Time to psychiatric hospitalization in patients with bipolar disorder treated with a mood stabilizer and adjunctive atypical antipsychotics: A retrospective claims database analysis

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<ul><li><p>Clinical Therapeutics/Volume 31, Number 4, 2009</p><p>836 Volume 31 Number 4</p><p>This work was presented at the 60th Annual Institute on Psychiatric Services, October 25, 2008, Chicago, Illinois, the Annual European Congress of the International Society for Pharmacoeconomics and Outcomes Research, November 811, 2008, Athens, Greece, and the World Psychiatric Association Congress, April 14, 2009, Florence, Italy. </p><p>Accepted for publication April 17, 2009.doi: 10.1016/j.clinthera.2009.04.0220149-2918/$ - see front matter</p><p> 2009 Excerpta Medica Inc. All rights reserved.</p><p>ABSTRACTObjective: This study compared the time to psychi-</p><p>atric hospitalization in commercially insured patients with bipolar disorder who were treated with a mood stabilizer plus adjunctive aripiprazole versus adjunctive ziprasidone, olanzapine, quetiapine, or risperidone. </p><p>Methods: This was a retrospective, propensity score matched cohort study using the Ingenix I3/LabRx in-tegrated insurance claims data set. Patients with bipolar disorder were included if they had 180 days of pre-index enrollment in the health plan without atypical antipsychotic exposure. Patients received mood stabi-lizers and subsequently received adjunctive atypical antipsychotic agents; they were then monitored for up to 90 days after the index antipsychotic prescription. The primary analysis was a Cox proportional hazards analysis to evaluate the time until psychiatric hospi-talization comparing adjunctive aripiprazole with ziprasidone, olanzapine, quetiapine, or risperidone after adjusting for age, sex, and preindex hospitaliza-tion. </p><p>Results: Adjunctive aripiprazole was associated with a longer time until hospitalization than adjunctive ziprasidone, olanzapine, quetiapine, or risperidone (hazard ratios 1.7, 1.6, 1.5, and 1.5, respectively; all, P &lt; 0.05). Mean initial and maximum doses of all drugs were below those recommended by the package insert or clinical practice guidelines. Sensitivity analy-ses suggested the robustness of the results in the gen-eral population of patients with bipolar disorder re- cently treated with atypical antipsychotics.</p><p>Conclusions: This retrospective claims-data analy-sis suggests that in these adults with bipolar disorder treated with mood stabilizers, the addition of adjunc-tive aripiprazole was associated with a longer time to </p><p>hospitalization than adjunctive ziprasidone, olanza- pine, quetiapine, or risperidone during a 90-day fol-low-up period. (Clin Ther. 2009;31:836848) 2009 Excerpta Medica Inc.</p><p>Key words: bipolar disorder, adjunctive treatment, aripiprazole.</p><p>INTRODUCTIONBipolar disorder is a chronic, recurring disorder asso-ciated with periodic mood swings. The economic bur-den of bipolar disorder is substantial. Treatment costs are estimated at $7200 to $12,100 per year of which 20% is attributable to hospitalizations.1,2 Acute ma-nia is frequently a medical emergency requiring hospi-talization for behavioral control, rapid resolution of irritability and agitation, de-escalation of mood, and a decrease in risk-taking behavior. Patients who present with an acute episode require fast intervention to minimize hospitalization. Despite the availability of multiple efficacious medications, &gt;75% of patients with bipolar disorder report 1 lifetime psychiatric hospitalization.3 </p><p>Medication is an essential part of successful treat-ment for bipolar disorder. Recent prescription data indicate that 42% to 64% of patients with bipolar </p><p>Time to Psychiatric Hospitalization in Patients With Bipolar Disorder Treated With a Mood Stabilizer and Adjunctive Atypical Antipsychotics: A Retrospective Claims Database Analysis</p><p>Edward Kim, MD, MBA1; Ross Maclean, MD1; Diane Ammerman, PharmD1; Yonghua Jing, PhD1; Andrei Pikalov, MD, PhD2; Min You, MS1; Quynh Van-Tran, PharmD2; and Gilbert LItalien, PhD3</p><p>1Bristol-Myers Squibb, Plainsboro, New Jersey; 2Otsuka America Pharmaceutical, Inc., Rockville, Maryland; and 3Bristol-Myers Squibb, Wallingford, Connecticut</p></li><li><p>April 2009 837</p><p>E. Kim et al.