Economic Burden of Long-Term Complications of Deep Vein Thrombosis after Total Hip Replacement Surgery in the United States

Authors


Address correspondence to: F. Botteman, Executive Director, International Health Economics, HERQuLES: Health Economic Research & Quality of Life Evaluation Services, Abt Associates Clinical Trials, 4800 Montgomery Lane, Suite 600, Bethesda MD 20814.
E-mail: marc_botteman@abtassoc.com

ABSTRACT

Background: Estimates of the cost of long-term complications of a primary deep vein thrombosis (DVT), including the post-thrombotic syndrome (PTS) and recurrent venous thromboembolism (VTE), may be relevant for resource allocation decisions.

Objective: The objective of this study was to provide US cost estimates of the long-term complications of a primary DVT, which occurs in approximately 5% to 20% (with adequate thromboprophylaxis) and 50% (in the absence of thromboprophylaxis) of total hip replacement surgeries (THRS).

Methods: A literature-based model was used to project the excess long-term complication costs of DVT following THRS. The model simulated the natural history of DVT complications using published estimates of the incidence and prognosis of PTS and recurrent VTE. Each complication was assigned a cost obtained by multiplying the amount of resources used in its management by the unit price of these resources.

Results: The annual per-patient cost of each complication was as follows: mild-to-moderate PTS, $839 in the first year and $341 in subsequent years; severe PTS, $3817 in the first year and $1677 in subsequent years; DVT, $3798; and pulmonary embolism, $6604. The average discounted lifetime cost of DVT complications was estimated to be $3069 (95% interval $2091–$4279).

Conclusions: The long-term complications of a primary DVT represent a significant economic burden. Preventing a DVT could arguably lead to substantial savings in long-term DVT complications.

Introduction

Deep vein thrombosis (DVT) is a major complication of total hip replacement surgery (THRS), which occurs in 5% to 20% of patients receiving adequate thromboprophylaxis and 50% in the absence of DVT prevention [1,2]. In the short term, DVT can result in morbidity and mortality from pulmonary embolism (PE). The long-term clinical course following DVT can be further complicated by excess mortality, recurrent venous thromboembolism (VTE), and post-thrombotic syndrome (PTS) [3,4]. PTS is a constellation of signs and symptoms that frequently follows a vascular thrombosis, ranging from pain, skin pigmentation, and swelling in the lower extremities to the formation of recurring venous leg ulcers resulting in chronic pain, decreased mobility, and ongoing medical resource utilization [5–7]. The PTS results from the increased venous pressure owing to residual obstruction or valvular reflux as well as general damage to or destruction of the venous valves and walls of the deep veins and communicating veins of the leg following DVT and obliteration of the thrombosed veins rather than recanalization [1,8]. Although the clinical manifestations of PTS are well known, the quality-of-life (QOL) and socioeconomic impacts of PTS have not been extensively documented, except for the most severe forms of the syndrome, such as venous leg ulcer [7,8]. To the best of our knowledge, only one study in Europe [9] and another study in the United States [10] have attempted to determine the costs associated with the entire range of long-term complications of DVT. Costs-of-illness estimates are important inputs for policy decisions. However, such estimates are lacking in the context of the long-term complications of DVT. Our objective was to provide a baseline measure of the resources used and costs to manage the long-term complications of DVT. These estimates were derived in the context of a DVT occurring after THRS for several reasons. First, as opposed to idiopathic DVT or DVT resulting from the use of drug therapy, such as oral contraceptive or hormone replacement therapy, DVT-complicating surgeries such as THRS are extremely common, if not inevitable, without preventive measures [2]. Fortunately, DVT following surgery can actually be prevented with aggressive thromboprophylaxis using oral anticoagulants and compression stockings, unlike other idiopathic or drug-induced DVT. Finally, to date, a large part of the literature on the economics of DVT prevention has focused on orthopedic surgery and in particular THRS. Accordingly, a baseline estimate of the costs associated with long-term complications of DVT in the context of THRS should help decision makers better appreciate the overall value of aggressive thromboprophylaxis measures.

Materials and Methods

Model Overview

A literature-based Markov model using probabilistic sensitivity analysis via Monte Carlo simulation was developed to project the clinical, QOL, and economic burden of long-term complications of a primary DVT following THRS in the United States. The target population for this analysis was composed of two hypothetical cohorts of patients. Both cohorts were similar in age at 72 years old and in sex at 65% women to the population of all patients undergoing THRS in the United States as reported in the 1995–1996 Health Care Utilization Project (HCUP, Agency for Healthcare Research and Quality, Rockville, MD). However, one of the two cohorts was representative of patients who would have developed and survived a primary DVT following a THRS (i.e., the cases), while the other was representative of patients not experiencing a DVT following THRS (i.e., the controls). By comparing the lifetime costs and survival of cases and controls, the model allows the estimation of the long-term economic cost and survival impact attributable to the development of a primary DVT following THRS.

