Keywords
venous thromboembolism - myeloproliferative neoplasm - polycythemia vera - essential
thrombocytosis - primary myelofibrosis
Introduction
Philadelphia-negative myeloproliferative neoplasms (MPNs) are highly prevalent hematological
malignancies that include polycythemia vera (PV), essential thrombocytosis (ET), and
primary myelofibrosis (PMF).[1]
[2] These malignancies have been associated with a higher risk of venous thromboembolism
(VTE) compared with the general population, leading up to one-third of patients with
MPN experiencing VTE at any point in their disease.[3]
[4]
[5] The higher incidence of VTE in patients with MPN has led to development of recommendations
of risk-adapted strategies to decrease their thromboembolism rate.[6]
Despite risk-adapted preventive strategies, VTE remains one of the leading causes
of death and healthcare expenditure in patients with cancer.[7]
[8]
[9] For instance, in a recent systematic review by Grosse et al, VTE had an estimated
incremental cost of $12,000 to 15,000 (2014 U.S. dollars [USD]) per patient for first-VTE
survivors and complications were estimated to increase cumulative costs up to $18,000
to 23,000; adding up to a total annual cost of 7 to 10 billion USD to the U.S. healthcare
system.[10] Similarly, Barco et al estimated that VTE has a total annual cost of €1.5 to 2.2
billion and hospital-associated cost of €1.0 to 1.5 billion in the European Union.[11]
Although there is emerging information of overall VTE-related costs, there is paucity
of data of MPN-associated VTE mortality and healthcare expenditure in hospitalized
patients. In this study, we aim to study annual rates of VTE-related admissions, length
of inpatient stay (LOS), its associated cost, and in-hospital mortality in patients
with MPN.
Methods
Study Design and Data Source
We queried the National Inpatient Sample (NIS) databases from 2006 to 2014 and conducted
a retrospective analysis of hospitalizations in patients with Philadelphia-negative
MPN. The NIS is a national database administered by the Healthcare Cost and Utilization
Project sponsored by the Agency of Healthcare Research and Quality (AHRQ). The NIS
consists of a stratified sample of approximately 20% of discharges from all community
hospitals in the United States and provides weighted discharges to allow for national
estimates.
Population
We identified patients aged 18 or above, admitted with a diagnosis of PV, ET, and
MF using International Classification of Diseases-Ninth Edition-Clinical Modification
(ICD-9-CM) coding. Patients with PV were identified using ICD-9CM codes 238.4; patients
with ET were identified using code 238.71; and patients with PMF were identified using
codes 238.76 and 289.83.
Variables
We obtained patients' baseline characteristics using variables provided by the NIS
databases. These included age, gender, race, and healthcare payer.
We defined VTE-related hospitalization as an admission that included a VTE event in
the primary discharge diagnosis or the initial two secondary diagnoses. A VTE event
was allocated using ICD-9-CM codes 415.11, 415.13, and 415.19 for pulmonary embolism;
451.11, 451.2, 451.81, 453.40, 453.41, and 453.42 for deep vein thrombosis (DVT) of
lower extremity; 453.0 for Budd-Chiari syndrome (BCS); and 451.19, 451.83, 451.84,
451.89, 451.9, 452.0, 453.2, 453.3, 453.8, 453.82, 453.83, 453.84, 453.85, 453.86,
453.87, 453.88, 453.89, and 453.90 for other types of VTE. Superficial vein thromboses
were excluded.
Hospitalization costs were obtained using the total charges reported by hospitals
to the NIS database. LOS in days was coded as a continuous variable. In-hospital mortality
was coded as a binary variable coded from the discharge disposition of patient reported
to the NIS database.
Outcomes
Our primary outcomes included inpatient mortality, hospitalization cost, and LOS of
all VTE-related admissions. In addition, we aimed to measure the trends of the annual
rates of VTE-related admissions, cost of hospitalization, LOS, and in-patient mortality.
Statistical Analysis
We used descriptive statistics to summarize the baseline characteristics of the cohort
and subgroups. Continuous variables are expressed as mean and standard deviation (SD)
or median and interquartile range (IQR) as appropriate. Categorical variables are
expressed as absolute numbers and percentages.
National estimates for the annual rates of VTE-related hospitalizations were made
using weights provided by the NIS database. We used simple linear regression to analyze
the trends of annual rates of VTE-related hospitalizations and inpatient mortality.
We compared the trends in annual cost of hospitalization and LOS between groups using
Mann–Whitney U-test. All statistical analyses were performed using SPSS version 22.0 (IBM Corp.,
Armonk, NY).
