etexilate is a prodrug that is quickly hydrolyzed in plasma and liver by esterase.
The dabigatran molecule is made up of an aromatic group that interacts with the protein’s hydrophobic centre and a peptidomimetic benzamidine group that attaches to thrombin’s active site. Dabigatran functions as a strong, competitive, reversible inhibitor of thrombin that is both free and clot-bound because to its structure.
Dabigatran blocks thrombin directly, which stops the coagulation cascade in several places:
- It stops fibrinogen from becoming fibrin.
- It prevents coagulation factors V, VIII, XI, and XIII from becoming activated.
- stops the activation of platelets mediated by thrombin.
These processes contribute to the anticoagulant effect of dabigatran and result in a marked decrease in the formation of clots. Dabigatran targets thrombin exclusively, unlike other anticoagulants like warfarin, and doesn’t influence other clotting factors. This may help explain why it has a favourable safety and effectiveness profile.
Uses
Dabigatran is used to treat and prevent a number of thrombosis-related conditions. Its primary use in individuals with non-valvular atrial fibrillation is to avoid stroke and systemic embolism. A common cardiac arrhythmia called atrial fibrillation significantly raises the chance of blood clots developing in the heart, which can then go to the brain and result in a stroke.
In a research that was published in the journal Thrombosis and Haemostasis, Carmo et al. assessed the safety and effectiveness of dabigatran in atrial fibrillation patients treated in actual clinical settings. The outcomes validated data from earlier clinical studies, demonstrating that dabigatran had satisfactory safety profile along with excellent stroke prevention.
Dabigatran is also recommended for the treatment and prevention of pulmonary emboli and deep vein thrombosis (DVT) (PE). A blood clot in a deep vein, generally in the legs, is called deep vein thrombosis (DVT). PE is a potentially fatal consequence that can occur if the clot breaks off and goes to the lungs. Numerous clinical trials have shown that dabigatran is an effective therapy and preventive for many illnesses.
Furthermore, dabigatran is utilised to shield patients having orthopaedic surgery, such as complete hip or knee replacements, against venous thromboembolic illness (VTE). The danger of blood clots arising from these surgeries is higher because of the surgical damage to the vasculature and the immobilisation that follows the procedure.
Dabigatran is now being researched for possible novel uses outside of its approved indications. Its use is being researched, for instance, to stop thromboembolic episodes in cancer patients, who are especially vulnerable to thrombosis. Additionally, dabigatran is being researched as a potential therapy for a number of cardiovascular diseases, including acute coronary syndrome.
Dabigatran is not appropriate for many people, despite the fact that it has several advantages over earlier anticoagulants. Its usage needs to be tailored to each patient’s unique features and medical history, taking into consideration things like bleeding risk, renal function, and co-administration of other medications.
Dabigatran Side Effects
Dabigatran can have adverse effects, much like any medication, albeit not everyone experiences them. While the majority of side effects are minor and temporary, some might be more significant and need medical treatment.
Common Dabigatran Side Effects
Gastrointestinal side effects include diarrhoea, nausea, stomach discomfort, and indigestion are among the most frequent adverse effects of dabigatran. These adverse effects typically emerge with therapy and go away with time. Anaemia, bleeding gums or nose, and easy bruising are other typical adverse effects.
In clinical studies, the rates of discontinuation owing to side effects were comparable for warfarin and dabigatran, as per a study by Sanford and Plosker published in the journal Drugs. As opposed to warfarin, dabigatran was linked to greater incidence of dyspepsia.
Rare but Possible Dabigatran Side Effects
Allergy-related adverse symptoms like rash, itching, or swelling of the lips, tongue, or face are less frequent side effects of dabigatran. Anaphylaxis, a severe allergic reaction that has to be treated right once, can happen in certain situations.
Liver dysfunction is another uncommon adverse effect that might include symptoms including weariness, dark urine, and skin or eye yellowing. Serious skin responses, including toxic epidermal necrolysis and Stevens-Johnson syndrome, have been described in extremely rare occasions.
Serious Dabigatran Side Effects
Like other anticoagulants, dabigatran’s greatest drawback is its elevated risk of bleeding. Dabigatran may raise the risk of gastrointestinal bleeding, especially in senior individuals, despite the fact that it is typically linked to a decreased risk of cerebral haemorrhage when compared to warfarin.
