Key Points

  • Use of LMWH is associated with a lower risk of HIT and HITT compared with use of UFH.

  • The Avoid-Heparin Initiative resulted in a dramatic reduction in the burden of suspected HIT, adjudicated HIT, HITT, and associated costs.

Abstract

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction occurring in up to 5% of patients exposed to unfractionated heparin (UFH). We examined the impact of a hospital-wide strategy for avoiding heparin on the incidence of HIT, HIT with thrombosis (HITT), and HIT-related costs. The Avoid-Heparin Initiative, implemented at a tertiary care hospital in Toronto, Ontario, Canada, since 2006, involved replacing UFH with low-molecular-weight heparin (LMWH) for prophylactic and therapeutic indications. Consecutive cases with suspected HIT from 2003 through 2012 were reviewed. Rates of suspected HIT, adjudicated HIT, and HITT, along with HIT-related expenditures were compared in the pre-intervention (2003-2005) and the avoid-heparin (2007-2012) phases. The annual rate of suspected HIT decreased 42%, from 85.5 per 10 000 admissions in the pre-intervention phase to 49.0 per 10 000 admissions in the avoid-heparin phase (P < .001). The annual rate of patients with a positive HIT assay decreased 63% from 16.5 to 6.1 per 10 000 admissions (P < .001), adjudicated HIT decreased 79% from 10.7 to 2.2 per 10 000 admissions (P < .001), and HITT decreased 91% from 4.6 to 0.4 per 10 000 admissions (P < .001). Hospital HIT-related expenditures decreased by $266 938 per year in the avoid-heparin phase. To the best of our knowledge, this is the first study demonstrating the success and feasibility of a hospital-wide HIT prevention strategy.

Introduction

Heparin-induced thrombocytopenia (HIT) is a transient, limb- and life-threatening, immune-mediated adverse drug reaction in patients exposed to heparin. HIT is characterized by immunoglobulin G antibodies against platelet factor 4 (PF4)-heparin complexes which trigger a highly prothrombotic state through intravascular platelet aggregation, intense platelet activation, and excessive thrombin generation.1  The diagnosis of HIT is based on a significant decrease in the platelet count with or without venous or arterial thrombosis combined with serologic evidence of HIT antibodies in patients exposed to unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH).2-4  Treatment of HIT involves discontinuing all forms of heparin and administering an alternative nonheparin anticoagulant.4 

HIT occurs in up to 5% of patients exposed to UFH, one of the drugs most commonly prescribed to hospital patients.5-7  The recognition and evaluation of suspected HIT is often delayed.4,6,8,9  Even with prompt cessation of heparin and implementation of a HIT-safe anticoagulant, thromboembolic complications occur in 20% to 50% of patients, and death or limb amputation occurs in approximately 5% to 10%.4,8,10-14  In addition to the significant disease burden, HIT is associated with substantial resource use. An economic analysis study from our center reported that the direct costs to the hospital for HIT were $456 787 over a 1-year period.15 

Although improved surveillance and management may reduce the burden of HIT, comprehensive initiatives to prevent HIT are likely to be more effective in decreasing the morbidity, mortality, and costs associated with HIT. It is well established that LMWH is associated with a five- to 10-fold lower risk of HIT than UFH.16-21  Furthermore, thrombosis is less likely to occur when HIT is triggered by LMWH than by UFH.21  Therefore, reducing patient exposure to UFH and substituting LMWH for UFH may improve patient safety related to HIT. The aim of this quality improvement study was to evaluate the impact of an avoid-heparin intervention on the incidence of HIT, its clinical consequences, and associated costs over a 10-year period.

Methods

Study setting

In 2005, a multidisciplinary committee was created to develop strategies to reduce the burden of HIT at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada. Sunnybrook is a tertiary care university-affiliated hospital with more than 450 adult acute care beds, a large cardiac surgery program, and a thromboembolism service that manages all cases of established HIT. The intervention selected was an institution-wide, avoid-heparin program that was implemented during 2006. The components of this program included (1) systematic replacement of most intravenous and subcutaneous UFH with subcutaneous LMWH in prophylactic or therapeutic doses (the remaining uses of UFH were for hemodialysis, intraoperative use for cardiovascular surgery, and for some patients with acute coronary syndrome), (2) replacement of heparinized saline in arterial and central venous lines with saline flushes, (3) modification of order sets to exclude UFH options, and (4) removal of UFH stores from most nursing units.

Most care providers were not aware that heparin was being replaced by LMWH as part of an avoid-heparin initiative, and none were aware that this practice change was being studied. There were also no efforts to educate staff about HIT nor were there any changes in the approach to its diagnosis.

