Costs of Venous Thromboembolism Associated with Hospitalization for Medical Illness

Abstract

Objective

To determine population-based estimates of medical costs attributable to venous thromboembolism (VTE) among patients currently or recently hospitalized for acute medical illness.

Study Design

Population-based cohort study conducted in Olmsted County, Minn.

Methods

Using Rochester Epidemiology Project (REP) resources, we identified all Olmsted County, MN residents with objectively-diagnosed incident VTE within 92 days of hospitalization for acute medical illness over the 18-year period, 1988–2005 (n=286). One Olmsted County resident hospitalized for medical illness without VTE was matched to each case on event date (± 1 year), duration of prior medical history and active cancer status. Subjects were followed forward in REP provider-linked billing data for standardized, inflation-adjusted direct medical costs (excluding outpatient pharmaceutical costs) from 1 year before their respective event or index date to the earliest of death, emigration from Olmsted County, or 12/31/2011 (study end date). We censored follow-up such that each case and match control had similar periods of observation. We also controlled for length of follow-up from index to up to 5-years post-index. We used generalized linear modeling (controlling for age, sex, pre-existing conditions and costs 1 year before index) to predict costs for cases and controls.

Results

Adjusted mean predicted costs were 2.5-fold higher for cases ($62,838) than for controls ($24,464) (P=<0.001) from index to up to 5-years post-index. Cost differences between cases and controls were greatest within the first 3 months after the event date (mean difference=$16,897) but costs remained significantly higher for cases compared to controls for up to 3 years.

Conclusions

VTE during or after recent hospitalization for medical illness contributes a substantial economic burden.

INTRODUCTION

Venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) and it’s complication, pulmonary embolism (PE), causes substantial morbidity, disability, and mortality.¹ Complete and valid estimates of VTE-associated medical care utilization and costs are essential for informing allocation of scarce resources, targeting efforts toward prevention, identifying best practices, addressing future care needs, and implementing cost-effective treatments.² However, existing estimates of VTE-associated costs^2–5 are problematic. Previous studies typically failed to control for age, sex, comorbid conditions and other events that place patients at risk for VTE, particularly hospitalization for major surgery or acute medical illness, trauma or major fracture, and cancer.¹ Together, these latter risk exposures account for over 75% of all incident VTE in the population.⁶ Although VTE is increasingly diagnosed and managed solely in office-based settings,⁷ the majority of population-based cost estimates were limited to patients admitted to emergency department (ED) and/or hospital; patients diagnosed and managed solely within office-based or chronic care (e.g., nursing home) settings were excluded. Moreover, case ascertainment almost always relied on discharge diagnosis codes obtained from billing data or death certificates.^4,5 The limitations of discharge diagnosis codes for identifying incident VTE are well recognized.^8–11

In those very few cost studies which validated VTE using medical record review, cost estimates were often obtained using self-reported utilization and applying national average estimates of hospital costs per day, ignoring differences in daily costs between persons with and without VTE. Many estimates of VTE-associated medical costs are also limited to costs accrued during the initial encounter.^12,13 To address these limitations, we performed a population-based matched-cohort study to estimate excess medical costs attributable to VTE that occurred during or recently after hospitalization for acute medical illness, independent of potential confounding due to VTE risk factors. We took advantage of Rochester Epidemiology Project (REP) resources, including a previously identified population-based inception cohort consisting of all Olmsted County, MN residents with objectively diagnosed incident VTE as well as previously identified matched non-VTE controls drawn from the same population.¹⁴ REP resources also afforded provider-linked objective medical cost estimates based on line item detail for every service and procedure over extended periods of time.¹⁵ Combining objectively-diagnosed VTE cases and controls with objective cost data for each individual afforded the opportunity to estimate medical care costs attributable to VTE, 1) across the full spectrum from symptomatic through fatal events, 2) from before the event until death or emigration from the area, 3) adjusting for age, sex and calendar year, and 4) adjusting for prevalent co-morbid conditions. Thus, we were able to estimate the excess cost of medical care that is attributable to VTE independent of potential confounding due to VTE risk factors.

