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Cost-Effectiveness of Postoperative Drug Rehabilitation for Injection Drug Users
Journal Pre-proof Cost-Effectiveness of Postoperative Drug Rehabilitation for Injection Drug Users Zachary Tyerman, MD, MSc, Shawn Shah, BS, J Hunter Mehaffey, MD, MSc, Tanya Wanchek, PhD, Robert B. Hawkins, MD, MSc, Elizabeth T. Rogawski McQuade, PhD, Alexander Shannon, MD, Gorav Ailawadi, MD, MBA, Kenan W. Yount, MD, MBA PII:
S0003-4975(19)31924-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.11.011
Reference:
ATS 33346
To appear in:
The Annals of Thoracic Surgery
Received Date: 19 February 2019 Revised Date:
30 October 2019
Accepted Date: 4 November 2019
Please cite this article as: Tyerman Z, Shah S, Mehaffey JH, Wanchek T, Hawkins RB, Rogawski McQuade ET, Shannon A, Ailawadi G, Yount KW, Cost-Effectiveness of Postoperative Drug Rehabilitation for Injection Drug Users, The Annals of Thoracic Surgery (2020), doi: https:// doi.org/10.1016/j.athoracsur.2019.11.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 by The Society of Thoracic Surgeons
1 Cost-Effectiveness of Postoperative Drug Rehabilitation for Injection Drug Users Running Head: Postoperative Management of Endocarditis
Zachary Tyerman MD, MSc1, Shawn Shah BS1, J Hunter Mehaffey MD, MSc1, Tanya Wanchek PhD1, Robert B Hawkins MD, MSc1, Elizabeth T. Rogawski McQuade PhD2, Alexander Shannon MD1, Gorav Ailawadi MD, MBA1, Kenan W Yount MD, MBA1
1
Division of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, VA
2
Department of Public Health Sciences, University of Virginia Health System, Charlottesville, VA
Meeting Presentation: Society of Thoracic Surgeons 55th Annual Meeting and Exhibition, Jan 27-29th, 2019, San Diego, CA
Classifications: Adult, Cardiac, Endocarditis, Health policy, Surgery
Word Count: 4493/4500
Corresponding Author: Kenan W Yount, MD MBA, University of Virginia, PO Box 800679, Charlottesville, VA 22908; Email: [email protected]
2 Abstract Background: With the opioid crisis showing no sign of abating, strategies are needed to facilitate postoperative care for injection drug use (IDU)-related endocarditis. The current standard, six weeks of intravenous antibiotics, yields frequent reoperation and IDU relapse. We examined the cost-effectiveness of inpatient rehabilitation postoperatively to optimize outcomes and costs. Methods: Two postoperative strategies were assessed: hospital-only care (HC) versus HC plus inpatient drug rehabilitation (DR). Monte-Carlo simulation evaluated effectiveness in quality adjusted life-years (QALY) and cost/patient calculated over a 20-year time horizon in 100,000 iterations. Willingness-to-pay (WTP) was set to $100,000/QALY. To determine probabilities of continued postoperative IDU, recurrent infection, and mortality, best available evidence was combined with institutional data from IDU patients. Baseline probability of postoperative IDU was set to 35% after DR vs 60% after HC, and the cost of inpatient rehabilitation to $30,000. Results: Addition of inpatient drug rehabilitation to standard hospital care is the favorable strategy, with incremental per-patient cost of $36,920 and 0.93 QALYs gained over 20 years. Sensitivity analysis demonstrates DR is within our WTP of $100,000/QALY if post-operative IDU is reduced by at least 7% (from 60% to 53%). Conclusions: Addition of postoperative inpatient drug rehabilitation for IDU-related endocarditis is costeffective even if only a modest reduction in IDU is achieved. Collaboration between hospitals and payors to launch pilot programs that provide postoperative addiction treatment and intravenous antibiotics after cardiac surgery could dramatically improve endocarditis care. (234/250)
3 Since the 1990s, abuse of prescription opioids in the United States has reached epidemic levels, contributing to the first sustained decrease in life expectancy since 1962 (1). Over the last two decades, more than 200,000 people in the United States died from prescription-opioid related overdoses, with a 5fold increase between 1999 and 2016 (2). In 2010 Purdue Pharma released a reformulated OxyContin. The new “abuse-deterrent” version was more difficult to crush and dissolve, thereby discouraging the most dangerous method of abuse, injection, while maintaining oral efficacy. Although this change decreased OxyContin abuse (35.6% to 12.8% over 21 months), rates of overdose mortality from heroin and other synthetic opioids nearly doubled within the next year (3). Consistent with this trend, as other prescription opioids became less available (due to Prescription Drug Monitoring Programs and rescheduling of hydrocodone compounds), use of more accessible, injectable drugs, such as heroin and fentanyl, increased (4, 5). Between 20022016, overdose mortalities from heroin and fentanyl increased 7.6x and 22x, respectively (6). Furthermore, inpatient admissions for opioid-related complications in 18-30 year-olds increased by 622% (7). As more opiate addicted Americans turn toward injection drugs, rates of injection-related morbidities are increasing (8, 9). One of the most lethal complications of injection drug use is endocarditis, often requiring urgent operation with prolonged hospitalization (10). This acuity places a massive burden on the health system; a recent statewide report found admissions for IDU-related endocarditis increased 12-fold and hospital costs increased 18-fold ($1.1 million to $22.2 million) from 2010-2015 (11). Continued injection drug use after surgery increases risks of prosthesis infection and the need for complicated and resource-intensive re-operation (12-14). Unfortunately, most IDU patients receive suboptimal addiction care postoperatively. An analysis of 102 IDU-related endocarditis cases demonstrated that approximately half of charts mentioned addiction at all, and only 7.8% contained an addiction-related plan at discharge (15). These deficiencies imply the postoperative strategy at most centers—intravenous (IV) antibiotics for six weeks–often fails to address the underlying addiction.