Results
We identified 1,046,666 admissions for patients with Philadelphia-negative MPNs from
2006 to 2014. Patients had a median age of 66 years (IQR: 26 years) and were predominantly
Caucasians (n = 686,104; 65.6%) and female (n = 552,016; 52.7%). The most common MPN type was ET (n = 565,644; 54%), followed by PV (n = 313,588; 30%) and PMF (n = 167,434; 16%).
Patients were predominantly over 60 years of age in all the three subgroups: 54.1,
62.9, and 89.9% in ET, PV, and PMF, respectively. Patients had similar demographic
and health insurance payer among all MPN types as detailed in [Tables 1] and [2].
Table 1
Demographic characteristics of cohort by type of hospitalization
|
Characteristics
|
VTE hospitalization
|
Non-VTE hospitalization
|
|
n = 39,124
|
n = 1,007,542
|
|
Age
|
≥60 y—n (%)
|
23,084 (59)
|
622,265 (61.7)
|
|
Gender
|
Female—n (%)
|
21,230 (54.3)
|
530,786 (52.7)
|
|
Race
|
White—n (%)
|
25,953 (75.4)
|
660,151 (73.6)
|
|
African American—n (%)
|
4,802 (13.9)
|
121,856 (13.6)
|
|
Hispanic—n (%)
|
2,222 (6.5)
|
68,849 (7.7)
|
|
Asian or Pacific Islander—n (%)
|
385 (1.1)
|
18,931 (2.1)
|
|
Native American—n (%)
|
132 (0.4)
|
4,878 (0.5)
|
|
Other—n (%)
|
944 (2.7)
|
22,755 (2.5)
|
|
Insurance
|
Medicare—n (%)
|
20,310 (51.9)
|
568,699 (56.6)
|
|
Medicaid—n (%)
|
3,948 (10.1)
|
111,371 (11.1)
|
|
Private insurance—n (%)
|
10,967 (28.0)
|
233,965 (23.3)
|
|
Self-pay—n (%)
|
2,288 (5.9)
|
56,268 (5.6)
|
|
No charge—n (%)
|
300 (0.8)
|
6,278 (0.6)
|
|
Other—n (%)
|
1,261 (3.2)
|
29,080 (2.9)
|
|
Tumor type
|
PV—n (%)
|
13,057 (33.3)
|
300,531 (29.8)
|
|
ET—n (%)
|
20,520 (52.4)
|
545,124 (54.1)
|
|
PMF—n (%)
|
5,548 (14.1)
|
161,886 (16.1)
|
Abbreviations: ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PMF,
primary myelofibrosis; PV, polycythemia vera; VTE, venous thromboembolism.
Table 2
Demographic characteristics of cohort by tumor type
|
Characteristics
|
MPN type
|
|
PV
|
ET
|
PMF
|
|
n = 313,588
|
n = 565,644
|
n = 167,434
|
|
Age
|
≥60 y—n (%)
|
197,156 (62.9)
|
305,972 (54.1)
|
142,220 (89.9%)
|
|
Gender
|
Male—n (%)
|
182,482 (58.2)
|
227,978 (40.3)
|
84,149 (50.3)
|
|
Race
|
White—n (%)
|
222,551 (81.1)
|
343,926 (67.9)
|
119,627 (79.5)
|
|
African American—n (%)
|
22,580 (8.2)
|
89,569 (17.7)
|
14,508 (9.6)
|
|
Hispanic—n (%)
|
16,839 (6.1)
|
45,360 (8.9)
|
8,873 (5.9)
|
|
Asian or Pacific Islander—n (%)
|
4,758 (1.7)
|
11,000 (2.2)
|
3,558 (2.4)
|
|
Native American—n (%)
|
1,369 (0.5)
|
3,165 (0.6)
|
476 (0.3)
|
|
Other—n (%)
|
6,388 (2.3)
|
13,809 (2.7)
|
3,501 (2.3)
|
|
Insurance
|
Medicare—n (%)
|
180,976 (57.8)
|
281,991 (49.9)
|
126,041 (75.4)
|
|
Medicaid—n (%)
|
27,920 (8.9)
|
79,649 (14.1)
|
7,750 (4.6)
|
|
Private insurance—n (%)
|
74,685 (23.9)
|
141,961 (25.1)
|
28,285 (16.9)
|
|
Self-pay—n (%)
|
18,680 (6.0)
|
37,569 (6.7)
|
2,308 (1.4)
|
|
No charge—n (%)
|
1,954 (0.6)
|
4,353 (0.8)
|
271 (0.2)
|
|
Other—n (%)
|
8,737 (2.8)
|
19,092 (3.4)
|
2,512 (1.5)
|
|
Type of hospitalization
|
Non-VTE related—n (%)
|
301,125 (95.8)
|
545,757 (96.5)
|
162,082 (96.8)
|
|
VTE related—n (%)
|
13,057 (4.2)
|
20,520 (3.5)
|
5,548 (3.2)
|
Abbreviations: ET, essential thrombocythemia; MPN, myeloproliferative neoplasms; PMF,
primary myelofibrosis; PV, polycythemia vera; VTE, venous thromboembolism.
