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Worrisome gaps persist in heparin therapy monitoring

Percentile distribution of monitoring anticoagulation effect and the degree of anticoagulation achieved

January 2004

Karen Lusky

Taking a statistical picture can be worth a thousand words in illuminating patient safety opportunities. And a recent CAP Q-Probes study looking at heparin therapy monitoring and outcomes in an inpatient practice setting does exactly that.

The study, “Inpatient Anticoagulation,” compared how well 140 hospitals and medical centers (all Q-Probes subscribers) monitored 3,431 inpatients receiving intravenous unfractionated heparin therapy for at least 72 hours during hospitalization. The study’s authors also evaluated how quickly the patients moved into the therapeutic anticoagulation range and stayed there without becoming over coagulated during the three-day timeframe.

Somewhat alarmingly, one-fifth of the patients in the study didn’t make it into the therapeutic anticoagulation range within 24 hours of starting therapy, leaving them at increased risk for clotting. And one-third of the patients entered the supra-therapeutic range on at least two occasions during the first 72 hours of heparin therapy, which meant they were more likely to suffer hemorrhagic complications.

Considering that heparin has a narrow therapeutic window, “these failures to bring patients into the therapeutic range—and keep them there—poses a significant patient safety issue,” says study coauthor Paul Valenstein, MD, president of Pathology and Laboratory Management Associates, Ann Arbor, Mich.

The good news is that the institutions in the study weren’t lax in monitoring their heparin patients. The median laboratory measured aPTT or anti-Factor Xa levels at least once on 98 percent of the patients during the first 12 hours of heparin administration. (See “Percentile distribution of monitoring anticoagulant effect and the degree of anticoagulation achieved,” below.) The median hospital also obtained a platelet count within 72 hours of heparin administration 93 percent of the time. “That’s an important monitoring intervention, considering that heparin can induce thrombocytopenia which can lead to intravascular thrombosis, the drug’s most serious preventable side effect,” says study coauthor Frederick A. Meier, MD, director of regional pathology services in the Henry Ford Health System, Detroit.

The study also unveiled an unexpected wide variance between institutions’ therapeutic anticoagulation ranges for aPTT testing, which reflected a lack of agreement about what constitutes over or under anticoagulation.

The study’s authors expected the therapeutic ranges to differ from one institution to the next because of the variation between lots of reagents. “Yet the differences in reagent sensitivity could not account for the wide differences in therapeutic ranges that we observed among institutions,” says Dr. Valenstein. “If we’d seen that finding coming, we would have asked hospitals more questions about how they set their therapeutic range.”

Hospitals at the 10th percentile had a lower limit of 40 seconds for aPTT compared with 65 seconds for the hospitals at the 90th percentile. The upper limit for aPTT ranged from 65 seconds to 116 seconds.

Five institutions in the study were using anti-Factor Xa to measure patients’ levels of anticoagulation. Given the small number of hospitals using anti-Factor Xa, the authors did not measure variation in anti-Factor Xa therapeutic ranges.

Hospitals participating in the study were asked to identify 30 patients who had received standard dose intravenous unfractionated heparin for at least three days in a row during hospitalization. The participants then recorded the following information for each study patient:

  • Date and time of initial heparin dose.
  • Whether anticoagulation effect was monitored within 12 hours of the first heparin dose by measurement of an aPTT or anti-Factor Xa test.
  • Whether a platelet count was monitored within 72 hours of the first heparin dose.
  • Whether the patient had at least one therapeutic anticoagulant level within the first 24 hours of heparin administration.
  • Whether the patient had two or more supra-therapeutic anticoagulated levels within the first 72 hours of administration.

The study excluded outpatients, ambulatory surgical and emergency department patients, and nursing home and outreach patients. Patients receiving low-dose heparin (5,000 units/dose) or low-molecular-weight heparin also were excluded. The study’s authors looked for statistically significant associations (p-value of .05 or less) between the hospitals’ rates of monitoring and the degree of anticoagulation achieved, and a number of demographic and practice variables.

