Heparin: Improving Treatment and Reducing Risk of ... - CareFusion

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HEPARIN:IMPROVING TREATMENT AND
Reducing Risk
of Harm
Clinical, Laboratory and Safety Challenges
T
he short-acting, reversible
anticoagulant heparin is
widely used in hospitalized
patients to prevent
the development or extension of
potentially life-threatening blood
clots. However, numerous issues
make the use of this high-risk agent
particularly challenging and errorprone.
As shown by media reports
of heparin-related infant deaths
and injury in Indiana, California,
and Texas, heparin-related medication
errors can have devastating
impact on patients, families, staff,
and the reputation of a healthcare
institution and its leadership.
Safe and effective use of heparin requires maintaining a delicate
balance—dosing low enough to minimize the risk of bleeding,
yet high enough to treat or prevent thrombosis. Achieving a
therapeutic level of heparin within 24 hours significantly
reduces the risk for recurrent venous thromboembolism (VTE)
(Raschke et al., 1993; Hull et al., 1997; Anand et al., 1996; Anand
et al., 1999). However, non-protocol-driven practice achieves
this outcome only 40% of the time (Wheeler et al., 1988).
By
William E. Dager, PharmD, FCSHP
Robert C. Gosselin, CLS
Robert Raschke, MD, MS
Tim Vanderveen, PharmD, MS
Image Courtesy of Cardinal Health
20 Patient Safety & Quality Healthcare ■ January/February 2009 www.psqh.com

Medication errors involving unfractionated heparin (UFH)
are among the most common and serious in clinical practice.
More than 17,000 heparin-related medication errors were
reported to the U.S. Pharmacopoeia (USP) MEDMARX from
2003 to 2007; 556 of these resulted in harm to patients, including
seven deaths (Santell, 2008).
An expert advisory panel of The Joint Commission (TJC)
recognized that “anticoagulation is a high-risk treatment
which commonly leads to adverse drug events because of the
complexity of dosing, monitoring and patient compliance”
and that “the use of standardized practices can reduce the risk
of adverse drug events.” In 2008 TJC issued National Patient
Safety Goal 3E (NPSG 3E) to “Reduce the risk of harm associated
with the use of anticoagulant therapy.” Hospitals were
required to be fully compliant with this goal by January 1,
2009 (TJC NPSG, 2008).
Key clinical, laboratory, and safety issues surrounding heparin
were addressed in a nationwide webcast on “Improving
Heparin Safety,” hosted by the Center for Safety and Clinical
Excellence on July 11, 2008. In this article, we summarize
important information and recommendations, focusing on the
three stages of heparin use that account for 67% of heparinrelated
errors—dosing, monitoring and administration (Santell,
2008).
Dosing
Significant errors in dosing heparin and interpreting reported
aPTT values can result from unnecessary variation in physician
practice. Standardized protocols for dosing heparin can help
reduce such variability. Although physicians sometimes are perceived
as being resistant to change, in fact they are more resistant
to having change mandated. For this reason, prescribers need to
participate in the development and adoption of heparin-related
standards, guidelines or protocols.
The Deep Vein Thrombosis Prevention program at the University
of California, San Diego Medical Center used a multidisciplinary
consensus-building process to develop and
implement a standardized, physician-friendly, risk-assessment
process and VTE-prevention order set. Results showed that
appropriate VTE prophylaxis increased from 55% to over 95%
of patients and was accompanied by a documented decrease in
thromboembolic events (Peterson et al., 2008).
Approaches to initiating heparin infusion to reach targets
were also reviewed. A study by
Raschke et al. showed that compared
to a standard, “one-size-fitsall,”
initial heparin dosing scheme, a
weight-based protocol increased the
percent of patients within the therapeutic
range within 24 hours from
77% to 97% (p=0.002) and significantly
reduced the risk of recurrent
venous thromboembolism (RR 0.2,
p=0.02). The incidence of bleeding
complications was the same in both
groups, despite more aggressive dosing in the weight-based
group (Raschke et al., 1993).
A subsequent study showed that improvements were maintained
over a 5-year period with a nearly 95% protocol implementation
rate. Initial heparin infusion rates increased from
1,185 to 1,420 units/hour (p

HEPARIN SAFETY
changes its thromboplastin reagent and can go in either direction.