Prolonged or severe bleeding, intense headaches, lightheadedness, weakness, and paleness are all indicators of severe bleeding. If a patient has these symptoms, they should notify their physician right once. It could be essential to cease taking dabigatran and give the targeted antidote, idarucizumab, in situations of severe bleeding.
Since the kidneys play a major role in the elimination of dabigatran, individuals with poor renal function are more likely to have substantial adverse effects. To ensure proper dosage modification, renal function must be determined before to beginning dabigatran medication and again at regular intervals throughout the course of treatment.
Warnings
As a potent anticoagulant, dabigatran must be used carefully and under constant observation to reduce the possibility of side effects. Patients should disclose to their doctor any medical problems or drugs that may enhance the risk of bleeding before beginning dabigatran therapy.
Dabigatran should not be administered to anyone who have blood coagulation abnormalities, a history of severe bleeding, or active pathological bleeding. Furthermore, individuals with significant renal impairment should not use dabigatran since decreased renal excretion of the medication might result in an increased anticoagulant effect.
Eisert et al. note that patients using concurrent antiplatelet medicines, nonsteroidal anti-inflammatory drugs (NSAIDs), and serotonin reuptake inhibitors (SSRIs) should use dabigatran with care as these treatments might impact hemostasis. When these medications are used with dabigatran, the risk of bleeding increases substantially.
To reduce the risk of perioperative bleeding, patients having invasive procedures or surgeries might need to temporarily stop taking dabigatran. The type of procedure and the patient’s renal health determine how long the interruption will last. Patients should speak with their surgeon prior to any planned procedure.
When undergoing dabigatran therapy, women who are potentially fertile should utilise reliable contraception. Dabigatran should not be taken during pregnancy unless the benefits are clearly greater than the risks, as evidenced by animal research suggesting that it may cause damage to the foetus.
Dabigatran may be less effective at preventing thromboembolic events if doses are skipped. It is important for patients to consistently take their medicine as prescribed by their physician. Unless the following dosage is practically due, a missing dose should be taken as soon as possible.
To summarise, dabigatran presents notable advantages for individuals who are susceptible to thromboembolic incidents; yet, its administration necessitates prudence and a customised strategy. Patients should be continuously watched for indications of problems and adequately informed about any possible hazards. For many people, dabigatran can be a safe and effective therapeutic choice with the right patient selection and supervision.
Precautions
When using dabigatran in specific patient categories, vigilance is necessary. Modest renal impairment patients (creatinine clearance 30–50 mL/min) would need to have their dosage adjusted and have their renal function closely monitored. Dabigatran should be taken cautiously in individuals with mild to severe hepatic impairment since the drug’s metabolism may be impacted.
Using dabigatran may put elderly patients—especially those over 75—at higher risk of bleeding problems. As noted by Carmo et al., renal failure and comorbidity are more common in the senior population, which might account for some of this. As a result, renal function and patient characteristics should be taken into account while choosing and monitoring a dosage.
Patients with gastritis, esophagitis, or gastroesophageal reflux disease should use dabigatran with care since it may raise the risk of bleeding in the gastrointestinal tract. Patients should be constantly watched for indications of gastrointestinal bleeding, especially while starting treatment.
Contraindications
In some cases, dabigatran should not be used since the hazards of the medication clearly outweigh any potential advantages. Dabigatran should not be administered to patients with severe renal impairment (creatinine clearance <30 mL/min) because drug buildup may result in an excessive anticoagulant effect and an increased risk of bleeding.
Dabigatran should not be administered to anybody who has active pathological bleeding or is at high risk of bleeding, such as individuals who have trauma, stomach or intestinal ulcers, or recent cerebral haemorrhage. According to Sanford and Plosker, individuals who have previously had hypersensitivity to dabigatran or any of its excipients should not use the medication.
Dabigatran shouldn’t be administered to patients with severe liver impairment or liver illness that is anticipated to have a detrimental effect on survival because liver impairment can alter the pharmacokinetics and pharmacodynamics of the medication. Additionally, individuals taking strong P-glycoprotein inhibitors, like ketoconazole, should not take dabigatran since this might result in overexposure to the drug and a higher risk of bleeding.
Interactions
Dabigatran’s pharmacokinetics and pharmacodynamics may be impacted by interactions with other medications. Strong P-glycoprotein inhibitors can raise dabigatran plasma levels dramatically, which can increase bleeding risk. Examples of these inhibitors are ketoconazole, cyclosporine, and itraconazole. As a result, using these medications concurrently with dabigatran has to be avoided.
