- Email: [email protected]
Cost-utility analysis of smoking cessation to prevent operative complications following elective abdominal colon surgery
Accepted Manuscript Cost-utility analysis of smoking cessation to prevent operative complications following elective abdominal colon surgery Audrey S. Kulaylat, Christopher S. Hollenbeak, David I. Soybel PII:
S0002-9610(18)30836-5
DOI:
10.1016/j.amjsurg.2018.08.010
Reference:
AJS 12984
To appear in:
The American Journal of Surgery
Received Date: 11 June 2018 Revised Date:
14 August 2018
Accepted Date: 23 August 2018
Please cite this article as: Kulaylat AS, Hollenbeak CS, Soybel DI, Cost-utility analysis of smoking cessation to prevent operative complications following elective abdominal colon surgery, The American Journal of Surgery (2018), doi: 10.1016/j.amjsurg.2018.08.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Abstract BACKGROUND: Smoking is a known risk factor for postoperative complications after
the pharmacologic interventions for smoking cessation.
RI PT
colectomy. Using the perspective of the provider, this study evaluated the cost-effectiveness of
METHODS: A decision tree model was constructed to represent a provider’s decision to
provide either bupropion, nicotine replacement therapy, varenicline, or no cessation therapy to
SC
all patients presenting for elective colectomy. Incremental cost per quality-adjusted life year (QALY) was the primary outcome.
M AN U
RESULTS: The base case analysis suggests that bupropion is cost-effective with an incremental cost-effectiveness ratio of approximately $75,000 per QALY. Sensitivity analyses established ranges for which each medication might be cost-effective and dominant compared to offering no cessation therapy.
TE D
CONCLUSIONS: From a provider perspective, offering bupropion for smoking cessation to patients scheduled for elective colon resection is cost-effective. Furthermore, these results provide benchmarks to inform providers about whether targeted, short-term smoking cessation
AC C
EP
therapies represent good value in colectomies.
ACCEPTED MANUSCRIPT 1
Cost-utility analysis of smoking cessation to prevent operative complications following elective abdominal colon surgery
RI PT
Audrey S. Kulaylat, MDa, Christopher S. Hollenbeak, PhDa,b,c David I. Soybela
a
EP
TE D
M AN U
SC
Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA USA b Department of Public Health Sciences, The Pennsylvania State University, College of Medicine, Hershey, PA USA c Department of Health Policy and Administration, The Pennsylvania State University, University Park, PA USA
AC C
Corresponding Author: David I. Soybel, MD The Pennsylvania State University College of Medicine Department of Surgery Division of General Surgery Specialties and Surgical Oncology 500 University Drive Hershey, Pa 17033-0850 Tel #: 717-531-5272 Fax #: 717-531-0884 Email: [email protected]
ACCEPTED MANUSCRIPT 2 Summary From the perspective of healthcare providers, identifying interventions that improve quality and reduce costs remains a central goal of providing surgical care. Among smoking cessation aids,
RI PT
bupropion appears to be cost-effective with an incremental cost-effectiveness ratio of
approximately $75,000 per quality-adjusted life year. Further sensitivity analyses established thresholds at which bupropion and varenicline would be costlier and less effective compared to
AC C
EP
TE D
M AN U
SC
no additional therapy.
ACCEPTED MANUSCRIPT 3
AC C
EP
TE D
M AN U
SC
RI PT
KEYWORDS: smoking cessation; operative complications; colorectal surgery
ACCEPTED MANUSCRIPT 4 Introduction Elective colon resections are performed commonly, with an estimated 110,000 cases performed annually in the United States.1 Previous studies suggest that as much as 20% of this
RI PT
population are current tobacco smokers, and a similar proportion are former smokers.2 Compared to nonsmokers, patients who continue to smoke preoperatively are more prone to a variety of postoperative complications, ranging from hypercoagulability with venous thromboembolic
SC
events to surgical site occurrences and anastomotic leaks.3-5 Patients who are not smoking prior to major abdominal operations have a lower likelihood, compared to those who smoke, of post-
M AN U
operative adverse events such as respiratory complications, surgical site infections, and improvement in long-term outcomes such as less frequent hernia formation.4-6 Active programs of smoking cessation for at least 4 weeks have been shown to be consistently beneficial,6-9 with each pre-operative week of smoking cessation translating to an increasing level of benefit.3
TE D
Along with dependence on nicotine, the psychological and socioeconomic drivers of persistent tobacco use are complex.3, 4 In addition, there is considerable variation in the success rates for pharmacologic approaches to smoking cessation, even if they can be shown to have
EP
some efficacy and be cost-effective in the most challenging populations.10-12 In a recent randomized controlled trial comparing the most common pharmaceutical cessation aids, use of
AC C
varenicline (Chantix) was associated with 3.6-higher odds of smoking cessation compared with placebo, while use of either bupropion (Zyban, Wellbutrin) or nicotine replacement therapy was associated with over twice the odds of cessation when compared to placebo.13 With these results, the aforementioned considerations suggest that short-term efforts to restrain or eliminate smoking altogether might be cost effective, even if limited to the interval between the decision to perform a major abdominal operation and the follow-up that would capture outcomes and
ACCEPTED MANUSCRIPT 5 adverse events that might be influenced by tobacco use. In this regard, a recent decision-analysis from the Washington State Surgical Care and Outcomes Assessment Program (SCOAP)14 suggested that among patients undergoing colon and/or rectal operations, costs of care for active
RI PT
or recent smokers who participated in a pre-operative smoking cessation program were on
average $304 (95% CI: $40-$571) lower for those who did not participate in such a program. This analysis suggested that adoption of smoking cessation programs for such patients would,
SC
under certain conditions, yield a net cost-savings to the system providing their care.
In this report, we have combined literature-validated estimates on outcomes of colectomy
M AN U
in patients who smoke and those who quit in anticipation of surgery; integrating these estimates with our own institutional data on costs, we have asked, for abdominal colectomy procedures specifically, whether commonly recognized pharmacologic interventions (varenicline, bupropion, or nicotine replacement therapy) meet the cost-thresholds identified by the type of
TE D
analysis performed for patients in the SCOAP registry.14 Using the perspective of the provider system (hospital and health care decision-makers), we have also performed a detailed, intervention-focused decision analysis showing the conditions under which short-term, peri-
EP
operatively focused pharmacologic smoking cessation programs would prove cost-effective. By focusing on costs to the institution and providers, rather than those of third-parties, we have also
AC C
developed a perspective on how patients and providers--independent of payers-- might cooperate in the sharing of risks, costs and decisions.
ACCEPTED MANUSCRIPT 6 Methods Conceptual framework In this study, cost-effectiveness analysis (CEA) was used to estimate the relative value of
RI PT
different programs for preoperative smoking cessation, projected over a one-year postoperative time horizon. Because the outcomes and costs of interventions were analyzed within a relatively short, one-year time horizon, we utilized a decision tree model rather than the Markov model
SC
frequently utilized in other studies. The decision model was parameterized using data from the literature regarding both the postoperative benefits of preoperative smoking cessation and the
M AN U
known limitations in effectiveness of available therapies. Cost data were obtained from analysis of aggregate patient experiences undergoing colon resection procedures at our institution. For each smoking cessation strategy, we estimated an incremental cost-effectiveness ratio.
TE D
Model structure
The decision tree (Fig. 1) was constructed using TreeAge Pro software (TreeAge Software, Inc., Williamstown, MA, USA). The initial decision node in the model represents the
EP
provider’s decision to provide either nicotine replacement therapy (NRT), bupropion, varenicline, or no smoking cessation strategy to all patients who are current smokers presenting
AC C
for elective colectomy. After selecting a particular strategy, smoking cessation was determined to be “effective” or “ineffective.” “Effective” cessation was defined as continuous abstinence of tobacco use during weeks 9-12 after initiation of therapy, regardless of whether full compliance with the treatment regimen was achieved. Regardless of whether or not the chosen strategy is effective, the patient was then assumed to undergo surgery. After surgery, outcomes included death, complications without mortality, or an uneventful post-operative course (Fig. 1).