4 Financial strains and resource limitations prevent a more comprehensive approach, as there is a paucity of literature analyzing the economics and impact of inpatient drug rehabilitation postoperatively. To our knowledge, there are no studies examining the effect of post-operative drug rehabilitation and drug use cessation on outcomes for IDU-related endocarditis patients. This project explores how enrollment in intensive, inpatient drug rehabilitation after valve surgery could decrease continued injection drug use, and therefore reinfection and death. We attempt to highlight starting points for negotiation between providers, payors, and hospital systems that could facilitate comprehensive treatment of IDU-related endocarditis. We hypothesize providing inpatient drug rehabilitation, in addition to standard hospital care, is a cost-effective strategy compared to standard care alone. Patients and Methods Approach A Markov model with cycle lengths of one year was constructed comparing estimated costs and benefits of two postoperative strategies for IDU-associated endocarditis patients: standard hospital-only care (HC), consisting of 6 weeks of IV antibiotics versus hospital care plus inpatient drug rehabilitation (DR). Outcomes were analyzed over a 20-year time horizon. The cycle lengths and time horizon were chosen because of the lack of more precise time-to-event data on relapse in injection drug users after cardiac surgery and a common “injection career” of IDU being rarely more than 20 years (16, 17). The primary economic outcome was total costs over 20 years, and the primary efficacy outcome was quality adjusted life-years (QALYs) gained. The perspective was assumed a single payor, i.e., the health system caring for the patient. QALYs were obtained by calculating the number of cycles spent outside of the terminal death health state and multiplying by a disutility factor for the current-IDU state. We determined the incremental cost-effectiveness ratio (ICER) by calculating the difference in 20-year costs between HC and DR and dividing by the differences in QALYs. Using guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA), an ICER less than $50,000/QALY gained
5 is considered high value, whereas an ICER more than $150,000/QALY gained is considered a low value(18). In accordance with recommendations from the Panel on Cost-effectiveness in Health and Medicine, global discounting was applied, at of 3% per annum (19). Model structure and Inputs A state transition diagram summarizes the model structure in Figure 1 (Full model in Supplemental Figure 1). All patients are assumed to survive 30 days, and enter the model in the postoperative state, as part of the DR or HC strategy. Patients from each strategy then transition into one of three states: IDU, former-IDU (permanent cessation of injection drug use), or dead. The transition between these states is based on the yearly probabilities of successful rehabilitation, continued injection drug use postoperatively, repeat endocarditis and reoperation, and mortality. The Society of Thoracic Surgeons (STS) clinical database captures preoperative, operative and outcomes data on all cardiac surgery cases. All endocarditis operative cases in our institutional STS database from 2000-2017 were captured for analysis. Annual probabilities of mortality and reoperation were estimated using Weibull and lognormal distributions, respectively, based on time-to-event data from our institutional cohort of 68 IDU and 290 Non-IDU followed for a mean of 10.2 years and 6.1 years, respectively. We estimated mortality/reoperation probabilities for IDU patients at the mean value of age, sex, comorbidities and prosthesis type among observed IDU patients. We estimated mortality/reoperation probabilities for patients who quit IDU by standardizing the observed estimates from non-IDU to the mean age, sex, comorbidities and prosthesis type of IDU. In the absence of observed data on individuals who quit IDU, this strategy allowed us to extrapolate from non-IDU appropriately, while accounting for significant differences between the typical IDU/non-IDU. The variables used to standardize the estimates are shown in Supplemental Table 1. In our analysis we examined each yearly probability on a triangular distribution with a +/-30% upper and lower range (Table 1 and Figure 2). This study was approved by University of Virginia’s institutional review board (IRB# 19762).
6 The probability of IDU after surgery was estimated using 2 studies that measured rates of continued IDU before IDU-endocarditis reoperation(13, 20). QALYs were estimated using a disutility factor of 0.62 for active IDU, which was derived from a study examining the quality of life in 307 opioid addicted patients (21, 22). These variables were examined using a triangular distribution in our analysis using the upper and lower limits in Table 1. Surgical cost data were captured from our institution’s finance center based on cost-to-charge ratios. Dollar amounts were inflation-adjusted to year 2017 using conservative estimates from the Centers for Medicare and Medicaid Services Inpatient Prospective Payment System. Mean surgical costs were used for initial and re-do endocarditis surgeries, which were sampled using gamma distributions in our model. The costs of inpatient drug rehabilitation were estimated based on industry estimates obtained from the literature, and sampled with a triangular distribution, which can be found in Table 2. Statistical Analysis All rates from our institutional data and from the literature were converted to 1-year probabilities before imputation into the model. The base case was a fully probabilistic sampling analysis, drawing from 100,000 Monte Carlo simulations. The costs and benefits, presented as mean +/- standard deviation, for the 100,000 simulations were used to calculate the base case incremental cost effectiveness ratio (ICER). A cost-effectiveness acceptability curve was used to demonstrate variable uncertainty at different willingness-to-pay thresholds. Cost effectiveness modeling was conducted using TreeAge Pro 2018 (TreeAge, Williamstown, MA). Sensitivity Analysis A series of deterministic, one-way sensitivity analyses were performed to study the impact of key parameters in our model. All probabilities were held constant except the variable being examined, which was tested over a range as detailed in Tables 1 and 2. Where available, literature was used to inform a
7 reasonable range for each variable. Willingness-to-pay, and thus our threshold of cost effectiveness, was set at $100,000/QALY. Results Base Case Over the 20-year time horizon, average total cost of the HC strategy was $170,073 (±109,748), compared to $206,993 (± $111,985) for the DR strategy. The QALYs gained were 7.23 (± 0.33) and 8.16 (± 0.27) for HC and DR, respectively. Therefore, the incremental cost was $36,920 and the incremental gain in QALYs was 0.93, resulting in an ICER of $39,699/QALY gained in the DR strategy (Table 3). Probabilistic sensitivity analysis indicated 89.3%of 100,000 Monte Carlo iterations were under the $100,000/QALY gained willingness-to-pay threshold when DR was compared to HC. In the scatter plot of DR vs HC in Figure 3, each dot represents an iteration of the model. All dots to the right of the willingness to pay line of $100,000 identify DR as the preferred strategy. Dots under the x-axis represent instances where DR is more effective and less costly than HC (completely dominant). To demonstrate the uncertainty in determining the preferred strategy (HC vs. DR), the cost-effectiveness acceptability curve for HC vs. DR is shown in Figure 4 for a willingness-to-pay threshold ranging from 0 to $200,000. At our willingness-to-pay of $100,000/QALY there is 89.3% probability that the DR strategy is preferred. Furthermore, at a willingness-to-pay of $50,000/QALY, DR is still preferred in 64.3% of iterations. Deterministic Sensitivity Analysis In a series of one-way deterministic sensitivity analyses, all costs and transitional probabilities were examined at a willingness-to-pay threshold of $100,000/QALY gained. The ICER exceeded the willingness-to-pay when the probability of continuing IDU despite inpatient rehabilitation was greater than 53.0% (Figure 5). If the average risk of mortality in former-IDU patients becomes similar to active IDU (above 14.6% in former-IDU vs the baseline of 19% in IDU), HC becomes the dominant strategy (Figure 6). If the average probability of mortality in IDU becomes close to that that of Former-IDU
8 (below 5.6% vs the baseline of 7.0% in former-IDU, HC becomes the preferred strategy (Figure 7). The model was insensitive to all other variables and ranges, as reported in Table 1 and 2. Comment The present study investigated the cost-effectiveness of the traditional IDU-related endocarditis postoperative strategy, hospital-based care only (6 weeks of IV antibiotics), to that of a strategy where intensive, inpatient drug rehabilitation was also provided. Providing DR was cost-effective with an ICER of $39,699/QALY gained. Probabilistic sensitivity analysis with 100,000 Monte Carlo simulations demonstrated in 89.3% of trials, the DR strategy was within our willingness-to-pay of $100,000/QALY despite variability in all model inputs. These findings support the hypothesis that provision of postoperative inpatient drug rehabilitation in addition to standard hospital-based care is cost-effective for IDU patients. The proposed approach not only prevents repeat endocarditis operations but also targets the source of the national opioid epidemic, addiction. To our knowledge, this is the first cost-effectiveness analysis focusing on prevention of endocarditis in injection drug users. The key probability of our model was continued IDU despite receiving inpatient drug rehabilitation postoperatively. In our deterministic sensitivity analysis, if continued IDU decreased by a modest 7.0% (from 60% in the HC strategy to 53% in the DR strategy), our ICER fell within our willingness-to-pay of $100,000/QALY. A paucity of literature exists examining the continuation of IDU after inpatient drug rehabilitation, however, the authors believe the assumption that DR reduces long term injection drug use is logical. Previous studies have documented significant reductions in heroin use after long-term residential rehabilitation programs(23). Similarly, one study reported a readmission-free period of at least 6 months in 75% of patients after three to four weeks of inpatient DR, though the long-term outcomes of this group were not followed (24). Similarly, in a study of 308 adults with opioid use disorder, patients enrolled in a month-long inpatient rehabilitation had long-term abstinence of 23%, while patients supplemented with extended release naloxone showed a long-term abstinence rate of 31% (25). As medication assisted strategies and new opioid antagonists are developed, inpatient drug
9 rehabilitation programs will become more effective. However, further research investigating outcomes after DR in this population is warranted, and would validate the assumptions in this study. Further innovation in postoperative care, namely novel strategies for antibiotic administration, could also decrease the overall cost of hospital care, further offsetting the cost of inpatient drug rehabilitation treatment. If the cost of inpatient drug rehabilitation is below $20,000, the ICER for DR strategy is less than $20,000/QALY. This is an achievable mark. Collaboration between hospitals and regional centers to develop a single facility for patients to receive intensive drug rehabilitation could lower cost, as could flexible antibiotic administration strategies. For example, in a study of 205 IDUs requiring IV antibiotics, Jewell and colleagues examined administration of IV antibiotics at an inpatient addiction treatment facility. Due to shorter hospital stays, the program was projected to save $2.42 million over six years (26). Early transition from IV to oral antibiotics postoperatively may also save costs and resources. A recent study by Iversen et.al. demonstrated similar outcomes in 400 left-sided endocarditis patients when antibiotics were transitioned from IV to oral after 10 days (27). Such a paradigm shift could reduce costs by decreasing hospital length of stay and medication costs (28), plus eliminating the need to discharge a patient with an indwelling IV access line. Endocarditis is a complex, highly morbid, and deadly condition, particularly in IDU. Long-term mortality of IDU-related endocarditis was extremely high in our cohort, especially in re-operative cases, and has been demonstrated in similar studies (13, 29, 30). Effort should focus on prevention of reinfection and reoperation, as these surgeries carry the highest mortality and highest costs. Postoperative inpatient rehabilitation can reduce re-infection by terminating injection altogether, but as rehabilitation techniques continue to evolve, a multipronged approach needs to be undertaken. For those unable to discontinue use, safe needles, and clean injection teaching should be provided. Given the effectiveness in preventing infectious disease spread through safer injection sites (31-33), these programs would likely decrease incidence of IDU-related endocarditis. Furthermore, other preoperative strategies may augment care, such as addiction counseling and post discharge planning before surgery.
