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Thrombosis and anticoagulation: Highlights from the ASH Annual Meeting
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The American Society of Hematology Annual Meeting and Exposition, held from Dec. 6-10, 2013, in New Orleans, featured relatively few new data on thrombosis and anticoagulation with direct clinical impact.
The most clinically relevant abstract probably was Abstract #3588, in which Refaai and colleagues presented new data from a phase 3 study on the reversal of warfarin before urgent surgery.
I detected no practice-changing abstract, although the meeting included a number of good general education sessions on thrombosis and anticoagulation.
Educational sessions
Special Symposium on Quality: Clinical practice guidelines
Stephan Moll
ASH has embarked on the development of diagnostic and treatment guidelines in the various fields of hematology. This symposium critically reviewed the methodologies to be applied to create meaningful and high-quality clinical practice guidelines. The next steps will be the development of guidelines by ASH.
‘Choosing Wisely’
To prevent physicians from ordering unnecessary tests and medical interventions, ASH became involved in the national Choosing Wisely campaign and produced five recommendations about tests and procedures physicians should avoid.
Three of the recommendations are relevant to thrombosis and anticoagulation:
- Avoid thrombophilia testing in patients who have a deep vein thrombosis or pulmonary embolism in the setting of a transient major risk factor (eg, major surgery, trauma or prolonged immobility).
- Avoid placing inferior vena cava (IVC) filters in patients with DVT or PE, except in special circumstances (eg, patients with acute DVT who cannot be anticoagulated).
- Avoid giving fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) to patients on warfarin who have elevated international normalized ratios but are not bleeding.
Consultative hematology course
This clinical–practical course aimed at hematology–oncology physicians in community practice covered commonly encountered hematological problems, including thrombosis and anticoagulation. It was well attended, with more than 300 participants.
Abstracts and scientific presentations
Reversal of warfarin for urgent surgery
Kcentra (CSL Behring), a 4-factor PCC, received FDA approval in April for the treatment of major bleeding in patients on warfarin based on a phase 3 study by Sarode and colleagues of patients with major bleeding on warfarin.
At ASH, the results of a similarly designed study of patients on warfarin requiring urgent surgery were presented (Refaai MA. Abstract #3588). This study led the FDA in December to extend Kcentra approval to include the indication of reversal of warfarin for urgent surgeries.
Methods: Patients who required rapid reversal of warfarin and other vitamin K antagonists before an urgent surgical or invasive procedure were randomly assigned to a single dose of Kcentra or FFP. Per routine practice, patients also were to receive vitamin K as early as possible. The primary endpoints were effective perioperative hemostasis and rapid INR reduction (INR ≤1.3 at 0.5 hours after end of infusion).
Results: The study included 168 patients (Kcentra, n=87; FFP, n=81). Effective hemostasis was achieved in 89.7% of patients in the Kcentra vs. 75.3% in the FFP group, demonstrating superiority of Kcentra (difference, 14.3%; 95% CI, 2.8-25.8). Rapid INR reduction was achieved in 55.2% of patients in the Kcentra group vs. 9.9% in the FFP group, demonstrating superiority of Kcentra (difference, 45.3%; 95% CI, 31.9-56.4). Side effects were similar between treatment groups. Significantly fewer fluid overload events occurred with Kcentra.
Conclusion: Kcentra was superior to FFP for hemostatic efficacy and for rapid INR reduction, with a favorable safety profile.
Clinical relevance: If there is a need for urgent reversal of warfarin before surgery, it makes sense to give vitamin K IV plus Kcentra.
New oral anticoagulants
- Edoxaban
Edoxaban (Savaysa; Daiichi Sankyo) is not FDA approved for the treatment of venous thromboembolism, but its manufacturer applied for FDA approval on Jan. 8 based on the results of the Hokusai trial. A response from the FDA is awaited in the next several months.
In a subanalysis of the Hokusai acute VTE treatment study, 208 patients with active cancer were analyzed (Raskob GE. Abstract #211). Of them, 109 received edoxaban (Daiichi Sankyo) and 99 received warfarin.