Eisert et al. have shown that medications that impact hemostasis, such SSRIs, NSAIDs, and antiplatelet medicines (like aspirin and clopidogrel), can raise the risk of bleeding when used with dabigatran. In the event that concurrent usage is required, patients should have vigilant monitoring for bleeding symptoms.
Drugs like carbamazepine and rifampicin that cause P-glycoprotein might lower the plasma levels of dabigatran and perhaps lessen its efficacy. It is important to take caution when taking these medications concurrently with dabigatran; a dosage change for dabigatran may be necessary.
Overdose
Dabigatran overdosing can result in increased anticoagulant activity and a markedly elevated risk of bleeding. Any location of bleeding, hematuria, dark or bloody faeces, strange bruises, lightheadedness, or weakness are examples of overdose symptoms.
If a dabigatran overdose occurs, therapy should be discontinued right once, and supportive care should be started. Hemodialysis can be used to eliminate dabigatran from the bloodstream, activated charcoal can be used to limit medication absorption, and blood transfusions or clotting factors can be given to counteract severe anticoagulation.
In situations of life-threatening or uncontrollably bleeding, idarucizumab, a specialised dabigatran antidote, can be used to quickly reverse the anticoagulant effect of dabigatran, as reported by Sanford and Plosker in their paper “Dabigatran etexilate” published in the journal Drugs. Dabigatran binds to idarucizumab with a high affinity, counteracting its anticoagulant action.
To prevent major bleeding consequences, individuals with suspected dabigatran overdose need to be closely monitored and get prompt medical examination. Healthcare providers should be knowledgeable with dabigatran overdose prevention techniques and equipped to respond quickly and appropriately in these situations.
Additional important information
Development of resilience
Over the course of long-term treatment, it is crucial to take dabigatran resistance into account. It has been proposed that alterations in P-glycoprotein expression and function may contribute to the emergence of dabigatran resistance, despite the fact the precise mechanism is still unclear. Monitoring the clinical response closely and adjusting the dosage as needed might help resolve this problem.
Preclinical and Clinical Studies
Many preclinical and clinical trials have assessed the safety and effectiveness of dabigatran. Dabigatran showed strong anticoagulant activity and effectiveness in averting thromboembolic events in animal models in preclinical investigations. In preclinical studies, dabigatran showed a good safety profile without hepatotoxicity or other notable side effects, according to Eisert et al.’s article “Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin” published in the journal Arteriosclerosis, Thrombosis, and Vascular Biology.
Dabigatran has been demonstrated in phase III clinical studies to be either equally or more effective than warfarin in preventing stroke in people with atrial fibrillation, while also carrying a comparable or decreased risk of serious bleeding. Several clinical trials have shown that dabigatran is effective in treating and preventing pulmonary emboli and deep vein thrombosis.
Post-approval studies, Pharmacovigilance and Pharmacokinetic characteristics
Dabigatran has been the subject of ongoing research and monitoring since it was approved in order to assess its efficacy and safety in actual use. Research on pharmacovigilance has revealed few instances of severe bleeding, especially in older individuals with impaired kidney function. Carmo et al. have noted that, in clinical practice, the overall risk of significant bleeding with dabigatran appears to be either reduced or equivalent to that of warfarin.
The pharmacokinetic properties of dabigatran are predictable; it rapidly absorbs when taken orally and reaches peak plasma concentrations in one to three hours. Dabigatran has a bioavailability of about 6.5% and is primarily excreted through the kidneys. In individuals with normal renal function, the half-life of dabigatran is around 12–17 hours; however, in patients with renal impairment, this half-life may be greatly extended.
It’s crucial to remember that dabigatran is more convenient for patients because it has less documented interactions with food and other medications than warfarin. However, the lack of a particular antidote (until recently with the release of idarucizumab) and the lack of readily accessible ways to monitor anticoagulant activity have been regarded as drawbacks of dabigatran treatment.
All things considered, dabigatran is a major advancement in anticoagulant treatment, providing a simple, safe, and effective choice for a variety of indications. Our knowledge about the best way to utilise this medication in clinical practice will continue to grow as a result of ongoing study and observation.
Comparative effectiveness
Numerous studies have assessed dabigatran’s relative efficacy in comparison to other anticoagulant medications. Dabigatran has demonstrated comparable or greater efficacy in avoiding stroke in individuals with atrial fibrillation when compared to warfarin, while also carrying a decreased risk of cerebral haemorrhage. Nonetheless, several studies linked dabigatran to an increased risk of gastrointestinal bleeding.
