Cost-Effectiveness of Different Combinations of Bupropion SR Dose and Behavioral Treatment for Smoking Cessation: A Societal Perspective

Objectives: To determine the differential cost effectiveness of 2 dosing regimens of bupropion sustained release (SR) in combination with behavioral interventions of minimal intensity (tailored mailings [TM]) or moderate intensity (proactive telephone calls [PTC]) for smoking cessation in an actual practice setting. Study Design: Open-label, randomized trial, with 1-year followup, conducted in a large health system based in Seattle, Washington.

Patients and Methods: A total of 1524 adult smokers interested in quitting smoking were randomly assigned to receive 150 mg bupropion SR daily and PTC (n = 382), 150 mg bupropion SR daily and TM (n = 381), 300 mg bupropion SR daily and PTC (n = 383), or 300 mg bupropion SR daily and TM (n = 378). Sufficient medication for 8 weeks of dosing was provided to patients. The primary outcome measure was self-reported point-prevalence 7-day nonsmoking status at 12 months after the target quit date.

Results: Although the 300-mg dose was associated with a higher 12-month nonsmoking rate relative to the 150-mg dose with both PTC and TM, the additional cost resulted in lower cost effectiveness. The PTC behavioral intervention was more expensive than TM, but the additional effectiveness resulted in almost equivalent cost effectiveness at the 150-mg dose. Costs per additional 12-month nonsmoker (above that expected for placebo) for the 150-mg dose groups averaged $950 and per additional lifetime quitter averaged $1508; for the 300-mg groups these costs were $1342 and $2129, respectively. Cost per life-year and quality-adjusted life-years (QALYs) saved varied substantially by age and treatment, but were no greater than $1100 for all treatment groups when averaged across the age and sex distribution for the study population.

Conclusions: Although the cost per life-year and QALYs saved were sufficiently low for all doses to rate these smoking cessation interventions as among the most cost effective of life-saving medical treatments, within the regimens tested 150 mg bupropion combined with either PTC or TM was the most cost effective.

(Am J Manag Care. 2004;10:217-226)

Cigarette smoking has been associated with approximately 440 000 premature deaths in the United States annually during 1995 through 1999.¹ Although smoking cessation treatments are more cost effective than many other commonly provided clinical services,² obtaining the maximal benefits requires identification of cost-effective treatments. Using quit rates from a clinical efficacy trial reported by Jorenby and colleagues,³ Nielsen and Fiore⁴ compared the costto- benefit ratio of bupropion sustained release (SR) at a dose of 300 mg per day with those of placebo, the nicotine transdermal patch (NTP), and a combination of bupropion SR plus NTP. The primary outcome evaluated was the point-prevalence rate of nonsmoking at 12 months of follow-up, and drug costs were based on the average wholesale price for bupropion SR and the NTP. All treatment arms received the same counseling, which included 9 supportive telephone calls, 9 weekly individual smoking-cessation counseling sessions, and relapse prevention counseling during 4 follow-up clinic visits. Even though intensive counseling was provided, Nielsen and Fiore estimated the midpoint cost for behavioral treatment ($37.50) as if the behavioral intervention consisted of a single brief counseling session with a healthcare provider. (Essentially, Nielsen and Fiore conducted their cost analysis under the assumption that the smoking cessation rates for intensive and brief counseling would be the same.) Including costs for "brief medical counseling," the cost per 12-month nonsmoker for placebo, NTP, bupropion SR, and bupropion SR + NTP groups, were estimated to be $240, $1724, $663, and $1257, respectively.

The purpose of the present study was to examine the issue of cost effectiveness for smoking cessation treatment based on results from a large effectiveness trial of various combinations of bupropion and behavioral counseling in a healthcare setting. We assessed the effects of 2 doses of bupropion SR and 2 behavioral counseling approaches that would be more likely to be used in actual practice than the intense counseling in the Jorenby clinical trial.