Consecutive inpatients with a clinical suspicion of HIT who underwent enzyme-linked immunosorbent assay (ELISA) testing for PF4-heparin antibodies from January 1, 2003, to December 31, 2012, were identified through the Special Coagulation Laboratory database. A confirmatory serotonin release assay (SRA), which was performed at McMaster University, was ordered at the discretion of the patient’s attending physician or consultant service. Electronic and paper medical records were reviewed for demographic and clinical data in all patients with a positive HIT ELISA. The incidence and complications of HIT and associated costs were compared in the pre-intervention phase (2003-2005) and the avoid-heparin phase (2007-2012). Because the avoid-heparin intervention was implemented over the year 2006, cases during this year were excluded from all comparisons. This study was approved by the research ethics board of Sunnybrook Health Sciences Centre.

Case definitions

Explicit definitions of the various study groups were established a priori (supplemental Table 1, available on the Blood Web site). Suspected HIT was defined as a clinical suspicion of HIT with a HIT ELISA performed. A positive HIT ELISA was defined as a HIT ELISA optical density (OD) ≥0.4. Patients with a positive HIT ELISA who were excluded were those who underwent follow-up testing for a previously positive HIT assay, those whose heparin exposure occurred exclusively as an outpatient or at another hospital, and those who had no documented heparin exposure despite an extensive search. The following data were abstracted: demographic information, admitting service, duration and type of heparin exposures, date of suspected HIT, presence of HIT-related complications, and length of hospital stay.

All patients with a positive HIT ELISA were adjudicated by the investigators who used information available in the medical record. Adjudicated HIT was defined as suspected HIT with (1) positive SRA or (2) positive HIT ELISA, SRA not done, and diagnosed and treated as HIT by the thromboembolism service at the time of the suspected HIT and confirmed at the independent adjudication review by using standardized criteria outlined in supplemental Table 1. HIT negative was defined as suspected HIT with (1) negative HIT ELISA, (2) negative SRA, or (3) positive HIT ELISA, SRA not done, but not diagnosed with or treated as HIT by the thromboembolism service at the time of suspected HIT and also classified as HIT negative during adjudication review.

Cases were labeled HIT uncertain if the HIT ELISA was positive but the diagnosis could not be confirmed or ruled out at adjudication. In the small number of cases with a positive HIT ELISA that were not seen by the thromboembolism service or when the adjudication process yielded a different HIT status for a patient than that made at the time of clinical suspicion, the case was re-reviewed, and consensus among investigators was used based on the diagnostic criteria in supplemental Table 1. HIT with thrombosis (HITT) was defined as HIT positive with proven venous and/or arterial thrombosis less than 7 days before or up to 30 days after the date of suspected HIT. For thrombotic events that occurred less than 7 days before the date of suspected HIT, each case was carefully reviewed to determine the probable sequence of events. Patients with thromboembolism prior to heparin exposure who subsequently developed HIT were not labeled as HITT. Major bleeding was defined as overt bleeding in a patient who was receiving a HIT-safe anticoagulant and who met at least one of the following criteria: required 2 or more units of packed red blood cells, had prolonged hospital admission, had fatal or life-threatening bleeding at a critical site such as intracranial or retroperitoneal, or had bleeding that required an intervention such as endoscopic or endovascular treatment or surgery.22 

Anti-PF4-heparin HIT ELISA

Throughout the study period, the Special Coagulation Laboratory detected polyspecific PF4-heparin antibodies by using the Genetic Testing Institute PF4 ELISA (GTI Diagnostics, Waukesha, WI).23  An OD value of ≥0.4 was used as the threshold for a positive test as suggested by the manufacturer and locally validated by the laboratory.

Outcomes

The rates of suspected HIT, positive HIT ELISA, adjudicated HIT, and HITT in the pre-intervention and the avoid-heparin phases were compared. Annual rates per 10 000 admissions were determined by using admission data from the Health Data Resources Department. The additional costs for suspected HIT, adjudicated HIT, and HITT were based on a published cost-analysis done at our institution and the observed events in this study.15  HIT-related costs in the pre-intervention phase were compared with those in the avoid-heparin phase.

Statistical analyses

Statistical analyses were performed with SPSS 16.0 (SPSS, Chicago, IL). Continuous variables were summarized as medians with interquartile ranges (IQRs) because of non-normal distributions. The Mann-Whitney U test was used to detect differences in continuous variables, and the Pearson χ2 test or Fisher’s exact test was used to detect differences between categorical variables. All tests were two sided, and P < .05 was accepted as statistically significant.

