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INTRODUCTION
Thrombosis is the major cause of morbidity and mortality. There are many advances in the
medical therapy for the treatment of thromboembolic events but the morbidity and mortality rates
are still high[1]. So there is a need for therapy which may be more effective in this condition.
Thrombin plays an important role in the generation of a thrombus. Because thrombin is the last
serine protease in the blood coagulation cascade that causes conversion of fibrinogen to fibrin clot.
One approach is the inhibition of thrombin activity by direct thrombin inhibitors[2]. While another
approach is the inhibition of thrombin production by blocking the proteases in the blood
coagulation cascade, such as factor Xa(FXa). Experiments show that FXa inhibitors have a low risk
of bleeding as compared to thrombin inhibitors in animals[3,4]. Hence the inhibition of FXa appears
to be important for anticoagulant therapy[5,6]. Apixaban, a direct FXa inhibitor, is a newly developed
compound which is highly potent and has more than 30000 fold selectivity than other coagulation
proteases[7]. It inhibits both free and cell bound factor Xa and activated prothrombinase[8,9]. It is
relatively bio available with a half life of 12 hour and it has also low potential for drug-drug
interactions[10,11]. So the desirable pharmacological profile makes apixaban an improved treatment
option than other anticoagulants. Apixaban is currently evaluated for multiple indications, including
venous thromboembolism (VTE) prophylaxis, VTE treatment and acute coronary syndrome
(ACS)[12]. It has been evaluated for prevention of venous thromboembolic events in patients after
knee replacement surgery[13] and was also efficacious in acute symptomatic deep vein thrombosis
(DVT)[14].
DISCOVERY OF APIXABAN
In 1990 the DuPont scientists made efforts in the development of inhibitors of glycoprotein
IIb/IIIa receptor. By the mid-1990 scientists at DuPont had observed that there are similarities
between the platelet glycoprotein IIb/IIIa peptide sequence Arg-Gly-Asp and the prothrombin
substrate FXa sequence, Glu-Gly-Arg. By using molecular modelling and structure-based design,
FXa inhibitor containing benzamidine with enhanced potency was developed[15,16].
Thrombin is the key enzyme responsible for the fibrin clot formation and platelet activation.
It plays an important role in the formation of thrombi in arteries or veins which may lead to
thrombotic disease. Thus the thrombin inhibition either directly or via blockade of other proteases
that are involved in thrombin generation such as FXa has been investigated as a novel means to
treat thrombotic disease. There are some hypotheses that inhibition of FXa may be valuable for
effective and safe antithrombotic therapy. In the process of blood coagulation the generation of one
molecule of FXa can lead to the activation of hundreds of thrombin molecules[17]. So the inhibition
of FXa may reduce fibrin clot formation than the direct inhibition of thrombin activity.
Experimental evidence from animal studies suggests that the antithrombotic efficacy of FXa
inhibitors is accompanied by a lower risk of bleeding when compared with thrombin inhibitors[18,19].
Apixaban is a direct, highly selective and reversible inhibitor of FXa, with a rapid onset of
action with relatively wide therapeutic index and few food and drug interactions. So there is no
need for frequent coagulation monitoring and dose adjustment and the pharmacokinetic and
pharmacodynamic profile of apixaban also allows fixed oral dosing.
CHEMISTRY
Apixaban is a potent, selective, and orally bio available FXa inhibitor containing the novel,
neutral, phenyl piperidinone P4 group. The chemical name of apixaban is described as 1-(4methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7
tetrahydro-1H-pyrazolo[3,4-
c]pyridine-3-carboxamid[20]. The molecular formula for apixaban is C25H25N5O4 and molecular
weight is 459.5.
