provoked thromboembolism: longterm anticoag

 A recent article found that adults with a provoked venous thromboembolism (VTE) and enduring risk factors are still at risk for a recurrent VTE event and do benefit from long-term anticoagulation, in the company-funded HI-PRO study  (see dvt provoked prolonged anticoag NEJM2025 in dropbox, or DOI: 10.1056/NEJMoa2509426)

 

Details:

-- 600 adults who had had an objectively-confirmed symptomatic venous thromboembolism (VTE) after a transient provoking risk factor (eg, autoimmune disorders, chronic lung disease, obesity) and had completed the at least 3-month course of anticoagulation were randomized to apixaban 2.5mg twice a day vs placebo for 12 months, in this single-center, double-blind trial done at the Brigham and Women's Hospital in Boston from November 2020 through November 2023

--mean age 59.5, 57% female, 81% white/12% Black/ 9% Latino

-- BMI 31, current smokers 5%

 -- coexisting conditions: VTE prior to this trial in 21%; diabetes 12%; hypertension 49%; coronary artery disease 17%; PAD 4%; stroke/TIA 6%; heart failure 3%; dyslipidemia 54%; occlusive carotid disease 2%

-- family history of VTE: 26%

-- use of aspirin at baseline: 21%, with 20% taking aspirin during the follow-up.

-- VTE diagnoses: only DVT in 48%, isolated calf DVT 20%, only a pulmonary embolus 24%, right ventricular dysfunction 13%, both pulmonary embolism and DVT 28%

-- provoking risk factors: acute medical illness (asthma, Crohn's disease, heart failure, COPD, other inflammatory condition) 18%, surgery 35%, trauma 20%, pregnancy 2%, infection 16%, hormonal contraceptive or replacement therapy 13%, hospitalization less than 3 months before the VTE 9%, immobility 30%, blood transfusion 0.1%, covid infection 8%, long-haul travel 16%, other less common factors 9%

-- enduring risk factors: persistent immobility 6%, BMI >=30 in 48%, heart failure 3%, COPD 24%, chronic inflammatory or autoimmune disorder 51%, atherosclerotic cardiovascular disease 29%, CKD 11%, chronic liver disease 3%

-- median duration of anticoagulant treatment before randomization: 7 months

-- the most common provoking factors in this study were surgery, immobility, trauma, and acute medical illness

-- the most common enduring risk factors were chronic inflammatory or autoimmune disorder, BMI of at least 30, atherosclerotic cardiovascular disease (ASCVD), and chronic lung disease

-- exclusion criteria: an indication for long-term anticoagulation (including VTE without provoking factors or active cancer), pregnancy or lactation, severe hepatobiliary or renal disease, taking more than 81 mg of aspirin or P2Y₁₂ platelet receptor antagonist

-- Virtual visits every 3 months during the trial, in-person visit at 12 months, with assessment of medication adherence, serious adverse events, adverse drug reactions, and trial outcomes

-- primary efficacy outcome: first symptomatic, recurrent, objectively-confirmed VTE (i.e. a positive assessment for DVT, pulmonary embolism, or both) during the 12 months of follow-up

-- secondary efficacy outcome: first occurrence of a composite of death from cardiovascular causes, nonfatal MI, stroke or TIA, systemic embolism, major adverse limb event, or coronary or peripheral ischemia resulting in revascularization

-- exploratory composite outcome: first symptomatic recurrent VTE or any components of the secondary efficacy outcome, and a composite of fatal or nonfatal symptomatic recurrent VTE, MI, stroke or TIA, or systemic embolism

-- primary safety and point: first occurrence of major bleeding, as defined by the International Society on Thrombosis and Hemostasis criteria

-- secondary safety outcome: first occurrence of clinically-relevant nonmajor bleeding

-- prespecified subgroup analyses: those having pulmonary embolism, age of at least 65, sex, chronic kidney disease (eGFR<60), atherosclerotic cardiovascular disease, baseline aspirin use, and the number of provoking factors (at least 2 vs <2)

Results:

-- symptomatic recurrent VTE:

    -- apixaban group: 4 of 300 patients (1.3%)

    -- placebo group: 30 of 300 patients (10.0%)

        -- 87% reduction with apixaban, HR 0.13 (0.04 to 0.36), p<0.001

-- secondary composite income (first occurrence of a composite of death from cardiovascular causes, nonfatal MI, stroke or TIA, systemic embolism, major adverse limb event, or coronary or peripheral ischemia resulting in revascularization) was rare and with similar frequencies in the apixaban group (0.7%) and the placebo group (1.0%), HR 0.67 (0.11 to 3.89), not statistically significant

-- major bleeding:

    -- apixaban: one patient, someone with a very small subdural hematoma after a fall from a horse that resulted in neither hospitalization nor discontinuation of the apixaban

    -- placebo: no patients

-- clinically-relevant nonmajor bleeding:

    -- apixaban: 14 of 294 patients (4.8%)

    -- placebo: 5 of 294 patients (1.7%)

        -- 2.68-fold in those on apixaban, HR 2.68 (0.96-7.43), p=0.06

    -- most common sites for nonmajor bleeding: vaginal 1.7%, hematuria 1.4%, rectal 1.0% in the apixaban group and vaginal in 1.0% in the placebo group

-- one patient in the apixaban group and 3 patients in the placebo group died, neither attributed to cardiovascular or hemorrhagic causes