10 As with any cost effectiveness analysis, results and their implications should be considered in the context of the target community. A willingness-to-pay of $100,000/QALY may be acceptable in one setting and prohibitive in another. However, as our cost effectiveness acceptability curve demonstrates, at a WTP of $50,000/QALY (the historically accepted threshold based on dialysis costs(34, 35)), 64.3% of iterations still favored the DR strategy. Limitations Like any theoretical model of a complex patient population, this model has inherent limitations. As a supplement to our own institutional data, best available literature was used to derive clinical probabilities and costs to establish a reasonable distribution over which to test our variables. Although they were reviewed for methodological quality, there exists a chance they do not accurately reflect reality and may not be generalizable to all IDU cohorts and health systems. To address this, we utilized probabilistic and deterministic sensitivity analysis, examining all inputs in our model over a wide range, to capture a more realistic variability in model inputs. We did not include other hospital-based costs that IDU may incur after discharge from cardiac surgery (such as unrelated soft tissue infection and overdose resuscitation), which may affect the accuracy of the model. We also assume that IDU cessation is permanent in our model. Though IDU is likely a complex pattern of cessation and relapse, we informed our model probabilities using the limited number of studies on long term relapse rates, and assumptions that we believe to be reasonable. Mortality and reoperation time-to-event probabilities were estimated based on 298 patients undergoing 362 operations at our quaternary cardiac surgery center. To improve generalizability, we sampled our mortality and reoperation curves over a wide range of probabilities. Finally, the absolute risk reduction in continued IDU after inpatient rehabilitation is unknown, as studies have variable definitions of treatment success, and the ethical pitfalls of conducting a randomized trial in drug addicted patients. However, based on best available evidence, we believe it is logical that
11 inpatient rehabilitation programs do reduce continued IDU, and that cessation of IDU decreases overall mortality. Conclusion This analysis underscores the complex nature of IDU-related endocarditis and need for innovative strategies in the opioid crisis. Postoperative care represents an opportunity for intervention, to affect the cycle of addiction, reoperation, and death. We present data that can encourage providers, hospital systems, and payors to investigate financial strategies to improve outcomes. Investing in inpatient rehabilitation for injection drug users has the potential not only to reduce costs on our already overburdened health care system but also to preserve the lives of our patients.
12 References 1. Woolf SH, Aron L. Failing health of the united states. BMJ 2018;360:k496. 2. 2017 Prescription opioid data. Available at https://www.cdc.gov/drugoverdose/data/prescribing.html. Accessed 2018 9/23/2018. 3. Cicero TJ, Ellis MS, Surratt HL. Effect of abuse-deterrent formulation of oxycontin. N Engl J Med 2012;367(2):187-189. 4. 2018 What is the scope of heroin use in the united states? Available at https://www.drugabuse.gov/publications/research-reports/heroin/scope-heroin-use-in-united-states. 5. Jones CM, Logan J, Gladden RM, Bohm MK. Vital signs: Demographic and substance use trends among heroin users - united states, 2002-2013. MMWR Morb Mortal Wkly Rep 2015;64(26):719-725. 6. 2018 Overdose death rates. Available at https://www.drugabuse.gov/related-topics/trendsstatistics/overdose-death-rates. Accessed 2018 7. 2018 Persons who inject drugs (pwid). Available at https://www.cdc.gov/pwid/index.html. Accessed 2018 8. Peters PJ, Pontones P, Hoover KW et al. Hiv infection linked to injection use of oxymorphone in indiana, 2014-2015. N Engl J Med 2016;375(3):229-239. 9. Tookes H, Diaz C, Li H, Khalid R, Doblecki-Lewis S. A cost analysis of hospitalizations for infections related to injection drug use at a county safety-net hospital in miami, florida. PLoS One 2015;10(6):e0129360. 10. Weymann A, Borst T, Popov AF et al. Surgical treatment of infective endocarditis in active intravenous drug users: A justified procedure? J Cardiothorac Surg 2014;9:58. 11. Fleischauer AT, Ruhl L, Rhea S, Barnes E. Hospitalizations for endocarditis and associated health care costs among persons with diagnosed drug dependence - north carolina, 2010-2015. MMWR Morb Mortal Wkly Rep 2017;66(22):569-573. 12. Ortiz-Bautista C, Lopez J, Garcia-Granja PE et al. Current profile of infective endocarditis in intravenous drug users: The prognostic relevance of the valves involved. Int J Cardiol 2015;187:472-474. 13. Osterdal OB, Salminen PR, Jordal S, Sjursen H, Wendelbo O, Haaverstad R. Cardiac surgery for infective endocarditis in patients with intravenous drug use. Interact Cardiovasc Thorac Surg 2016;22(5):633-640. 14. Welton DE, Young JB, Gentry WO et al. Recurrent infective endocarditis: Analysis of predisposing factors and clinical features. Am J Med 1979;66(6):932-938. 15. Rosenthal ES, Karchmer AW, Theisen-Toupal J, Castillo RA, Rowley CF. Suboptimal addiction interventions for patients hospitalized with injection drug use-associated infective endocarditis. Am J Med 2016;129(5):481-485. 16. Des Jarlais DC, Arasteh K, Perlis T et al. The transition from injection to non-injection drug use: Long-term outcomes among heroin and cocaine users in new york city. Addiction 2007;102(5):778-785. 17. White SR, Hutchinson SJ, Taylor A, Bird SM. Modeling the initiation of others into injection drug use, using data from 2,500 injectors surveyed in scotland during 2008-2009. Am J Epidemiol 2015;181(10):771-780. 18. Anderson JL, Heidenreich PA, Barnett PG et al. Acc/aha statement on cost/value methodology in clinical practice guidelines and performance measures: A report of the american college of cardiology/american heart association task force on performance measures and task force on practice guidelines. J Am Coll Cardiol 2014;63(21):2304-2322. 19. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996;276(15):1253-1258.