The analysis was performed from the perspective of payers responsible for the direct medical costs in both the inpatient and the outpatient setting. Indirect costs, such as time loss to seek care and productivity losses, were therefore not included in this analysis. We included time preference by discounting future economic and health consequences at an annual rate of 3%.

The Markov model depicts the natural history of post-DVT complications (i.e., PTS, recurrent VTE, and death) as an evolving sequence of 16 “health states” defined to capture important traits (i.e., QOL and cost) of these complications (Fig. 1). Of these 16 health states, 13 were actually used in the simulation and the additional 3 were included to help frame the clinical problem at hand. Specifically, following THRS, an individual can experience a DVT and survive the short-term period following this event, experience DVT but die from its complications from PE or treatment-related complications, or experience no DVT and therefore survive. Once patients have gone through these three states, the simulation effectively begins with the survivors in the two main groups: the “cases,” patients who survived a primary DVT following surgery, and the “controls,” patients who survived without experiencing a primary DVT following surgery. As time passes, individuals who have survived a primary DVT after surgery (i.e., the cases) can remain in this post-DVT state, develop signs and symptoms of mild-to-moderate PTS, signs and symptoms of severe PTS, or die. Patients who did not experience a primary DVT after surgery (i.e., the controls) are also assumed to experience idiopathic PTS, albeit less frequently. The model established a distinction between the first and subsequent years after the development of PTS to allow for differences in diagnostic and treatment patterns and associated costs that occur at different rates in the first and subsequent years. Once patients entered in the PTS states, they remained in these states until they died or the end of the simulation at the age of 100 years. Because of limited epidemiologic data, the model further assumed no movements of patients between the mild-to-moderate PTS and severe PTS states. Finally, patients also incur costs as a result of VTE events, which were accounted for as isolated clinical events rather than as health states. VTE also occurred relatively more frequently among patients with a history of DVT.

Figure 1.

Overview of the model.

The definition of PTS used in the model followed the clinical-etiologic-anatomic distribution-pathophysiologic (CEAP) dysfunction system [15]. As its name indicates, the clinical classification of the CEAP is based on a combination of etiologic classification (congenital, primary, or secondary), anatomic distribution (superficial, deep, or perforating, including subclassifications for each), and pathophysiologic dysfunction (reflux, obstruction, or both). Table 1 presents the six classes included in the CEAP. In the model, mild-to-moderate PTS and severe PTS refer to clinical classes 1–4 and 5–6, respectively. All patients developing severe PTS for the first time were classified as “severe, open ulcer,” following the assumption that an ulcer must be open before being healed. In addition, although an ulcer may heal (clinical class 5), patients who had developed an ulcer were assumed to remain in the severe PTS health state, alternating between healed and open ulcer status, for the rest of their lives.

Table 1.  PTS by the CEAP classification system
Clinical symptomsClass
  1. Note: In addition to the above classification, the CEAP requires the categorization of each limb as symptomatic or asymptomatic. Adapted from Bebbe et al. [15].

No visible or palpable signs of venous disease0
Telangiectases, reticular veins, malleolar flare1
Varicose veins2
Edema without skin changes3
Skin changes ascribed to venous disease (e.g., pigmentation,
venous eczema, lipodermatosclerosis)
4
Skin changes as described above with healed ulceration5
Skin changes as described above with active ulceration6

Data and Assumptions

Natural history and clinical outcomes. Data from Prandoni et al. [16] were used to estimate the incidence rate of PTS following a DVT (i.e., among cases). This 8-year observational prospective study followed 528 consecutive patients with a first episode of symptomatic, venographically confirmed DVT to monitor the development of complications of a primary DVT, such as PTS, recurrent VTE, and mortality. The rate of idiopathic PTS among controls was assumed to be similar to that of the general population and was taken from a population-based study in the United States [17].

Patients that developed leg ulcers because of venous insufficiency were considered to have severe PTS. Accordingly, all patients in whom severe PTS developed for the first time were considered by definition to have an open ulcer. Although ulcers can heal, the underlying condition remains, as the damage to the venous system is serious and irreversible. Therefore, from the second year onward, patients were assumed to remain in the severe PTS state, with alternating periods of time during which they would have open and healed ulcers. Specifically, at any given time after the first year with severe PTS, 31.5% and 68.5% of patients would have an open and a healed ulcer, respectively.