ACCEPTED MANUSCRIPT 7 Probabilities Model parameters and references are listed in Table 1. Estimates of the effectiveness of each of the four therapeutic strategies (including placebo) were obtained from a recent large,
RI PT
prospective trial comparing the strategies.13 Probabilities associated with complication rates required comparisons between current smokers and former smokers, rather than non-smokers. Of note, the proportion of current smokers observed in our patient cohort was approximately 15%,
SC
which approximates the proportion observed in the prior study from which risk-adjusted
M AN U
estimates of the probabilities of complications were obtained.2
Utilities
To estimate the utility of both complicated and uncomplicated postoperative courses after colectomy, results from a study measuring utilities using the Short Form 6D (SF-6D) in post-
TE D
colectomy patients were used (Table 1).15 Utility estimates are used to reflect and compare an individual’s preference for various health states. They are measured from 0 to 1.0, whereby a value of 1.0 represents a state of perfect health, and a value of 0 represents a state of the poorest
EP
health or death, placing all other states on a continuum between these two values. The values obtained from the aforementioned study were then used to compute the quality-adjusted life
Costs
AC C
years (QALYs) associated with the four intervention arms.
Costs were estimated using institutional cost data from Penn State Hershey Medical
Center. Patients undergoing colectomy procedures over a four-year period (July 2012 through June 2015) at our academic center were identified through Diagnosis Related Group (DRG)
ACCEPTED MANUSCRIPT 8 codes indicating colectomy without complications (DRG 331), colectomy with minor complications (DRG 330), and colectomy with major complications (DRG 329). Emergent procedures were identified as those with line items for emergency department services, and were
RI PT
excluded from analysis. Total costs for both current and former smokers were then calculated based on the weighted average of the probability of minor and major complications observed in these two populations. Patients who died during the index hospitalization formed a separate
SC
cohort in order to estimate healthcare costs associated with in-hospital mortality. Total costs were adjusted to 2016 dollars using records from the first half of 2016 dollars from the medical
Analysis of cost-effectiveness
M AN U
care component of the Consumer Price Index (CPI).
The incremental cost-effectiveness ratio was calculated for the base case scenario, and
TE D
then recalculated after eliminating strategies based on extended dominance. The willingness-topay threshold was set at $150,000 per QALY, which has been recently suggested as a more appropriate threshold than the historic threshold of $50,000 per QALY that has held popularity
EP
since the mid-1990s.16 One-way sensitivity analyses were performed to estimate the values of the parameters at which the incremental cost-effectiveness ratio fell below the accepted willingness-
AC C
to-pay threshold. The primary one-way sensitivity analyses were focused around the cost and clinical effectiveness of the pharmaceutical agents, the utilities associated with complicated and uncomplicated postoperative courses, and the probabilities associated with experiencing a postoperative complication. Two-way sensitivity analyses were performed to identify the dominant strategy by varying the estimates for two parameters simultaneously. For the two medications that were not eliminated by extended dominance, bupropion and varenicline, the
ACCEPTED MANUSCRIPT 9 probabilities of quitting using either medication and the costs associated with each were varied. Additionally, the costs associated with complication profiles in both current and former smokers
RI PT
were varied in the sensitivity analyses.
Results Costs
SC
A total of 1,438 patients at our institution were identified who underwent colon resections with subsequent hospitalizations; of these, 440 patients had uncomplicated postoperative courses,
M AN U
773 patients experienced minor complications, 214 patients experienced major complications, and 10 patients experienced in-hospital mortality. After determining costs using institutional data, patients whose hospitalizations involved either minor complications or major complications had significantly higher costs, both for the index hospitalization as well as for the year following
TE D
the procedure (Table 1).
Expected costs and benefits
EP
Our base-case model was built on estimates of the incremental improvement in cost effectiveness, starting with the condition in which no intervention is provided, as compared to
AC C
each intervention (bupropion, nicotine replacement therapy, and varencline) in the order of least to most expensive. It should be noted that the analysis did not ask whether the most costly intervention, varencline, is cost-effective in comparison with no intervention, but rather, whether it would be considered incrementally cost-effective in comparison to the other less expensive alternatives. As shown in Table 2, the bupropion strategy added the least amount of cost to care of the three alternatives and was more effective than not offering a pharmaceutical smoking
ACCEPTED MANUSCRIPT 10 cessation aid. In addition, the incremental cost-effectiveness ratio was $74,255 per QALY; therefore, at a willingness-to-pay threshold of $150,000 per QALY, this intervention was considered cost effective. The next most costly strategy, NRT, was only $12 more costly than
RI PT
bupropion, but was associated with such a small marginal effectiveness that its incremental costeffectiveness ratio when compared to bupropion was $936,096. The incremental cost-
effectiveness ratio between the most costly strategy, varenicline, and NRT was also high
SC
($897,265), but less so than that of the previous pairing (NRT versus bupropion); therefore, the NRT strategy was eliminated due to the extended dominance of the bupropion and varenicline
M AN U
strategies.17 As a result, the incremental cost-effectiveness ratio for varenicline relative to bupropion was $898,244 per additional QALY (Table 2), which remains above the acceptable willingness-to-pay threshold.
TE D
Sensitivity analyses
When comparing bupropion to no therapy, the use of bupropion became cost-effective when the probability of quitting was slightly below 25% (Fig. 2a). Comparing NRT to no
EP
therapy, this value is 25%; comparing varenicline to no therapy, it is approximately 55%. Costs of the pharmaceutical agents were then varied to determine values for which each agent became
AC C
cost-effective relative to using no therapy (Fig. 2b). For bupropion, the associated cost was $220, and for NRT was $225, both of which are higher than the current retail costs of these agents. For varenicline, the cost at which this medication became cost-effective relative to no therapy was approximately $440, which is lower than the current retail costs of this strategy. The utilities associated with the states of experiencing postoperative complications and having uncomplicated postoperative courses were varied over a range of 0 to 1 (Fig. 3).
ACCEPTED MANUSCRIPT 11 Regardless of the utility associated with having a complicated postoperative course, bupropion remained below the willingness-to-pay threshold for all utility values from 0 to 1. For uncomplicated postoperative courses, bupropion was cost-effective for all values over 0.84; for
and fewer QALYs than the strategy involving no medications.
RI PT
all values below 0.70, all three pharmaceutical regimens are dominated, involving higher costs
Two-way sensitivity analyses are presented in Fig. 4. At probabilities of quitting with
SC
bupropion above 29.4%, bupropion dominates no therapy, while at probabilities of quitting with varenicline above 79.6% varenicline dominates no therapy (Fig. 4a). At costs below $145 for a
M AN U
course of therapy, the bupropion strategy dominates no therapy, and at costs of varenicline below $285, varenicline dominates no therapy (Fig. 4b). If the cost of varenicline was reduced to below $143 for a course of therapy, then the varenicline strategy would be less costly and more effective than both the bupropion and no standardized therapy strategies. At increasingly higher
TE D
annual costs for current smokers and lower costs for former smokers, bupropion becomes the dominant strategy, followed by varenicline therapy (Fig. 4c).
