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Thrombosis and anticoagulation: Clinically relevant abstracts from ISTH conference
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The biannual meeting of the International Society on Thrombosis and Haemostasis took place from June 29 to July 4 in Amsterdam.
The clinically relevant highlights about thrombosis and anticoagulation are summarized below.
None of the scientific–clinical data presented at the meeting are immediately practice changing — and they probably shouldn’t be anyway, as abstracts are not peer reviewed in detail. However, several presentations are noteworthy, as they indicate clinically relevant changes to come in the next few years.
New oral anticoagulants
Stephan Moll
The most relevant and outstanding development for me was the publication of the AMPLIFY trial, which evaluated the new oral anticoagulant apixaban (Eliquis; Bristol-Myers Squibb, Pfizer) in patients with acute venous thromboembolism.
The trial included 5,395 patients with symptomatic deep vein thrombosis and/or pulmonary embolism.
Currently, apixaban is FDA approved only for the treatment of atrial fibrillation. On the same day of the oral presentation of AMPLIFY, The New England Journal of Medicine published the full study.
The results showed apixaban was as effective as warfarin and led to less major and clinically relevant bleeding than warfarin. Hopefully, the drug will be FDA approved soon and become clinically available. We will then have two new oral anticoagulant (NOAC) drugs for the treatment of DVT and PE to choose from — apixaban and rivaroxaban (Xarelto, Janssen Pharmaceuticals).
Both apixaban and rivaroxaban were started in their respective trials without bridging therapy with low–molecular-weight heparin (LMWH), making them very attractive and easy to use in acute DVT and PE management. Both are to similar degrees cleared by the kidney (25% for apixaban, 33% for rivaroxaban). Apixaban is dosed twice daily, rivaroxaban once daily.
The impressive finding in the apixaban study is that the drug was safer than warfarin, having led to less major bleeding.
Antidotes to major bleeding
No antidote is currently available to reverse the anticoagulant effect of NOACs and, thus, to treat major bleeding that occurs on these drugs.
Whether prothrombin complex concentrates (PCCs) such as Kcentra (Beriplex, CSL Behring), Bebulin (Baxter) and Profilnine (ABO Pharmaceuticals) have any clinical benefit in this situation is unclear.
A. Dabigatran
A reversal agent for dabigatran (Pradaxa, Boehringer Ingelheim) is in development. It is an antibody fragment directed against dabigatran, which can neutralize the drug’s anticoagulant effect in vitro, referred to as “BI 655075.”
Detailed, thorough pharmacokinetic and pharmacodynamic data on this antidote, as studied in rats, were presented (van Ryn J. Abstract #OC 36.2). The reversal agent is now in a human volunteer phase 1 study (clinicaltrials.gov: NCT01688830).
B. Rivaroxaban, apixaban and edoxaban
A different strategy is being used in the development of a drug that can neutralize the anti-Xa anticoagulants rivaroxaban, apixaban and edoxaban (Daiichi Sankyo).
PRT064445 (Andexant, Portola) is in development and an inactivated Factor X that cannot work as a coagulation factor, but it is available to bind and, thus, remove the anti-Xa drugs.
Data were presented at ISTH (Crowther M. Abstract #AS 20.1) of a phase 2 human volunteer study. The anticoagulation effect of apixaban, as measured ex vivo in the blood of the volunteers, was successfully and completely reversed by PRT064445, which was well tolerated. Further human volunteer studies reversing rivaroxaban and edoxaban with PRT064445 are on the way (clinicaltrials.gov: NCT01758432).
C. Prothrombin complex concentrates
It is not known whether PCCs have any clinical benefit when used to treat major bleeding in patients on one of the NOACs. A number of studies have shown some benefit of PCCs on reversal of prolonged/abnormal coagulation tests in in vitro mixing studies and plasma of human volunteers on NOACs who received a PCC, as well as in rat and mouse bleeding models.
However, other studies have shown no benefit. Whether any benefit demonstrated in such studies (ie, the normalization of a prolonged clotting test in vitro) indicates any efficacy in a patient with major bleeding is not known.
At ISTH, no patient data were presented and no clinical trial is ongoing to test a potential benefit of PCCs in patients with major bleeding on NOACs.
Interesting, though: In a healthy human volunteer study (Levi M. Abstract #OC 36.5), individuals were given rivaroxaban 20 mg twice daily and then received the 3-factor PCC Profilnine (50 U/kg), the 4-factor PCC Kcentra (50 U/kg) or normal saline.