PRECLINICAL STUDIES
A number of studies have evaluated the efficacy and safety of apixaban in animals. Wong et
al. reported that minimum or moderate effective doses of apixaban enhanced the antithrombotic
effect of aspirin and clopidogrel without increasing bleeding time in a rabbit model of arterial
thrombosis[21,22]. It has also been reported that apixaban tend to improve the efficacies of
antiplatelet therapies, aspirin alone or aspirin plus clopidogrel[23,24]. Studies were conducted in
rabbit models of electrically induced carotid artery thrombosis and cuticle bleeding time. Apixaban
0.3 mg/kg/h or aspirin 1 mg/kg/h were infused intravenous continuously before artery injury or
cuticle bleed. Clopidogrel at 3 mg/kg was given orally once daily for three days. These drugs can
reduce formation of arterial thrombosis without excessive increases in bleeding time in rabbits[25].
The pharmacokinetic parameters of apixaban in rabbits after oral and IV administration are
shown in Table 1[26].The plasma concentration of apixaban was rapidly declined after IV
administration. The systemic clearance was 2.55 l/h/kg which is high but the half life was short
about 0.6 h. After oral administration plasma apixaban exposure was low, with an absolute oral
bioavailability of 3%. After IV administration about 24.8% and 62.4% of apixaban was excreted in
the urine and feces respectively in 48 hrs in rabbits. While after oral administration, about 1.8% and
54.3% was excreted in the urine and feces respectively[26].
Apixaban has a low bioavailability and a short systemic clearance in rabbits while the rats,
dogs and chimpanzees have greater oral bioavailability, much lower clearance rates and a low
volume of distribution[27,28]. It is also interesting that the half life of apixaban in rabbit model after
oral dosing is relatively longer than after IV administration. The clotting time was also prolonged
by apixaban in a concentration-dependent manner. Wong et al. have demonstrated that apixaban
was effective for the prevention of venous and arterial thrombosis in rabbits[29]. Fourteen different
inactive metabolites of apixaban have been identified[30]. From which O-Demethyl-apixaban was
the most important metabolite that is primarily formed via CYP3A4 and undergoes subsequent
sulphation to O-Demethyl-apixaban sulphate[31].
CLINICAL STUDIES
Pharmacokinetics of apixaban
There were many clinical trials completed and many are still continuing regarding the use of
apixaban as an anticoagulant in different conditions. Apixaban has a 50% bioavailability and peak
levels are achieved within 3 hours and the plasma half-life is 8 to 14 hours as shown in Table 2[32].
Metabolism of apixaban primarily involves CYP3A4 and sulfotransferase. Potent inhibitors of
CYP3A4, such as ketoconozole can increase the drug levels. About 25% of the drug is excreted via
the kidneys and 55% is excreted in the feces[33]. Pharmacokinetic analyses demonstrate rapid
absorption of apixaban after oral administration in healthy male subjects. In the metabolism of
apixaban there are several metabolites and the most important is O-demethyl apixaban sulfate. The
metabolic pathways for apixaban include O-demethylation, hydroxylation, and sulfation of
hydroxylated O-demethyl apixaban. The O-demethyl apixaban sulfate is present in the human
faeces which show that it is stable in the gastrointestinal tract during its excretion[34]. After an oral
dose of 20 mg of apixaban, 66–72% of the compound is found in the plasma[35]. Food and weight
does not have any effect on the absorption of apixaban. The accumulation of drug was also not
reported. There was no significant difference on absorption by difference in the age or gender as
shown in Table 2[36].
Apixaban can be used in different condition as an anticoagulant like prevention of stroke in
patients with atrial fibrillation, venous thromboembolism (VTE) prevention, for secondary
prevention in acute coronary syndrome or to prevent the thrombosis in patients with metastatic
cancer[12].
Stroke in Atrial Fibrillation
Atrial fibrillation (AF) causes about 75,000 cases of ischemic stroke per year in the United
States. There are several risk factors for stroke including age greater than 75 years, hypertension,
diabetes and smoking[37]. AF causes stroke by thrombus formation in the left atrium with embolism
to the brain[38]. Apixaban can be used for prevention of stroke in patients with atrial fibrillation.
