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Cost-Effectiveness of Single-Dose Methotrexate Compared With Laparoscopic Treatment of Ectopic Pregnancy

MORLOCK, ROBERT J. MA; LAFATA, JENNIFER ELSTON PhD; EISENSTEIN, DAVID MD

ORIGINAL RESEARCH
Free

Objective To evaluate the cost-effectiveness of treatment with intramuscular (IM) methotrexate compared with fallo-pian tube–sparing laparoscopy for small unruptured ectopic pregnancy.

Methods A decision-analytic model accounting for varying resolution rates, complication rates, and cost estimates was built to compare the use of methotrexate with laparoscopy. Meta-analysis results of studies identified by a MEDLINE search for IM methotrexate resolution rates and tube-sparing laparoscopy resolution rates were used in model estimation. A similar process was used to generate model complication rates. Data on associated resource use were derived from established clinical guidelines. Estimates of 1998 costs incurred by provider organizations were calculated using data from a large managed care organization.

Results The average methotrexate resolution rate among the studies included was 87% (range 75–90%). The average laparoscopy resolution rate was 91% (range 72–100%). Complication rates for methotrexate ranged from 0% to 22%, with an average of 10% for minor complications, and from 0% to 11% for serious complications, with an average of 7%. Complication rates for laparoscopy ranged from 0% to 8% for intraoperative complications, with an average of 2%, and from 0% to 15% for postoperative complications, with an average of 9%. Baseline model estimates indicated an average cost saving of more than $3000 per resolved ectopic pregnancy with methotrexate treatment compared with laparoscopy. Results of extensive sensitivity analyses supported the finding of a cost saving with methotrexate treatment.

Conclusion Single-dose methotrexate is a cost-saving, nonsurgical, fallopian tube–sparing treatment for ectopic pregnancy.

Treatment with methotrexate is a cost-saving alternative to laparoscopy for ectopic pregnancy.

Henry Ford Health System, Detroit, Michigan.

Address reprint requests to: Robert J. Morlock, MA, Henry Ford Health System, One Ford Place, 3A, Detroit, MI 48202. E-mail: rmorlocl@hfhs.org

Supported by the Blue Cross Blue Shield of Michigan Foundation, Detroit, Michigan.

Received May 17, 1999. Received in revised form August 16, 1999. Accepted September 2, 1999.

Until the 1970s, management of ectopic pregnancy followed dicta set forth in the 19th century: open exploratory surgery was the mainstay of diagnosis, and treatment was removal of the affected tube, affected ovary, or both.1 Today, high-resolution ultrasound and sensitive serum assays for β-hCG allow prompt, reliable, noninvasive diagnosis of ectopic pregnancy.2,3 Rapid advances in technique and instrumentation over the past 20 years have made minimally invasive surgery the treatment of choice.4

Nonsurgical treatment is also an option. Li and colleagues5 were the first to report the effective use of methotrexate for treatment of gestational trophoblastic disease, publishing their findings in 1956. Tanaka et al6 reported successful treatment of ectopic pregnancy with methotrexate in 1982. Treatment protocols have evolved from multidose schedules to the current one-dose (50 mg/m2 of body surface) protocol described by Stovall and Ling.7 Experience with the single-dose protocol has been described in the literature for more than 700 cases, with success rates varying between 71% and 100%.8–20 Despite published successes, use of methotrexate remains somewhat controversial.15,21,22 Its critics point to variable therapeutic effectiveness, risk of side effects, and complications.

Economic costs associated with different treatments for ectopic pregnancies were addressed in three studies.23–25 Although each of those studies found cost advantages with methotrexate therapy, none considered that management with single-dose methotrexate does not always result in resolution or that potential side effects and complications add costs to the use of methotrexate. In two of the studies,23,25 the comparative treatments (laparotomy and inpatient laparoscopy) were not current standard care in the United States. We sought to build on prior efforts by comparing cost-effectiveness of single-dose methotrexate with that of outpatient laparoscopy. We developed a model with varying resolution rates that included the medical care costs of treating common side effects and complications associated with both treatments.

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Materials and Methods

We evaluated two first-line therapies for ectopic pregnancy: outpatient, fallopian tube–sparing laparoscopy (salpingostomy or salpingotomy) and up to two doses of intramuscular (IM) methotrexate following the protocol of Stovall and Ling.7 A decision-analytic model was developed to estimate the health outcomes and economic costs for each treatment. For model estimation, the perspective of a provider organization was adopted and all costs were estimated using 1998 dollars. The model was built in DATA Software (TreeAge Inc., Willamstown, MA), and one-way and multiway sensitivity analyses were conducted using Crystal Ball (Decisioneering Inc., Denver, CO).

As illustrated in Figures 1 and 2, the model initially considered whether the therapy resulted in resolution of the ectopic pregnancy. Next considered was the likelihood of associated complications. For simplicity, complications associated with laparoscopy were classified as intraoperative and postoperative. Intraoperative complications included injury and other events that led to conversion to laparotomy. Postoperative complications included hemorrhage and wound infection that led to a hospital stay.