Results

Suspected HIT, positive HIT ELISA, adjudicated HIT, and HITT

From 2003 to 2012, there were 1118 cases of suspected HIT. Among these, 175 patients (16%) had a positive HIT ELISA. An additional 16 patients with a positive HIT ELISA were excluded because they received heparin exclusively as an outpatient or at another institution (10), there was no documented heparin exposure (2), the HIT assay was ordered for a clinical trial (2), or it was performed in error (1), or for previous HIT (1). Among the 175 patients with a positive HIT ELISA, 89 (51%) were adjudicated HIT positive, 84 (48%) HIT negative and, in two cases, the HIT status remained uncertain after adjudication. An SRA was performed in 40% of patients (70 of 175) with a positive HIT ELISA (supplemental Table 2). Among the 84 patients adjudicated as HIT negative, 46 (55%) had a negative SRA, 37 (44%) did not have an SRA performed, 1 had an SRA reported as equivocal, and none had a positive SRA. Among the 37 patients adjudicated HIT negative who did not have an SRA performed, only 5 had a HIT ELISA OD >1.0. A HIT ELISA OD ≥1.0 was observed in 75 patients (84%) with adjudicated HIT compared with 16 patients (19%) with a positive HIT ELISA who were adjudicated HIT negative (P < .001). Over the 10-year period, 31 patients (35%) with adjudicated HIT developed HITT. In 10 of these patients, the thromboembolic event occurred 1 to 5 days before the diagnosis of HIT and 4 were diagnosed with thromboembolism and HIT on the same day.

Comparison of the pre- and postintervention periods

There were 424 patients with suspected HIT in the pre-intervention phase and 576 patients with suspected HIT in the avoid-heparin phase. The annual incidence of suspected HIT cases per 10 000 admissions decreased from 85.5 in the pre-intervention phase to 49.0 in the avoid-heparin phase (relative risk reduction [RRR], 41.7%; P < .001; Figure 1). The annual incidence of patients with a positive HIT ELISA decreased from 16.5 to 6.1 per 10 000 admissions in the pre-intervention and avoid-heparin phases, respectively (RRR, 62.9%; P < .001; Figure 1), and corresponding rates of patients with a HIT ELISA ≥1.0 decreased from 10.1 to 2.5 per 10 000 admissions (RRR, 75.1%; P < .001). The annual incidence of adjudicated HIT cases decreased from 10.7 to 2.2 per 10 000 admissions in the pre-intervention and avoid-heparin phase (RRR, 79.0%; P < .001), and HITT decreased from 4.6 to 0.4 per 10 000 admissions (RRR, 90.7%; P < .001; Figure 1). The annual rates of HIT and HITT over the study period are shown in Figure 2.

Figure 1

Annual incidence of suspected HIT, positive HIT assay, adjudicated HIT, and HITT per 10 000 admissions, 2003-2005 and 2007-2012. *P < .001 for each comparison.

Figure 1

Annual incidence of suspected HIT, positive HIT assay, adjudicated HIT, and HITT per 10 000 admissions, 2003-2005 and 2007-2012. *P < .001 for each comparison.

Figure 2

Annual incidence of adjudicated HIT and HITT, 2003-2012.

Figure 2

Annual incidence of adjudicated HIT and HITT, 2003-2012.

Demographic and clinical characteristics of HIT-positive patients in the pre-intervention phase (n = 53) and the avoid-heparin phase (n = 26) were similar (Table 1). Approximately 60% of patients with HIT in both phases were admitted under the cardiovascular surgery service. The durations of UFH and/or LMWH exposure and median lengths of hospital stay were similar between the groups. The median HIT ELISA OD among patients with HIT was significantly higher in the avoid-heparin phase (2.79; IQR, 1.76-2.89) compared with the pre-intervention phase (2.07; IQR, 1.21-2.40; P = .001). Whereas the overall use of LMWH increased fourfold (based on doses purchased) over the study period, the annual rate of HIT associated with LMWH remained constant at 0.9 cases per 10 000 admissions in the pre-intervention and avoid-heparin phases (P = .78; Figure 3). There were no significant differences in patient age, sex, duration of UFH or LMWH exposure, or length of hospital stay among patients with HIT exposed to UFH compared with LMWH (supplemental Table 3). HIT was reduced 77% in cardiovascular surgery, 77% in other surgery, 75% in cardiology patients, and 62% in medical patients (supplemental Figure 1).

Table 1

Characteristics of patients with HIT in pre-intervention and avoid-heparin phases