In addition, patients in the model were at risk for recurrent VTE. Prandoni et al. [16] provides the incidence rate of recurrent DVT and PE in cases. It was assumed that 20.8% of recurrent VTEs would be PEs [16]. Finally, patients who did not develop a DVT following surgery were assumed to experience idiopathic DVT and PE at the incidence rates observed in the general population (i.e., 160 DVT per 100,000 and 70 PE per 100,000) [1].

Survival curves were constructed to model the life expectancy of patients in both groups. Patients who survive THRS surgery typically have a very favorable life expectancy [20,21]. In contrast, there is evidence that the long-term survival of patients who have experienced a DVT is compromised [3,9,16]. In the baseline model, survival curves for the first 15 years of the simulation were modeled based on an observational study of long-term complications and survival after acute DVT [9]. This study found that the survival of patients who had an acute DVT was shorter than for age- and sex-matched controls that did not experience a DVT. To complete survival curves up to the age of 100 years, US life tables [22] were used, explicitly assuming patients in both groups would experience the life expectancy of the general population. In the sensitivity analyses, a scenario in which no difference in survival was assumed between cases and controls was conducted. In this scenario, all patients had a life expectancy identical to the age- and sex-matched control group as reported in Bergqvist et al. [9] for the first 15 years, and, for subsequent years, patient survival was based on the US life tables provided by Anderson [22].

Health-related quality-of-life adjustments. Life expectancy was adjusted for quality of life by using health state utilities (Table 2). Utilities represent an individual patient's preferences for a given health state and are scaled from 0 to 1. Quality-adjusted life years (QALY) are calculated by multiplying the time spent in a given health state by the utility value of that state. For the health state associated with no complications after DVT, weighted age- and sex-specific utilities obtained using the Quality of Well-Being Scale from a community sample of adults were used [23]. QALY weights for mild-to-moderate PTS and severe PTS were based on standard gamble utilities obtained from healthy volunteers [24]. Decrements in utility for recurrent VTE and treatment complications were expressed in days lost equivalent to the length of hospital stay [25].

Table 2.  Utility weights
VariableEstimateRange testedReference
  • Note: Adapted from Gould et al. [25].

  • *

    Standard deviation around the mean used to construct log normal distribution function for probabilistic sensitivity analysis according to Doubilet et al. [13].

  • Utilities are expressed as a ratio from age- and sex-specific estimate.

  • Decrements in utility expressed as days lost equivalent to the duration of hospitalization.

  • Abbreviation: M/M, mild-to-moderate.

Age- and sex-specific estimate
 Women
  65–740.710.10*[23]
  75–840.670.11*[23]
  85+0.670.10*[23]
 Men
  65–740.730.11*[23]
  75–840.680.10*[23]
  85+0.610.07*[23]
M/M PTS0.980.04*[23]
Severe PTS0.930.07*[24]
DVT5.9 days2.65–8.85[25]
PE7.1 days3.55–10.65[25]

Estimation of costs. The costs for diagnosis and treatment of PTS and VTE were estimated in several steps. First, patient care protocols were defined by the literature to specifically identify the key, direct cost resource use items required for managing patients with PTS. The cost was expressed in US$2000 for each of these protocols and was then determined. This was accomplished by first estimating the type and amount of resources that would be used with each protocol. Resource use items included physician/ nurse office visits, diagnostic tests, medical supplies, medications, hospitalizations, and surgeries. The annual cost of these complications was then obtained by multiplying the amount of resource use by their unit costs. Appendix A details the patient care protocols and associated costs for PTS.

Patient care protocol for mild-to-moderate PTS. Limited information is available in the literature regarding standard care protocols for patients with mild-to-moderate PTS. While several surgical procedures are available, conservative management is largely preferable [8]. Diagnosis of mild-to-moderate PTS includes a clinical evaluation by a physician and ultrasonography of the vascular system in legs [8].The cornerstone of therapy is indefinite use of Grade 2 elastic compression stockings to reduce venous hypertension, improve tissue microcirculation, and prevent progression to severe PTS and open venous ulcers [6]. Some patients may benefit from surgical intervention early on to prevent progression to severe PTS [26]. While perceptions of managing PTS are slowly changing, the American Venous Forum recognizes that for many years venous disease has been considered the “stepchild” of vascular surgery, resulting in less than optimal care for many patients, such as clinic care by medical students for open ulcers [27]. For primary care practitioners, training in the diagnosis and management of venous disease is lacking and diagnosis/intervention may not occur until patients progress beyond the mild/moderate stage, at which point they are then referred to a vascular surgeon [27]. Therefore, because the symptoms of PTS often go unrecognized or are ignored for months or even years, we assumed that only about 50% of mild-to-moderate PTS patients would actually be identified and receive care for PTS. In sensitivity analyses, this proportion ranged from 25% to 75%. We also used the clinical expertise and experience of two of our authors, J.A.C. and A.T.C., to supplement the gaps in the literature such as selection of specific procedure codes for applying costs and specific frequency of some resources used.