We abstracted 39,124 (3.7%) VTE-related admissions during the study period. VTE hospitalizations
were higher in patients with PV (n = 13,057, 4.2%) followed by ET (n = 20,520; 3.5%) and PMF (n = 5,548, 3.2%; [Table 2]).
In our cohort, the overall mortality rate was similar in patients with VTE-related
hospitalization compared with non-VTE admissions (3.3 vs. 3.2%; p = 0.646). Nonetheless, in MPN subgroups, patients with PV had a mortality in VTE-related
admissions compared with non-VTE–related admissions (3.5 vs. 3.1%; p = 0.009). Mortality was similar among VTE- and non-VTE admissions for patients with
ET (2.5 vs. 2.3%; p = 0.053) and PMF (5.6 vs. 6.6%; p = 0.002). The case-fatality rate for VTE-related admissions was 0.12% ([Table 3]).
Table 3
Outcomes by VTE event in the entire cohort
|
Outcomes
|
Non-VTE hospitalization
|
VTE hospitalization
|
p-Value
|
|
Mortality—n (%)
|
32,617 (3.2)
|
1,283 (3.3)
|
0.646
|
|
Total cost of hospitalization (USD)—median (IQR)
|
28,426 (42,572)
|
31,549 (46,097)
|
0.001
|
|
Total length of stay (days)—median (IQR)
|
5 (5)
|
6 (6)
|
<0.001
|
Abbreviations: IQR, interquartile range; VTE, venous thromboembolism.
Overall, patients with a VTE-related hospitalization had a higher median cost of hospitalization
(USD 31,549 vs. 28,426; p = 0.001) and longer LOS (6 vs. 5 days; p ≤ 0.001) compared with non-VTE hospitalizations. Among VTE admissions, patient with
ET had the highest cost (median: USD 35,703 [IQR = 53,703]) and LOS (median: 6 days
[IQR = 7]) compared with PV (median: USD 25,745; median LOS: 5 days [IQR = 4]) and
PMF (median: USD 33,213; median LOS: 6 days [IQR = 7]; [Tables 3] and [4]).
Table 4
Outcomes of VTE hospitalizations by tumor type
|
Outcomes
|
PV
|
ET
|
PMF
|
p-Value
|
|
Non-VTE
|
VTE
|
Non-VTE
|
VTE
|
Non-VTE
|
VTE
|
PV vs. ET (VTE vs. VTE)
|
PV vs. PMF (VTE vs. VTE)
|
ET vs. PMF (VTE vs. VTE)
|
|
Hospitalization
|
301,125 (95.8)
|
13,057 (4.2)
|
545,757 (96.5)
|
20,520 (3.5)
|
162,082 (96.8)
|
5,548 (3.2)
|
<0.001
|
<0.001
|
<0.001
|
|
Mortality—n (%)
|
9,290 (3.1)
|
457 (3.5)
|
12,633 (2.3)
|
518 (2.5)
|
10,694 (6.6)
|
308 (5.6)
|
<0.001
|
<0.001
|
<0.001
|
|
Total cost of hospitalization (USD)—median (IQR)
|
23,542 (32,083)
|
25,745 (34,962)
|
31,729 (48,947)
|
35,805 (53,703)
|
28,942 (43,096)
|
33,213 (47,337)
|
<0.001
|
<0.001
|
0.115
|
|
Total length of stay (days)—median (IQR)
|
4 (4)
|
5 (4)
|
5 (7)
|
6 (7)
|
5 (5)
|
6 (7)
|
<0.001
|
<0.001
|
0.300
|
Abbreviations: ET, essential thrombocythemia; PMF, primary myelofibrosis; PV, polycythemia
vera; VTE, venous thromboembolism.
Acute DVT was the most common VTE event in patients with PV (n = 5,731, 43.9%) and PMF (n = 1824, 32.9%), and PE was more common in patients with ET (n = 8,733, 42.6%). BCS was the third most common VTE event in all the three MPNs (PV:
4.4%, ET: 1.2%, PMF: 7.7%; [Table 5]).