METHODS

Study Design

Data used for the cost-effectiveness analyses were obtained from a field trial of the effectiveness of bupropion SR in an actual practice setting. The trial, conducted at Group Health Cooperative (GHC) in Seattle, Washington, consisted of 4 treatment groups defined by crossing 2 bupropion SR doses (150 and 300 mg per day) with 2 counseling approaches of varying intensity. The more intensive counseling program was the Free & Clear Program, which involved proactive telephone calls (PTC), and the less intensive program was a modified version of the Zyban Advantage Plan program, which relied primarily on tailored mailings (TM). A total of 1524 participants were enrolled and randomly assigned but not blinded to treatment. The primary outcome measure was self-reported point-prevalence 7-day nonsmoking status at 12 months after the target quit date (not biochemically confirmed). Using an intent-totreat approach, we assigned the status of smoker to the 14.1% of participants who were survey nonrespondents. Details concerning trial methodology and trial outcomes are presented elsewhere.^5,6

Population Characteristics

Participants, all members of GHC, were enrolled over a 13-month period between April 1998 and May 1999. GHC is a nonprofit consumer-governed healthcare system, headquartered in Seattle, Washington, serving approximately 600 000 residents of Washington State. The study was advertised in various publications mailed to GHC members and in brochures distributed to GHC clinics. Primary care physicians were informed of the study and were asked to refer eligible patients. A total of 2979 smokers interested in the study underwent detailed telephone screening; 1909 of these recruits were determined to be eligible. Inclusion and exclusion criteria were modeled after a previously conducted bupropion SR efficacy trial3 and focused predominantly on conditions, including use of medications, that may lower seizure threshold. The pretreatment questionnaire and informed consent were obtained from 1524 smokers who were randomized into 1 of 4 treatment groups. Of the 385 smokers who did not end up in the final sample, 323 (84%) did not return their enrollment materials or subsequently refused participation, 23 (6%) were found not to have proper coverage, and the remaining 10% either reported exclusion criteria after screening or were excluded by their personal physician. The final sample of 1524 had an average age of 45.1 years, was 57.4% female, 89.7% white, had 13.7 years of formal schooling, smoked an average of 23.2 cigarettes per day for an average of 26.5 years, and had made 5.9 previous quit attempts. Approximately one-third (30.7%) had previously quit for 6 or more months, and most (63.3%) had previously used nicotine patches or gum.

Interventions

In the PTC program, all registrants received an outgoing call from a smoking cessation counselor a few days before the estimated quit date. After this call an average of 4 follow-up outgoing calls were made, each taking an average of 11.5 minutes (including time for unsuccessful call attempts), with follow-up letters being sent after 3 unsuccessful attempts to complete a call. Participants could also call an ad hoc support line, with an average usage of 21 minutes per enrollee. In the TM program, the participant was sent an individualized action plan prior to the quit date. On the quit date, the participant received a scripted outgoing call from a customer service representative. At 1, 8, 11, and 24 weeks after the quit date, participants received brief questionnaires that could be completed by mail or by using an automated, interactive voice-response telephone system. Participants who responded to a questionnaire were mailed a tailored relapse prevention/recovery plan. In addition, participants could access an automated tip line or talk to a program specialist; these latter interactions averaged just under a minute (54 seconds) per enrollee.

Cost Estimates

Costs for the various components were estimated (as of January 2003) based on the amount and type of personnel time involved, wage rates and overhead benefits, facilities costs, time spent on indirect tasks related to an ongoing smoking cessation behavioral intervention program (departmental meetings, quality control activities, etc), telephone costs, management costs, printing, and postage. Drug costs were estimated based on contract pricing, pharmacy dispensing costs, and allocable pharmacy overhead. Costs were not included for advertising, training or informing physicians or other medical staff, staff hiring and training, program development costs, materials development costs, or information technology infrastructure investment, because these would be primarily nonrecurring costs. Based on Bureau of Labor Statistics regional employment cost indices for March 2003, differences in regional employment costs could alter the costs of the behavioral intervention by -2.4% (for the South) to +0.6% (for the Midwest).

Cost-effectiveness Calculations

Meta-analyses of smoking cessation studies4,7,8 have shown that control group cessation rates range from 6% to 12%. To adjust for the background quit rates among smokers who are motivated to quit, a 12-month "placebo-adjusted" nonsmoking rate was calculated by subtracting 11% from the observed 12-month nonsmoking rates.

The cost per additional nonsmoker at 12 months was derived by dividing the cost per enrollee by the 12-month placebo-adjusted quit rate. The incremental cost per 12- month quitter for various treatment pairs was also calculated. Previous research^9,10 had estimated a 35% to 40% lifetime probability of relapse from smoking cessation after 1 year of abstinence, so lifetime nonsmoking rates were calculated assuming a 37% relapse rate.

The cost effectiveness of the interventions in increasing life expectancy was calculated using the mortality rates given by Croghan and associates.¹¹ The impact of smoking on health-related quality of life was calculated using the Healthy People 2000 years of healthy life measure,^9,12 extrapolating the measures down to age 18 years and up to 100 years using piecewise linear extrapolation.

