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REVIEW ARTICLE
Year : 2016  |  Volume : 2  |  Issue : 2  |  Page : 63-68

Apixaban: An oral anticoagulant having unique mechanism of action with better safety and efficacy profile


Department of Pharmacology, Viswabharathi Medical College, Kurnool, Andhra Pradesh, India

Date of Web Publication19-May-2016

Correspondence Address:
Z A Fazeel
Department of Pharmacology, Viswabharathi Medical College, Near Penchikalapadu, Kurnool - 518 463, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2394-7438.182723

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  Abstract 

Anticoagulants are routinely used in stroke, embolism, infarct, etc. Blood clotting profile in such patients needs to be monitored frequently. Anticoagulants which can be administered orally such as warfarin and dicoumarol are preferred in such patients. Injectable anticoagulants such as heparin are prescribed when anticoagulation therapy is required for short duration. Absence of oral form of heparin makes it impractical for long-term use. Currently, warfarin and coumarone derivatives are the best available oral anticoagulants in market. They act by inhibiting decarboxylation of blood clotting factors II, VII, IX, and X. Pharmacological response of warfarin and dicoumarol needs to be monitored by frequent assessments of prothrombin time (PT) and international normalized ratio (INR). There is a need for a drug which can overcome these limitations. Apixaban is an oral anticoagulant which acts by inhibiting factor Xa. It does not require laboratory monitoring of PT and INR. Hence, it overcomes the limitations of heparin and warfarin. It acts by selectively inhibiting the activated factor Xa in a reversible manner. Apixaban has an oral bioavailability of ~50%. It is administered as twice daily dose. It is excreted in urine and feces. Apixaban is useful in atrial fibrillation, venous thromboembolism, and pulmonary embolism. Bleeding is the major side effect of apixaban. It has been found that apixaban has superiority over warfarin and aspirin in terms of efficacy and safety. Further studies are required to monitor and assess the pharmacokinetics, efficacy, adverse effects, and drug interaction data in many populations and sub-populations throughout the world.

Keywords: Anticoagulant, apixaban, pulmonary embolism, venous thromboembolism


How to cite this article:
Fazeel Z A. Apixaban: An oral anticoagulant having unique mechanism of action with better safety and efficacy profile. MAMC J Med Sci 2016;2:63-8

How to cite this URL:
Fazeel Z A. Apixaban: An oral anticoagulant having unique mechanism of action with better safety and efficacy profile. MAMC J Med Sci [serial online] 2016 [cited 2019 Oct 22];2:63-8. Available from: http://www.mamcjms.in/text.asp?2016/2/2/63/182723


  Introduction Top


Anticoagulants are widely used in patients having stroke, embolism, or infarct. Blood clotting profile in such patients has to be maintained in such a way that normal coagulation process in response to intervention-induced trauma should be inhibited while also taking care to prevent hemorrhage.[1],[2] Damaged endothelium provokes blood coagulation and platelet plug formation which obliterates the lumen of artery thus leading to decrease of blood supply (ischemia) to the target tissue resulting in loss of viability of the supplied cells/tissue (infarct).[3],[4]

Anticoagulants which can be administered orally are preferred in stroke patients as they need to take the drug for prolonged periods, for example, warfarin and dicoumarol. Heparin, an injectable anticoagulant, is prescribed when anticoagulation therapy is required for short duration, for example, after cardiac surgery. Absence of oral form of heparin makes it impractical for long-term use. Hence currently, warfarin and coumarone derivatives are the best available oral anticoagulants. They act by inhibiting decarboxylation of blood clotting factors II, VII, IX, and X. Pharmacological response of these drugs needs to be monitored by frequent assessments of prothrombin time (PT) and international normalized ratio (INR).[1]

Warfarin and heparin are also the preferred anticoagulants in atrial fibrillation (AF). In AF, atrial contractions occur at a rate of 120–160 beats/min and in certain cases, rate of atrial contractions reaches even >200 beats/min. Such high rate of contraction and relaxation leads to incomplete emptying of atria leading to stasis of blood in atria. Stasis of blood leads to coagulation resulting in embolism. Anticoagulants have to be prescribed to patients with AF to prevent coagulation and facilitate blood flow out of the atria preventing stasis and thus avoiding embolism.[5],[6],[7]

For those patients who cannot tolerate warfarin/coumarone or those in whom therapeutic target is not achieved, antiplatelet drugs are prescribed, for example, aspirin and clopidogrel. Antiplatelet drugs act by inhibiting platelet activation and/or platelet aggregation. Antiplatelet drugs are more effective for arterial thrombi, whereas anticoagulants are better responsive toward venous thrombi.[1],[8]