Table 5
VTE events per MPN type
|
VTE subtype
|
PV
|
ET
|
PMF
|
p-Value
|
|
PV vs. ET
|
PV vs. PMF
|
ET vs. PMF
|
|
Acute DVT—n (%)
|
5,731 (43.9%)
|
7,490 (36.5%)
|
1,824 (32.9%)
|
<0.001
|
<0.001
|
0.003
|
|
Pulmonary embolism—n (%)
|
4,586 (35.1%)
|
8,733 (42.6%)
|
1,724 (31.1%)
|
<0.001
|
<0.001
|
<0.001
|
|
Bud-Chiari syndrome—n (%)
|
568 (4.4%)
|
250 (1.2%)
|
428 (7.7%)
|
<0.001
|
0.007
|
<0.001
|
|
Other—n (%)
|
2,172 (16.6%)
|
4,047 (19.7%)
|
1,572 (28.3%)
|
<0.001
|
<0.001
|
<0.001
|
Abbreviations: DVT, deep vein thrombosis; ET, essential thrombocythemia; MPN, myeloproliferative
neoplasm; PMF, primary myelofibrosis; PV, polycythemia vera; VTE, venous thromboembolism.
During the study period, there was a trend toward a decreased total VTE-related admissions
(2006 = 4.18% vs. 2014 = 3.53%; p < 0.001) and increased mortality (2006 = 2.77% vs. 2014 = 4.94%; p < 0.001) and costs per hospitalization (2006 = USD 22,702 vs. 2014 = USD 37,100;
p < 0.001). Notably, there was a trend toward an increased yearly rate of PE-related
admissions (2006 = 1.1% vs. 2014 = 1.49%; p < 0.001), PE-related in-hospital mortality (2006 = 6.21% vs. 2014 = 7.96%; p < 0.001), and PE hospitalization costs (2006 = USD 27,027 vs. 2014 = USD 42,959;
p ≤ 0.001; [Figs. 1]
[2]
[3]).
Fig. 1 Trends for VTE events in the entire cohort. VTE, venous thromboembolism.
Fig. 2 Trends of in-hospital mortality of VTE-related hospitalizations. DVT, deep vein thrombosis;
VTE, venous thromboembolism.
Fig. 3 Trends in total costs per VTE admission in U.S. dollars. DVT, deep vein thrombosis;
VTE, venous thromboembolism.
Discussion
This retrospective analysis was designed to examine the annual trends in VTE-related
hospitalizations among patients with Philadelphia-negative MPNs and their associated
cost, LOS, and inpatient mortality.
We studied hospitalizations during the period of 2006 to 2014 in our cohort of MPN
patients. From a total of 1,046,666 admissions, we abstracted 39,124 (3.7%) VTE-related
admissions. ET was the most frequently identified MPN from all VTE hospitalizations
(20,520; 52.4%) followed by PV (13,057; 33.3%) and PMF (5,548; 14.1%).
The majority of patients in our cohort were 60 years or older, particularly in the
PMF subgroup (89.9%). Age is a well-recognized risk factor for thrombosis in patients
with MPN. For instance, the European Collaboration on Low-dose Aspirin in PV (ECLAP)
study demonstrated that age over 65 years led to increased risk of a thromboembolic
event in PV patients.[12] Similarly, elderly patients with ET have an increased risk for VTE. Consequently,
well-validated risk stratification models like the International Prognostic Scoring
for Thrombosis in ET patients (IPSET) criteria incorporate age over 60 years as a
criterion for prediction of thrombotic events.[13]
When we analyzed VTE hospitalizations by MPN tumor types, we observed a higher rate
of VTE admissions in patients with PV compared with ET and PMF (4.2 vs. 3.5 vs. 3.2%;
p ≤ 0.001). The higher incidence of VTE in patients with PV compared with other MPN
has been previously and extensively described.[14] It is plausible that the higher incidence of VTE in patients with PV would lead
to a higher rate of VTE-related hospitalizations when compared with other MPNs as
observed in our study population.
When examining VTE subtypes in our cohort, DVT was more common in patients with PV
(43.9% of VTE events in PV group), while PE was more common in ET patients (42.6%
of VTE events within ET group). Specific risk factors for development of PE in MPN
patient have not been previously described and remain an area of investigation.
