Cost-Effectiveness Analysis of Fibrinolysis versus Thoracoscopic Decortication for Early Empyema

Abstract

Background:

Surgical decortication is recommended by national guidelines for management of early empyema, but intrapleural fibrinolysis is frequently used as a first-line therapy in clinical practice. This study compared the cost effectiveness of video-assisted thoracoscopic surgery (VATS) decortication with intrapleural fibrinolysis for early empyema.

Methods:

A decision analysis model was developed. The base clinical case was a 65-year-old male with early empyema treated either by VATS decortication or intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease. The likelihood of key outcomes occurring was derived from the literature. Medicare diagnosis-related groups and manufacturers’ drug prices were used for cost estimates. Successful treatment was defined as complete or near-complete resolution of empyema on imaging. Effectiveness was defined as health utility one-year post-empyema.

Results:

Intrapleural tPA and deoxyribonuclease was more cost-effective than VATS decortication for treating early empyema for the base scenario. Surgical decortication had a slightly lower cost than fibrinolysis ($13,345 vs $13,965), but fibrinolysis had a marginally higher effectiveness at one year (health utility of 0.80 vs. 0.71) resulting in fibrinolysis being the more cost-effective option. Sensitivity analyses found that fibrinolysis as the initial therapy was more cost-effective when the probability of success was greater than 60% or the initial cost was less than $13,000.

Conclusions:

Surgical decortication and intrapleural fibrinolysis have nearly equivalent cost-effectiveness for early empyema in patients that can tolerate both procedures. Surgeons should consider patient-specific factors as well as the cost and effectiveness of both modalities when deciding the initial treatment for early empyema.

Introduction

Empyema remains an important clinical problem with high morbidity and mortality.^1,2 Approximately 20-40% of the one million patients hospitalized in the United States annually with pneumonia develop parapneumonic effusion, and 5-10% of those go on to develop empyema.^3-5 Empyema proceeds classically in three stages: stage I, the sterile exudative phase, which may be managed with antibiotics alone; stage II, the fibropurulent phase, which involves the invasion of bacteria and white blood cells into the pleural space, creating fibrin membranes with locations; and stage III, the organizing stage, in which fibroblasts create a rind in the pleural space that encases the lung.^2,4

Image-guided tube thoracostomy is clearly indicated for early empyema.⁴ However, the effectiveness of intrapleural adjuncts to thoracostomy drainage have not been demonstrated in the literature despite their frequent clinical use.^6-8 Intrapleural treatment of empyema is thought to work by lysing fibrin in stage II of the empyema, preventing progression to an established pleural rind (stage III).^6,8 Tissue plasminogen activator (tPA) is the most commonly used fibrinolytic based on recent trials, including the Multicenter Intrapleural Sepsis Trial 2 (MIST2). Deoxyribonuclease (DNAse) has also been added as an adjunct to help degrade extracellular DNA in the pleural space, decreasing fluid viscosity and facilitating drainage through tube thoracostomy.⁹A cost-effectiveness analysis performed with data from the MIST2 trial showed the combination of tPA and DNAse to be the most cost-effective intrapleural treatment option (compared to either drug alone and placebo).¹⁰

The recent American Association of Thoracic Surgery (AATS) consensus guidelines for the management of empyema did not recommend the routine use of intrapleural fibrinolytics for complicated pleural effusions and early empyemas, due to limited and/or contradictory evidence and patient heterogeneity.⁴ They instead concluded surgical intervention was the gold standard for empyemas. However, intrapleural therapy with tPA/DNAse remains in widespread and increasing clinical use and, in a recent meta-analysis, was concluded to be beneficial for select patients with early empyemas.⁸ Additionally, when surgical resources are limited or place hospital staff at higher risk (such as during infectious disease epidemics), clinicians may seek alternative treatment modalities despite recommended guidelines.

Interpretation of the literature describing use of intrapleural fibrinolytics is difficult as the publications have different clinical populations, use different lytic agents, have different definitions of successful treatment (for example, may use percent reduction in effusion rather than complete resolution), and compare to different strategies (for example, to placebo, or one agent vs. two agents, etc.). These issues make direct comparison of fibrinolysis versus VATS difficult. Only one small randomized trial directly compared intrapleural fibrinolysis to surgical decortication, which found surgical treatment to be superior, but this conclusion is over 20 years old and based off of a small sample of patients.¹¹

This study sought to use decision analysis modeling to compare the cost and effectiveness of video-assisted thoracoscopic surgery (VATS) decortication to intrapleural fibrinolysis with tPA/DNAse in early empyema.

