Stephan Moll, MD writes… The annual meeting of the American Society of Hematology (ASH) took place this month (Dec 6-12th, 2013) in New Orleans. The clinically relevant highlights about thrombosis and anticoagulation are summarized below.
There were relatively few abstracts and presentations of new data dealing with clinical thrombosis and anticoagulation. I found no practice-changing abstract. The abstract clinically most relevant was probably abstract #3588 (discussed below) which presented new, unpublished data from a study using the 4-factor prothrombin complex concentrate (PCC) Kcentra® to reverse warfarin prior to urgent surgery.
I. EDUCATIONAL SESSIONS
There were a number of good general education events of relevance for thrombosis and anticoagulation:
- “Special Symposium on Quality: Clinical Practice Guidelines”. 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. Next steps will be the development of guidelines.
- “ASH Choosing Wisely® List” presentation. To prevent physicians from ordering unnecessary tests and medical interventions ASH has become involved in the national Choosing Wisely® campaign and has produced 5 recommendations so far about tests and procedures physicians should avoid, 3 of which deal with thrombosis issues. The 3 topics relevant to thrombosis and anticoagulation are have previously been discussed here.
- “Consultative Hematology Course”. This course geared towards hematology-oncology physicians in community practice covered commonly encountered hematological clinical problems, including thrombosis and anticoagulation.
II. ABSTRACTS AND SCIENTIFIC PRESENTATION
A. Reversal of Warfarin for Urgent Surgery (Abstract #3588)
Kcentra®, a 4-factor PCC (prothrombin complex concentrate), was FDA approved in April 2013 for the treatment of major bleeding in patients on warfarin, based on a phase III clinical study of patients with major bleeding on warfarin (previously discussed here). At ASH, the results of a study of patients on warfarin requiring urgent surgery was presented. This study lead the FDA on Dec 13, 2-13 to extend Kcentra® approval to also include the indication of “reversal of warfarin for urgent surgeries” – previously discussed here.
Methods: Patients requiring rapid reversal of warfarin and other vitamin K antagonists prior to an urgent surgical or invasive procedure were randomized to receive either Kcentra® at a single dose or plasma (fresh frozen plasma = FFP). Per routine practice, patients were also to receive vitamin K as early as possible. The primary endpoints were (a) effective peri-operative hemostasis and (b) rapid INR reduction (INR ≤1.3 at 0.5 h after end of infusion).
Results: 168 patients were included (Kcentra® n=87; FFP n=81). Effective hemostasis was achieved in 89.7% of patients in the Kcentra® group versus 75.3% in the FFP group, demonstrating superiority of Kcentra® over plasma (difference 14.3% [95%CI 2.8;25.8]). Rapid INR reduction was achieved in 55.2% of patients in the Kcentra® group versus 9.9% in the FFP group, demonstrating superiority of Kcentra® over FFP (difference 45.3% [95%CI 31.9;56.4]). Side effects were similar between treatment groups. Significantly fewer fluid overload events occurred with Kcentra® than with FFP.
Conclusion: Kcentra® was superior to FFP for hemostatic efficacy and for rapid INR reduction, with a favorable safety profile.
Relevance for the Clinician: If there is a need for urgent reversal of warfarin prior to surgery, it makes sense to give vitamin K iv plus Kcentra® – the dosing is included in the FDA approved Kcentra® package insert and is as follows:
- If INR 2 to 4: 25 U/kg
- If INR 4-6: 35 U/kg
- If INR > 6: 50 U/kg
B. New Oral Anticoagulants (NOACs)
Edoxaban in Cancer Patients (Abstract #211)
“Edoxaban For Long-Term Treatment Of Venous Thromboembolism In Cancer Patients”
In this sub-analysis of the Hokusai acute VTE treatment study [full VTE study published in NEJM 2013,369:1406-1415], 208 patients with active cancer were analyzed (109 on edoxaban, 99 on warfarin). Recurrent VTE occurred in 3.7% treated with edoxaban and in 7.1% treated with warfarin (hazard ratio 0.55, 95% CI 0.16 to 1.85). Clinically relevant bleeding occurred in 18.3% on edoxaban and 25.3% on warfarin (hazard ratio 0.72, 95% CI 0.40 to 1.30).