13 20. Shrestha NK, Jue J, Hussain ST et al. Injection drug use and outcomes after surgical intervention for infective endocarditis. Ann Thorac Surg 2015;100(3):875-882. 21. Uyei J, Fiellin DA, Buchelli M, Rodriguez-Santana R, Braithwaite RS. Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for hiv prevention in people who inject drugs: A cost-effectiveness modelling study. Lancet Public Health 2017;2(3):e133-e140. 22. Aden B, Dunning A, Nosyk B, Wittenberg E, Bray JW, Schackman BR. Impact of illicit drug use on health-related quality of life in opioid-dependent patients undergoing hiv treatment. J Acquir Immune Defic Syndr 2015;70(3):304-310. 23. Hubbard RL, Craddock SG, Anderson J. Overview of 5-year followup outcomes in the drug abuse treatment outcome studies (datos). J Subst Abuse Treat 2003;25(3):125-134. 24. Barnett PG, Swindle RW. Cost-effectiveness of inpatient substance abuse treatment. Health Serv Res 1997;32(5):615-629. 25. Nunes EV, Gordon M, Friedmann PD et al. Relapse to opioid use disorder after inpatient treatment: Protective effect of injection naltrexone. J Subst Abuse Treat 2018;85:49-55. 26. Jewell C, Weaver M, Sgroi C, Anderson K, Sayeed Z. Residential addiction treatment for injection drug users requiring intravenous antibiotics: A cost-reduction strategy. J Addict Med 2013;7(4):271-276. 27. Iversen K, Ihlemann N, Gill SU et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2018. 28. Li HK, Agweyu A, English M, Bejon P. An unsupported preference for intravenous antibiotics. PLoS Med 2015;12(5):e1001825. 29. Frater RW. Surgical management of endocarditis in drug addicts and long-term results. J Card Surg 1990;5(1):63-67. 30. Rabkin DG, Mokadam NA, Miller DW, Goetz RR, Verrier ED, Aldea GS. Long-term outcome for the surgical treatment of infective endocarditis with a focus on intravenous drug users. Ann Thorac Surg 2012;93(1):51-57. 31. Des Jarlais DC, Marmor M, Paone D et al. Hiv incidence among injecting drug users in new york city syringe-exchange programmes. Lancet 1996;348(9033):987-991. 32. Hurley SF, Jolley DJ, Kaldor JM. Effectiveness of needle-exchange programmes for prevention of hiv infection. Lancet 1997;349(9068):1797-1800. 33. Nguyen TQ, Weir BW, Des Jarlais DC, Pinkerton SD, Holtgrave DR. Syringe exchange in the united states: A national level economic evaluation of hypothetical increases in investment. AIDS Behav 2014;18(11):2144-2155. 34. Grosse SD. Assessing cost-effectiveness in healthcare: History of the $50,000 per qaly threshold. Expert Rev Pharmacoecon Outcomes Res 2008;8(2):165-178. 35. 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(9):796-797. 36. 2018 How much does drug rehab cost? Available at https://www.drugrehab.com/treatment/how-much-does-rehab-cost/. Accessed 2018
14 Figure Legends Figure 1: State Transition Diagram. Patients enter model in post-operative state, as part of DR or HC strategy. Patients then transition into 1 of 3 long term states: continued IDU, former-IDU or dead. Transition between states is based on probabilities of successful rehabilitation, continued IDU postoperatively, reoperation, and 1-year mortality, which are available in Table 1.
Figure 2: A) Annual mortality probability curve for IDU. B) Adjusted annual mortality probability curve for Former-IDU. C) Annual reoperation probability curve for IDU. D) Adjusted annual reoperation probability curve for IDU
Figure 3: Scatter plot illustrating incremental costs and effectiveness of DR vs. HC. Dots represent an iteration of the model. Dots right of the willingness to pay (WTP) line of $100,000 identify DR as the preferred strategy.
Figure 4: Proportion of cost-effective iterations as a function of different willingness-to-pay thresholds. At a willingness-to-pay of $50,000/QALY and $100,000/QALY, DR is preferred strategy in 89.3% and 64.3% of iterations, respectively.
Figure 5. One-way deterministic sensitivity of continuing IDU despite inpatient rehabilitation (relapse). At or below a 53.0% relapse rate in the DR strategy (compared to a baseline 60% in the HC strategy), the willingness-to-pay threshold of $100,000/QALY is achieved, and the DR strategy becomes preferred.
15 Figure 6: One-way deterministic sensitivity analysis of average mortality in Former-IDU. If the probability of mortality is over 14.6% (compared to 19% baseline in IDU), the DR strategy is preferred.
Figure 7: One-way deterministic sensitivity analysis of average mortality in IDU. If the probability of mortality falls below 5.4%, (compared to 7.0% baseline in Former-IDU), the DR strategy is preferred.
16
Table 1: Model Input Probabilities
Hospital Only Care (HC) Variable Proportions
Baseline
Lower
Continued Postoperative IDU 0.60(20) 0.50 IDU QoL Depreciation factor 0.62(21, 22) 0.30 Figure 2A Yearly Mortality IDU Figure 2 B Yearly Mortality Former-IDU Figure 2 C Yearly Reoperation IDU Figure 2 D Yearly Reoperation Former-IDU *= Institutional Data; IDU= Injection Drug User.
