VTE risk high even if negative D-dimer

A recent study looked at the 5 year incidence of recurrent VTE in men and women who stopped anticoagulants after an unprovoked VTE and had negative d-dimer both before stopping therapy and one month afterwards. This is a follow-up to their 2.2 year results (see prior article eval/blog: https://gmodestmedblogs.blogspot.com/2015/01/stopping-anticoagulation-after-first-dvt.html ), confirming that the incidence of recurrence was very high in men, lower in women, and quite low in those women who were on estrogens and stopped them (see dvt normal d-dimer not help jthrombhem2019 in dropbox, or DOI: 10.1111/jth.144).

Details:

-- 410 patients in the initial prospective interventional cohort study, who had 3 to 7 months of oral anticoagulants (OACs) with INR goal of 2.0-3.0; d-dimer was negative on therapy and still negative one month subsequently.

-- Women who had a VTE while on estrogen therapy were eligible if they stopped estrogen therapy

-- mean age 51, BMI 31, duration of anticoagulation 5 months, previous unprovoked VTE 4%, proximal DVT only in 45%/PE 55%, number of risk factors for bleeding (e.g. previous stroke, peptic ulcer disease, GI bleed, GU bleed, diabetes, antiplatelet therapy) was 0 in 87%, and one in 11%, diabetes 7%, statins 19%, family history of VTE 21%, fully active 91%

-- 231 of the initial patients remained off anticoagulants and were the basis for this current study (the majority stopped because of either their clinical centers did not continue to participate or the patients did not consent to participation)

--Mean follow-up 5.0 years after stopping OAC therapy

Results:

-- recurrent VTE: 5.1% per patient year (3.6%-6.5%), with the cumulative five-year rate of 21.5%

    -- for men: 7.5% per patient year (5.5-10.0%), cumulative five-year rate of 29.7% (22.1-37.3%)

    -- for women not on estrogens: 3.8% per patient year (2.0-6.6%), cumulative five-year rate of 17.0% (8.1-25.9%)

    -- for women who had been on estrogens: 0.4% per patient year (0.4-2.3%), only one event in the 58 women who stopped anticoagulation, for a cumulative rate of 2.3% over 5 years

        -- p<0.001 for comparisons between these groups

-- looking at the probability for recurrent VTE over time:

    -- for men there was some flattening out of the curve after about 2 years, with the probability of recurrent event approximately 21% at that time, but this increased to about 35% by about 6 years

    -- for women who had not been on estrogens: the probability of a recurrent event after 2 years was about 12%, which gradually increased to about 17% by 3 ½ years, with no subsequent increase up to 7 years

    -- for women who had been on estrogens and stopped, ther one woman who developed a VTE did so after about 2.7 years

-- in those patients who did not stop OAC because the d-dimer test was positive, there were 4 recurrent episodes of VTE during a total of 244 patient years of follow-up, recurrence rate of about 1.6% per patient year

-- major bleeding: 1.6% per patient year: 9 events; minor bleeding 21 events

-- diagnosis of cancer during follow-up: diagnosed in 8 of the 320 patients with a negative d-dimer at enrollment and one month subsequently

-- deaths: 12 people died: one from PE, one from bleeding, 4 from cardiovascular disease, 2 from sepsis, one from lupus, one from cancer (mesothelioma, diagnosed prior to study), one from ischemic colitis, and one from unknown cause. [Of note, not clear if these people were on or off OAC, esp the person dying form PE and from bleeding.]

Commentary:

-- this study followed prior studies finding the risk of recurrent VTE was about one half for patients with an unprovoked VTE who had a negative d-dimer. That prompted some of us (myself included) to discuss the risk and benefits of stopping OAC in this situation, given the clinical risks of OAC as well as the continued medicalization around recurrence/follow-up INR etc. And, a meta-analysis, confirmed the 2+-fold increase in recurrent VTE in those with positive vs negative d-dimer, bringing the annualized risk down to a much more reasonable 3.0 vs 7.4 per 100 patient-years (see Douketis J. Ann Intern Med 2010; 153: 523).  There was no significant benefit in checking d-dimer in men, as in the above study

-- it seems pretty clear from this study that men with an unprovoked VTE should continue on anticoagulation independent of their d-dimer results (i.e., men should understand the very high risk of recurrent VTE, which far outweighs the likelihood of a major bleed, and there does not seem to be much utility in checking d-dimers)

-- for women who had a VTE in the setting of taking estrogens and then stopping them, their risk is quite low of a recurrent event (i.e., they should understand that the risk of having a major bleed outweighs that of a recurrent VTE). It seems that being on estrogens should not be really considered an “unprovoked VTE”.

-- for women who had not been on estrogens, the risk of a recurrent event is somewhat higher than the risk of major bleed, and they should make an informed decision as to whether to continue OACs. 

    -- a study of 630 women (333 being estrogen users) that did not use d-dimer testing, followed 69 months after stopping OACs found: those who were estrogen users had a cumulative VTE recurrence rate of 1% at 1 year, 1% at 2 years and 6% at 5 years, also suggesting that it may not be really necessary to check d-dimers in them either, since the event rate was so low independent of d-dimer testing (see Eischer L. J Thromb Haemost 2014;12:635). But, in this study the cumulative recurrence rate in women not on estrogens was 5% at 1 year, 9% at 2 years, and 17% at 5 years. Pretty similar to the results of the study using d-dimers.

    -- But, for women not on estrogens, the other studies finding the twofold increased risk of recurrent VTE in those with positive d-dimers, does suggest that we should be continuing to check d-dimer levels both before and one month after stopping anticoagulation as part of the discussion for continuing off OAC [ie, women should be aware of the conflicting results in the above studies about their residual VTE recurrence risk, but that it is likely that those who are d-dimer negative both before and 1 month after stopping OACs may well have a much lower risk of recurrent VTE]

-- also, though it is important to look at recurrent VTE vs major bleeding as endpoints, perhaps the most profound endpoint really is death from one of these factors. The numbers of deaths likely related to the use or discontinuance of OAC was not clear in the study (presumably the person dying from a PE was off OAC and the one dying from bleeding was on them, but not clear in the supplementary materials). In any case, the incidence of death is quite low, which is reassuring in terms of the overall decision-making for this complex and common problem

-- one untested approach in this study is that it might be useful to check d-dimer levels every 2 months for one year. One study found that doing so picked up several patients who became d-dimer positive after being negative 1 month after stopping OACs, and that those who became positive had a 7.9-fold increased risk of VTE (7 in 31 patients who became positive after being negative in the first month had a VTE, vs 4 of 149 who remained negative: see Cosmi B. Blood 2010; 115: 481). Though the maximum follow-up in this study was only 13 months. Would be great to have an updated followup…

-- another recent concern is that many people are being treated with the newer direct-acting oral anticoagulants.  Not sure how the above approach of checking d-dimers would apply to them

So, the bottom line for this study:

-- in men having a 1^st unprovoked VTE, in general they should probably continue lifelong OAC, and no need to check the d-dimer

-- in women on estrogens, stopping the estrogens seems to be sufficient, no need to check d-dimer

-- in women not on estrogens, the decision analysis is more complex, women should be apprised of the statistical outcomes, and make their own decisions on continuing OACs. And, at this point, it probably does make sense to check a d-dimer level both before stopping anticoagulation as well as one month subsequently, as part of the decision-making of the safety of stopping OAC therapy. I personally like the approach from the other study mentioned above, of continuing to check d-dimers every couple of months for a year in those who choose to stop OACs, as a means to pick up higher risk women

geoff​

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