For the initial work-up of mild-to-moderate PTS, 50% of patients would receive a level 5 (CPT 99215) physician office visit and a duplex ultrasound scan of the venous anatomy. A small proportion of patients equaling 7.5% without palpable pedal pulses would also receive an arterial Doppler as part of the differential diagnostic evaluation. Once diagnosis was confirmed, 50% of patients would receive Grade 2 elastic compression stockings, with 30 to 40 mmHg pressure at the ankle, as first-line management. During follow-up care in the first year, 50% of the patients would receive approximately 4 level 3 (CPT 99213) follow-up office visits. Some patients would also receive level 1 nurse visits (CPT 99211) for education or skin care. In addition, 20% of patients would receive vein legation and stripping.

In subsequent years, routine follow-up care consisted of regular physician office visits and appropriate nurse visits, periodic reevaluation with duplex ultrasound and arterial Doppler, and use of Grade 2 compression stockings.

Patient care protocol for severe PTS. For severe PTS, the comprehensive patient care protocol to achieve healing of an open ulcer was based on published guidelines for the management of venous leg ulcers, supplemented with expert panel opinion for utilization frequencies of various resources and selection of procedure codes for costing purposes [6,28]. All patients with severe PTS were assumed to seek and receive care.

Components of care included physician office visits, nurse visits for wound care, compression bandages (Unna's paste boot or long- or short- compression bandages), medications such as antibiotics, home health care, hospitalization, outpatient surgical debridement of wounds, and skin grafting [28]. For costing severe, open-ulcer PTS, a study by Marston et al. [29] was used. This study outlined the care and associated costs required to heal an open ulcer based on its size. Of those patients with open ulcers, 36% had an ulcer size of < 5 cm2, 37% were size 5 to 20 cm2, and 27% were size > 20 cm2.

For patients with open ulcers, 75% received a prescription for a fluoroquinolone to manage infection on an outpatient basis as part of wound care. Hospitalization for severe cellulitis and/or uncontrolled edema was required in approximately 7% of severe, open-ulcer PTS patients [29]. In some rare instances, patients were assumed to undergo amputation (0.4%), skin graft (2%), and debridement (2%). After ulcer healing in the first year, 10% of severe PTS patients would receive vein legation and stripping procedures and about 5% would receive subcutaneous endoscopic perforator surgery (SEPS).

Follow-up care for patients with healed ulcers included 4 level 4 (CPT 99214) physician office visits per year. Duplex ultrasound scan was repeated annually for all severe PTS patients and arterial Doppler was used for follow-up care in 20% of patients. All patients received Grade 2 elastic compression stockings as the primary maintenance measure after the ulcer healed.

Patient care protocol for VTE. Acute inpatient care costs for recurrent VTE (DVT and PE) were based on the average Medicare reimbursement for DRG 128 and 78, respectively. Follow-up outpatient care included oral anticoagulation therapy for three months [2,30] with warfarin (Dupont Pharmaceuticals, Wilmington, DE), using an average of 6 mg per day to maintain the international normalized ratio between 2 and 3, and an average of 9.25 prothrombin time laboratory tests and two outpatient follow-up visits.

Costing of patient care protocols. For inpatient care, costs consisted of the average Medicare DRG payment [31] plus the physician fees for the number of days of inpatient follow-up care based on the mean length of stay published with the DRG. Physician fees were based on designated CPT-4 codes. Medicare reimbursements for physician fees were gathered from Medicode's National Fee Analyzer [32].

For all outpatient care, such as vascular laboratory testing, office visits, and minor surgeries, costs consisted of the Medicare reimbursement rates for physician or laboratory fees (based on CPT-4 codes) plus the outpatient facility fee for that procedure. Outpatient facility fees were gathered from the Federal Register using Medicare Ambulatory Payment Classification (APC) codes [33]. Home healthcare equipment costs were from the Centers for Medicare and Medicaid Service's (formerly Health Care Financing Administration) Durable Medical Equipment, Prosthetics/Orthotics, and Supplies (DMEPOS) Fee Schedule [34]. Jobst Compression stocking costs were estimated using retail prices. Drug costs were estimated using average wholesale prices (AWP) from the RedBook [35].

For severe PTS with open ulcers, a literature-based estimate of the comprehensive cost to heal ulcers was used [29]. The average cost of out-patient care to heal an open ulcer (adjusted to US$2000 prices) was $1372 for an ulcer size of <5 cm2, $2045 for a size of 5 to 20 cm2, and $5567 for a size of >20 cm2[29]. This study included Medicare reimbursement levels of physician fees for evaluation and nonsurgical procedures; blood, vascular, and other labs; and home health care. Hospital costs were used to estimate costs of wound dressing materials. No surgery was performed until ulcers healed. The hospital cost component of inpatient SEPS was also based on the literature [36].

