International Journal of the Cardiovascular Academy 1 (2015) 1–4
`
`Contents lists available at ScienceDirect
`
`International Journal of the Cardiovascular Academy
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j c a c
`
`Review
`Will NOACs become the new standard of care in anticoagulation therapy?
`Ergene Oktay ⁎
`
`Department of Cardiology, Izmir Dokuz Eylul University Faculty of Medicine, Turkey
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 14 June 2015
`Received in revised form 14 June 2015
`Accepted 15 June 2015
`Available online 21 August 2015
`
`Keywords:
`Atrial fibrillation
`Warfarin
`Oral anticoagulants
`
`Contents
`
`Atrial fibrillation is the most common cardiac arrhythmia in the general population, with a prevalence of 1–3%,
`which increases with age, reaching 15% in elderly people. Prophylaxis of ischemic stroke with warfarin was the
`gold standard of medical management for many years. On the other hand heparin and warfarin was the main phar-
`macologic agents for the prophylaxis/treatment of venous thromboembolism. In the last 5 years warfarin is getting
`replaced by non-vitamin K antagonist oral anticoagulants at least partly. In this article it is attempted to foresee
`whether new oral anticoagulants will become the new standard of care in anticoagulation therapy.
`© 2015 The Society of Cardiovascular Academy. Production and hosting by Elsevier B.V. All rights reserved. This is
`an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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`Introduction .
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`Discussion .
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`Will NOACs continue their upward trend and replace warfarin as the standard of care in upcoming years
`Conclusion .
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`Disclosure statement
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`References .
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`1
`2
`2
`3
`3
`3
`
`Introduction
`
`In recent years, the development of novel oral anticoagulant agents
`(NOACs) such as dabigatran, rivaroxaban, apixaban and edoxaban has
`given health-care providers better treatment alternatives to aspirin,
`clopidogrel, heparin and warfarin, mainly for stroke prophylaxis in
`patients with non-valvular atrial fibrillation (NVAF), for prophylaxis/
`treatment of venous thromboembolism (VTE) and also for the second-
`ary prophylaxis of acute coronary syndromes (ACS).1–3
`Atrial fibrillation (AF) is the most frequently encountered dysrhyth-
`mia, which may lead to an increased risk of stroke. It may result in
`significant unfavorable health outcomes that include but are not limited
`to a 5-fold increased risk of stroke, hospitalization, impaired quality of
`life, and decreased work productivity. Stroke is a costly disease
`
`⁎ Department of Cardiology, Izmir Dokuz Eylul University Faculty of Medicine,
`Mithatpasa cad. no 1606 inciralti yerleskesi, 35340 Balcova, İzmir, Turkey. Tel.: +90 232
`412 22 22; fax: +90 232 412 97 97.
`E-mail address: oktayergene@yahoo.com.tr.
`Peer review under responsibility of The Society of Cardiovascular Academy.
`
`from the perspective of individual, family, and society. AF-related stroke
`may lead to devastating consequences in terms of health and well-being
`of an individual.
`In patients with AF-related adverse events
`(e.g., thromboembolic infarctions), the outcomes are often poor, and
`may result in severe permanent neurologic deficit or mortality.4–8
`Venous thromboembolism is the third most common cardiovascular
`condition after ACS and stroke.9 Although the exact incidence of VTE
`remains unknown, it is estimated that there are approximately 1 million
`cases in the United States per year, many of which represent recurrent
`disease.10 Nearly two thirds of all VTE events result from hospitalization
`and approximately 300,000 of these patients die.11 Pulmonary embo-
`lism is the third most common cause of hospital-related death.12,13
`The standard effective treatment of venous and arterial thromboem-
`bolism includes the use of unfractionated and low-molecular weight
`heparins as well as warfarin, which is associated with major disadvan-
`tages. In recent years, new anticoagulants have been developed in an
`attempt to overcome the known limitations of the established treat-
`ment approach and to provide improved therapies for the affected
`patients.14–17
`A meta-analysis published in 2007, of all currently available
`randomized trials that extend observations about the efficacy and safety
`
`http://dx.doi.org/10.1016/j.ijcac.2015.06.007
`2405-8181/© 2015 The Society of Cardiovascular Academy. Production and hosting by Elsevier B.V. All rights reserved. This is an open access article under the CC BY-NC-ND license
`(http://creativecommons.org/licenses/by-nc-nd/4.0/).