Inpatient Drug Rehabilitation (DR)
Upper
Baseline
0.70(13) 1.0
0.45 0.62(21, 22)
Lower 0.35 0.30 Figure 2 A Figure 2 B Figure 2 C Figure 2 D
Upper 0.55 1.0
17
Table 2: Cost and utilities for transitions and health states Hospital Based Care (HC) Resource Index Surgery
Cost (SD) $92,205 ($87,148)*
Inpatient Drug Rehabilitation (DR)
Lower
Upper
$46,898*
$109,179*
Cost (SD) $92,205 ($87,148)*
Lower $46,898*
Inpatient Drug Rehabilitation
-
-
-
$30,000(36)
$6,000(36)
Redo Surgery
$99,056 ($88,070)*
$50,563*
$126,952*
$99,056 ($88,070)*
$50,563*
*= Institutional Data
Upper $109,179* $70,000(36) $126,952*
18
Table 3: Base Case Results
Hospital Only Care (HC)
Total Cost (SD)
Total Effectiveness in QALYs (SD)
Incremental Cost/ Incremental Effectiveness
Incremental Cost Effectiveness Ratio (ICER)
$170,073 ($109,748)
7.23 (0.33)
--
--
Inpatient $206,993 $36,920/0.93 Drug 8.16 (0.27) $39,699/QALY ($111,985) QALY Rehabilitation (DR) IQR = interquartile range; BMI = body mass index, *=used at inputs in our model
Acceptability at WTP of $100k/QALY
10.7%
89.3%
19 Abbreviations DR = drug rehabilitation HC = hospital care IDU = injection drug use ICER = incremental cost of effectiveness ratio QALY = Quality adjusted life year SD = standard deviation WTP = willingness to pay
S0003-4975(19)31924-1
DOI:
https://doi.org/10.1016/j.athoracsur.2019.11.011
Reference:
ATS 33346
To appear in:
The Annals of Thoracic Surgery
Received Date: 19 February 2019 Revised Date:
30 October 2019
Accepted Date: 4 November 2019
Please cite this article as: Tyerman Z, Shah S, Mehaffey JH, Wanchek T, Hawkins RB, Rogawski McQuade ET, Shannon A, Ailawadi G, Yount KW, Cost-Effectiveness of Postoperative Drug Rehabilitation for Injection Drug Users, The Annals of Thoracic Surgery (2020), doi: https:// doi.org/10.1016/j.athoracsur.2019.11.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. 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. © 2019 by The Society of Thoracic Surgeons
1 Cost-Effectiveness of Postoperative Drug Rehabilitation for Injection Drug Users Running Head: Postoperative Management of Endocarditis
Zachary Tyerman MD, MSc1, Shawn Shah BS1, J Hunter Mehaffey MD, MSc1, Tanya Wanchek PhD1, Robert B Hawkins MD, MSc1, Elizabeth T. Rogawski McQuade PhD2, Alexander Shannon MD1, Gorav Ailawadi MD, MBA1, Kenan W Yount MD, MBA1
1
Division of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, VA
2
Department of Public Health Sciences, University of Virginia Health System, Charlottesville, VA
Meeting Presentation: Society of Thoracic Surgeons 55th Annual Meeting and Exhibition, Jan 27-29th, 2019, San Diego, CA
Classifications: Adult, Cardiac, Endocarditis, Health policy, Surgery
Word Count: 4493/4500
Corresponding Author: Kenan W Yount, MD MBA, University of Virginia, PO Box 800679, Charlottesville, VA 22908; Email: [email protected]
2 Abstract Background: With the opioid crisis showing no sign of abating, strategies are needed to facilitate postoperative care for injection drug use (IDU)-related endocarditis. The current standard, six weeks of intravenous antibiotics, yields frequent reoperation and IDU relapse. We examined the cost-effectiveness of inpatient rehabilitation postoperatively to optimize outcomes and costs. Methods: Two postoperative strategies were assessed: hospital-only care (HC) versus HC plus inpatient drug rehabilitation (DR). Monte-Carlo simulation evaluated effectiveness in quality adjusted life-years (QALY) and cost/patient calculated over a 20-year time horizon in 100,000 iterations. Willingness-to-pay (WTP) was set to $100,000/QALY. To determine probabilities of continued postoperative IDU, recurrent infection, and mortality, best available evidence was combined with institutional data from IDU patients. Baseline probability of postoperative IDU was set to 35% after DR vs 60% after HC, and the cost of inpatient rehabilitation to $30,000. Results: Addition of inpatient drug rehabilitation to standard hospital care is the favorable strategy, with incremental per-patient cost of $36,920 and 0.93 QALYs gained over 20 years. Sensitivity analysis demonstrates DR is within our WTP of $100,000/QALY if post-operative IDU is reduced by at least 7% (from 60% to 53%). Conclusions: Addition of postoperative inpatient drug rehabilitation for IDU-related endocarditis is costeffective even if only a modest reduction in IDU is achieved. Collaboration between hospitals and payors to launch pilot programs that provide postoperative addiction treatment and intravenous antibiotics after cardiac surgery could dramatically improve endocarditis care. (234/250)
3 Since the 1990s, abuse of prescription opioids in the United States has reached epidemic levels, contributing to the first sustained decrease in life expectancy since 1962 (1). Over the last two decades, more than 200,000 people in the United States died from prescription-opioid related overdoses, with a 5fold increase between 1999 and 2016 (2). In 2010 Purdue Pharma released a reformulated OxyContin. The new “abuse-deterrent” version was more difficult to crush and dissolve, thereby discouraging the most dangerous method of abuse, injection, while maintaining oral efficacy. Although this change decreased OxyContin abuse (35.6% to 12.8% over 21 months), rates of overdose mortality from heroin and other synthetic opioids nearly doubled within the next year (3). Consistent with this trend, as other prescription opioids became less available (due to Prescription Drug Monitoring Programs and rescheduling of hydrocodone compounds), use of more accessible, injectable drugs, such as heroin and fentanyl, increased (4, 5). Between 20022016, overdose mortalities from heroin and fentanyl increased 7.6x and 22x, respectively (6). Furthermore, inpatient admissions for opioid-related complications in 18-30 year-olds increased by 622% (7). As more opiate addicted Americans turn toward injection drugs, rates of injection-related morbidities are increasing (8, 9). One of the most lethal complications of injection drug use is endocarditis, often requiring urgent operation with prolonged hospitalization (10). This acuity places a massive burden on the health system; a recent statewide report found admissions for IDU-related endocarditis increased 12-fold and hospital costs increased 18-fold ($1.1 million to $22.2 million) from 2010-2015 (11). Continued injection drug use after surgery increases risks of prosthesis infection and the need for complicated and resource-intensive re-operation (12-14). Unfortunately, most IDU patients receive suboptimal addiction care postoperatively. An analysis of 102 IDU-related endocarditis cases demonstrated that approximately half of charts mentioned addiction at all, and only 7.8% contained an addiction-related plan at discharge (15). These deficiencies imply the postoperative strategy at most centers—intravenous (IV) antibiotics for six weeks–often fails to address the underlying addiction.
4 Financial strains and resource limitations prevent a more comprehensive approach, as there is a paucity of literature analyzing the economics and impact of inpatient drug rehabilitation postoperatively. To our knowledge, there are no studies examining the effect of post-operative drug rehabilitation and drug use cessation on outcomes for IDU-related endocarditis patients. This project explores how enrollment in intensive, inpatient drug rehabilitation after valve surgery could decrease continued injection drug use, and therefore reinfection and death. We attempt to highlight starting points for negotiation between providers, payors, and hospital systems that could facilitate comprehensive treatment of IDU-related endocarditis. We hypothesize providing inpatient drug rehabilitation, in addition to standard hospital care, is a cost-effective strategy compared to standard care alone. Patients and Methods Approach A Markov model with cycle lengths of one year was constructed comparing estimated costs and benefits of two postoperative strategies for IDU-associated endocarditis patients: standard hospital-only care (HC), consisting of 6 weeks of IV antibiotics versus hospital care plus inpatient drug rehabilitation (DR). Outcomes were analyzed over a 20-year time horizon. The cycle lengths and time horizon were chosen because of the lack of more precise time-to-event data on relapse in injection drug users after cardiac surgery and a common “injection career” of IDU being rarely more than 20 years (16, 17). The primary economic outcome was total costs over 20 years, and the primary efficacy outcome was quality adjusted life-years (QALYs) gained. The perspective was assumed a single payor, i.e., the health system caring for the patient. QALYs were obtained by calculating the number of cycles spent outside of the terminal death health state and multiplying by a disutility factor for the current-IDU state. We determined the incremental cost-effectiveness ratio (ICER) by calculating the difference in 20-year costs between HC and DR and dividing by the differences in QALYs. Using guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA), an ICER less than $50,000/QALY gained
5 is considered high value, whereas an ICER more than $150,000/QALY gained is considered a low value(18). In accordance with recommendations from the Panel on Cost-effectiveness in Health and Medicine, global discounting was applied, at of 3% per annum (19). Model structure and Inputs A state transition diagram summarizes the model structure in Figure 1 (Full model in Supplemental Figure 1). All patients are assumed to survive 30 days, and enter the model in the postoperative state, as part of the DR or HC strategy. Patients from each strategy then transition into one of three states: IDU, former-IDU (permanent cessation of injection drug use), or dead. The transition between these states is based on the yearly probabilities of successful rehabilitation, continued injection drug use postoperatively, repeat endocarditis and reoperation, and mortality. The Society of Thoracic Surgeons (STS) clinical database captures preoperative, operative and outcomes data on all cardiac surgery cases. All endocarditis operative cases in our institutional STS database from 2000-2017 were captured for analysis. Annual probabilities of mortality and reoperation were estimated using Weibull and lognormal distributions, respectively, based on time-to-event data from our institutional cohort of 68 IDU and 290 Non-IDU followed for a mean of 10.2 years and 6.1 years, respectively. We estimated mortality/reoperation probabilities for IDU patients at the mean value of age, sex, comorbidities and prosthesis type among observed IDU patients. We estimated mortality/reoperation probabilities for patients who quit IDU by standardizing the observed estimates from non-IDU to the mean age, sex, comorbidities and prosthesis type of IDU. In the absence of observed data on individuals who quit IDU, this strategy allowed us to extrapolate from non-IDU appropriately, while accounting for significant differences between the typical IDU/non-IDU. The variables used to standardize the estimates are shown in Supplemental Table 1. In our analysis we examined each yearly probability on a triangular distribution with a +/-30% upper and lower range (Table 1 and Figure 2). This study was approved by University of Virginia’s institutional review board (IRB# 19762).