EP
Discussion
Smoking remains an independent risk factor for increased complications and costs after
AC C
any major operation, including colectomy.3, 5, 18-20 In addition, it is clear that− if only for the duration of the peri-operative period and a bit beyond− quitting makes a difference in surgical outcomes.5, 6, 8, 9, 14 In the recent study of patients undergoing colectomy within the Washington State SCOAP program,14 it was somewhat surprising and a bit disheartening that cost savings associated with pre-operative quitting were not very high-- about $330 per patient in the first ninety days of care after surgery. Our study differs in several ways from prior efforts to
ACCEPTED MANUSCRIPT 12 understand the costs and implications of quitting at the time of a major abdominal operation.3, 14 The first is that the time horizon for study was chosen for a full year, rather than ninety days, after operation. This extended period allowed us to capture not only additional costs, but also
RI PT
addressed, to some extent, the real possibility that some smokers who quit before surgery might have restarted, thereby weakening the influence of pre-operative smoking cessation. A second difference is that our study reflects institutional costs at a tertiary-care, academic center, rather
SC
than an aggregate of hospital profiles that comprises the SCOAP program or hospitals that operate within a single layer system such as the Veterans Health Administration.3 A third
M AN U
difference is that our calculations of annual costs of care began with the cohort overall (Table 1) under baseline conditions and then for the sub-cohort in whom complications occurred, major and minor, according to the criteria used by Hawn et al.3 While the SCOAP study focused on the differences in cost of care in patients with known histories of smoking, based on institutional
TE D
charge/cost ratios,14 our analysis has focused on determining whether the added costs of pharmacologic interventions would mitigate costs of care and improve utility to the patient. With these differences in design in mind, our analysis confirms that taking care of
EP
complications after colectomy is expensive and taking care of such complications in smokers is more expensive.3 Our analysis also shows that, under current conditions, none of the
AC C
pharmacologic smoking cessation aids actually would decrease costs to the provider system. As previously shown, the cost-savings of smoking cessation are not very high14 and the added cost of any of the pharmacologic approaches to smoking cessation does not save money. Moreover, as shown in Table 2, the high incremental increase in cost over the other agents makes the most clinically effective agent (varenicline) the least cost-effective choice among the three interventions. The sensitivity analyses demonstrate how realistic it would be to expect each of
ACCEPTED MANUSCRIPT 13 the interventions to become more cost-effective, based upon a change in the clinical effectiveness (Fig. 2a), cost (Fig. 2b), or changes in utility functions in the presence of absence of complications (Fig. 3). These sensitivity analyses illustrate how much more cost-effective
RI PT
bupropion is than the other interventions and how relatively small changes in clinical
effectiveness or cost might negate the benefits of any pharmacologic aid for smoking cessation (Fig. 3). This analysis thus identifies price thresholds at which these agents might become cost-
SC
saving and in addition provides evidence that even at current costs, at least one of the agents-bupropion-- would offer recognizable value. At the same time, our analysis emphasizes the need
M AN U
to keep searching for more effective strategies at equal or lower cost.
This current effort has specific limitations: first, the calculated costs of care for uneventful and complicated cases will be sensitive not only to the proportion of smokers in the cohort, but also the proportions of other higher-risk attributes such as obesity and poorly
TE D
controlled diabetes—which are not explicitly taken into account and could influence utilities; second, the study does not directly address the possibility that any of the interventions might independently influence the utilities used in the analysis, through side-effects of the medications
EP
themselves; third, the utilities used in the model merged the effects of major and minor complications and, as a first approximation, was based on an assumption that the complications
AC C
occurred early enough after surgery to influence utilities for the entire post-operative year. In addition, the analysis does not take into account the effectiveness of different pre-operative intervals of therapy on short-term success in quitting, outcome of operation or the likelihood of returning to smoking behaviors.8, 21-23 With regard to compliance, it has also been suggested that in addition to the therapy itself, adherence to therapy is influenced by the availability of financial coverage, increasing the quit-rate by almost 10%.22 It should be emphasized that our model is
ACCEPTED MANUSCRIPT 14 parameterized with results from a randomized controlled trial analyzed on an intention-to-treat basis, in which documented compliance (both partial and full compliance) only reached 80%.22 Thus, to some extent the parameterized model takes into account suboptimal compliance and the
RI PT
time horizon of one year takes provides for the possibility of recidivism. In this regard, data were not yet available to assess the impact and costs of behavioral adjuncts to pharmacologic
therapy.23, 24 As such information becomes available, it might turn out that support for behavioral
calculation of cost-savings, even in a one-year time-frame.
SC
adjuncts would lead to higher and more sustainable quit-rates, which would, in turn, alter the
M AN U
Our analysis indicates that additional value (lower complication rates, higher utility) is offered to smoking patients undergoing colectomy through smoking cessation therapies, with bupriopion therapy as most cost-effective at $75,000/QALY. This level of effectiveness meets a recognized standard of less than $150,000/QALY,16 while the other therapies (NRT, varencline)
TE D
exceed this incremental cost-effectiveness ratio threshold considerably. For an actively smoking patient facing colectomy, the benefits of intervention, however, come at an increased cost, raising the question: who should pay for the benefit? Our analysis suggests an opportunity for
EP
health-delivery systems to partner with both patients and payers to determine the solution. It might make sense, for example, that the health system would be willing to pay for smoking
AC C
cessation therapies up to, but not more than, the amount of money it already knows it would be spending to take care of the higher risk patient. It might also make sense for the patient -- as a consumer-- to be asked to pay the difference; or, in the event of a complication that might have been avoided had the patient actually entered the smoking cessation program and stopped smoking, to have consequent charges to the patient reflect the increased costs of caring for that complication. It has been justly argued that denial of care to smokers is ethically questionable
ACCEPTED MANUSCRIPT 15 and might lead to worse outcomes and costs to the system.25 Guided by analyses such as those used in this study, the use of co-pays and sharing of cost for modification of high-risk behaviors seems to be a rational alternative to outright denial of services as incentives for encouraging
RI PT
responsible behaviors by health systems and patients in order to improve outcomes and cost-
AC C
EP
TE D
M AN U
SC
effective use of resources.26
ACCEPTED MANUSCRIPT 16 Acknowledgements The authors thank Kimberly Walker for her professional assistance in editing and submitting this
RI PT
manuscript.
Funding: This research did not receive any specific grant from funding agencies in the public,
AC C
EP
TE D
M AN U
SC
commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT 17 References 1.
Zogg CK, Najjar P, Diaz AJ, et al. Rethinking priorities: cost of complications after elective colectomy. Ann Surg 2016;264:312-22. Sharma A, Deeb AP, Iannuzzi JC, et al. Tobacco smoking and postoperative outcomes after colorectal surgery. Ann Surg 2013;258:296-300.
Hawn MT, Houston TK, Campagna EJ, et al. The attributable risk of smoking on surgical complications. Ann Surg 2011;254:914-20.
4.
SC
3.
RI PT
2.
Sorensen LT. Wound healing and infection in surgery: the pathophysiological impact of
Surg 2012;255:1069-79. 5.
M AN U
smoking, smoking cessation, and nicotine replacement therapy: a systematic review. Ann
Sorensen LT. Wound healing and infection in surgery. The clinical impact of smoking and smoking cessation: a systematic review and meta-analysis. Arch Surg 2012;147:373-
6.
TE D
83.
Mills E, Eyawo O, Lockhart I, et al. Smoking cessation reduces postoperative complications: a systematic review and meta-analysis. Am J Med 2011;124:144-54 e8. Sadr Azodi O, Lindstrom D, Adami J, et al. The efficacy of a smoking cessation
EP
7.
programme in patients undergoing elective surgery: a randomised clinical trial.
8.
AC C
Anaesthesia 2009;64:259-65.
Lindstrom D, Sadr Azodi O, Wladis A, et al. Effects of a perioperative smoking cessation intervention on postoperative complications: a randomized trial. Ann Surg 2008;248:73945.
ACCEPTED MANUSCRIPT 18 9.
