Important Data On 3 New Oral AnticoagulantsJuly 2015
By William Faloon
There are a host of medical issues that can necessitate anticoagulant drug therapy. These include atrial fibrillation, mechanical heart valve replacement, deep vein thrombosis, severe atherosclerosis, prior stroke, and coagulation disorders.
Today’s medical journals are filled with advertisements for new anticoagulant drugs such as Pradaxa®, Eliquis®, and Xarelto®. The implication is that these newer drugs have advantages over warfarin (Coumadin ®), which has been the standard anticoagulant drug in clinical use for over 60 years.1
A careful review of the research on these newer drugs compared to warfarin finds they have important problems of their own (including potential lack of reversibility of their anticoagulation effects).2 A huge advantage of these newer drugs over warfarin, however, is that they do not function by antagonizing vitamin K.3
Warfarin users are vulnerable to suffer severe system-wide calcification.4,5
This article contains technical descriptions of the three new anticoagulant drugs that may be used in place of warfarin. The data is not sufficient, however, to definitely recommend one of these newer drugs over the other. The experience your physician has with any one of these three alternatives to warfarin is likely to be the most important factor when considering their safe and effective use.
The unique advantage of this data is that it is unbiased, which is a major issue nowadays as pharmaceutical companies make tremendous efforts to influence physician prescribing practices.
In this article, Life Extension® describes the pros and cons of three newer anticoagulant drugs and then compares their effects to warfarin (Coumadin®). We know this is highly technical reading, but it is meant primarily for our many physician readers. This information is also relevant to those in need of anticoagulant drug therapy.
Dabigatran (Pradaxa ® )
A direct thrombin inhibitor, dabigatran (Pradaxa®) is approved in the US for use in the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation, for the treatment of deep venous thrombosis and pulmonary embolism in patients, and to reduce the risk of recurrence of deep vein thrombosis and pulmonary embolism.6-8
The RE-COVER study in patients with acute venous thromboembolism showed:9
- The six-month incidence of recurrent symptomatic acute venous thromboembolism or related deaths was similar (test for non-inferiority), 2.4% in patients treated with dabigatran vs 2.1% in those treated with warfarin.
- The rates of major bleeding episodes were similar in the dabigatran and warfarin groups (1.6 vs 1.9%). However, the incidence of all bleeding events was lower with dabigatran use (16.1 vs 21.9%).
The RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy, Warfarin, compared with Dabigatran) study in patients with nonvalvular atrial fibrillation and at risk of thromboembolism showed:10
- The rate of stroke and systemic embolism per year was lower with 150 mg dabigatran twice daily (1.11%) and statistically equivalent (non-inferiority test) with 110 mg dabigatran twice daily ( 1.54%) compared with warfarin (1.71%).
- The rate per year of major bleeding with a 150 mg dabigatran dose was not significantly different (3.32%;P=0.31) compared with warfarin (3.57%). However, the rate of major bleeding was significantly lower with a 110 mg dose of dabigatran (2.87%; P=0.003) than either the 150 mg dabigatran dose or warfarin. The rates per year of hemorrhagic stroke with the 110 and150 mg dabigatran doses were both significantly lower than with warfarin (0.12% and0.10% vs 0.38% respectively; P<0.001), as were the rates of intracranial hemorrhage ( 0.23% and 0.32% vs 0.74%; P<0.001).
An analysis of seven trials involving over 30,000 patients, including two studies of stroke prophylaxis in atrial fibrillation, one in acute venous thromboembolism, one in acute coronary syndrome, and three of short-term prophylaxis of deep vein thrombosis showed:11
- Dabigatran was associated with a significantly higher risk of mycardial infarction or acute coronary syndrome (dabigatran, 1.19% vs control, 0.79%; P=0.03).
- The risk of mycardial infarction or acute coronary syndrome was similar when using revised criteria to exclude short-term trials and was consistent when using different methods and measures of association.
Rivaroxaban (Xarelto ® )
A direct factor Xa inhibitor, rivaroxaban (Xarelto®) is approved in the US for reducing stroke risk and systemic embolism in nonvalvular atrial fibrillation, treatment of deep vein thrombosis and pulmonary embolism as well as reduction in the risk of recurrence of deep vein thrombosis and of pulmonary embolism, and prophylaxis of deep vein thrombosis after knee replacement surgery and hip replacement surgery.12-15
The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study evaluated rivaroxaban for prevention of stroke or embolization in patients with nonvalvular atrial fibrillation at risk of stroke, and showed:16,17
- Rivaroxaban was similar to warfarin (2.1% vs 2.4% per year; non-inferiority test) for risk of stroke and embolism.
- Similar rates were observed between patients taking rivaroxaban and those taking warfarin in terms of all clinically relevant nonmajor bleeding events (14.9% vs 14.5% per 100 patient years) and major bleeding events (3.6% vs 3.4% per 100 patient years).