Conclusion: The results suggest that edoxaban is as effective, and possibly more effective, than warfarin in patients with active cancer and VTE.
Relevance for the Clinician: None. Low molecular weight heparin (LMWH) is still the gold standard in patients with cancer and VTE (as LMWH is more effective than warfarin). Additional studies of edoxaban (or any of the other NOACs) for therapy of VTE in cancer patients are indicated, with LMWH as the comparator. In addition, edoxaban is not FDA approved and not available in the US.
Dabigatran is not FDA approved at present for the treatment of VTE, but the company making the drug (Boehringer-Ingelheim) applied for FDA approval in August 2013 (details previously discussed here). A response from the FDA about approval is being awaited in the next few months. A number of data sub-analyses are now being published from the two phase III VTE treatment trials, RE-Cover and RE-Cover II. Data are helpful to learn more about how dabigatran performs in various patient populations with VTE.
a) Dabigatran in Patients with Acute VTE [Schulman S et al; Circulation 2013,Dec 16. Epub ahead of print]. “Treatment of Acute Venous Thromboembolism with Dabigatran or Warfarin and Pooled Analysis”.
This was not an ASH abstract, but a full publication in December 2013. It reports the 2nd of the large VTE treatment trials, called RECOVER II and also summarizes the data of the first dabigatran VTE trial [Schulman S et al, NEJM 2009] and the present trial in a pooled analysis. The overall data show a hazard ratio for dabigatran versus warfarin for recurrent VTE of 1.09 (95% CI, 0.76 to 1.57), major bleeding of 0.73 (95% CI, 0.48 to 1.11).
Conclusion: Dabigatran has a similar effect on VTE recurrence and on major bleeding compared to warfarin in the treatment of acute VTE.
Relevance for the Clinician:FDA review of data is ongoing and decision on approval for VTE treatment is being awaited.
b) Dabigatran in Patients with VTE and Mild or Moderate Renal Dysfunction (Abstract #212)
“Influence Of Renal Function On The Efficacy And Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II”.
As dabigatran is cleared via the kidney to 80 %, patients with a creatinine clearance of < 30 ml/min were excluded from the RECOVER VTE trials. In the trials patients with creatinine clearance of > 30 ml/min were randomized to dabigatran 150 mg twice daily or warfarin.
Conclusions: Across renal function groups there was no apparent difference in recurrent VTE or bleeding. While 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/min.
Relevance for the Clinician: None at present. I do not use off label dabigatran for VTE . FDA review of data is ongoing and decision on approval for VTE treatment is being awaited.
c) Dabigatran in the Elderly with VTE (Abstract #2375)
“Influence Of Age On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis Of RE-Cover and RE-Cover II”
No differences in recurrent VTE or efficacy were apparent across age groups (< 65 years, 65-75 years, > 75 years). Bleeding events increased with increasing 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.
Relevance for the Clinician: None at present. I do not use dabigatran for VTE off label. FDA review of data is ongoing and decision on approval for VTE treatment is being awaited.
- Major Bleeding on NOACs
It is not known how to best treat major bleeds that occur on the NOACs. The efficacy of plasma (FFP), prothrombin complex concentrate (PCC) and recombinant factor VIIa (rVIIa) have only been tested in vitro, animal bleeding models, or 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.
- (Abstract #214)
“Pattern and Management Of Bleeding Complications With Novel Oral Anticoagulants – Results Of The Prospective Dresden NOAC Registry”. Data from a large prospective German registry of patients treated with novel direct oral anticoagulants (NOAC) were presented. 2,249 patients were enrolled, of whom 77% received rivaroxaban, 16% dabigatran and 7% apixaban. During follow-up (2,674 patient years), 6.9% of patients had major bleeding: of these, 8 patients received FFP, 9 PCCs, none rVIIa.