Estimates in the literature for spontaneous quit rates for smokers range from 0.5% to 2.5%.^9,10,13-15 Historical estimates for the spontaneous quit rate were used to minimize the portion of spontaneous quits that were aided (ie, through physician counseling, use of prescription or over-the-counter nicotine replacement aids, telephone quit lines, etc). For cost-estimation purposes, we estimated the rate of spontaneous unaided quits followed by a minimum of 12 months of reported nonsmoking to be 1.5%. (However, because this rate may now be higher as a result of increased awareness of the deleterious effects of tobacco, we also examined the effect of increasing the unaided spontaneous quit rate to 2.5% and 3.5%.) Spontaneous quitters who remained nonsmokers for at least 12 months were also subject to later relapse using the 37% relapse rate described above.

The cost per life-year saved was calculated as the cost per lifetime quitter divided by the number of lifeyears saved per lifetime quitter. The latter quantity was estimated by subtracting the number of life-years remaining for a lifetime quitter of a specified sex and age (at the time of quitting) by the number of life-years remaining for a current smoker of the same sex and age. Monte Carlo simulation was used to estimate the number of life-years remaining for a current smoker, taking into account the possibility each year that a smoker would permanently quit without assistance, and the appropriate mortality rates based on that smoker's age, sex, and years since quitting (if any). The cost per quality- adjusted life-year (QALY) was similarly estimated. Both calculations used a 3% discount rate for future lifeyears and QALYs.

Economic analyses of the medical costs of smoking have shown conflicting findings.^16-22 Given the difficulties inherent in demonstrating a net lifetime medical cost advantage to smoking cessation, we have not attempted to estimate the corresponding cost advantage.

RESULTS

Years of Life and Quality-adjusted Life-years Saved

The years of life (YOL) saved after smoking cessation are shown under 6 different scenarios in Table 1. Without adjusting (discounting) for the spontaneous quit rate of smokers (scenario A), smoking cessation saves between 2.16 and 9.11 life-years for men and between 2.91 and 9.09 life-years for women. Using the age and sex distribution of participants in our study, the average YOL saved would be 7.83 years. Discounting by 3% (scenario B) reduces the average YOL saved to 2.60. Adjusting for the estimated spontaneous unaided quit rate of smokers (1.5%) (scenario C) reduces the average YOL saved to 2.17. Increasing the spontaneous unaided quit rate to 2.5% (scenario D) or 3.5% (scenario E) reduces the average YOL saved to 1.89 and 1.72, respectively. Discounting by 5% (scenario F) reduces the average YOL saved to 1.17. The pattern for QALYs (shown in Table 2) is similar to that for YOL saved, with larger variability across age than YOL saved when discounting is not used and smaller variability when discounting is used.

12-Month and Lifetime Cessation Rates, and Related Costs

z

P

Study results in the baseline scenario with respect to cost per abstainer are presented in Table 3. Although the 300-mg dose groups exhibited slightly larger 12-month nonsmoking rates (33.2% with PTC and 25.7% with TM) than the 150-mg dose groups (31.4% with PTC and 23.6% with TM), these differences were not statistically significant (either within or across behavioral intervention). The groups using the TM program had statistically significantly lower 12- month placebo-adjusted cessation rates (12.6% and 14.7%) than the PTC groups (20.4% and 22.2%; > 2.11, < .05). The order of the groups by 12-month placebo-adjusted cessation rate was also the order of the groups by total cost per enrollee, which ranged from $119 to $283. When costs were expressed per additional 12-month abstainer (above the number expected from placebo), the 150-mg/TM and 150- mg/PTC groups had almost identical cost effectiveness ($944 and $956). Relative to 150 mg/TM, the incremental cost effectiveness of 150 mg/PTC was $974, and for the 300-mg groups was $1708 (PTC) and $4190 (TM). The costs per lifetime quitter ranged from $1499 to $2235 across the 4 groups.

Cost per Life-year and Quality-adjusted Life-years Saved

Study results with respect to cost per YOL saved under baseline assumptions are shown in Table 4. The cost per YOL saved varied by age and sex with generally less cost effectiveness at young ages (because mortality rates are low for both smokers and nonsmokers and future YOL saved are heavily discounted) and at older ages (because fewer YOL remain). Costs per YOL saved ranged from $528 to $2194. The incremental costs per YOL saved versus 150-mg/TM (that is, the cost per additional YOL saved beyond that which would be achieved using 150-mg/TM treatment) were reasonable for the 2 PTC groups ($712 for the 150-mg group and $1248 for the 300-mg group), whereas those for the 300-mg/TM group were substantially higher ($3061). Costs per QALY saved followed the same pattern by treatment group but showed less variability by age.