Failure to account for such change by updating heparin
dosing schemes would have resulted in systematic underdosing
of the vast majority of patients. For this reason, it is important
that each institution adjust heparin dosing guidelines as necessary
to the aPTT assay reagent currently in use.
patients with lower UFH infusion rates can lead to underestimation
of UFH anticoagulation. The presence of a heparin
effect may not be appreciated because the ACT test is not
designed to measure effects in the lower target range. Thus,
while POC testing devices provide rapid results, such devices
may sacrifice accuracy and precision.
Pre-analytical Variables
Pre-analytical variables that adversely affect aPTT test results
include poor phlebotomy technique, incorrect or improperly
filled blood collection tubes, delays in sample testing, temperature,
and inadequate sample centrifugation prior to testing.
Some drugs and disease states can also affect test results (Table
2). Increased levels of fibrinogen and factor VIII (both acute
phase reactants) may also reduce the aPTT result, leading to
“heparin resistance.”
Impact of Bolus Dosing
Depending on the size of a heparin bolus, it can affect aPTT values
for more than 6 hours. For example, 4 hours after a 5,000-
unit bolus the aPTT result may suggest adequate heparinization,
but a subsequent aPTT result may show that the continuous
infusion is subtherapeutic. Earlier determination of aPTT value
may be of benefit to determine if a rate increase should occur if
the value is low.
Point-of-Care (POC) Testing
Test results will vary among POC devices and typically do not
match laboratory aPTT results, because of differences in the
sample type, clot-detection method, and incubation period.
There are also differences between ACT manufacturers and cartridge
types. A different ACT test may be used depending on the
desired degree of heparin effect is being followed, which can
vary between methods. Use of high-dose ACT cartridges in
• Preanalytical
• Poor phlebotomy technique!!!!
• Time and temperature (for UFH monitoring, sample should be tested
within 2 hours of collection)
• Centrifugation-platelet poor (300 reagent—Instrument combinations
• No standardization of reagents (despite attempts)
• Reagent variability
• Phospholipid concentration
• Activator type
• Influences on test
• Increases in factor levels-acute phase ( aPTT)
• Decreases in factor levels ( aPTT)
• Drug effect ( or aPTT)
• Lupus anticoagulant (may aPTT)
Table 2. aPTT Test Variables
Anti-Xa monitoring of UFH treatment
Most institutions that measure anti-Xa activity use either a clot
based or a chromogenic method. While this test is more robust
than the aPTT and may be less adversely affected by pre-analytical
variables, test calibration variability and methodology differences
can result in a wide range of anti-Xa levels reported,
(CAP, 2008).
Administration
The most common type of heparin-related error is also the type
most likely to be associated with patient harm—administration
of an improper dose or quantity (Santell, 2008). Pooled data
from 54 hospitals using smart IV pumps revealed that heparin
was the number one drug associated with averted errors, i.e.,
smart pump alerts that resulted in reprogramming. Some
errors, if not averted, would have infused dosages 50- to 100-
times above or below the pre-established drug-library
limits.(Cardinal Health, 2008) Analysis of smart-pump data at a
regional healthcare system showed that 93% of high-risk heparin
errors averted by smart pump use occurred in non-criticalcare
settings (Williams et al., 2006).
A frequent, potentially dangerous practice involves administering
bolus doses from continuous infusions, rather than
preparing a loading dose or subsequent bolus dose in a separate
container such as a syringe or mini-bag. Serious errors can also
occur in calculating dosage changes from an initial loading dose
in units/kg to continuous infusion in units/kg/hr or units/hr.
Unnecessary variability in heparin
concentrations, nomenclature and dosing
units further increases opportunities
for error. A review of smart-pump
drug libraries in 207 hospitals identified
14 different heparin concentrations
being used in various facilities.
Heparin nomenclature also varied
widely, with 191 different namedescriptors
(Bates et al., 2005). Data
from a 54-hospital sample showed that
48% of hospitals had standardized dosing
units on units/kg/hr, 22% used only
units/hr and 30% allowed either
weight-based or non-weight-based
dosing units. When both dosing units
were available, there was a four-fold
increase in smart pump alerts that led
to infusion reprogramming, i.e., averted
errors (Cardinal Health, 2008).
To reduce opportunities for such
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Patient Safety & Quality Healthcare ■ January/February 2009 www.psqh.com

errors, NPSG 3E requires hospitals to standardize heparin concentrations.
