dvt recurrence in unprovoked dvts -- HERDOO2 tool

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 dvt women HERDOO2 bmj2017 in dropbox, or doi.org/10.1136/bmj.j1065​).

Details:

-- 2747 participants with a 1^st 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 1^st 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 http://gmodestmedblogs.blogspot.com/search/label/venous%20thromboembolism  for a slew of articles on VTE, with my concerns about the novel anticoagulants (NOACs)