Analyses

The model projects the cumulative incidence of PTS and VTE, the average number of years of life spent in the various health states, the life expectancy and the quality-adjusted life expectancy of the patients in the case and control groups. The annual costs associated with each health state were estimated based on the treatment protocols. These cost estimates were subsequently used to project the lifetime costs of cases and controls and the subset of patients who developed PTS.

All analyses were performed using probabilistic sensitivity analysis via Monte Carlo simulation to account for parameter uncertainty [13,37]. This method generated 5000 runs or trials of the model using a different set of values for the model parameters selected from the assumed distribution of the parameters for each run. All variables in the model were included in the Monte Carlo simulation, with the exception of mean age of surgery and discount rate, which remained held at their baseline values, as recommended by Briggs [38]. In general, the exact distribution of the value taken by the parameter was unavailable. In these cases, triangular distributions were used. In triangular distributions, the likeliest value, that is, the baseline value, falls between the minimum and maximum values, assumed to be ± 50% from baseline, forming a triangular-shaped distribution, which shows that values near the minimum and maximum are less likely to occur than those near the likeliest value [39,40]. However, in a few instances with sex-specific utility and utility for time spent with PTS, log normal distributions were used, following the transformation proposed by Doubilet et al. [13]. The results of the 5000 simulations were then analyzed to determine mean and uncertainty intervals by taking the 2.5 and 97.5 percentile values to represent endpoints (for a 95% interval) for the outcomes of the model. Following Briggs [38], we use the term “uncertainty interval” as a generic term rather than employing the frequently used “confidence interval” or the Bayesian equivalent “credible interval.” We conducted additional univariate and multivariate sensitivity analyses to further 1) determine the robustness of the results and conclusions; 2) identify the parameters that contributed the most to the results; and 3) identify important model uncertainties. This was accomplished by testing the impact on results of adding or subtracting 50% from the baseline estimate of key parameters. Finally, the model was run using alternative discount rates (0% and 5%).

Finally, a separate scenario analysis was conducted to test the impact of setting survival for all cases equal to that of controls, as opposed to assuming that cases have a shorter life expectancy than controls.

Results

Projected Incidence of Long-term Complications

The cumulative proportion of patients who survived an initial acute, postsurgery DVT who developed mild-to-moderate PTS was 21.47% (95% UI 13.08%, 29.83%) compared to 1.34% (95% UI 0.82%, 1.85%) in the control group. The cumulative proportions of patients who survived an initial acute, postsurgery DVT who developed severe PTS, recurrent DVTs and PE were 8.11% (95% UI 5.04%, 11.22%), 24.38% (95% UI 15.17%, 34.20%), and 6.52% (95% UI 3.54%, 10.42%), respectively. Corresponding figures for the control group were 0.39% (95% UI 0.24%, 0.55%), 2.36% (95% UI 1.34%, 3.58%), and 1.00% (95% UI 0.49%, 1.68%), respectively. Therefore, the excess cumulative proportion for mild-to-moderate PTS was 20.13% (95% UI 11.66%, 28.55%). Similarly, the excess cumulative proportions of cases developing severe PTS, DVTs, and PEs were estimated at 7.72% (95% UI 4.63%, 10.83%), 22.02% (95% UI 12.69%, 31.88%), and 5.52% (95% UI 2.44%, 9.45%), respectively.

Life Expectancy and Quality-adjusted Life Expectancy

On average, cases and controls were projected to live for 11.21 years (95% UI 8.51, 14.93) and 14.55 years (95% UI 12.21, 17.72), respectively. Therefore, the net long-term life-expectancy reduction associated with developing a primary DVT was estimated to be 3.34 years (95% UI 0.99, 7.59). The model also projected differences in the amount of time cases and controls spent with mild-to- moderate PTS (2.44 vs. 0.18 years), severe PTS (0.91 vs. 0.05 years), and without PTS (7.86 vs. 14.32 years). After adjustment for quality of life, the model projected that cases lose about 2.31 (95% UI 0.54, 5.18) QALYs compared to controls.

Annual Cost of PTS and VTE

Based on the treatment protocols (Appendix A), the annual costs of mild-to-moderate PTS during the first year of diagnosis and subsequent years were $839 and $341, respectively (Table 3). The reduction in costs from the first year to subsequent ones was primarily attributable to a reduction in surgery-related costs. By definition, all severe PTS patients have open ulcers during the first year and incur the highest level of resource use and cost, amounting to $3817 per patient. After the initial year, severe PTS can take the form of either open or healed ulcers. For patients with open ulcers, direct medical costs were estimated to be $3295 per year. For healed ulcers, annual costs were estimated to be $933 per year, 76% lower than the cost for a first-year open ulcer. A weighted average of the annual costs of open ulcer ($3395 in 31.5% of patients) and healed ulcer ($933 in 68.5% of patients) was used as the estimated cost of severe PTS, in the second year and beyond, totaling $1677. The annual cost of diagnosis and treatment of DVT and PE events occurring in the long term were estimated at $3798 and $6404, respectively.