NPSG 3E also mandates the use of “ programmable”
infusion pumps, with a strong consensus among
JC advisory panel members that smart pumps should be used
for all heparin infusions (Peterson et al., 2008).
The introduction of barcode label scanning as a new smart
pump-feature allows the manufacturer’s barcode label on a
pre-mixed heparin container to be scanned and the correct
drug and concentration to be automatically selected from the
pump library. Connecting the pumps to the hospital’s wireless
communication system allows rapid uploading of any needed
drug-library changes and frequent downloading of data on
averted programming errors and compliance.
St. Joseph’s/Candler Medical Center in Savannah, Georgia,
has used smart infusion pumps for more than 6 years. Smart
pump continuous quality improvement (CQI) data were analyzed
using a unique Harm Index to determine the potential
harm of averted programming errors. Results showed that heparin
administration in medical/surgical units posed the highest
risk of harm for all IV infusions. To address heparin safety,
the hospital system standardized IV heparin concentrations,
streamlined the dose calculation process, eliminated the need
for nurses and pharmacists to calculate infusion rates, standardized
heparin dosing units, educated providers on revised
dosing protocols (Williams et al., 2006), and implemented an
inpatient anticoagulation management service whereby all
UFH dosing is managed by pharmacy.
Special Cases
Heparin-induced thrombocytopenia (HIT)
HIT is an uncommon but potentially devastating complication
of treatment characterized by a drop in the platelet count to <
100,000/mm3 and/or to < 50% of baseline, typically after 4 to
14 days of heparin or low-molecular weight heparin exposure.
Two other onset patterns, delayed and rapid should also be considered
(Dager et al., 2007). The decrease in platelets is due to
the formation of antibodies that lead to platelet clumping. Activation
of the platelets leads to a hypercoagulable state and
potential for thrombosis. Bleeding secondary to reduced platelet
counts is rare. Failure to discontinue heparin and initiate alternative
anticoagulation will result in thromboembolic complications
in the majority of patients. HIT-probability nomograms
can be used to assess the likelihood that a patient has HIT
(Peterson et al., 2008; Janatapour et al., 2007).
Pediatrics
Heparin errors in the pediatric population have recently been of
notable concern and may be as or more common than in adults.
Children vary greatly in size and weight and require different
drug concentrations and dosage. Dosing in infants is particularly
important, in part because there is little margin for error. Yet
information on optimal drug use and how to adjust infusion or
interpret laboratory data is scant, and support systems such as
computerized physician order entry may be problematic. Chil-
January/February 2009 ■ Patient Safety & Quality Healthcare
23

HEPARIN SAFETY
dren can be more difficult to monitor and often are unable to
provide the sort of feedback that adults can. Additional commitment
to children’s safety is needed at every level of the healthcare
community (Peterson et al., 2008).
Anticoagulation Service
As shown with pharmacists, having an anticoagulation service
to oversee heparin therapy has been associated with a significant
reduction in death, length of stay, cost of therapy, and bleeding
complications (Bond & Raehl, 2004). An effective oversight
team might include the responsible physician, bedside nurse,
pharmacist, and laboratory technician. Overall, good working
relationships need to be fostered among clinical, pharmacy and
laboratory staffs, so that knowledge about heparin therapeuticrange
determinations and coagulation testing is readily shared
and disseminated.
After a series of serious and potentially tragic heparin
errors, Fairview Health Services (FHS), a fully integrated,
seven-hospital health system in the Minneapolis area, conducted
a formal heparin failure mode effects analysis (FMEA)
of the medication management use process. Based on the
FMEA results, an FHS team took a three-pronged approach
to improving heparin safety. This included revised storage
and distribution of heparin, use of pre-typed protocols, a
heparin dosing service, improved drug checking, use of smart
FURTHER INFORMATION
“Improving Heparin Safety,” a recorded webcast by W. E. Dager, R.
C. Gosselin, R. Raschke, and T. Vanderveen, available at
www.cardinalhealth.com/clinicalcenter—click on webcasts.