Materials and Methods

Decision model design

We developed a decision analysis model to evaluate two initial treatment strategies for early empyema: VATS decortication and intrapleural fibrinolysis with tPA/DNAse. We chose to model stage II empyema because it is the stage most amenable to treatment with fibrinolytics, whereas stage I empyema can typically be managed with antibiotics and drainage via thoracostomy tube, and stage III empyema requires surgical decortication to remove the pleural rind. We used TreeAge Pro version 2018 (TreeAge Software, Inc.) to construct the decision tree model. Literature review and expert opinion (when published data was not available) were used to estimate relative costs and effectiveness.

Patients

Our base clinical case was a 65-year-old male presenting with early empyema. We selected this base case such that the patient would be a candidate for both tube thoracostomy with fibrinolytic therapy and surgical decortication, and that he would be hospitalized at a healthcare facility staffed with pulmonologists and thoracic surgeons experienced with both treatment modalities. The study perspective was that of the patient.

Treatment strategies

The simplified decision tree for the two treatment strategies is shown in Figure 1. Terminal nodes include death, survival with complications, survival without complications, and (for an unresolved empyema) chronic fibrothorax.

Figure 1: Simplified decision analysis tree.

Blue square: decision node, whether to choose VATS decortication or fibrinolysis as the initial treatment of early empyema

Green circles: chance nodes

Red triangles: terminal nodes

Note that this tree is truncated for simplicity. The full decision tree is available as eFigure 1 in the Supplement.

A patients initially treated with VATS decortication either have full expansion of the lung with resolution of the empyema or incomplete expansion, requiring conversion to open thoracotomy decortication. The possible outcomes after surgery include survival without complications, survival with complications, or death. We assumed that all surgical patients treated with decortication for early empyema would have complete re-expansion of their lung either through the VATS or open approach.

A patient initially managed with intrapleural tPA/DNAse fibrinolysis undergoes tube thoracostomy and is given doses of lytics (10mg tPA and 5mg DNAse) twice daily for three days. After this three-day course the patient either has complete radiographic resolution of the empyema, incomplete resolution of the empyema, or a bleeding complication requiring an operation. Patients with incomplete resolution of the empyema either proceed to observation, a second three-day course of tPA/DNAse, or surgical decortication. After observation, patients either achieve outpatient resolution of the empyema, progress to require an elective open decortication, or develop a chronic fibrothorax (not shown in Figure 1).

Patients who fail to have resolution of the empyema after a second course of fibrinolysis either go on to operative decortication or observation. Observation after two courses of fibrinolysis was followed by outpatient resolution of the empyema, elective open decortication, or a chronic fibrothorax.

Model variables

Event probabilities for the various chance nodes were estimated using published reports derived from literature, where available (Table 1). We defined successful treatment with either surgery or fibrinolysis as complete or near-complete resolution of empyema on imaging. Based on literature review, we used a 70% probability of empyema resolution with intrapleural fibrinolysis for early empyema. Because of data paucity, we broadened our literature review to include reports that used fibrinolytics other than tPA/DNAse in order to calculate the probability of empyema resolution and bleeding complications after fibrinolysis. These included tPA alone, streptokinase, and urokinase. Some model parameters were estimated using expert opinion of pulmonologists and thoracic surgeons due to a lack of published reports, and this is noted in Table 1. These uncertainties were addressed with sensitivity analyses (see below).

Table 1:

Model parameters

Chance parameter	Median (IQR)	Values for sensitivity analysis	References
VATS decortication
Mortality	0.08 (0.06-0.10)	0.06, 0.10	8-10,13
Morbidity	0.11 (0.05-0.22)	0.05, 0.22	8,11,14
Incomplete resolution req. open decortication	0.11 (0.08-0.17)	0.08, 0.17	8-12
Open decortication
Mortality	0.16	0.05, 0.25	10
Morbidity	0.45	0.25, 0.65	14
Fibrinolysis
Complete resolution	0.70 (0.48-0.80)	0.48, 0.80	7,8,15-25
VATS (vs open)	0.70*	0.60, 0.80	-
Failure to completely resolve
Observation alone	0.10*	0.01, 0.20	-
Complete resolution	0.12	0.05, 0.25	15
Chronic fibrothorax	0.05	0.01, 0.20	15
Elective open decortication	0.80*	0.60, 0.80	-
Repeat fibrinolysis	0.20*	0.05, 0.35	-
Complete resolution	0.50*	0.25, 0.75	-
After observation, complete resolution	0.15*	0.05, 0.25	-
Elective open decortication	0.85*	0.75, 0.95	-
Bleeding requiring operative intervention	0.10	0.01, 0.25	17,18,24,26
Proceed to operation	0.70*	0.55, 0.85	-
VATS	0.70*	0.60, 0.80	-
Incomplete resolution req. open decort.	0.30*	0.20, 0.40	-
Bleeding requiring operative intervention	0.03 (0.02-0.04)	0.02, 0.04	7,15,17,18,24,26

IQR, interquartile range

^*Expert opinion due lack of published evidence

IQR included where available. Due to insufficient data on outcomes of VATS or open decortication specifically after failed fibrinolysis or bleeding related to fibrinolysis, these same chance parameters are used throughout the rest of the tree

Costs and Utilities

We defined effectiveness as the health utility at one year post-empyema, taking the patient’s perspective. Health utility ranges from 0 (death) to 1 (perfect health). Health utilities were estimated for patients after VATS decortication, open decortication, fibrinolytic therapy followed by resolution, and failure of empyema resolution with a chronic fibrothorax (Table 2). The one year time point was selected to better allow for complete resolution of reversible peri-operative morbidity and declines in health utility.

