American Association for Clinical Chemistry
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December 2009 Clinical Laboratory News: New Heparin Standards

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December 2009: Volume 35, Number 12

New Heparin Standards
Will the Change Make a Discernable Difference in Coagulation Monitoring?
By Genna Rollins

Heparin's essential role in the prevention and treatment of thrombosis has been recognized for decades, yet keeping the dosage in a therapeutic range always has been a delicate balancing act. Too little drug, and the patient will be inadequately anticoagulated and at-risk for clots; too much drug, and hemorrhage is possible. Although clinicians rely on tests such as activated partial thromboplastin time (aPTT) and activated clotting time (ACT) to monitor the effects of the drug, properly titrating the dose is challenging due to the heterogeneity of unfractionated heparin and patients’ individualized dose-response. Now, a recent update to the U.S. Pharmacopeia (USP) heparin monograph has added another potential confounding factor in dosing and monitoring, leaving coagulation experts wondering about the ultimate impact of the change. The update, which became effective October 1, 2009, resulted in an approximate 10% reduction in heparin potency in the U.S. and brought U.S. and international units of unfractionated heparin in line with each other.

Many coagulation experts recommend a watch-and-wait approach for now. “The question is, what, if any, clinical implications this change in potency will have,” said Jawed Fareed, PhD, clinical professor of pathology and pharmacology at Loyola University Medical Center in Maywood, Ill. “At this stage, all that's called for is extra caution and monitoring of patients, and watching at the bedside if any changes would be noted.”

For Further Information

American College of Chest Physicians Antithrombotic and Thrombolytic Therapy: Evidence-Based Clinical Practice Guidelines (8th Edition), Hirsh J, Guyatt G, Albers G, Harrington R, et al, Chest 2008; 133:71-105S. A letter advising ACCP members about the new heparin monograph as well as the recommendations of an expert panel convened to evaluate the changes is available on online.

U.S. Pharmacopeia. A series of documents and background materials about the updated USP heparin monograph are available on the USP website. Go to Hot Topics: USP Heparin Information.

U.S. Food and Drug Administration. The FDA Public Health Alert regarding the updated USP monograph is available on the FDA website. Go to drugs, drug safety and availability, postmarket drug safety information for patients and providers.

Addressing Safety Concerns

USP updated the monograph in response to more than 200 deaths worldwide associated with adulterated heparin. In the U.S. the problem was first publicized in January 2008 when Baxter International, one of the major suppliers of heparin, noted a spike in deaths among patients taking the drug and recalled certain lots. Baxter subsequently recalled all remaining lots and the U.S. Food and Drug Administration (FDA) found the source of the problem to be contamination with over-sulfated chondroitin sulfate, which comes from the dietary supplement chondroitin and can mimic heparin's blood-thinning actions. The problem subsequently was linked to a Baxter contractor’s plant in China.

Apparently the over-sulfated chondroitin sulfate passed existing quality tests, so USP first revised its heparin monograph standards in June 2008 to include new tests manufacturers must use to detect the contaminant. The second phase of USP's update included a new potency assay for heparin, the chromogenic anti-Factor IIa test, along with a new potency reference standard. This new standard is calibrated to WHO's international standard for unfractionated heparin. According to USP, there had been an estimated 10% drift over the past three decades between USP's heparin unit and WHO’s international unit. Since the new USP heparin sodium for assays reference standard is directly traceable to the 5th international standard for unfractionated heparin, the disparity between U.S. and international units has been eliminated. In the long run, this harmonization of standards is a positive development, but in the meantime, laboratorians, pharmacists, and physicians will need to monitor the transition closely.

A Divergence of Opinion

When phase two of the monograph became effective, USP indicated that it did not anticipate the change would have clinical significance. However, FDA issued a public health alert on October 1 advising that the change in heparin potency could have clinical significance in some situations, such as when the drug is administered via bolus and “an immediate anticoagulant effect is clinically important.” FDA urged providers to consider the change in potency when making decisions about what dose to administer. In addition, the agency advised that new and old lots of heparin might be available at the same time, that the potency change might require more frequent or intensive aPTT or ACT monitoring, and that clinical judgment would be essential in determining the dose of heparin for individual patients.

