Abstract
Objective
The mainstay of therapy for patients with venous thromboembolic disease (VTE) is anticoagulation. In the inpatient setting, majority of these patients are treated with heparin or low molecular weight heparin. The prevalence and outcomes of heparin-induced thrombocytopenia (HIT) in hospitalized patients with venous thromboembolic disease (VTE) is unknown.
Methods
This nationwide study identified patients with VTE from the National Inpatient Sample database between January 2009 and December 2013. Among these patients, we compared in-hospital outcomes of patients with and without HIT using a propensity score-matching algorithm. The primary outcome was in-hospital mortality. Secondary outcomes included rates of blood transfusions, intracranial hemorrhage, gastrointestinal bleed, length of hospital stay, and total hospital charges.
Results
Among 791,932 hospitalized patients with VTE, 4948 patients (0.6%) were noted to have HIT (mean age, 62.9 ±16.2 years; 50.1% female). Propensity-matched comparison showed higher rates of in-hospital mortality (11.01% vs 8.97%; P < .001) and blood transfusions (27.20% vs 20.23%; P < .001) in patients with HIT compared with those without HIT. No significant differences were noted in intracranial hemorrhage rates (0.71% vs 0.51%; P > .05), gastrointestinal bleed (2.00% vs 2.22%; P > .05), length of hospital stay (median, 6.0 days; interquartile range [IQR], 3.0-11.0 vs median, 6.0 days; IQR, 3.0-10.0 days; P > .05), and total hospital charges (median, $36,325; IQR, $17,798-$80,907 vs median, $34,808; IQR, $17,654-$75,624; P > .05).
Conclusions
This nationwide observational study showed that 0.6% of hospitalized patients with VTE in the United States have HIT. The presence of HIT was associated with higher in-hospital mortality and blood transfusion rates compared with those without HIT.
Keywords: Heparin-induced thrombocytopenia, Venous thromboembolic disease, Hypercoagulable state, Antithrombotic therapy, Platelets
Article Highlights.
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Type of Research: Multicenter, retrospective analysis of prospectively collected registry data, the National Inpatient Sample, and the Healthcare Cost and Utilization Project
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Key Findings: In this large population-based study from 2009 to 2013, the in-hospital outcomes of patients with venous thromboembolic disease (n = 791,931) with and without heparin-induced thrombocytopenia (HIT) were compared using a propensity score matching algorithm. The prevalence, outcomes, and resource use were evaluated. The prevalence of HIT (n = 4948) with venous thromboembolic disease was 0.6%; the in-hospital mortality was (11.01% vs 8.97%; P < .001) in a matched cohort.
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Take Home Message: Short-term outcomes of patients with venous thromboembolic disease and HIT are poor and clinicians should be vigilant in monitoring for thrombocytopenia. The diagnosis of HIT should be high on the differential diagnosis in patients exposed to heparin products, with prompt consideration to transitioning to other non-heparin-based anticoagulation regimens.
Venous thromboembolic disease (VTE), including deep vein thrombosis and pulmonary embolism, occurs in 1 to 2 persons per 1000 people and accounts for 60-100,000 deaths annually in United States alone.1 It causes more deaths than breast cancer, motor vehicle accidents, and human immunodeficiency virus combined; it is the most preventable cause of in-hospital death.1 Majority of these patients are treated with systemic anticoagulation, which includes parenteral heparin or low-molecular-weight heparins.2,3
Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication that affects patients who are exposed to heparin products for at least 5 consecutive days.4 Patients who develop HIT have greater than 50% risk of developing thrombosis within 30 days, with an overall 4:1 predominance of a venous vs an arterial thrombotic event.5
Objective
Studies looking at prevalence of HIT have a relatively small sample size, except one large population-based study by Dhakal et al6; however, this study excluded patients with VTE. In this study, we wanted to evaluate the prevalence of HIT in hospitalized patients with VTE and compare their in-hospital outcomes with those patients who did not have HIT.