In deep venous thrombosis and venous thromboembolism (VTE), sluggish flow of blood leads to activation of blood clotting factors and formation of fibrin meshwork, resulting in entrapment of platelets, ultimately leading to thrombus formation. Since platelets are involved in the last step in the above pathophysiology, antiplatelet drugs do not show much efficacy. Usage of anticoagulants is always a wiser decision as the first step itself is interrupted.[9],[10] Warfarin is the drug of choice in deep venous thrombosis and VTE.[11]

If warfarin is not tolerated, heparin is the second choice. The drawbacks of these two drugs are, regular monitoring of PT and INR required in former and lack of oral formulation in the latter.[12] As a result, there is a need for a drug which can overcome the above limitations.[13]

Factor Xa: A new target for anticoagulation

Current anticoagulants act by activating antithrombin III (e.g., heparin) or by inhibiting synthesis of clotting factors – II, VII, IX, and X (e.g., warfarin).[1],[14]

Activated factor X is the first step in the common pathway of coagulation cascade marking the point of confluence of intrinsic and extrinsic pathways [14],[15] [Figure 1].
Figure 1: Blood coagulation cascade

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Apixaban is an anticoagulant, which acts by inhibiting factor Xa. It does not require laboratory monitoring of PT and INR. Hence, it overcomes the limitations of heparin and warfarin.[14]

Chemistry

Chemically, apixaban is 1-(4-methoxyphenyl) -7-oxo-6-(4-(2-oxopiperidin-1-yl) phenyl) -4, 5, 6, 7-tetrahydro -1H-pyrazolo [3,4-c] pyridine-3-carboxamide.

Molecular formula of apixaban is C25H25N5O4 and its molecular weight is 459.50. Apixaban remains nonionized at physiological pH. Apixaban tablets are available in the strengths of 2.5 mg and 5 mg.[16],[17] Structure of apixaban is shown in [Figure 2].
Figure 2: Structure of apixaban

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Mechanism of action

Apixaban selectively inhibits the activated factor Xa in a reversible manner. It inhibits both free factor Xa and also clot bound factor Xa. Inhibition of factor Xa also leads to reduced formation of factor II (thrombin) as seen in [Figure 1].

Unlike heparin, apixaban does not require antithrombin III. Apixaban does not have any direct action on platelet aggregation.

Coagulation parameters such as PT, INR, and activated partial thromboplastin time are prolonged by apixaban, but to a much lesser extent than warfarin or coumarin derivatives. Hence, these parameters cannot be relied upon for monitoring the anticoagulant effect of apixaban in its therapeutic dose.[16]

Pharmacokinetics

Apixaban has an oral bioavailability of approximately 50%. Orally administered apixaban is absorbed throughout the gastrointestinal tract. Majority of absorption occurs in distal small intestine and ascending colon. Food does not affect absorption. Apixaban is administered twice daily. Maximal plasma concentration is seen at 3–4 h. Apixaban demonstrates linear pharmacokinetics up to 10 mg.

Apixaban gets approximately 87% bound to plasma proteins: Vd = 21 h.

Unchanged apixaban is the only active drug. There is no active metabolite of apixaban. Twenty-five percent of the orally administered dose undergoes metabolism. CYP3A4 is the major enzyme involved in the metabolism of apixaban. CYP1A2, 2C8, 2C9, and 2J2 play a minor role in apixaban metabolism. 3-oxopiperdinyl moiety is commonly involved in biotransformation, which undergoes O-demethylation and hydroxylation. Apixaban is excreted in urine and feces. Renal clearance contributes to 27% of total elimination. t½ of apixaban is ~5 h on intravenous injection, but apparent t½ is ~12 h on oral administration. Prolonged absorption of apixaban is the reason for such a wide difference in half lives on oral and intravenous routes.

P-gp is also involved in the elimination of apixaban.[16],[18]


  Pharmacokinetics in Specific Populations Top


Gender

No pharmacokinetic difference has been reported between healthy adult males and females.[16],[19]

Race

Studies have failed to demonstrate significant pharmacokinetic differences among Caucasians, Asians, and Africans.[16],[20]

Dose adjustments are not required based on sex and ethnicity.