-- non-hemorrhagic, nonfatal adverse events occurred in 6 patients in each group

-- medication adherence, by pill counts every 3 months along with pill diary review:

    -- apixaban: median number of days 350 of the maximum of 365 

    -- placebo: median number of days 339 of the maximum of 365 

-- In their prespecified subgroup analyses: no difference if pulmonary embolism was the initial event; age above or below 65yo (however, zero patients on apixaban and 9.8% on placebo having VTE were at least 65 years old); sex (though much less common in females); CKD (though low numbers of patients with CKD in the study); history of ASCVD; baseline use of  low-dose aspirin (small number of people); the number of provoking risk factors whether below or above 2; long-haul travel as a provoking risk factor; provoking risk factors of surgery, major trauma, and prolonged immobility; or whether there was a prior history of a VTE (very low number of patients)

-- and, even aldosteronism is associated with chronic inflammation (https://pmc.ncbi.nlm.nih.gov/articles/PMC7891246/), as a pean to my recent blogs on this: https://gmodestmedblogs.blogspot.com/2025/09/resistant-hypertension-are-diuretics.html and https://gmodestmedblogs.blogspot.com/2025/09/hyperaldosteronism-2025-guidelines.html

Commentary:

--extended-duration anticoagulation is typically prescribed for patients with unprovoked venous thromboembolism (VTE), given the high risk of recurrence of 6% to 10% per year after discontinuing the anticoagulation

    -- of importance, in this study the placebo group had a risk of recurrent VT that was 10%!!

    -- which means that in this group of patients with provoked VTE but enduring risk factors, their risk of a recurrent event seems to be equivalent to that of those with unprovoked VTE!!!

-- prior to this trial, there was no clear evidence of what to do for people with provoked VT and concomitant enduring risk factors such as autoimmune disorders, chronic lung disease, or obesity

-- so, this trial had several important results:

    -- provoked VTE has similar recurrent VTE as an unprovoked one if untreated with anticoagulants, challenging the importance of the utility of trying to stratify VTE by provoked status, and using different treatment strategies for these entities

    -- anticoagulation with apixaban, at the low dose of 2.5mg bid, decreases recurrent VTEs from 10% in those on placebo to 1.3% if on apixaban, an 87% decrease

    -- low-dose apixaban is well-tolerated, with few adverse effects and, specifically, a very low risk of major bleeding

        -- though it is important to remember that non-major bleeding episodes are not insignificant and can lead to anxiety, decreased quality of life and increased heath care utilization

    -- the benefit of apixaban was independent of the type of provoking risk factors, whether considered major or minor transient provoking factors (though patients with active cancer were excluded from the study)

    -- in this study setting, there was remarkably high medication adherence to apixaban

-- one concern with this study is that they have a not-so-clear definition of "chronic inflammatory disorder". by the text, it seems likely that they include rheumatologic disorders as well as chronic infections. But the actual array of issues associated with chronic systemic inflammation is quite large and includes depression, situational stress, air pollution, microplastics, chemical exposures at work, visceral obesity (as opposed to just weight or BMI, since non-visceral obesity is not associated with chronic inflammation), as well as an array of medical conditions including chronic kidney and lung disease, cardiovascular disease, diabetes, allergies, etc: see https://www.ncbi.nlm.nih.gov/books/NBK493173/ and https://gmodestmedblogs.blogspot.com/2023/10/update-ascvd-risk-factor-critique.html

Limitations:

-- this was a 12-month study. it is unclear if patients should be considered for longer-term anticoagulation with a non-provoked VTE, as with a provoked one (https://pmc.ncbi.nlm.nih.gov/articles/PMC6601085/), when the risk/benefit analysis leans toward benefit

-- no presentation in the study of the actual bleeding risk of the participants assessed at the time of initiation of the study

-- this was a single study in a single hospital in a single community with likely very different patients with different exposures/medical problems and likely different enduring risk factors (especially if one incorporates the vast array of known risk factors for increased systemic inflammation, including stress, air pollution, etc as noted above), all of which may limit generalizability to other areas. it would be very useful to have other studies done in different localities (and best with a broader definition and documentation of pre-existing systemic inflammation) before adopting the quite profound and game-changing conclusions of this study (serum CRP levels may be related to increased VTE risk: https://pubmed.ncbi.nlm.nih.gov/28718029/)

 

 so, although there is the rather well-defined VTE categories of “provoked” vs “unprovoked", biologically this really does not make much sense:

-- provoked: clearly only some people get VTEs after going for a long trip on an airplane, or having surgery. Why? Perhaps they have some procoagulant proclivity??  a known or unknown predisposition to clotting such as factor S or C? prothrombin variants? factor V Leiden? etc. And even in an absence of a “provoking” event, were they at increased risk of a unprovoked" VTE at some future date???

-- unprovoked: was it really unprovoked? Did they cross their legs for a long time while sitting at home or work and created venous stasis leading to a VTE? Or had some unremembered trauma to their lower legs??

     -- bottom line here: our binary assessment of whether VTE was provoked or not may well actually be a biological spectrum and not a clear-cut difference

-- and this study raises clearly this lack of clarity:

    -- it does reinforce the likely benefit of chronic anticoagulation (?for how long) in patients with enduring risk factors with low-dose apixaban if they have low risk of bleeding (?how measured and at what cutpoint?)

geoff

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