- In addition, the rates of intracranial hemorrhage were less with rivaroxaban therapy (0.5% vs 0.7%, P=0.02 and 0.4% vs 0.8%, P=0.003, respectively).
- The EINSTEIN study included a comparison of oral rivaroxaban to traditional therapy with low molecular weight heparin (enoxaparin) and a vitamin K antagonist in patients with acute, symptomatic deep vein thrombosis.18
- Rivaroxaban therapy was similar (non-inferiority test) to enoxaparin/vitamin K antagonists therapy with respect to recurrent acute venous thromboembolism (2.1% vs 3.0%; P<.001).
- The principal safety outcome of major or clinically relevant non-major bleeding occurred at similar rates in both treatment arms (rivarox-aban vs enoxaparin/vitamin K antagonists).
Apixaban (Eliquis ® )
An inhibitor of free and clot-bound factor Xa as well as prothrombinase activity, apixaban (Eliquis®) is approved in the US for the treatment of deep vein thrombosis and pulmonary embolism, for the reduction in the risk of recurrent deep vein thrombosis and pulmonary embolism following initial therapy, to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, and prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism, in patients who have undergone hip or knee replacement surgery.19-22
The Apixaban after the initial Management of PuLmonary embolism and deep vein thrombosis with First-line therapy–EXTended treatment (AMPLIFY-EXT) trial evaluated the efficacy and safety of different doses of apixaban compared with placebo in patients who had a venous thromboembolism and completed prior anticoagulation therapy. The results showed:23
- The incidence of recurrent acute venous thromboembolism and acute venous thromboembolism-related mortality was 1.7% in both the apixaban dose groups (2.5 mg or 5 mg twice daily) compared with 8.8% in the placebo group ( P<0.001).
- The rates of major bleeding were similar across the treatment groups (placebo: 0.5%; 2.5 mg of apixaban: 0.2%; and 5 mg of apixaban: 0.1%).
- The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban at a dose of 5 mg twice daily with the vitamin K antagonists warfarin in patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke and showed:24
- Compared with warfarin, apixaban therapy was better in preventing stroke or embolism (1.27% vs 1.60% per year; P<0.001 for non-inferiority and P=0.01 for superiority).
- The rate of major bleeding per year with apixaban use was better, 2.1% compared to nearly 3.1% with warfarin (P<0.001).
Using These New Anticoagulant Drugs As Alternatives To Warfarin (Coumadin ® )
For approximately 60 years, vitamin K antagonists like warfarin (Coumadin®) were the only orally bioavailable anticoagulant drugs. (Aspirin is not an anticoagulant drug but rather reduces the effectiveness of platelets to stick together in primary hemostasis, a separate function from the body’s very complex system of clotting homeostasis involved in secondary hemostasis [for a thorough review of the complex nature of this topic, please review: http://www.lifeextension.com/Protocols/Heart-Circulatory/Blood-Clot.])
However, use of vitamin K antagonists like warfarin in patients has been plagued by problems.
Warfarin treatment risks multiple medication (and food) interactions,25 the problem of variable pharmacologic effect,26 a narrow, brittle therapeutic index,2 and a relatively slow onset of action,27 all of which serve to place patients at risk.
For example, an underappreciated analysis showed just how clinically problematic warfarin’s narrow therapeutic window can be. A hefty 44% of bleeding complications with oral anticoagulants (largely warfarin) were found in patients anticoagulated excessively, and a whopping 48% of clotting events (thromboembolic) occurred in patients anticoagulated inadequately. 28
However, over the past several years, several novel, orally bioavailable anticoagulant drugs have become available in the US.
These new medications target critical anticoagulant factors like factor Xa and thrombin (factor IIa). They include dabigatran (Pradaxa ®; Boehringer Ingelheim), rivaroxaban (Xarelto®; Bayer HealthCare AG and Janssen Research & Development LLC, a Johnson & Johnson Company), and apixaban (Eliquis®; Pfizer, and Bristol-Myers Squibb).
A fourth oral anticoagulant, Daiichi Sankyo’s edoxaban (Savaysa®), was recently approved by the FDA (January, 2015). It is used to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation that is not caused by a heart valve problem.29
Be aware that although there appear to be a variety of advantages associated with the new oral anticoagulants in comparison with warfarin, there is also controversy.
For example, many of the studies submitted for FDA approval with the new, oral anticoagulants utilized so-called non-inferiority designs and statistical tests in order to show that the newer drugs are at least as good as the vitamin K antagonists warfarin in reducing the risk of thromboembolic events as well as supporting safety, in particular in the context of major bleeding like intracranial hemorrhage (ICH). However, one criticism of the use of the non-inferiority test suggests that the relative benefits of these newer drugs versus warfarin have been overstated (given the limitations of the trial designs).