Age

Studies on the comparison of pharmacokinetic parameters in geriatric age group (≥65 years) to adult population of 18–40 years age group have shown no change in Cmax, but slightly higher area under the curve (AUC). However, rise in AUC of geriatric age group was <1.5 times of adult population which was well within the 90% confidence interval [16],[19] [Figure 3].
Figure 3: Effect of age extremes on the pharmacokinetics of apixaban

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Body weight

Comparison of pharmacokinetic data in obese individuals (≥120 kg) to healthy adult population (65–85 kg) revealed that apixaban attains lower Cmax and AUC in obese individuals compared to healthy adults such that the ratio of Cmax and AUC in obese to healthy was <1 and was within the 90% confidence interval [21],[22] [Figure 4].
Figure 4: Effects of extremes of body weight on the pharmacokinetics of apixaban

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In lean individuals (≤50 kg), apixaban attained higher Cmax and AUC such that the ratio of Cmax and AUC in lean to healthy adult population was between 1 and 1.5. This was within 90% confidence interval [19],[21] [Figure 4].

No dose adjustments are recommended based on age and body weight unless the situation demands.

Hepatic impairment

Individuals having mild to moderate hepatic impairment have exhibited lower Cmax and higher AUC of apixaban, such that the ratio of Cmax in individuals having moderate hepatic impairment to Cmax of normal individuals was <1, whereas AUC of individuals having moderate hepatic impairment to AUC of individuals without hepatic impairment was more than one. However, these differences were within 90% confidence interval [23] [Figure 5].
Figure 5: Effects of hepatic impairment on the pharmacokinetics of apixaban

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Dose adjustment has not been suggested for mild–moderate hepatic impairment cases, but apixaban is contraindicated in severe hepatic impairment.[23],[24]

Renal impairment

In patients having renal impairment, Cmax was observed to be almost same as that of normal individuals. However, AUC was higher in renal failure compared to healthy individuals. The rise in AUC was directly proportional with the degree of renal impairment. Some individuals with severe renal impairment exhibited AUC more than 1.5 times to that of individuals without renal impairment [25],[26] [Figure 6].
Figure 6: Effects of renal impairment on the pharmacokinetics of apixaban

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  Indications Top


Atrial fibrillation

Apixaban was devised with the intention of prescribing it for nonvalvular AF so as to reduce the risk of stroke and systemic embolism.

A multi-centric double blind study was performed in patients with nonvalvular AF to study the efficacy and safety of apixaban in comparison with warfarin. This study was carried out simultaneously in many countries and was named ARISTOTLE. In this study, patients were randomized into two groups – one group was prescribed apixaban 5 mg orally twice daily and second group was prescribed warfarin targeted to INR 2.0–3.0. In the apixaban group, patients having at least two of the following three characteristics were given apixaban 2.5 mg twice daily:

  • Age ≥80 years
  • Body weight ≤60 kg
  • Serum creatinine ≥1.5 mg/dl.


The primary end point of ARISTOTLE was the ratio of stroke and systemic embolism which was measured as “Time to First Event” (one episode per subject).

Warfarin-treated group had experienced more episodes of stroke/embolism than apixaban-treated group at any given time throughout the study. This difference of first appearance of stroke/embolism was statistically significant between both study groups [27] [Figure 7].
Figure 7: Kaplan-Meier estimate of time to first stroke or systemic embolism in ARISTOTLE (intent-to-treat population)

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Total number of episodes of strokes/systemic embolism during the study was 212 in apixaban group and 265 in warfarin group (P = 0.01). Thus, ARISTOTLE has proved better efficacy of apixaban over warfarin.[16]

Similarly, another multi-centric study was performed to compare the safety and efficacy of apixaban with aspirin. This study was named as AVERROES. In this study, patients with nonvalvular AF were randomized into two groups – one group was administered apixaban 5 mg orally twice daily and second group was given aspirin 81–324 mg (depending on patient's compliance) once daily. Apixaban 2.5 mg was administered to patients having at least two of the following three characteristics:

  • Age ≥80 years
  • Body weight ≤60 kg
  • Serum creatinine ≥1.5 mg/dl.


