An update on the pharmaceutical management of thrombosis

ABSTRACT

Introduction: Anticoagulants such as heparins and vitamin K antagonists (VKA) are effective for thrombosis prevention and treatment, but are associated with the risk of bleeding and other limitations, spurring the search for improved drugs.

Areas covered: to evaluate the newer anticoagulants, focusing on those tested in phase III clinical trials such as direct oral anticoagulants (DOACs), antisense oligonucleotides (ASO) and warfarin analogues. DOACs such as dabigatran, rivaroxaban, apixaban and edoxaban are licensed for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, dabigatran, rivaroxaban and apixaban for postoperative thromboprophylaxis in patients undergoing elective hip or knee arthroplasty and rivaroxaban for secondary prevention of acute coronary syndromes. ASO interfering with Factor XI hepatic synthesis were effective and safe for thromboprophylaxis in elective knee arthroplasty.

Expert opinion: DOACs have overcome some limitations of anticoagulants such as VKA, but are still associated with a risk of bleeding and they lack both standardized and widely available tests measuring their anticoagulant effect and a reversal agent, except for idarucizumab, specific for dabigatran, in case of major or life threatening bleeding or emergency surgery. Agents targeting Factor XI and possibly Factor XII may be ideal anticoagulants, as they can prevent thrombosis with low bleeding risk.

KEYWORDS:

• Acute coronary syndromes
• stroke
• atrial fibrillation
• venous thromboembolism
• deep vein thrombosis
• pulmonary embolism
• thromboprophylaxis
• oral anticoagulation
• heparins
• direct oral FIIa inhibitors
• direct oral FXa inhibitors
• antisense oligonucleotides
• warfarin analogues

Article highlights

• Anticoagulants for thrombosis prevention and treatment such as heparins and VKA are associated with the risk of bleeding and have several limitations, which have prompted the search for improved drugs

• Direct oral anticoagulants (DOACS- targeting FIIa such as dabigatran or FXa such as rivaroxaban, apixaban, edoxaban) have overcome several of the limitations of heparins and VKA and can be administered at fixed doses without the need for laboratory monitoring.

• DOACs have been licensed for thromboprophylaxis in major orthopedic surgery, VTE treatment and stroke prevention in atrial fibrillation, secondary prevention after ACS in adults with elevated cardiac biomarkers in combination with standard antiplatelet therapy (for the latter only rivaroxaban).

• DOACs are associated with a similar or lower risk of bleeding, higher for gastrointestinal bleeding and half for intracranial bleeding, when compared to VKA.

• Idarucizumab, specific for dabigatran, is the only reversal agent licensed for DOACs in case of major or life-threatening bleeding.

• Agents targeting factors of the contact pathway, such as FXI or FXII, are being developed for clinical use and they may come closer to the ideal anticoagulant, which can prevent thrombosis with a very low risk of bleeding, as these factors are involved in thrombosis but have a very limited role in hemostasis.

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Declaration of interest

B Cosmi received speaker’s fees from Bayer and Boerhinger Ingleheim and honoraria from Sanofi-Aventis, Alfa Wassermann and Daiichi Sankyo in the last five years. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.