“Implementing NPSG 3E,” a guide prepared by members of the
Clinical Affairs and the Quality and Regulatory Affairs teams of
Cardinal Health, available at
www.cardinalhealth.com/clinicalcenter—click on NPSG 3E
Resources.
pumps and barcoding, error detection using the anticoagulation
management service, flow sheets, specialized software,
and incorporation of anticoagulant-reversal protocols into
dosing protocols. As a result of these actions, heparin errors
decreased by 42% (Peterson et al., 2008).
A Heparin Error Reduction Workgroup at a large Minnesota
healthcare organization examined heparin administration
procedures, identified types and sources of errors, and developed
solutions to reduce heparin errors. Actions taken based on
human factors analysis included the revision of ambiguous protocols;
use of standardized, more self-explanatory terminology;
improved access to computers and printers; and modification of
the computer interface to guide users through the ordering process
more smoothly. Implementation of these actions reduced
heparin errors by 37.8% (Peterson et al., 2008).
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Patient Safety & Quality Healthcare ■ January/February 2009 www.psqh.com

Summary
While newer parenteral agents now provide preferred alternatives
for anticoagulation, heparin will likely continue to play an
important role in clinical situations where a shorter-acting,
reversible agent is needed, e.g., when bleeding risks are high or
invasive procedures require rapid adjustments in anticoagulation
intensity. Implementation of safety recommendations and other
measures can help to improve safety and heparin therapy, which
can be expected to contribute to improved outcomes. ❙PSQH
William Dager received his doctorate in pharmacy from the
University of California, San Francisco (UCSF), and served his
residency at the University of California, Davis Medical Center
(UCDMC) in Sacramento. He also completed a Nephrology
Pharmaceutical Care Preceptorship at the University of Pittsburgh,
School of Pharmacy. Dager currently holds two academic positions,
one as clinical professor of pharmacy at UCSF School of Pharmacy
and the other as a clinical professor of Medicine at the UCD School of
Medicine. As a clinical specialist at UCDMC he is responsible for
difficult cases in anticoagulation, pharmacokinetics, or other critical
care related situations. He also is clinically active with the cardiology
service.
Dager is a fellow of the California Society of Hospital Pharmacists.
He also currently serves as an instructor and regional affiliate faculty
in ACLS for the American Heart Association and as chair of the
Editorial Advisory Board panel on anticoagulation for the Annals of
Pharmacotherapy. He is also a site coordinator for the ASHP
foundation anticoagulation preceptorship.
Robert Gosselin is a technical coagulation specialist at the
University of California, Davis Health System. He started working in
the coagulation laboratory in 1977, while assigned to the U.S. Naval
Hospital in San Diego. After his naval discharge, he passed the
California boards to become a licensed medical technologist. He has
worked in the U.C. Davis Health System department of pathology
since 1988. Since that time, he has been involved in numerous
research studies, focusing mainly on technical coagulation issues and
the impact of trauma and disease on coagulation. In 1995, he
received board certification from the International Board of Clinical
and Applied Hemostasis, Thrombosis and Vascular Medicine. He has
authored or co-authored more than 50 peer-reviewed publications, 8
distant learning courses, and currently is an active member of the
International Society of Thrombosis and Hemostasis.
Robert Raschke is director of critical care services at Banner Health
in Phoenix, Arizona. He holds a faculty appointment at the University
of Arizona as assistant professor of clinical medicine. He received his
master’s degree from the University of Michigan in clinical research
design and medical biostatistics and is board-certified in Internal
Medicine and Critical Care Medicine.
Tim Vanderveen is vice president of the Center for Safety and
Clinical Excellence. He is responsible for ensuring Cardinal Health’s
commitment to education and innovation to reduce variation in
clinical practice, and to supporting hospitals’ patient safety initiatives.
Prior to this position, Vanderveen was the director of clinical affairs,
medication management systems, for ALARIS Medical Systems. He
has been instrumental in the development of many of the innovations
and safety and performance enhancements in drug infusion.
Vanderveen served a hospital pharmacy residency at Bronson
Methodist Hospital in Kalamazoo, Michigan. From 1972 to1983 he
was on the faculty of the College of Pharmacy at Medical University
of South Carolina and was Director of the Division of Clinical
Pharmacy. He also had a faculty appointment in the College of
Medicine and was on staff at the Charleston VA Hospital.Vanderveen
received his BS and MS degrees from Purdue University School of
Pharmacy and his PharmD degree from the Medical University of
South Carolina. He may be contacted at
tim.vanderveen@cardinal.com.
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