The ARISTOTLE study was double-blind study including about 18,000 patients with AF
from more than 1,000 centres in about 40 countries. The study drug was apixaban 5 mg BD and
warfarin 2 mg was used as a control for the reduction of stroke in atrial fibrillation. The primary
efficacy outcome is the time to first occurrence of stroke or systemic embolism and the primary
safety endpoint is time to first occurrence of confirmed major bleeding. The study will determine
whether apixaban is superior to warfarin in preventing stroke and systemic embolism, whether it
reduces the combined rate of stroke, systemic embolism, and death and whether it impacts bleeding
or not[39]. This study is ongoing but not recruiting new participants.
AVERROES was a double blind and parallel design study. About 5000 patients were
enrolled in the study. The study is ongoing but not recruiting new participants. It compares
apixaban 5 mg twice daily with acetylsalicylic acid 81 to 324 mg once daily for the prevention of
stroke or systemic embolism in patients with AF and in the patients who have failed or are
unsuitable for vitamin K antagonist treatment. The primary efficacy outcome is stroke or systemic
embolism and the primary safety outcome is major bleeding[40]. Apixaban users had a significantly
lower risk of stroke and systemic embolic events without increase in bleeding as compared to
patients treated with aspirin.
Stuart JC et al have conducted the study at 522 centres in 36 countries. About 5599 patients
with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist
therapy was unsuitable were randomly assigned to the study. They received either apixaban 5 mg
twice daily or aspirin 81 to 324 mg per day. The primary efficacy outcome was the occurrence of
stroke or systemic embolism. The primary safety outcome was the occurrence of major bleeding.
The stroke or systemic embolism was reported in 51 patients assigned to apixaban and in 113
patients assigned to aspirin. The rates of death were 3.5% per year in the apixaban group and 4.4%
per year in the aspirin group. There were 11 cases of intracranial bleeding with apixaban and 13
with aspirin. It was concluded that in patients with atrial fibrillation for whom vitamin K antagonist
therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without
significantly increasing the risk of major bleeding or intracranial haemorrhage[41].
Orthopaedic Replacement Surgery
The venous thromboembolism including deep venous thrombosis and pulmonary embolism
is life- threatening condition after the major orthopaedic surgery like total knee replacement (TKR)
or total hip replacement (THR). The prophylactic treatments available include unfractionated
heparin, low-molecular-weight heparins, and vitamin K antagonists[42]. The thromboprophylaxis
with low-molecular weight heparins can reduces the venous thromboembolism, but the treatment is
costly and daily injections are required on the other hand vitamin K antagonists can also be used for
long-term management but regular monitoring is needed, it also interacts with food and is also
associated with increased occurrence of bleeding[43]. These limitations show that a standard
prophylactic drug is required which can reduce the frequency of venous thromboembolism without
causing bleeding and other complications in postoperative patients.
The APROPOS study compared apixaban vs. enoxaparin or warfarin for VTE prevention
after total knee replacement. It was a randomized, double-blind, phase II study in which about 1217
patients were enrolled. The dose of apixaban was 5–20 mg per day while enoxaparin 30mg twice
daily for 12 days began 12–24 h after skin wound closure and warfarin was used in a dose to
maintain international normalization ratio (INR) 1.8 to 3.0. Apixaban showed similar efficacy as
compared with enoxaparin and warfarin for reducing the VTE. The incidence of major bleeding was
0.0–3.3% for the apixaban doses as compared to no incidence of bleeding in enoxaparin and
warfarin groups[44]. The incidence of alanine aminotransferase (ALT) elevation was lower in the
apixaban treatment groups than the enoxaparin group.
Several phase III apixaban studies for VTE prevention after orthopaedic surgery has been
initiated. There were three ADVANCE studies conducted which determined the efficacy and safety
of apixaban 2.5 mg twice daily compared with enoxaparin in patients who had undergone the major
orthopaedic surgery[45].
The first phase III orthopedic prophylaxis trial named ADVANCE-1has been completed
which randomized 3195 patients, in double-blind fashion. Patients received either apixaban 2.5 mg
orally twice a day or enoxaparin 30 mg subcutaneously every 12 hours. Both the treatments were
started 12 to 24 hours after surgery. All patients underwent venography after 2 weeks. The primary
efficacy outcome was VTE and all cause mortality and the primary safety outcome was major
bleeding[46].The primary event occurred in 8.99% of patients in apixaban group and 8.85% in the
enoxaparin group. Major bleeding was seen in 0.7% patients of apixaban group and 1.4% for
enoxaparin group[47].