Wong J, Lam DP, Abrishami A, et al. Short-term preoperative smoking cessation and postoperative complications: a systematic review and meta-analysis. Can J Anaesth 2012;59:268-79. Peckham E, Brabyn S, Cook L, et al. Smoking cessation in severe mental ill health: what
RI PT
10.
works? an updated systematic review and meta-analysis. BMC Psychiatry 2017;17:252. 11.
Athanasakis K, Souliotis K, Tountas Y, et al. A cost-utility analysis of hypertension
SC
treatment in Greece: assessing the impact of age, sex and smoking status, on outcomes. J Hypertens 2012;30:227-34.
Knight C, Howard P, Baker CL, et al. The cost-effectiveness of an extended course
M AN U
12.
(12+12 weeks) of varenicline compared with other available smoking cessation strategies in the United States: an extension and update to the BENESCO model. Value Health 2010;13:209-14.
Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of
TE D
13.
varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.
14.
EP
Lancet 2016;387:2507-20.
Gaskill CE, Kling CE, Varghese TK, Jr., et al. Financial benefit of a smoking cessation
15.
AC C
program prior to elective colorectal surgery. J Surg Res 2017;215:183-9. Lee L, Elfassy N, Li C, et al. Valuing postoperative recovery: validation of the SF-6D health-state utility. J Surg Res 2013;184:108-14.
16.
Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold. N Engl J Med 2014;371:796-7.
ACCEPTED MANUSCRIPT 19 17.
Petitti D. Meta-Analysis, Decision Analysis and Cost-effectivness Analysis: Methods for Quantitative Synthesis in Medicine, 2nd Ed. New York, NY: Oxford University Press; 2000. Nolan MB, Martin DP, Thompson R, et al. Association between smoking status,
RI PT
18.
preoperative exhaled carbon monoxide levels, and postoperative surgical site infection in patients undergoing elective surgery. JAMA Surg 2017;152:476-83.
Gajdos C, Hawn MT, Campagna EJ, et al. Adverse effects of smoking on postoperative
SC
19.
outcomes in cancer patients. Ann Surg Oncol 2012;19:1430-8.
Singh JA, Houston TK, Ponce BA, et al. Smoking as a risk factor for short-term
M AN U
20.
outcomes following primary total hip and total knee replacement in veterans. Arthritis Care Res (Hoboken) 2011;63:1365-74. 21.
Carlson BB, Burton DC, Jackson RS, et al. Recidivism rates after smoking cessation
22.
TE D
before spinal fusion. Orthopedics 2016;39:e318-22.
Berlin NL, Cutter C, Battaglia C. Will preoperative smoking cessation programs generate long-term cessation? A systematic review and meta-analysis. Am J Manag Care
23.
EP
2015;21:e623-31.
Shi Y, Warner DO. Brief preoperative smoking abstinence: is there a dilemma? Anesth
24.
AC C
Analg 2011;113:1348-51.
Cropley M, Theadom A, Pravettoni G, et al. The effectiveness of smoking cessation interventions prior to surgery: a systematic review. Nicotine Tob Res 2008;10:407-12.
25.
Shaw D. Delaying surgery for obese patients or smokers is a bad idea. BMJ 2016;355:i5594.
ACCEPTED MANUSCRIPT 20 Porter ME, Teisberg EM. Redefining Health Care. Boston: Harvard Business School
EP
TE D
M AN U
SC
RI PT
Press; 2006.
AC C
26.
ACCEPTED MANUSCRIPT 21 Table 1 Model parameters Estimate
0.145 0.126
0.05 0.02
0.013 0.01
0 0
0.2 0.2
14 14 14 14 2 2 2 2 2 2
n/a 4 4 4
n/a 500 500 1500
Institutional Data Institutional Data Institutional Data Institutional Data Institutional Data
$14,914 $21,093 $48,070 $117,892
n/a n/a n/a n/a
n/a n/a n/a n/a
Institutional Data Institutional Data Institutional Data Institutional Data
$34,199 $59,027 $109,360 $117,892 $46,811 $46,538
n/a n/a n/a n/a $15,000 $15,000
n/a n/a n/a n/a $75,000 $75,000
0.897 0.938 0
0 0 n/a
1 1 n/a
Institutional Data Institutional Data Institutional Data Institutional Data Institutional Data, 2 Institutional Data, 2 15 15 15 15
M AN U TE D
AC C
n/a 1 1 1
Reference
RI PT
n/a 0 0 0
0.25 0.22
SC
0.137 0.261 0.264 0.380
$0 $184 $199 $772
EP
Parameter Probabilities Probability of cessation No medication Bupropion Nicotine replacement therapy Varenicline Probability of complication Current smoker Former smoker Probability of mortality Current smoker Former smoker Costs Strategy No medication Bupropion Nicotine replacement therapy Varenicline Costs during index hospitalization Baseline Minor complications Major complications In-hospital mortality Annual costs Baseline Minor complications Major complications In-hospital mortality Annual costs in current smoker Annual costs in former smoker Utilities Complicated postoperative course Uncomplicated postoperative course In-hospital mortality
Sensitivity analysis Lower Upper
ACCEPTED MANUSCRIPT 22 Table 2 Base-case cost effectiveness analysis results
Strategy
Cost
Marginal cost
Effectiveness
Marginal effectiveness
Incremental costeffectiveness ratio ($/QALY)
All strategies $41,819.40
Bupropion
$41,858.02
$38.62
0.92087
0.00052
$74,255.23
NRT
$41,869.69
$11.67
0.92088
0.00001
$936,096.28
Varenicline
$42,306.56
$436.87
0.92137
0.00049
$897,265.39
Non-dominated strategies 0.92035
Bupropion
$41,858.02
$38.62
Varenicline
$42,306.56
$448.54
0.92087
EP AC C
0.00052
$74,255.23
0.00050
$898,244.32
M AN U
$41,819.40
0.92137
TE D
None
SC
0.92035
RI PT
None
ACCEPTED MANUSCRIPT 23 Figure Legends Figure 1 Decision tree structure. Figure 2 (a) From left to right, results of one-way sensitivity analyses for the probability of
RI PT
quitting with bupropion, NRT, and varenicline vs. no cessation therapy. (b) From left to right, results of one-way sensitivity analyses for the baseline costs of bupropion, NRT, and varenicline vs. no cessation therapy. Horizontal line represents a willingness-to-pay threshold of $150,000
SC
per QALY.
Figure 3 One-way sensitivity analysis of utilities associated with complicated and
M AN U
uncomplicated hospitalizations. Horizontal line represents a willingness-to-pay threshold of $150,000 per QALY.
Figure 4 (a) Two-way sensitivity analysis of the probability of quitting with bupropion and with varenicline, (b) two-way sensitivity analysis of the costs of bupropion and varenicline, and (c)
AC C
EP
TE D
two-way sensitivity analysis of the costs of complications in current and former smokers.
ACCEPTED MANUSCRIPT
0.4
0.6
Utility of Complication
0.8
1.0
1000 S500 CR IP T −500 −1000
EP AC C 0.2
0
M AN U TE D
1000 500 0.0
Marginal Cost ($1000) per QALY
1500
No Complications
Bup Vs. None NRT vs. Bup Var vs. NRT
0
Marginal Cost ($1000) per QALY
Complications
0.0
0.2
0.4
0.6
0.8
Utility of No Complication
1.0
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights •
At baseline, bupropion therapy is cost-effective with an incremental cost-effectiveness ratio of approximately $75,000 per QALY. Reducing the cost of varenicline therapy to less than $143 per course results in
RI PT
•
varenicline being less costly and more effective than offering no smoking cessation therapy.
SC
Results of the base case and sensitivity analyses provide thresholds to inform providers about whether uniformly providing targeted, short-term smoking cessation therapies to
EP
TE D
M AN U
patients undergoing elective colectomy represents good value.
