Healthcare e-Compendium

A joint initiative of DPSRU & DRSC


Alriza, A Novel Oral Anticoagulant Rivaroxaban With Direct Factor Xa Inhibitor And Convenient Dosing

Author: Dr. Nirmal Jain

M.B.B.S, MD, DM, Director, Manisha Universal Multispeciality Hospital, Mumbai

download Article



Rivaroxaban treats and manages venous thromboembolism as a post-operative thromboprophylaxis for patients going through surgery to avert stroke in patients with non-valvular atrial fibrillation and recently has received аррrоvаl аs аn аdd-оn drug for seсоndаry рreventiоn of асute соrоnаry syndrome and рeriрherаl аrteriаl disease.  It is а novel оrаl аntiсоаgulаnt (NОАС) and is соmmоnly referred to as а blооd thinner agent. 

Keywords: COVID-19, Anti-coagulants, Atrial fibrillation, Intracerebral haemorrhage, Ischemic stroke, Rivaroxaban



The rise of prevalence of thromboembolism associated to COVID-19 has become a worldwide concern, with many surveys reporting increased rate of mortality. Thrombogenic possibility of the SARS-CoV-2 virus has been assumed by hypothesis to arise from its ability to produce an exaggerated inflammatory response leading to endothelial dysfunction. Anticoagulants have remained the primary modality of treatment of thromboembolism for decades [1, 2].


COVID-19 and the Development of Blood Clots

During COVID-19 infection, SARS-CoV-2 after entering into systemic circulation, binds with the ACE2 expressing endothelial cells (endothelium) present on blood vessels lining. Binding helps the virus internalization, inflicting contamination and harm inside the vascular wall of blood vessels [3]. The vascular damage may result in vasoconstriction, which can also further lessen the blood float on the site of injury. Also, damage to endothelial cells reduces the expression of fibrinolytic heparin and thrombomodulin. Conversely, high expression and secretion of the Von Willebrand factor enhance the aggregation of platelets at the site of injury in blood vessels and activate the coagulation cascade for the formation of blood clots (figure 1) [4].


Figure 1: Schematic representation showing the mechanism of clot formation in the blood vessels when the endothelial cells rich in ACE2 receptors are targeted by SARS-CoV-2 and resulted in the haemorrhagic injury, resulting in the cascade of blood clot formation


Anticoagulant Boost Survival Rates of COVID-Infected Patients

The research establishes orally, subcutaneously, or intravenously taken anticoagulants may play a vital role in taking care for COVID-19 patients, and these may prevent possible deadly events associated with coronavirus, including heart attack, stroke, and pulmonary embolism.

Treatment with anticoagulants were associated with improved hospital survival among COVID-19 patients both in and out of the ICU setting [5].



Rivaroxaban is an orally administered highly selective direct inhibitor of factor Xa that has been approved in many countries to reduce the risk of stroke in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism.

FDA Approved Indications

Rivaroxaban is a novel oral anticoagulant (NOAC) drug. It has several FDA-approved and off-label clinical uses [6, 7].

  • Primary and secondary stroke prevention in people with cardiac arrhythmia, maximum generally in non-valvular Atrial fibrillation
  • Acute venous thromboembolism occasion and recurrence of blood clots
  • Reduce the continued risk of venous thromboembolism


Mechanism of Action

Rivaroxaban is the first oral direct inhibitor of Factor Xa, a small molecule is a derivative of oxazolidinone. Rivaroxaban binds directly and reversibly to Factor Xa via the S1 and S4 pockets [6]. Factor Xa is competitively inhibited by Rivaroxaban, establishing more than 10,000-fold selectivity for Factor Xa than other related serine proteases. Cofactors (such as anti-thrombin) are not required to exert its anticoagulant effect [6]. This activity is in contrast to the effects of the coagulation cascade in the final co-path, preventing the formation of thrombin (figure 2).

