Edoxaban for Stroke Prevention

1. Indication (86words)

Edoxaban, a drug part of the direct factor Xa group is licensed on two indications. The first indication, treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT). (1). Treatment is only conducted following the use of parenteral anticoagulants on a minimum 5-day course. Second, prevention of systemic embolism (SE) and stroke in nonvalvular atrial fibrillation (NVAF). Treatment conducted in line with risk factors such as transient ischaemic attack (TIA), diabetes mellitus, congestive heart failure, hypertension, prior stroke, or age>75 years. (2)

2. Design (278)

Edoxaban is part of NOAC, which includes apixaban and rivaroxaban. The development of edoxaban is primarily focused on overcoming the drawbacks of warfarin which requires frequent monitoring, unpredictable dosing and interactions with various food and drugs. (3) The API of edoxaban, edoxaban tosilate is accessible in two polymorphic forms, form I and form II with form I being the most thermodynamically stable. The crystalline form I of edoxaban tosilate is synthetically produced with no conversion of forms during the drug manufacturing process. (4)

Edoxaban is available in 15, 30 and 60 mg immediate release film coated tablets that disintegrates quickly. Having a relatively long half-life of up to 14 hours, with dose-dependent, linear pharmacokinetic parameters, it is suitable for once a day dosing. Oral bioavailability is approximated to be at 62% and concentration levels reach a steady state within 3 days of oral administration and is unaffected by food. Edoxaban is 50% renally cleared, requiring doses for elderly and renally impaired patients to be reduced. The pharmacodynamics effects are usually produced within 1-2 hours in correspondence to the peak exposure levels of edoxaban. (5)

Edoxaban tablets are manufactured from common granulate and are quantitatively proportional when manufactured. API particle sizes are reduced during the final steps of the API manufacturing process utilising milling. The final manufacturing process involves four main stages, fluid bed granulation; blending; tableting and film coating. Final product requires no special storage as it is photostable and is packaged in a PVC and aluminium blister. Storage of edoxaban ranges from 24 months for long and intermediate conditions and as low as 6 months in accelerated conditions. All excipients used in this formulation are compliant to European Pharmacopoeia Standards. (4)

Figure 1: Structure of Rivaroxaban, Apixiban and Edoxaban. (6)

3) Safety (199 words)

Warfarin is the current GOLD standard indicator for DVT and AF. Large scale pivotal phase II studies have been conducted to compare the safety and efficacy profile of edoxaban and warfarin. The results of studies; ENGAGE AF(7) and Hokusai VTE(8), are tabulated for analysis below in Table 1.

Findings of the study place the adverse events (AE) among patients of each drug be well within tolerable range with only mild to moderate events occurring. However, the Treatment-emergent adverse event (TEAE) and serious TEAR were found be higher in warfarin. This is clearly seen in Table 2.

Major bleeding is the primary safety endpoint for safety as defined by the International Society on Thrombosis and Haemostasis (ISTH). The ENGANGE AF study showed reduced major bleeding against warfarin with the annualized rate of 3.43% as compared to 2.75% for Edoxaban. Intracranial, major or nonmajor relevant bleeding and fatal bleeding were found to be significantly lower compared to warfarin (p<0.001). Gastrointestinal bleeding however was found to be higher in the edoxaban group as shown in Table 3. Hokusai VTE showed comparable results with clinically relevant major bleeding occurring in 10.3% of patients using warfarin as opposed to 8.3% for patients on edoxaban.

 

Study		Dosage	Trial duration
Edoxaban	ENGAGE AF-TIME (Stroke prevention in AF)	60mg	2.5 years
	Hokusai-VTE (VTE treatment)	60mg	3-12 months
Warfarin	ENGAGE AF-TIME (Stroke prevention in AF)	Dose-adjusted to achieve an INR of 2.0 to 3.0	2.5 years
	Hokusai-VTE (VTE treatment)	Dose-adjusted to achieve an INR of 2.0 to 3.0	3-12 months

Table 1. Studies used to evaluate safety profile of edoxaban and warfarin (7,8)

Adverse Events	ENGAGE AF-TIME		Hokusai VTE
	Edoxaban	Warfarin	Edoxaban	Warfarin
TEAE (%)	28.2	32.1	24.8	32.7
Serious TEAE (%)	4.7	6.6	2.6	5.1
Drug discontinuation due to TEAE (%)	12.7	15	7.1	6.9

Table 2. Percentage of TEAE events in Edoxaban and warfarin studies.(7,8)

Safety outcome	ENGAGE AF-TIME		Hokusai-VTE
	Edoxaban 60mg Patients/year, %	Warfarin Patients/year, %	Edoxaban 60mg Patients/year, %	Warfarin Patients/year, %
Major bleeding	2.75	3.43	1.4	2.9
CRNMB	8.67	10.15	7.2	8.9
CRNMB and major bleeding	11.01	13.02	8.5	10.3
Fatal bleeding	0.21	0.38	<0.1	0.2
Intracranial bleeding	0.39	0.85		0.1
Life threatening bleeding	0.40	0.78	–	–
Gastrointestinal bleeding	1.51	1.23	<0.1	<0.1