Table 3.  Annual cost of diagnosis and treatment of PTS by year and severity
 M/M PTSSevere PTS
Year 1Year 2+Year 1
(open ulcer)
Year 2+
(open ulcer)
Year 2+
(healed ulcer)
  • *

    The costs of office visits and vascular lab tests are included in the comprehensive ulcer treatment.

  • Abbreviation: M/M, mild-to-moderate.

Office visits$161$107**$291
Vascular lab tests$185$104**$381
Medical supplies$130$130 $202 $202$260
Medications $66 $66
Vein ligation and stripping$363 $182
SEPS procedure $103
Comprehensive ulcer treatment$2712$2712
Other hospitalizations/procedures $552 $314
Total$839$341$3817$3295$933

Lifetime Costs of Long-term DVT Complications

The model projected that cases would experience a discounted remaining lifetime cost of $3311 (95% UI $2312, $4539), an excess of $3069 (95% UI $2091, $4279) compared to controls (Table 4). Approximately half (55%) of the total excess costs were incurred within the first five years of the simulation (Fig. 2). After 15 years, the total discounted excess lifetime cost was $2814. Sixty-three percent (95% UI 46%, 79%) of the discounted excess lifetime cost was attributable to PTS-related costs as opposed to VTE-related costs. Approximately two-thirds (64%) of the excess PTS costs were attributable to severe PTS and one-third to mild-to-moderate PTS. Over two-thirds (70%) of the excess VTE costs was due to DVT as opposed to PE.

Table 4.  Discounted lifetime cost of diagnosis and treatment of long-term DVT complications
 CasesControlsDifference
Mean95% UIMean95% UIMean95% UI
Mild-to-moderate PTS $751 $330–$1351 $51 $23–$90 $700 $295–$1278
Severe PTS$1320 $720–$2116 $71 $40–$111$1249 $658–$2023
DVT $857 $441–$1408 $70 $34–$118 $787 $391–$1319
PE $383 $173–$694 $50 $21–$94 $333 $135–$636
Total$3311$2312–$4539$242$166–$334$3069$2091–$4279
Figure 2.

Discounted lifetime cost of long-term DVT complications over time: cases, controls, and net excess cost.

Lifetime Costs of PTS

Among cases and controls, patients who developed PTS were projected to incur $7,053 (95% UI $4,665, $10,158) and $7,072 (95% UI $4,683, $9,890) in PTS-related discounted cost over the remainder of their lives, respectively.

Univariate Sensitivity Analyses

As Table 5 indicates, the net excess cost associated with the long-term complications of a surgery-related DVT is most influenced by the incidence of severe PTS, recurrent VTE, and the mortality rate among cases. Changes in the cost of managing patients with PTS and recurrent VTE are also associated with important changes in the net excess cost. All other variables appear to have significantly less influence. When the several critical parameters were simultaneously varied by ± 50%, the estimate of discounted lifetime excess cost typically ranged between approximately $1500 and approximately $4500. Finally, in an analysis of extremes, all parameters were varied simultaneously by ± 50% to estimate the lowest and the highest estimates of costs. Based on these analyses, the estimate of discounted lifetime excess cost ranged from an absolute minimum of $449 to an absolute maximum of $9554.

Table 5.  Sensitivity analyses
ParametersParameters at 50%
Below baselineAbove baseline
Univariate sensitivity analyses
 Proportion of
  Cases developing mild-to-moderate PTS$2673$3419
  Cases developing severe PTS$2394$3699
  Cases developing recurrent VTE$2446$3647
  Recurrent VTE that are PEs in cases$2971$3121
  Controls developing mild-to-moderate PTS$3071$3021
  Controls developing severe PTS$3082$3011
  Controls developing recurrent VTE$3088$3005
  Recurrent VTE that are PEs in controls$3053$3039
 Annual cost of
  Mild-to-moderate PTS (Year 1)$2967$3125
  Mild-to-moderate PTS (Year 2+)$2777$3315
  Severe PTS (open ulcer) (Year 1)$2913$3179
  Severe PTS (open ulcer) (Year 2+)$2747$3346
  Severe PTS (healed ulcer) (Year 2+)$2862$3231
 Proportion of severe PTS that are open ulcers (Year 2+)$2832$3261
 Cost of a DVT episode$2654$3438
 Mortality rate in
  Cases$3725$2641
  Controls$2988$3083
 Discount rate$3620$2760
 (rate at 0%)(rate at 5%)
Multivariate sensitivity analyses
 Proportion of cases developing
  PTS$2021$4072
  PTS or recurrent VTE$1421$4672
 Annual cost of PTS$2082$4011
 Cost of an episode of a DVT or a PE$2488$3605