6 The probability of IDU after surgery was estimated using 2 studies that measured rates of continued IDU before IDU-endocarditis reoperation(13, 20). QALYs were estimated using a disutility factor of 0.62 for active IDU, which was derived from a study examining the quality of life in 307 opioid addicted patients (21, 22). These variables were examined using a triangular distribution in our analysis using the upper and lower limits in Table 1. Surgical cost data were captured from our institution’s finance center based on cost-to-charge ratios. Dollar amounts were inflation-adjusted to year 2017 using conservative estimates from the Centers for Medicare and Medicaid Services Inpatient Prospective Payment System. Mean surgical costs were used for initial and re-do endocarditis surgeries, which were sampled using gamma distributions in our model. The costs of inpatient drug rehabilitation were estimated based on industry estimates obtained from the literature, and sampled with a triangular distribution, which can be found in Table 2. Statistical Analysis All rates from our institutional data and from the literature were converted to 1-year probabilities before imputation into the model. The base case was a fully probabilistic sampling analysis, drawing from 100,000 Monte Carlo simulations. The costs and benefits, presented as mean +/- standard deviation, for the 100,000 simulations were used to calculate the base case incremental cost effectiveness ratio (ICER). A cost-effectiveness acceptability curve was used to demonstrate variable uncertainty at different willingness-to-pay thresholds. Cost effectiveness modeling was conducted using TreeAge Pro 2018 (TreeAge, Williamstown, MA). Sensitivity Analysis A series of deterministic, one-way sensitivity analyses were performed to study the impact of key parameters in our model. All probabilities were held constant except the variable being examined, which was tested over a range as detailed in Tables 1 and 2. Where available, literature was used to inform a
7 reasonable range for each variable. Willingness-to-pay, and thus our threshold of cost effectiveness, was set at $100,000/QALY. Results Base Case Over the 20-year time horizon, average total cost of the HC strategy was $170,073 (±109,748), compared to $206,993 (± $111,985) for the DR strategy. The QALYs gained were 7.23 (± 0.33) and 8.16 (± 0.27) for HC and DR, respectively. Therefore, the incremental cost was $36,920 and the incremental gain in QALYs was 0.93, resulting in an ICER of $39,699/QALY gained in the DR strategy (Table 3). Probabilistic sensitivity analysis indicated 89.3%of 100,000 Monte Carlo iterations were under the $100,000/QALY gained willingness-to-pay threshold when DR was compared to HC. In the scatter plot of DR vs HC in Figure 3, each dot represents an iteration of the model. All dots to the right of the willingness to pay line of $100,000 identify DR as the preferred strategy. Dots under the x-axis represent instances where DR is more effective and less costly than HC (completely dominant). To demonstrate the uncertainty in determining the preferred strategy (HC vs. DR), the cost-effectiveness acceptability curve for HC vs. DR is shown in Figure 4 for a willingness-to-pay threshold ranging from 0 to $200,000. At our willingness-to-pay of $100,000/QALY there is 89.3% probability that the DR strategy is preferred. Furthermore, at a willingness-to-pay of $50,000/QALY, DR is still preferred in 64.3% of iterations. Deterministic Sensitivity Analysis In a series of one-way deterministic sensitivity analyses, all costs and transitional probabilities were examined at a willingness-to-pay threshold of $100,000/QALY gained. The ICER exceeded the willingness-to-pay when the probability of continuing IDU despite inpatient rehabilitation was greater than 53.0% (Figure 5). If the average risk of mortality in former-IDU patients becomes similar to active IDU (above 14.6% in former-IDU vs the baseline of 19% in IDU), HC becomes the dominant strategy (Figure 6). If the average probability of mortality in IDU becomes close to that that of Former-IDU
8 (below 5.6% vs the baseline of 7.0% in former-IDU, HC becomes the preferred strategy (Figure 7). The model was insensitive to all other variables and ranges, as reported in Table 1 and 2. Comment The present study investigated the cost-effectiveness of the traditional IDU-related endocarditis postoperative strategy, hospital-based care only (6 weeks of IV antibiotics), to that of a strategy where intensive, inpatient drug rehabilitation was also provided. Providing DR was cost-effective with an ICER of $39,699/QALY gained. Probabilistic sensitivity analysis with 100,000 Monte Carlo simulations demonstrated in 89.3% of trials, the DR strategy was within our willingness-to-pay of $100,000/QALY despite variability in all model inputs. These findings support the hypothesis that provision of postoperative inpatient drug rehabilitation in addition to standard hospital-based care is cost-effective for IDU patients. The proposed approach not only prevents repeat endocarditis operations but also targets the source of the national opioid epidemic, addiction. To our knowledge, this is the first cost-effectiveness analysis focusing on prevention of endocarditis in injection drug users. The key probability of our model was continued IDU despite receiving inpatient drug rehabilitation postoperatively. In our deterministic sensitivity analysis, if continued IDU decreased by a modest 7.0% (from 60% in the HC strategy to 53% in the DR strategy), our ICER fell within our willingness-to-pay of $100,000/QALY. A paucity of literature exists examining the continuation of IDU after inpatient drug rehabilitation, however, the authors believe the assumption that DR reduces long term injection drug use is logical. Previous studies have documented significant reductions in heroin use after long-term residential rehabilitation programs(23). Similarly, one study reported a readmission-free period of at least 6 months in 75% of patients after three to four weeks of inpatient DR, though the long-term outcomes of this group were not followed (24). Similarly, in a study of 308 adults with opioid use disorder, patients enrolled in a month-long inpatient rehabilitation had long-term abstinence of 23%, while patients supplemented with extended release naloxone showed a long-term abstinence rate of 31% (25). As medication assisted strategies and new opioid antagonists are developed, inpatient drug
9 rehabilitation programs will become more effective. However, further research investigating outcomes after DR in this population is warranted, and would validate the assumptions in this study. Further innovation in postoperative care, namely novel strategies for antibiotic administration, could also decrease the overall cost of hospital care, further offsetting the cost of inpatient drug rehabilitation treatment. If the cost of inpatient drug rehabilitation is below $20,000, the ICER for DR strategy is less than $20,000/QALY. This is an achievable mark. Collaboration between hospitals and regional centers to develop a single facility for patients to receive intensive drug rehabilitation could lower cost, as could flexible antibiotic administration strategies. For example, in a study of 205 IDUs requiring IV antibiotics, Jewell and colleagues examined administration of IV antibiotics at an inpatient addiction treatment facility. Due to shorter hospital stays, the program was projected to save $2.42 million over six years (26). Early transition from IV to oral antibiotics postoperatively may also save costs and resources. A recent study by Iversen et.al. demonstrated similar outcomes in 400 left-sided endocarditis patients when antibiotics were transitioned from IV to oral after 10 days (27). Such a paradigm shift could reduce costs by decreasing hospital length of stay and medication costs (28), plus eliminating the need to discharge a patient with an indwelling IV access line. Endocarditis is a complex, highly morbid, and deadly condition, particularly in IDU. Long-term mortality of IDU-related endocarditis was extremely high in our cohort, especially in re-operative cases, and has been demonstrated in similar studies (13, 29, 30). Effort should focus on prevention of reinfection and reoperation, as these surgeries carry the highest mortality and highest costs. Postoperative inpatient rehabilitation can reduce re-infection by terminating injection altogether, but as rehabilitation techniques continue to evolve, a multipronged approach needs to be undertaken. For those unable to discontinue use, safe needles, and clean injection teaching should be provided. Given the effectiveness in preventing infectious disease spread through safer injection sites (31-33), these programs would likely decrease incidence of IDU-related endocarditis. Furthermore, other preoperative strategies may augment care, such as addiction counseling and post discharge planning before surgery.