METHODS

Study Setting and Design

Olmsted County, MN (2010 census population=144,248), provides a unique opportunity for investigating the natural history of VTE.^6,16,17 Rochester, the county seat, is approximately 80 miles from the nearest major metropolitan area. Mayo Clinic, together with Olmsted Medical Center (OMC), a second group practice and their affiliated hospitals, provide over 95% of all medical care delivered to local residents.¹⁸ Since 1907, every Mayo patient has been assigned a unique identifier; all information from every provider contact is contained within a unit record for each patient. Diagnoses assigned at each visit are coded and entered into continuously updated files. Under auspices of the REP, the unique identifiers, diagnostic index, and medical records linkage were expanded to include the few other providers of medical care to local residents, including OMC and the few private practitioners in the area, thereby linking the medical records for community residents at the individual level.^14,19 Using REP resources, we performed a cohort study. The study was approved by the Mayo Clinic and OMC Institutional Review Boards.

Study Population

All Olmsted County, MN residents with incident DVT or PE over the 40-year period, 1966–2005, were identified as previously described.⁶ REP records of individuals who refused authorization for use of medical records in reseach were excluded from review.^18,20 The medical records for remaining individuals were reviewed from date first seen until date last seen at any REP provider to identify, confirm, and characterize each VTE event. Incident events were limited to persons residing in Olmsted County for whom this was a first life-time symptomatic VTE. Record review was performed by trained, experienced nurse abstractors. The review included all outpatient general history notes, ED notes and hospitalization records, nursing notes, radiological, ultrasound and nuclear medicine imaging reports, surgical records, vascular laboratory reports, echocardiography reports, autopsy reports and death certificates.

Study nurses recorded method of VTE diagnosis, VTE event type (DVT, PE, or both; chronic thromboembolic pulmonary hypertension), date of VTE (i.e., “index date” for cases), location at onset of VTE symptoms and/or signs (hospital, nursing home, community), sex; age and active cancer and cancer type as of index date. The present study was limited to “objectively-diagnosed” events, as previously described,^1,6,9,17 and included all incident VTE cases with recent hospitalization for medical illness (i.e., within 92 days [365 days / 4 or ~3 months] before index); residents admitted to hospital solely for VTE treatment were not included. The hospitalization closest to but before VTE or the hospitalization during which VTE occurred was selected as the “index hospitalization”. Cases with a surgical hospitalization within 92 days before index were excluded.

REP also provides enumeration of the entire Olmsted County population from which potential controls can be sampled.¹⁴ Using this system, we identified all Olmsted County residents with hospitalization for acute medical illness within ±1 year of each case’s VTE date, similar length of medical record and no prior VTE.¹⁶ For patients with multiple hospitalizations per year, one hospitalization was randomly chosen to comprise the sampling frame. From this, a random sample of potential controls was identified, of which two were matched on case VTE event year and active cancer status. One control was randomly chosen for the current study. The hospitalization identified in the sampling frame was selected as the control’s “index hospitalization”. Assignment of control’s index date depended on whether the matched case’s VTE event occurred during or after the case’s index hospitalization (Figure 1). For cases whose VTE occurred during the index hospitalization, the control’s index date was randomly assigned to be a day within the control’s index hospitalization admission and discharge dates. For cases whose VTE occurred within 92 days after discharge from the index hospitalization, the control’s index date was randomly assigned to be a day within 92 days after the control’s index hospitalization discharge date. Medical records of potential controls were reviewed to confirm Olmsted County residency as of index, absence of surgical hospitalizations within 92 days before index, and that they matched the case with respect to active cancer as of index.

Figure 1.

Flow diagram on the identification and selection of a matched non-VTE control for each VTE case.

Collection of Medical Costs

Through an electronic data-sharing agreement between Mayo Clinic and OMC, patient-level administrative data on healthcare utilization and associated billed charges incurred at these institutions are shared and archived within the Olmsted County Healthcare Expenditure and Utilization Database (OCHEUD) for use in approved research studies. Data are electronically linked, affording complete information on all hospital and ambulatory care delivered by these providers to area residents from 1/1/1987 through 12/31/2011. OCHEUD includes information on all Olmsted County residents (i.e., both sexes, all ages, and all payer types, including the uninsured) and contains line-item detail on date, type, frequency, and billed charge for every good or service provided. Recognizing discrepancies between billed charges and true resource use, OCHEUD employs widely accepted valuation techniques to generate a standardized inflation-adjusted estimate of the costs of each service or procedure in constant dollars. Cost estimates in this study were adjusted to 2011 dollars.²¹ Because cost data are only available electronically since 1987 and we wished to obtain costs in the year before index, the present study was limited to all Olmsted County residents with a first lifetime objectively-diagnosed DVT or PE, 1988–2005.^1,6 Each case and control was followed forward in time for costs from 1 year before their respective index date to earliest of death, emigration from Olmsted County, or 12/31/2011 (study end date). We ensured similar periods of observation for each case and matched control by censoring both members of each pair as of the shortest length of follow-up for either member.