Scenario Analysis

When long-term survival for cases was set equal to the survival of controls, the difference in QALY between the two groups was reduced from 2.31 to 0.09 (95% UI 0.02, 0.26), but the cost difference increased from $3069 to $3441 (95% UI $2372, $4678). This is not surprising because as patients with a history of DVT live longer, they should have a longer exposure to the cost of DVT complications.

Discussion

Our model projects that the discounted excess lifetime costs of managing the long-term complications of DVT after THRS can be substantial: $3069 (95% UI $2091, $4279; range $449–$9554). The model also estimates that patients who develop PTS will incur close to $7000 in discounted PTS-related costs over the rest of their lives. Finally, surgery-related DVTs are projected to continue to negatively impact a patient's quality-adjusted life expectancy over the long term. For instance, we found that the net impact of developing a primary DVT was estimated to be a reduction in life expectancy of 3.34 years and a reduction in quality-adjusted life expectancy of 2.31 QALYs.

Most payers share the heavy burden imposed by the long-term complications of DVT. However, because most patients developing DVT tend to be of older age, and this is even more so the case for patients developing DVT after THRS, which is typically performed in the eighth decade of life, the cost of long-term DVT complications falls more heavily on the Medicare program and other public payers for older patients. In some cases, one can speculate that the entire lifetime cost of DVT complications will have to be carried by these public payers and the patients themselves and their families. Ultimately, however, society as a whole is responsible for covering the expenditures related to these complications, either via social contributions or via insurance premiums.

In their Swedish study, Bergqvist et al. [9] found that the total additional health care cost of treating PTS was approximately $4285 over 15 years, based on a 1990 dollar value. In our study, these costs were lower: approximately $2814 after 15 years and $3069 over the patients’ remaining lifetimes. Bergqvist et al. also found that the 15-year costs of long-term complications represent approximately 75% of the cost of a primary DVT. In our study, similar findings were found: long-term complications represent 74% after 15 years and 81% in a lifetime of the cost of a primary DVT. Finally, among patients with a history of primary DVT, more than one-third of the treatment cost was attributable to recurrent DVT in Bergqvist et al. versus 37% in the present study. In contrast, approximately 75% of the total costs were incurred within the first 5 years in the Bergqvist et al. study, whereas we found that only 55% of these costs were incurred within this very short time frame.

Thus, despite the use of significantly different methods, our estimate of the lifetime costs of late complications of DVT, albeit lower in absolute value, appear to be consistent with that reported for Sweden by Bergqvist et al. [9]. It is interesting to note that both estimates are higher than the one used by Gould et al. [25] in an analysis of the cost-effectiveness of DVT treatments. In the latter study, the lifetime cost of late complications of DVT was approximately $2350 and was obtained by a crude extrapolation of the Swedish data to the US setting.

In an attempt to generalize the validity of our results, all analyses were performed using probabilistic sensitivity analysis via Monte Carlo simulation. This resulted in estimates of long-term excess cost of DVT with a 95% uncertainty interval of $2091 to $4279. Although one could argue that this interval is relatively broad, it does provide some useful information regarding the cost of long-term complications of DVT.

There is no systematic data collection source in this country that allows comprehensive, nationally representative PTS medical cost information to be obtained. In our study, we employed a method commonly used to determine costs [41,42]. Specifically, we developed a model based on protocols for patient care based on a review of the clinical literature and current clinical practice regarding appropriate treatment and expected outcomes and cost for patients with PTS. Our cost estimates are intended to reflect resource utilization associated with good clinical practice and therefore do not necessarily represent the amounts that would actually be incurred by any particular patient, provider, or third-party payer. Our cost estimates may be different had we employed alternative assumptions regarding patient management, prices, incidence rate, and prognosis.