Results: Recurrent VTE occurred in 3.7% of patients treated with edoxaban and 7.1% of those treated with warfarin (HR=0.55; 95% CI, 0.16-1.85). Clinically relevant bleeding occurred in 18.3% on edoxaban and 25.3% on warfarin (HR=0.72; 95% CI, 0.4-1.3).
Conclusion: The results suggest that edoxaban is as effective, and possibly more effective, than warfarin in patients with active cancer and VTE. As all treatment guidelines recommend low–molecular-weight heparin (LMWH) as the gold standard in patients with cancer and VTE, additional studies of edoxaban — or any of the other new oral anticoagulants (NOAC) — for therapy of VTE in patients with cancer are indicated, with LMWH as the comparator.
Clinical relevance: None. LMWH is still the recommended treatment in patients with cancer and VTE. In addition, edoxaban is not FDA approved and is not available in the United States.
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Dabigatran
Dabigatran (Pradaxa, Boehringer-Ingelheim) is not FDA approved for the treatment of VTE, but its manufacturer applied for FDA approval in August. A response from the FDA is expected in the next few months.
Several subanalyses are being published from the two phase 3 VTE treatment trials, RE-COVER and RE-COVER II. Data are helpful to learn more about the performance of dabigatran in various VTE patient populations.
Schulman and colleagues published a paper in Circulation in December examining dabigatran in patients with acute VTE.
This paper reports the second of the large VTE treatment trials, RE-COVER II, and also summarizes the data of the first dabigatran VTE trial, published in 2009 in The New England Journal of Medicine, and the present trial in a pooled analysis.
The overall data show an HR for dabigatran vs. warfarin of 1.09 (95% CI, 0.76-1.57) for recurrent bleeding and 0.73 (95% CI, 0.48-1.11) for major bleeding.
Conclusion: Dabigatran has a similar effect on VTE recurrence and on major bleeding compared with warfarin in the treatment of acute VTE.
Two other subanalyses were presented at ASH:
1. Influence of renal function on the efficacy and safety of dabigatran vs. warfarin for the treatment of acute VTE: A pooled analysis from RE-COVER and RE-COVER II (Schulman S. Abstract #212).
As dabigatran is cleared via the kidney to 80%, patients with a creatinine clearance of <30 mL/minute were excluded from the RE-Cover VTE trials. In the trials, patients with creatinine clearance of >30 mL/minute were randomly assigned to dabigatran 150 mg twice daily or warfarin.
Conclusion: Across renal function groups, there was no apparent difference in recurrent VTE or bleeding. Although bleeding events increased with declining renal function, they were similar between dabigatran and warfarin. The results suggest that there is no need for dose adjustment of dabigatran in patients with renal dysfunction as long as the creatinine clearance is >30 mL/minute.
2. Influence of age on the efficacy and safety of dabigatran vs. warfarin for the treatment of acute VTE: A pooled analysis of RE-Cover and RE-Cover II (Schulman S. Abstract #2375).
Conclusion: No differences in recurrent VTE or efficacy were apparent across age groups (<65 years, 65-75 years, or >75 years). Bleeding events increased with age but numerically were similar or lower with dabigatran than with warfarin, regardless of age. The results suggest that there is no need for dose adjustment of dabigatran according to age for the treatment of VTE.
Clinical relevance: None at present, unless one uses dabigatran for VTE off label. FDA review of data is ongoing and a decision on approval for VTE treatment is awaited.
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Major bleeding on NOACs
It is not known how to best treat major bleeds that occur on NOACs. The efficacy of FFP, PCC and recombinant Factor VIIa (rVIIa) have only been tested in vitro, in animal bleeding models or in human volunteers. No data beyond case reports exist on the efficacy of such interventions in patients with bleeding. No abstracts were presented at ASH that fill this knowledge vacuum.
Related abstracts included:
1. Pattern and management of bleeding complications with novel oral anticoagulants — Results of the prospective Dresden NOAC Registry (Förster K. Abstract #214).
This abstract included data from a large prospective German registry of 2,249 patients treated with NOAC. Of them, 77% received rivaroxaban (Xarelto, Janssen Pharmaceuticals), 16% received dabigatran and 7% received apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). During 2,674 patient-years of follow-up, 6.9% of patients had major bleeding; of these, eight patients received FFP, nine received PCC and none received rVIIa.