AC C
•
S0002-9610(18)30836-5
DOI:
10.1016/j.amjsurg.2018.08.010
Reference:
AJS 12984
To appear in:
The American Journal of Surgery
Received Date: 11 June 2018 Revised Date:
14 August 2018
Accepted Date: 23 August 2018
Please cite this article as: Kulaylat AS, Hollenbeak CS, Soybel DI, Cost-utility analysis of smoking cessation to prevent operative complications following elective abdominal colon surgery, The American Journal of Surgery (2018), doi: 10.1016/j.amjsurg.2018.08.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Abstract BACKGROUND: Smoking is a known risk factor for postoperative complications after
the pharmacologic interventions for smoking cessation.
RI PT
colectomy. Using the perspective of the provider, this study evaluated the cost-effectiveness of
METHODS: A decision tree model was constructed to represent a provider’s decision to
provide either bupropion, nicotine replacement therapy, varenicline, or no cessation therapy to
SC
all patients presenting for elective colectomy. Incremental cost per quality-adjusted life year (QALY) was the primary outcome.
M AN U
RESULTS: The base case analysis suggests that bupropion is cost-effective with an incremental cost-effectiveness ratio of approximately $75,000 per QALY. Sensitivity analyses established ranges for which each medication might be cost-effective and dominant compared to offering no cessation therapy.
TE D
CONCLUSIONS: From a provider perspective, offering bupropion for smoking cessation to patients scheduled for elective colon resection is cost-effective. Furthermore, these results provide benchmarks to inform providers about whether targeted, short-term smoking cessation
AC C
EP
therapies represent good value in colectomies.
ACCEPTED MANUSCRIPT 1
Cost-utility analysis of smoking cessation to prevent operative complications following elective abdominal colon surgery
RI PT
Audrey S. Kulaylat, MDa, Christopher S. Hollenbeak, PhDa,b,c David I. Soybela
a
EP
TE D
M AN U
SC
Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA USA b Department of Public Health Sciences, The Pennsylvania State University, College of Medicine, Hershey, PA USA c Department of Health Policy and Administration, The Pennsylvania State University, University Park, PA USA
AC C
Corresponding Author: David I. Soybel, MD The Pennsylvania State University College of Medicine Department of Surgery Division of General Surgery Specialties and Surgical Oncology 500 University Drive Hershey, Pa 17033-0850 Tel #: 717-531-5272 Fax #: 717-531-0884 Email: [email protected]
ACCEPTED MANUSCRIPT 2 Summary From the perspective of healthcare providers, identifying interventions that improve quality and reduce costs remains a central goal of providing surgical care. Among smoking cessation aids,
RI PT
bupropion appears to be cost-effective with an incremental cost-effectiveness ratio of
approximately $75,000 per quality-adjusted life year. Further sensitivity analyses established thresholds at which bupropion and varenicline would be costlier and less effective compared to
AC C
EP
TE D
M AN U
SC
no additional therapy.
ACCEPTED MANUSCRIPT 3
AC C
EP
TE D
M AN U
SC
RI PT
KEYWORDS: smoking cessation; operative complications; colorectal surgery
ACCEPTED MANUSCRIPT 4 Introduction Elective colon resections are performed commonly, with an estimated 110,000 cases performed annually in the United States.1 Previous studies suggest that as much as 20% of this
RI PT
population are current tobacco smokers, and a similar proportion are former smokers.2 Compared to nonsmokers, patients who continue to smoke preoperatively are more prone to a variety of postoperative complications, ranging from hypercoagulability with venous thromboembolic
SC
events to surgical site occurrences and anastomotic leaks.3-5 Patients who are not smoking prior to major abdominal operations have a lower likelihood, compared to those who smoke, of post-
M AN U
operative adverse events such as respiratory complications, surgical site infections, and improvement in long-term outcomes such as less frequent hernia formation.4-6 Active programs of smoking cessation for at least 4 weeks have been shown to be consistently beneficial,6-9 with each pre-operative week of smoking cessation translating to an increasing level of benefit.3
TE D
Along with dependence on nicotine, the psychological and socioeconomic drivers of persistent tobacco use are complex.3, 4 In addition, there is considerable variation in the success rates for pharmacologic approaches to smoking cessation, even if they can be shown to have
EP
some efficacy and be cost-effective in the most challenging populations.10-12 In a recent randomized controlled trial comparing the most common pharmaceutical cessation aids, use of
AC C
varenicline (Chantix) was associated with 3.6-higher odds of smoking cessation compared with placebo, while use of either bupropion (Zyban, Wellbutrin) or nicotine replacement therapy was associated with over twice the odds of cessation when compared to placebo.13 With these results, the aforementioned considerations suggest that short-term efforts to restrain or eliminate smoking altogether might be cost effective, even if limited to the interval between the decision to perform a major abdominal operation and the follow-up that would capture outcomes and
ACCEPTED MANUSCRIPT 5 adverse events that might be influenced by tobacco use. In this regard, a recent decision-analysis from the Washington State Surgical Care and Outcomes Assessment Program (SCOAP)14 suggested that among patients undergoing colon and/or rectal operations, costs of care for active
RI PT
or recent smokers who participated in a pre-operative smoking cessation program were on
average $304 (95% CI: $40-$571) lower for those who did not participate in such a program. This analysis suggested that adoption of smoking cessation programs for such patients would,
SC
under certain conditions, yield a net cost-savings to the system providing their care.
In this report, we have combined literature-validated estimates on outcomes of colectomy
M AN U
in patients who smoke and those who quit in anticipation of surgery; integrating these estimates with our own institutional data on costs, we have asked, for abdominal colectomy procedures specifically, whether commonly recognized pharmacologic interventions (varenicline, bupropion, or nicotine replacement therapy) meet the cost-thresholds identified by the type of
TE D
analysis performed for patients in the SCOAP registry.14 Using the perspective of the provider system (hospital and health care decision-makers), we have also performed a detailed, intervention-focused decision analysis showing the conditions under which short-term, peri-
EP
operatively focused pharmacologic smoking cessation programs would prove cost-effective. By focusing on costs to the institution and providers, rather than those of third-parties, we have also
AC C
developed a perspective on how patients and providers--independent of payers-- might cooperate in the sharing of risks, costs and decisions.
ACCEPTED MANUSCRIPT 6 Methods Conceptual framework In this study, cost-effectiveness analysis (CEA) was used to estimate the relative value of
RI PT
different programs for preoperative smoking cessation, projected over a one-year postoperative time horizon. Because the outcomes and costs of interventions were analyzed within a relatively short, one-year time horizon, we utilized a decision tree model rather than the Markov model
SC
frequently utilized in other studies. The decision model was parameterized using data from the literature regarding both the postoperative benefits of preoperative smoking cessation and the
M AN U
known limitations in effectiveness of available therapies. Cost data were obtained from analysis of aggregate patient experiences undergoing colon resection procedures at our institution. For each smoking cessation strategy, we estimated an incremental cost-effectiveness ratio.
TE D
Model structure
The decision tree (Fig. 1) was constructed using TreeAge Pro software (TreeAge Software, Inc., Williamstown, MA, USA). The initial decision node in the model represents the
EP
provider’s decision to provide either nicotine replacement therapy (NRT), bupropion, varenicline, or no smoking cessation strategy to all patients who are current smokers presenting
AC C
for elective colectomy. After selecting a particular strategy, smoking cessation was determined to be “effective” or “ineffective.” “Effective” cessation was defined as continuous abstinence of tobacco use during weeks 9-12 after initiation of therapy, regardless of whether full compliance with the treatment regimen was achieved. Regardless of whether or not the chosen strategy is effective, the patient was then assumed to undergo surgery. After surgery, outcomes included death, complications without mortality, or an uneventful post-operative course (Fig. 1).
