Factor Xa inhibitors

Factor Xa inhibitors

Factor X is also known as Stuart-Prower factor. Activated Factor X (Factor Xa) converts prothrombin to thrombin, an important step in the coagulation cascade. Heparin, warfarin and fondaparinux inhibit Factor X to varying extents. Factor X is a vitamin K dependent clotting factor synthesized in the liver and it is a serine endopeptidase. Rivaroxaban, apixaban, betrixaban and edoxaban are Factor Xa inhibitors in clinical use. They are orally active direct Factor Xa inhibitors.

Rivaroxaban

Rivaroxaban has a bioavailability of eighty percent after oral administration. Factor Xa inhibition after administration of rivaroxaban lasts about a day. Two thirds of the drug is metabolized by the liver and half of the metabolites are excreted each by the kidney and the liver. Hence rivaroxaban use will not be recommended in severe hepatic or renal dysfunction. Phase II evaluation of rivaroxaban was by ATLAS ACS TIMI 46 trial [1]. The study involved about three thousand and five hundred patients. It was a dose escalation trial in the setting of acute coronary syndrome. There was an excess of bleeding complications though it reduced the incidence of a composite of death, myocardial infarction and stroke.
Rivaroxaban was further evaluated in the phase III trial ATLAS ACS 2–TIMI 51 [2] in patients with recent acute coronary syndrome. The doses used were 2.5 mg and 5 mg twice daily. As expected, the lower dosage has fewer fatal bleeding events, in this study involving over fifteen thousand patients. Rivaroxaban significantly reduced the primary end point which was a composite of cardiovascular death, myocardial infarction or stroke.

Rivaroxaban alone or in combination with aspirin has been evaluated in stable coronary artery disease in COMPASS, a randomized trial involving 27,395 patients [3]. They concluded that those assigned to rivaroxaban 2.5 mg twice daily plus aspirin had better cardiovascular outcome, but more major bleeding than aspirin alone.

Apixaban

Apixaban has a half life of about twelve hours and is eliminated mainly by non renal mechanisms. Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial was a phase II trial which evaluated apixaban in the setting of recent ST elevation and non ST elevation acute coronary syndrome, in about one thousand and seven hundred patients [4]. There was a dose related increase in bleeding with apixaban and a trend towards lower ischemic events. The benefits were lesser and bleeding higher in those receiving dual antiplatelet therapy compared to those who received only aspirin.

The role of apixaban in acute coronary syndrome was further evaluated in Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), a phase III trial [5]. This study involving about seven thousand four hundred patients, was terminated prematurely due to higher bleeding risks at a dose of 5 mg twice daily and there was no significant reduction of ischemic events. It may be noted that the drug was added over and above standard antiplatelet therapy in the setting of acute coronary syndrome.

AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) study on the other hand compared the use of same dose of apixaban with varying doses of aspirin (81 to 325 mg) [6]. In this study, apixaban reduced the chance of stroke or systemic embolism without increasing major bleeding or intracranial hemorrhage. These were patients with atrial fibrillation who were not candidates for warfarin therapy and hence the results are commendable.

Edoxaban

Edoxaban has been compared with dalteparin in cancer associated venous thromboembolism in the VTE Cancer trial [7]. The study concluded that oral edoxaban was non inferior to subcutaneous dalteparin with respect to recurrent venous thromboembolism or major bleeding. Efficacy was more, but bleeding was also more with edoxaban.

Betrixaban

Betrixaban was evaluated in 7513 patients with acute medical illnesses having a risk of venous thromboembolism in the APEX trial [8]. Primary outcome measure was a composite of asymptomatic proximal deep vein thrombosis and symptomatic venous thromboembolism. There was no difference between extended duration betrixaban and standard regimen of enoxaparin in the primary efficacy outcome.

Andexanet Alfa – Antidote for factor Xa inhibitors

References

1. Mega JL, Braunwald E, Mohanavelu S, Burton P, Poulter R, Misselwitz F, Hricak V, Barnathan ES, Bordes P, Witkowski A, Markov V, Oppenheimer L, Gibson CM: Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS TIMI 46): a randomised, double-blind, phase II trial. Lancet 2009;374:29-38.
2. Mega JL, Braunwald E, Wiviott SD, Bassand JP, Bhatt DL, Bode C, Burton P, Cohen M, Cook-Bruns N, Fox KA, Goto S, Murphy SA, Plotnikov AN, Schneider D, Sun X, Verheugt FW, Gibson CM; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Jan 5;366(1):9-19.
3. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo P, O’Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Störk S, Keltai M, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S; COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Oct 5;377(14):1319-1330.
4. APPRAISE Steering Committee and Investigators, Alexander JH, Becker RC, Bhatt DL, Cools F, Crea F, Dellborg M, Fox KA, Goodman SG, Harrington RA, Huber K, Husted S, Lewis BS, Lopez-Sendon J, Mohan P, Montalescot G, Ruda M, Ruzyllo W, Verheugt F, Wallentin L. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation. 2009 Jun 9;119(22):2877-85.
5. Alexander JH, Lopes RD, James S, Kilaru R, He Y, Mohan P, Bhatt DL, Goodman S, Verheugt FW, Flather M, Huber K, Liaw D, Husted SE, Lopez-Sendon J, De Caterina R, Jansky P, Darius H, Vinereanu D, Cornel JH, Cools F, Atar D, Leiva-Pons JL, Keltai M, Ogawa H, Pais P, Parkhomenko A, Ruzyllo W, Diaz R, White H, Ruda M, Geraldes M, Lawrence J, Harrington RA, Wallentin L; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011 Aug 25;365(8):699-708.
6. Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O’Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364(9):806-17.
7. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR; Hokusai VTE Cancer Investigators. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018 Feb 15;378(7):615-624.
8. Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, Gold A, Hernandez AF, Gibson CM; APEX Investigators. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016 Aug 11;375(6):534-44.