Filtering out Clots

Motivation: Anti-coagulation for acute DVT and PE does not make complete sense to me.  I understand that anti-coagulation stops clot extension, but what about the big DVT stranded in the vein?  Nothing really prevents it from chipping off in the next few days to the pulmonary vasculature.  Seems to me that a temporary IVC filter while beginning anti-coagulation may prevent PE while buying time for the DVT to be naturally absorbed.  Two days ago, while contemplating this apparently novel strategy, I was surprised to see that this idea had not only been thought about but also been tested through a randomized trial.

Paper: Decousus, H. et. al. "A Clinical Trial of Vena Caval Filters in the Prevention of Pulmonary Embolism in Patients with Proximal Deep-Vein Thrombosis." NEJM (1998); 338: 409-416.

Methods: Multicenter, open label randomized trial in France.  Two-by-two factorial design randomizing patients with proximal DVT to permanent IVC filter vs no filter and to low molecular weight heparin (LMWH) vs unfractionated heparin.  Patients on LMWH and UFH were transitioned to coumadin treatment starting on day 4.  Inclusion criteria were adults with proximal DVT with or without concomitant PE.  Important exclusion criteria were contraindication to anti-coagulation and hereditary thrombophilia.  Primary outcome was occurrence of pulmonary embolism within first 12 days after randomization.  All patients were evaluated first by V/Q scan and then by pulmonary angiography if necessary.  Patients were followed for two years.

Results:

Cohort: In total, 400 patients were recruited and randomized to IVC filter (200 to filter, 200 to no filter) and anti-coagulation (195 to LMWH and 205 to UFH).  Mean age was 72 years and 47.5% were male.  49% of patients presented with PE in addition to DVT.  About 35% had prior thromboembolism and 14% had known cancer.  About 11% had surgery in the past 60 days.

Primary Outcome: Within the first 12 days, there were 2 PE in group with filter compared to 9 in the group with no filter (OR: 0.22, CI: 0.05-0.90), p=0.03.  There were 5 deaths in each group.  Within the first 12 days, there were no differences in PE incidence, major bleeding, or death between the LMWH or unfractionated heparin.

2 Year Follow-Up: At two years post-randomization, patients with IVC filter had significantly more DVT compared to no filter (20.8% vs. 11.6%, OR: 1.87, CI: 1.10-1.45), p = 0.02.  There were no differences in symptomatic PE or mortality.  For patients treated initially with UFH or LMWH, there were no differences in outcomes after two years.

Discussion: This trial shows that while IVC filter may prevent PE in the short term, presence of a filter increases risk of DVT in the long term.  The paper also shows that on average, there is no difference between LMWH and UFH for acute treatment of DVT.  The trial still leaves open the possibility though that an IVC filter inserted for the short tem may decrease the incidence of PE.  While there was no difference in mortality between the two groups, a larger cohort may have shown mortality benefit in addition to the short-term decrease in PE.  This question, however, is probably going to be hard to address since this trial is one of the very few randomized trials evaluating IVC filter.  Perhaps, the makes of the IVC filter may be interested in supporting such a trial!

DVT Prophylaxis - Surprising Truths

Motivation: Frankly, DVT prophylaxis seems like a lot of voodoo to me.  Most patients who become hospitalized have probably been sick in bed at home for some days, and many continue to be bed-bound after discharge.  During the few days of hospitalization, I often wonder what difference is made by daily stabs in the stomach with heparin.  Yet, there is increasing institutional push to remember to use heparin prophylaxis.  I was browsing for some evidence for DVT prophylaxis when I came across American College of Physician systematic review about this very topic published this year.  The results are surprising.

Paper: Qaseem, A., Chou, R., Humphrey, L., et. al. "Venous Thromboembolism Prophylaxis in Hospitalized Patients: A Clinical Practice Guideline from the American College of Physicians."  Ann. Intern Med. (2011) 155: 625-632.

Methods: Systematic review of published randomized trials from 1950 to 2011.  Primary outcome was total mortality 120 days after randomization.  Secondary outcomes were symptomatic DVT, all PE, fatal PE, all bleeding, and major bleeding.  The review separated analysis for patients with and without acute stroke.

Results:
Effect of heparin prophylaxis versus no prophylaxis:
Medical patients without stroke - The review found ten trials (total of 20,717 patients) of patients without stroke.  There was NO significant effect on mortality at 120 days (RR: 0.94, CI: 0.84-1.04).  Heparin was associated with reduced risk for PE (RR: 0.69, CI: 0.52-0.90) but also increased risk of any bleeding (RR: 1.34, CI: 1.08-1.66). The differences in major bleeding and symptomatic DVT were not significant. In summary, heparin use prevents 4 PE per 1000 treated but causes 9 events of any bleeding per 1000 treated.
Acute Stroke - Review found 8 trials (total of 15,405 patients).  Pooled results showed NO significant reduction in mortality, PE, or symptomatic DVT. Prophylaxis was associated with increased risk for major bleeding (RR: 1.66, CI: 1.20-2.28). Pooled data was, however, pretty heterogenous in findings (wide spread in data).  The largest randomized trial with acute stroke had 14,578 patients and found NO reduction in mortality or PE.  However, a significant reduction in recurrent ischemic stroke was detected (RR: 0.65, CI: 0.54-0.80) at the risk of increased risk of hemorrhagic stroke or serious extracranial hemorrhage (RR: 1.73, CI: 1.22-2.46).

Low-Molecular Weight Heparin versus Unfractionated Heparin:
Medical patients without acute stroke: NO statistical difference in mortality, PE, or major bleeding events.
Acute Stroke: NO statistical difference in mortality, PE, or bleeding events.

Compression Stockings versus no stockings:
Sparse data (three trials, 2518 patients) making separation of general medical patients from patients with acute stroke difficult.  Overall, compression stockings did NOT reduce mortality, symptomatic DVT, or PE.  Risk for lower extremity skin damage was significantly increased among patients wearing stockings (RR: 4.02, CI: 2.34-6.91) conferring risk of 39 events per 1000 treated.

Discussion: To me, the most surpirsing part of the review was that despite the large pooled cohort size (>20,000 patients), there was no mortality benefit with heparin prophylaxis four months post-randomization.  The reduction in PE risk by about 30% presumably involves decreased risk of small PE.  As expected, the cost of reducing PE is increased bleeding events.  Amazingly, acute stroke patients did not have similar PE risk reduction despite a large cohort size.  Heparin use in acute stroke is a different balance between reduction in recurrent stroke (reduction by about 35%) compared to increased risk of major bleeds, including intracranial bleeds.  The review also helped clarify a couple of other misconceptions that I had.  Overall, low molecular weight heparin is no better than unfractionated heparin other than once a day dosing versus three times daily dosing.  I had thought that LMWH was better than unfractionated heparin.  Also, compression stockings proved to be pretty useless.  There is no demonstrable benefit while incurring increased risk of lower extremity skin damage.  On balance, there appears to be increased harm.  The review did not cover pneumatic compression devices.

One caveat to keep in mind in these large systematic reviews is that by pooling data, a lot of granular differences among subgroups are lost.  For example, ICU patients may have different risks and benefits.  There are also number of other cohorts such as patients with cirrhosis or kidney disease who may benefit variably with heparin.  When evaluating 30,000 patients, only effects that are consistent across entire groups are apparent.  One way in which this paper changes my perspective on DVT prophylaxis is that I will be less hesitant to hold prophylaxis in patients at risk for bleeding (after all, not saving lives with heparin).  And, I will stop pushing for stockings - good for Christmas but probably not for preventing PE.