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The top clinically relevant publications in thrombosis and anticoagulation
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Stephan Moll
Several major developments occurred in 2012 in the field of clinical thrombosis and anticoagulation.
They included the publication of the new edition of the evidence-based American College of Chest Physicians guidelines in February; FDA approval of rivaroxaban for the acute treatment and long-term secondary prevention of venous thromboembolism in November, and of apixaban for the prevention of stroke and systemic arterial embolism in patients with nonvalvular atrial fibrillation in December; and the publication of two studies that investigated aspirin in the prevention of VTE.
The published papers I consider the top 10 are listed below.
1. ACCP guidelines
The American College of Chest Physicians (ACCP) released the new edition of the respected Antithrombotic Guidelines, with extensive chapters on antithrombotic drugs (warfarin and new oral anticoagulant drugs, antiplatelet drugs); VTE prevention (medical and surgical patients); VTE diagnosis; treatment of VTE, atrial fibrillation, stroke, peripheral arterial vascular and cardiovascular disease; and special patient populations (children and pregnant women).
The ACCP summarized the 24 chapters and 801 pages of the guideline in a visually appealing, user-friendly document reference guide.
The ACCP guidelines and reference guide are highly relevant for anybody involved in clinical decision-making regarding antithrombotic therapy in patients at risk for or with established venous or arterial thromboembolism.
An executive summary with all 600-plus recommendations can be purchased in print at https://accp.chestnet.org/storeWA/StoreAction.do?method=view&pcrNum=16.
The full guideline and abbreviated reference guides are available on the Web at journal.publications.chestnet.org/issue.aspx?journalid=99&issueid=23443. They also are available as mobile apps.
2. Rivaroxaban in PE
EINSTEIN-PE Investigators. N Engl J Med. 2012;366:1287-1297.
EINSTEIN-PE, a phase 3 trial that included 4,832 patients, compared 3 to 12 months of open-label rivaroxaban (Xarelto, Janssen Pharmaceuticals) treatment with warfarin therapy in patients with newly diagnosed PE. It showed rivaroxaban was noninferior to warfarin in its efficacy, caused the same amount of clinically relevant bleeding (composite of major and clinically relevant nonmajor bleeding) and caused less major bleeding.
Consequence of this study: This study, as well as the previously published rivaroxaban deep vein thrombosis trial, led to the FDA approval of rivaroxaban on Nov. 2, 2012, for the acute treatment and long-term secondary prevention of VTE. The dose is 15 mg twice daily for the first 3 weeks after an acute episode of VTE, followed by 20 mg once daily, if the glomerular filtration rate (GFR) is >30 mL/min. Patients with VTE and creatinine clearance <30 mL/min should not be treated with rivaroxaban.
3. Apixaban in atrial fibrillation
Granger CB. N Engl J Med. 2011;365:981-992.
The phase 3, double blind ARISTOTLE study included 18,201 patients with nonvalvular atrial fibrillation who were randomly assigned to treatment with apixaban 5 mg twice daily or warfarin.
Apixaban (Eliquis, Bristol-Myers Squibb) was more effective than warfarin in preventing stroke and systemic embolism. Apixaban led to less mortality, and it caused fewer major bleeds and intracranial bleeds.
Consequence of this study: Based on this study, the FDA approved apixaban on Dec. 28, 2012, for atrial fibrillation. It is, therefore, listed as one of the top 10 2012 publications, although it technically is a 2011 paper.
Full-dose apixaban is 5 mg twice daily. If two or more of the following criteria are present, a dose of 2.5 mg twice daily should be used: ≥80 years of age; weight ≤60 kg; and creatinine ≥1.5 mg/dL.
4. Rivaroxaban inatrial fibrillation
Patel MR. N Engl J Med. 2011;365:883-891.
In the phase 3, double blind RELY study, 14,264 patients with nonvalvular atrial fibrillation were randomly assigned to treatment with rivaroxaban 20 mg once daily or warfarin.
Rivaroxaban was noninferior to warfarin in preventing stroke and systemic embolism. Rivaroxaban had the same risk for major bleeding as warfarin but caused fewer intracranial and fatal bleeds.
Consequence of this study: Based on this study, the FDA approved rivaroxaban for atrial fibrillation. The approved dose is 20 mg once daily if GFR is >50 mL/min, and 15 mg once daily if GFR is 15 mL/min to 50 mL/min. If GFR is less than 15 mL/min, the drug should not be used. Because this study led to FDA approval of the drug, the publication is listed as one of the top 2012 publications, although it technically is a 2011 paper.