The factor Xa is active in circulating and clot-bound forms. Unlike indirect Factor Xa inhibitors like fondaparinux or heparin, both free and clot-bound Factor Xa is inhibited by rivaroxaban, as well as prothrombinase activity, thereby prolonging clotting times [7]. The metabolism of the drug in the liver by oxidation and degradation, catalyzed by the mechanism of CYP3A4/5 and CYP2J2. Excretion occurs mostly via urine 66% and partly via faeces 28%.

Frontiers | The discovery of rivaroxaban: translating preclinical  assessments into clinical practice | Pharmacology

Figure 2: The blood coagulation pathway


Administration and Convenient Dosing of Alriza does not require Monitoring (Rationale for Dosing Regimens in Different Indications)

Administration of Rivaroxaban is orally with a half-life of 5 to 9 hours (maybe longer in older individuals, example, 11 to 13 hours) [8]. 2.5 mg BID to 20 mg OD is the range of dose and does not require any monitoring. Rivaroxaban, the anticoagulant protein-bound to a high level. Dosing is commonly at a fixed dose without any monitoring and there is no established therapeutic range for the drug.

The dose for the common indications of rivaroxaban is mentioned in table 1:

Table 1: Dosing and administration of Rivaroxaban


Comparative Analysis of Oral Anticoagulative Drugs

Properties of Rivaroxaban can be compared with other anticoagulative drugs to show its effectiveness (table 2) [9].

Table 2: Comparison of Dabigatran, Rivaroxaban, Apixaban and Edoxaban







IIIa (Thrombin)




Hours to maximum concentration

1 -3

2 -4

3 - 4

1 - 2

Half Life

12 – 17

5 - 13


9 - 11

Renal Clearance %






P - gp#

P - gp#

P - gp#

P - gp#

Cytochrome P 450 Metabolism, %



< 32


*33%  renally Cleared ; 33 % excreted unchanged in Urine; #P-gp: P-glycoprotein


Clinical Trial

Analysed Trial on the clinical efficacy and tolerability of rivaroxaban and enoxaparin in patients undergoing total knee arthroplasty (box 1) [10].

Objective: This article analysed the clinical efficacy and tolerability of rivaroxaban and enoxaparin in patients undergoing total knee arthroplasty (TKA) [10].

Methods: Five randomized, controlled clinical trials on rivaroxaban versus enoxaparin in patients who underwent TKA were identified and included in this meta-analysis.

Results: The meta-analysis indicated that rivaroxaban prophylaxis was associated with lower rates of symptomatic venous thromboembolism (VTE) (relative risk[RR]:0.55; 95% confidence interval [CI]: 0.35–0.86; P=.009), symptomatic deep vein thrombosis (DVT) (RR 0.44, 95% CI 0.25–0.80, P=.007), asymptomatic DVT (RR: 0.57; 95% CI: 0.37–0.89; P=.01), distal DVT (RR:0.62; 95% CI: 0.45–0.85; P=.003) and proximal DVT (RR: 0.42; 95% CI: 0.24–0.75; P=.004). Compared with the enoxaparin group, the incidence of symptomatic pulmonary embolism (PE) (RR: 0.48; 95% CI: 0.19–1.24; P=.13) in the rivaroxaban group was not significantly different. A non-significant trend towards all-cause death (RR: 0.38; 95% CI: 0.03–4.92; P=.46) or major bleeding (RR: 1.59; 95% CI: 0.77–3.27; P=.21) risk between rivaroxaban and enoxaparin prophylaxis was found.

Conclusion: Compared with the enoxaparin group, the group using rivaroxaban after TKA had a significantly lower rate of symptomatic VTE, symptomatic DVT, asymptomatic DVT, distal DVT, and proximal DVT. Our study shows that rivaroxaban after TKA is more effective than enoxaparin and did not increase major bleeding or all-cause mortality.


