Affiliations of authors: Gastrointestinal Unit and The Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA.
Correspondence to: Chin Hur, MD, MPH, 101 Merrimac St., 10th Fl., Boston, MA 02114 (e-mail: chur{at}partners.org)
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ABSTRACT |
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INTRODUCTION |
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The use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced esophageal cancer rates (9,10). Most recently, a meta-analysis of nine epidemiologic studies pooling 1813 cancer cases (11) showed a 43% decreased rate of esophageal cancer in patients who use NSAIDs (50% for aspirin), with a trend toward a dose response. Increased expression of the enzyme cyclooxygenase-2 has been detected in patients with Barrett's esophagus and esophageal adenocarcinoma, and the inhibition of cyclooxygenase-2 by NSAIDs has been postulated as the mechanism for the observed decrease in cancer incidence. Growing public awareness about the potential benefits of NSAID therapy has led both the medical and lay community to consider the prophylactic use of NSAIDs for chemoprevention. However, no prospective data have proven NSAID efficacy for cancer prevention, and a formal, quantitative analysis comparing potential benefit to harm has not been published to support this practice.
In an attempt to address the need for recommendations regarding the use of NSAIDs for chemoprevention in patients with Barrett's esophagus, while recognizing the limited amount of clinical trial data, a Markov Monte Carlo decision model was constructed to determine and compare the effectiveness and cost-effectiveness of aspirin, with or without endoscopic surveillance.
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METHODS |
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Model Design
A Markov model is a mathematical model that can be used to determine outcomes and calculate costs for patients as they progress through disease states and undergo diagnostic tests and/or therapeutic interventions. It may be used to model clinical situations for which there is a repeated risk over time and in which events (such as progression from high-grade dysplasia to adenocarcinoma) can occur at various times with potentially different outcomes (13,14). For example, one patient might progress to cancer at age 70, whereas another patient may develop cancer at age 80. The development of cancer later in life can have important clinical implications and may affect the patient's clinical outcome (e.g., the patient may no longer be eligible for resection.
A commercially available software package (DATA Professional; TreeAge Software, Williamstown, MA) was used to create the model. Health states in the model included Barrett's esophagus (no dysplasia), low-grade dysplasia, high-grade dysplasia, cancer without symptoms, cancer with symptoms, post-successful esophagectomy for either high-grade dysplasia or cancer, ineligible for resection for either high-grade dysplasia or cancer, incomplete resection for cancer, and death (see Fig. 1 for simplified schematic of the endoscopic surveillance strategy). The Markov cycle length or time between state transitions was 1 month.
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In the base-case analysis in all four strategies, the simulation begins with a 55-year-old man [Barrett's esophagus is more common in men, and the average age at diagnosis is 55 years (15)] who has endoscopic biopsyproven Barrett's esophagus. In all four strategies, in each cycle (1-month period) the simulated patient can progress to low-grade dysplasia, continue in the Barrett's esophagus without dysplasia state, or die from age-related all-cause mortality. If a patient progresses to low-grade dysplasia, he will start the next cycle in the low-grade dysplasia state and can either regress to Barrett's esophagus without dysplasia, stay in low-grade dysplasia, progress to high-grade dysplasia, or die from age-related all-cause mortality. This process is repeated until he dies. To mimic clinical reality, our model allows for each patient to have a true biologic state and a perceived state. The model internally follows each patient's true biologic state, although the patient's management is dictated by the perceived state. In the two strategies without endoscopy (no therapy and aspirin), neither the patient nor the caregiver knows which biologic state the patient is in at any given time unless the patient develops cancer symptoms. In the two strategies involving endoscopic surveillance, if the biopsies are accurate (see "Biopsy Characteristics" section below) then the patient's perceived state will be correctly updated every time he undergoes endoscopy. This scenario may be clinically relevant in a situation in which a patient has cancer but is not perceived to have it until either he develops symptoms or his next endoscopy.
No Therapy
In the no-therapy strategy (see Fig. 2 for simplified schematic), the patient comes to medical attention only if he develops cancer symptoms. At that point, if he is still eligible for resection, he will undergo a surgical esophagectomy with potential for cure. The rate of curative esophagectomy is based on the length of time it took to diagnose the cancer; consequently, patients without endoscopic surveillance are more likely to have cancers that are not surgically resectable (see "Parameter Estimates" section).