Characteristic Pre-intervention phase, 2003-2005 (n = 53) No. (%)* Avoid-heparin phase, 2007-2012 (n = 26) No. (%)* P 
Median age, years (IQR) 68 (60-74) 72 (61-78) .280 
Female 30 (57) 10 (38) .130 
Primary admitting service   .950 
 Cardiovascular surgery 32 (60) 15 (58)  
 Other surgical service 13 (24) 6 (23)  
 Cardiology 4 (8) 2 (8)  
 Medicine 4 (8) 3 (11)  
Median duration of UFH or LMWH exposure before the diagnosis of HIT, days (IQR) 10 (8-12) 11 (8-13) .526 
Median HIT ELISA OD (IQR) 2.07 (1.21-2.40) 2.79 (1.76-2.89) .001 
HIT ELISA OD   .123 
 <1.0 11 
 1.0-2.0 15 
 >2.0 27 18 
Median total length of stay, days (IQR)† 24 (17-42) 21 (14-28) .224 
Median length of stay after HIT suspected, days (IQR)‡ 14 (7-26) 9 (6-20) .198 
Characteristic Pre-intervention phase, 2003-2005 (n = 53) No. (%)* Avoid-heparin phase, 2007-2012 (n = 26) No. (%)* P 
Median age, years (IQR) 68 (60-74) 72 (61-78) .280 
Female 30 (57) 10 (38) .130 
Primary admitting service   .950 
 Cardiovascular surgery 32 (60) 15 (58)  
 Other surgical service 13 (24) 6 (23)  
 Cardiology 4 (8) 2 (8)  
 Medicine 4 (8) 3 (11)  
Median duration of UFH or LMWH exposure before the diagnosis of HIT, days (IQR) 10 (8-12) 11 (8-13) .526 
Median HIT ELISA OD (IQR) 2.07 (1.21-2.40) 2.79 (1.76-2.89) .001 
HIT ELISA OD   .123 
 <1.0 11 
 1.0-2.0 15 
 >2.0 27 18 
Median total length of stay, days (IQR)† 24 (17-42) 21 (14-28) .224 
Median length of stay after HIT suspected, days (IQR)‡ 14 (7-26) 9 (6-20) .198 
*

Values are No. (%) unless otherwise indicated.

Date of admission to date of discharge.

Date HIT was first suspected to date of discharge.

Figure 3

Incidence of UFH- and LMWH-associated HIT cases per 10 000 admissions per year, 2003-2012.P < .001 for UFH-associated HIT time trends and P = .78 for LMWH-associated HIT time trends.

Figure 3

Incidence of UFH- and LMWH-associated HIT cases per 10 000 admissions per year, 2003-2012.P < .001 for UFH-associated HIT time trends and P = .78 for LMWH-associated HIT time trends.

Comparison of HIT with and without thrombosis

Patients with HIT in the pre-intervention phase more frequently developed HITT (43%) than patients with HIT in the avoid-heparin phase (19%; P = .035; Table 2). The most frequently observed HIT complication in both phases was venous thromboembolism. The median length of stay from date of suspected HIT to discharge among patients with HITT was 22 days (IQR, 13-44 days) compared with 8 days (IQR, 6-14 days) for patients with HIT without thrombosis (P < .001). Over the entire study period, the HIT ELISA OD values were similar among patients with HIT without thrombosis (median OD, 1.96; IQR, 1.24-2.74) and those with HITT (median OD, 2.34; IQR, 1.86-2.70; P = .157).

Table 2

Complications associated with HIT in pre-intervention and avoid-heparin phases

Specific complications* Pre-intervention phase (n = 53) No. (%) Avoid-heparin phase (n = 26) No. (%) 
HITT† 23 (43.4) 5 (19.2) 
Venous thromboembolism 20 
 DVT or PE 17 
 Adrenal vein thrombosis 
Arterial thromboembolism 
 Leg ischemia 
 Leg ischemia with amputation 
 Acute bowel ischemia 
Transient global amnesia 
Death related to HIT 
Major bleeding on treatment of HITT 
Specific complications* Pre-intervention phase (n = 53) No. (%) Avoid-heparin phase (n = 26) No. (%) 
HITT† 23 (43.4) 5 (19.2) 
Venous thromboembolism 20 
 DVT or PE 17 
 Adrenal vein thrombosis 
Arterial thromboembolism 
 Leg ischemia 
 Leg ischemia with amputation 
 Acute bowel ischemia 
Transient global amnesia 
Death related to HIT 
Major bleeding on treatment of HITT 
*

Four patients in the pre-intervention phase and no patients in the avoid-heparin phase had more than 1 thromboembolic complication.

P = .035.

Patient age, sex, admitting service, exposure to LMWH only, duration of heparin exposure, and alternative anticoagulant use were similar among patients with HITT and those with HIT without thrombosis (supplemental Table 4).

HIT-related treatment and costs

The mean number of suspected HIT cases per year decreased from 141.3 in the pre-intervention phase to 96.0 in the avoid-heparin phase (supplemental Table 5). The mean number of patients per year with a positive HIT ELISA, adjudicated HIT, and HITT per year decreased from 27.3 to 11.8, 17.7 to 4.3, and 7.7 to 0.8, respectively, in the pre-intervention and avoid-heparin phases. HIT was treated with lepirudin and danaparoid more frequently in the pre-intervention phase whereas fondaparinux and argatroban were used more frequently in the avoid-heparin phase (supplemental Table 6). On the basis of a published study from our institution,15  the average estimated costs of HIT care per year were reduced by $266 938, from $322 321 in the pre-intervention phase to $55 383 in the avoid-heparin phase, using 2007 Canadian dollars (Table 3).