Adverse Effects of Rivaroxaban

The adverse effects, depending on the frequency of occurrence and severity, are as follows:

  • >10%: Hemorrhage (5% to 28%)
  • Major hemorrhage (≤4%)- including GI, retinal, intracranial, epidural hematoma, adrenal bleeding

The common complication is bleeding, and risk factors for bleeding including underlying congenital, bacterial endocarditis or vascular retinopathy, acquired bleeding disorders, thrombocytopenia, stroke, neuraxial procedures, recent procedure/surgery, renal impairment, uncontrolled hypertension, concomitant use of other drugs which affect hemostasis, recent major bleeding and advanced age. For any unexplained decrease, clinical evaluation is necessary in haemoglobin or blood pressure [10].


Contraindications of Rivaroxaban

Major contraindications include [11]:

  • Allergy: Severe hypersensitivity to rivaroxaban (or any component of the formulation) can occur
  • Hematologic: Active pathological bleeding is a contraindication of the usage of rivaroxaban

Other contraindications are drug-disease interactions, which includes:

  • Hepatic impairment: Avoid rivaroxaban in patients with moderate to severe hepatic impairment (Child-Pugh classes B and C) or in patients with coagulopathy related to liver disease [11].
  • Renal impairment: Caution is necessary for patients with moderate to severe renal impairment (CrCl 30-50 ml/min) and in patients with impaired renal function. For deep vein thrombosis/ pulmonary embolism and venous thromboembolism prophylaxis, avoid use in patients with CrCl <30 mL/minute. Clinicians should discontinue the drug in patients who develop acute renal failure. If the CrCl declines to <50 mL/min, reduce the rivaroxaban dose from 20 mg to 15 mg [10]. If the CrCl falls below 15 mL/min, discontinue rivaroxaban [11]. Rivaroxaban is not recommended for patients with atrial fibrillation with end-stage CKD or on hemodialysis with CrCl <15 mL/min [11].
  • Valvular disease: Rivaroxaban is not recommended in patients with prosthetic heart valves or rheumatic heart disease and should be avoided in patients with mechanical valves or moderate to severe mitral stenosis.
  • Patients with increased bleeding risk: Congenital or acquired bleeding disorders, Uncontrolled severe arterial hypertension, Active ulcerative GI disease, vascular retinopathy, and bronchiectasis or history of pulmonary bleeding [12].
  • During pregnancy and lactation: Not recommended.


Monitoring of Rivaroxaban

Previous to the initiation of Rivaroxaban, laboratory tests are important to assess and document the status of coagulation, including platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT) and bleeding time. For potential dose adjustment in cases of or hepatic or renal insufficiency, a measurement of liver function tests and serum creatinine should be done as well. Routine coagulation testing is not necessary for rivaroxaban. Assessment of renal function and CBC before initiation, when clinically indicated, and at least annually is essential in all patients [13].


Toxicity of Rivaroxaban

Patients with minor bleeding are managed in a conservative manner, and a single dose of anticoagulation is skipped or delayed [14]. While patients with major bleeding receive initial management with anti-fibrinolytic agents like Tranexamic acid or Epsilon-aminocaproic acid has off-label usage as a haemostatic agent in major NOAC-associated bleeds, but currently, there is no enough data on its efficacy. Andexanet alfa or inactivated 4-factor PCC can be used for patients who have life-threatening bleeding associated with direct factor Xa inhibitor anticoagulation [14].

Patients who are experiencing major bleeding, a careful reassessment of the risks and benefits of reinitiating anticoagulation is necessary [15].



Rivaroxaban, a novel oral anticoagulant has various benefits over warfarin, including, rapid onset of action, faster time to achieve the effect, pharmacodynamics and predictable pharmacokinetics, lack of need for routine INR monitoring, fewer documented food and drug interactions and improved patient satisfaction. Warfarin is now being substituted by Rivaroxaban as a choice of oral anticoagulants, because warfarin has a narrow therapeutic index, interaction with food or drug that acts via CYP isoenzyme inhibiting or inducing pathway, which needs frequent lab monitoring, and has a high bleeding risk profile.