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The aspirin strategy (see Fig. 3 for simplified schematic) is similar to the no-therapy strategy, except the patient takes a 325-mg enteric-coated aspirin daily. As a result, his rate of cancer progression is decreased (base case = 50%), but he can also have an aspirin-associated complication, such as a gastrointestinal or genitourinary bleed, or a hemorrhagic stroke. If a patient develops an aspirin complication and survives, he is modeled to discontinue the aspirin and returns to the standard cancer progression rate. Patients were not modeled to receive any other benefit from the aspirin, such as a cardiac benefit or chemoprevention of other cancers (see "Discussion" section for details).
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In the endoscopic surveillance strategy (see Fig. 1 for simplified schematic), the patient undergoes an upper endoscopy with biopsies at set intervals per the American College of Gastroenterology's guidelines (5) depending on the histology obtained from the previous biopsy. For patients with Barrett's esophagus without dysplasia, the interval is every 3 years. If the patient is found to have low-grade dysplasia, the interval decreases to every year. If a patient is found to have high-grade dysplasia by endoscopic biopsy, he undergoes a surgical esophagectomy assuming he is eligible for resection at the time of diagnosis in the base case. It is possible that, either because of a false-negative biopsy reading or in the interval between endoscopies, a patient will develop cancer, although it will most probably be detected by the next endoscopy. After esophagectomy, annual endoscopic surveillance continues on the patient.
Aspirin and Endoscopy Strategy
In the aspirin and endoscopy strategy, the patient is modeled to take aspirin and to also have endoscopic surveillance in a combination of the two strategies described above.
Model Inputs and Parameter Estimates
Parameter estimates. Model parameters were based on estimates from the literature. Base-case values and ranges used in sensitivity analyses are summarized in Table 1. When published estimates were not available, an expert in the field was consulted to provide an expert estimate for the parameter.
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Transition Probabilities
The transition probabilities among the various states of Barrett's esophagus (i.e., Barrett's esophagus [no dysplasia], low-grade dysplasia, high-grade dysplasia, and cancer) are pivotal to the model's validity. By far, the greatest amount of data exists for the overall transition rate from Barrett's esophagus to cancer. Shaheen et al. (20) performed a systematic analysis of 25 individual studies that reported the risk of esophageal adenocarcinoma in Barrett's esophagus. The authors concluded that, as a result of publication bias, the previously reported risk of cancer in Barrett's esophagus was overstated, and they estimated the true annual incidence at 0.5%. Numerous published studies (4,20,3440) have estimated transition probabilities among the various Barrett's esophagus histological states (no dysplasia, low-grade dysplasia, high-grade dysplasia, cancer). These estimates were used in conjunction with the overall Barrett's esophagus to cancer rate (20) to provide the individual transition estimates listed in Table 1.
Procedure Characteristics
The published mortality rates for esophagectomy vary widely. Base-case estimates used in the model for esophagectomy mortality depended on the indication and were 2.0% for high-grade dysplasia, 4% for cancer detected during endoscopic surveillance, and 8.1% for cancer found because of symptoms (21). Whether or not a patient was eligible for resection was determined using National Health Interview Survey data (Centers for Disease Control and Prevention) on activities of daily living. With increasing age, an increasing percentage of the population requires assistance with activities of daily living. This percentage was used as a surrogate for age-related comorbidity to determine eligibility for resection.
The probability of surgical cure after esophagectomy was dependent on length of time that had passed between the cancer's inception and surgery. In the ideal situation, when the cancer is detected almost immediately, an 80% surgical cure rate was modeled (22). In the worst-case scenario, when the cancer was discovered by symptoms, the cure rate was estimated to be 33% (25). Endoscopic complication rates were estimated from published reports.
Biopsy Characteristics
Pathological interpretation of an endoscopic biopsy is an attempt to determine a patient's true biologic state. The model accounts for the possibility of discordance between the biopsy results and a patient's true state. At the start of the simulation, the patient's perceived or biopsy state matches the true biologic state, which is Barrett's esophagus without dysplasia. However, when the simulation begins, each time a biopsy is taken during endoscopy, the model allows for a "misreading or sample error" of the histology. The patient's course is dictated by the perceived state (e.g., decision to perform surgery); however, the true state determines internal parameters such as esophagectomy mortality and surgical cure rates. Assuming the patient continues endoscopic surveillance, the discrepancy between the perceived and true state is likely to be corrected, as false reading rates are relatively low.
