The Hematologist

November-December 2018, Volume 15, Issue 6

Updates on Usefulness of HERDOO2 Score and on Direct Oral Anticoagulant Use in Antiphospholipid Syndrome

Stephan Moll, MD Professor of Medicine, Division of Hematology/Oncology
University of North Carolina School of Medicine, Chapel Hill, NC

Published on: October 29, 2018

Rodger MA, Le Gal G, Langlois NJ, et al. "HERDOO2" clinical decision rule to guide duration of anticoagulation in women with unprovoked venous thromboembolism. Can I use any d-Dimer?. Thromb Res. 2018;169:82-86.

Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018;132:1365-1371.

The original HERDOO2 score publication1 and subsequent validation study2 were discussed in the July August 2017 issue of The Hematologist.3 Since then, further analysis of the latter study has been published evaluating whether using D-dimer assays other than the originally tested VIDAS® D-dimer assay could similarly predict women at low risk for recurrent venous thromboembolism (VTE) after stopping anticoagulation. The Table shows the components of the HERDOO-2 score: Women with zero to one point can stop anticoagulation because of a low risk of recurrent VTE; women with two or more points should continue anticoagulation because of a high risk of recurrence.3

Table. HERDOO2 Scoring
 PredictorScoring
HHyperpigmentation1 point total, if any one of these criteria is present
EEdema
RRedness of either leg
DD-dimer ≥ 250 μg/L while anticoagulated1 point
OObesity with BMI ≥ 30 kg/m21 point
OOlder age, i.e. ≥ 65 years1 point

Decision Making: Women: 0-1, discontinue anticoagulation; ≥2, continue anticoagulation. All men: continue long-term anticoagulation.

In the current study, frozen plasma samples from 248 female validation study participants were tested using five different D-dimer assays including VIDAS®, Innovance®, HemosIL®, Tina-quant® and Liatest®. The study had two parts. First, from 50 samples, the D-dimer cut-off value was determined for each of the D-dimer assays that corresponded with the VIDAS® cut-off value of 250 μg/L used in the HERDOO-2 score. In the second part of the study, 198 different samples were tested with the five different D-dimer assays to determine concordance between each tested D-dimer at the respective optimal cut-off and the VIDAS® D-dimer at 250 μg/L. The findings were that the concordance was poor for all D-dimer assays. The authors concluded that: 1) The concordance of low D-dimer values is poor, reflecting that D-dimer assays are poorly standardized, particularly at low levels; 2) The HERDOO2 score only differentiates a low risk and high risk of recurrence group if the VIDAS® D-dimer assay is used; using other D-dimer assays in the HERDOO2 score will falsely label some women so that anticoagulants are unnecessarily continued in women at low risk for recurrence and, conversely, anticoagulation is stopped in women at high risk for recurrent VTE.

The TRAPS study was discussed in the March April 2018 issue of The Hematologist4 and has since been published. This randomized open-label trial compared rivaroxaban with warfarin (target international normalized ratio, 2.5) in high-thrombosis-risk patients with antiphospholipid syndrome (APS) who were “triple positive” (i.e., positive for anticardiolipin and anti-β2-glycoprotein-I antibodies and lupus anticoagulant) and had had a thrombotic event (venous, arterial, or microthrombosis). The primary study endpoint was the composite of occurrence of thromboembolism, major bleeding, and vascular death. After enrollment of 120 patients, the study was prematurely terminated because of an excess of events in the rivaroxaban arm: 11 events (19%) in the rivaroxaban arm, and two events (3%) in the warfarin arm (HR, 6.7; 95% CI, 1.5-30.5; p=0.01). Thromboembolic events, all arterial (4 ischemic strokes, 3 myocardial infarctions), occurred in seven patients (12%) randomized to rivaroxaban, with no event in the warfarin group (time in therapeutic range, 67%). Major bleeding occurred in four patients (7%) in the rivaroxaban group and two patients (3%) in the warfarin group. The authors of the study concluded that in high-risk patients with APS, the use of rivaroxaban was associated with an increased risk of events (thrombotic event plus bleeding) and thus showed no benefit over warfarin, but instead demonstrated excess risks.