When compared to other direct oral anticoagulants (DOACs), dabigatran seems to be just as safe and effective as rivaroxaban and apixaban. The choice of medicinal drug may be influenced by variations in side effect profiles and patient preferences, though.
Systematic reviews and meta-analyses
A number of systematic reviews and meta-analyses have compiled the information currently known about the safety and effectiveness of dabigatran. Dabigatran was shown to be at least as efficient as warfarin in avoiding stroke in patients with atrial fibrillation, according to a meta-analysis by Sanford and Plosker that was published in the journal Drugs. However, dabigatran has a similar risk of severe bleeding and a reduced risk of cerebral haemorrhage.
Dabigatran has been compared with other DOACs in various meta-analyses. Dabigatran and other DOACs for the prevention of stroke in atrial fibrillation did not vary significantly in terms of efficacy or safety, according to an analysis by Carmo et al. that was published in the journal Thrombosis and Haemostasis. To validate these results, the authors did note out that further direct comparative research is necessary.
Current research directions and future perspectives
Dabigatran is the subject of various areas of current study. The creation of better techniques for dosage titration and anticoagulant activity monitoring is a major topic of focus, especially for individuals with renal impairment or other risk factors. Another area of ongoing research is personalised therapy based on biomarkers and patient features.
Furthermore, research is being done to assess the efficacy of dabigatran in novel patient groups and indications, such as the treatment of thrombosis in individuals with antiphospholipid syndrome or the avoidance of thromboembolic events in cancer patients. Another key topic of interest is the ongoing investigation of dabigatran resistance mechanisms and strategies to counter them.
In the future, efforts will concentrate on improving the clinical practice of dabigatran use, based on new data from real-world research and continuous pharmacovigilance. Future study might also focus on creating novel treatment regimens and examining any possible synergistic effects with existing antithrombotic medications.
To sum up, dabigatran is a significant advancement in anticoagulant therapy that provides a reliable, secure, and easy substitute for conventional treatments. many though it has already greatly altered clinical practice, continued research and development should enhance its use and enable it to assist many more people in the future.
Briefly
An oral anticoagulant medication called dabigatran is used to treat and prevent thromboembolic conditions. It is a member of the class of direct thrombin inhibitors and inhibits the development of clots by blocking the transformation of fibrinogen into fibrin. Dabigatran is primarily prescribed to treat and prevent pulmonary emboli and deep vein thrombosis in individuals with non-valvular atrial fibrillation, as well as to avoid stroke.
Compared to conventional anticoagulants like warfarin, the medication has a number of benefits, including as consistent anticoagulant activity, less monitoring requirements, and fewer food and drug interactions. Dabigatran, like all anticoagulants, has a risk of bleeding, thus patients who have renal impairment or other risk factors should use caution when using it.
All things considered, dabigatran is a significant advancement in anticoagulant treatment, providing a simple, safe, and effective choice for a variety of indications. Future research looks to expand its advantages to even more people and enhance its use even more. Like any medication, dabigatran should be used according to each patient’s unique needs and medical history, and it should be closely monitored for any potential side effects or consequences.
ATTENTION: It is of vital importance to never take any medication without the supervision and guidance of a specialised doctor. Consult the package insert of each prescribed medicinal product, as each pharmaceutical company accurately describes the specific specifications for the product, which may undergo regular updates. Note that the trade names mentioned in this article correspond to well-known medicinal products that contain the active substances under analysis. However, there may be variations depending on the composition of each drug. This article focuses on the active substance analysis rather than the drug’s trade name. The reference to trade names is made exclusively for the convenience of readers, who should carefully study the instruction leaflet for each commercial preparation they use. It is necessary to have close cooperation with your attending physician and your pharmacist. The self-administration of any medication carries serious health risks and should be strictly avoided.
Bibliography
- WG Eisert, N Hauel, J Stangier, W Wienen, H-J Clemens, JMA van Ryn. Dabigatran: an oral novel potent reversible nonpeptide inhibitor of thrombin. Arteriosclerosis, Thrombosis, and Vascular Biology, 2010. ahajournals
- J Carmo, FM Costa, J Ferreira, P Mendes. Dabigatran in real-world atrial fibrillation. Thrombosis and Haemostasis, 2016. thieme-connect
- M Sanford, GL Plosker. Dabigatran etexilate. Drugs, 2008. link.springer
