Worrisome gaps persist in heparin therapy monitoring
of monitoring anticoagulation effect and the degree of anticoagulation achieved
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
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
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
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
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
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
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,
“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.