In the hospital and immediately after discharge, developing venous thromboembolism (VTE) is a serious risk. Patients with pulmonary embolism or a deep vein thrombosis have poorer outcomes. VTEs can be fatal, especially in those patients whose conditions are already fragile. But the best strategy to combat this complication prophylactically remains unclear.
With years of use in the medical community, heparin offers the advantage of familiarity but bleeding risks are higher for patients on heparin and it isn’t well tolerated in patients with impaired renal function. Even if unfractionated heparin and low-molecular weight heparins, such as dalteparin, come from the same animal, so to speak, they have moderately different risks.
Results of a survey published in 2014 confirm the top concerns physicians have with using low-molecular weight heparin. These included cost, bleeding risk, inadequate education among residents and bioaccumulation in patients with impaired kidney function, in weight-ranked order (J Crit Care 2014;29:471.e1-9). Physicians also find low-molecular weight heparin trickier to dose and have concerns that antidotes such as protamine may not work as quickly or effectively as needed.
VTE: A preventable event
While physicians may balk at prescribing low-molecular weight heparin, hospitals facing pushback from funding sources such as the Centers for Medicare & Medicaid Services (CMS) may feel pressed to find an appropriate prophylactic treatment. “[CMS] in many circumstances won’t reimburse for VTE which occurs after a discharge because they have said it’s a completely preventable event,” says Mark Crowther, MD, MSc, director of laboratory hematology at McMaster University in Hamilton, Canada. “As a result of that, there’s lots of enthusiasm for providing prophylaxis.”
Crowther has participated in several studies about heparin usage to reduce VTE risk. He states that while resistance to low-molecular weight heparin is longstanding and strong, it is “completely baseless.”
He notes that clinicians fear increased risk of bleeding from low-molecular weight heparin because it is “seen to be more potent. There was no evidence of excess bleeding in general in both PROTECT and the study published before it called DIRECT, where we showed there was no bioaccumulation with renal function. That should allay the fears of practicing clinicians around whether or not they can actually choose dalteparin in critically ill patients.”
The PROTECT (Prophylaxis for Thromboembolism in Critical Care Trial) study compared dalteparin, a low-molecular weight heparin, to unfractionated heparin in critically ill patients in a clinical setting and at a global scale (N Engl J Med 2011;364:1305-3014). Patients were dosed once daily with dalteparin and a placebo, while patients taking unfractionated heparin were given the recommended twice daily dose to prevent thromboembolism. Sixty-seven intensive care units in Canada, Brazil, Australia, Saudi Arabia, the United Kingdom and the United States participated.
Crowther noted that worldwide, the one country that has the most concern with using low-molecular weight heparin as opposed to unfractionated heparin is the U.S. “The major area where this [the findings from PROTECT and DIRECT] could have a big impact is in the U.S. because in the rest of the world, this bridge about what’s best for prophylaxis has been crossed a long time ago.”
They found that low-molecular weight heparin had a significantly lower risk for heparin-induced thrombocytopenia, or HIT, and also use correlated to significantly lower rates of pulmonary embolism. At the time, the study did not find significant difference in detected deep vein thrombosis between low-molecular weight heparin and unfractionated heparin but a later analysis attributed the lack of difference to how they defined these leg clots.
“There’s very good evidence that when you ultrasound, you will find a lot of irrelevant clots that aren’t going to go on to cause trouble. And we suffered from that in this analysis in that we would have had a lot of thrombotic events that showed up that would have been of minimal clinical importance,” Crowther says.
Point on price
Secondary analysis of the PROTECT findings revealed another significant advantage with using low-molecular weight heparin: cost. In an economic evaluation, Robert A. Fowler, MDCM, MS, of the Sunnybrook Health Sciences Centre at the University of Toronto, and colleagues, found that low-molecular