The findings:
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Kcentra shortened the prolonged prothrombin time (PT) some, Profilnine did not;
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Both PCCs improved the endogenous thrombin potential to a similar extent; and
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Most noteworthy: Anti-Xa levels did not change.
The conclusion: Some laboratory parameter changes suggest that the PCC might have a beneficial effect if given to a patient with a major bleed, but other data suggest PCCs would not be beneficial. Thus, it remains unclear whether PCCs have any benefit in the patient on NOACs who has a major bleed. However, if one were to empirically use a PCC, a 3-factor PCC may just be as good as a 4-factor PCC, as both had a similar effect on endogenous thrombin potential.
D. Major bleeding does not equal major bleeding
The new oral anticoagulants have a different bleeding pattern compared with warfarin.
- All three NOACs (dabigatran, rivaroxaban and apixaban) led to fewer intracranial bleeds, and apixaban led to less major bleeding in the atrial fibrillation and VTE trials.
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Intracranial bleeds are, appropriately, the most feared of major bleeds. This is supported by a study of major bleeding on warfarin, which found that patients with intracranial bleeds had a high mortality, whereas patients with major gastrointestinal bleeds had a low mortality (Vigue B. Abstract #OC 36.1). Thus, the decreased intracranial bleeding rate with the NOACs may be an important advantage in routine clinical practice.
Performance of coagulation tests on the NOACs
The performance of coagulation tests depends on the sensitivity of the assay to be influenced by the NOAC, as well as when the last dose of drug was taken.
A. Tests that can measure NOACs anticoagulant effect (see Table).
A number of publications in the past 2 to 3 years have shown that:
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For dabigatran: (a) the PT and aPTT are insensitive and are often normal despite therapeutic dabigatran levels; (b) the tests of choice to accurately assess dabigatran’s anticoagulant effect are the ecarin clotting time (ECT), chromogenic ecarin time (ECA) or dilute thrombin time (dTT); and (c) the thrombin time (TT) is very sensitive to dabigatran levels and, thus, if the TT is normal, no significant dabigatran is on board.
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For rivaroxaban: (a) the aPTT and typically also the PT are rather insensitive and are often normal despite therapeutic rivaroxaban levels; (b) the test of choice to accurately assess rivaroxaban’s anticoagulant effect is an anti-Xa assay (with rivaroxaban calibrators).
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For apixaban: (a) the PT and aPTT are insensitive and are often normal despite therapeutic apixaban levels; (b) the test of choice to accurately assess apixaban’s anticoagulant effect is an anti-Xa assay (with apixaban calibrators).
B. Interferences with thrombophilia labs
Source: Modified after Lindhoff-Last E. Abstract #SAS10-03. Presented at: International Society on Thrombosis and Haemostasis; June 29-July 4, 2013; Amsterdam.
Many coagulation tests — thrombophilia and individual clotting factor assays — can be influenced by NOACs. Antigen levels (protein S, protein C, antithrombin) are reliable, but all clotting factor activity assays are potentially influenced by the NOACs, yielding falsely low or high values.
The topic was presented at ISTH by Edelgard Lindhoff-Last, MD (see Table).
D-dimer as a predictor of recurrent VTE
In a number of studies during the past few years, the D-dimer — tested on or off warfarin — has been found to be a helpful predictor for recurrent VTE.
Several abstracts from ISTH add to our knowledge of D-dimer’s role in the prediction of recurrent VTE.
It is clear that there are still several unknowns about the performance of D-dimer assays and how clinicians should use results for clinical decision making.
A. What D-dimer assay does a lab use?
Different D-dimer assays have varying sensitivities to detect elevated D-dimer levels and are, thus, referred to as highly sensitive, intermediate sensitive and low sensitive.
Before making any decisions on the results of a D-dimer test — either when ruling out VTE after a pre-test probability assessment has been done via a clinical prediction rule such as the Wells Score, or when using the D-dimer for clinical decision making regarding the length of anticoagulation therapy — a clinician should know what D-dimer assay his/her laboratory uses and what sensitivity the assay has.
B. Is the D-dimer useful in men as well as in women?
The summary of the REVERSE I and II studies (Rodger M. Abstract #OC 12.3) confirmed that a negative D-dimer on warfarin is a predictor of a low risk of VTE recurrence in women. However, men have a high risk of recurrence, no matter whether D-dimer is positive or negative. Therefore, this does not add clinically useful information regarding men.
