by Dr Geoffrey Modest
One perplexing issue in primary care is the appropriate duration of anticoagulation for people with unprovoked venous thromboses. A recent international study found that a specific clinical decision rule was effective in predicting recurrent DVT in women and could permit individualizing different therapies (see doi.org/10.1136/bmj.j1065).
Details:
— 2747 participants with a 1st unprovoked venous thromboembolism, VTE (either DVT with a noncompressible segment in the popliteal vein or more proximal leg veins and/or documented pulmonary embolism) who had completed 5 to 12 months of short-term anticoagulant treatment were followed prospectively from 44 healthcare centers in 7 countries (from North America, Europe, India, Australia), from 2008 to 2015.
— Mean age 54, 84% white, 75% on vitamin K antagonists for anticoagulation, VTE event was isolated DVT 41%/isolated PE 40%/DVT and PE 21%
— They used the HERDOO2 clinical decision rule: Hyperpigmentation, Edema, or Redness in either leg; D-dimer level ≥ 250 µg/L; Obesity with BMI ≥ 30; or Older age ≥ 65. D-dimer levels were drawn during anticoagulant treatment.
— Of these components: 24% had hyperpigmentation, edema or redness of leg/50% D-dimer ≥250 µg/ 32% >65 yo/ 43% BMI ≥30.
— Low risk patients (women with HERDOO2 score ≤1) were to discontinue anticoagulants (and almost all did); for high risk women and men it was left to the discretion of the clinicians and patients
— primary outcome was an adjudicated symptomatic major VTE
Results:
— of 1213 women, 631 (51.3%) were classified as low risk
— 17 who discontinued anticoagulants developed a recurrent VTE during 564 patient years of follow-up (3.0% per patient year)
— of 323 high risk women and men who discontinued anticoagulants, 25 had VTE during 309 patient years of follow-up (8.1% per patient year).
–7.4% in high risk women and 8.4% in high-risk men.
— of 1802 high risk women and men who continued anticoagulants, 28 had recurrent VTE during 1758 patient years of follow-up (1.6% for patient year)
— secondary outcomes:
–1 recurrent PE death (in a high-risk person who continued anticoagulation); risk of major bleeds was nonsignificant in any who stopped anticoagulation, and was 1.2% per patient year in men and high risk women who continued oral anticoagulants. 2 major bleeds were fatal.
–subgroup analyses: in women <50 yo (n=429) rate of recurrent VTE was 2.0% (not related to estrogen use) vs 5.7% in those >50 yo. No difference by country, type of index VTE, or type of anticoagulation
Commentary:
— patients with provoked VTE, such as after surgical procedure, have a 1% chance of VTE recurrence, whereas those with unprovoked VTE have a 10% chance in the 1st year after stopping short-term anticoagulants, 5% in the subsequent year, and 30% at 8 years. 3.6% of recurrent VTEs are fatal. Oral anticoagulation reduces the risk of recurrent VTE by 80-90%.
— The International Society on Thrombosis and Hemostasis suggest that it is safe to discontinue anticoagulants if the risk of recurrent VTE is <5% at one year after discontinuing treatment (with an upper bound of the 95% confidence interval being <8%).
— The HERDOO2 clinical decision rule has been found to be clinically effective in discriminating low risk versus high risk women, though not for men. This study was a large randomized trial in patients with unprovoked VTE.
— of note, over ½ of the women with unprovoked VTE in their study were low risk and could stop their anticoagulants (ie, less than the 5% cutpoint that they noted above). So, the potential effect of this decision rule is quite high for women.
— so, where does this HERDOO2 rule come from?? A study done in 2008 (see doi:10.1503/ cmaj.080493 ) prospectively looked at 600 people with first unprovoked VTE and followed 18 months, finding an overall annual recurrent DVT rate of 9.3%. They focused on the 91 patients with confirmed recurrent DVTs to assess potential risk factors, and developed the HERDOO2 clinical rule, finding annual recurrent VTEs in 1.6% with scores ≤1 and 14.1% in those with higher scores.
— issues about generalizability:
–this study had only an 11.6 month followup (and the original study was only a bit longer), and, as per the above statisitics, lots of recurrent VTE events happen after the 1-year mark
–they excluded the few people with known high-risk thrombophilia (this is not routinely assess after a first event, so not sure why those patients had the test done and if this exclusion could affect the results)
–there were few non-white patients, and the risk of thrombophilia may vary by groups, though there are large deficits in our knowledge here, but there are some data suggesting that factor V Leiden and the prothrombin G20210A mutation are less common in African-Americans, though Black Africans in another study of patients who had strokes tended to have lower levels of protein S, protein C, and antithrombin III levels.
–subgroup analysis in the above study of women >50 yo had a higher VTE recurrence rate of 5.8% and would be good to see if this were a better cutpoint than the ≥ 65 in the HERDOO2 algorithm
–continuing anticoagulants in the high risk groups was left to the discretion of the clinicians/patients, so unclear who the group was who continued or discontinued the meds and how that might skew those results.
— Overall, would be great to have another study of longer duration and including a more mixed group of patients, to assess generalizability of the results
so, bottom line: this study may well have far-reaching implications, given that a large number of women (not men) might be able to stop long-term (perhaps life-long) anticoagulation for unprovoked first VTE (including PEs, where the risk of a recurrent PE is higher). And, I would add the results of this study to my general gestalt in discussing the pros and cons of stopping anticoagulation. But, to me, this is still such a difficult clinical decision, with potentially life-threatening implications either way, that there should be another confirmatory study in a more mixed population of patients.
See here for a slew of articles on VTE, with my concerns about the novel anticoagulants (NOACs)