Sensitivity Analysis

We examined the sensitivity of our results to parameter values by developing 2 scenarios that modified parameters so as to minimize or maximize cost effectiveness (denoted as the pessimistic and optimistic scenarios), as shown in Table 5. Under the pessimistic scenario (see upper half of Table 6), the cost per each additional 12-month quitter (above the expected rate in a placebo group) ranged from $1525 to $2515. The cost per lifetime quitter ranged from $2824 to $4657. In this scenario, 150 mg/PTC is somewhat more cost effective than 150 mg/TM, the opposite of the situation under the baseline scenario. The cost per YOL saved ranged from $2605 to $4295 and the cost per QALY saved ranged from $2177 to $3590. Under the optimistic scenario (see lower half of Table 6), the cost for each additional 12-month abstainer (above the expected rate in a placebo group) ranged from $560 to $861, and the cost per lifetime quitter ranged $756 to $1164. The cost per YOL saved ranged from $106 to $163 and the cost per QALY saved range from $116 to $179.

Comment

The cessation rates we found after treatment with various combinations of bupropion and counseling in the present study were comparable to those reported by Nielsen and Fiore.⁴ The costs of the behavioral interventions in our study ($28 for TM and $104 for PTC) were similar to costs cited in the literature for other comparable programs ($26 and $148).²³ The costs for the 300-mg groups in our study were somewhat higher than those calculated by Nielsen and Fiore⁴ because of the higher costs for the TM and PTC treatments relative to the authors' underestimated costs of intervention in the Jorenby study. No group in our study was as expensive as their bupropion + NTP group ($446 per enrollee), nor as inexpensive as their placebo group ($38 per enrollee, including counseling costs).

The costs per lifetime quitter in our study ($1499 to $2235) were lower than those reported by Cromwell and associates²⁴ for placebo, nicotine gum, or NTP combined with 5 levels of counseling intensity. Their costs ranged from a low of $2186 for group intensive counseling without nicotine replacement to a high of $8962 for nicotine gum with minimal counseling. The cost per YOL saved (after adjusting for placebo) in our study was generally lower than those reported in the smoking cessation literature,^{9,13,14,24,25} and considerably lower for the 150-mg dose groups (an average of $700 less). Thus, 150 mg bupropion combined with either PTC or TM would appear to be one of the most costeffective smoking cessation treatments available.

The smoking cessation interventions in our study also compared favorably with other generally accepted preventive health strategies with respect to cost per YOL saved.^9,17,26-29 Tengs and co-workers²⁶ reviewed 500 life-saving interventions, and after adjusting for inflation (to 1993 dollars), discount rate (5%), and excluding indirect costs, the median intervention cost was $42 000 per life-year saved. Warner³⁰ stated "a lifeyear saved at a cost of less than $20 000 (the highest cost estimate in the smoking-cessation treatment literature) constitutes a very worthwhile investment." In addition, as noted by Oster and associates,¹⁴ the relative cost effectiveness of smoking cessation treatments may be underestimated because the treatments are relatively brief and incur only relatively minor adverse effects. Under the optimistic scenario the cost per YOL and QALY saved range from $106 to $179, putting these treatments into the cost effectiveness neighborhood of vaccines.

As impressive as the cost-effectiveness measures were for our 150-mg dose groups, they might be improved. Because a substantial portion of total costs were attributable to the pharmacotherapy, and because smoking cessation trials show that smoking during the first 1 or 2 weeks of NTP therapy is predictive of relapse,^31-33 we speculate that the cost effectiveness of bupropion treatment might be improved by having physicians initially prescribe a 3-week supply of bupropion SR with a recommendation that the patient fill a subsequent prescription for an additional 5 weeks only if he or she remains abstinent for the initial 3-week time period. In addition, bupropion is still patent protected. When the patent expires and the formula becomes available generically, historical experience with other medications suggests that the costs will decline. Using current prices, however, we concluded that following the manufacturer's recommendation of using a 300-mg dose will result in a less cost-effective program than use of a 150-mg dose. (The manufacturer's recommendation for dose appears to be based on a comparison of the 6-week continuous abstinence rates for doses of placebo, 100, 150, and 300 mg bupropion. In the clinical trial³⁴ providing the 6-week continuous abstinence rates, no statistically significant difference was noted in the point-prevalence rates at 12 months for 150 and 300 mg bupropion [22.9% and 23.1%, respectively], and the trial did not consider medication costs or cost effectiveness.)

