Journal of Applied Hematology

REVIEW ARTICLE
Year
: 2015  |  Volume : 6  |  Issue : 4  |  Page : 141--147

The new, direct, target-specific oral anticoagulants


Nevine A Kassim 
 Department of Clinical Pathology, Professor of Clinical Pathology, Ain Shams University, Cairo, Egypt

Correspondence Address:
Nevine A Kassim
Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Abbassya, Cairo
Egypt

Abstract

In recent years, numerous alternatives to VKAs have been developed, the first competitors to warfarin are the novel oral anticoagulants (NOAC) or better referred to as Direct Oral Anti-Coagulant (DOAC) or Target Specific Oral Anti-coagulant (TSOAC): These drugs have definite advantages and disadvantages that should be clear to the physicians before prescribing any of them for patients. Many clinical trials, which involved thousands of patients provided definite information about the efficacy and the safety of DOACs, yet, many physicians remain reluctant to prescribe these drugs due to lack of answers to real world questions. The concerns are directed towards appropriate patient selection (The choice should be made according to age, renal function, compliance, cost, clinical condition, intake of other drugs), the mechanism of switching between agents. How to manage regarding any procedural measurement? How these drugs affect routine laboratory tests and when do we need monitoring? Knowledge of other drugs that interact with the DOAC and management of severe bleeding will be reviewed and recommendations will be given to all these concerns.



How to cite this article:
Kassim NA. The new, direct, target-specific oral anticoagulants.J Appl Hematol 2015;6:141-147


How to cite this URL:
Kassim NA. The new, direct, target-specific oral anticoagulants. J Appl Hematol [serial online] 2015 [cited 2020 Jul 11 ];6:141-147
Available from: http://www.jahjournal.org/text.asp?2015/6/4/141/171993


Full Text

 Introduction



Heparin and Vitamin K antagonist (VKA) are the two main drugs widely used from the early and mid-20th century in the treatment of vaso-occlusive events. Although heparins are safe and effective agents for the rapid initiation of treatment in acute thrombotic events and VKAs are reliable and inexpensive treatment options when long-term anticoagulation treatment is indicated, there are several limitations to their use despite of their extensive efficacy. Warfarin interacts with a multitude of drugs and foods has a delayed onset of action, has a narrow therapeutic range, requires routine therapeutic monitoring, and exhibits variability in patient response as influenced by genetic factors. Limitations of unfractionated heparin and low molecular weight heparins include hospitalization, hemorrhagic complications, frequent monitoring and adjustment dosing, and the potential development of heparin-induced thrombocytopenia.[1] The need for new orally administered anticoagulants with improved characteristics is essential.

During the last decades, excessive research has been carried out into the pathogenesis of thrombotic diseases. This has led to major efforts to produce orally administered anticoagulants with improved characteristics that probably will replace the older antithrombotic agents.

The first competitors to warfarin are the novel oral anticoagulants or better referred as direct oral anticoagulant (DOAC) or target-specific oral anticoagulant (TSOAC): Dabigatran (Pradaxa) became the first alternative to VKA as a direct thrombin inhibitor in 2010,[2] Rivaroxaban (Xarelto) became the first factor Xa inhibitor available,[3] this was followed by Apixaban (Eliquous) in 2012,[4] then Edoxaban in 2015 [Figure 1].[5]{Figure 1}

The DOAC have definite advantage and disadvantages that should be clear to the physicians before prescribing any of them for patients.

Advantages of Direct Oral Anticoagulant

Some advantages include quick onset/offset of action from the drugs (short half-lives). This allows for no required bridging with injectable anticoagulants since time from dosing to therapeutic effectiveness is short. It also allows for easy perioperative or procedure management. They have predictable kinetics and small inter-individual variation which supports use of fixed dosing regimens that are the same for all patients. No routine laboratory monitoring is needed. Medications are efficacious and relatively safe, proven to be at least noninferior to warfarin and similar/improved bleed rates in trials.[6] All three agents had reductions in intracranial hemorrhage compared to warfarin.