Table 2:

Health utility parameters

Health utility for one year after empyema	Value	Values for sensitivity analysis	Reference(s)
VATS decortication, before or after fibrinolysis
Without complications	0.80	0.70, 0.90	29-31
With complications	0.75*	0.65, 0.85	-
Open decortication, before or after fibrinolysis
Without complications	0.70	0.60, 0.80	29
With complications	0.65*	0.55, 0.75	-
Fibrinolysis
Complete resolution	0.85*	0.75, 0.95	-
Chronic fibrothorax	0.39	0.20, 0.55	32, 33
Death	0.00	-

^*Expert opinion due lack of published evidence

Medicare diagnosis-related group (DRG) and manufacturers’ drug prices (for tPA/DNAse) were used for cost estimates (see Table 3 for representative costs, individual costs of tree parameters can be found in Supplemental Table 3). We used Medicare DRG reimbursement based on the Medicare 2018 Inpatient Prospective Payment System for facility cost estimates and Medicare Current Procedure Terminology (CPT) codes with proposed Relative Value Unit (RVU) reimbursement for physician professional fees to define price of hospital procedures (see Supplemental Tables 1 and 2). Drug prices were calculated based on six doses of tPA at 10 mg per dose and a cost of $64.30 per 1 mg, and six doses of DNAse at 5 mg per dose and a cost of $27 per 2.5 mg ampule.

Table 3:

Representative cost parameters based on expected Medicare reimbursement, 2018 U.S. Dollars

Cost parameter	Average Value ($)
VATS decortication	14,552
Open decortication	14,211
Hospitalization for tPA/DNAse, one course
No further procedures	11,915
Ultimately requiring operative intervention	19,047
Hospitalization for tPA/DNAse, two courses
No further procedures	19,369
Ultimately requiring operative intervention	23,407

Payoffs were calculated for each terminal node in the decision tree based on chance and cost parameters as well as the health utilities for each state.

Sensitivity analyses

One-way sensitivity analysis was performed by varying the effectiveness of fibrinolytics to the 25^th and 75^th quartile (0.48, 0.80) while holding all other variables constant. Additional one-way sensitivity analyses were conducted in second tier variables for which expert opinion was used to estimate values due to lack of published evidence, and for variables with published values to their 25^th and 75^th quartiles (see Table 1 and Table 2). Two-way sensitivity analyses were performed by simultaneously varying the effectiveness and the cost of intrapleural tPA/DNAse fibrinolysis while holding all other variables constant.

Results

Base case scenario

For the base case scenario, intrapleural tPA/DNAse was more cost-effective than VATS decortication for treating early empyema. VATS decortication had a slightly lower cost than fibrinolysis ($13,345 vs $13,965), but fibrinolysis had a marginally higher effectiveness at one year (health utility of 0.80 vs. 0.71) resulting in tPA/DNAse being the more cost-effective option (Table 4).

Table 4:

Results of the decision tree analysis

Strategy	Total Cost ($)	Incremental Cost ($)	Health Utility	Incremental Effectiveness	Cost/ Effectiveness	ICER ($/health utility)
Base case
VATS decortication	13,445	-	0.71	-	18,874	-
tPA/DNAse	13,965	520	0.80	0.09	17,471	6,214
Sensitivity analysis: fibrinolysis 48% effective
tPA/DNAse	15,535	2,090	0.77	0.05	39,347	20,295

ICER, Incremental cost effectiveness ratio, is the ratio of the differences in the cost of decisions divided by the differences in health utility, where VATS decortication is the reference decision.

Sensitivity analyses

Upon one-way sensitivity analysis, VATS decortication became more cost-effective than intrapleural tPA/DNAse fibrinolysis when the effectiveness of fibrinolytic therapy to resolve empyema was set at the 25^th percentile of 48% (rather than the median of 70%), generating a health utility of 0.77 for $20,295 (Table 4). Similarly, decreasing the effectiveness of both the first round of fibrinolysis and the repeat round of fibrinolysis resulted in VATS becoming the most cost-effective option. Further one-way sensitivity analyses were performed on intermediate parameters indirectly related to overall efficacy or cost. Those parametric changes in individual underlying result probabilities or utility (Table 1 and Table 2) did not change the preferred decision result between VATS and fibrinolysis.