Pre-index Comorbid Conditions

To compare baseline characteristics and comorbidities between cases and controls, we obtained all International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses codes assigned to each individual in OCHEUD 1 year before index and categorized every diagnosis code assigned each individual into the 17 ICD-9-CM chapters and 114 subchapters. A summary measure of medical conditions in the year before index was obtained using Johns Hopkins Adjusted Clinical Groups (ACG) System® software.²² ACG software categorizes individual’s diagnosis codes into groupings based on persistence, severity, and etiology of the condition, as well as diagnostic certainty, and need for specialty care.²² ACG software was also used to assign a Resource Utilization Band (RUB) value to each individual. RUB categories are aggregations of ACGs that have similar expected resource use, with values ranging from 0 (no relevant diagnosis codes) to 5 (diagnosis codes associated with very high use).²³

Statistical Analyses

Analyses were conducted in SAS version 9.02 (SAS Institute, Cary, NC). Statistical testing used the two-tailed alpha level of 0.05. The principal outcome was direct medical costs attributable to VTE. As done previously for several medical conditions,^13,15,21,24 we analyzed costs from 1 year before index to index (providing an internal control) to a maximum of 5 years post index. Post-index analyses were also subdivided into: index-3 months, 3–6 months, 6-months-1 year, 1–2 years, 2–3 years, 3–4 years, and 4–5 years. In initial analyses, the unadjusted costs for each control were subtracted from costs for his/her case in each time period; statistical significance was assessed using Wilcoxon signed-rank test to account for the highly skewed nature of cost data and paired observations.^{15,21,24–26} For purposes of illustration we observed this difference for time periods of interest. We then used general linear multivariate modelling to examine the extent to which age, sex, RUB measure of pre-index comorbidity, and pre-index costs accounted for post-index cost differences between cases and controls. This adjusted approach employed two-part models to account for zero costs^27,28 when appropriate, and incorporated a generalized linear model with family distribution based on the modified Park test recommended by Manning and Mullahy.²⁹ This analytic approach accounts for the skewed cost distribution while enabling coefficients to be directly back transformed into the original dollar scale.^30,31 We analyzed differences in costs between cases and controls using the method of recycled predictions, setting all individuals as cases with VTE or as controls without VTE, while all other individual characteristics remain as observed.^32,33 Mean values and bootstrapped 95% confidence intervals of the mean difference were calculated.

RESULTS

Baseline characteristics

We identified 286 VTE cases and matched controls who were hospitalized for medical illness within 92 days before index [percent male=45% for cases and 41% for controls (p=0.27); mean age (±SD)=65.0±18.9 years for cases and 58.7±21.4 years for controls (p<0.001), with 104 VTE cases (36%) and 80 controls (28%) age >75 years. The length of follow-up post-index ranged from 1 day to 15 years. Of all VTE events, 130 (45%) occurred during index hospitalization and 156 (55%) occurred within 92 days after discharge. VTE event type distribution was DVT alone (n=182; 64%), PE alone (n=69; 24%), PE with DVT (n=33; 12%) and chronic thromboembolic pulmonary hypertension (n=2; 0.7%). In the year before index, differences between cases and controls were observed in 13 of 17 ICD-9-CM chapters (Supplementary Table). Within the 13 chapters, there were several significant differences at the subchapter level. Figure 2 provides the RUB summary measure of comorbidity for cases and controls. Two-thirds (n=181; 63%) of cases had a RUB value indicative of very high use compared to one-third (n=98; 34%) of controls. On the opposite side of the spectrum, no use, healthy use, and low use was 0.7%, 0.7%, 0.7% and 1.4%, 0.4%, 3.5% for VTE cases and non-VTE controls, respectively.

Figure 2.

Distribution of RUB values in the 1-year before index for VTE cases and non-VTE control.

Observed cost comparisons

Table 1 provides unadjusted direct mean, median (interquartile range [IQR]), minimum and maximum medical costs for case/control pairs and mean cost differences between case/control pairs 1 year before index, all 5 years post-index, and selected periods within the 5-years post-index. In the year before index, both mean and median costs for cases were nearly two-fold higher compared to controls, in part reflecting the broad costs range for cases compared to that for controls. The unadjusted mean difference in pre-index annual costs between cases and controls was $17,026 (95% CI: $11,942–$22,335). Overall 5-years post-index and within each post-index period, mean unadjusted cost differerences were significantly higher for cases in each post-index period.