Methods
Study design
This study is an observational nationwide study. The Institutional Review Board at Temple University Hospital waived the formal review because patient identifiers are not a part of this dataset.7
Setting and data source
The National Inpatient Sample (NIS) database from Healthcare Cost and Utilization Project contains information from more than 7 million annual hospital discharges, which represents approximately 20% of hospital discharges in the United States. It is compiled from 1050 hospitals across 45 states and can be used to approximate all the hospital discharges in the United States through a weighted algorithm. This study looked at patients over 5 years from January 2009 to December 2013.8
Participants
International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes were used to identify all patients with a discharge diagnosis of VTE, which included deep vein thrombosis (ICD-9-CM code 453.0, 453.2, 453.40-42, 453.80-89),9,10 pulmonary embolism (ICD-9-CM code 415.11-13, 415.19, 415.0),10 and chronic venous embolism and thrombosis (ICD-9-CM code 453.50-52, 453.71-79).11 We then identified patients who had a diagnosis of HIT (ICD-9-CM code 289.84) within this patient cohort. The validation studies of the ICD-9-CM code of HIT from 2009 to 2013 showed that it was 91% sensitive and 94% specific; we chose to use this period to be certain of the patients we are selecting.6 We included all patients 18 years of age and older. Patients under 18 years of age and those in whom the age variable was missing were excluded from analysis. The patient selection flow diagram is shown in Fig 1.
Fig 1.
Patient selection diagram. HIT, heparin-induced thrombocytopenia; VTE, venous thromboembolism.
Variables
To adjust for the anticipated baseline differences in comorbidities and demographic characteristics between the HIT and non-HIT groups and to decrease the effect of selection and indication biases, we used a 1:1 propensity score matching algorithm to compare outcomes and resource uses. We identified 42 relevant clinical, hospital, and demographic variables; variables with a low prevalence as well as ones that would confound our results were excluded (ie, coagulopathy). Thereafter, the remaining 29 covariates were incorporated in our propensity-matching model (Table I).
Table I.
Baseline characteristics before and after matching
| Baseline characteristics | Unmatched cohort |
Matched cohort |
||||
|---|---|---|---|---|---|---|
| Non-HIT (n = 786,983) | HIT (n = 4948) | P value | Non-HIT (n = 4948) | HIT (n = 4948) | P value | |
| Age, years | 63.52 ± 17.95 | 62.86± 16.15 | <.001 | 63.24 ± 17.48 | 62.86± 16.15 | .2596 |
| Race | <.001 | .3275 | ||||
| White | 64.15 | 61.08 | 63.06 | 61.08 | ||
| Black | 16.22 | 16.88 | 16.88 | 16.88 | ||
| Hispanic | 6.43 | 7.88 | 6.97 | 7.88 | ||
| Asian | 1.17 | 1.50 | 1.27 | 1.50 | ||
| Native American | 0.42 | 0.38 | 0.38 | 0.38 | ||
| Other | 2.34 | 3.19 | 3.11 | 3.19 | ||
| Missing | 9.23 | 9.09 | 8.33 | 9.09 | ||
| Sex (male) | 51.96 | 50.23 | .015 | 50.04 | 50.23 | .856 |
| Active smoking | 11.90 | 9.86 | <.001 | 9.20 | 9.86 | .257 |
| Arrhythmia | 22.20 | 32.88 | <.001 | 74.64 | 32.88 | .695 |
| Chronic kidney disease | 12.47 | 14.77 | <.001 | 40.20 | 14.77 | .314 |
| Chronic pulmonary disease | 22.02 | 22.15 | .831 | 33.06 | 22.15 | .831 |
| Coagulopathy | 8.96 | 97.37 | <.001 | 14.37 | 97.37 | .569 |
| Congestive heart failure | 13.49 | 18.97 | <.001 | 21.87 | 18.97 | .501 |
| Coronary artery disease | 13.11 | 18.04 | <.001 | 8.45 | 18.04 | .465 |
| Acute deep vein thrombosis | 63.26 | 74.28 | <.001 | 18.71 | 74.28 | .738 |
| Deficiency anemias | 25.76 | 39.20 | <.001 | 18.21 | 39.20 | .835 |
| Depression | 11.32 | 10.67 | .147 | 10.53 | 10.67 | .819 |
| Diabetes with chronic complications | 4.84 | 6.51 | <.001 | 6.00 | 6.51 | .299 |
| Fluid and electrolyte disorders | 30.83 | 48.43 | <.001 | 49.09 | 48.43 | .52 |
| Hyperlipidemia | 23.77 | 23.92 | .338 | 58.71 | 23.92 | .581 |
| Hypertension | 55.66 | 59.26 | <.001 | 23.76 | 59.26 | .841 |
| Hypothyroidism | 12.02 | 11.80 | .683 | 11.52 | 11.80 | .684 |
