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Efficacy of prescribed injectable diacetylmorphine in the Andalusian trial: Bayesian analysis of responders… Perea-Milla, Emilio; Ayçaguer, Luis C S; Cerdà, Joan C M; Saiz, Francisco G; Rivas-Ruiz, Francisco; Danet, Alina; Vallecillo, Manuel R; Oviedo-Joekes, Eugenia Aug 14, 2009

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ralssBioMed CentTrialsOpen AcceResearchEfficacy of prescribed injectable diacetylmorphine in the Andalusian trial: Bayesian analysis of responders and non-responders according to a multi domain outcome indexEmilio Perea-Milla1,2, Luis Carlos Silva Ayçaguer*3, Joan Carles March Cerdà2,4, Francisco González Saiz5, Francisco Rivas-Ruiz1,2, Alina Danet2,4, Manuel Romero Vallecillo2,4 and Eugenia Oviedo-Joekes6Address: 1Research Support Unit, Hospital Costa del Sol, Ctra Nacional 340, km 187, 29603 Marbella, Spain, 2CIBER Epidemiología y Salud Pública (CIBERESP), Spain, 3National Center for Medical Science Information (INFOMED), 27 St N#110. Vedado, 10400 Ciudad de la Habana, Cuba, 4Andalusian School of Public Health, Campus Universitario de Cartuja, Cuesta del Observatorio 4, Apartado 2070, 18080, Granada, Spain, 5Andalusian Foundation for Drug Abuse Attendance (FADA), Avda. Hytasa Edf. Toledo II Planta 2 Oficina 3, 41006, Seville, Spain and 6School of Population and Public Health, University of British Columbia & Centre for Health Evaluations and Outcomes, Providence Health Care, Vancouver, BC, CanadaEmail: Emilio Perea-Milla - eperea@hcs.es; Luis Carlos Silva Ayçaguer* - lcsilva@infomed.sld.cu; Joan Carles March Cerdà - joancarles.march.easp@juntadeandalucia.es; Francisco González Saiz - pacogonzalez@comcadiz.com; Francisco Rivas-Ruiz - frivasr@hcs.es; Alina Danet - alina.danet.easp@juntadeandalucia.es; Manuel Romero Vallecillo - manolorv@gmail.com; Eugenia Oviedo-Joekes - eugenia@mail.cheos.ubc.ca* Corresponding author    AbstractBackground: The objective of this research was to evaluate data from a randomized clinical trial that tested injectablediacetylmorphine (DAM) and oral methadone (MMT) for substitution treatment, using a multi-domain dichotomous index, witha Bayesian approach.Methods: Sixty two long-term, socially-excluded heroin injectors, not benefiting from available treatments were randomizedto receive either DAM or MMT for 9 months in Granada, Spain. Completers were 44 and data at the end of the study periodwas obtained for 50. Participants were determined to be responders or non responders using a multi-domain outcome indexaccounting for their physical and mental health and psychosocial integration, used in a previous trial. Data was analyzed withBayesian methods, using information from a similar study conducted in The Netherlands to select a priori distributions. Onadding the data from the present study to update the a priori information, the distribution of the difference in response rateswere obtained and used to build credibility intervals and relevant probability computations.Results: In the experimental group (n = 27), the rate of responders to treatment was 70.4% (95% CI 53.287.6), and in thecontrol group (n = 23), it was 34.8% (95% CI 15.354.3). The probability of success in the experimental group using the a posterioridistributions was higher after a proper sensitivity analysis. Almost the whole distribution of the rates difference (the one fordiacetylmorphine minus methadone) was located to the right of the zero, indicating the superiority of the experimentaltreatment.Conclusion: The present analysis suggests a clinical superiority of injectable diacetylmorphine compared to oral methadone inthe treatment of severely affected heroin injectors not benefiting sufficiently from the available treatments.Published: 14 August 2009Trials 2009, 10:70 doi:10.1186/1745-6215-10-70Received: 15 April 2009Accepted: 14 August 2009This article is available from: http://www.trialsjournal.com/content/10/1/70© 2009 Perea-Milla et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 6(page number not for citation purposes)Trial Registration: Current Controlled Trials ISRCTN52023186Trials 2009, 10:70 http://www.trialsjournal.com/content/10/1/70BackgroundOpioid addiction is a chronic relapsing disease that affectsthe lives of sufferers in very different ways [1]. Opioid-dependent people continue using these drugs despite theconsequences for their health, legal situation, social inte-gration and personal relations [2]. Opioid substitutiontherapies (such as methadone, buprenorphine or diacetyl-morphine) are intended to reduce illicit opioid use,deaths, disease and crime, as well as to improve patients'health, quality of life and psychosocial integration. There-fore, the effectiveness of a treatment may be reflected indifferent areas of patients' lives and as a consequence atreatment can be evaluated in different ways.Various studies have provided evidence of the effective-ness, safety, viability and cost-effectiveness of prescribingdiacetylmorphine (DAM) for the treatment of long termopioid-dependent persons who have not benefited fromother treatments [3-11]. DAM is currently prescribed, as aregular programme or in the context of a clinical trial, insix countries: the