By Dr. Geoffrey Modest MD
One somewhat confusing issue is whether to anti-coagulate a patient with a symptomatic calf deep vein thrombosis. A recent article addressed this issue (see .org/10.1016/ S2352-3026(16)30131-4 ).
Details:
- Randomized double-blind controlled study of low-risk outpatients (no active cancer or previous thromboembolic disease), with a 1st symptomatic DVT in the calf
- 259 patients from 23 centers in Canada, France, and Switzerland were randomized to low molecular weight heparin (LMWH, in this case nadroparin which is not available in the US) vs. subcutaneous placebo, and treated for 6 weeks. All patients were prescribed 30 mmHg compression stockings and followed for 90 days.
- 50% women, mean age 52, 45% of the DVTs were in the posterior tibial or peroneal vein, 55% gastrocnemius or soleus. 6% were on daily low-dose aspirin, and 6% were on NSAIDs
- Risk factors: 19% had family history of venous thromboembolic disease (VTE), 17% were on estrogen therapy, 10% recent surgery, 6% plaster immobilization, 13% travel, 9% bedrest
- Calf DVT was determined if: there were non-compressible venous segments in the deep calf veins (posterior tibial, peroneal, anterior tibial) or muscular veins (gastrocnemius or soleus)
- DVT extension was defined as ultrasonographically-proven extension to the popliteal, femoral, iliac, and cava veins
- The primary outcome was a composite of proximal extension of the calf DVT, contralateral proximal DVT, and symptomatic pulmonary embolism at day 42. Prespecified secondary outcomes included the individual components of the primary outcome, assessed at day 42 and 90.
Results:
- There was no significant difference between the groups in the composite primary outcome, which happened in 4 patients (3%) on LMWH and 7 patients (5%) on placebo
- DVD extension was detected at day 3-7 in one patient in the LMWH group and 3 in the placebo group; 5 additional patients in the LMWH group and 4 in the placebo group were diagnosed during the 1st 42 days.
- 2 patients had a nonfatal symptomatic pulmonary embolism, both in the LMWH group, at the 42 week checkup
- No difference in primary outcome between patients with isolated muscular calf DVT vs those with peroneal or posterior tibial calf DVT
- One additional venous thromboembolic events occurred between days 42 and 90, in a patient on placebo who developed a symptomatic nonfatal pulmonary embolism at day 89
- Significant bleeding (1 major bleed, 4 others with clinically relevant bleeding) occurred in 5 patients (4%) in the LMWH group and none with placebo.
- One patient was diagnosed with heparin-induced thrombocytopenia type 2 with LMWH
Commentary:
- This study was pretty underpowered, given that they only enrolled 50% of the pre-specified sample size (the steering committee decided to discontinue the study because of poor enrollment). As a result, the current number of patients would have a 90% power detect a 70% risk reduction in the rate of the primary outcome, assuming an incidence of the primary outcome of 10% in the placebo group. However, an additional issue was that the actual number of events in the placebo arm was only 5.4% (vs the expected 10.0%); therefore, mathematically, it would have been necessary to include 1891 patients in each arm to have the initial scheduled statistical power.
- There was an important study done a long time ago which fed into being more aggressive in treating distal DVTs, and it definitely changed my practice for many years (see Lagerstedt CI. Lancet 1985; 2: 515). This was a 3-month study of 51 patients with symptomatic calf-vein thromboses using open-label warfarin vs no medication, which found that in the non-anticoagulated group, 8 patients (29%) had DVT recurrences (6 symptomatic), 5 with proximal DVT extension and 1 with a pulmonary embolism, but 0% with warfarin (though in 3 of the 8 patients who had recurrences, they were high-risk having had a previous history of thrombosis).
- One larger concern raised by this article is that sometimes we get way too much data from our diagnostic studies than we know how to deal with. This is certainly true in the MRI studies of low back pain (e.g., see Jensen MC, N Engl J Med. 1994:69, where they did an MRI on 98 asymptomatic patients, finding that only 36% had a normal MRI, 52% had a bulge on at least one level, 27% had protrusion, and 1% extrusion. Another study of asymptomatic people found that 21% had spinal stenosis!!). In the DVT case we do have many studies over the years showing that following serial ultrasounds one week apart looking for proximal extension of a distal clot seems to work well for predicting who was at risk for thromboembolism. Whole-leg ultrasound was not available in the past, and we seemed to do quite well without it… and, it turns out, its use leads us to anticoagulating more patients vs just checking for proximal DVT!!!
So, perhaps the safest algorithm, is just to look only for proximal DVT in low-risk patients (ie, avoid ordering the whole-leg imaging). Then repeating the ultrasound in one week if the first did not show a proximal DVT, providing only symptomatic care, including compression stockings as needed. And only anticoagulating if the second ultrasound shows proximal extension. This is consistent with the American College of Chest Physicians clinical practice guidelines (see Chest 2012; 141: e351S), which suggest that in patients with moderate pretest probability of a first DVT, to get D-dimer testing or proximal vein ultrasound, and to do whole-leg US only if patient unable to return for serial US testing. In those getting whole-leg ultrasound and finding an isolated distal DVT, “we [the guideline writers] suggest serial testing to rule out proximal extension over treatment”. And, though the above study was underpowered to elicit a clear conclusion, it was reassuring that only about 5% of the patients had a proximal extension and the number of significant adverse events was really low (3 of 259 in 90 days of followup, about 1%)