ADVANCE-2 was the second phase III study among the three trials of efficacy and safety of
apixaban for prevention of venous thromboembolism after elective total knee or hip replacement[48].
It was a multicenter, double-blinded, randomized phase III study comparing apixaban 2.5 mg BD
for thromboprophylaxis after total knee replacement. As a control enoxaparin 40 mg
subcutaneously daily was used. About 3221 patient were enrolled in the study[47].The primary
efficacy outcome was deep vein thrombosis, non-fatal pulmonary embolism and all-cause death.
The primary safety outcome was bleeding[48].The deep vein thrombosis, non-fatal pulmonary
embolism and death were reported in 15.1% in apixaban patients and 24.4% in enoxaparin patients.
Clinically relevant bleeding occurred in 3.5% and 4.8% patients treated with apixaban and
enoxaparin, respectively. These data indicates that apixaban can prevent the thromboembolic events
with decreased bleeding as compared to enoxaparin[47].This study fails to show the superiority
against venous thromboembolism, which is widely accepted as the efficacy endpoint. The reports of
adverse events were similar in each study group and four patients died during study from which one
was from enoxaparin group and three were from apixaban group[48].
ADVANCE-3 which was the third phase III study comparing apixaban to enoxaparin for
VTE prevention in the patients undergoing elective total hip replacement surgery. It was a parallel
group, double blind study involving about 5000 patients from whom 2708 patients randomized to
apixaban 2.5 mg twice daily for 35 days given 12 to 24 hours following surgery and 2699
randomized to enoxaparin 40mg once daily for 35 days started the evening before surgery. The
primary efficacy endpoint was DVT, pulmonary embolism and death and the primary safety
outcome was occurrence of bleeding. The DVT, pulmonary embolism and death was observed in
1.4% patients receiving apixaban and 3.9% in patients receiving enoxaparin. The occurrence of
bleeding was 4.8% and 5.0% respectively in apixaban group and enoxaparin group while the
incidence of non fatal pulmonary embolism was 0.1% and 0.2% in apixaban group and enoxaparin
group respectively[47].
For the secondary treatment of VTE the Botticelli DVT (Deep Vein Thrombosis) doseranging study was conducted which was the first phase II study to evaluate the safety and efficacy
of apixaban for treatment post symptomatic DVT[49]. It was a multicenter, double-blinded study
involving 520 patients with acute symptomatic proximal DVT. They were randomized either to
different doses of apixaban 5 mg BD, 10 mg BD or 20 mg daily or the low molecular weight
heparin (LMWH) followed by vitamin K antagonist (VKA) with target INR 2.0–3.0. The primary
efficacy outcome was the symptomatic recurrent VTE. The primary safety outcome was clinically
relevant bleeding. The symptomatic recurrent VTE occurred in 4.7% of apixaban patients and 4.2%
of LMWH/VKA patients. Bleeding occurred in 7.3% and 7.9% of patients in the apixaban and
LMWH/VKA groups respectively. During study it was noted that symptomatic recurrent VTE
decreased in the higher doses of the apixaban, it was concluded that all 3 doses of apixaban showed
similar efficacy and safety. So the lowest dosage regimen, 5 mg BD has been used in follow-up
phase III trials[47].
The AMPLIFY trial was the follow-up trial to the Botticelli DVT trial. It was a double blind
study involving randomization of 4816 patients to either apixaban 10 mg BD for 7 days followed by
5 mg BD for 6 months versus enoxaparin 1mg/kg twice daily until INR≥2 followed by warfarin for
an INR between 2-4, once daily for 6 months[50].The primary endpoint was venous thromboembolic
recurrence or death and the primary safety outcome was bleeding. This study is still ongoing.