</p><p>through December 31, 2006. The data set is a propri-etary sample of individuals receiving health insurance benefits from United Health Care (UHC). UHC data include the inpatient, outpatient, and prescription drug claims of &gt;15 million covered lives across the United States. </p><p>Patients were monitored for up to 90 days after the index date for psychiatric hospitalization, medical hospitalization, discontinuation of the index atypical antipsychotic, and prescription of a nonindex atypical antipsychotic during the follow-up period. The index date was the date of the first prescription claim for an adjunctive atypical antipsychotic. </p><p>Inclusion CriteriaThe study included outpatients aged 18 to 65 years </p><p>with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)27 code for bipolar disorder (manic, mixed, or hypomanic [296.0x, 296.1, 296.4x, 296.6x, 296.7x, 296.8x]). Eligible patients were required to have continuous health-plan enrollment for 180 days before and 90 days after the index date, and a supply of mood stabilizer (lithium carbonate, carbamazepine, lamo- trigine, divalproex sodium, oxcarbazepine, or topira-mate) of 30 days before the index date. Patients were included if they were treated with a single atypical antipsychotic.</p><p>Exclusion CriteriaPatients were excluded from the analysis if they re-</p><p>sided in a nursing home, hospice, or another type of long-term care facility; received mail-order prescrip-tions; or were diagnosed with a schizophrenia spectrum disorder (295.xx) during the pre- or postindex study period. Patients were also excluded if they used any atypical antipsychotic during the 180-day preindex period or were hospitalized at the time of index pre-scription or within 7 days after the index prescription.</p><p>Assessments and Statistical AnalysesThe primary outcome of interest was the time to </p><p>first psychiatric hospitalization during the 90-day postindex follow-up period. Patients were censored for the following events: psychiatric hospitalization, medical hospitalization, discontinuation of the index antipsychotic (&gt;15 days of gap in coverage), or pre-scription of a different antipsychotic during the follow- up period.</p><p>disorder receive traditional mood stabilizers, such as lithium, valproate, or carbamazepine, and 44% to 60% receive antipsychotic augmentation therapy.46 Antipsychotics are used increasingly in the treatment of bipolar disorder because of their properties as anti-manic or mood-stabilizing agents, coupled with favor-able tolerability profiles, compared with conventional agents.4,5 Updated treatment guidelines reflect this expanded role for atypical antipsychotics in the treat-ment of bipolar disorder.7,8 Severe manic episodes are typically treated with mood stabilizers in combination with atypical antipsychotics as a first-line treatment.711 For patients with milder symptoms, combination therapies are a second-line approach, but mood stabi-lizers augmented with atypical antipsychotics are com- monly used.7,12 Few data are available on the com-parative effectiveness of combined treatments with a mood stabilizer and atypical antipsychotic for the prevention of hospitalization in patients with bipolar disorder.13</p><p>Aripiprazole is an atypical antipsychotic with par-tial agonist activity at dopamine D2 and D3 recep-tors1417 and serotonin 5-hydroxytryptamine (HT)1A receptors, and antagonist activity at 5-HT2A recep- tors.18,19 Aripiprazole has been approved for the treat-ment of manic and mixed episodes associated with bipolar I disorder, with or without psychotic features, in adults and in pediatric patients aged 10 to 17 years, as both monotherapy and adjunctive therapy to either lithium or valproate.20 In patients with an inadequate response to lithium or valproate, adjunctive aripipra-zole provided a greater improvement in mania symp-toms from week 1 to study end (week 6) compared with lithium or valproate alone.21 The safety and tolerabili- ty profile of adjunctive aripiprazole was similar to that observed in previous studies of aripiprazole mono- therapy in patients with bipolar mania.2226</p><p>The objective of the present study was to compare the time to psychiatric hospitalization in commercially insured patients with bipolar disorder who were treated with a mood stabilizer plus adjunctive aripiprazole versus adjunctive ziprasidone, olanzapine, quetiapine, or risperidone.