Although the new monograph went into effect October 1, FDA asked manufacturers to wait until at least October 8 to start shipping products manufactured and tested in accordance with the new monograph. The delay was designed to give providers and pharmacies “time to make the necessary adjustments in their prescribing and dispensing practices,” according to John Jenkins, director of FDA's Office of New Drugs. “Although the FDA-approved labeling for heparin has not changed, including the recommended doses, it is essential that healthcare professionals be aware of the potential difference in potency between the old and new vials of heparin when administering the drug.”

Even though the heparin contamination problems were well-known, the change in USP's monograph and the FDA alert came as surprises to many in the field, according to Charles Eby, MD, associate professor of pathology and immunology at Washington University School of Medicine in St. Louis. Likewise, many healthcare providers were unaware of the potency drift between USP and WHO standards that had taken place over the years. As a result, initially there was some alarm in the coagulation field, but as experts had time to contemplate the impact, the concerns have diminished, he said.

A key consideration for many hospitals has been whether therapeutic ranges for PTT would be invalidated by the change in potency. In his networking with colleagues, Eby found “unanimous consensus that no, the therapeutic ranges would not be impacted.” However, since both PTT and antifactor Xa assays are used to develop heparin sensitivity curves, a second issue centered on the calibrations for antifactor Xa assays, which use heparin. “We were concerned about how our industry colleagues were calibrating the antifactor Xa assays and whether they were using the same USP heparin activity that had just changed or had been calibrating with an international heparin unit that's related back to the WHO standard,” Eby explained. As it turns out, all of the major manufacturers of antifactor Xa assay kits contacted by Eby and his colleagues already had been calibrating their tests to the international standard. Still, labs will do well to verify manufacturers' standards for the various assays, according to Michael Laposata, MD, PhD, pathologist-in-chief and professor of pathology and medicine at Vanderbilt University Hospital in Nashville. “We have a call in to the company that makes our reagents, and we're asking them whether they plan to change their standard in light of the planned changes to unfractionated heparin.”

With USP suggesting the potency change will have little importance clinically and FDA warning that it could have a significant impact, at least in certain populations, exactly what effect it actually will have remains to be seen. The picture is murky for several reasons, most notably because of the well-known, highly variable dose-response to unfractionated heparin. For instance, one study found that even when the aPTT reached a therapeutic range of 55 to 85 seconds, the next two consecutive measurements remained in that range in less than one-third of patients (Arch Intern Med 2003; 163:621–627). In addition, patients received an average of four different heparin doses over the first 3 days of treatment, and only 7% maintained the therapeutic range on each of 4 sequential days. Similarly, a 2003 CAP Q-Probe study found that 20% of patients were not in the therapeutic anticoagulation range within 24 hours of starting therapy. On the flip side, one-third of patients were considered in the supra-therapeutic range on at least two occasions during their first 72 hours on heparin, putting them at risk for hemorrhagic complications. The study also reported a wide variation in therapeutic aPTT times.

Patient Populations of Concern

Laposata believes any effect will be most noticeable in patients at the borderline therapeutic range after an initial bolus injection of heparin. "My guess is that if it is 10 percent less potent, the potential danger would be for the person who is right at the edge of the therapeutic range. So you may be shooting for a 60 second aPTT and come out several seconds lower," he explained. “I'm guessing that people will do as they have in the past, and that is to give a bolus, and if the aPTT isn't in the therapeutic range, they'll give some more.” For example, Laposata noted, a standard heparin bolus dose is 80 units/kg of patient weight and a standard maintenance dose is 18 units/kg/hour. If a patient either wasn’t in or was borderline for the therapeutic range after the bolus, the maintenance dose might be increased slightly.

Obese patients are another population that deserves special scrutiny, according to Fareed. “If you give 7,500 units to a 70 kilogram patient, a 10 percent change in potency may not make that much of a difference. But in giving 7,500 units to a 100 kilogram patient, a 10 percent potency difference might have a considerable therapeutic impact,” he explained.

Another expert believes that the greatest potential impact of the potency change could be in two situations where heparin bioavailability is not always closely monitored. One is when heparin is given twice daily to prevent blood clots in high-risk patients. The other is in circumstances in which patients receive much higher doses of heparin, such as those undergoing kidney dialysis or cardiac procedures involving cardio-pulmonary bypass. “In those settings a 10 percent potency decrease is more likely to have clinical significance because if you're giving X and in the past it didn't cause clotting of the circuit, what we don't know is if we give 10 percent less, are we crossing a threshold at which clotting becomes more frequent,” explained Mark Crowther, MD, MSc, FRCPC, acting chief of laboratory medicine at St. Joseph's Healthcare and Hamilton Health Sciences Corporation and professor of Medicine and Pathology and Molecular Medicine at McMaster University in Hamilton, Ontario, Canada. However, he emphasized, “we don’t truly understand the implications of this change.” Crowther also serves as vice chair of the thrombosis section of American College of Chest Physicians (ACCP) guidelines on antithrombotic therapy and was part of a panel of experts convened by ACCP to evaluate the USP changes.