UK, Switzerland, the Netherlands, Ger-many, Spain and Canada [12].In the Dutch trial testing co-prescribed diacetylmorphinevs. methadone for long-term opioid dependence, treat-ment effectiveness was evaluated by means of a multi-domain outcome index (MDO) in order to obtain anoverall measure of treatment success or failure [10,13].The goal of the MDO is to assess response by means of adichotomous variable addressing, as a combined meas-ure, different aspects involved in the process of stabilizingdrug-dependent patients: their physical and mental healthand psychosocial integration.It has been remarked that although a MDO allows to cap-ture the complexity of drug-dependence and summarizesvarious measures by means of a single index, it does notenable the weighting of each dimension making difficultto evaluate in which particular aspects the patient hasimproved; moreover, a MDO makes it more complicatedto perform comparisons with other studies [14,15]. Thefirst of these problems may be addressed by separating thedimensions constituting the MDO, in order to determinetheir individual performance, as we have done in a previ-ous analysis [11]. The goal of the present study is to over-come the second obstacle: we seek to evaluate the resultsof the DAM prescription trial carried out in Andalusia(Spain) with the multi-domain dichotomous index pro-posed in the Dutch study [10]. Here we analyze data fromthe Andalusian study by formally applying prior empiricalevidence reported on the evidence of this treatment. Inaddition, we discuss the contribution of the results to thestate of the art.MethodsWe analyzed data from a randomized controlled trialcomparing injectable DAM vs. oral MMT conducted inAndalusia, Spain, from February 2003 to December 2004.Study design, methods and results have been publishedelsewhere [11]. Briefly, 62 long-term, opioid dependentindividuals with severe health and other drug relatedproblems were randomized to receive either injectableDAM (plus oral methadone) or oral methadone alone. Atotal of 44 participants completed the 9 month treatmentperiod and 50 completed the follow-up evaluations.For the present study we analyse data from the Andalusiantrial using a multi-domain outcome measure reported ina previous study conducted in The Netherlands, also com-paring injectable DAM and oral MMT [10]. The MDO is adichotomous index, imputing success when the patientshows at least 40% improvement at 9 months, comparedto the baseline values, in physical health (MAP-H) [16], ormental status (SCL-90)[17], or social functioning (illegalactivities and/or contact with non drug users), without adeterioration superior to 40% in any of these dimensionsand no substantial increase (20%) in cocaine use. Moredetails about this MDO can be found elsewhere [13].Statistical analyses were performed using a Bayesianapproach in order to take advantage of previous informa-tion, a strategy highly appropriated when working withsmall sample sizes (small samples are very common in tri-als aimed at treating conditions with low-incidence in thecommunity). Previous information in big samples wouldhave virtually no impact in the results. We calculated suc-cess rates, the relative risk (RR) and the respective 95%confidence intervals (CI). Using data derived from theDutch study, a priori information was obtained for analy-sis of the Andalusian study data using Bayesian methods[18-21]. Analyses were performed by intention to treat,with no imputation for missing values. We denote by θ1the percentage of patients who responded to the experi-mental treatment (DAM), while θ2 represents the percent-age of those responding to the conventional treatment(methadone). Bayesian analysis enables us to calculatethe probability of θ1 being greater than θ2 by a specifiedmagnitude, based on the data from our trial and priorinformation from the Dutch trial. Upon clinical judgmentand based on the target populations (i.e. treatment-refrac-tory opioid-dependent individuals) and outcome expecta-tions (i.e. stabilization, long-term treatment), we assumedas clinically relevant a minimal difference of 15% betweenthe rates of responders in each group, and assessed theprobability of this being fulfilled under different assump-tions.Page 2 of 6(page number not for citation purposes)For each of the parameters θ1 and θ2 we selected three apriori distributions from the family of beta distributionsTrials 2009, 10:70 http://www.trialsjournal.com/content/10/1/70with parameters a and b which approximately representthe implicit number of responders and non-responders inthe prior distribution. These three scenarios represent dif-ferent degrees of incorporation of prior evidence. In thefirst scenario ('No use' of historical data) Jeffreys' priorswere used, which are non-informative prior beta distribu-tions with parameters a = b = 0.5 for both, θ1 and θ2. Theremaining two pair of priors were set on the basis of theknowledge derived from a previous clinical trial usinginjected DAM. [10] The respective CI associated with theseprior data were calculated, and parameters were chosen (aand b in the beta distribution) such that the maximumdensity intervals of these distributions coincided approxi-mately with the CI obtained previously. The