Figure 1

Figure 1

Figure 2

Figure 2

Complications and side effects of methotrexate were classified as minor, serious, or life threatening. Minor complications and side effects included stomatitis, alopecia, and other events that led to an office or emergency department visit without hospitalization or additional treatment. Serious complications and side effects included abdominal pain, leukopenia, and other events that led to hospital admission for observation, additional treatment, or both. Life-threatening complications included hemorrhage and other events that led to hospitalization and surgery.

Among those with persistent pregnancies who underwent laparoscopy (Figure 1), there was a probability of instability and need for laparotomy (as opposed to repeat laparoscopy). Those with persistent pregnancies who received methotrexate (Figure 2) were given a second dose of methotrexate. The one exception to that was when a woman had a life-threatening complication with the first dose. In those cases, the second dose was not given and the woman had surgery. For those who received a second dose, the likelihood of resolution and associated complications was considered in the model. Women with persistent ectopic pregnancies after two doses were assumed to undergo surgery and have resolution.

Two types of clinical data were needed to estimate the model: resolution rates and complication rates. Studies conducted between 1980 and 1998 of single-dose methotrexate and fallopian tube–sparing laparoscopy were identified through an extensive MEDLINE and reference search. Results from studies involving more than 30 cases were retained for estimating resolution rates. Resolution rates for baseline model estimation were calculated with simple and weighted averages (weights equal to the sample) for included studies. Complication rates were reported less frequently and often in a manner that did not allow direct linkage to sample sizes, so complication rates for baseline model estimation were estimated with all identified studies and simple averages only. We also calculated 95% confidence intervals, but to facilitate understanding of the effect of model assumptions on results and conclusions, we allowed resolution and complication rates to vary over the entire range identified within the literature for sensitivity analyses.

Resource use associated with methotrexate was estimated using the single-dose protocol of Stovall and Ling.7 Resource use associated with routine laparoscopy was estimated using the care protocol of our institution. The costs incurred by a provider organization delivering care associated with these protocols and costs associated with any resulting complications were estimated using cost-to-charge ratios available at our institution. Professional- and facility-related costs were included. Costs associated with diagnosis of ectopic pregnancy were assumed to be equal across treatments and therefore were omitted. Monte Carlo simulation was used to evaluate the sensitivity of the baseline model finding to the assumptions used in the model. In the Monte Carlo simulations, random sampling was used to choose resolution and complication rates from the ranges reported in Tables 1 and 2. All costs were allowed to vary within a 20% range.

Table 1

Table 1

Table 2

Table 2

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Results

Resolution rates for women treated with laparoscopy and single-dose methotrexate used in the baseline model are summarized in Table 1. The published resolution rate of studies of laparoscopy ranged from 72% to 100%,4,10,15,22,26–36 whereas the overall resolution rate for methotrexate therapy ranged from 75% to 90%.9–11,13,14,16,18,19 The simple and weighted averages of laparoscopy resolution were 90% and 91%, respectively. The simple and weighted resolution rates for studies whose reports included first- and second-dose methotrexate resolution rates were 84% and 87%, respectively.

Average and ranges of complication rates identified in the literature are presented in Table 2.4,10–20,26,27,29,31,33–35,37–40 Baseline complication rates associated with laparoscopy were estimated at 2% and 9% for intraoperative and postoperative complications, respectively, regardless of ectopic pregnancy resolution. We estimated that 7% of patients with persistent pregnancies were hemodynamically unstable and required laparotomies. Baseline complication rates associated with methotrexate treatment were estimated at 10% and 7% for minor and serious complications, respectively, for pregnancies that resolved and at 10%, 7%, and 14% for minor, serious, and life-threatening complications, respectively, for pregnancies that persisted.

We assumed that each woman who received methotrexate treatment had six serum assays for β-hCG, one complete blood count, one serum assay each for asparate aminotransferase, and creatinine, seven venipunctures, and one follow-up office visit. We assumed that each woman who underwent a laparoscopy used operating and recovery rooms and had one surgical pathology evaluation, anesthesia, four β-hCG assays, one complete blood count, five venipunctures, and one follow-up office visit. We also assumed that women who had life-threatening complications after methotrexate injections or who were unstable after initial laparoscopies had laparotomies. We assumed that methotrexate recipients who had laparotomies had emergency department visits in addition to their laparotomies. Further, we assumed that patients who underwent laparoscopies and needed laparotomies did not have emergency department visits and incurred only laparotomy and related costs. The total costs associated with each treatment are reported in Table 3.