The results of the study appropriately caution about the use of rivaroxaban in the very prothrombotic triple-positive APS patients. A few things about this study are noteworthy: 1) All thrombotic events on rivaroxaban were arterial. This is in keeping with an observation in the ongoing ASTRO-APS trial,5 which led to a protocol modification of that study. It is not clear why patients in the rivaroxaban group had a high rate of arterial thrombosis while thrombosis did not occur in the warfarin group. As aspirin use was similar in the two groups (16-19% of patients were on aspirin), the finding cannot be explained on that basis. It is possible that the different mode of action of rivaroxaban and warfarin leads to this discrepancy.  2) The arterial events in the rivaroxaban group occurred not only in patients with a previous arterial qualifying event (n=4), but also in patients with a previous VTE (n=30). Thus, rivaroxaban use is of concern in APS patients with a history of an arterial, as well as a venous thrombotic event. 3) Several of the arterial thrombotic events occurred several months after the patient had initially done well on rivaroxaban — four (57%) of seven arterial events occurred eight to 23 months after randomization to rivaroxaban. This argues that based on this study, one may want to change a triple-positive APS patient who is currently on rivaroxaban and has done well for months to warfarin. 4) The study does not describe how long patients had been on an anticoagulant for their history of thrombosis and what anticoagulant drug they had been on before randomization and study enrollment. Given that patients with APS were enrolled and a diagnosis of definite APS can only be made once antiphospholipid antibody (APLA) tests have been repeatedly positive (at least three months apart), I assume that the enrolled patients had been on some anticoagulant for at least three months before they were found to be eligible for this study and enrolled. If I assume that this drug was typically warfarin, then it is possible that warfarin failure occurred during those three months before study enrollment, which would skew the risk profile of enrolled patients toward patients who tend to do well on warfarin. The only conclusion one could then draw from the current study is that if a triple-positive APS patient is doing well on warfarin, do not switch to rivaroxaban. 5) Finally, the data from the current study of a high failure rate of rivaroxaban cannot be translated to APS patients who are not triple positive.

Prior to publication by Dr. Rodger and colleagues, I had not routinely used the HERDOO2 score for decision-making on length of anticoagulation as previously discussed.3 Based on the publication of this study, I continue not to use the HERDOO2 score for clinical decision-making in women with unprovoked VTE (the clinic where I practice does not use the VIDAS® D-dimer assay). I recommend continuing to use the “VTE recurrence triangle” concept discussed previously3 to help with length of anticoagulation decision-making, coupled with an assessment of risk for bleeding and of patient preference, based on a patient’s anticoagulation “hate factor.”

The TRAPS study has had several consequences for my practice. First, I am hesitant to use rivaroxaban, and, for that matter, any other direct oral anticoagulant (DOAC), in patients with newly diagnosed arterial or venous thrombosis who are found to be triple positive for APLA, even if not yet confirmed to be repeatedly positive. I would use warfarin in such de novo diagnosed patients. I would switch a patient who has triple-positive APS but has been on a DOAC for several months and has done well to warfarin. In APS patients who are not triple-positive, one must make individualized, non–evidence-based decisions on whether to use a DOAC or warfarin. Finally, I would like the authors of the TRAPS study to clarify the prerandomization anticoagulant length and drug issue raised above to better elucidate their study results.

References

  1. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179:417-426.
  2. Rodger MA, Le Gal G, Anderson DR, et al. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ. 2017;356:j1065.
  3. Moll S, Houghton D. HERDOO2 Score: How long to treat with anticoagulation. The Hematologist. 2017;14:4.
  4. Moll S. Antiphospholipid syndrome: can the direct oral anticoagulants be used?. The Hematologist. 2018;15:2.
  5. Woller SC, Stevens SM, Kaplan A, et al. Protocol modification of apixaban for the secondary prevention of thrombosis patients with antiphospholipid syndrome study. Clin Appl Thromb Hemost. 2018;24:192.

Conflict of Interests

Dr. Moll indicated no relevant conflicts of interest. back to top