unprovoked dvt: longterm anticoag??

A large 10-year analysis found that the risk of recurrent venous thromboembolism (VTE) after an unprovoked initial VTE increased signficantly after taking only 3-6 months of anticoagulation (see dvt unprovoked longterm anticoag bmj2019 in dropbox, or doi.org/10.1136/bmj.l4363.

Details:
--18 studies with 7515 patients were analyzed (4 studies were prospective observational cohort studies; 14 were RCTs); all were considered high-quality studies
--they did not include studies with: persistent risk factors of patients having active cancer; major transient risk factors of surgery with anesthesia for >30 minutes, confined to bed for >2 days with acute illness, or C- section; minor transient risk factors of surgery with anesthesia for < 30 minutes, admitted to  hospital for < 3 days with acute illness, estrogen therapy, pregnancy/puerperium, confined to bed outside of hospital for >2 days, or leg injury with reduced mobiltiy for >2 days
--all patients had completed at least 3 months of anticoagulation prior to their discontinuation

Results:
--pooled rate of recurrent VTE per 100 person-years after discontinuation of anticoagulants:
    --in first year: 10.3 events (8.6-12.1)
        --for DVT: 6.2 per 100 person-years
        --for PE: 3.3 per 100 person-years
        --for DVT plus PE: 0.3 per 100 person-years [this relative distribution of specific recurrrent VTEs was similar in the longer followup data below]
    --in the second year: 6.3 events (5.1-7.7)
    --in years 3-5: 3.8 events/yr (3.2-4.5)

    --in years 6-10: 3.1 events/yr (1.7-4.9)

--cumulative incidence of recurrent VTE:

    --at 2 years: 16.0% (13-19%)

    --at 5 years: 25.2% (21-29%)

    --at 10 years: 36.1% (28-45%)

        --for DVT: cumulative incidence was 25.1%

        --for PE: cumulative incidence was 11.2%

        --for DVT plus PE: cumulative incidence was 0.8%

--for women, recurrent rate per 100 person-years:

    --in the first year: 8.9 events (6.8-11.3)

    --cumulative incidence at 10 years: 28.8% (20-38%)

--for men, recurrent rate per 100 person-years:

    --in the first year: 11.9 events (9.6-14.4)

    --cumulative incidence at 10 years: 41.2% (28-56%)

--risk of recurrent VTE according to site of initial event, cumulative incidence at 2 years:

    --distal DVT: % not available, though was 1.9 per 100 person-years

    --proximal DVT: 16.4%, at 10.6 per 100 person-years

    --isolated PE: 11.9%, at 7.7 per 100 person-years

    --PE plus DVT: 17.0%, at 10.2 per 100 person-years

--case fatality rate for recurrent VTE was 3.8% (2.0-6.1%)

Commentary: 

--several studies have found that the recurrence rate of VTE was high after stopping anticoagulants after 3-6 months, but the guidelines for continued anticoagulation are pretty weak (grade B recommentdation, "in large part as a result of uncertainty in estimates of the long term risk of major bleeding if treatment is continued, and, importantly, the long term risk of recurrent VTE if anticoagulation is discontinued" (see http://gmodestmedblogs.blogspot.com/2016/01/antithrombotic-therapy-guidelines.html for a review of the 2016 guidelines).  and prior analyses were from relatively short-term studies or did not include more recent studies

--this trial puts in perspective the longterm effects of stopping anticoagulation in terms of both recurrent VTEs as well as the case fatality rate.  there is no inclusion of the risk of bleeding from continued anticoagulation, or even the risk of recurrent VTEs if continuing anticoagulants. But it does provide information to discuss with patients about their risks of stopping vs continuing anticoagulation, with a few points:

    --the recurrent VTE rates for men were 1.4 times those of women, so there may be increased incentive to continue anticoagulation in men

    --for distal DVTs, the rate of recurrences was 1/5 that of those with proximal DVTs, so harder to make the argument to continue anticoagulation if it were started

    --from their data, the risk of a recurrent fatal VTE after 10 years would be about 1.5%; other studies suggest that the risk of fatal major bleeding is about 1.3% (ie, not much difference). so, this would sway the argument against long-term anticoagulation if the patient has a greater than average risk of bleeding.

        --for men, the mortality benefit of not stopping anticoagulation was 1.6%, but 1.3% risk of fatal bleed after 10 yrs

        --for women, fatal VTE risk was 1.2%, risk of fatal bleed was 1.3%

--it should be noted that there are no RCTs that directly compare anticoagulation for 3-6 months, then longterm continuation or cessation of anticoagulation. or continuing anticoagulation for longer periods of time and then stopping it (eg, is it better to have 2 years of anticoagulation than 3-6 months, and then discontinuing the meds?? there was a marked increase in recurrent VTE in the first 2 years. would stopping the anticoagulation after 2 years be better than after 3-6 months? or would it just be putting off the higher risk period of the first 2 years?)

--one unexpected finding in this study is that those with an unprovoked PE actually had a lower rate of recurrent VTE after discontinuing anticoagulation than those with a proximal DVT (40% higher likelihood in the latter case)

--also, since the risk of a recurrent VTE was so much higher in the first 2 years, there is less imperative for patients to resume anticoagulation if they had stopped it more than 2 years before

so, this study does argue that there probably are benefits of continuing anticoagulation, though there are insufficient data to state this unequivocally (no data on actual bleeding risk in this long-term study, or recurrent VTE risk in those on continued anticoagulation). Which really means that there needs to be an open discussion with patients:

--it seems quite probable that men may benefit from continued anticoagulation, given their higher risk of recurrent VTE, and their possible overall likely mortality benefit (albeit small)

--women should be aware that there is about a 30% increased risk of recurrent VTE over 10 years, though the likelihood of having a fatal one is only about 1%. However, there are potential other benefits from reducing the risk of a recurrent VTE that should be incorporated into the analysis, including risk of post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension

    --there is a validated risk calculator for women's risk of recurrent VTE (HERDOO2), which includes the initial  risk factors of hyperpigmentation, edema or redness; d-dimer >250; BMI >30; age >65: those with 2 or more of these risk factors had almost 3x the risk of recurrent VTE after discontinuing anticoagulation (see dvt women HERDOO2 bmj2017 in dropbox, or https://www.bmj.com/content/bmj/356/bmj.j1065.full.pdf )

other prior blogs of note:

http://gmodestmedblogs.blogspot.com/2019/05/vte-risk-high-even-if-negative-d-dimer.html assessed VTE recurrence risk in men and women with unprovoked initial VTE, based on negative d-dimer testing prior and one month after stopping anticoagulation, finding that after 2 years the recurrence rate was still high in men, somewhat lower on women, but still supported continued anticoagulation (ie, adding the d-dimer testing did not change the risk of recurrence much)

http://gmodestmedblogs.blogspot.com/2016/12/not-anticoagulate-symptomatic-calf-dvt.html is an RCT of patients with symptomatic calf DVT, finding that anticoagulation was not helpful

geoff

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