On two-way sensitivity analysis, intrapleural fibrinolysis with tPA/DNAse as the initial therapy was more cost-effective when the probability of success for tPA/DNAse was greater than 60% or the initial cost of fibrinolysis was less than $13,000.

The morbidity and mortality of VATS decortication and open decortication were further investigated with sensitivity analysis. However, small changes to the morbidity and mortality rates of surgery (in isolation or in combination) did not affect the ultimate outcome favoring fibrinolysis unless they were set at <0.01. Similarly, penalizing the effectiveness or health utility of surgical procedures after fibrinolysis to account for potentially more difficult procedures did not affect the outcome.

Comment

In our primary analysis of cost and effectiveness, VATS decortication and intrapleural tPA/DNAse perform similarly for patients with early empyema who could tolerate either treatment option. Intrapleural fibrinolysis with tPA/DNAse is slightly favored as the more cost-effective treatment option through sensitivity analyses when effectiveness is >60% and cost is <$13,000.

There have not been any randomized trials comparing the effectiveness of intrapleural tPA/DNAse to VATS decortication despite its common clinical usage, hence the need for comparing these two treatment options in the management of early empyema with decision analysis methods. There have been eight prospective, randomized-controlled trials (RCTs) of various fibrinolytics for empyemas and parapneumonic effusions in the last two decades. These include six trials since 2000, most notably the MIST trials.^7,9,18,23-25 In the MIST1 trial, streptokinase increased pleural fluid drainage but did not reduce mortality, the frequency of surgical intervention, or hospital length of stay.⁷ In the MIST2 trial, intrapleural tPA/DNAse resulted in a statistical and clinical improvement in pleural drainage, however the outcome studied was a reduction of effusion rather than complete resolution and was not directly compared to a surgical treatment arm.⁹ The MIST 3 trial is ongoing and aims to address this with a clinically relevant outcome as well as the inclusion of a surgical arm.³⁴ Only one small RCT in 1997 directly compared fibrinolytic therapy with VATS decortication. Wait et al. compared intrapleural streptokinase with VATS in 20 patients, and VATS had a superior success rate and hospital length of stay.¹¹

This study has several limitations. We chose to model stage II or fibropurulent empyema because it is the stage most amenable to fibrinolytic therapy and the stage for which the most clinical equipoise exists regarding treatment options. However, significant heterogeneity exists among patients and disease severity, necessitating individualized decision-making. The ability of a decision analysis to model what happens in real life is limited by the accuracy and quality of the data informing the variable estimates. Thus, the heterogeneous definition of successful treatment with intrapleural fibrinolytics (not synonymous with empyema resolution) used in published reports, as well as our reliance on expert opinion in the absence of robust evidence for multiple chance parameters used in our decision tree directly affected the outcomes and limit the quality of our conclusions. Furthermore, we used the health utility at one year as our effectiveness endpoint, extrapolating reported outcomes in the literature out to a longer-term endpoint. Although the quality of the data is limited for many of these variables, sensitivity analyses were used to mitigate this limitation as they can demonstrate which estimates are key drivers of the outcome and identify the ranges necessary to change an outcome. Additionally, Medicare DRG and CPT prices for inpatient hospital care were used to estimate cost. They are commonly used in the literature but do not reflect actual costs to hospitals or patients and are significantly lower than prices to private insurers and may effect the generalizability of the results. Finally, our decision analysis only studied the outcomes for a patient with early empyema who was a candidate for both treatment modalities in a hospital staffed with pulmonologists and thoracic surgeons, and this may not reflect real-life complexities.

The AATS guidelines on the management of empyema recently concluded that, “under the care of a dedicated thoracic surgeon, a thoracoscopic or open intervention remains the gold standard for treating complicated pleural effusions/empyemas”.⁴ Our analysis found surgical treatment and intrapleural tPA/DNAse to be nearly equivalent in cost and effectiveness. However, surgeons must continue to consider patient factors when making the decision for fibrinolysis or early operative intervention. Patients who are managed non-operatively are typically older, have more comorbidities, and are more acutely ill at the time of presentation,⁵ which differs significantly from the patient chosen for our base clinical case. Furthermore, in a resource-limited setting or infectious pandemic, the consumption of scarce resources or risk to hospital staff must also be included in the decision analysis. Finally, our base case involved an early empyema while many patients are referred to surgeons after weeks of symptoms which may sway decision making toward surgery.

In conclusion, we found the initial management of early empyema with VATS decortication and intrapleural tPA/DNAse to be nearly equivalent when considering quality of life at one year post-empyema. Intrapleural fibrinolytics remained the more cost-effective option when the effectiveness was >60% and the cost was <$13,000. However, consideration of patient-specific factors must ultimately drive the choice to use intrapleural tPA/DNAse versus VATS decortication as the initial management strategy for early empyemas.