The hunt for associations left them curiously empty-handed.

Says Dr. Meier: “We looked at factors known to be associated with efficacy in other therapeutic drug monitoring situations, such as how the drug is ordered or the use of nomograms or other pharmokinetic measures to try to predict the drug response.” None of those interventions appeared to affect the percentage of patients who achieved and maintained a therapeutic and safe level of anticoagulation.

Nor did the type of hospital (public versus private), initiation of therapy on weekends versus weekdays, or the presence of dedicated anticoagulation services appear to affect hospitals’ performance. Institutions that had not been accredited by the Joint Commission on Accreditation of Healthcare Organizations performed better than those that had been accredited. The study authors note, however, that it’s “difficult to believe that JCAHO inspection could be a cause of poor performance.”

In retrospect, Drs. Valenstein and Meier wish they had asked participants more questions to ferret out what might be driving superior outcomes. “For example, we should have asked more specifically how many times a day the hospitals were monitoring patients, and how often they were making dose adjustments per day,” says Dr. Valenstein. Other questions he would ask if he were to repeat the study: Do physicians round once or twice per day? Are pharmacists involved in dosing adjustment? What brand of heparin is the institution using? “It’s possible that hospitals that monitored their patients more frequently were making more frequent dosage adjustments and that this extra effort caused their patients to stabilize more rapidly at the right level of anticoagulation. But we don’t know that for sure,” he says.

Dr. Meier believes that differences in the patients’ diagnoses and conditions could not have affected the study’s findings in a significant way. “Heparin is mostly prescribed for acute deep vein thrombosis, pulmonary embolism, and postoperatively for vascular surgeries or post myocardial infarction,” he says “So that mix of diagnoses is probably representative of the case mix in general hospitals included in the study. Also, heparin therapy is not being used much anymore for patients with disseminated intravascular coagulation, who might otherwise appear in the supra-therapeutic range.”

Could differences in the brand of heparin used have affected performance? Dorothy Adcock, MD, medical director of Esoterix Coagulation, Aurora, Colo., believes there might be some relationship there. “The difference [in the heparin] could be due to how variable the actual potency of the drug is compared to the stated potency,” she says. “The accuracy of the assigned potency of the particular brand of heparin or even individual lot may vary between different manufacturers.”

Maureane Hoffman, MD, professor of pathology at Duke University Medical Center, agrees: “Unfractionated heparin is a heterogeneous mixture of molecules from a biological source—pig intestines or lungs—so the variability from one manufacturer to the next can be quite significant in terms of aPTT results.”

The unexplained wide variation in how hospitals defined a therapeutic level of anticoagulation clouds the study’s findings to some extent. The variation in therapeutic ranges for aPTT is “such a confounding factor,” says Dr. Meier, “that it’s hard to be sure what the variables are that determined therapeutic outcome endpoints.”

For example, when Drs. Valenstein and Meier examined individual results from patients in the study who appeared to be over anticoagulated, it was difficult to determine whether the patients had received too much heparin or whether the therapeutic range was not set properly. Study sites that had higher upper limits of their therapeutic aPTT range tended to have fewer patients with two or more supra-therapeutic values.

Yet the variation in therapeutic ranges is only part of the story. “Even when the statisticians netted out the differences due to where the therapeutic range was set, the findings still revealed a large variation in the ability of sites to bring patients into the therapeutic range and keep them out of supra-therapeutic values,” Dr. Valenstein says.

The study’s primary recommendation is the need to address the wide variance in therapeutic ranges among institutions. “Institutions must calculate therapeutic ranges using approved methods and should be suspicious of adopting ranges that deviate too much from the norm,” Dr. Valenstein says.

A heparin therapeutic range for aPTT that falls somewhere between 60 and 100 seconds is fairly average, says Elizabeth Van Cott, MD, director of the coagulation laboratory at Massachusetts General Hospital, Boston, and a member of the CAP Coagulation Resource Committee. “Some sensitive reagents may legitimately have a therapeutic range that extends above 100 seconds, and other reagents may be relatively insensitive to heparin, but labs may not be comfortable with that and may look for another reagent.”