Conclusion: Bleeding occurs on NOACs. Treatment used for major bleeds is typically supportive, with occasional use of FFP or PCC.
Clinical relevance: None. This study does not allow any conclusion on efficacy of treatment interventions.
2. Four-factor prothrombin complex concentrate (4-PCC) effectively reverses edoxaban-induced bleeding in a rabbit model of acute injury (Herzog E. Abstract #1133).
This is another animal bleeding model. In an in vivo rabbit kidney injury model of acute bleeding, 4-PCC (25 U/kg to 75 U/kg) compared with placebo decreased time to hemostasis and total blood loss.
Conclusion: 4-PCC treatment effectively decreased edoxaban-induced hemorrhage in an animal model of acute bleeding.
Clinical relevance: None. It is not known whether PCC is beneficial for treatment of patients on NOACs with major bleeding.
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NOACs for VTE treatment
Each of the four big NOACs has been compared with warfarin in the acute treatment of VTE, and all studies have led to publication in The New England Journal of Medicine.
At this time, only rivaroxaban is FDA approved for VTE treatment. It is, therefore, the only drug I use for the VTE indication.
However, based on all of the published trials in which each of the NOACs was at least as effective and safe as warfarin, it is not unreasonable to consider use of the non–FDA-approved drugs (apixaban or dabigatran) off label. Edoxaban, however, is not on the market in the United States. When comparing efficacy and safety of the NOACs among each other, it has to be highlighted that they have not been compared with one another in any clinical trials. Thus, conclusions about whether any NOAC is more efficacious and/or safer than another are scientifically not possible.
One presentation at ASH (Simon M. Abstract #3640) reported data and conclusions from an indirect comparison between NOACs using the five phase 3 trials that compared dabigatran, rivaroxaban, apixaban and edoxaban with a vitamin K antagonist for the acute treatment of VTE.
Results: There was no difference in between the four NOACs regarding recurrent VTE and mortality. Fewer major bleeds occurred on apixaban compared with dabigatran and edoxaban, and results showed a trend toward less major bleeding with apixaban compared with rivaroxaban.
Conclusion: In this indirect comparison, all four NOACs were similarly effective as vitamin K antagonists. Apixaban had an advantage with respect to major bleeding.
Clinical relevance: Apixaban is not FDA approved for VTE. If one were to consider apixaban off label for acute VTE treatment, then apixaban appears attractive, as it was associated with less major bleeding than warfarin in the large phase 3 AMPLIFY trial. The indirect comparison of the four NOACs in this abstract further suggests that apixaban may have an advantage regarding a lower major bleeding risk compared with other NOACs. However, a dedicated randomized trial directly comparing the NOACs would be needed to confirm the results from this abstract.
Postthrombotic syndrome
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The SOX trial, results of which appeared online in The Lancet in December 2013, is a practice-changing study that examined whether compression stockings prevent postthrombotic syndrome (PTS).
In this multicenter, randomized, placebo-controlled trial, patients with acute first episode of proximal DVT wore either 30 mm Hg to 40 mm Hg graduated elastic compressions stockings or “placebo stockings” with identical appearance but less than 5 mm Hg compression at the ankle. The follow-up period was 2 years.
Results: Researchers enrolled 806 patients; of them, 410 received elastic compression stockings and 396 received placebo stockings. PTS, assessed by Ginsberg’s criteria (leg pain and swelling lasting 1 month or longer), developed in 14.2% of the active stocking group and 12.7% of the placebo stocking group (HR=1.13; 95% CI, 0.73-1.76). By the Villalta score (a different PTS scoring system), there was no difference in PTS development between the two groups (7.5% in the active stocking group vs. 5.8% in the placebo stocking group). Rates of moderate PTS (8.3% vs. 10. 5%), mild PTS (33% vs. 32.1%) and no PTS (51.3% vs. 51.4%) also were similar.
Conclusion: Elastic compression stockings did not prevent PTS after a first proximal DVT.