The AMPLIFY-EXT study is investigating apixaban at 2.5 mg or 5 mg BD for 12 months
compared with placebo following symptomatic VTE treatment[50]. It is a phase III multicenter,
double-blind, randomized study involving about 2430 patients. The primary efficacy outcome is
venous thromboembolic recurrence or death and primary safety outcome is bleeding. This study is
ongoing.
Apixaban is also being evaluated for thromboprophylaxis in acutely ill medical patients
during and following hospitalization in ADOPT trial. It is a phase III, multi-centre, double-blind,
randomized study involving about 6524 patients. The patients receive either apixaban 2.5mg twice
daily for 30 days or enoxaparin 40mg subcutaneously once daily for 6-14 days. The primary
efficacy endpoint is VTE and VTE-related death and secondary outcome is all causes of death,
major bleeding, and clinically relevant non-major bleeding. The study is still ongoing and currently
recruiting participants[51].
Cancer
The cancer patients have a high risk for thrombosis such as VTE. The cancer-associated
thrombosis is the major cause of morbidity and mortality. The incidence of VTE increases from
0.1% in the general population to 0.5% in patients with cancer annually[52].The rate of occurrence of
VTE varies depending on the types of patients. Chemotherapy increases the risk of VTE by 6-fold
and the cancer patients have an estimated annual incidence of VTE of about 1 in 200[53].Generally
anticoagulants are used to prevent and treat the thrombosis but current anticoagulants are
problematic in cancer patients. Parenteral anticoagulants like heparin or low-molecular heparin
require daily subcutaneous injection and oral anticoagulant such as warfarin requires coagulation
monitoring and dose adjustments.
Apixaban has been evaluated in small phase II study involving about 125 patients with
advance or metastatic cancer receiving chemotherapy. The patients received either apixaban 5 mg
daily for 12 week or placebo. The study result shows that apixaban is well tolerated, with very few
thrombotic and bleeding events but to demonstrate the efficacy larger studies are required[54].
Acute Coronary Syndrome
In case of acute coronary syndrome (ACS), either ST-elevation or non–ST-elevation, the
patients remain at increased risk for recurrent ischemic events[55]. A number of therapeutic options
are available for ACS. The anticoagulants are one of them. Oral anticoagulants have been shown to
prevent recurrent ischemia after ACS[56]. Apixaban is a newer oral anticoagulant which may be used
to prevent the reoccurrence of ACS.
The APPRAISES-I study was conducted to evaluate the effect of apixaban for prevention of
acute ischemia. It was a phase II, double-blind, placebo-controlled study involving 1715 patients
with recent ST-elevation or non–ST-elevation acute coronary syndrome. The patients were either
randomized to apixaban or placebo. The four different doses of apixaban were used. 317 patients
received 2.5 mg twice daily, 318 patients received 10 mg once daily, 248 patients received 10 mg
twice daily and 611 patients received 20 mg once daily. 221 patients received placebo for 6 months.
All patients received aspirin and about 76% received clopidogrel. The primary efficacy outcome
was the severe recurrent ischemia, cardiovascular death, myocardial infarction or recurrent stroke.
The primary safety outcome was major or clinically significant bleeding[57].
Apixaban 2.5 mg twice daily and 10 mg once daily resulted in a dose-dependent increase in
bleeding as compared to placebo. Apixaban 2.5 mg twice daily and 10 mg once daily resulted in
lower rates of ischemic events compared with placebo. The two higher-doses of apixaban were
discontinued because of excess total bleeding. The patients who took aspirin plus clopidogrel had
more bleeding and less reduction in ischemic events compared to those taking aspirin alone. Overall
event rates and the benefits of apixaban were greater among patients not taking clopidogrel. So the
safety and efficacy of apixaban may vary depending on concomitant antiplatelet therapy. This trial
was unable to detect a statistically significant difference in the rates in the composite efficacy
endpoint of severe recurrent ischemia, nonfatal heart attack and cardiovascular death[57].