We took great care in selecting assumptions for highly sensitive variables. For instance, we conservatively assumed that no new case of PTS would occur beyond five years and adjusted our estimates of the long-term cost of DVT by accounting for the cost that patients would have experienced in the absence of a DVT. Our assumption about the incidence of PTS was based on a recent prospective epidemiologic study [16] in which patients were aggressively managed to prevent the onset of PTS and recurrent VTEs. Our selection of this study is consistent with previous economic research in which this study was also used [25,43]. The cumulative incidence rate of PTS reported in this population was close to 30%, a conservative figure compared to the pooled weighted average of 50% (range 21–87%) based on 19 epidemiologic reports [8]. Yet, some recent US studies seem to indicate that the rate of PTS and long-term complications after DVT, in particular among patients undergoing THRS, is lower than assumed in the present analysis. For instance, in a large retrospective epidemiologic study of Olmsted County, Minnesota, patients, Heit et al. [17] found that the cumulative incidence rate of venous stasis syndrome following a DVT was only 16.3% at 5 years but it was 24.1% after 20 years. More surprising, Ginsberg et al. [44] found that the rate of PTS following an orthopedic surgery-related DVT event was low (4.0–6.1%) and comparable to similar percentage of patients who did not develop a DVT following surgery (4.3%). As discussed by Ginsberg et al. [44], the likely explanation for these lower rates may be due to the increasingly widespread universal DVT prophylaxis, which reduces the incidence of VTE and the subsequent risk of associated long-term complications. One way to reconcile our results with the recent US epidemiologic data would be to consider that the projected cost of PTS reported here are representative of the costs incurred when aggressive DVT prophylaxis is not adopted. We have also assumed that all cases of severe PTS reported by Prandoni et al. [16] were venous ulcers. This assumption may overestimate the actual rate of ulcers found in this study, but is nevertheless consistent with the range of rates reported in the literature. In addition, it is possible that the cost of managing patients with severe PTS, but no active or healed ulcer, would nevertheless require the level of attention and care administered to manage ulcers due to the severity and chronic nature of their condition. To the extent that this is true, our estimate probably provides an adequate estimate of the lifetime cost of long-term DVT complications.

Finally, in the main analysis, survival for cases was shorter than for controls. This assumption was based on epidemiologic observations [3,9]. However, because patients who survive THRS surgery typically have a very favorable life expectancy, it is possible that cases could in fact enjoy a survival similar to controls. Therefore, a scenario was conducted in which cases and controls had identical survival. This analysis showed that difference in QALY between the two groups decreased from 2.31 (95% UI 0.54, 5.18) in the baseline analysis to 0.09 (95% UI 0.02, 0.26), but the cost difference increased from $3069 to $3441 (95% UI $2362, $4678). This finding suggests that our cost estimate in the baseline may actually be somewhat conservative. On the other hand, assuming that survival between the cases and control is identical, our estimate of QALY loss should be considered an overestimate.

The annual or per-case costs of long-term complications of DVT that served as intermediate inputs in the projection of lifetime costs were derived using the protocols described above. A comparison of these figures with other published analyses suggests that our costing method is reasonable. For instance, our costs of DVT ($3798) and PE ($6404) are consistent with estimates from the literature [25,41–43,45]. Our estimate of the cost of treatment of venous ulcers is also consistent with figures reported in the literature. For instance, Olin et al. [46] recently reported an average cost of treatment of venous ulcer to be $9685 per patient per year. The authors pointed out that their study might underestimate true cost to the extent that it did not include the cost of frequent recurrences [47–49]. Our cost estimates are likely underestimated to the extent that indirect costs, such as productivity losses and time spent seeking care, were not included.

The present estimates of the costs of long-term complications of DVT were derived in the context of THRS. However, these estimates can readily be used in the context of DVT resulting from other causes such as other surgeries, drug-induced DVT, or idiopathic DVT, provided that the incidence of long-term complications and prognosis, including survival, do not differ significantly from our assumptions. The broad applicability of these estimates is due in part to the reliance on epidemiologic data representative of DVT following a wide range of etiologies.

Despite its limitations, we believe that our study provides a useful estimate for the cost of long-term complications of DVT in the United States. It suggests that DVTs result in a significant long-term economic burden for patients. Fortunately, the ability to sharply decrease these high costs currently exists. Although it is unclear that treatment of the initial DVT with anticoagulant therapy or thrombolysis reliably prevents PTS, primary DVT prevention with compression stockings and pharmacotherapy is likely more effective [6]. The American Heart Association [30] states that the most effective way to reduce the morbidity from PTS is to institute a comprehensive institutional policy of primary prophylaxis in patients at risk for VTE. Our cost estimates suggest that adherence to primary prevention measures could significantly reduce health-care costs. For instance, should the rate of DVT occurring in 5% to 20% of 160,000 THRS performed in the United States [50] be reduced by half, savings of approximately $12 million to $50 million could be achieved.

We conclude that our results provide yet another justification for the routine use of measures designed to prevent VTE and its long-term complications. At the same time, we recommend additional research to determine via prospective or cross-sectional primary data collection the incidence, quality-of-life, and economic impact of the long-term effects of a venous thromboembolic event, months and years after the initial event.

We thank Aventis Pharmaceuticals, Bridgewater, NJ, for financial support of this research.

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