TABLE 1.

Unadjusted Direct Medical Costs for Venous Thromboembolism Case/Control Pairs by Time Period

Time Period	Case/Control Pairs (n)	Case ($)	Control ($)	Mean Difference ($)	Wilcoxon Signed Rank P-Value
Year before Index	286
mean (SD)		35,039 (39,725)	18,013 (21,798)	17,026 (43,286)	<0.001
median		20,487	10,495	9,080
P25a		11,386	4,861	−1,951
P75a		43,866	21,728	33,162
Index to 5 years	286
mean (SD)		66,250 (97,067)	19,693 (40,311)	46,556 (104,269)	<0.001
median		33,993	7,270	21,553
P25		16,112	2,121	5,424
P75		70,564	22,520	55,894
Index to 3 months	286
mean (SD)		23,831 (27,131)	4,731 (9,209)	19,100 (27,339)	<0.001
median		14,040	1,835	11,371
P25		7,074	158	4,635
P75		30,340	5,335	25,968
3 to 6 months	207
mean (SD)		5,704 (10,422)	1,961 (6,984)	3,743 (12.626)	<0.001
median		1,126	157	624
P25		324	0	0
P75		5,433	828	4,972
6 months to 1 year	188
mean (SD)		11,601 (20,552)	3,524 (8,856)	8,077 (22,044)	<0.001
median		2,546	599	1,395
P25		584	116	−188
P75		14,849	2,698	13,033
1 year to 2 years	167
mean (SD)		17,110 (41,271)	6,997 (27,876)	10,113 (51,070)	<0.001
median		3,725	1,351	1,824
P25		1,141	349	−1,007
P75		14,158	5,008	10,521
2 years to 3 years	147
mean (SD)		15,023 (33,341)	4,945 (10,147)	10,078 (35,363)	<0.001
median		3,442	1,142	1,312
P25		1,010	302	-817
P75		9,716	4,440	7,212
3 years to 4 years	130
mean (SD)		13,900 (32,258)	5,865 (13,688)	8,035 (35,773)	P=0.001
median		2,556	1,072	662
P25		909	219	−1,237
P75		12,288	4,816	10,793
4 years to 5 years	113
mean (SD)		16,790 (43,250)	4,892 (10,139)	11,898 (45,144)	P=0.001
median		2,665	1,067	570
P25		545	232	−1,123
P75		13,015	3,876	9,327

^a25^th and 75^th interquartile range (IQR)

Adjusted cost comparisons

Table 2 provides adjusted mean predicted direct medical costs and mean predicted cost differences for cases and controls for the overall time period from 1988–2005 (index-5-years). After adjusting for group differences in age at index, sex, costs incurred 1 year prior to index and RUB values, the mean predicted costs for cases ($62,838) were significantly higher than those for controls ($24,464), with a mean predicted difference of $38,374 (Bootstrapped 95% CI: $26,975–49,435). The adjusted predicted mean difference in costs were significantly higher for VTE cases than controls for time periods index-3 months, 3–6 months, 6 months-1 year, and 2–3 years post index. Adjusted predicted costs were higher for cases but not significantly different from controls for periods 1–2, 3–4 and 4–5-years post-index, possibly due to the high estimated variability in predicted costs.

TABLE 2.

Adjusted^a Mean Direct Medical Costs for Venous Thromboembolism Case/Control Pairs by Time Period

Time Period	Cases ($)	Controls ($)	Mean Difference (Bootstrapped 95% CI; $)
Index to 5 years	62,838	24,464	38,374 (26,975; 49,435)
Index to 3 months	22,646	5,749	16,897 (13,761; 19,973)
3 to 6 months	4,626	2,610	2,016 (210; 3,597)
6 months to 1 year	10,125	5,058	5,068 (1,717; 8,167)
1 to 2 years	13,804	9,761	4,043 (−7,210; 12,686)
2 to 3 years	13,211	6,921	6,290 (1,373; 11,797)
3 to 4 years	11,273	9,661	1,611 (−5,510; 7,290)
4 to 5 years	20,617	12,674	7,943 −5,373; 21,806)

^aPredicted cost adjusted for age, sex, costs in the year prior to index and Resource Utilization Band.

