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Thrombosis and anticoagulation: Highlights from the ASH Annual Meeting
The ASH Annual Meeting and Exposition, held from Dec. 6-9, 2014, in San Francisco, featured several presentations related to thrombosis and anticoagulation.
This review summarizes the abstracts that have the greatest potential clinical impact.
Factor XI-lowering drug
Stephan Moll
A phase 2 study by Büller and colleagues, presented at ASH as a late-breaking abstract and published at the same time in The New England Journal of Medicine, showed that lowering coagulation Factor XI with an anti-sense oligonucleotide drug was effective for prevention of post-operative deep vein thrombosis without increasing the risk for perioperative bleeding.
These findings challenge the long-held belief that an anticoagulant automatically increases the risk for bleeding. Maybe it is possible that a drug works as an anticoagulant and prevents thrombosis, yet does not increase the risk for bleeding.
Conclusion: These are interesting early data but are of no clinical consequence at this point.
DOAC antidotes
Three main antidotes for direct oral anticoagulants (DOACs) are in development: andexanet alfa (Portola Pharmaceuticals) for the anti-Factor Xa drugs [rivaroxaban (Xarelto, Janssen), apixaban (Eliquis; Bristol-Myers Squibb, Pfizer) and edoxaban (Savaysa, Daiichi)]; idarucizumab (Boehringer Ingelheim) for dabigatran (Pradaxa, Boehringer Ingelheim); and aripazine (PER977, Perosphere) as a more global reversal agent for all DOACs.
A. Andexanet alfa — Crowther and colleagues presented results of a phase 2 randomized, placebo-controlled trial that investigated the effectiveness of andexanet alfa for reversal of the anti-Factor Xa anticoagulant edoxaban in healthy participants. Andexanet alfa rapidly reversed edoxaban’s anticoagulant effect, as measured by coagulation tests. This study provides background efficacy and safety data on the use of andexanet alfa and is the prelude for a planned phase 3 clinical trial that will evaluate the drug in patients who present with major bleeding (ClinicalTrials.gov Identifier: NCT02329327).
B. Idarucizumab — Glund and colleagues presented results of a phase 1 randomized, double blind, placebo-controlled study that investigated IV idarucizumab as a specific antidote for dabigatran. Findings showed effective reversal of dabigatran-induced anticoagulation. A phase 3 clinical trial in patients with major bleeding or those who need urgent reversal of dabigatran is ongoing (ClinicalTrials.gov Identifier: NCT02104947).
C. PCCs — Perlstein and colleagues evaluated the reversal of apixaban anticoagulation by non-activated 4-factor prothrombin complex concentrates (PCC; Beriplex/Kcentra, CSL Behring) in healthy participants. Fifteen healthy volunteers who took apixaban 10 mg twice daily received a 4-factor PCC. PCC reversed apixaban’s anticoagulant effect as measured by several coagulation parameters (endogenous thrombin potential), suggesting that 4-factor PCCs may be useful in the management of major bleeding in patients on apixaban.
Shaw and colleagues presented results of a retrospective single-center chart review that evaluated activated PCC (FEIBA, Baxter) in five patients on NOACs who required urgent reversal of anticoagulation for surgery. All patients received FEIBA before surgery. The researchers concluded that FEIBA “was effective and not associated with adverse thrombotic complications.”
Conclusion: The development of several antidotes is promising. Non-activated and activated PCCs may be effective reversal agents for DOAC-associated major bleeding. A guidance document from the University of North Carolina at Chapel Hill for the management of major bleeding on various antithrombotic drugs is available on the Web (bit.ly/1BdDDu2).
Cancer and VTE
A. VTE treatment — Lee and colleagues presented results of the CATCH trial, a randomized, open-label, multicenter international trial in which 900 patients with cancer and acute venous thromboembolism were randomly assigned to either the low–molecular-weight heparin (LMWH) tinzaparin (Innohep, Leo Pharma) for 6 months or low–molecular weight heparin for 5 to 10 days overlapping with warfarin to a target international normalized ratio (INR) of 2 to 3. Symptomatic DVT was significantly less in the tinzaparin group compared with the warfarin group (2.7% vs 5.3%; HR = 0.48; 95% CI, 0.24-0.96). Major bleeding was the same in both groups, but non-major clinically relevant bleeding was lower in the tinzaparin group (11% vs 16%).