Table 3

Estimated costs associated with HIT care in pre-intervention and avoid-heparin phases

 Additional costs/case ($)* Pre-intervention phase, 2003-2005 Avoid-heparin phase, 2007-2012 
Cases/year Cost/year ($) Cases/year Cost/year ($) 
HIT negative 119 123.7 14 716 91.7 10 908 
HIT without thrombosis 4 575 10.0 45 750 3.5 16 012 
HITT 34 155 7.7 261 855 0.8 28 462 
Total   322 321  55 383 
 Additional costs/case ($)* Pre-intervention phase, 2003-2005 Avoid-heparin phase, 2007-2012 
Cases/year Cost/year ($) Cases/year Cost/year ($) 
HIT negative 119 123.7 14 716 91.7 10 908 
HIT without thrombosis 4 575 10.0 45 750 3.5 16 012 
HITT 34 155 7.7 261 855 0.8 28 462 
Total   322 321  55 383 

Costs are given in 2007 Canadian dollars.

*

From a cost-of-illness study performed at Sunnybrook Health Sciences Centre.15 

Discussion

Following the implementation of a hospital-wide quality improvement program based on replacing UFH with LMWH, we observed a dramatic reduction in the burden of HIT with a 42% decrease in suspected HIT, 63% decrease in patients with positive HIT ELISA, 79% decrease in adjudicated HIT, 91% decrease in HITT, and 83% decrease in HIT-related costs of care. Although the greatest overall impact of the program was in cardiac surgery, the HIT burden was also reduced in other surgical and medical patients. The heparin avoidance strategy that we used was not complex or costly and would be feasible in other centers.

A lower risk of HIT and its thrombotic complications among patients exposed to LMWH compared with UFH has been previously demonstrated.7,16-21  LMWH is thought to induce a less robust antibody response when complexed to PF4 than observed with UFH-PF4 because of stoichiometric differences of heparin-PF4 complexes.24  Despite the fourfold increase in use of LMWH over the study period, the incidence of HIT in patients who received LMWH was low and remained stable over the 10-year study period. Others have also demonstrated stable rates of HIT despite substantial increases in LMWH use.7,25  Our results expand on observations from studies with limited target groups and focused interventions. Replacement of UFH with LMWH in orthopedic surgery has been shown to reduce both venous thromboembolism and HIT.26 

The literature has emphasized early recognition and treatment of HIT, but its prevention has been largely overlooked.27  Guidelines recommend platelet count monitoring for patients receiving heparin who have a HIT risk greater than 1%.4  However, adherence to platelet count monitoring, testing for HIT antibodies if thrombocytopenia develops, and switching to HIT-safe anticoagulation when HIT is suspected is challenging, resource intensive, and may not reduce the adverse consequences of HIT.6,9,28-30  Previous studies have demonstrated that more than half the thrombotic events in HIT occur after the cessation of heparin without additional treatment of HIT.8,11  In our study, we observed that more than half the HITT cases (17 of 31) had the thromboembolic event diagnosed after the diagnosis of HIT and while they were receiving HIT-safe anticoagulation, which emphasizes not only the need for early recognition and treatment but also the need to prevent HIT. We observed that patients with HIT in the avoid-heparin phase were 2 times less likely to develop HITT. A previous study from our center demonstrated that the incremental hospital cost of suspected and confirmed cases of HIT was $456 787 over a 1-year period, and 90% of these costs were attributed to HITT.15  Together, these findings suggest that a hospital-wide, avoid-heparin program leads to a substantial reduction in the morbidity, mortality, and institutional costs associated with HIT.

Consistent with published literature, the positive predictive value of the HIT assay was 51% (89 of 175) over the entire study period.31,32  Among the 84 patients with a HIT ELISA OD between 0.4 and 1.0, only 17% were found to have HIT. False-positive HIT assays were found with OD values as high as 2.4, emphasizing that HIT cannot be diagnosed by laboratory evidence alone.4,33  The median HIT ELISA OD in patients with HIT was higher in the avoid-heparin phase than the pre-intervention phase (2.79 vs 2.07, respectively; Table 1). Because the likelihood of true HIT increases with increasing OD, this could suggest that there were more false-positive diagnoses in the pre-intervention phase. Recently, Chan et al34  reported that the HIT ELISA OD cutoff could be increased from 0.4 to 1.00 to improve the positive predictive value without losing sensitivity.