Limitations of the Direct Oral Anticoagulant in Comparison to Warfarin

They are more expensive. There is no antidote for easy reversibility in the management of bleeds or when urgent surgery is needed. There is a lack of accurate monitoring in suspected toxicity cases. They need to be dose adjusted for renal dysfunction (and require renal monitoring) so cannot be used in patients with moderate-severe renal impairment or prosthetic heart valves. There are some adherence concerns. Due to the short half-life of the new drugs, a missed dose can place a patient at increased risk of an adverse event or under anticoagulation. Furthermore, those DOACs with BID dosing regimen may negatively impact compliance.[6]

The new oral anticoagulants differ in their pharmacokinetic properties. While they all have a quick onset of action having an effect within 2–3 h and similar half-lives approximately 12 h. Their bioavailability, metabolism, and clearance are different [Table 1].[7]{Table 1}

 Dabigatran



Dabigatran is indicated for the (1) prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), (2) prevention of venous thromboembolic events (VTE) in patients who have undergone elective total hip replacement or total knee replacement surgery, (3) treatment/prevention of deep vein thrombosis and pulmonary embolism.[2]

Dosing differ for each indication and dosage adjustment is required for patients with moderate renal impairment and those considered at higher risk of bleeds (active peptic ulcer disease, on antiplatelets or interacting medication). Patients can also experience many gastrointestinal tract (GIT) issues; the most common is acid reflux. Ten percent of patients complain of symptoms of dyspepsia with dabigatran. It can be taken with food to minimize GIT upset but if the symptoms are not tolerable, they should be reassessed and switched to other drugs.

Dabigatran is used with special instructions for the patients.

Since the DOACs have a fast onset and offset, missing a dose puts patient at risk of events due to under anticoagulation. Specific patient instructions on how to deal with missed doses should be reviewed with patients.

Dabigatran needs to be swallowed whole; it cannot be crushed, chewed, or the capsule opened. It cannot be sprinkled as pellets in food or mix in liquids. The bioavailability may be increased 75% if the capsules are opened; this could dramatically increase blood drug levels and the risk of bleeding.

Dabigatran is hygroscopic and the capsule should therefore only be removed from the manufactures packaging at the time of ingestion and cannot be put into dosettes or pill boxes. If a patient needs a dosette or pill box, the best suggestion is to manually cut foil around capsule and place capsule into dosette in its original blister foil. This storage information is very important since it could have life-threatening consequences of subtherapeutic levels of dabigatran-related to reduced drug potency from not following the instructions.

 Rivaroxaban



It has the same indications as dabigatran. Available as 10 mg, 15 mg, and 20 mg tablets rivaroxaban only has a dosage adjustment for the AF stroke prevention in patients with moderate renal dysfunction.[3]

Special Patient Information

It is recommended to take with food to increase absorption, crushing the tablet, and mixing with applesauce helps in oral administration. It can also be crushed and suspended in water (50 mL) then administered via nasogastric tube within 4 h of mixing.

Rivaroxaban also has specific instructions for managing missed doses; these directions differ depending on the indication and dosing regimen.

 Apixaban



It has indications for the prevention of stroke and systemic embolism in patients with nonvalvular AF and prevention of VTE in patients who have undergone orthopedic arthroplasty.

A dosage adjustment is recommended for moderate renal dysfunction and patients at higher bleeding risk if used for AF stroke prevention.[4]

Like the other DOACS, apixaban is quite well-tolerated with a similar side effect profile.

Apixaban has some minimal special patient information. It includes missed dose instructions, not to chew the tablets and to take with food if have any stomach upset.

Although many clinical trials, which involved thousands of patients provided definite information about the efficacy and the safety of TSOACs, many physicians still remain reluctant to prescribe these drugs due to lack of answers to real world questions. The concerns are directed toward appropriate patient selection, switching between agents, periprocedural management, laboratory monitoring, interaction with other drugs and diet, and management of severe bleeding.

 Selection of Patients



The choice should be made according to age, renal function, compliance, cost, clinical condition, and intake of other drugs. Some patients will have many of these characteristics so it will take clinical judgment to guide the choice of drugs.[8]

Age – for younger patients with good kidney function – DOAC is preferred. When patients get to 75 or 80 years old, its likely DOAC is still the preferred agent but may need to use lower doses or choose apixaban for its less bleeds and ability to be used at greater kidney impairment.