This study confirms what the CLOT study — which compared dalteparin vs. warfarin in patients with cancer and VTE — showed more than 10 years ago: LMWH is superior to warfarin in this patient population. However, it is noteworthy that (a) the warfarin failure rate in the CATCH trial was much less than in the CLOT trial, and (b) the benefit of LMWH vs. warfarin also was much less pronounced in the CATCH trial.
It remains to be seen how well the DOACs perform in patients with cancer and VTE in comparison to warfarin and LMWH. A recent publication of all the DOACs-in-VTE trials found that DOACs were at least as effective as warfarin in the patients with cancer enrolled into the trials. However, it is important to point out that none of these trials were dedicated VTE-in-cancer trials. Two such cancer trials are underway or in the planning stages: One by Young and colleagues designed to evaluate rivaroxaban vs. dalteparin in selected patients with cancer at risk for VTE recurrence (the SELECT-D trial) is ongoing and enrolling; the other, designed to evaluate edoxaban vs. dalteparin (NCT02073682), is in the planning stages.
Conclusion: LMWH is still the standard of care in patients with cancer with acute VTE. However, if a patient cannot afford LMWH or objects to the subcutaneous injections, then either a DOAC or warfarin are appropriate treatment choices.
B. Unsuspected/incidental PE — A literature review by van der Hulle and colleagues assessed risk for recurrent VTE and major bleeding in cancer-associated incidental pulmonary embolism among both untreated and treated patients. The analysis included 926 patients with cancer and incidental PE who participated in 11 observational studies. The key finding was that there was a 12% 6-month risk for symptomatic recurrent VTE in patients with cancer-associated incidental PE who did not receive anticoagulant treatment, which is more than double the risk of patients who were anticoagulated.
Conclusion: Patients with incidentally discovered PE may benefit from anticoagulation.
C. IVC filters — Cull and colleagues reported results of a prospective single-institution registry of inferior vena cava (IVC) filters in patients with active malignancy or those receiving adjuvant therapy for a recent active malignancy. In the study, 179 filters were placed. The results showed that (a) 31% of filters were placed without the patient having a contraindication for anticoagulant therapy (which is the only clear-cut indication for filter placement); (b) 20% of these filters were not removed; and (c) the overall cost of filter placements and filter removals was more than $2 million (an average of more than $11,500 per IVC filter).
Conclusion: IVC filters are commonly placed in patients with cancer and malignancy, at a significant financial cost.
Comment: The only clear indication for IVC filter placements is for patients with acute DVT who cannot be anticoagulated. Other indications — such as recurrent DVT in spite of therapeutic anticoagulation, large DVT burden and limited cardio-pulmonary reserve are softer indications, and a lack of evidence exists about whether IVC filters are beneficial in these situations.
Splanchnic vein thrombosis
A. Antithrombotic treatment — Ageno and colleagues evaluated outcomes of 604 consecutive patients with splanchnic vein thrombosis enrolled in a multicenter international registry. Researchers assessed patients for recurrent thrombosis, major bleeding and mortality over a 2-year follow-up period. The majority (77%) of patients were on anticoagulants.
Results showed the risk for bleeding and recurrent thrombosis depended on the etiology of the first thrombotic event (patients with liver cirrhosis had the highest bleeding and recurrent VTE rate). Major bleeding occurred at a rate of 3.8 per 100 patient-years, and recurrent thrombosis occurred at a rate of 7.3 per 100 patient-years, not an unsubstantial risk for either event.
Conclusion: Limited data exist on best management of patients with splanchnic vein thrombosis. Individualized decisions need to be made based on cause of the thrombotic event, risk factors for recurrence and risk factors for bleeding.
B. Vitamin k antagonists — Nicoletta and colleagues presented results of a retrospective study designed to evaluate the safety of vitamin K antagonists in 375 patients with splanchnic vein thrombosis.
In 63% of patients, there was an explanation for the thrombosis (hematologic disease, liver cirrhosis, cancer, abdominal surgery, intra-abdominal inflammation or infection), yet 37% were unexplained. The majority (94%) of patients were treated with warfarin, with a target INR of 2 to 3. Major bleeding occurred at a rate of 1.24 per 100 patient-years, and recurrent thrombosis on treatment occurred at a rate of 1.37 per 100 patient-years. Presence of esophageal varices was a predictor of major bleeding.