ACCEPTED MANUSCRIPT 7 Probabilities Model parameters and references are listed in Table 1. Estimates of the effectiveness of each of the four therapeutic strategies (including placebo) were obtained from a recent large,
RI PT
prospective trial comparing the strategies.13 Probabilities associated with complication rates required comparisons between current smokers and former smokers, rather than non-smokers. Of note, the proportion of current smokers observed in our patient cohort was approximately 15%,
SC
which approximates the proportion observed in the prior study from which risk-adjusted
M AN U
estimates of the probabilities of complications were obtained.2
Utilities
To estimate the utility of both complicated and uncomplicated postoperative courses after colectomy, results from a study measuring utilities using the Short Form 6D (SF-6D) in post-
TE D
colectomy patients were used (Table 1).15 Utility estimates are used to reflect and compare an individual’s preference for various health states. They are measured from 0 to 1.0, whereby a value of 1.0 represents a state of perfect health, and a value of 0 represents a state of the poorest
EP
health or death, placing all other states on a continuum between these two values. The values obtained from the aforementioned study were then used to compute the quality-adjusted life
Costs
AC C
years (QALYs) associated with the four intervention arms.
Costs were estimated using institutional cost data from Penn State Hershey Medical
Center. Patients undergoing colectomy procedures over a four-year period (July 2012 through June 2015) at our academic center were identified through Diagnosis Related Group (DRG)
ACCEPTED MANUSCRIPT 8 codes indicating colectomy without complications (DRG 331), colectomy with minor complications (DRG 330), and colectomy with major complications (DRG 329). Emergent procedures were identified as those with line items for emergency department services, and were
RI PT
excluded from analysis. Total costs for both current and former smokers were then calculated based on the weighted average of the probability of minor and major complications observed in these two populations. Patients who died during the index hospitalization formed a separate
SC
cohort in order to estimate healthcare costs associated with in-hospital mortality. Total costs were adjusted to 2016 dollars using records from the first half of 2016 dollars from the medical
Analysis of cost-effectiveness
M AN U
care component of the Consumer Price Index (CPI).
The incremental cost-effectiveness ratio was calculated for the base case scenario, and
TE D
then recalculated after eliminating strategies based on extended dominance. The willingness-topay threshold was set at $150,000 per QALY, which has been recently suggested as a more appropriate threshold than the historic threshold of $50,000 per QALY that has held popularity
EP
since the mid-1990s.16 One-way sensitivity analyses were performed to estimate the values of the parameters at which the incremental cost-effectiveness ratio fell below the accepted willingness-
AC C
to-pay threshold. The primary one-way sensitivity analyses were focused around the cost and clinical effectiveness of the pharmaceutical agents, the utilities associated with complicated and uncomplicated postoperative courses, and the probabilities associated with experiencing a postoperative complication. Two-way sensitivity analyses were performed to identify the dominant strategy by varying the estimates for two parameters simultaneously. For the two medications that were not eliminated by extended dominance, bupropion and varenicline, the
ACCEPTED MANUSCRIPT 9 probabilities of quitting using either medication and the costs associated with each were varied. Additionally, the costs associated with complication profiles in both current and former smokers
RI PT
were varied in the sensitivity analyses.
Results Costs
SC
A total of 1,438 patients at our institution were identified who underwent colon resections with subsequent hospitalizations; of these, 440 patients had uncomplicated postoperative courses,
M AN U
773 patients experienced minor complications, 214 patients experienced major complications, and 10 patients experienced in-hospital mortality. After determining costs using institutional data, patients whose hospitalizations involved either minor complications or major complications had significantly higher costs, both for the index hospitalization as well as for the year following
TE D
the procedure (Table 1).
Expected costs and benefits
EP
Our base-case model was built on estimates of the incremental improvement in cost effectiveness, starting with the condition in which no intervention is provided, as compared to
AC C
each intervention (bupropion, nicotine replacement therapy, and varencline) in the order of least to most expensive. It should be noted that the analysis did not ask whether the most costly intervention, varencline, is cost-effective in comparison with no intervention, but rather, whether it would be considered incrementally cost-effective in comparison to the other less expensive alternatives. As shown in Table 2, the bupropion strategy added the least amount of cost to care of the three alternatives and was more effective than not offering a pharmaceutical smoking
ACCEPTED MANUSCRIPT 10 cessation aid. In addition, the incremental cost-effectiveness ratio was $74,255 per QALY; therefore, at a willingness-to-pay threshold of $150,000 per QALY, this intervention was considered cost effective. The next most costly strategy, NRT, was only $12 more costly than
RI PT
bupropion, but was associated with such a small marginal effectiveness that its incremental costeffectiveness ratio when compared to bupropion was $936,096. The incremental cost-
effectiveness ratio between the most costly strategy, varenicline, and NRT was also high
SC
($897,265), but less so than that of the previous pairing (NRT versus bupropion); therefore, the NRT strategy was eliminated due to the extended dominance of the bupropion and varenicline
M AN U
strategies.17 As a result, the incremental cost-effectiveness ratio for varenicline relative to bupropion was $898,244 per additional QALY (Table 2), which remains above the acceptable willingness-to-pay threshold.
TE D
Sensitivity analyses
When comparing bupropion to no therapy, the use of bupropion became cost-effective when the probability of quitting was slightly below 25% (Fig. 2a). Comparing NRT to no
EP
therapy, this value is 25%; comparing varenicline to no therapy, it is approximately 55%. Costs of the pharmaceutical agents were then varied to determine values for which each agent became
AC C
cost-effective relative to using no therapy (Fig. 2b). For bupropion, the associated cost was $220, and for NRT was $225, both of which are higher than the current retail costs of these agents. For varenicline, the cost at which this medication became cost-effective relative to no therapy was approximately $440, which is lower than the current retail costs of this strategy. The utilities associated with the states of experiencing postoperative complications and having uncomplicated postoperative courses were varied over a range of 0 to 1 (Fig. 3).
ACCEPTED MANUSCRIPT 11 Regardless of the utility associated with having a complicated postoperative course, bupropion remained below the willingness-to-pay threshold for all utility values from 0 to 1. For uncomplicated postoperative courses, bupropion was cost-effective for all values over 0.84; for
and fewer QALYs than the strategy involving no medications.
RI PT
all values below 0.70, all three pharmaceutical regimens are dominated, involving higher costs
Two-way sensitivity analyses are presented in Fig. 4. At probabilities of quitting with
SC
bupropion above 29.4%, bupropion dominates no therapy, while at probabilities of quitting with varenicline above 79.6% varenicline dominates no therapy (Fig. 4a). At costs below $145 for a
M AN U
course of therapy, the bupropion strategy dominates no therapy, and at costs of varenicline below $285, varenicline dominates no therapy (Fig. 4b). If the cost of varenicline was reduced to below $143 for a course of therapy, then the varenicline strategy would be less costly and more effective than both the bupropion and no standardized therapy strategies. At increasingly higher
TE D
annual costs for current smokers and lower costs for former smokers, bupropion becomes the dominant strategy, followed by varenicline therapy (Fig. 4c).