This study has limitations that warrant consideration. It was conducted at a single tertiary care hospital whose HIT-related practices may differ from those of other centers. Because there is no reference standard for the diagnosis of HIT and because only 40% of patients with a positive HIT ELISA had an SRA, we cannot determine the accuracy of our case allocation in all patients. However, the observations in this study were based on a review of all cases with suspected HIT over a 10-year period and therefore reflect routine clinical practice. We attempted to minimize potential bias in adjudication of HIT by establishing case definitions a priori. In only 5 cases did the final case allocation after adjudication differ from that made by the clinical team at the time of suspected HIT. Although this study’s findings are based on a prospective quality improvement project, patient data were abstracted, and cases were adjudicated retrospectively. This could have led to possible bias in case definition by the investigators. We were unable to calculate the 4Ts score for patients with suspected HIT retrospectively.35,36  However, patient characteristics in the pre-intervention and avoid-heparin phases were similar, and we were unable to identify any other factors that could have accounted for the dramatic reductions in suspected HIT, adjudicated HIT, and HITT during the study period. The long duration of observation showing a sudden and sustained reduction in HIT after implementation of the avoid-heparin strategy was designed to demonstrate that this was not a random observation. Finally, we were unable to determine hospital-wide, patient-level data on exposures to UFH and LMWH; however, LMWH use increased more than fourfold on the basis of overall changes in drug use over the study period. Clearly, the cost reductions we observed are specific to our center and will differ in other centers, depending on overall HIT burden and the local costs of investigating and treating HIT.

Our findings cannot be explained by an overall reduction in the number of admissions or length of stay over the study period. In fact, total patient admissions increased 21% whereas the mean length of stay decreased only 9% over the study period. The decision to test each patient was at the discretion of the patient’s clinical service and was not influenced by the investigators or the thromboembolism team. Moreover, the greater reduction in cases of HIT (79%) and HITT (91%) than in suspected HIT (42%) suggests a decrease in the actual disease burden rather than a biased increase in diagnostic threshold (Figure 1). The temporal pattern of this study’s findings show that the reduction in HIT was not gradual but occurred in 2006 and was maintained beyond the intervention year (Figure 2), suggesting that it is unlikely that secular trends in decreased use of UFH could explain these findings. The study’s observations can also not be accounted for by use of direct oral anticoagulants because rivaroxaban was approved only for hip and knee arthroplasty thromboprophylaxis in 2009 and dabigatran was approved for atrial fibrillation in 2011.

In conclusion, the introduction of a hospital-wide, avoid-heparin program led to a dramatic decrease in the burden of suspected HIT, diagnosed HIT, and HITT, as well as in the costs of HIT care. To the best of our knowledge, this is the first study demonstrating the success of a HIT prevention strategy. Our findings suggest that a highly feasible heparin avoidance intervention can improve patient safety and reduce hospital costs.

The online version of this article contains a data supplement.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Authorship

Contribution: W.G. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis; W.G., C.B., A.D., and R.S. developed the study concept and design; W.G., K.E.M., J.M., A.D., C.B., and P.R. acquired the data; W.G., K.E.M., J.M., A.D., C.B., and R.S. analyzed and interpreted the data; W.G., K.E.M., J.M., A.D., and C.B. drafted the manuscript; all authors critically revised the manuscript; and W.G., J.M., A.D., C.B., and R.S. provided administrative, technical, and material support.

Conflict-of-interest disclosure: J.M. received financial support from Bayer Healthcare for an institutional fellowship. A.D. was supported by a hospital account that had contributions from the Canadian Patient Safety Institute and Sanofi, consulted for Leo Pharma and Sanofi, served on an advisory board for Sanofi, and received support for educational activities from Bayer Healthcare, Leo Pharma, Pfizer, and Sanofi. C.B. received support for educational activities from AstraZeneca and Bayer Healthcare, consulted for AstraZeneca, Bayer Healthcare, Bristol-Myers Squibb, and Pfizer, and served on an advisory board for AstraZeneca, Bristol-Myers Squibb, and Pfizer. P.R. was supported by an unrestricted educational grant for a studentship from Bayer Healthcare. R.S. was supported by a grant from Boehringer-Ingelheim, consulted for Instrumentation Laboratories, and was supported by Bristol-Myers Squibb and Pfizer for educational activities. W.G. received partial salary support from a hospital account that had contributions from the Canadian Patient Safety Institute and Sanofi, consulted for Bayer Healthcare, Boehringer-Ingelheim, Leo Pharma, Pfizer, Janssen, Bristol-Myers Squibb, and Sanofi, and received support for educational activities from Bayer Healthcare, Boehringer-Ingelheim, Leo Pharma, Pfizer, GlaxoSmithKline, and Sanofi. The remaining author declares no competing financial interests.

Correspondence: William Geerts, Sunnybrook Health Sciences Centre, University of Toronto, Room D674, 2075 Bayview Ave, Toronto, ON, Canada M4N 3M5; e-mail: william.geerts@sunnybrook.ca.