Dose of aspirin was adjusted as per patient's requirement and tolerability. Primary endpoint of AVERROES was the rate of stroke and systemic embolism which was measured as “Time to First Event.” Total number of strokes/embolisms in apixaban-treated group was 51 and that in aspirin-treated group was 113. There was statistically significant difference between these two groups (P< 0.0001). AVERROES has proved better efficacy of apixaban over aspirin.[28]

Venous thromboembolism

Agnelli et al. conducted AMPLIFY trial to study the safety and efficacy of apixaban in comparison with conventional anticoagulant therapy in VTE and pulmonary embolism (PE). AMPLIFY is a multi-centric double-blinded study. Sites of the study were located in many countries. After randomization, patients received either apixaban 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months or enoxaparin 1 mg/kg body weight 12 hourly for approximately 5 days and warfarin for 6 months to adjust INR between 2.0 and 3.0. Incidence of recurrent symptomatic VTE-related compilation including death due to VTE was taken as a primary endpoint. It was found that apixaban-treated group had similar incidence of VTE and PE (2.3%) compared to conventional therapy-treated group (2.7%). Statistical analysis revealed P < 0.001 for noninferiority of apixaban compared to conventional therapy. Hence, apixaban is an effective alternative for VTE and PE.[29]


  Adverse Effects Top


Bleeding is the major reported side effect of apixaban.[30] This side effect was evaluated in ARISTOTLE and AVERROES.

In ARISTOTLE, 3.6% cases of apixaban reported “major bleeding” and 5.1% cases of warfarin reported “major bleeding.” Difference between these two groups was statistically significant (P< 0.0001).[28] Definition of “major bleeding” was set as clinically obvious bleeding accompanied by at least one of the following factors:

  • Decline in hemoglobin by at least 2 g/dl.
  • Requirement of ≥ 2 units of packed red blood cells transfusion
  • Any one of the following factors: Intracranial/intraspinal/intraocular/pericardial/intraarticular/retroperitoneal/intramuscular bleeding with compartment syndrome
  • Bleeding resulting in death.


In ARISTOTLE, 10 of 9088 patients of apixaban group suffered fatal bleeding whereas 37 of 9052 patients in warfarin group suffered fatal bleeding.[28]

In AVERROES, “major bleeding” was observed in 1.61% cases of apixaban group and 1.04% cases of aspirin group. P value between these two groups was found to be 0.07. Definition of “major bleeding” was same in AVERROES like that of ARISTOTLE.[29] Five incidents of fatal bleeding were observed each in apixaban- and aspirin-treated groups (n = 2798 and 2780 for apixaban and aspirin, respectively).[29]

Apart from bleeding, hypersensitivity reactions such as rash, edema, and syncope were also observed in few patients receiving apixaban.

Safety of apixaban in pregnancy, lactation, and children has not yet been studied clinically. It has been found that apixaban crosses placental barrier easily. Risk of hemorrhage during pregnancy and delivery is expected to increase. US – Food and Drug Administration has classified apixaban under category B.[31]

Apixaban has been found to be free of carcinogenic and mutagenic activity.[16]


  Contraindications Top


Hypersensitivity to apixaban and active pathological bleeding are recommended contraindications for apixaban.[16]


  Drug Interactions Top


Bleeding risk is increased when apixaban is administered along with antiplatelet agents (clopidogrel and aspirin), anticoagulants (heparin), and fibrinolytics (streptokinase).[16],[32]

CYP3A4 inducers and P-gp inducers such as rifampicin, carbamazepine, phenytoin, and St. John's wort enhance apixaban metabolism and decrease its efficacy. Hence, co-administration of apixaban with these drugs should be avoided.[16]

CYP3A4 inhibitors and P-gp inhibitors such as ketoconazole, itraconazole, ritonavir, and clarithromycin inhibit apixaban metabolism and raises its concentration in serum.[16]

In patients requiring co-administration of apixaban and any one of the above drugs, apixaban dose has to be lowered to 2.5 mg once daily. If a patient is already on 2.5 mg, then co-administration should better be avoided.[32]

Vitamin K and protamine sulfate have no effect on anticoagulant activity of apixaban. In case of patients posted for elective surgeries, apixaban has to be stopped 24–48 h before surgery.[16]

For apixaban poisoning/overdose cases, there is no specific antidote. Absorption can be controlled by gastric lavage with activated charcoal.[33] Transfusion of prothrombin complex concentrate or recombinant factor VIIa could be given, if required.[16]


  Conclusions Top


Orally administrable anticoagulants which do not require laboratory monitoring are the need of present era. Inhibition of factor Xa serves as a new target for preventing blood coagulation. There are few drugs under trial, which inhibit FXa–rivaroxaban.

Currently, apixaban is the only FXa inhibitor which has recently been launched in the market. Apixaban provides desired efficacy in AF, VTE, and PE with few expected side effects. However, efficacy and safety data are limited to multi-centric clinical trials. Further studies are required to monitor and assess the pharmacokinetics, efficacy, adverse effects, and drug interaction data in many populations and sub-populations throughout the world.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]


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