10 As with any cost effectiveness analysis, results and their implications should be considered in the context of the target community. A willingness-to-pay of $100,000/QALY may be acceptable in one setting and prohibitive in another. However, as our cost effectiveness acceptability curve demonstrates, at a WTP of $50,000/QALY (the historically accepted threshold based on dialysis costs(34, 35)), 64.3% of iterations still favored the DR strategy. Limitations Like any theoretical model of a complex patient population, this model has inherent limitations. As a supplement to our own institutional data, best available literature was used to derive clinical probabilities and costs to establish a reasonable distribution over which to test our variables. Although they were reviewed for methodological quality, there exists a chance they do not accurately reflect reality and may not be generalizable to all IDU cohorts and health systems. To address this, we utilized probabilistic and deterministic sensitivity analysis, examining all inputs in our model over a wide range, to capture a more realistic variability in model inputs. We did not include other hospital-based costs that IDU may incur after discharge from cardiac surgery (such as unrelated soft tissue infection and overdose resuscitation), which may affect the accuracy of the model. We also assume that IDU cessation is permanent in our model. Though IDU is likely a complex pattern of cessation and relapse, we informed our model probabilities using the limited number of studies on long term relapse rates, and assumptions that we believe to be reasonable. Mortality and reoperation time-to-event probabilities were estimated based on 298 patients undergoing 362 operations at our quaternary cardiac surgery center. To improve generalizability, we sampled our mortality and reoperation curves over a wide range of probabilities. Finally, the absolute risk reduction in continued IDU after inpatient rehabilitation is unknown, as studies have variable definitions of treatment success, and the ethical pitfalls of conducting a randomized trial in drug addicted patients. However, based on best available evidence, we believe it is logical that
11 inpatient rehabilitation programs do reduce continued IDU, and that cessation of IDU decreases overall mortality. Conclusion This analysis underscores the complex nature of IDU-related endocarditis and need for innovative strategies in the opioid crisis. Postoperative care represents an opportunity for intervention, to affect the cycle of addiction, reoperation, and death. We present data that can encourage providers, hospital systems, and payors to investigate financial strategies to improve outcomes. Investing in inpatient rehabilitation for injection drug users has the potential not only to reduce costs on our already overburdened health care system but also to preserve the lives of our patients.
12 References 1. Woolf SH, Aron L. Failing health of the united states. BMJ 2018;360:k496. 2. 2017 Prescription opioid data. Available at https://www.cdc.gov/drugoverdose/data/prescribing.html. Accessed 2018 9/23/2018. 3. Cicero TJ, Ellis MS, Surratt HL. Effect of abuse-deterrent formulation of oxycontin. N Engl J Med 2012;367(2):187-189. 4. 2018 What is the scope of heroin use in the united states? Available at https://www.drugabuse.gov/publications/research-reports/heroin/scope-heroin-use-in-united-states. 5. Jones CM, Logan J, Gladden RM, Bohm MK. Vital signs: Demographic and substance use trends among heroin users - united states, 2002-2013. MMWR Morb Mortal Wkly Rep 2015;64(26):719-725. 6. 2018 Overdose death rates. Available at https://www.drugabuse.gov/related-topics/trendsstatistics/overdose-death-rates. Accessed 2018 7. 2018 Persons who inject drugs (pwid). Available at https://www.cdc.gov/pwid/index.html. Accessed 2018 8. Peters PJ, Pontones P, Hoover KW et al. Hiv infection linked to injection use of oxymorphone in indiana, 2014-2015. N Engl J Med 2016;375(3):229-239. 9. Tookes H, Diaz C, Li H, Khalid R, Doblecki-Lewis S. A cost analysis of hospitalizations for infections related to injection drug use at a county safety-net hospital in miami, florida. PLoS One 2015;10(6):e0129360. 10. Weymann A, Borst T, Popov AF et al. Surgical treatment of infective endocarditis in active intravenous drug users: A justified procedure? J Cardiothorac Surg 2014;9:58. 11. Fleischauer AT, Ruhl L, Rhea S, Barnes E. Hospitalizations for endocarditis and associated health care costs among persons with diagnosed drug dependence - north carolina, 2010-2015. MMWR Morb Mortal Wkly Rep 2017;66(22):569-573. 12. Ortiz-Bautista C, Lopez J, Garcia-Granja PE et al. Current profile of infective endocarditis in intravenous drug users: The prognostic relevance of the valves involved. Int J Cardiol 2015;187:472-474. 13. Osterdal OB, Salminen PR, Jordal S, Sjursen H, Wendelbo O, Haaverstad R. Cardiac surgery for infective endocarditis in patients with intravenous drug use. Interact Cardiovasc Thorac Surg 2016;22(5):633-640. 14. Welton DE, Young JB, Gentry WO et al. Recurrent infective endocarditis: Analysis of predisposing factors and clinical features. Am J Med 1979;66(6):932-938. 15. Rosenthal ES, Karchmer AW, Theisen-Toupal J, Castillo RA, Rowley CF. Suboptimal addiction interventions for patients hospitalized with injection drug use-associated infective endocarditis. Am J Med 2016;129(5):481-485. 16. Des Jarlais DC, Arasteh K, Perlis T et al. The transition from injection to non-injection drug use: Long-term outcomes among heroin and cocaine users in new york city. Addiction 2007;102(5):778-785. 17. White SR, Hutchinson SJ, Taylor A, Bird SM. Modeling the initiation of others into injection drug use, using data from 2,500 injectors surveyed in scotland during 2008-2009. Am J Epidemiol 2015;181(10):771-780. 18. Anderson JL, Heidenreich PA, Barnett PG et al. Acc/aha statement on cost/value methodology in clinical practice guidelines and performance measures: A report of the american college of cardiology/american heart association task force on performance measures and task force on practice guidelines. J Am Coll Cardiol 2014;63(21):2304-2322. 19. Weinstein MC, Siegel JE, Gold MR, Kamlet MS, Russell LB. Recommendations of the panel on cost-effectiveness in health and medicine. JAMA 1996;276(15):1253-1258.
