THE TOP 10 CLINICALLY RELEVANT PUBLICATIONS IN 2012
ON THROMBOSIS AND ANTICOAGUALTION
Stephan Moll
University of North Carolina School of Medicine, Chapel Hill, NC
1. ACCP Guidelines 2012
The ACCP came out with the new edition of the respected, evidence-based Antithrombotic Therapy
Guidelines, with extensive chapters on (a) antithrombotic drugs (warfarin and new oral anticoagulant
drugs, anti-platelet drugs), (b) VTE prevention (medical and surgical patients), (c) VTE diagnosis, (d)
treatment of VTE, atrial fibrillation, stroke, peripheral arterial vascular and cardiovascular disease,
and (e) special patient populations (children; pregnant women). The 24 chapters and 801 pages of
the guideline have been summarized by the ACCP into a visually appealing, clinician-user friendly
document, referred to as “ACCP 2012 Reference Guide”.
The ACCP guidelines and the reference guide are highly relevant for anybody involved in clinical
decision-making in regard to antithrombotic therapy in patients at risk for or with established venous
or arterial thromboembolism. How to get access to them?
 An executive summary with all > 600 recommendations can be purchased in print
(https://accp.chestnet.org/storeWA/StoreAction.do?method=view&pcrNum=16).
 The full guideline is available on the web and as a mobile aps, not in print version
(http://www.chestnet.org/accp/guidelines/accp-antithrombotic-guidelines-9th-ed-nowavailable).
 The abbreviated Reference Guide is available on the web and as a mobile aps, not in
print version (http://www.chestnet.org/downloads/AT9-Quick-Reference-Guide.pdf).
2. Rivaroxaban in PE
The Einstein Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
NEJM 2012;366:1287-97.
The large (4,832 patients) phase 3 (EINSTEIN-PE) clinical trial compared 3-12 months of open-label
rivaroxaban treatment with warfarin therapy in patients with newly diagnosed PE. It showed that
rivaroxaban was (a) noninferior to warfarin in its efficacy, (b) caused the same amount of clinically
relevant bleeding (composite of major and clinically relevant nonmajor bleeding), and (c) caused less
major bleeding. Consequence of this study: This study, as well as the previously published
rivaroxaban DVT 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 GFR is > 30 mL/min. Patients with VTE and
creatinine clearance < 30 mL/min should not be treated with rivaroxaban.
1
3. Apixaban in A. Fib
Granger CB et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2011;
365:981-992.
This phase 3, double-blind (ARISTOTLE) study, randomized 18,201 patients with non-valvular atrial
fibrillation to treatment with apixaban 5 mg twice daily or warfarin. Apixaban was more effective than
warfarin in preventing stroke and systemic embolism; and apixaban led to less mortality, caused less
major bleeds, and less intracranial bleeds. Consequence of this study: Based on this study,
apixaban was approved by the FDA on Dec 28th, 2012 for atrial fibrillation. It is, therefore listed here
as one of the top ten 2012 publications, even though, technically, it is a 2011 paper.
4. Rivaroxaban in A. Fib
Patel MR et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.
2011;365:883-91.
In this phase 3, double-blind (RELY) study, 14,264 patients with non-valvular atrial fibrillation were
randomized to treatment with rivaroxaban 20 mg once daily or warfarin. Rivaroxaban was as effective
(non-inferior) as warfarin in preventing stroke and systemic embolism; rivaroxaban had the same risk
of major bleeding as warfarin, but caused less intracranial and fatal bleeds. Consequence of this
study: Based on this study, Rivaroxaban was approved by the FDA in November 2011 for atrial
fibrillation. Approved dose: 20 mg once daily, if GFR is > 50 mL/min, and 15 mg once daily if it is 1550 mL/min; below 15 ml/min the drug should not be used. Because this study led to FDA approval of
the drug, the publication is listed here as one of the top ten 2012 publications, even though,
technically, it is a 2011 paper.
5. Aspirin for Secondary VTE Prevention - WARFASA trial
Becattini C et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med.
2012 May 24;366(21):1959-67.
Is aspirin benefical in preventing recurrent VTE? Patients with unprovoked VTE who had been treated
with warfarin for 6-18 months, were enrolled and randomized to Aspirin 100 mg /day or placebo and
treated in a double-blind design for a median of 2 years. Primary endpoints were symptomatic VTE
and fatal PE. Primary safety outcome was major bleeding. 403 patients with unprovoked VTE were
enrolled: 205 received aspirin, 197 placebo. Median study period was 26.6 months. VTE recurred in
13.7% of patients treated with Aspirin, and in 21.8 % on placebo, i.e. 6.6 % vs. 11.2 % per year
(hazard ratio, 0.58; 95 % confidence interval, 0.35 to 0.93). This equals a 40 % risk reduction with
aspirin. Major bleeding and clinically relevant non-major bleeding occurred was similar in both
treatment groups. Conclusion of THIS study: Aspirin reduces the risk of recurrent VTE in patients
with unprovoked VTE once they have finished standard length of anticoagulant therapy, with no
apparent increase in the risk of major bleeding.
2
6. Aspirin for Secondary VTE Prevention - ASPIRE trial
Brighton TA et al. Low-dose aspirin for preventing recurrent venous thromboembolism. N Engl J Med.