Richard CB et al have studied the effect of apixaban on D-dimer, prothrombin fragment 1+2
(F1+2), C- reactive protein, fibrinogen and other inflammatory markers. The D-dimer and
prothrombin fragment 1+2 level was elevated in most of patients at baseline as shown in Table 3.
Both of this decreased in 3 week in all groups, but the decrease was more with apixaban than with
placebo. The prothrombin fragment 1+2 was suppressed more rapidly by 10 mg QD than 2.5 mg
BID. The C- reactive protein and fibrinogen levels declined in all patients. So it was concluded that
apixaban reduced D-dimer and prothrombin fragment 1+2 levels more rapidly toward normal
values as compared to placebo[58].
CONCLUSION
The apixaban is a factor Xa inhibitor which acts as an anticoagulant. Several trials have been
done for investigating its anticoagulant activity in different conditions. Apixaban has been shown to
decrease the risk of stroke events without increase in bleeding when compared with the patients
taking aspirin. In patients whom vitamin K antagonist therapy was unsuitable, apixaban reduced the
risk of stroke or systemic embolism without increasing the risk of bleeding in atrial fibrillation.
Apixaban also shows superiority for VTE prevention in the patients undergoing total hip
replacement surgery as compared to enoxaparin. More bleeding has been reported at higher doses of
apixaban than at lower doses during treatment of post symptomatic deep vein thrombosis. Apixaban
is also effective to prevent VTE in patients with metastatic cancer receiving chemotherapy.
Apixaban has been also shown to reduce the ischemic events in acute coronary syndrome but the
risk of bleeding was more. There are many conditions where apixaban can be a better alternative
than other anticoagulants. Its efficacy profile is acceptable but further evaluation is necessary to
prove its safety profile.
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TABLE 1: PHARMACOKINETIC PARAMETERS OF APIXABAN IN RABBIT AFTER A
SINGLE IV OR ORAL DOSE
Sr no.
1.
2.
3.
4.
5.
6.
7.
8.
Pharmacokinetic parameter
Dose (mg/kg)
Tmax (h)
Cmax (µM)
AUC0-t (µM h)
AUCInf (µM h)
Vdss (l/kg)
Clearance (l/h/kg)
Absolute bioavailability (%)
IV (mean ± SD)
2.5
NA
10.25 ± 3.07
2.36 ± 0.98
2.37 ± 0.99
0.88 ± 0.22
2.55 ± 0.91
NA
Oral (mean ± SD)
10
1.00 ± 0.87
0.03 ± 0.01
0.12 ± 0.03
0.25 ± 0.06
NA
NA
3.00 ± 1.66
TABLE 2: PHARMACOKINETICS AND PHARMACODYNAMIC PARAMETERS OF
APIXABAN IN HUMAN
Sr no.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Pharmacokinetic parameter
Pro drug
Bioavailability
Tmax
Reversible
Half-life
Mode of
excretion
Accumulation
Food
Age effect
Weight effect
Gender effect
Apixaban
No
50%
3h
Yes
8–15 h
70% in faeces and 25%
renal
Not reported
Not reported
Not reported
Not reported
Not reported
TABLE 3: EFFECT OF APIXABAN ON DIFFERENT BIO-MARKERS
Sr.
No.
1.
2.
3.
4.
Reference
Time
Biomarker
interval duration
D-dimer
(ng/ml)
F1+2
(pmol/L)
C-reactive
protein
(mg/L)
Fibrinogen
(mg/dl)
0-251
87-325
0.068-8.2
206-382
Apixaban
Placebo
Pre dose
Week 3
317
2.5 mg
BID
325
10 mg
QD
325
10 mg
BID
314
20 mg
QD
321
258
206
185
176
185
Week 26
207
172
163
-
-
Pre dose
299
309
307
328
332
Week 3
267
201
161
167
157
Week 26
246
191
184
-
-
Pre dose
Week 3
23.1
22.7
21.7
25.5
21.7
4.45
3.81
4.21
4.34
4.41
Week 26
3.65
3.07
3.52
-
-
Pre dose
478
472
458
470
471
Week 3
372
367
372
359
375
Week 26
331
325
337
-
-