Conclusion: Oral anticoagulation is safe in many patients with splanchnic vein thrombosis, and presence of esophageal varices leads to a higher risk for major bleeding.
Thrombophilia
Schulman and colleagues conducted a post-hoc subgroup analysis of the phase 3 RE-MEDY trial, designed to assess the influence of thrombophilia on the efficacy of dabigatran vs. warfarin for the extended treatment of VTE.
The trial had not required thrombophilia testing, but in routine practice about 48% of patients had thrombophilia testing done. As expected, the majority of thrombophilias detected were Factor V Leiden. The prothrombin 20210 mutation, Protein C, S and antithrombin deficiencies, and antiphospholipid antibodies were less common. The analysis showed that patients with or without thrombophilia did equally well, and treatment efficacy was not affected by the presence of thrombophilia.
Conclusion: This analysis appropriately argues that the finding of a thrombophilia does not need to be a reason to deny a patient treatment with a DOAC. This is of clinical relevance.
Warfarin management
A. Bleeding — Morton and colleagues summarized their experience with 4-factor PCC for the reversal of warfarin, focusing on patterns of use and safety outcomes.
In this real-world patient management situation, 33 patients at one institution underwent treatment with 4-factor PCC (Kcentra, CSL Behring) for warfarin-associated coagulopathy. The authors found Kcentra to be effective for the rapid reversal of INR. It also demonstrated a low complication rate, with only one patient developing a thrombotic event (acute coronary event) within 72 hours of administration.
B. Low-dose vitamin K — Crowther and colleagues conducted a randomized four-center trial in which 253 patients on warfarin were randomly assigned either 150 µg of daily vitamin K or placebo. After a maximum of 9 months of follow-up, 235 patients were deemed appropriate for analysis (vitamin K, n = 117; placebo, n = 118). The time-in-therapeutic INR range (TTR) increased in both the placebo and vitamin K group over the trial, from 53.2% to 65.6%, but the vitamin K group did no better than the placebo group. The authors appropriately concluded that, in unselected patients on warfarin, the addition of vitamin K does not lead to a better TTR.
Conclusion: Vitamin K supplementation for all patients on warfarin is not indicated and not beneficial. However, previous studies have shown it is beneficial in selected patients who have unstable INRs.
Editor’s note: On March 10, we corrected the description of a study by Glund and colleagues, who investigated IV idarucizuamb as a specific antidote for dabigatran. The results they presented at the ASH Annual Meeting were from a phase 1 study. The Editors regret the error.
References:
Büller HR, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1405760/.
Lee AYY, et al. N Engl J Med. 2003;349:146-153.
UNC Healthcare Anticoagulation Reversal Guidelines. Available at: professionalsblog.clotconnect.org/wp-content/uploads/2014/06/UNCH-Anticoagulation-Reversal-Guideline-June-2014.pdf. Accessed on Feb. 3, 2015.
Vedovati MC, et al. Chest. 2014;doi:10.1378/chest.14-0402.
The following were presented at ASH Annual Meeting; Dec. 6-9, 2014; San Francisco:
Ageno W, et al. Abstract 592.
Büller HR, et al. Abstract LBA-1.
Crowther MA, et al. Abstract 4269.
Crowther MA, et al. Abstract 2872.
Cull EH, et al. Abstract 4247.
Glund S, et al. Abstract 344.
Lee AYY, et al. Abstract LBA-2.
Nicoletta R, et al. Abstract 4276.
Perlstein I, et al. Abstract 345.
Schulman S, et al. Abstract 1544.
Shaw J, et al. Abstract 4259.
van der Hulle T, et al. Abstract 590.
For more information:
Stephan Moll, MD, is professor of medicine in the department of medicine and division of hematology-oncology at the University of North Carolina School of Medicine in Chapel Hill, N.C. He also is medical director of the Clot Connect patient education program (www.clotconnect.org), an initiative of the University of North Carolina Hemophilia and Thrombosis Center. He can be reached at UNC School of Medicine, Campus Box 7036, Chapel Hill, NC 27599; email: smoll@med.unc.edu.
Disclosure: Moll has been a consultant for CSL Behring, Daiichi and Janssen.