Heparin & VTE: Effective, Affordable But Still Shunned

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CritCareRounds.jpg - SunnybrookHealthSciencesCentre
The critical team at Sunnybrook Health Sciences Centre at the University of Toronto assesses patient data to identify those at risk of developing venous thromboembolism.

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[3]: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[14]: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 weight heparin beat out unfractionated heparin in terms of total hospital costs (JAMA 2014;312[20]:2135-2145).

“We looked at the sum total of costs—not just the drug acquisition cost, but the costs for all medications associated with various categories of the stay in ICU [intensive care unit] and the hospital in addition to the cost of various events and length of stay in ICU and hospital to try to answer the question [of cost],” he says.

The hospital stay for patients taking low-molecular weight heparin cost around $1,297 less per patient than those taking unfractionated heparin. The total cost difference favored dalteparin by $2,773,635 over the course of the study. This cost difference was largely attributable to fewer pulmonary embolisms and a reduction in HIT. Because fewer patients were experiencing venous thromboembolisms and complications to treatment, fewer hospital resources were being used.

Which means, he notes, that low-molecular weight dalteparin offers not only a clinical benefit over unfractionated heparin but it also is more economically viable. “Even at the lowest cost for unfractionated heparin and even if it was free, because low-molecular weight heparin seems to be more effective with fewer episodes of side effects and results in less use of hospital resources, there’s really no scenario where a different price point would favor the use of unfractionated heparin,” Fowler says.

New source, new medicine?

As heparin is made from pigs, several additional issues exist for production. Growth, care and size of the harvest create their own barriers. Part of previous contamination scares involved prions in the supply.

Robert Lindhardt, PhD, MS, professor of chemistry and chemical biology at Rensselaer Polytechnic Institute in Troy, New York, and his lab develop synthetic heparins in an effort to provide a reliable supply for medical use. “The FDA would agree that the food chain and the drug chain are not regulated with the same level of rigor,” he says. “It’s hard to control a drug that begins at slaughter houses and ends up in a [compounding] pharmaceutical plant. They are just not as well regulated as one would like.”

Lindhardt has been working on synthetic heparins since 2008 with the goal of creating a well-controlled bioengineered source of the drug, akin to the shift from porcine pancreatic insulin to recombinant insulin. So far, his lab has had some successes. They designed low-molecular weight heparin that can be completely neutralized by protamine. They also developed an ultra-low-molecular weight heparin that can be cleared by the liver rather than the kidneys, making it safer for patients with impaired renal function.

The third area they’re working on is HIT. They’re trying to make an HIT-free heparin. “It’s not incredibly common. Maybe a 2 percent at most side effect, but it really is dangerous,” Lindhardt says. “The real difficulty in that is that there aren’t really good animal models right now. That means you have to get a good human clinical trial to prove that it’s HIT negative.” They haven’t reached clinical trial stage, but they are gearing up for an animal model study in the near future.

He recognizes that once they overcome clinical challenges they then must address the market realities. “Heparin is a very inexpensive drug and the market size is very large. We’re talking about 100 metric tons a year. So the challenges there aren’t making something equivalent to the animal-sourced heparin, which we’ve already done, but to scale up production in an economically feasible way.”

Crowther shared similar concerns about synthetic heparins. “It’s an extremely interesting area. Unfractionated heparin and low-molecular weight heparin, in the grand scheme of things, are pretty cheap, so unless these products are very inexpensive, they’re not going to get much of a market.”

Until clinical trials occur, though, it will be a waiting game to see how the drugs Lindhardt’s team develop fare.

Program uses EHR to flag VTE cases in radiology reports

An EHR search could help hospitals improve how they spot venous thromboembolism (VTE) cases. Using a bag-of-words approach, a model accurately and swiftly identified deep vein thrombosis and pulmonary embolism cases from radiology reports.

A McGill University research team in Montreal and colleagues developed an automated model to identify cases of VTE and improve accuracy of a computer model without resorting to a more labor-intensive manual method (J Am Med Inform Assoc online Oct 20, 2014). The research team noted that identifying these patients quickly and accurately from radiology reports can help focus hospital improvement efforts to reduce adverse events. They considered development of a computer model to be a first step in creating a near-real time monitoring approach of adverse events that is scalable to entire hospital systems.

“We know that patients are under-exposed to [prophylaxis] while they are in hospital,” says Christian M. Rochefort, RN, PhD, of the Clinical and Health Informatics Research Group at McGill. “And the main reason for that is that physicians have trouble identifying patients at risk of developing the disease. Currently in the U.S., there are discussions about financially penalizing or stopping reimbursement to hospitals for patients who develop this complication.”
The model was built using data extracted from McGill University Health Center databases and the initial analysis spanned 2008 through 2012. The initial sample included 2,000 patients suspected of deep vein thrombosis or pulmonary embolism. Two sets of models were developed, one to search for deep vein thrombosis and the other for pulmonary embolism. Both were initially manually coded to create a reference standard and a matrix was created from the list of terms developed through initial coding. The word lists were improved on to include word combinations.

“The technique is called natural language processing and it works with the frequency distribution of words within a text document. Depending on the words you use, you can train a computer to learn the characteristics, the patterns of the words that are used in the report and classify those to positive or negative to the condition of interest,” says Rochefort.

The programs successfully identified deep vein thrombosis in 80 percent of radiology reports, with a false positive rate of about 11 percent. Pulmonary embolism was identified in 79 percent of cases, with 16 percent false-positive rate. These rates were an improvement over those noted in prior research in this area.
According to the researchers, VTE is seen in up to 40 percent of medical and general surgical patients, with even higher rates in patients undergoing major orthopedic procedures. Current estimates on 30-day fatality rates in patients who develop VTEs range from 5 percent to 15 percent and it is the second most common cause of increased hospital stay lengths.

They propose this approach also could significantly improve patient outcomes and be used to detect other types of adverse events.