| Metastatic cancer | 7.57 | 7.88 | .481 | 8.06 | 7.88 | .738 |
| Neurologic disorders | 9.77 | 9.46 | .452 | 8.85 | 9.46 | .296 |
| Nontraumatic shock | 5.08 | 14.91 | <.001 | 14.03 | 14.91 | .219 |
| Obesity | 14.41 | 17.24 | <.001 | 17.50 | 17.24 | .73 |
| Paralysis | 4.40 | 4.91 | .083 | 4.87 | 4.91 | .926 |
| Peripheral vascular disorders | 6.41 | 9.56 | <.001 | 8.97 | 9.56 | .315 |
| Pulmonary circulation disorders | 20.89 | 24.79 | <.001 | 4.81 | 24.79 | .474 |
| Pulmonary embolism | 43.07 | 39.16 | <.001 | 25.38 | 39.16 | .501 |
| Renal failure | 16.17 | 26.05 | <.001 | 38.66 | 26.05 | .621 |
| Uncomplicated diabetes | 20.01 | 24.51 | <.001 | 25.59 | 24.51 | .597 |
| Venous thromboembolism | 9.62 | 8.04 | <.001 | 24.43 | 8.04 | .926 |
Values are mean ± standard deviation or percent.
The primary end point of the study was in-hospital mortality. Secondary end points included intracranial hemorrhage (ICH), gastrointestinal (GI) bleeding, blood transfusion rates, length of stay, and hospital charges. In addition, multinomial logistic regression was used to identify the predictors of death in this patient population.
Statistical methods
Descriptive summary statistics are presented as means with standard deviations for continuous variables and frequencies with percentages for categorical variables. Comparison among the two unmatched groups and matched groups for categorical variables was made using Pearson’s χ2 test and Wilcoxon signed-rank test was used to compare continuous variables. A P value of less than .05 was considered statistically significant.
A total of 29 variables were used in the nearest neighbor 1:1 variable ratio, parallel, balanced propensity score matching to create two matched groups. In-hospital outcomes were compared between the two matched groups. All statistical analyses were performed using SPSS version 25 (IBM, Armonk, NY) and SAS version 9.3 (SAS Institute, Cary, NC). Nearly all variables had less than 1% missing data except race, which had 14.2% missing data; a dummy variable adjustment method was used to preserve the full sample size. The dummy variable was matched in our statistical model.
A sensitivity analysis was performed to analyze the reliability of the results. Propensity score matching was done with 1:2, 1:3, 1:4, and 1:5 matching in addition to the case control matching, which was performed 1:2 and 1:3. Furthermore, a multivariate analysis was completed to analyze the predictors of death within this cohort.
Results
Participants
Between January 2009 and December 2013, a total of 791,931 patients with a discharge diagnosis of VTE were identified in the NIS database (representing a national estimate of 3.96 million patients). Within this cohort, we identified 4948 patients (0.6%) who had a diagnosis of HIT.
Descriptive data
Patients with HIT had a mean age of 62.8 ±16.1 years and 50.2% were female. The annual prevalence rate of HIT did not change over the study period (P > .05 for Cochran-Armitage test for trends) (Fig 2). Unmatched baseline characteristics of the study patients are shown in Table I.
Fig 2.
Prevalence of heparin-induced thrombocytopenia (HIT) among patients with venous thromboembolism (VTE) in the United States.
Comparative outcomes
Unmatched cohorts of patients with VTE disease vs patients with HIT with VTE disease showed a statistically significant increase in mortality (primary outcome), as well as secondary outcomes of blood transfusions, ICH, and GI bleeding. There was no significant difference in hospital charges or length of stay (Table II).
Table II.
Outcomes of patients with heparin-induced thrombocytopenia (HIT) vs without HIT in the unmatched cohort
| Outcome | HIT (n = 4948) | Non-HIT (n = 786,983) | P Value |
|---|---|---|---|
| Death | 11.01 | 5.55 | <.001 |
| Blood transfusion | 27.20 | 13.78 | <.001 |
| ICH | 0.71 | 0.38 | <.001 |
| GI bleed | 2.00 | 1.56 | .013 |
| Length of stay, days | 6.0 (3.0-11.0) | 6.0 (3.0-10.0) | >.05 |
| Charges, $ | 36,325 (17,798-80,907) | 35,201 (17,426-77,510) | >.05 |
GI, Gastrointestinal; ICH, intracranial hemorrhage.