EP
Discussion
Smoking remains an independent risk factor for increased complications and costs after
AC C
any major operation, including colectomy.3, 5, 18-20 In addition, it is clear that− if only for the duration of the peri-operative period and a bit beyond− quitting makes a difference in surgical outcomes.5, 6, 8, 9, 14 In the recent study of patients undergoing colectomy within the Washington State SCOAP program,14 it was somewhat surprising and a bit disheartening that cost savings associated with pre-operative quitting were not very high-- about $330 per patient in the first ninety days of care after surgery. Our study differs in several ways from prior efforts to
ACCEPTED MANUSCRIPT 12 understand the costs and implications of quitting at the time of a major abdominal operation.3, 14 The first is that the time horizon for study was chosen for a full year, rather than ninety days, after operation. This extended period allowed us to capture not only additional costs, but also
RI PT
addressed, to some extent, the real possibility that some smokers who quit before surgery might have restarted, thereby weakening the influence of pre-operative smoking cessation. A second difference is that our study reflects institutional costs at a tertiary-care, academic center, rather
SC
than an aggregate of hospital profiles that comprises the SCOAP program or hospitals that operate within a single layer system such as the Veterans Health Administration.3 A third
M AN U
difference is that our calculations of annual costs of care began with the cohort overall (Table 1) under baseline conditions and then for the sub-cohort in whom complications occurred, major and minor, according to the criteria used by Hawn et al.3 While the SCOAP study focused on the differences in cost of care in patients with known histories of smoking, based on institutional
TE D
charge/cost ratios,14 our analysis has focused on determining whether the added costs of pharmacologic interventions would mitigate costs of care and improve utility to the patient. With these differences in design in mind, our analysis confirms that taking care of
EP
complications after colectomy is expensive and taking care of such complications in smokers is more expensive.3 Our analysis also shows that, under current conditions, none of the
AC C
pharmacologic smoking cessation aids actually would decrease costs to the provider system. As previously shown, the cost-savings of smoking cessation are not very high14 and the added cost of any of the pharmacologic approaches to smoking cessation does not save money. Moreover, as shown in Table 2, the high incremental increase in cost over the other agents makes the most clinically effective agent (varenicline) the least cost-effective choice among the three interventions. The sensitivity analyses demonstrate how realistic it would be to expect each of
ACCEPTED MANUSCRIPT 13 the interventions to become more cost-effective, based upon a change in the clinical effectiveness (Fig. 2a), cost (Fig. 2b), or changes in utility functions in the presence of absence of complications (Fig. 3). These sensitivity analyses illustrate how much more cost-effective
RI PT
bupropion is than the other interventions and how relatively small changes in clinical
effectiveness or cost might negate the benefits of any pharmacologic aid for smoking cessation (Fig. 3). This analysis thus identifies price thresholds at which these agents might become cost-
SC
saving and in addition provides evidence that even at current costs, at least one of the agents-bupropion-- would offer recognizable value. At the same time, our analysis emphasizes the need
M AN U
to keep searching for more effective strategies at equal or lower cost.
This current effort has specific limitations: first, the calculated costs of care for uneventful and complicated cases will be sensitive not only to the proportion of smokers in the cohort, but also the proportions of other higher-risk attributes such as obesity and poorly
TE D
controlled diabetes—which are not explicitly taken into account and could influence utilities; second, the study does not directly address the possibility that any of the interventions might independently influence the utilities used in the analysis, through side-effects of the medications
EP
themselves; third, the utilities used in the model merged the effects of major and minor complications and, as a first approximation, was based on an assumption that the complications
AC C
occurred early enough after surgery to influence utilities for the entire post-operative year. In addition, the analysis does not take into account the effectiveness of different pre-operative intervals of therapy on short-term success in quitting, outcome of operation or the likelihood of returning to smoking behaviors.8, 21-23 With regard to compliance, it has also been suggested that in addition to the therapy itself, adherence to therapy is influenced by the availability of financial coverage, increasing the quit-rate by almost 10%.22 It should be emphasized that our model is
ACCEPTED MANUSCRIPT 14 parameterized with results from a randomized controlled trial analyzed on an intention-to-treat basis, in which documented compliance (both partial and full compliance) only reached 80%.22 Thus, to some extent the parameterized model takes into account suboptimal compliance and the
RI PT
time horizon of one year takes provides for the possibility of recidivism. In this regard, data were not yet available to assess the impact and costs of behavioral adjuncts to pharmacologic
therapy.23, 24 As such information becomes available, it might turn out that support for behavioral
calculation of cost-savings, even in a one-year time-frame.
SC
adjuncts would lead to higher and more sustainable quit-rates, which would, in turn, alter the
M AN U
Our analysis indicates that additional value (lower complication rates, higher utility) is offered to smoking patients undergoing colectomy through smoking cessation therapies, with bupriopion therapy as most cost-effective at $75,000/QALY. This level of effectiveness meets a recognized standard of less than $150,000/QALY,16 while the other therapies (NRT, varencline)
TE D
exceed this incremental cost-effectiveness ratio threshold considerably. For an actively smoking patient facing colectomy, the benefits of intervention, however, come at an increased cost, raising the question: who should pay for the benefit? Our analysis suggests an opportunity for
EP
health-delivery systems to partner with both patients and payers to determine the solution. It might make sense, for example, that the health system would be willing to pay for smoking
AC C
cessation therapies up to, but not more than, the amount of money it already knows it would be spending to take care of the higher risk patient. It might also make sense for the patient -- as a consumer-- to be asked to pay the difference; or, in the event of a complication that might have been avoided had the patient actually entered the smoking cessation program and stopped smoking, to have consequent charges to the patient reflect the increased costs of caring for that complication. It has been justly argued that denial of care to smokers is ethically questionable
ACCEPTED MANUSCRIPT 15 and might lead to worse outcomes and costs to the system.25 Guided by analyses such as those used in this study, the use of co-pays and sharing of cost for modification of high-risk behaviors seems to be a rational alternative to outright denial of services as incentives for encouraging
RI PT
responsible behaviors by health systems and patients in order to improve outcomes and cost-
AC C
EP
TE D
M AN U
SC
effective use of resources.26
ACCEPTED MANUSCRIPT 16 Acknowledgements The authors thank Kimberly Walker for her professional assistance in editing and submitting this
RI PT
manuscript.
Funding: This research did not receive any specific grant from funding agencies in the public,
AC C
EP
TE D
M AN U
SC
commercial, or not-for-profit sectors.
ACCEPTED MANUSCRIPT 17 References 1.
Zogg CK, Najjar P, Diaz AJ, et al. Rethinking priorities: cost of complications after elective colectomy. Ann Surg 2016;264:312-22. Sharma A, Deeb AP, Iannuzzi JC, et al. Tobacco smoking and postoperative outcomes after colorectal surgery. Ann Surg 2013;258:296-300.
Hawn MT, Houston TK, Campagna EJ, et al. The attributable risk of smoking on surgical complications. Ann Surg 2011;254:914-20.
4.
SC
3.
RI PT
2.
Sorensen LT. Wound healing and infection in surgery: the pathophysiological impact of
Surg 2012;255:1069-79. 5.
M AN U
smoking, smoking cessation, and nicotine replacement therapy: a systematic review. Ann
Sorensen LT. Wound healing and infection in surgery. The clinical impact of smoking and smoking cessation: a systematic review and meta-analysis. Arch Surg 2012;147:373-
6.
TE D
83.
Mills E, Eyawo O, Lockhart I, et al. Smoking cessation reduces postoperative complications: a systematic review and meta-analysis. Am J Med 2011;124:144-54 e8. Sadr Azodi O, Lindstrom D, Adami J, et al. The efficacy of a smoking cessation
EP
7.
programme in patients undergoing elective surgery: a randomised clinical trial.
8.
AC C
Anaesthesia 2009;64:259-65.
Lindstrom D, Sadr Azodi O, Wladis A, et al. Effects of a perioperative smoking cessation intervention on postoperative complications: a randomized trial. Ann Surg 2008;248:73945.
ACCEPTED MANUSCRIPT 18 9.