second sce-nario ('Partial use') down-weighted the Dutch study bydividing a and b by 5. Finally, we repeated the processusing the values a and b without modification ('Full use'),essentially equivalent to a full pooling of the trial resultsin a meta-analysis.In order to perform a sensitivity analysis, several scenariosneed to be imagined. The one considered when we do a'partial use' of previous data is placed between twoextreme situations: no use of previous data (meaningthere are no similarities between contexts) and full use ofthem (meaning both contexts are equal). These extremepositions are extreme, since we cannot assume the Dutchand Andalusian context are the same, or that they havenothing in common either. The chosen halfway scenariotakes into account this argument. A division by 5 of theparameters derived from the Beta-distribution was chosenin order to substantially increase the distribution disper-sion attributed to previous data, allowing an adequatesensitivity analysis.For each one of these prior choices, we obtained the con-jugate beta distributions for the response rate in each armof the trial using our binomial data. A total of 20.000 sim-ulations were made from these a posteriori distributions,and the corresponding 20.000 differences θ1 - θ2 were cal-culated providing an a posteriori distribution of the differ-ence between the proportions: Δ = θ1 - θ2. This was used toderive simulation-based estimates of the probability ofrelevant magnitudes concerning Δ: P(Δ larger than 0), P(Δlarger than 0.15) and a maximum density interval (prob-ability interval for Δ) at 95%. EPIDAT 3.1 was used for allcomputations [22].ResultsThe a priori beta distributions, as stated above, wereobtained using the data from the Dutch clinical trial. Thiswas carried out with a sample of 98 patients in the exper-imental group (injectable DAM) and 76 in the controlabove-mentioned informative a priori distributions, webegan by calculating the 95% CI (frequentist) associatedwith the preceding data. Confidence intervals for the per-centage of patients who responded to treatment in thecontrol and experimental groups in the Dutch trial were(4666) and (2141) respectively; and the a priori beta dis-tributions consistent with them were a1 = 55, b1 = 43, anda2 = 24, b2 = 52 respectively. Following the steps describedin the methods section, the analysis was performed for thethree possible scenarios, as described in Table 1.Among the patients in the experimental group (n = 27),the rate treatment responders was 70.4% (95% CI53.287.6), while for those in the control group (n = 23) itwas 34.8% (95% CI 15.354.3). The difference in responserates between the two groups was 36.6% in favour of theexperimental group. The probability of a positiveresponse to treatment by participants allocated to experi-mental group (RR) was 2.2 times greater than for those ofthe control group (95% CI 1.24.3; p = 0.012). The numberneeded to treat was 2.8 (IC 95% 1.610.0).After using the data from the present study to update thea priori information, the nonparametric distributionsobtained from the simulated differences in success rates(experimental less conventional) in the 3 scenarios isshown in Figure 1. This shows that the probability of suc-cess in the experimental group is higher than in the con-trol group. In the last two cases, the whole distributionsare located to the right of the zero, above the 6% level; inthe first one, the distribution includes a very small frac-tion of negative values. The 95% probability intervals forthe difference and probabilities of Δ >0 and Δ >0.15 arepresented in Table 2.DiscussionOur analysis of the Andalusian trial data using a multi-domain outcome measure as a treatment response crite-rion shows that the group receiving injectable diacetyl-morphine had a greater probability of responding totreatment than the group that receive only oral metha-done, both in clinical and in statistical terms.Table 1: a and b values for each parameter θ1 and θ2 among the three groups of the a priori distributions used.Dutch information θ1 θ2a1 b1 a2 b2No use 0.5 0.5 0.5 0.5Partial use 11.0 8.6 4.8 10.4Page 3 of 6(page number not for citation purposes)group (oral methadone). Twelve month success rates of56% and 31%, respectively, were obtained. To define theFull use 55.0 43.0 24.0 52.0Trials 2009, 10:70 http://www.trialsjournal.com/content/10/1/70The results obtained with this MDO are remarkable giventhat this indicator has a high level of exigency, as much byits complex definition, the magnitude of the demandedchange (40%) and by the inclusion of the criterion of thecocaine consumption. Also, the MDO is a dichotomousvariable, being less sensitive to change than the dimen-sional measures. For a fixed sample size a binary outcomemeasure would be able to detect a change of a 10% of thevariance, whereas a dimensional measurement coulddetect changes of 1% [23].It is important to note that the results come from a smallsample and this limits their generalizability; other limita-tions derived from the design of the study have been dis-cussed elsewhere [11]. When comparing the present studywith the one conducted in the Netherlands [10], it shouldbe taken into account that the control group in