`
`BMS 2008
`MYLAN v. BMS
`IPR2018-00892
`
`

`

`2
`
`E. Oktay / International Journal of the Cardiovascular Academy 1 (2015) 1–4
`
`of antithrombotic therapies for preventing stroke in patients who have
`AF showed that compared with the control, adjusted-dose warfarin and
`antiplatelet agents reduced stroke by 64% and 22% respectively.1 In
`2013 a meta-analysis reported that new oral anticoagulants (NOACs)
`significantly reduced stroke or systemic embolic events by 19% com-
`pared with warfarin. New oral anticoagulants also significantly reduced
`all-cause mortality compared with warfarin.2
`NOACs can be divided into two broad classes: (i) Direct thrombin
`inhibitors (dabigatran), which inhibit thrombin (Factor IIa), and (ii)
`Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban), which inhibit
`factor Xa. Rivaroxaban, apixaban and edoxaban are oral, selective factor
`Xa inhibitors which block the active site of factor Xa, and these agents
`do not require a co-factor to exert their effects. The oral direct thrombin
`inhibitor, dabigatran, prevents the formation of thrombin through inhi-
`bition of the thrombin-dependent conversion of fibrinogen to fibrin.
`Dabigatran, rivaroxaban, apixaban and edoxaban inhibit both free and
`clot-bound fibrin, and indirectly inhibit thrombin-induced platelet
`aggregation.18,19
`NOACs offer major pharmacological advantages over vitamin K
`antagonists (e.g., warfarin), including rapid onset/offset of action, few
`drug interactions, and predictable pharmacokinetics, which eliminates
`the requirement for regular coagulation monitoring associated with
`conventional anticoagulant therapy.18 From 2008, regulatory agencies
`in EU and US have approved several NOACs for specific indications
`based on the results obtained in clinical trials demonstrating efficacy
`and safety that are at least non-inferior, if not superior, compared to
`warfarin (for stroke prevention in AF as well as for treatment and sec-
`ondary prevention of venous thromboembolism) or the injectable
`agent, low-molecular-weight heparin (Table 1).
`The aim of this paper is to predict whether NOACs will become the
`new standard of care for the treatment of patients with NVAF and
`VTE. References are made to IMS (International Medical Statistics)
`Healthcare data to understand the trends in the global anticoagulation
`market.
`Disclosure of global anticoagulant market sales was requested from
`IMS to investigate the development of the global anticoagulant market
`and to predict whether NOACs are likely to become the standard of
`care in their approved indications such as stroke prevention in NVAF
`and treatment of VTE. The claims in this paper are based on IMS Health
`global anticoagulant market sales data from 2008 to 2014.
`
`Discussion
`
`The decline in stroke mortality over the past decades has resulted
`from reduced stroke incidence and lower case fatality rates. The signif-
`icant improvements in stroke outcomes are concurrent with cardiovas-
`cular risk factor control interventions. US health statistics shows that
`from 2001 to 2011, the relative rate of stroke death fell by 35% and the
`actual number of stroke deaths declined by 21%.20 Stroke prevention
`is central to the appropriate control of hypertension, diabetes, high
`
`cholesterol, smoking cessation and management of atrial fibrillation.
`Until recently, the focus was to identify high-risk patients who would
`be given warfarin. Warfarin works best with high-quality anticoagulation
`(INR adjusted) control. High times in therapeutic range (N70%) are asso-
`ciated with the best efficacy and safety of vitamin K antagonists, with low
`rates of stroke and bleeding.