For any compromised renal dysfunction or creatinine clearance (CrCl) <50 mL/min, warfarin is the safest as it is mainly eliminated through the liver. For moderate renal dysfunction defined as CrCl 30–50 mL/min, lower doses of the DOACs is an option.

If time in therapeutic range (TTR) is >65%, the patient is already stable on warfarin and has no bleeding, might as well continue therapy. If patient has history of poor international normalized ratio (INR) control, despite good compliance with warfarin as indicated by TTR <65%, DOAC may be better option.

If patient has compliance issue, none of the drugs are preferred as likely they are not regularly taking any of them. Warfarin is preferred since it can be monitored by INR. This is not possible with the DOACs.

DOAC is contraindicated in severe liver and/or renal disease, mechanical heart valves, rheumatic heart disease, valvular AF, recent major bleeding, acute stroke or systemic embolism, pregnancy or breastfeeding, and interacting medications.

The ideal candidate for DOAC is new diagnosis of nonvalvular AF since they work as well or maybe even better than warfarin depending on drug and dosage.

Patients with recent coronary artery disease or those that have had angioplasty and are required to take dual antiplatelet therapy with drugs such as acetylsalicylic acid, clopidogrel, prasugrel or ticagrelor – should be on warfarin if they require an oral anticoagulant. There is not much experience or trial information on the use of DOAC in this patient population. Dabigatran also showed a possible trend for increased myocardial infarctions. Patients that do want to use warfarin may be able to use a DOAC later on, either after elapsed time from their coronary event or when they are not taking multiple antiplatelets/anticoagulants together.

Dabigatran and rivaroxaban had trial evidence for more gastrointestinal bleeds, so these patients should be on warfarin or could use apixaban as the DOAC option.

Patients with dyspepsia should not be on dabigatran as it is its most common side-effect. The other DOACs are good choices.

Any patient who has had issue with past warfarin uses such as therapy failure, side-effects, allergy, or barriers to laboratory monitoring should be on a DOAC.

Patients with high bleeding risk would have warfarin as agent of preference. Apixaban may be an option since it seems to have lesser bleeds when compared to other DOAC.

 Switching between Agents



Patients in many occasions will switch between anticoagulants for a variety of reasons in a variety of settings, switching from warfarin to DOAC or from DOAC to warfarin or between DOACs [Table 2].[9]{Table 2}

 Periprocedural Management



Patients may need to interrupt their oral anticoagulant therapy for any surgical procedures, or major dental work. The duration of holding the drug depends on the type of procedure or surgery, its bleeding risk, and the patient's renal function.[10] There is no drug administration the day of surgery. If a patient has good kidney function and is performing a major procedure (cardiac surgery, neurosurgery, major cancer), he/she should not take the drugs for a full 2 days. If the same patient is going for a low bleeding risk procedure, he/she should not take the drugs for 1 full day. If patient has reduced renal function, he/she should hold medications for longer.

Resuming therapy: It is important that patients are aware they need to resume their oral anticoagulant therapy postprocedure or surgery. Usually, resumption of therapy occurs when adequate hemostasis has been achieved or clinical situation allows.[11] This is usually 24 h postoperatively for a low bleeding risk surgery and 48 h for a high bleeding risk surgery. For patients at high risk of thromboembolism, consider administering a reduced dose of the oral anticoagulant on the evening after surgery and on the 1st postoperative day for high bleeding risk surgeries. This needs to be decided on an individual basis.

 Laboratory Monitoring



While routine monitoring of DOAC is not required and it is one of the advantages of these drugs, yet there are certain circumstances in which measuring and quantifying the degree of anticoagulation is beneficial, such as hemorrhagic events, assessing of compliance, assess of efficacy or overtreatment in patients with severe renal or liver insufficiency, drug interaction and evaluation of anticoagulant effect, and monitoring of patients with treatment failure, and recurrent thrombotic episode.

