By: Dr. Geoffrey Modest
JAMA published the PADIS-PE trial of patients having a first unprovoked pulmonary embolism (PE), randomized to stopping anticoagulation after 6 months vs continuing an additional 18 months (see JAMA. 2015;314(1):31-40).
Details:
–371 patients (mean age 58, 40% >65yo, 50% women, mean BMI 27, 45% with high bleeding risk per the Am College of Chest Physicians rating) with a first episode of unprovoked, symptomatic PE, initially put on 6 months of a vitamin-K antagonist, who were then randomized from 2007-2014 in 14 French centers to continued warfarin vs placebo for 18 months. Target INR = 2.0-3.0. Patients with known major thrombophilia were excluded. Blood was sent for thrombophilia workup on day 0.
–minor thrombophilia (heterozygous factor V Leiden or heterozygous G20210A prothrombin mutation, or factor VIII >90th %) was found in 24% and major thrombophilia (antithrombin deficiency, anticardiolipin antibodies >99th %, or homozygous factor V Leiden or combined thrombophilia) in 4%.
–primary outcome: composite of recurrent venous thromboembolism (VTE) or major bleeding at 18 months; secondary outcome: this composite at 42 months, each component of the composite, and death unrelated to PE or bleeding at 18 and at 42 months (24 months after the end of the study).
Results:
–Mean % of time in the target INR range was 69.1%.
–During the treatment period
–primary outcome in 6/184 patients in the warfarin group (3.3%, or 2.3 events per 100 person-years) vs 25/187 in placebo (13.5%, or 10.6 events per 100 person-years), with HR 0.22 (0.09-0.55, p=0.001).
–in the warfarin group, 3 patients (1.7%) had a symptomatic recurrent VTE, all after discontinuation of warfarin. in the placebo group, 25 patients (13.5%) had symptomatic recurrence, only one of which was after stopping the placebo (p<0.001).
— major bleeding occurred in 4 patients in warfarin group and 1 in the placebo group (statistically nonsignificant)
–After treatment discontinuation
–composite outcome in 27 warfarin-treated (17.7%; 10.0 events per 100 person-years) and 17 placebo-treated (10.3%, 5.7 events per 100 person-years)
–in the warfarin group, 25 patients had symptomatic VTE (9.3 events per 100 person-years, all in the absence of anticoagulation, 4 of which were fatal). in the placebo group, symptomatic recurrence was in 14 patients (4.7 events per 100 person-years, all in the absence of anticoagulation)
–major bleeding occurred in 2 patients on warfarin group (1 while taking warfarin and 1 fatal event happened after stopping it), and 4 in the placebo group (all nonfatal; 2 while on warfarin)
–Review of the graphs showed a dramatic difference during the 18 months after randomization, and a gradual reduction in warfarin protection over the next 24 months of observation when all were off warfarin (see below for the primary endpoint)
–After 42 months, composite outcome in 33 patients on warfarin (20.8%) and 42 on placebo (24.0%) [HR 0.75 (0.47-1.18)] — the benefit of extended warfarin Rx was not maintained
–No difference in rate of recurrent VTE, major bleeding, and unrelated deaths
–The risk of recurrent VTE was greatest in the first 6 months after stopping anticoagulation, then increased linearly by 4-5% per year. the risk of major bleeding with continued warfarin was low, increasing by <2% per year
So, a few issues:
–this study confirms that when anticoagulation is discontinued, the patient at is at risk for recurrent VTE, whether anticoagulation is for 3-6 month or longer. Also that the risk of major bleeding with anticoagulation is pretty low (confirmed by other studies)
–in the decision analysis of how long to anticoagulate, it is important to remember that the natural history of a venous thrombosis is different from a PE: the likelihood of a recurrent PE is much higher in the latter group, and the case-fatality rate is 4-fold higher than after a proximal DVT. In the above study, 80% of the recurrent VTE events in both groups were from symptomatic PEs.
–if you and patient decide to stop anticoagulants, there are some potentially useful approaches: for other articles, including one on different and safer ways to stop anticoagulation by checking d-dimer levels, see here and especially here)
–if you decide to stop the anticoagulation, 2 studies have found some efficacy of low dose aspirin (about 30% decreased risk of aspirin vs placebo — better than placebo but not as good as continuing the anticoagulation).
–an (unfortunately) untested hypothesis might be: check for underlying thrombophilia; 6 months of anticoagulation; check d-dimer; in those who are d-dimer negative, offer aspirin and discontinue anticoagulation (after discussing risks/benefits with patient); also look to see if the underlying thrombophilia actually matters (and, if so, then preferentially continue life-long anticoagulation). Short of that, this study adds to other observational studies finding a high risk of recurrent PEs in those with initial symptomatic unprovoked PE, so my inclination (and what I have been doing) is to offer life-long anticoagulation (especially to low risk-of-bleeding patients), with a fallback to checking the d-dimer and changing to aspirin if all is okay.