DISCUSSION

There is a shortage of reliable data regarding the extent to which hospital-associated VTE contributes to excess medical costs and for how long any excess costs occur. The present population-based study followed individuals who were hospitalized for acute medical illness to compare total direct medical costs between patients who did and did not experience an objectively-confirmed VTE during or 92 days after hospitalization, the time period of highest VTE risk. The adjusted predicted mean direct medical costs were significantly higher for cases than for controls from index to 5-years post-index. The adjusted predicted mean cost for VTE cases was $62,838 versus $24,464 for non-VTE controls (mean difference=$38,374). Although comparisons of across-study findings should be interpreted with caution, the VTE-attributable costs appear to exceed medical care costs attributable to osteoporotic hip fracture³⁴, Parkinson’s Disease²⁴, complications of percutaneous coronary intervention³⁵ and traumatic brain injury.²¹

VTE-attributable costs were highest within 3-months following VTE; the adjusted predicted mean difference in direct medical costs between persons who did and did not experience VTE was $16,897. This is possibly related to early costs for VTE diagnosis and acute management. Importantly, however, costs remained about two-fold higher for VTE cases compared to controls from 3-months to 3-years after index. This difference reached significance for all periods up to 3-years except for 1–2-years post-index. During the 1–2 year period, 1 control and 2 cases incurred total costs >$200,000, substantally more than any other case or control during that period. The control was hospitalized for 3 months with respiratory failure requiring mechanical ventilatory support in intensive care. One case underwent 24 surgeries (most orthopedic) in that period; the other case underwent heart transplantation. If these outliers are excluded, the adjusted predicted mean difference in direct medical costs ($3,215) was still higher in cases compared to controls, but the difference was not significant (95% CI: -$890; $8,545). Nevertheless, we suspect that costs are significantly higher for cases than controls for at least 3 (and possibly 5) years after index. This prolonged cost difference could reflect incremental costs for management of VTE complications (i.e., post thrombotic syndrome, chronic thromboembolic pulmonary hypertension) and VTE recurrence. Over the 5-year post-index time period, 51 (18%) VTE cases had recurrent VTE with a median time to recurrence of 180 days (IQR: 2 days-5 years). From index to 5 years post-index, the adjusted predicted mean cost for the 51 VTE cases with recurrent VTE cases was $106,005 versus $21,950 for non-VTE controls (mean difference=$84,055; 95% CI: $55,993; $127,457). The adjusted predicted mean cost of the 235 VTE cases without recurrent VTE was $54,426 compared to $24,653 for the control (mean difference=$29,773; 95% CI: $18,705; $42,827).

Two previous studies reported mean ± SD (median) costs of $8,331 ± $18,667 ($4,003) for persons with a VTE³⁶ and average hospital costs of $8,794 associated with treating PE, respectively.⁴ However, these studies did not include a control group such that costs attributable to VTE could not be estimated. In the only previous study that included a control group, reimbursed hospitalization costs were $10,804 and $16,644 for primary diagnoses of DVT and PE², respectively, estimates that are comparable to our index-3 months ($16,897) costs. However, all previous studies likely underestimated the direct medical cost attributable to VTE by over 50% due to failure to identify long-term costs of VTE.

Our study has a number of limitations. The estimates are for a single geographic population which in 2010 was 90% white. The age- sex- and racial-distribution of Olmsted County is similar to that for Minnesota, the upper mid-west, and the U.S. white population; however, residents of Olmsted County exhibit higher median income and education level compared to these geographic regions.^14,18 While no single geographic area is representative of all others, the under-representation of minorities may compromise the generalizability of our findings to different racial and ethnic groups. Costs associated with pharmacologic treatments were not included in this analysis due to lack of electronically available data on outpatient pharmacological costs throughout the total time period. However, the incremental costs of VTE pharmacologic treatment likely would increase the cost difference between cases and controls. Certain sequelae of VTE, such as pulmonary hypertension and post-phlebitic syndrome, were not identified following incident VTE during most of this time period so costs specific to these conditions could not be collected. Finally, cost estimates were limited to direct medical care costs and did not include indirect or nursing home costs.

In conclusion, VTE associated with a recent hospitalization for medical illness contributes a substantial economic burden to society across all hospital and ambulatory care delivered. This finding will help to inform models that assess the cost-effectiveness of alternative interventions to reduce VTE occurrence and guide reimbursement policy.

Take-away points.

Venous thromboembolism (VTE) during or shortly after hospitalization for acute medical illness contributes a substantial economic burden; VTE-attributable costs are highest in the initial 3 months but persist even 3 years beyond the VTE event date. This finding will help to inform models that assess the cost-effectiveness of alternative interventions to reduce VTE occurrence and guide reimbursement policy.