`Previously the only available anticoagulant was a vitamin K antago-
`nist, but clinicians now have a choice and can fit the drug to the patient,
`and vice versa. In the last 5 years management of stroke prevention has
`changed with the availability of NOAC's. Thus, contemporary guidelines
`have focused on the initial identification of low-risk patients. Several
`NOACs now exist, offering similar (or better) effectiveness, safety, and
`convenience to the vitamin K antagonists. Dabigatran, rivaroxaban,
`apixaban and edoxaban is highly effective in reducing the risk of
`thromboembolic stroke with a more favorable safety profile. Although
`the bleeding risk is not negligible with NOAC's it is much better than
`anticoagulation with INR adjusted warfarin. NOACs have been released
`to the market in 2008, and the question of whether these agents will
`replace warfarin and heparins, which have been accepted as the
`gold standard for many years, is one that needs to be answered
`after a thorough evaluation of several aspects. Will NOACs continue
`their upward trend and replace warfarin as the standard of care in
`upcoming years?
`In order to answer this question, the present paper will seek the
`answers to the following:
`
`1. Are the new agents used in all indications for which standard therapy
`with warfarin and heparin can be used?
`2. What are the benefits of NOACs over standard treatment in indica-
`tions approved by the authorities?
`3. To what extent are the physicians aware of these benefits and how
`much do they adapt to these advantages?
`4. Are the new agents superior to standard therapy in terms of
`treatment costs?
`5. Starting from the release of the new agents in the market, how has
`the dynamics changed for the global anticoagulant market?
`
`Will NOACs continue their upward trend and replace warfarin as the
`standard of care in upcoming years
`
`1. All of the pivotal trials comparing VKAs with NOACs in AF have
`enrolled patients with so-called NVAF, and excluded patients at
`particularly high risk of thromboembolism, such as those with AF ac-
`companied by mitral stenosis or patients with mechanical prosthetic
`valves. The reasons for excluding these patients in trials evaluating
`NOACs included the possibility that the pathogenesis of thromboem-
`bolism may be substantially different from other types of AF.21 In this
`context, it is not possible to use NOACs in patients with valve related
`conditions in light of the available data.
`
`Table 1
`Approved NOAC's in EU and US.
`http://ec.europa.eu/health/documents/community-register/html/alfregister.htm.
`http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
`
`NOACs
`
`Prevention of venous thromboembolism in patients
`undergoing hip/knee replacement surgery
`
`Stroke prevention in
`non-valvular atrial fibrillation
`
`Treatment/secondary prophylaxis of deep
`vein thrombosis and pulmonary embolism
`
`Secondary prevention of acute
`coronary syndromes
`
`Dabigatran
`Rivaroxaban
`
`US
`–
`July '11
`
`March '14
`Apixaban
`na⁎
`Edoxaban
`⁎ Only in Japan, not in EU/US.
`
`EU
`
`Mar '08
`Sept '08
`
`May '11
`na⁎
`
`US
`
`Oct '10
`Nov '11
`
`Dec '12
`Jan '15
`
`EU
`
`Aug '11
`Dec '11
`
`Nov '12
`–
`
`US
`
`June '14
`Nov '12
`
`July '14
`Jan '15
`
`EU
`
`April '14
`Dec '11 (DVT)
`Nov'12 (PE)
`Aug '14
`–
`
`US
`–
`–
`
`–
`–
`
`EU
`–
`May '13
`
`–
`–
`
`

`

`E. Oktay / International Journal of the Cardiovascular Academy 1 (2015) 1–4
`
`3
`
`2. All of these NOACs evaluated for the indication of stroke prevention
`in patients with NVAF have shown non-inferiority compared to
`Vitamin K antagonists.22–24 All new generation oral anticoagulants
`have significantly decreased the risk of hemorrhagic stroke and in-
`tracranial bleeding, and they have not been associated with an
`apparent increase in major bleeding risk compared to warfarin.22–24
`Consistent with the findings of the major studies, results of meta-
`analysis have demonstrated significantly decreased rates of stroke
`or systemic embolism and hemorrhagic stroke with these treatments
`compared to warfarin.25 However, because of the heterogeneity of
`different studies and the lack of head-to-head clinical trials with