Also, although some outcomes may “appear” better (or safer) with specific new anticoagulants, the patient populations are similar, but not the same (nor are the trial designs), and the idea that one agent is necessarily better than another at the current time is not supportable. However, one of the new oral agents (dabigatran) has a potential danger signal. Though very controversial at the current time, some data suggest an increase in heart attack and acute coronary syndrome in some patients with the use of this new drug.11
General advantages of the new oral anticoagulants include:30-32
- More rapid onset of action compared with warfarin,
- No need for frequent blood test monitoring compared with warfarin,
- Far more predictable, consistent pharma-cologic effects compared with warfarin,
- Dramatically reduced drug-drug, and drug-food, interactions compared with warfarin,
- Similar (or better) short-term efficacy for reduction of clotting events (thrombo-embolism) compared with warfarin,
- Similar (or improved) short-term safety (e.g. major bleeding risk) compared with warfarin.
General disadvantages of the new oral anticoagulants include:11,32-37
- High(er) cost relative to warfarin;
- No specific antidote to counteract bleeding (in contrast to high-dose vitamin K to reverse warfarin’s effects), though protein C concentrate has been used;
- Lack of long-term safety data and adequate data to support use in pregnancy, patients with mechanical heart valves, and patients with severe kidney disease.
- Potential safety signal observed with at least one of the new drugs (dabigatran), suggesting an increase in heart attack and acute coronary syndrome risk in at least some vulnerable patients.
When it comes to anticoagulant drugs, there are no definitive best choices that can be made. They all have dangerous side effects. The dilemma is that failure to use an anticoagulant drug when one is indicated predisposes the patient to an unacceptably high risk of thrombosis, and ensuing ischemic stroke, heart attack, pulmonary embolism, deep vein thrombosis, etc.
The main advantage of the new anticoagulant drugs over warfarin is that they don’t antagonize vitamin K and they don’t require the patient to avoid vitamin K-containing foods. Warfarin users are predisposed to systemic calcification.
Switching from warfarin to one of these new anticoagulant drugs requires expert physician intervention.
In addition to the traditional warfarin (Coumadin®) here are three new oral anticoagulants on the market—Dabigatran (Pradaxa®), rivaroxaban (Xarelto®), and apixaban (Eliquis®). All have their advantages and disadvantages. Some of the advantages of the new drugs include more rapid onset of action compared to Coumadin®, no more need for frequent blood testing, fewer interactions, similar or better efficacy, and similar or improved risk. The main advantage of the new oral anticoagulants over warfarin is they don’t antagonize vitamin K and a patient no longer has to avoid foods containing this nutrient. Disadvantages include a higher cost to consumers, no specific antidote for bleeding, and lack of long-term data supporting use.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
- Kimmel SE. Warfarin therapy: in need of improvement after all these years. Expert Opin Pharmacother. 2008 Apr;9(5):677-86.
- Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol. 2006 Nov;62(5):509-11.
- McMahon BJ, Kwaan HC. The new or non-vitamin k antagonist oral anticoagulants: what have we learned since their debut. Semin Thromb Hemost. 2015 Mar;41(2):188-94.
- Howe AM, Webster WS. Warfarin exposure and calcification of the arterial system in the rat. Int J Exp Pathol. 2000 Feb;81(1):51-6.
- Zhang YT, Tang ZY. Research progress of warfarin-associated vascular calcification and its possible therapy. J Cardiovasc Pharmacol. 2014 Jan;63(1):76-82.
- Stangier J, Stähle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47(1): 47-59.
- Available at: http://www.drugs.com/history/pradaxa.html. Accessed April 16, 2015.
- Available at: http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/04-07-14-fda-approves-pradaxa-dabigatran-etexilate-mesylate-treatment-reduction-risk-of-recurrence-deep-venous-thrombosis-pulmonary-embolism.html.Accessed April 16, 2015.
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- Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010 Sep 18;376(9745):975-83.
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- Hillarp A, Baghaei F, Fagerberg Blixter I, et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost. 2011 Jan;9(1):133-9.
- Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278646.htm. Accessed April 16, 2015.
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- Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011 Oct;32(19):2387-94.
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- Available at: http://www.drugs.com/newdrugs/fda-approves-eliquis-apixaban-deep-vein-thrombosis-pulmonary-embolism-4073.html. Accessed April 16, 2015.
- Available at: http://news.bms.com/press-release/rd-news/us-fda-approves-eliquis-apixaban-reduce-risk-stroke-and-systemic-embolism-pati. Accessed April 16, 2015.
- Available at: http://news.bms.com/press-release/us-fda-approves-eliquis-apixaban-reduce-risk-blood-clots-following-hip-or-knee-replace. Accessed April 16, 2015.
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- Daiichi Sankyo. US FDA Cardiovascular and Renal Drugs Advisory Committee makes recommendation on Daiichi Sankyo’s once-daily Savaysa (edoxaban) for the reduction in risk of stroke and systemic embolic events in patients with non-valvular atrial fibrillation [press release]. October 31, 2014.
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- Hanley CM, Kowey PR. Are the novel anticoagulants better than warfarin for patients with atrial fibrillation? J Thorac Dis. 2015 Feb;7(2):165-71.
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