Outcome Adjustments
The model allowed for death from age-related all-cause mortality. Probabilities were obtained from the 1998 U.S. Life Tables (41). QALYs were used as the primary endpoint by which the effectiveness of the two competing strategies was compared. Numerous adjustments were made to years of life to produce QALYs including weighting each year according to age and sex-adjusted population values (42) and making reductions to reflect procedure recuperation. The model assumed that the post-procedure quality of life was 70% that of the pre-procedure quality of life. This adjustment was made for 1 day following an endoscopy (7), for 1 week following an endoscopy with complications (7), and for 4 weeks following esophagectomy. Years of life were also weighted by specific health or disease state quality-of-life values to calculate QALYs. The adjustment factor for quality of life post-esophagectomy in the base-case analysis was 0.97 (7), with a range of values used in sensitivity analyses. This published value reflects the morbidities associated with life after the surgery and assumes that life after esophagectomy is worth 97% of life before esophagectomy. However, extensive sensitivity analyses were performed on this factor relative to the factor assigned for the quality of life post-esophagectomy.
Costs
Base-case costs and ranges used in sensitivity analyses are summarized in Table 1. Cost was estimated from a societal perspective, which included all direct medical costs and indirect costs, such as time lost from work. Costs from prior years were converted to year 2000 dollars using the medical care component of the Consumer Price Index (U.S. Bureau of Labor Statistics). For the base-case analysis, all cost and QALYs were discounted at a real annual rate of 3% (43), to adjust for the relative value of present dollars or a present year of life.
The cost of 1 month's supply of 325-mg enteric-coated aspirin (as well as a regular uncoated aspirin used in sensitivity analysis) was obtained from the Drug Topics Red Book (29). Facility (or technical) and professional costs of medical procedures were determined by the Medicare payment schedule. We describe below the method used to calculate the cost of a surgical esophagectomy (inpatient procedure) and an upper endoscopy (outpatient procedure) as an example of the process we used to estimate many of the costs for the model.
The direct medical cost of an esophagectomy was derived from the Medicare reimbursement rates corresponding to the appropriate Diagnosis Related Group (DRG) and Current Procedural Terminology (CPT) codes, based on Resource-Based Relative Value Scale. DRG codes were used to derive estimates for hospital (part A) costs, and CPT codes were used to derive cost estimates for physician (part B) costs. Two specific DRG codes were relevant for esophagectomy: DRG 154 (stomach, esophageal, or duodenal procedures with comorbidity/complications) and DRG 155 (stomach, esophageal, or duodenal procedures without comorbidity/complications). We used a weighted average of the reimbursement rates associated with these DRG codes, based on an analysis of the coding of all patients who underwent esophagectomy at our institution in fiscal year 1998. A similar approach was used to calculate the cost of an endoscopic perforation requiring surgery.
The cost of an endoscopy with biopsies was estimated using CPT codes as described above for the professional fee and using Ambulatory Payment Classification (APC, Medicare) codes for the facility fee. Cancer care cost estimates were derived from a recent publication (33) in which the investigators calculated these costs on the basis of a review of a group of patients at their institution who were diagnosed with esophageal adenocarcinoma. A day's wages used in calculating indirect costs was estimated using data from the U.S. Bureau of Labor.
Model Verification
To demonstrate the ability of the model to reflect those variables of interest that can be identified and measured and to calibrate the parameters of the model to account for influences that cannot be measured directly, we identified outcomes of the model that have a published counterpart and compared them for approximate equivalency. Specifically, we compared the resulting life expectancy with that of the general population and with the previously published life expectancy of a patient with Barrett's esophagus (see "Results" section). This process helped to ensure accurate and realistic outcome projections.