Conclusion: Bleeding occurs on the NOACs; treatment used for major bleeds is typically supportive, with occasional use of FFP or PCCs.
Relevance for the Clinician: None. This study does not allow any conclusion on efficacy of treatment interventions.
- (Abstract #1133)
“Four-Factor Prothrombin Complex Concentrate (4-PCC) Effectively Reverses Edoxaban Induced Bleeding In a Rabbit Model Of Acute Injury”.
This is another animal bleeding model. In an in vivo rabbit kidney injury model of acute bleeding, 4-factor PCC (25-75 U/kg) compared to placebo decreased the time to hemostasis and the total blood loss.
Conclusion: 4-factor PCC treatment effectively decreased edoxaban induced hemorrhage in an animal model of acute bleeding.
Relevance for the Clinician: None. It is not known whether PCC is beneficial in treating patients on NOACs with major bleeding.
- (Abstract #214)
- Comparing the Different NOACs for the Treatment of VTE (Abstract #3640)
Background: Each of the 4 big NOACs has been compared to warfarin in the acute treatment of VTE and all studies have lead to NEJM publications. At this time, only rivaroxaban (Xarelto®) 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 also not unreasonable to consider use of the non-FDA-approved drugs (apixaban, dabigatran) off label. Edoxaban however, is not on the market in the US at this point. When comparing efficacy and safety of the NOACs amongst each other, it has to be highlighted that they have not been compared to one another in any clinical trials. Thus, conclusion whether any NOAC is better (more efficacious and/or safer) than another are scientifically not possible.
Methods: This abstract reports data and conclusions from an indirect comparison between NOACs using the five phase III trials comparing dabigatran, rivaroxaban, apixaban and edoxaban to a vitamin K antagonist for the acute treatment of VTE.
Results: Regarding recurrent VTE and mortality, there was no difference in between the 4 NOACs. In respect to major bleeding, less major bleeds occurred on apixaban compared to dabigatran and edoxaban, and a trend to less major bleeding with apixaban compared to rivaroxaban.
Conclusion: In this indirect comparison, all 4 NOACs were similarly effective as vitamin K antagonists. Apixaban had an advantage in respect to major bleeding.
Relevance for the Clinician: When one has the choice between FDA-approved drugs for a certain indication and drugs that are not FDA approved yet have scientifically been shown to be as effective and safe as the approved drug, there are two ways to practice medicine: (a) use the drug that has been reviewed and then approved by the FDA. This is my preference in regards to the NOACs. That’s why at present I discuss with a patient Xarelto® as a treatment choice, but not in detail the other NOACs. (b) Another way to practice is to consider non-FDA drugs; in that case the consideration of apixaban in VTE treatment appears attractive, as the drug was associated with less major bleeding than warfarin in the large phase III clinical (AMPLIFY) trial and the indirect comparison of the 4 NOACs in this abstracts further suggests that apixaban may have an advantage leading a lower major bleeding risk. However, only a dedicated randomized trial directly comparing the NOACs would be needed to confirm the results from this abstract. As of now, the company making apixaban does not appear to have applied for FDA approval of the drug for the VTE treatment indication.
C. Postthrombotic Syndrome
- Compression Stockings (Kahn S et al. Lancet Dec 6, 2013; pre-published on the web)
The Sox trial is a practice-changing study. It was published on Dec 6th, 2013 (previously discussed in detail here).
The study examined whether compression stockings prevent postthrombotic syndrome (PTS).
Methods: Multicenter, randomized, placebo-controlled trial in patients with acute first episode of proximal DVT. Patients wore either 30-40 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: 806 patients were enrolled: 410 received elastic compression stockings, 396 placebo stockings. PTS (as assessed by the so-called “Ginsberg’s criteria”) developed in 14.2 % in the active stocking group, and in 12.7 % in the placebo stocking group (hazard ratio 1.13, 95% CI 0.73-1.76; p=0.58). By the so-called Villalta score (a different PTS scoring system) there was also no difference in PTS development between the 2 groups: 7.5 % and 5.8 % developed severe PTS in the active stocking group and the placebo stocking group, respectively; 8.3 % and 10. 5 % moderate PTS; 33 % and 32.1 % mild PTS; and 51.3 % and 51.4 % no PTS.