Wong J, Lam DP, Abrishami A, et al. Short-term preoperative smoking cessation and postoperative complications: a systematic review and meta-analysis. Can J Anaesth 2012;59:268-79. Peckham E, Brabyn S, Cook L, et al. Smoking cessation in severe mental ill health: what
RI PT
10.
works? an updated systematic review and meta-analysis. BMC Psychiatry 2017;17:252. 11.
Athanasakis K, Souliotis K, Tountas Y, et al. A cost-utility analysis of hypertension
SC
treatment in Greece: assessing the impact of age, sex and smoking status, on outcomes. J Hypertens 2012;30:227-34.
Knight C, Howard P, Baker CL, et al. The cost-effectiveness of an extended course
M AN U
12.
(12+12 weeks) of varenicline compared with other available smoking cessation strategies in the United States: an extension and update to the BENESCO model. Value Health 2010;13:209-14.
Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of
TE D
13.
varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.
14.
EP
Lancet 2016;387:2507-20.
Gaskill CE, Kling CE, Varghese TK, Jr., et al. Financial benefit of a smoking cessation
15.
AC C
program prior to elective colorectal surgery. J Surg Res 2017;215:183-9. Lee L, Elfassy N, Li C, et al. Valuing postoperative recovery: validation of the SF-6D health-state utility. J Surg Res 2013;184:108-14.
16.
Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness--the curious resilience of the $50,000-per-QALY threshold. N Engl J Med 2014;371:796-7.
ACCEPTED MANUSCRIPT 19 17.
Petitti D. Meta-Analysis, Decision Analysis and Cost-effectivness Analysis: Methods for Quantitative Synthesis in Medicine, 2nd Ed. New York, NY: Oxford University Press; 2000. Nolan MB, Martin DP, Thompson R, et al. Association between smoking status,
RI PT
18.
preoperative exhaled carbon monoxide levels, and postoperative surgical site infection in patients undergoing elective surgery. JAMA Surg 2017;152:476-83.
Gajdos C, Hawn MT, Campagna EJ, et al. Adverse effects of smoking on postoperative
SC
19.
outcomes in cancer patients. Ann Surg Oncol 2012;19:1430-8.
Singh JA, Houston TK, Ponce BA, et al. Smoking as a risk factor for short-term
M AN U
20.
outcomes following primary total hip and total knee replacement in veterans. Arthritis Care Res (Hoboken) 2011;63:1365-74. 21.
Carlson BB, Burton DC, Jackson RS, et al. Recidivism rates after smoking cessation
22.
TE D
before spinal fusion. Orthopedics 2016;39:e318-22.
Berlin NL, Cutter C, Battaglia C. Will preoperative smoking cessation programs generate long-term cessation? A systematic review and meta-analysis. Am J Manag Care
23.
EP
2015;21:e623-31.
Shi Y, Warner DO. Brief preoperative smoking abstinence: is there a dilemma? Anesth
24.
AC C
Analg 2011;113:1348-51.
Cropley M, Theadom A, Pravettoni G, et al. The effectiveness of smoking cessation interventions prior to surgery: a systematic review. Nicotine Tob Res 2008;10:407-12.
25.
Shaw D. Delaying surgery for obese patients or smokers is a bad idea. BMJ 2016;355:i5594.
ACCEPTED MANUSCRIPT 20 Porter ME, Teisberg EM. Redefining Health Care. Boston: Harvard Business School
EP
TE D
M AN U
SC
RI PT
Press; 2006.
AC C
26.
ACCEPTED MANUSCRIPT 21 Table 1 Model parameters Estimate
0.145 0.126
0.05 0.02
0.013 0.01
0 0
0.2 0.2
14 14 14 14 2 2 2 2 2 2
n/a 4 4 4
n/a 500 500 1500
Institutional Data Institutional Data Institutional Data Institutional Data Institutional Data
$14,914 $21,093 $48,070 $117,892
n/a n/a n/a n/a
n/a n/a n/a n/a
Institutional Data Institutional Data Institutional Data Institutional Data
$34,199 $59,027 $109,360 $117,892 $46,811 $46,538
n/a n/a n/a n/a $15,000 $15,000
n/a n/a n/a n/a $75,000 $75,000
0.897 0.938 0
0 0 n/a
1 1 n/a
Institutional Data Institutional Data Institutional Data Institutional Data Institutional Data, 2 Institutional Data, 2 15 15 15 15
M AN U TE D
AC C
n/a 1 1 1
Reference
RI PT
n/a 0 0 0
0.25 0.22
SC
0.137 0.261 0.264 0.380
$0 $184 $199 $772
EP
Parameter Probabilities Probability of cessation No medication Bupropion Nicotine replacement therapy Varenicline Probability of complication Current smoker Former smoker Probability of mortality Current smoker Former smoker Costs Strategy No medication Bupropion Nicotine replacement therapy Varenicline Costs during index hospitalization Baseline Minor complications Major complications In-hospital mortality Annual costs Baseline Minor complications Major complications In-hospital mortality Annual costs in current smoker Annual costs in former smoker Utilities Complicated postoperative course Uncomplicated postoperative course In-hospital mortality
Sensitivity analysis Lower Upper
ACCEPTED MANUSCRIPT 22 Table 2 Base-case cost effectiveness analysis results
Strategy
Cost
Marginal cost
Effectiveness
Marginal effectiveness
Incremental costeffectiveness ratio ($/QALY)
All strategies $41,819.40
Bupropion
$41,858.02
$38.62
0.92087
0.00052
$74,255.23
NRT
$41,869.69
$11.67
0.92088
0.00001
$936,096.28
Varenicline
$42,306.56
$436.87
0.92137
0.00049
$897,265.39
Non-dominated strategies 0.92035
Bupropion
$41,858.02
$38.62
Varenicline
$42,306.56
$448.54
0.92087
EP AC C
0.00052
$74,255.23
0.00050
$898,244.32
M AN U
$41,819.40
0.92137
TE D
None
SC
0.92035
RI PT
None
ACCEPTED MANUSCRIPT 23 Figure Legends Figure 1 Decision tree structure. Figure 2 (a) From left to right, results of one-way sensitivity analyses for the probability of
RI PT
quitting with bupropion, NRT, and varenicline vs. no cessation therapy. (b) From left to right, results of one-way sensitivity analyses for the baseline costs of bupropion, NRT, and varenicline vs. no cessation therapy. Horizontal line represents a willingness-to-pay threshold of $150,000
SC
per QALY.
Figure 3 One-way sensitivity analysis of utilities associated with complicated and
M AN U
uncomplicated hospitalizations. Horizontal line represents a willingness-to-pay threshold of $150,000 per QALY.
Figure 4 (a) Two-way sensitivity analysis of the probability of quitting with bupropion and with varenicline, (b) two-way sensitivity analysis of the costs of bupropion and varenicline, and (c)
AC C
EP
TE D
two-way sensitivity analysis of the costs of complications in current and former smokers.
ACCEPTED MANUSCRIPT
0.4
0.6
Utility of Complication
0.8
1.0
1000 S500 CR IP T −500 −1000
EP AC C 0.2
0
M AN U TE D
1000 500 0.0
Marginal Cost ($1000) per QALY
1500
No Complications
Bup Vs. None NRT vs. Bup Var vs. NRT
0
Marginal Cost ($1000) per QALY
Complications
0.0
0.2
0.4
0.6
0.8
Utility of No Complication
1.0
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights •
At baseline, bupropion therapy is cost-effective with an incremental cost-effectiveness ratio of approximately $75,000 per QALY. Reducing the cost of varenicline therapy to less than $143 per course results in
RI PT
•
varenicline being less costly and more effective than offering no smoking cessation therapy.
SC
Results of the base case and sensitivity analyses provide thresholds to inform providers about whether uniformly providing targeted, short-term smoking cessation therapies to
EP
TE D
M AN U
patients undergoing elective colectomy represents good value.
AC C
•