Analyses Performed
After construction of the model, a base-case analysis using best estimates for all model parameters and probabilities was performed. The model was analyzed as a Monte Carlo simulation using cohorts of 50 000 patients. Base-case analysis was performed using cohorts of 55-year-old men and a 3% discount rate (43) for both cost and effectiveness in all four management strategies, as described above (discounting is performed in cost-effectiveness analyses to convert future dollars and health outcomes to present values). Sensitivity analyses were then performed to investigate the effects of changes in model parameters on estimated costs and effectiveness outcomes across a wide range of assumptions including patient age, efficacy of aspirin chemoprevention, complication rate of aspirin therapy, Barrett's esophagusto-cancer progression, esophagectomy mortality rate, post-esophagectomy quality of life, costs, and discount rate.
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RESULTS |
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To provide external validity for the model and its results, we attempted to verify the model's outputs with published counterparts. The mean life expectancy for a 55-year-old man in the United States is 23.5 years (41). The mean life expectancy of a 55-year-old man with Barrett's esophagus in the endoscopic surveillance arm was 21.97 years, for a net reduction in life span of 1.53 years. Provenzale et al. (6) published a Markov model of Barrett's esophagus and studied various endoscopic screening intervals and surgical treatments. In their model, the age of the patient at the start of the simulation was also 55, and they found that endoscopic surveillance with surgical esophagectomy for high-grade dysplasia was the optimal strategy to maximize unadjusted life years; this strategy resulted in a life expectancy reduction of 1.46 years compared with that of the general population. Thus, our model yielded reductions in life expectancy similar to those in a previously published model, which supports the validity of our models and its results.
Base-Case Analysis
In the base-case analysis (Table 2), the aspirin strategy dominated (i.e., was more effective and less costly than) the no-therapy strategy, resulting in 0.19 more QALYs and costing U.S.$2900 less on average. Endoscopic surveillance also resulted in more QALYs than no therapy but cost U.S.$24 800 more, resulting in an ICER of U.S.$118 100/QALY. The combination of aspirin and endoscopy produced 0.27 more QALYs than no therapy at a cost of only U.S.$13 400 more, for an ICER of U.S.$49 600/QALY when compared with no therapy and U.S.$203 800/QALY when compared with aspirin alone. The combination strategy also dominated endoscopic surveillance alone. To summarize, the addition of aspirin to either no therapy or to endoscopic surveillance resulted in a strategy that was dominant.
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Sensitivity Analysis
The results of the sensitivity analysis are summarized in Table 3. The primary question we were attempting to address in this study was the effect of aspirin on either no therapy or the currently recommended endoscopic surveillance. Consequently, the ICERs that we present in this table were calculated for when aspirin alone was compared with no therapy and when combination therapy was compared with no therapy or endoscopy alone.
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Sensitivity analyses on the benefits of aspirin showed aspirin continuing to dominate no therapy until the benefit (or decrease in the rate of progression to cancer) was down to 10%. When combination therapy was compared with endoscopy alone, the combination therapy became less effective when aspirin's benefits were 30% or less. Because the model was sensitive to this fundamental parameter estimate, we present the effectiveness data for the four strategies with various aspirin benefits in Fig. 4. (It should be noted that the "No-therapy" and "Endoscopy" strategies do not change with aspirin's characteristics because these strategies do not involve aspirin use.)
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The results of the model were not sensitive to varying the annual rate of Barrett's esophagus to cancer progression. However, at a rate of 0.1% per year, the cost of aspirin therapy alone exceeded that of no therapy, although at a very low ICER (U.S.$7400).
The value assigned to the quality of life after an esophagectomy did not affect the cost-effectiveness of the aspirin strategies, although the endoscopy-alone strategy was sensitive to lower post-esophagectomy quality-of-life estimates.
Aspirin strategies were not sensitive to complication rates associated with aspirin therapy, esophagectomy mortality rates, or varying the discount rate. Varying the costs of aspirin, esophagectomy, or endoscopy also did not substantially affect the outcome of the model. The sensitivity analysis of aspirin at 50% of the base-case cost is clinically important because uncoated aspirin costs about half as much as enteric-coated aspirin (29). In summary, the aspirin strategies were sensitive to older starting ages, lower chemoprevention rates of aspirin, and substantial delays in the benefits of aspirin.
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DISCUSSION |
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A previously published model by Provenzale et al. (7) also examined the cost-effectiveness of various surveillance regimens for Barrett's esophagus. In their model, the ICER for endoscopic surveillance every 3 years when compared with no surveillance was U.S.$137 000/QALY. Our equivalent ICER (when using a 5% discount rate, as they used in their analysis; see Table 3) was U.S.$142 800/QALY. The similarities in these results add further validity to our model's findings.