Clinical relevance: Compression stockings used to be fairly strongly recommended by many physicians because of the belief that they prevented PTS. We now have evidence from this large and well-done trial that they do not prevent PTS. Therefore, although patients can wear them if they improve leg symptoms, stockings do not have a lasting beneficial effect. Thus, if they do not improve leg symptoms or are more uncomfortable than beneficial, there is no reason to wear them.
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The effectiveness of 30 mm Hg to 40 mm Hg compression stockings to treat acute leg pain associated with proximal DVT: Results from the SOX randomized controlled trial (Kahn SR. Abstract #1126).
This abstract presented selected data from the SOX trial looking at the effect of compression stockings on leg pain at various time points after an acute DVT. Surprisingly, the compression stockings did not improve leg pain at any point.
Clinical relevance: The findings are at variance with my clinical experience. In practice, a number of patients report that compression stockings improve leg symptoms (less discomfort, heaviness and pain). The full publication of this abstract will be interesting to see, particularly the data related to whether compression stockings improved leg swelling, heaviness and patients’ quality of life. At this point, I would prescribe compression stockings to patients with leg discomfort due to previous DVT and see whether symptoms improve.
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Inflammation markers and the risk of postthrombotic syndrome: results from the Bio-SOX study (Rabinovich A., Abstract #36).
Methods: This study assessed differences between median biomarker levels (ICAM-1, CRP, IL-6 and IL-10) in PTS-positive and PTS-negative patients as defined by the Villalta scale applied over time, starting at the 6-month visit.
Results and conclusion: Findings suggest that inflammation plays an important role in PTS development. Among the studied biomarkers, ICAM-1 appeared to be most strongly associated with PTS development. Future therapeutic trials should be aimed at targeting the ICAM-1 pathway.
Clinical relevance: None at this point, but the findings are interesting. Inflammation appears to play a role in the development of PTS and support us of anti-inflammatory drugs in a study to investigate whether they can decrease the risk of PTS development.
IVC filters
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Predictors of vena cava filter use for VTE in cancer patients (Ho G. Abstract #935).
Methods: In this retrospective study conducted in California, researchers reviewed hospital discharge records of patients who presented with acute VTE to determine the frequency of vena cava filter placement in patients with cancer hospitalized for acute VTE, identify the factors associated with vena cava filter use in these patients, and compare these findings with patients without cancer hospitalized for acute VTE.
Results: The frequency of vena cava filter placement among patients with cancer varied widely across hospitals.
Conclusion: Given the large variation in the frequency of use of vena cava filters between hospitals, more research is needed to better define outcomes of vena cava filter placement in patients with cancer and, thus, indications for vena cava filter placement.
Clinical relevance: None at this point. The wide variety of practices reflects that there are few data clarifying which patients with cancer and VTE benefit from vena cava filters and what the risk/benefit of filters is in this patient population.
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Outcomes after vena cava filter placement in cancer patients hospitalized for acute VTE (White RH. Abstract #936).
Methods: The same database as the one described in Abstract #935 was used.
Results: Use of vena cava filters in patients with cancer hospitalized for acute VTE was not associated with a significant reduction in the risk for death at 15 or 30 days. There was a statistically nonsignificant 20% reduction in risk for recurrent VTE manifested as PE at 180 days, but a 55% higher risk for recurrent VTE manifested as DVT.
Conclusion: Use of vena cava filters in patients with cancer with acute VTE did not change mortality, led to a lower rate of recurrent PE, and led to a higher rate of DVT.
Clinical relevance: None at this point, but the full publication will be interesting to see. Any data that clarify the risk/benefit ratio of vena cava placement in patients are helpful, as few such data exist.
References:
Hicks LK. Blood. 2013;doi:10.1182/blood-2013-07-518423.
Hokusai-VTE Investigators. N Engl J Med. 2013;369:1406-1415.
Kahn SR. Lancet. 2013;Published online ahead of print Dec. 6.
Sarode R. Circulation. 2013;128:1234-1243.
Schulman S. Circulation. 2013;Published online ahead of print Dec. 16.
Schulman S. N Engl J Med. 2009;361:2342-2352.
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 can be reached at the 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.
Disclosure: Moll has been a consultant for Boehringer-Ingelheim, CSL Behring, Daiichi and Janssen.