2012 Nov 22;367(21):1979-87.
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 randomized them to aspirin
100 mg per day or placebo. 822 patients were enrolled: 411 received Aspirin, 411 placebo. Median
study period was 37.2 months. The findings: (a) VTE (DVT or PE) recurred in 14 % of patients treated
with aspirin (i.e. 1 of 7 patients), and in 18 % on placebo (i.e. 1 of 6 patients) during the 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. While this is a numerically lower risk or recurrence on aspirin, this
difference was not statistically different. (b) Looking at all thrombosis-related complications together
(DVT, PE, MI, stroke, or death due to heart or vascular problems – defined in conglomerate as “major
vascular events”), the patients on Aspirin had significantly less major vascular events: 5.2 % per year
compared to 8.0 % per year in the placebo group. (c) Major bleeding and clinically relevant non-major
bleeding occurred was similar in both treatment groups. Conclusion of THIS study: While Aspirin
did not significantly lower the risk of recurrence of DVT or PE, it did have a statistically significant
benefit regarding the overall risk of major vascular events (arterial and venous event together). And
aspirin did not increase the risk of major bleeding.
Metaanalysis: This NEJM publication also combined the data from WARFASA and ASPIRE study
into a metaanalysis, as both studies studied a similar patient population and were similarly designed.
Thus, a total of 1,224 patients (616 on Aspirin, 608 on placebo) could be analyzed. The conglomerate
data show that aspirin (a) decreases the risk of recurrent DVT and PE; (b) decreases the risk of
“major vascular events” as defined above; and (c) does not lead to an increase in major and clinically
significant bleeding. The authors’ conclusion of this meta-analysis: 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 DVTs and PEs in patients with 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 Xarelto) for at least 3 months and in whom the anticoagulant is discontinued
(because the risk of VTE recurrence is assessed to be low enough to stop anticoagulants or
because the patient’s preference is not to be on an anticoagulant) I discuss with the patient to
take long-term Aspirin, rather than nothing.
 What dose do I recommend? In the U.S., where the 100 mg tablet size studied in the two N Engl
J Med studies is not available, I tell patients to take either a baby Aspirin (81 mg) or an adult
Aspirin (325 mg) – typically I recommend the 81 mg size.
 Would I recommend that patients who are on long-term warfarin or Xarelto now stop their
anticoagulant and switch to Aspirin instead? No. Warfarin and Xarelto are much more effective
than Aspirin. 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? Yes. However, such women were not
included in the two N Engl J Med studies. Thus, it is not known whether aspirin in these women
is beneficial.
3
7. Perioperative Management of Antithrombotics
Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Hematology Am
Soc Hematol Educ Program. 2012;2012:529-35.
This is a practical discussion of when to discontinue anti-platelet 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 3 new oral anticoagulants developed at the University of North Carolina, for
a. Dabigatran: http://professionalsblog.clotconnect.org/wp-content/uploads/2011/04/UNCPradaxa-5-2012.pdf
b. Rivaroxaban: http://professionalsblog.clotconnect.org/wp-content/uploads/2012/05/UNCXarelto-2012.pdf
c. Apixaban: http://professionalsblog.clotconnect.org/wp-content/uploads/2013/02/ApixabanUNC-2-2013.pdf
8. Contraceptives and arterial thrombosis
Lidegaard Ø et al. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J
Med 2012;366:2257-66.
Much is known about the association of contraceptives with VTE, less about the association with
arterial thrombosis. In this epidemiological study, data from more than 1.6 million women of
reproductive age were obtained from several Danish registries. The absolute risk of stroke and
myocardial infarction 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 per year an MI (10.1 per 100,000). Women using pills with an estrogen
content of 30 to 40 g had a 1.3 to 2.3 higher risk of arterial thrombosis than non-users, and women
using pills with 20 g 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 the 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 with antiplatelet therapy adjustment
Collet JP et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med
2012;367:2100-9.
Conclusion of this large randomized study is that platelet function testing (for Aspirin or Plavix
“resistance”) with antiplatelet therapy adjustment based on these results before and after coronary
stenting does not improve clinical outcomes.
10. The risk of bleeding when combining the new oral anticoagulants with anti-platelet agents
Dans AL et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the randomized
evaluation of long-term anticoagulation therapy (RE-LY) trial. N Engl J Med 2013;127:634-640.
Prepulished on the web in 2012 the paper was published in print in 2013. The question as to what the
risk of bleeding is when combining Aspirin and one of the new oral anticoagulants, or with the
combination of Aspirin plus Plavix and one of the new oral anticoagulants comes up in clinical
practice when patients with atrial fibrillation and coronary artery disease  coronary stent are being
treated. This very useful publication reports on the risk for bleeding with the combination of
dabigatran and single or double anti-platelet therapy, and compares it to the risk for bleeding with
4
warfarin taken with single or double anti-platelet therapy. Figure 3 of the publication provides a great
summary of the bleeding risks. Overall, the study shows that, not surprisingly, concomitant
antiplatelet use leads to a significant rise in overall risk of major bleeding when combined with any
oral anticoagulant: the risk increases by 50 % when a single antiplatelet drug, and doubles when
dual-antiplatelet drugs are given in addition to an oral anticoagulant. The relative bleeding risk
increase is similar with dabigatran 150 mg bid and with warfarin and is not higher with dabigatran
compared to warfarin.
Conclusion: When considering combining antiplatelet therapy with dabigatran, a similar assessment
regarding increased bleeding risk should occur as when considering antiplatelet therapy in addition to
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.
5