In our cohort, PMF patients had the highest rate of BCS compared with other MPN (PMF:
7.7% vs. PV: 4.4% vs. ET: 1.2%; p ≤ 0.001). Although the association of MPN to BCS is well known, PMF has been described
as having a lower prevalence among BCS patients. For instance, in a recent meta-analysis
of 1,062 patients with BCS, Smalberg et al reported the prevalence of PMF to be lowest
(6.7%; 95% confidence interval [CI]: 32.3–49.5%) when compared with PV (52.9%; 95%
CI: 42.2–63.4%) and ET (24.6%; 95% CI: 18–32.2%).[15] The higher incidence of BCS in our cohort could be caused by a selection of a high-risk
group of PMF patients with other concurrent tumor- and patient-dependent VTE risk
factors not included in the NIS database like JAK2V617F mutation burden.[16] Furthermore, the higher rate of thrombocytopenia in PMF may have led to higher VTE
hospitalization rate due to bleeding complications during anticoagulation therapy.
Comparison of In-Patient Mortality Rates, Cost, and Length-of-Stay in MPN Patients
with VTE Hospitalizations
In our cohort, mortality was similar in VTE versus non-VTE groups (3.3 vs. 3.2; p = 0.646). In contrast, cancer-associated thrombosis has been linked to a poorer prognosis
in hospitalized patients. For instance, in a cohort of 3,146,388 hospitalized patients
with cancer, Lyman et al demonstrated a higher in-hospital mortality for patients
with cancer-related VTE (15 vs. 5.5%) compared with non-cancer–related VTE.[17] This difference may be explained by a more indolent course of MPNs compared with
solid tumors included in other descriptive studies. Moreover, the presence of less
severe forms of VTE (e.g., upper extremity DVT and lower extremity DVT) in our cohort
could have contributed to comparable rates of mortality in the VTE- and non-VTE–related
hospitalization groups.
In our study population, VTE-related admissions in MPN patients were associated with
a higher cost (USD 31,549 vs. 28,426; p = 0.001) and a longer LOS (6 vs. 5 days, p ≤ 0.001), similar to findings of other descriptive studies.[18] The higher costs are commonly due not only to anticoagulation therapy but also to
diagnostic imaging studies and bleeding complications occurring in approximately 8%
of all MPN patients.[19]
Trends of Yearly Rates of VTE Hospitalizations in Patients with MPN
We observed a decline in VTE-related admissions of MPN patients over the study period
(2006: 3.94% vs. 2014: 2.43%; p < 0.001). This is potentially explained by a more widespread use of risk-adapted
strategies to decrease the risk of VTE in high-risk patients using antiplatelet drugs
and cytoreductive agents.[20]
[21] Moreover, changes in practice regarding outpatient management of DVT could have
potentially reduced DVT-related admissions throughout the study period.
Interestingly, we observed a trend toward an increase in incidence of PE-related admissions
during the study period (2006: 1.1% vs. 2014: 1.49%, p < 0.01). This change may reflect the increased detection of PE since the widespread
use of computed tomography angiography for diagnosis.[22] However, it is still possible that there are other biological or environmental factors
that predispose MPN patients to develop PE, particularly patients with ET.
The major strength of this study is that we used an NIS database. This allowed us
to abstract a large cohort of patients with MPN and thus obtain robust estimations
regarding outcomes of patients hospitalized for VTE. Limitations of the study include
those inherent to retrospective studies and the absence of a marker of severity of
VTE coded in NIS database, precluding our study from analyzing the impact of VTE severity
on overall mortality, cost, and LOS in VTE hospitalizations. In addition, other factors
like duration of MPN disease before occurrence of VTE, choice of anticoagulation,
or use of prior cytoreductive therapy could not be obtained from the NIS database.
One limitation of our study is the inability to estimate the costs of care after hospitalization.
It is unknown if the cost of care will eventually be similar in VTE- and non-VTE–related
admissions after hospitalization. However, the focus of our study was to examine in-hospital
outcomes to delineate strategies that would allow for the prevention of VTE in patients
with MPN which, in turn, would improve resource allocation for the care of this patient
population.
Another limitation of our study is that the exact timing of VTE in the NIS database
cannot be determined. Nonetheless, we accounted for this limitation by selecting patients
with a VTE event on the principal or the top-two secondary diagnosis, which can be
reliably assumed to be acute and a main concern during hospitalization. This allowed
an accurate selection of patients with a VTE-related hospitalization and enabled us
to provide an estimate of their outcomes.
In conclusion, VTE-related admissions in patients with MPN were associated with higher
costs and prolonged hospitalization. Furthermore, there is a decline in VTE-related
admissions of MPN patients, although yearly rates of PE-related admissions have increased
from 2006 to 2014, regardless of the type of MPNs. Further refining our risk-stratification
strategy to include clinical, cytogenetic, and biological data may assist in preventing
VTE in high-risk patients and decrease VTE-related mortality and cost burden in patients
with MPNs.