the Anda-lusian trial received larger average doses of methadone,and also they received an optimized version of MMT(involving greater psychosocial resources than the treat-ment that is normally provided). Also, the interventionlasted 12 months in the Dutch RCT, and 9 months in theAndalusian one. Nevertheless, the differences between thegroups in the Dutch RCT stabilized after approximately 10months.In the present study the Bayesian analysis reveals a clearsuperiority of the diacetylmorphine-based treatment overNon parametric distribution of success rates differences between the experimental and control groups for the three possible sce arios (without using the Dutch data in or er to d termin  the priors w th parti l and total use)Figure 1Non parametric distribution of success rates differences between the experimental and control groups for the three possible scenarios (without using the Dutch data in order to determine the priors with partial and total use).050010001500200025003000350040004500-0,100-0,0500,0000,0500,1000,1500,2000,2500,3000,3500,4000,4500,5000,5500,600ClassFrequencyJeffreyPartialFullTable 2: Probability values of the difference in success rates between the experimental and control groups being bigger than 0 and 0.15, and probability intervals (95%) for the possible three scenarios: without using the Dutch data in order to determine the priors, partial use, and total use).Dutch information P(Δ>0) P(Δ>0.15) Probability Interval (95%)No use 0.994 0.926 8.0  57.6Partial use 0.998 0.934 9.9  50.4Page 4 of 6(page number not for citation purposes)methadone. The fact that the probability of the experi-mental treatment surpassing the conventional one by atFull use 1.000 0.965 13.9  39.3Trials 2009, 10:70 http://www.trialsjournal.com/content/10/1/70least 15% gives such a high result (over 0.9 in the differentscenarios) is important, especially considering the case inwhich this value is derived from the formal integration ofearlier data with those from the present study. Our find-ings fit in with the a priori probability of the superiority ofinjectable DAM versus oral methadone in the case of treat-ment-refractory patients, and show how even partial useof the historical data reinforce the confidence in a clini-cally relevant difference.The results obtained using Bayesian analyses are similar tothose derived from the classical statistical approach whenlarge sample sizes are used. The Bayesian method used inthis analysis, however, was especially well suited becauseof the small sample size in our trial; in addition, it allowedto integrate previously obtained results into the currentstudy to a partial or full extent. Moreover, this method isin agreement with recommendations of paying specialattention to calculating the magnitude of the effect of thetreatment being studied, and not so much on its statisticalpower [24,25].ConclusionNational and European data shows a stabilization in theuse of heroin. However, a sub-group of heroin users withhigh health and social needs are not properly served bythe health care system. Pharmacological alternatives areneeded to attract and engage these individuals in treat-ment. The evidence for the greater efficacy of injectableDAM, in comparison with oral methadone, in the case oflong-term, treatment-refractory opioid-dependentpatients is supported by the present study and by others[4-6,10,26,27]. The next step would be to design a studyevaluating the provision of DAM in standard clinical prac-tice, i.e. in more ecological settings. However, the delay inthe approval of those programs still depends more on thepolitical and moral contexts than on the scientific conclu-sions reached over recent years [12,28].Competing interestsThe authors declare that they have no competing interests.Authors' contributionsEPM, EOJ, JCM, MRV and FGS designed the study andgathered the data. The senior statistician (LCS) performedthe data analyses. EPM, LCS and EOJ wrote the first draftof the paper and all authors contributed to the final ver-sion. The final decision about publishing the paper wasmade by all the authors. All authors vouch for the accu-racy of the data and analysis.AcknowledgementsThe authors gratefully acknowledge the advice of David Spiegelhalter. We Manuel Rodríguez, Salvador Rodríguez Rus, Francisco Carrasco Limón, Rosario Ballesta, Araceli Plaza. Furthermore, we thank the study partici-pants for their time and effort. Funded by the Drug Commission, Council for Equality and Social Welfare, Andalusian Government.References1. Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, BigelowGE: A comparison of levomethadyl acetate, buprenorphine,and methadone for opioid dependence.  N Engl J Med 2000,343:1290-1297.2. Ward J, Hall W, Mattick RP: Role of maintenance treatment inopioid dependence.  Lancet 1999, 353:221-226.3. Güttinger F, Gschwend P, Schulte B, Rehm J, Uchtenhagen A: Evalu-ating long-term effects of heroin-assisted treatment: theresults of a 6-year follow-up.  Eur Addict Res 2003, 9:73-79.4. Haasen C, Verthein U, Degkwitz P, Berger J, Krausz M, Naber D:Heroin-assisted treatment for opioid dependence: Ran-domised controlled trial.  Br J Psychiatry 2007, 191:55-62.5. 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