Table 3

Table 3

Also included in Table 3 are the complication-related costs of treatment. We assumed that intraoperative laparoscopy complications led to conversion to laparotomy and a 3-night stay in the hospital. We also assumed that postoperative laparoscopy complications led to additional echography, abdominal radiography, 1 night in the hospital, and an additional follow-up visit. Minor complications for a methotrexate recipient led to an additional office visit. Serious complications from methotrexate led to a visit to the emergency department, 1 night in the hospital, echography, blood tests, and an additional follow-up visit. We assumed that women with ectopic pregnancies that persisted after methotrexate treatment had additional laparoscopies, for non–life-threatening complications, or laparotomies, for life-threatening complications.

With those baseline assumptions, model results indicated an expected $3011 cost saving with methotrexate treatment compared with laparoscopy. Results of the 10,000-patient Monte Carlo simulation indicated that methotrexate treatment provided an average saving of $3087 per resolved ectopic pregnancy (range $1385–$3239 per treated patient). Results of these simulations indicated that the magnitude of cost saving was most sensitive to methotrexate-therapy resolution and complication rates.

To test further the sensitivity of the model's finding of a cost saving with use of methotrexate, we estimated the model using the lowest resolution rate (57%) and highest complication rates (22%, 11%, and 29% for minor, serious, and life-threatening complications, respectively) for methotrexate treatment, along with the highest methotrexate-treatment costs (10% above baseline costs), against the highest resolution rate (100%) and lowest complication rate (0%) for laparoscopy, along with the lowest laparoscopy costs (10% below baseline costs). With those extreme assumptions, which biased the results against methotrexate, model results still supported the use of methotrexate. With that best-case scenario for laparoscopy, a saving of $760 per resolution was expected with methotrexate use compared with laparoscopy.

Some studies have shown that methotrexate is a viable treatment for persistent ectopic pregnancy after unsuccessful surgery.29,41 We evaluated the sensitivity of our findings, allowing for administration of methotrexate after initial laparoscopy. When this treatment alternative was included, the average cost per resolution for laparoscopy was $4279. Under those conditions, use of methotrexate (as a first-line treatment) still provided a savings of $2744 per treated patient.

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Discussion

Methotrexate is a chemotherapeutic agent long known for its efficacy in gestational trophoblastic disease. Introduced as a novel therapy for ectopic pregnancy in 1982,6 methotrexate therapy has evolved from a cumbersome and morbid high-dose treatment to the simple, single-dose regimen used today, popularized by Stovall and Ling.7 It has placed medical treatment of ectopic pregnancy securely within the therapeutic armamentarium of generalist gynecologists because of application ease and low incidence of serious side effects. However, the high success rates reported by Stovall and Ling7 have been difficult to reproduce in other locations. The large range of resolution rates reported elsewhere,8 combined with often little information on the clinical characteristics of study populations, does little to facilitate identification of appropriate candidates for non-surgical management of ectopic pregnancy, leading many to demand randomized clinical trials before methotrexate treatment can be considered anything other than second-line or experimental therapy.

In this study, we developed a cost-effectiveness model that accounts for varying rates of ectopic pregnancy resolution, complications, and side effects among women receiving methotrexate therapy or undergoing fallopian–tube sparing laparoscopy. We used reports in the literature of outcomes of the two treatments. Thus, our model showed clinical and socioeconomic population variability reported in the literature and encompassed a wide range of reported success and complication rates. Resource use information and costs were drawn from experiences at our own institution and therefore may not be applicable to all institutions. However, they are consistent with published data.12,23 The results of the model provide clear evidence that a policy of offering methotrexate as a front-line therapy for early unruptured ectopic pregnancy results in cost savings of approximately $3000 per treated patient. The cost advantage persisted even with assumptions biasing model results against methotrexate treatment.

Although our findings illustrate the cost-effectiveness of methotrexate compared with laparoscopy, the broader question is whether that makes it the treatment of choice. In terms of fallopian tube–sparing therapy, laparoscopy successfully resolves pregnancies more than 90% of the time, with relatively low complication rates. Results of some studies of methotrexate treatment equaled those results, but results of others did not. Detractors of methotrexate identify that uncertainty regarding success rates, plus the 3- to 4-week follow-up necessary to ensure resolution, as a reason for choosing laparoscopy instead. However, patients who undergo laparoscopy also must be followed up, to rule out persistent trophoblastic disease, which occurs in up to 15% of cases and itself necessitates further therapy such as methotrexate injections. Thus the two approaches are arguably more comparable than not.

Our study findings support using methotrexate as front-line therapy for small unruptured ectopic pregnancy, but questions remain about how to maximize clinical effectiveness. Institutions that reported resolution rates of 90% or more23 have in place a detailed diagnostic and therapeutic protocol with departmental staff well versed in and devoted to the protocol, means for performing with little delay β-hCG assays and high-resolution vaginal ultrasound, and capability of follow-up by knowledgeable staff 24 hours a day. Institutions with less stringent application of protocols seem to have lower resolution rates.23 An overall cost saving with methotrexate and emerging evidence that many women prefer nonsurgical treatment of ectopic pregnancy42 point to the need to establish clinical environments that support effective use of this therapy.

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