5. WARFASA trial
Becattini C. N Engl J Med. 2012;366:1959-1967.
Is aspirin beneficial for prevention of recurrent VTE?
In the WARFASA trial, patients with unprovoked VTE who had been treated with warfarin for 6 to 18 months were randomly assigned to aspirin 100 mg/day or placebo. They were treated in a double blind design for a median of 2 years.
Symptomatic VTE and fatal PE served as primary endpoints. The primary safety outcome was major bleeding.
Becattini and colleagues enrolled 403 patients with unprovoked VTE. Of them, 205 received aspirin and 197 received placebo.
The median follow-up period was 26.6 months. VTE recurred in 13.7% of patients treated with aspirin and in 21.8% of patients on placebo (ie, 6.6% vs. 11.2% per year; HR=0.58; 95% CI, 0.35-0.93). This equals a 40% risk reduction with aspirin. Major bleeding and clinically relevant nonmajor bleeding was similar in both treatment groups.
Conclusion of this study: Aspirin reduces the risk for recurrent VTE in patients with unprovoked VTE once they have finished the standard length of anticoagulant therapy, with no apparent increase in the risk for major bleeding.
6. ASPIRE trial
Brighton TA. N Engl J Med. 2012;367:1979-1987.
Similar to the WARFASA study, the ASPIRE study enrolled patients with a history of unprovoked VTE who had been treated with standard length of a vitamin K antagonist and randomly assigned them to aspirin 100 mg per day or placebo.
Brighton and colleagues enrolled 822 patients, 411 of whom received aspirin and 411 of whom received placebo. Median treatment was 37.2 months.
There were several key findings:
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VTE (DVT or PE) recurred in 14% of patients treated with aspirin and in 18% of those on placebo during slightly more than 3 years of follow-up. This means a recurrence rate of 4.8% per year on aspirin vs. 6.5% per year when not on aspirin. Although this is a numerically lower risk for recurrence on aspirin, this difference was not statistically significant.
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Looking at all thrombosis-related complications together (DVT, PE, myocardial infarction, stroke, or death due to heart or vascular problems, defined in conglomerate as "major vascular events"), the patients on aspirin experienced significantly fewer major vascular events (5.2% per year compared with 8% per year in the placebo group).
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Major bleeding and clinically relevant nonmajor bleeding was similar in both treatment groups.
Conclusion of this study: Aspirin did not significantly lower the risk for recurrence of DVT or PE. However, it did have a statistically significant benefit regarding the overall risk for major vascular events (arterial and venous events together). Aspirin did not increase the risk for major bleeding.
The conglomerate data show aspirin decreases the risk for recurrent DVT and PE; decreases the risk for major vascular events as defined above; and does not lead to an increase in major and clinically significant bleeding. The researchers’ conclusion from this meta-analysis is that aspirin is effective and safe in patients with previous unprovoked DVT or PE who have been treated with warfarin.
My perspective of the two aspirin trials: The two studies showed discrepant results. WARFASA showed a benefit of aspirin on the VTE recurrence rate, ASPIRE did not. Thus, it is not clear whether aspirin can prevent DVT and PE in patients with a history of unprovoked VTE. However, aspirin is beneficial nonetheless (on arterial and venous clots together), with no detectable increase in major bleeding risk.
Consequences for my practice: In the patient with an unprovoked DVT or PE who has been treated with an anticoagulant (warfarin or rivaroxaban) for at least 3 months and in whom the anticoagulant is discontinued — either because the risk for VTE recurrence is assessed to be low enough to stop the anticoagulant or because the patient’s preference is not to be on an anticoagulant — I discuss taking long-term aspirin rather than nothing.
What dose do I recommend? In the United States, where the 100-mg tablet size studied in the WARFASA and ASPIRE studies is not available, I typically tell patients to take a baby aspirin (81 mg).
Would I recommend that patients who are on long-term warfarin or rivaroxaban now stop their anticoagulant and switch to aspirin instead? No. Warfarin and rivaroxaban are clearly effective in preventing VTE recurrence, whereas it is not clear whether aspirin prevents recurrent VTE. Aspirin is not a replacement for these anticoagulants. However, aspirin is better than nothing if the patient with unprovoked VTE has stopped anticoagulants.