Discounting has a substantial effect on the relative benefit of smoking cessation in increasing YOL saved for different age groups. Without discounting, lifetime smoking cessation for a 20-year old man resulted in a savings of 9.11 life-years, whereas smoking cessation for a 70-year old man resulted in a savings of only 3.88 life-years. However, with a discount rate of 3.0%, the savings advantage was reversed. These facts resulted in the counterintuitive finding that smoking cessation programs should be directed to the elderly to be most cost effective, even though, in the very long term, treating 1 000 000 young smokers per year would yield a greater YOL savings than treating an equal number of elderly smokers.

The findings of this study should be interpreted cautiously because of limitations inherent in the methodology and assumptions. The data used to derive mortality rates for quitters was derived from the Cancer Prevention Study II (CPS II) database, and the participants in that study are generally acknowledged to be healthier than the general US population. This will tend to result in an overestimation of YOL saved for the general population (although not necessarily for managed care populations of generally healthy individuals). However, no adequate method for adjusting for the better health status of the CPS II population (relative to the general US population) is apparent. Estimates of mortality rates were extrapolated to ages younger than 45 years and older than 79 years and quality of life was extrapolated to ages younger than 25 years and older than 69 years. Extrapolation involves assumptions concerning the applicability of relationships observed in some age groups to other age groups and may not be accurate.

The study sample used in these analyses was predominantly Caucasian and middle class, and consisted of volunteers who knew that they would receive bupropion SR. Smoking cessation rates achieved in this population may not be reflective of smoking cessation rates among the general population. The study also was not blinded, and did not include a placebo group or biochemical verification of smoking cessation. Biochemical verification would presumably have resulted in somewhat lower cost effectiveness, although the literature suggests that the rate of underreporting of smoking in a field trial of this type may be minimal.^35-37 For the field trial, an intent-totreat approach was used to code nonrespondents as smokers. This tactic may have led to slightly decreased 12-month cessation rates and estimates of cost effectiveness.

No adverse effects requiring hospitalization were reported in this study. Four patients were seen in the emergency department (although none with as serious a condition as anaphylaxis). Had costs for emergency department visits been included, cost effectiveness would have been slightly lower. In addition, an increase in minor adverse effects (such as insomnia) was seen with higher levels of bupropion SR. Given the transience of the minor adverse effects and the availability of written material and counselors to explain these effects, medical expenses associated with the minor adverse effects were probably minimal.

Our baseline scenario assumed a constant spontaneous unaided yearly quit rate of 1.5%. Other research38 suggests that quit rates increase with age. However, some of this increase may be due to poorer health status with increasing age, increased interventions by physicians to encourage their patients to stop smoking, or greater use of smoking cessation aids. More research is necessary to quantify the relationship between the spontaneous unaided quit rate and age.

In summary, smoking cessation treatment consisting of 150 mg bupropion combined with an intensive telephone-based counseling program or a less intensive tailored mailing counseling program were approximately equally cost effective, were more cost effective than treatments using a 300-mg dose, and were more cost effective than many other smoking cessation interventions discussed in the literature. Cost per YOL and QALY saved, which were less with the 150-mg dose than the 300-mg dose, were sufficiently low for all doses to rate any of these smoking cessation interventions as among the most cost effective of life-saving medical treatment.

Acknowledgments

We thank Ella Thompson, BA, Casey Luce, MPH, Rachel Grossman, BA, Gaye Courtney, MPH, and Kymberli Hemberger, MA, for their assistance in the conduct of this study.

From the Center for Health Sciences, SRI International, Menlo Park, Calif (HSJ, GES, LMJ); the Centers for Health Promotion (TAM) and Health Studies (SMZ, SJC), Group Health Cooperative, Seattle, Wash; and HealthAnswers, Inc, Pennington, NJ (DLD, RP). Dr Curry is now affiliated with the School of Public Health, University of Illinois at Chicago.

This work was supported by National Cancer Institute grant R01-CA71358. Study medication was provided by Group Health Cooperative Pharmacy.

Address correspondence to: Harold S. Javitz, PhD, Center for Health Sciences, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025. E-mail: harold.javitz@sri.com.

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