`NOACs, one cannot draw a conclusion to say which of these agents
`is the best option.26
`3. While it is not possible to exactly know to what extent physicians
`adopt the superiority that NOACs demonstrate in different therapeu-
`tic fields, investigating NOAC usage data in different countries may
`be informative. In this regard, market data may reflect that these
`agents are adopted at different levels in different parts of the
`world. Looking at the number of tablets patients use (standard
`units), it can be concluded that: While the use of NOACs is approxi-
`mately 35% of that of the agents accepted as standard (warfarin +
`heparin) in US, it is around 15% in “Emerging Markets” region,
`which also includes Turkey.27
`4. Stroke leads to substantial financial burden on healthcare systems, as
`well as on patients, family, and society. The lifetime cost of an ische-
`mic stroke was estimated to be over $90,000 for an individual patient
`in 1990, and the American Heart Association estimated that the total
`national cost (direct plus indirect costs) of stroke in the United States
`exceeded $34 billion in 2008.28,29
`Treatment cost often poses a concern with NOACs. However, the total
`exact cost of strokes and the provision of anticoagulation monitoring
`is not completely understood and considered when assessing
`the cost impact of NOACs. Costs incurred by patient visits to
`anticoagulation monitoring clinics, and the cost of hospital admis-
`sions and other factors of managing the adverse effects of warfarin,
`are not always taken into account.
`In 2013, Harrington et al. conducted a cost effectiveness study taking
`into consideration the aforementioned factors. Their study compared
`the cost effectiveness of warfarin to that of dabigatran, rivaroxaban
`and apixaban, which had been approved by authorities as of 2013.
`The modeled population in this study was a hypothetical cohort of
`70-year old patients with NVAF,
`increased risk for stroke
`(CHADS2 ≥ 1), renal creatinine clearance ≥50 mL/min, and no previ-
`ous contraindications to anticoagulation. The study findings demon-
`strated that all of the new generation agents were cost-effective
`compared to warfarin.30
`It may be predicted that growing data from such studies may re-
`sult in positive contributions in favor of NOACs from the policy
`maker perspective; and in this regard, one may suggest that
`NOACs are candidates to replace warfarin in anticoagulation
`therapy.
`5. When answering the question of whether NOACs may or may not re-
`place the widely accepted gold standard therapy with warfarin and
`heparin for their respective indications in certain therapeutic fields,
`one should also consider how the dynamics of the market have
`changed since the introduction of NOACs in 2008 to date.
`
`As per the IMS data regarding the global anticoagulant market,
`warfarin use has declined from 87,5% to 72% through 2008 to 2014. In
`contrast, NOACs have reached a market share of 15,5% as of 2014
`(Fig. 1).
`Fig. 1 presents the standard units (number of tablets the patients
`receive) data of 2014 showing a 1.35-fold higher usage rate for Factor
`Xa inhibitors compared to direct thrombin inhibitors. Standard units
`show that rivaroxaban as the most commonly preferred agent among
`Factor Xa inhibitors as of 2014.
`
`Fig. 1. Global AC Market Volume Shares in % (based on DoT*). Source: IMS MIDAS, Data-
`base: Current All 2014. *DoT = days of therapy, calculated based on volume in SU (stan-
`dard units). For dabigatran and apixaban: DOT = SU divided by 2 (assumption: two
`tablets per day). For VKA, rivaroxaban: DOT = SU (assumption: 1 tablet per day).
`
`Conclusion
`
`The success of these NOAC drugs means that warfarin will eventually
`become redundant in patients with NVAF, VTE and pulmonary embo-
`lism. This might take several years. In stroke prevention, these drugs
`are major breakthrough and stroke prevention is much more important
`than which drug is better than the others. That is a question hard to an-
`swer and at the moment is based more on opinions than fact.
`
`Disclosure statement
`
`The authors have no financial support or conflicts of interest to
`disclose.
`
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