Would I recommend aspirin therapy in women who had a VTE associated with the contraceptive pill, ring or patch and have now come off blood thinners? Such women were not included in the WARFASA or ASPIRE studies and it is, therefore, not known whether aspirin in these women is beneficial. Thus, no clear recommendation is possible. However, I discuss with the patient that it is not unreasonable to take a baby aspirin.
7. Perioperative management of antithrombotics
Ortel TL. Hematology Am Soc Hematol Educ Program. 2012;2012:529-535.
This is a practical discussion of when to discontinue antiplatelet drugs, warfarin and the new oral anticoagulants at times of surgery. It includes some guidance on when to use perioperative bridging anticoagulant therapy.
A supplementation to this publication can be the practical treatment guidelines for the three new oral anticoagulants developed at the University of North Carolina:
8. Contraceptives and arterial thrombosis
Lidegaard Ø. N Engl J Med. 2012;366:2257-2266.
Much is known about the association of contraceptives with VTE; less is known about the association with arterial thrombosis.
In this epidemiological study, researchers used several Danish registries to obtain data about more than 1.6 million women of reproductive age.
The absolute risk for stroke and MI was low: About 1 in 5,000 women had a stroke per year (21.4 per 100,000 per year), and about 1 in 10,000 had an MI per year (10.1 per 100,000 per year).
Women using pills with an estrogen content of 30 mcg to 40 mcg were 1.3 to 2.3 times more likely to develop arterial thrombosis than nonusers, and women using pills with 20 mcg had a 0.9 to 1.7 times higher risk. The risk was only minimally influenced by the type of progestin in combination pills. Progestin-only contraceptives did not increase the risk for arterial thrombosis.
Consequence of this study: In a woman with an arterial thrombotic event while on contraceptives, I discuss that the estrogen contraceptives contributed some to the stroke. If the woman was on progestin-only contraceptives, I discuss that they did not contribute to the event.
9. Platelet function testing
Collet JP. N Engl J Med. 2012;367:2100-2109.
The conclusion of this large randomized study is that platelet function testing for aspirin or clopidogrel “resistance” with antiplatelet therapy adjustment based on these results before and after coronary stenting does not improve clinical outcomes.
10. Combining oral anticoagulants with antiplatelet agents
Dans AL. Circulation. 2013;127:634-640.
This paper was published online in 2012 and in print earlier this year.
The question as to the risk for bleeding when combining aspirin and one of the new oral anticoagulants — or with the combination of aspirin plus clopidogrel and one of the new oral anticoagulants — comes up in clinical practice when patients with atrial fibrillation and coronary artery disease with or without coronary stents are being treated.
This useful publication reports on the risk for bleeding with dabigatran or warfarin combined with single or double antiplatelet therapy.
Figure 3 of the publication provides a very useful, visual summary of the bleeding risks. Overall, the study shows — not surprisingly — that concomitant anticoagulant and antiplatelet use leads to a significant increase in overall risk of major bleeding compared with oral anticoagulant treatment alone. The risk increases by 50% when a single antiplatelet drug is given with an oral anticoagulant, and doubles when dual antiplatelet drug therapy is given.
The relative bleeding risk increase is similar with dabigatran 150 mg twice daily and with warfarin, and it is not higher with dabigatran than with warfarin.
Conclusion: When considering combining antiplatelet therapy with dabigatran, a similar assessment regarding increased bleeding risk should occur as when considering antiplatelet therapy combined with warfarin. Data on the bleeding risk of patients treated with rivaroxaban or apixaban combined with single or dual antiplatelet therapy have not yet been published.
For more information:
Stephan Moll, MD, is an associate professor in the Department of Medicine and Division of Hematology-Oncology at the University of North Carolina School of Medicine in Chapel Hill, N.C., and medical director of the Clot Connect patient and health care professional education program (www.clotconnect.org), an initiative of the University of North Carolina Hemophilia and Thrombosis Center. He may be reached at UNC Hemophilia and Thrombosis Center, 170 Manning Drive, 3rd Floor Physicians Office Building, Campus Box 7035, Chapel Hill, NC 27599-7016; email: smoll@med.unc.edu.
Acknowledgement: Moll thanks Raj Kasthuri, MD, of the Division of Hematology and Oncology at the University of North Carolina School of Medicine, for critical discussions.
Disclosure: Moll has been a consultant for Janssen, Boehringer Ingelheim and Daiichi.