Values are percent or median (interquartile range).
Thereafter, propensity score matching was completed; we created two groups of patients with VTE one with HIT (n = 4948) and one without HIT (n = 4948). The baseline characteristics of the matched groups are shown in (Table I). The C statistics of the propensity model was 0.687. The primary outcome, in-hospital mortality, was significantly higher in the HIT group as compared with the non-HIT group (11.01% vs 8.97%; P < .0001). For secondary outcomes, there was no significant difference in ICH rates (0.71% vs 0.51%; P > .05), and GI bleed rates (2.00% vs 2.22%; P > .05). Patients with HIT required more blood transfusions (27.20% vs 20.23%; P < .001) during the hospital course (Fig 3). There was no difference in the length of stay (median, 6.0 days; interquartile range [IQR], 3.0-11.0 vs median, 6.0 days; IQR, 3.0-10.0; P > .05) and total hospital charges (median, $36,325; IQR, $17,798-$80,907 vs median, $34,808; IQR, $17,654-$75,624; P > .05) between the two groups (Table III). The distribution of the propensity scores after matching is shown Fig 4.
Fig 3.
Comparison of complications in patients with heparin-induced thrombocytopenia (HIT) vs without HIT. GI, gastrointestinal; ICH, intracranial hemorrhage.
Table III.
Outcomes of patients with heparin-induced thrombocytopenia (HIT) vs without HIT in the propensity-matched groups
| Outcome | HIT | Non-HIT | P Value |
|---|---|---|---|
| Death | 11.01 | 8.97 | <.001 |
| Blood transfusion | 27.20 | 20.23 | <.001 |
| ICH | 0.71 | 0.51 | >.05 |
| GI bleed | 2.00 | 2.22 | >.05 |
| Length of stay, days | 6.0 (3.0-11.0) | 6.0 (3.0-10.0) | >.05 |
| Charges, $ | 36,325 (17,798-80,907) | 34,808 (17,654-75,624) | >.05 |
GI, Gastrointestinal; ICH, intracranial hemorrhage.
Values are percent or median (interquartile range).
Fig 4.
Distribution of propensity scores after matching. HIT, heparin-induced thrombocytopenia
Multivariate analysis showed predictors of death as nontraumatic shock (odds ratio [OR], 7.458; 95% CI, 7.268-7.652; P < .001), ICH (OR, 2.985; 95% CI, 2.684-3.319; P < .001), metastatic cancer (OR, 2.514; 95% CI, 2.439-2.591; P < .001), and HIT (OR, 1.186; 95% CI, 1.073-1.310; P = .001) (see Fig 5).
Fig 5.
Predictors of death. CI, confidence interval; OR, odds ratio.
Sensitivity analysis
The outcomes based on 1:1 and 1:2 case control matching of the patients with HIT vs patients without HIT showed similar results. Additionally, the results did not change with 1:2, 1:3, 1:4, and 1:5 propensity score matching.
Discussion
HIT is caused by heparin binding to platelet factor-4, leading to the formation of IgG antibodies to this complex. The binding of the antibodies to the platelet factor-4-heparin complex leads to platelet activation and an intense hypercoagulable state and thrombosis.12, 13, 14
This nationwide observational study showed that the prevalence of HIT in patients with VTE is 0.6% and it remained steady over the 5-year study period. The incidence of HIT in the reported literature ranges from 0.02% to 4.89%.15 The reported nationwide prevalence of HIT among all hospital discharges is 0.07% in the United States.16 Our study showed nearly nine-fold higher prevalence among the VTE population, which is not surprising because many of these patients are treated with heparin.