 Dabigatran



Prolongs activated partial thromboplastin time (aPTT) in an insensitive manner, aPTT determination may vary according to the type of the coagulometer and the sensitivity of the reagents. It is insensitive to prothrombin time (PT). Thrombin time (TT) is sensitive and expresses a linear dose-related response in patients on therapeutic concentration.

Hemoclot assay is a diluted TT assay that is suitable for the measurement of the activity of thrombin inhibitors. A specific modification of this assay specific for the determination of Dabigatran will soon be commercially available.[12]

Ecarin clotting time (ECT) is an assay indicating thrombin generation. ECT probably provides a sensitive method for assessing the anticoagulant activity of direct thrombin inhibitors (research purposes).

As a conclusion, the International Society on Thrombosis and Haemostasis (ISTH) in 2013[13] recommended a calibrated diluted TT test to be used to determine the drug level. The aPTT can be used to determine the relative intensity of anticoagulation caused by dabigatran in emergency. Each laboratory should be aware of the sensitivity of their aPTT assay. This can be achieved by the use of commercially available plasma calibrators.

 Rivaroxaban



It induces a concentration-related INR prolongation. Results show significant variation related to the type of thromboplastin used [Figure 2]. Effect on aPTT is weak. Anti-Xa activity determination indicates rivaroxaban activity and is dependent on plasma concentration. It is time-consuming, not available in all laboratories and its utility needs further evaluation.[14] Dilute Russell's viper venom time can be used but needs further evaluation. Thrombin generation test is not widely available.{Figure 2}

As a conclusion, the ISTH in 2013 (recommended that anti-Factor X assay (without exogenous ATIII) can be used to determine drug level. A PT assay can be used to determine the relative intensity of anticoagulation caused by rivaroxaban in an emergency. Each laboratory should be aware of the PT reagent sensitivity using commercially available calibrators [Table 3].{Table 3}

The DOAC can affect other coagulation assays as the drug act as an inhibitor (incomplete correction with 1:1 mixing study), so there is a potential for false positive Lupus Anticoagulant and Bethesda assay. It may also interfere with clotting based methods (Protein S) and some chromogenic (ATIII) activity assay. On the other hand, there are assays that are not affected by the DOAC as D-Dimer, Factor V Leiden, and platelet function.[16]

 Interaction With Other Drugs and Diet



Although one of the advantages of the DOAC over warfarin is the little effect of interaction of drugs yet, there are many pharmacodynamics and pharmacokinetic effects with other medications, which can lead to increase or decrease the effect of the drug [Table 4].[17]{Table 4}

 Management of Bleeding



The lack of an effective antidote and lack of definitive information about how best to manage patients with DOAC-associated life-threatening bleeding probably leads many physicians to avoid prescribing DOACs. There are no evidence-based guidelines to how to manage major bleeding. Oral activated charcoal, red cell transfusion, hemodialysis, fresh frozen plasma, and activated Factor VII are all tried empirically.

The issue of bleeding is exaggerated. The half-life of the drug is short and during the RE-LY trial, during which 399 patients taking dabigatran 150 mg BID experienced a major hemorrhage. Only 2 (0.5%) and 7 (1.8%) received either PCC or rFVIIa, respectively.

This is indirect evidence that, in the majority of nearly 400 cases of dabigatran-related major bleeding, the treating physician saw no need to escalate beyond supportive care such as red blood cells transfusion.[18]

Recently an antidote to dabigatran is launched the idarucizumab, which will definitely encourage more the use of the drug by physicians.[19]

 Conclusion



DOACs have become viable alternatives to conventional oral anticoagulants and have advantages of fixed-dose oral dosing, relatively rapid onset and offset, and fewer drug–drug interactions compared with warfarin. Common errors related to DOAC use include prescribing to inappropriate patients, recommending an inappropriate dose or administration, and inappropriate monitoring. Optimal use of DOACs requires familiarity with pharmacokinetic/pharmacodynamic profiles various dosing strategies, laboratory monitoring, periprocedural strategies, switching strategies, and general approaches to bleed management.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

There are no conflicts of interest

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