  1. Wu Y, Ho W, Huang Y, et al. SARS-CoV-2 is an appropriate name for the new coronavirus. Lancet 2020; 395:949–50. doi:10.1016/S0140-6736(20)30557
  2. Miesbach W, Makris M. COVID-19: Coagulopathy, Risk of Thrombosis, and the Rationale for Anticoagulation. Clin Appl Thromb Hemost. 2020; 26:1076029620938149. doi:10.1177/1076029620938149
  3. Antoniak S., MacKman N. Multiple roles of the coagulation protease cascade during virus infection. Blood. American Society of Hematology. 2014; 123(17):2605–2613. doi: 10.1182/blood-2013-09-526277
  4. Berri F. ‘Plasminogen Controls Inflammation and Pathogenesis of Influenza Virus Infections via Fibrinolysis’, PLoS Pathogens. Edited by A. Pekosz. Public Library of Science. 2013; 9(3) doi: 10.1371/journal.ppat.1003229
  5. Ishan Paranjpe, Valentin Fuster, Anuradha Lala, Adam Russak, Benjamin S. Glicksberg, Matthew A. Levin, Alexander W. Charney, Jagat Narula, Zahi A. Fayad, Emilia Bagiella, Shan Zhao, Girish N. Nadkarni. Association of Treatment Dose Anticoagulation with In-Hospital Survival Among Hospitalized Patients with COVID-19. Journal of the American College of Cardiology, 2020; doi: 10.1016/j.jacc.2020.05.001
  6. Kubitza D, Becka M, Roth A, Mueck W. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008; 24(10):2757-2765. doi:10.1185/03007990802361499
  7. Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008; 47:47–59. doi: 10.2165/00003088-200847010-00005
  8. Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939--an oral, direct Factor Xa inhibitor--after multiple dosing in healthy male subjects. Eur J Clin Pharmacol.  2005; 61(12):873-80. doi: 10.1007/s00228-005-0043-5
  9. Weitz JI, Raskob GE, Spyropoulos AC, et al. Thromboprophylaxis with Rivaroxaban in Acutely Ill Medical Patients with Renal Impairment: Insights from the MAGELLAN and MARINER Trials. Thromb Haemost. 2020; 120(3):515-524. doi:10.1055/s-0039-1701009
  10. Huang HF, Li SS, Yang XT, Xie Q, Tian XB. Rivaroxaban versus enoxaparin for the prevention of thromboembolism after total knee Anthroplasty: A meta-analysis. Medicine 2018; 97:48 doi: 10.1097/MD.0000000000013465
  11. Moore KT, Kröll D. Influences of Obesity and Bariatric Surgery on the Clinical and Pharmacologic Profile of Rivaroxaban. Am J Med. 2017; 130(9):1024-1032. doi:10.1016/j.amjmed.2017.05.011
  12. Haas S, Bode C, Norrving B, Turpie AG. Practical guidance for using rivaroxaban in patients with atrial fibrillation: balancing benefit and risk. Vasc Health Risk Manag. Mar 10 2014; 10:101-114. doi:10.2147/VHRM.S55246
  13. Raval AN, Cigarroa JE, Chung MK, et al. Management of Patients on Non-Vitamin K Antagonist Oral Anticoagulants in the Acute Care and Periprocedural Setting: A Scientific Statement From the American Heart Association [published correction appears in Circulation. 2017 Mar 7;135(10 ):e647] [published correction appears in Circulation. 2017 Jun 13;135(24):e1144]. Circulation. 2017; 135(10):e604-e633. doi:10.1161/CIR.0000000000000477
  14. Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood. 2017; 130(15):1706-1712. doi:10.1182/blood-2017-05-782060
  15. Thomas S, Makris M. The reversal of anticoagulation in clinical practice. Clin Med (Lond). 2018; 18(4):314-319. doi:10.7861/clinmedicine.18-4-314