To establish a therapeutic range for aPTT, hospitals must collect specimens from patients on unfractionated heparin (but not those receiving warfarin). The next step is to perform an aPTT and a heparin assay (anti-Factor Xa assay) on each specimen. Then you plot the aPTT and anti-factor Xa results against each other on a graph, and construct a linear regression. “From the graph, you can determine what range of aPTT values correlate to anti-Factor Xa levels of 0.3 to 0.7 units/mL,” says Dr. Van Cott. “Suppose 0.3 U/mL anti-Factor Xa corresponds to 60 seconds for the aPTT, and 0.7 U/mL corresponds to 80 seconds. Then the heparin therapeutic range for the aPTT would be 60 to 80 seconds for the laboratory in this example.”

When the aPTT reagent lot changes, a simpler approach can be used that does not require heparin assays. With this alternative approach, the laboratory should perform aPTTs on specimens using the old lot and the new lot and then compare the results. “The mean aPTT using the new lot should be no greater than seven seconds different than the old lot,” Dr. Van Cott says. If the difference is less than seven, then the correlation is acceptable and the aPTT therapeutic range does not need to change (although a difference of five to seven seconds could be a concern). If the difference is greater than seven seconds, the lab could reassess the therapeutic range—or test a new reagent lot, Dr. Van Cott says.

Labs should also do a cumulative summary with each lot change, taking into account the previous years’ results, to make sure the difference over time doesn’t drift in either direction by more than seven seconds, Dr. Van Cott says. (This approach is described in more detail in Olson JD, Arkin CF, Brandt JT, et al. Arch Pathol Lab Med. 1998:122;782–798.)

The findings also provide a performance benchmark for hospitals. “The best quartile of participant hospitals in the study succeeded in getting at least 93 percent of their heparinized patients in the therapeutic range within 24 hours,” Dr. Meier says. “And they kept at least 79 percent of patients out of the supra-therapeutic range during the first 72 hours of heparin administration.”

Hospitals could do a quality probe on their own by seeing how well they are doing with the four parameters examined in the study:

  • Getting an aPTT within 12 hours.
  • Getting a platelet count on patients receiving heparin within 72 hours.
  • The percentage of patients in the therapeutic range within 24 hours.
  • The percentage of patients kept out of the supra-therapeutic range within the first 72 hours (fewer than two levels reported above the therapeutic range).

In Dr. Meier’s view, monitoring heparin and achieving therapeutic anticoagulation levels might also be a good study topic for the College’s Q-Tracks monitor. “In the Q-Tracks program, the [CAP] Quality Practices Committee talks to best performers and asks them what they are doing and then provides feedback to the Q-Tracks subscribers,” he says.

Or if a hospital knew that another institution had better outcomes, it could ask the physicians at that institution what they are doing and compare those practices with their own.

Eventually, monitoring patients might become unnecessary if physicians migrate from prescribing unfractionated heparin to prescribing low-molecular-weight heparin. “That is a way out of the issue, as LMW heparin produces predictable anticoagulation that does not require monitoring in most adult populations,” Dr. Meier says.

Yet Drs. Adcock and Hoffman predict that will not happen anytime soon. And even then they see a continuing role for unfractionated heparin, which is an inexpensive drug that physicians are well versed in administering, monitoring, and reversing.

“LMW heparin is efficacious in the prevention and treatment of venous thrombosis and is the drug of choice during pregnancy,” says Dr. Adcock, “and LMWH is increasingly used in patients with unstable angina.” But Dr. Adcock adds, “Unfractionated heparin is the agent used most often during percutaneous cardiac interventions and cardiopulmonary bypass. Furthermore, patients who may require urgent surgical intervention should be treated with unfractionated rather than LMW heparin.”

Karen Lusky is a writer in Brentwood, Tenn.