Similarly, the DODS study (Kearon C. Abstract #AS 18.3) also showed that:
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The D-dimer, obtained 4 weeks after having stopped warfarin, is not helpful in men to predict a low risk of recurrent VTE. Even men with negative D-dimer have a high risk of recurrence.
- Women with a negative D-dimer have a low risk of recurrent VTE, particularly if the first VTE episode was hormone associated. Of 58 women who had a hormone-associated VTE and who stopped anticoagulation, none had a VTE recurrence.
C. Does the degree of positivity predict anything more than a simple positive/negative result?
In Abstract #OC 12.5, Eichinger and colleagues showed that the degree of D-dimer positivity correlated slightly with the risk of VTE recurrence: A doubling of the D-dimer result led to an approximately 1.35-fold higher risk of recurrent VTE.
D. Should we use one D-dimer range, or age- and gender-specific D-dimer cut-offs?
In Abstract #OC 12.4, Cosmi and colleagues used age- and gender-specific D-dimer cut-offs and showed that the D-dimer — if used in that manner — helped predict VTE recurrence. Maybe at some point in the future we should routinely use age- and gender-specific cut-offs.
IVC filters in patients with PE
The PREPIC II study (van Montfoort M. Abstract #AS 18.2) was one of the most relevant clinical studies presented at ISTH.
It was conducted to assess whether placing an inferior vena cava (IVC) filter in patients with acute PE has any benefit.
Patients with acute PE who also had a leg DVT were randomly assigned to receive an IVC filter or no filter. Fifty percent of the 399 patients enrolled received a removable IVC filter, with the plan to remove it within 3 months.
Patients were routinely treated with anticoagulation.
The findings:
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The risk of recurrent PE was low and was no different between the two groups (3% in IVC filter group vs. 1.5% in no-filter group at 3 months, and 3.5% vs. 2% at 6 months);
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Filter complications were relatively low, occurring in 2.1% of IVC filter patients (two asymptomatic perforations and two hematomas at puncture site); and
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IVC filter removal was successful in 92.2% of patients and failed in 7.8%.
Conclusion: There is no benefit of routinely placing an IVC filter in patients with acute PE.
Bleeding risk scores for patients with VTE
Several risk scores exist to assess a patient’s risk for bleeding on warfarin. They include OBRI, Hemorr2hages, Riete Score, HAS-BLED, Atria score and ACCP 2012 score.
Using bleeding risk scores could potentially be a helpful tool when making decisions about length of anticoagulation therapy.
Most scores were developed from patients with atrial fibrillation, who often are older than patients with VTE.
A comparison of these scores (Piovell C. Abstract #OC 42.1; and Poli D. Abstract #42.3) in their ability to predict major bleeding in VTE patients showed that the scores perform suboptimally.
Further research is needed to optimize existing bleeding risk scores or create a new one that accurately assesses and predicts the risk of major bleeding in VTE patients on warfarin.
In addition, as the pattern of bleeding is different with the NOACs, warfarin bleeding-risk models may not accurately predict major bleeding on NOACs. A new bleeding prediction risk model specific for NOACs may have to be developed.
Interesting/relevant ongoing studies
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The primary objective of the ALIFE-2 study (Middeldorp S. Abstract #SC11-3.05, www.alife2study.org) — a randomized, international, multicenter study — is to evaluate the efficacy of LMWH in women with recurrent miscarriage and inherited thrombophilia.
Women will either receive once-daily prophylactic-dose LMWH or no pharmacologic intervention. The study has been enrolling since January 2013.
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The HIGHLOW study (Middeldorp S. Abstract #SC11-3.05, www.studies-obsgyn.nl/highlow) is a randomized, open-label trial designed to determine whether standard- prophylactic or intermediate-dose LMWH is more effective at preventing recurrent VTE in women with previous VTE. Patients receive either intermediate-dose LMWH (nadroparin; not routinely available in the United States), adjusted to actual body weight during pregnancy or fixed low-dose LMWH (ie, nadroparin 2,850 IU, the standard dose for prophylaxis of VTE). The study has been enrolling since April 2013.
References:
Adcock DM. Am J Clin Pathol. 2013;139:102-109.
Di Nisio M. J Thromb Haemost. 2007;5:296-304.
Douketis J. Ann Intern Med. 2010;153:523-531.
Lu G. Nat Med. 2013;19:446-451.
Mani H. Thromb Haemost. 2013;109:127-36.
Righini M. J Thromb Haemost. 2008;6:1059-1071.
Rodger MA. CMAJ. 2008;179:417-426.
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 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 reports consulting roles with Boehringer Ingelheim, Daiichi and Janssen.