References

References
1
Greinacher
A
CLINICAL PRACTICE. Heparin-Induced Thrombocytopenia.
N Engl J Med
2015
, vol. 
373
 
3
(pg. 
252
-
261
)
2
Warkentin
TE
Kelton
JG
Temporal aspects of heparin-induced thrombocytopenia.
N Engl J Med
2001
, vol. 
344
 
17
(pg. 
1286
-
1292
)
3
Warkentin
TE
Roberts
RS
Hirsh
J
Kelton
JG
An improved definition of immune heparin-induced thrombocytopenia in postoperative orthopedic patients.
Arch Intern Med
2003
, vol. 
163
 
20
(pg. 
2518
-
2524
)
4
Linkins
LA
Dans
AL
Moores
LK
, et al. 
 
Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e495S-e530S
5
Crespo
EM
Oliveira
GB
Honeycutt
EF
, et al. 
CATCH Registry Investigators
Evaluation and management of thrombocytopenia and suspected heparin-induced thrombocytopenia in hospitalized patients: The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry.
Am Heart J
2009
, vol. 
157
 
4
(pg. 
651
-
657
)
6
Cuker
A
Cines
DB
How I treat heparin-induced thrombocytopenia.
Blood
2012
, vol. 
119
 
10
(pg. 
2209
-
2218
)
7
Zhou
A
Winkler
A
Emamifar
A
, et al. 
Is the incidence of heparin-induced thrombocytopenia affected by the increased use of heparin for VTE prophylaxis?
Chest
2012
, vol. 
142
 
5
(pg. 
1175
-
1178
)
8
Warkentin
TE
Kelton
JG
A 14-year study of heparin-induced thrombocytopenia.
Am J Med
1996
, vol. 
101
 
5
(pg. 
502
-
507
)
9
Tafur
AJ
McBane
RD
II
Wysokinski
WE
Gregg
MS
Daniels
PR
Mohr
DN
Natural language processor as a tool to assess heparin induced thrombocytopenia awareness.
J Thromb Thrombolysis
2012
, vol. 
33
 
1
(pg. 
95
-
100
)
10
Nand
S
Wong
W
Yuen
B
Yetter
A
Schmulbach
E
Gross Fisher
S
Heparin-induced thrombocytopenia with thrombosis: incidence, analysis of risk factors, and clinical outcomes in 108 consecutive patients treated at a single institution.
Am J Hematol
1997
, vol. 
56
 
1
(pg. 
12
-
16
)
11
Wallis
DE
Workman
DL
Lewis
BE
Steen
L
Pifarre
R
Moran
JF
Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia.
Am J Med
1999
, vol. 
106
 
6
(pg. 
629
-
635
)
12
Warkentin
TE
Sheppard
JA
Horsewood
P
Simpson
PJ
Moore
JC
Kelton
JG
Impact of the patient population on the risk for heparin-induced thrombocytopenia.
Blood
2000
, vol. 
96
 
5
(pg. 
1703
-
1708
)
13
Lewis
BE
Wallis
DE
Leya
F
Hursting
MJ
Kelton
JG
Argatroban-915 Investigators
Argatroban anticoagulation in patients with heparin-induced thrombocytopenia.
Arch Intern Med
2003
, vol. 
163
 
15
(pg. 
1849
-
1856
)
14
Pearson
MA
Nadeau
C
Blais
N
Correlation of ELISA optical density with clinical diagnosis of heparin-induced thrombocytopenia: a retrospective study of 104 patients with positive anti-PF4/heparin ELISA.
Clin Appl Thromb Hemost
2014
, vol. 
20
 
4
(pg. 
349
-
354
)
15
Nanwa
N
Mittmann
N
Knowles
S
, et al. 
The direct medical costs associated with suspected heparin-induced thrombocytopenia.
Pharmacoeconomics
2011
, vol. 
29
 
6
(pg. 
511
-
520
)
16
Martel
N
Lee
J
Wells
PS
Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.
Blood
2005
, vol. 
106
 
8
(pg. 
2710
-
2715
)
17
Warkentin
TE
Sheppard
JA
Sigouin
CS
Kohlmann
T
Eichler
P
Greinacher
A
Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia.
Blood
2006
, vol. 
108
 
9
(pg. 
2937
-
2941
)
18
Lubenow
N
Hinz
P
Thomaschewski
S
, et al. 
The severity of trauma determines the immune response to PF4/heparin and the frequency of heparin-induced thrombocytopenia.
Blood
2010
, vol. 
115
 
9
(pg. 
1797
-
1803
)
19
Bucci
C
Geerts
WH
Sinclair
A
Fremes
SE
Comparison of the effectiveness and safety of low-molecular weight heparin versus unfractionated heparin anticoagulation after heart valve surgery.
Am J Cardiol
2011
, vol. 
107
 