The principal limitation of the model relates to the uncertainty that surrounds some of the parameter estimates. No prospective, long-term studies have shown the efficacy of aspirin for chemoprevention of esophageal adenocarcinoma. The possibility of conducting randomized controlled trials to show the benefits of aspirin in patients with Barrett's esophagus is unrealistic because the rate of progression from Barrett's esophagus to esophageal adenocarcinoma is low. Thus, a randomized controlled trial with sufficient power to detect a difference between two regimens would need to be exceedingly large and long. Indeed, this clinical situation provides the ideal setting in which to use the methodologies of decision analysis and disease modeling (such as our Markov model) to evaluate and compare the effectiveness of various management strategies for Barrett's esophagus.
As with every model, there is heterogeneity across patients with respect to virtually all model parameters, particularly those relating to cost and outcome. The model does not specifically assess the potential impact of population heterogeneity on the results because data are not available on all model parameters to base the range estimates. Additional data collection in this area may be useful in the future.
Our results have several policy implications. Along with recently published studies (911) suggesting that aspirin may prevent esophageal cancer, an observational study (46) suggested that long-term aspirin use may prevent cancers of the colon, stomach, and rectum. More recently, two randomized trials (47,48) showed that aspirin was effective in decreasing the incidence of colorectal adenomas, further substantiating existing evidence that aspirin is an effective chemoprevention for colon cancer.
There is also evidence that aspirin may decrease the incidence of coronary heart disease in patients who do not presently manifest the disease but have established risk factors for it (49). This has led various organizations, including the U.S. Preventive Services Task Force, to recommend aspirin for primary chemoprevention in adults who are at increased risk for coronary heart disease (50).
This growing body of evidence supporting the benefits of aspirin has received a great deal of attention in the medical community. Media attention has led to much public interest and influenced many healthy individuals to consider prophylactic aspirin therapy without a proper understanding of the potential risks. Our analyses suggest that the benefits of aspirin in a patient with Barrett's esophagus outweigh the potential risks from its complications. Nevertheless, the greatest benefit a typical individual will receive from primary aspirin therapy will be a cardiac benefit because coronary heart disease is the most common cause of death in Western society.
Our model did not attempt to incorporate any potential cardiac benefits of aspirin therapy for several reasons. First, our analysis was intended to focus on esophageal adenocarcinoma chemoprevention specifically. Second, because cardiac mortality accounts for a large percentage of deaths after age 50 in the U.S. population (51), a substantial theoretical modeling concern is mortality cause removal (52). Short-term data for the efficacy of aspirin for the prevention of primary coronary events exist (18), but long-term data are currently unavailable. To simply extrapolate and extend the estimated short-term benefits of aspirin over a lifetime would lead to a sizeable decrease in the cohort's age-related all-cause mortality rates and a substantial increase in life expectancy. Because data that detail the effect of aspirin therapy on a population's age-related all-cause mortality rates do not currently exist, a model that used extrapolated decreased cardiac estimates would be a gross oversimplification of reality, potentially leading to distorted and inaccurate results. To illustrate this point, if we modeled a 50% reduction in coronary events throughout a person's life, although in the simulation the individual may live longer, in reality, without long-term aspirin population data, it is not possible to predict the outcome in an elderly individual if a coronary event were to be prevented. For instance, the patient could die within a short period of time from a noncardiac, noncancer-related cause, negating any potential benefit gained from aspirin therapy. A more comprehensive model that incorporates the potential cardiac benefits as well as chemopreventive benefits for other cancers will be feasible when longer-term population data on the effects of aspirin therapy are available.
In conclusion, our study suggests that aspirin use in patients with Barrett's esophagus is effective when considered purely from the standpoint of esophageal cancer prevention. In a patient who has Barrett's esophagus and concomitant cardiac risk factors, aspirin use for primary prevention may be an obvious recommendation. In patients without cardiac risk factors, aspirin use may be a reasonable recommendation, assuming that more studies confirm that its efficacy exceeds the thresholds in our model.
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Manuscript received June 13, 2003; revised December 18, 2003; accepted January 8, 2004.
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