13 20. Shrestha NK, Jue J, Hussain ST et al. Injection drug use and outcomes after surgical intervention for infective endocarditis. Ann Thorac Surg 2015;100(3):875-882. 21. Uyei J, Fiellin DA, Buchelli M, Rodriguez-Santana R, Braithwaite RS. Effects of naloxone distribution alone or in combination with addiction treatment with or without pre-exposure prophylaxis for hiv prevention in people who inject drugs: A cost-effectiveness modelling study. Lancet Public Health 2017;2(3):e133-e140. 22. Aden B, Dunning A, Nosyk B, Wittenberg E, Bray JW, Schackman BR. Impact of illicit drug use on health-related quality of life in opioid-dependent patients undergoing hiv treatment. J Acquir Immune Defic Syndr 2015;70(3):304-310. 23. Hubbard RL, Craddock SG, Anderson J. Overview of 5-year followup outcomes in the drug abuse treatment outcome studies (datos). J Subst Abuse Treat 2003;25(3):125-134. 24. Barnett PG, Swindle RW. Cost-effectiveness of inpatient substance abuse treatment. Health Serv Res 1997;32(5):615-629. 25. Nunes EV, Gordon M, Friedmann PD et al. Relapse to opioid use disorder after inpatient treatment: Protective effect of injection naltrexone. J Subst Abuse Treat 2018;85:49-55. 26. Jewell C, Weaver M, Sgroi C, Anderson K, Sayeed Z. Residential addiction treatment for injection drug users requiring intravenous antibiotics: A cost-reduction strategy. J Addict Med 2013;7(4):271-276. 27. Iversen K, Ihlemann N, Gill SU et al. Partial oral versus intravenous antibiotic treatment of endocarditis. N Engl J Med 2018. 28. Li HK, Agweyu A, English M, Bejon P. An unsupported preference for intravenous antibiotics. PLoS Med 2015;12(5):e1001825. 29. Frater RW. Surgical management of endocarditis in drug addicts and long-term results. J Card Surg 1990;5(1):63-67. 30. Rabkin DG, Mokadam NA, Miller DW, Goetz RR, Verrier ED, Aldea GS. Long-term outcome for the surgical treatment of infective endocarditis with a focus on intravenous drug users. Ann Thorac Surg 2012;93(1):51-57. 31. Des Jarlais DC, Marmor M, Paone D et al. Hiv incidence among injecting drug users in new york city syringe-exchange programmes. Lancet 1996;348(9033):987-991. 32. Hurley SF, Jolley DJ, Kaldor JM. Effectiveness of needle-exchange programmes for prevention of hiv infection. Lancet 1997;349(9068):1797-1800. 33. Nguyen TQ, Weir BW, Des Jarlais DC, Pinkerton SD, Holtgrave DR. Syringe exchange in the united states: A national level economic evaluation of hypothetical increases in investment. AIDS Behav 2014;18(11):2144-2155. 34. Grosse SD. Assessing cost-effectiveness in healthcare: History of the $50,000 per qaly threshold. Expert Rev Pharmacoecon Outcomes Res 2008;8(2):165-178. 35. 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(9):796-797. 36. 2018 How much does drug rehab cost? Available at https://www.drugrehab.com/treatment/how-much-does-rehab-cost/. Accessed 2018
14 Figure Legends Figure 1: State Transition Diagram. Patients enter model in post-operative state, as part of DR or HC strategy. Patients then transition into 1 of 3 long term states: continued IDU, former-IDU or dead. Transition between states is based on probabilities of successful rehabilitation, continued IDU postoperatively, reoperation, and 1-year mortality, which are available in Table 1.
Figure 2: A) Annual mortality probability curve for IDU. B) Adjusted annual mortality probability curve for Former-IDU. C) Annual reoperation probability curve for IDU. D) Adjusted annual reoperation probability curve for IDU
Figure 3: Scatter plot illustrating incremental costs and effectiveness of DR vs. HC. Dots represent an iteration of the model. Dots right of the willingness to pay (WTP) line of $100,000 identify DR as the preferred strategy.
Figure 4: Proportion of cost-effective iterations as a function of different willingness-to-pay thresholds. At a willingness-to-pay of $50,000/QALY and $100,000/QALY, DR is preferred strategy in 89.3% and 64.3% of iterations, respectively.
Figure 5. One-way deterministic sensitivity of continuing IDU despite inpatient rehabilitation (relapse). At or below a 53.0% relapse rate in the DR strategy (compared to a baseline 60% in the HC strategy), the willingness-to-pay threshold of $100,000/QALY is achieved, and the DR strategy becomes preferred.
15 Figure 6: One-way deterministic sensitivity analysis of average mortality in Former-IDU. If the probability of mortality is over 14.6% (compared to 19% baseline in IDU), the DR strategy is preferred.
Figure 7: One-way deterministic sensitivity analysis of average mortality in IDU. If the probability of mortality falls below 5.4%, (compared to 7.0% baseline in Former-IDU), the DR strategy is preferred.
16
Table 1: Model Input Probabilities
Hospital Only Care (HC) Variable Proportions
Baseline
Lower
Continued Postoperative IDU 0.60(20) 0.50 IDU QoL Depreciation factor 0.62(21, 22) 0.30 Figure 2A Yearly Mortality IDU Figure 2 B Yearly Mortality Former-IDU Figure 2 C Yearly Reoperation IDU Figure 2 D Yearly Reoperation Former-IDU *= Institutional Data; IDU= Injection Drug User.
Inpatient Drug Rehabilitation (DR)
Upper
Baseline
0.70(13) 1.0
0.45 0.62(21, 22)
Lower 0.35 0.30 Figure 2 A Figure 2 B Figure 2 C Figure 2 D
Upper 0.55 1.0
17
Table 2: Cost and utilities for transitions and health states Hospital Based Care (HC) Resource Index Surgery
Cost (SD) $92,205 ($87,148)*
Inpatient Drug Rehabilitation (DR)
Lower
Upper
$46,898*
$109,179*
Cost (SD) $92,205 ($87,148)*
Lower $46,898*
Inpatient Drug Rehabilitation
-
-
-
$30,000(36)
$6,000(36)
Redo Surgery
$99,056 ($88,070)*
$50,563*
$126,952*
$99,056 ($88,070)*
$50,563*
*= Institutional Data
Upper $109,179* $70,000(36) $126,952*
18
Table 3: Base Case Results
Hospital Only Care (HC)
Total Cost (SD)
Total Effectiveness in QALYs (SD)
Incremental Cost/ Incremental Effectiveness
Incremental Cost Effectiveness Ratio (ICER)
$170,073 ($109,748)
7.23 (0.33)
--
--
Inpatient $206,993 $36,920/0.93 Drug 8.16 (0.27) $39,699/QALY ($111,985) QALY Rehabilitation (DR) IQR = interquartile range; BMI = body mass index, *=used at inputs in our model
Acceptability at WTP of $100k/QALY
10.7%
89.3%
19 Abbreviations DR = drug rehabilitation HC = hospital care IDU = injection drug use ICER = incremental cost of effectiveness ratio QALY = Quality adjusted life year SD = standard deviation WTP = willingness to pay