Institutional-Level Monitoring a Must

Because of the highly variable dose-response to heparin, any impact may not be detectible in individual patients, so institutional-level monitoring will be critical. “Where institutions are going to see an impact is whereas last year they had 35 clots in their dialysis circuits, this year they might have 40. In an individual patient it's going to be completely impossible to tease out,” Crowther predicted. St. Joseph’s is not alone in planning a systematic evaluation of any changes in thrombotic events. Eby explained that Barnes-Jewish Hospital in St. Louis also will be looking closely at event rates and changes in aPTT. “We’ll be looking at this as a case-control study, with controls being a retrospective review and cases being patients who receive heparin based on the new USP potency. We’ll need months of data. It’s not the kind of comparison that can be done in a week,” he noted.

ACCP indicated that it will reassess any guideline changes after its panel of experts has had an opportunity to review monitoring data. Meanwhile, the American Society of Hematology issued a notice alerting its members to the change, but has no plans to release additional guidance for now, according to Stephanie Kart, government relations manager.

In keeping with the need to monitor the impact of the potency change, lab testing will take on more importance, and some facilities may reconsider their testing strategies, predicts Paula Santrach, MD, co-director of point-of-care testing and associate professor of laboratory medicine and pathology at Mayo Clinic in Rochester, Minn. “In patients on low-dose heparin therapy, there’s been a back-and-forth lately. We used to follow them with aPTT, which is a measure of the function, the clotting time,” she explained. “But people are moving more and more to the antifactor Xa assay, which gives you results in units/mL. With the change in potency, you may not get the same kind of correlation between the concentration and the effect. So I think understanding your antifactor Xa assay and your nomograms will be important in relation to this change.”

Laboratorians may want to refer to ACCP and CAP guidelines, which recommend calibrating aPTT ranges based on antifactor Xa activity of 0.3 to 0.7 units/mL. The antifactor Xa assay has the advantage of less interlaboratory variability than aPTT assays. However, both markers have their challenges due to lack of robust data correlating them to efficacy and safety outcomes, according to Edith Nutescu, PharmD, FCCP, clinical professor in the department of pharmacy practice and center for pharmacoeconomic research and director of the antithrombosis center at the University of Illinois at Chicago Medical Center. “That’s why the guidelines don’t mandate or suggest going to antifactor Xa assay,” she said. Fareed believes the aPTT assay will remain the standard of care for heparin dose-response monitoring.

When the new monograph was issued, some organizations questioned whether they should proactively update their dosing nomograms to increase the rate of heparin infusion by 10%. Eby thinks it would be premature to do so based on his discussions with colleagues. “I think the answer to that will be retrospective after we’ve accumulated data,” he predicted.

Another concern brought forward by FDA was that lots of “old” and “new” potency heparin might be available at the same time, so providers would need to be able to distinguish between the two. Hospira reportedly is using lot numbers starting with 82 or higher, while the three other companies that market heparin in the U.S., APP, Baxter, and B. Braun, will denote new lots with the letter “N”. However, in early November several hospitals consulted for this article had not received any lots of the new potency heparin. The University of Illinois at Chicago Medical Center is one example. “We don’t have a firm date for receiving the new lots, but what we’re planning to do is roll them out so that practitioners are alerted that the new lots are going into effect,” explained Nutescu. “Ideally, there’ll be time in weaning out of the old and rolling in of the new lots that we can target it systematically so a given patient won’t be going back-and-forth between the old and new drug.”

As lots of the new heparin formulation make their way into hospitals across the country, laboratorians should be on the front lines of developing communication and monitoring plans with their pharmacist and physician colleagues, according to Santrach. “You have to talk about it so everyone is aware and there’s a plan,” she suggested. “Heparin monitoring isn’t necessarily standardized so you have to look at your own situation and determine what the potential impact could be and how you would mitigate that.”