Conclusion: Elastic compression stockings did not prevent PTS after a first proximal DVT.
Relevance for the Clinician: Compression stockings used to be fairly strongly recommended by many physicians, in the belief that they would prevent postthrombotic syndrome. We now have evidence from this large and well-done trial that they do NOT prevent PTS. Therefore, the discussion with the patient now is that (a) while he/she can/should wear stockings if they make the leg feel better, (b) stockings do NOT have a lasting beneficial effect – thus, if they do not make the leg feel better or are actually uncomfortable, then there is no reason to wear them.
- Abstract #1126
“The Effectiveness Of 30-40 mm Hg Compression Stockings To Treat Acute Leg Pain Associated With Proximal Deep Vein Thrombosis: Results From The Sox Randomized Controlled Trial”
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.
Relevance for the Clinician: The findings are at variance with my clinical experience: in practice a number of patients report that compression stockings make their legs feel better – less discomfort, heaviness, pain. I look forward to the full publication of this abstract, particularly data on whether compression stockings improved leg swelling, heaviness, and the patients’ quality of life. At this point I would prescribe compression stockings to the patient with leg discomfort due to previous DVT and see whether the patient’s symptoms improve.
- Abstract #36
“Inflammation Markers and The Risk Of Post Thrombotic Syndrome: Results From The Bio-Sox Study”.
Methods: Differences between median biomarker levels (ICAM-1, CRP, IL-6 and IL-10) in PTS positive and negative patients (as defined by the Villalta scale applied over time starting at the 6 month visit) were assessed.
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.
Relevance for the Clinician: None at this point. But the findings are interesting: Inflammation appears to play a role in the development of PTS and anti-inflammatory drugs may, in the future, be helpful in decreasing the risk of developing PTS.
D. Vena Cava Filters
- Abstract #935
“Predictors of Vena Cava Filter Use For Venous Thromboembolism In Cancer Patients”
Methods: In this retrospective study, hospital discharge records in California of patients presenting with acute VTE were reviewed to (a) determine the frequency of vena cava filter placement in cancer patients hospitalized for acute VTE, (b) identify the factors associated with vena cava filter use in these patients, and (c) compare these findings to patients without cancer hospitalized for acute VTE.
Main result: The frequency of vena cava filter placement among cancer patients 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 (a) outcomes of vena cava filter placement in cancer patients (addressed in the following abstract, #936) and, thus, (b) indications for vena cava filter placement.
Relevance for the Clinician: None at this point. This wide range of practices reflects that there are few data telling us which patients with cancer and VTE benefit from vena cava filters and what the risk/benefit of filters in this population is.
- Abstract #936
“Outcomes After Vena Cava Filter Placement In Cancer Patients Hospitalized For Acute Venous Thromboembolism”.
Methods: The same database as the one described above in abstract #935 was used.
Results: Use of vena cava filters in cancer patients hospitalized for acute VTE was not associated with a significant reduction in the risk of death at 15 or 30 days. There was a (non statistically significant) 20% reduction in the risk of recurrent VTE manifested as PE at 180 days, but a 55% higher risk of recurrent VTE manifested as DVT.
Conclusion: Use of vena cava filters in cancer patients with acute VTE (a) did not change mortality; (b) it lead to a lower rate of recurrent PE, but a higher rate of DVT.
Relevance for the Clinician: None at this point. But the full publication will be interesting to see. Any data clarifying risk/benefit of vena cava placement in patients are welcome, as few such data exist.
Disclosure: I have been a consultant for Boehringer-Ingelheim, Daiichi, Janssen, and CSL Behring.
Last Updated: Dec 31st, 2013