4
(pg. 
591
-
594
)
20
Falvo
N
Bonithon-Kopp
C
Rivron Guillot
K
, et al. 
RIETE Investigators
Heparin-associated thrombocytopenia in 24,401 patients with venous thromboembolism: findings from the RIETE Registry.
J Thromb Haemost
2011
, vol. 
9
 
9
(pg. 
1761
-
1768
)
21
Junqueira
DR
Perini
E
Penholati
RR
Carvalho
MG
Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients.
Cochrane Database Syst Rev
2012
, vol. 
9
 pg. 
CD007557
 
22
Schulman
S
Angerås
U
Bergqvist
D
Eriksson
B
Lassen
MR
Fisher
W
Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis
Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.
J Thromb Haemost
2010
, vol. 
8
 
1
(pg. 
202
-
204
)
23
Bakchoul
T
Giptner
A
Najaoui
A
Bein
G
Santoso
S
Sachs
UJ
Prospective evaluation of PF4/heparin immunoassays for the diagnosis of heparin-induced thrombocytopenia.
J Thromb Haemost
2009
, vol. 
7
 
8
(pg. 
1260
-
1265
)
24
Greinacher
A
Alban
S
Omer-Adam
MA
Weitschies
W
Warkentin
TE
Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings.
Thromb Res
2008
, vol. 
122
 
2
(pg. 
211
-
220
)
25
Jenkins
I
Helmons
PJ
Martin-Armstrong
LM
Montazeri
ME
Renvall
M
High rates of venous thromboembolism prophylaxis did not increase the incidence of heparin-induced thrombocytopenia.
Jt Comm J Qual Patient Saf
2011
, vol. 
37
 
4
(pg. 
163
-
169
)
26
Greinacher
A
Eichler
P
Lietz
T
Warkentin
TE
Replacement of unfractionated heparin by low-molecular-weight heparin for postorthopedic surgery antithrombotic prophylaxis lowers the overall risk of symptomatic thrombosis because of a lower frequency of heparin-induced thrombocytopenia.
Blood
2005
, vol. 
106
 
8
(pg. 
2921
-
2922
)
27
Smythe
MA
Koerber
JM
Mehta
TP
, et al. 
Assessing the impact of a heparin-induced thrombocytopenia protocol on patient management, outcomes and cost.
Thromb Haemost
2012
, vol. 
108
 
5
(pg. 
992
-
998
)
28
Riggio
JM
Cooper
MK
Leiby
BE
Walenga
JM
Merli
GJ
Gottlieb
JE
Effectiveness of a clinical decision support system to identify heparin induced thrombocytopenia.
J Thromb Thrombolysis
2009
, vol. 
28
 
2
(pg. 
124
-
131
)
29
ten Berg
MJ
van den Bemt
PM
Huisman
A
Schobben
AF
Egberts
TC
van Solinge
WW
Compliance with platelet count monitoring recommendations and management of possible heparin-induced thrombocytopenia in hospitalized patients receiving low-molecular-weight heparin.
Ann Pharmacother
2009
, vol. 
43
 
9
(pg. 
1405
-
1412
)
30
Rogers
BA
Cowie
AS
The monitoring of heparin induced thrombocytopenia following surgery: an audit and international survey.
J Perioper Pract
2010
, vol. 
20
 
2
(pg. 
66
-
69
)
31
Lo
GK
Sigouin
CS
Warkentin
TE
What is the potential for overdiagnosis of heparin-induced thrombocytopenia?
Am J Hematol
2007
, vol. 
82
 
12
(pg. 
1037
-
1043
)
32
Warkentin
TE
Sheppard
JI
Moore
JC
Sigouin
CS
Kelton
JG
Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays.
J Thromb Haemost
2008
, vol. 
6
 
8
(pg. 
1304
-
1312
)
33
Raschke
RA
Curry
SC
Warkentin
TE
Gerkin
RD
Improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem.
Chest
2013
, vol. 
144
 
4
(pg. 
1269
-
1275
)
34
Chan
CM
Woods
CJ
Warkentin
TE
Sheppard
JA
Shorr
AF
The Role for Optical Density in Heparin-Induced Thrombocytopenia: A Cohort Study.
Chest
2015
, vol. 
148
 
1
(pg. 
55
-
61
)
35
Lo
GK
Juhl
D
Warkentin
TE
Sigouin
CS
Eichler
P
Greinacher
A
Evaluation of pretest clinical score (4 T’s) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings.
J Thromb Haemost
2006
, vol. 
4
 
4
(pg. 
759
-
765
)
36
Cuker
A
Gimotty
PA
Crowther
MA
Warkentin
TE
Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis.
Blood
2012
, vol. 
120
 
20
(pg. 
4160
-
4167
)

Author notes

*

K.E.M., J.M., A.D., C.B., and W.G. contributed equally to this work.