Table 3. Rate of specific safety outcomes for both edoxaban and warfarin. (7,8)

4) Effectiveness ( 186 words)

The effectiveness of edoxaban were measured in the two studies with varying primary endpoints. ENGAGE AF indication was the time to first stroke (ischaemic or haemorrhagic) or systemic embolism (SE). The outcome of the study placed edoxaban with a primary endpoint of 1.50% non-inferior to warfarin 1.18% in reducing stroke and SE rates (HR0.79 97.5% CI 0.63-0.99). However, edoxaban did not meet the superiority test criteria to warfarin as p=0.08.  Furthermore, this study showed reduction of haemorrhagic strokes in patients that were treated with edoxaban, with the annualized rate of 0.26% with high dose edoxaban when compared to 0.47% of warfarin. Renal functions sub analysis suggests that renal function plays an important factor in the efficiency of edoxaban. Reduced effectiveness was trending in patients who had displayed good renal function or good control of warfarin therapies. (7)

Primary efficiency in the Hokusai study revolved around the incidence of adjudicated symptomatic recurrent VTE, which is a composite of DVT and PE. The study found that the VTE-related death rate was 3.5% in patients on warfarin and 3.2% for edoxaban. (HR 0.89 95% CI 0.70-1.13). (8)

5) Cost effectiveness (187 words)

Cost effectiveness of edoxaban is compared to warfarin and rivaroxaban in three different models. The Markov model evaluated the lifetime cost and the quality adjusted life expectancy (QALY) of NVAF patients that were treated with edoxaban and warfarin. The model concluded that 92.3% of simulations favoured edoxaban to be a more cost effective alternative when compared to warfarin. (9)

In the United States, a cost effectiveness models used the patient level data derived from Hokusai-VTE trials showed results where the incremental cost-effectiveness ratio (ICER) was $22,057 per QALY. This resulted in 67% of simulations with edoxaban having an ICER or less than $50,000 per QALY gain in comparison to warfarin. (10)

Truven Health Analytics company also performed a cost effectiveness against rivaroxaban. edoxaban also demonstrated a reduction of cost; Medicines Acquisition cost= -$1382 and an increase in QALY +0.061 over rivaroxaban, proving greater effectiveness at lowered costs. (11)

Drugs	Medicine Acquisition Cost	Quality Adjusted Life-Years (QALY)
Edoxaban	$48 090	7.299
Rivaroxaban	$49 472	7.238
Difference	-$1 382	+0.061

Table 4: Medicine Acquisition Cost and QALY comparing both edoxaban and rivaroxaban in NVAF patients. (11)

6) Conclusion (136 words)

In conclusion, edoxaban is potentially an excellent alternative for stroke prevention in NVAF and VTE patients who have an intolerance towards warfarin. Edoxaban also proves to be particularly applicable to patients that have difficulty in maintaining a therapeutic level of warfarin, caused by dietary or medication interactions. This makes edoxaban ideal in patients with compliance issues as it comes in a convenient daily dose. Safety and efficacy of edoxaban has been shown in two trials highlighted above, and is consistently more cost effective compared to warfarin. Its position as an alternative to traditional anticoagulants is challenged by its sensitivity towards renal functions and P-gp drug interactions. Overall edoxaban has proven to be a candidate as the second-line for stroke prevention when warfarin is found to be ineffective and should be recommended for NHS use in Scotland.

Reference list

1. NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (NICE), 2015. Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism. Technology appraisal guidance [TA354].
2. NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE (NICE),2015 Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation

Technology appraisal guidance [TA355]

3. Zachary A, William B, Golden L, Sara K, 2016. Edoxaban: A Comprehensive Review of the Pharmacology and Clinical Data for the Management of Atrial Fibrillation and Venous Thromboembolism. National Center for Biotechnology Information, [Online]. 5(1), 1-18. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906085/ [Accessed 8 February 2017].
4. European Medicines Agency. European Public Assessment Report: Edoxaban.              23 January 2017. Procedure No. EMEA/H/C/002629/0000 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Public_assessment_report/human/002629/WC500189047.pdf
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9. Rognoni, C. Marchetti, M. Quaglini, S. Liberato, NL. 2015. Edoxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis. Journal of Thrombosis and thrombolysis, [Online]. 39(2), 149-154. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24973057  [Accessed 4 February 2017].
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11. Miller, J.D. Xin, Y. Gregory, M. Amanda, M. Oth, V. Jackie, K. 2016. Cost-effectiveness of edoxaban versus rivaroxaban for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) in the US. ClinicoEconomics and Outcomes Research, [Online]. 8, 215-226. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881922/  [Accessed 17 February 2017].