This study with a large cohort of patients showed that hospitalized patients with VTE who have HIT have significantly higher in-hospital mortality compared with those without HIT. Previous studies involving a smaller cohorts of patients with HIT undergoing vascular, cardiac, and orthopedic surgeries have reported mortality ranging from 6.9 to 25.0%.6,15, 16, 17, 18 The present study used propensity score matching and, therefore, likely reflects the prevalence and the impact of HIT diagnosis in the larger context of hospitalized patients with VTE. In comparing the unmatched cohort with the propensity-matched group, it is clear that the VTE population has high rates of mortality and blood transfusions; however, patients with HIT are at an even higher risk, even after matching. Furthermore, among the VTE population, patients with HIT seem to have increased rates of ICH and GI bleeding; however, after matching, there is no statistically significant difference between the two groups. HIT was associated with significantly greater in-hospital mortality in patients with VTE as compared with those without HIT. We believe that, owing to this finding, it is important to have a high index of suspicion for an early diagnosis and consider using non-heparin-based systemic anticoagulation in these patients, such as direct thrombin inhibitors, until HIT is ruled out.
We also showed that, among patients with VTE, individuals with HIT required blood transfusions at a higher rate than patients without HIT. This is thought to be due to increased bleeding complications in patients with HIT, as well as prophylactic transfusions to prevent procedure-related bleeding complications. ICH and GI bleeds rates were not significantly different, which may be related to the very low incidence of these complications. Based on these results, clinicians need to keep bleeding risks in mind as they decide about the optimal regimen in these patients.
There was no increase in the length of stay or charges associated with the diagnosis of HIT in this study; however, we did notice a numerical increase in hospital costs that did not reach statistical significance. Other studies have shown increased length of hospital stay in patients with HIT, which ranged from 8.9 to 20.4 days.6,16,17,19,20 Our findings may be related to the fact that we performed a rigorous propensity matching, which made HIT by itself a less significant variable when assessing its impact on length of hospital stay and charges.
Limitations
The limitations of this study are as follows. (a) The effect of unmeasured confounding variables (such as detecting acute HIT vs history of HIT) is unknown; however, our rigorous propensity matching and sensitivity analyses makes it unlikely to effect the comparative outcomes analysis. (b) It has been proposed that using low-molecular-weight instead of unfractionated heparin decreases the burden of HIT.21 It was not possible from our database to determine which anticoagulants were used in individual patients to assess the effect based on the anticoagulant administered. (c) Our study data are subject to the limitations of the claims-based databases; however, because the discharge diagnoses codes for HIT have been shown to have greater than 90% sensitivity and specificity, we believe that our patient selection methods are reliable.6 (d) The NIS does not provide survival information beyond the inpatient hospital stay; thus, posthospitalization outcomes are unknown and our observations need to be confirmed in other data sets with longer term follow-up. (e) The impact of increasing adoption and use of direct oral anticoagulants in patients with VTE on the incidence of HIT cannot be assessed in this dataset.22
Interpretation
This study provides information on the prevalence of HIT in the larger context of patients admitted to hospital with VTE and, more important, on the high in-hospital mortality rate in these patients. Therefore, clinicians should be vigilant in monitoring for thrombocytopenia and the diagnosis of HIT should be high on the differential diagnosis in patients exposed to heparin products. Furthermore, for patients in whom the suspicion for HIT is high owing to progressive thrombocytopenia, we should look to avoid any heparin products to improve their outcomes.20
Generalizability
The present study encompasses a large population of propensity-matched patients, spanning across the United States, and a wide spectrum of hospitals all of which support the generalizability of findings. Fewer than 1% of patients with VTE have HIT and these patients have an increased in-hospital mortality. This study highlights that short-term outcomes of this patient population are poor and the need to consider using other non-heparin-based anticoagulation regimens.
Author Contributions
Conception and design: NS, PS, VL, RK, AKR, RB
Analysis and interpretation: NS, IS, AT, HZ
Data collection: Not applicable
Writing the article: NS, PS, AT, RB
Critical revision of the article: NS, PS, IS, HZ, VL, RK, AKR, RB
Final approval of the article: NS, PS, IS, AT, HZ, VL, RK, AKR, RB
Statistical analysis: NS, IS, HZ
Obtained funding: RB
Overall responsibility: RB
Appendix
The CME exam for this article can be accessed at http://www.jvsvenous.org/cme/home.
Footnotes
This work was funded by Temple University. Temple University had no involvement in the study design or collection, analysis, and interpretation of data. TUH was not involved in the decision to submit the manuscript for publication
Author conflict of interest: A.K.R. reports a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: Hemostasis and Thrombosis Research Society (Elected Office Bearer –General Secretary). R.B. reports grants from the NHLBI; royalties from Thrombolex; patents from Bashir Endovascular Catheter; and stock in Thrombolex INC.
The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest.
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