</p><p>PATIENTS AND METHODSStudy Design</p><p>This was a retrospective cohort study using the Ingenix I3/LabRx (Ingenix Health Intelligence, Salt Lake City, Utah) claims data set from January 1, 2003 </p></li><li><p>838 Volume 31 Number 4</p><p>Clinical Therapeutics</p><p>and limited evidence of titration to maximum dose. Mean starting and maximum doses were as follows: ziprasidone, 90.3 and 100.2 mg/d; olanzapine, 9.3 and 10.2 mg/d; quetiapine, 147.0 and 169.8 mg/d; and risperidone, 1.6 and 1.8 mg/d. The mean starting and maximum daily doses of atypical antipsychotics after propensity score matching are presented in Table V. After matching, a lower postindex hospitalization rate was observed with aripiprazole (6.5% [28/431]) than with any of the other atypical antipsychotics (ziprasi-done, 10.2% [44/431]; olanzapine, 8.7% [60/690]; quetiapine, 8.5% [71/840]; and risperidone, 8.6% [71/829]) (Table VI). </p><p>Regression AnalysesResults of the Cox proportional hazards regression </p><p>analyses indicated that, compared with aripiprazole, all the other atypical antipsychotics were associated with significantly shorter time to hospitalization (zip-rasidone: hazard ratio [HR] = 1.7; P = 0.04; olanza- pine: HR = 1.6; P = 0.03; quetiapine: HR = 1.5; P = 0.04; and risperidone: HR = 1.5; P = 0.04). Kaplan-Meier survival curves in Figure 2 demonstrate that adjunc-tive aripiprazole was associated with a longer time until hospitalization than adjunctive ziprasidone, olanza- pine, quetiapine, and risperidone.</p><p>Given the significant disparities between observed and label-recommended dosing, we conducted analy-ses within each treatment arm to compare subthera-peutic dosing (below the label-recommended dose) with therapeutic dosing (at or above the label- recommended dose). Because the labels of quetiapine, risperidone, and ziprasidone recommend either a start-ing dose and targeted dose for titration, or a dosing range, we compared the index dose with the recom-mended starting dose, and the maximum dose with the targeted dose, if applicable. For olanzapine and que-tiapine, a therapeutic starting dose was associated with a higher risk of hospitalization than a subthera-peutic starting dose (olanzapine: HR = 1.730; P = 0.01; quetiapine: HR = 1.371; P = 0.03). For risperidone, a therapeutic maximum dose was associated with a higher risk of hospitalization than a subtherapeutic maximum dose (HR = 1.780; P &lt; 0.01) (Table VII). Subtherapeutic doses were not associated with higher risks of hospitalization in any treatment arm. </p><p>To assess the generalizability of the results, we con-ducted a sensitivity analysis beyond the prespecified propensity scorematched study sample. Cox propor-</p><p>The primary analysis was a Cox proportional haz-ards analysis assessing the time until postindex psy-chiatric hospitalization. Covariates for adjustment in the model included age, sex, diagnosis or treatment of diabetes or hyperlipidemia, preindex psychiatric hos-pitalization, preindex lipid or glucose laboratory claims, choice of preindex mood stabilizer, and Charl-son comorbidity index.</p><p>To control for treatment selection bias, we used propensity score matching to construct comparison groups that shared similar demographic and clinical characteristics. Propensity scores were calculated for every patient using logistic regression, with indepen-dent variables of age, sex, region, preindex diagnosis or treatment of diabetes or hyperlipidemia, preindex psychiatric hospitalization, preindex lipid or glucose laboratory claims, choice of preindex mood stabilizer, and Charlson comorbidity index. The propensity score was the predicted probability of treatment calculated for each patient in the regression model. Patients in comparison treatment groups were matched if their propensity scores were within 0.25 SD of the logit of the propensity score. </p><p>RESULTSPatient Disposition and Characteristics</p><p>Of 198,919 patients with at least 1 prescription for an atypical antipsychotic, 13,774 had bipolar dis- order, of whom 6162 met the full inclusion criteria (Figure 1). Of these, 840 patients were taking aripip-razole, 446 ziprasidone, 1101 olanzapine, 2501 que-tiapine, and 1274 risperidone. Propensity score match-ing allowed the matching of 431 aripiprazole and ziprasidone patients, 690 aripiprazole and olanzapine patients, 840 aripiprazole and quetiapine patients, and 829 aripiprazole and risperidone patients. Base-line characteristics before and after matching are shown in Tables I to IV. The results demonstrate that propensity score matching successfully eliminated significant baseline and preindex differences in all variables.</p><p>Duration of therapy with atypical antipsychotics was generally comparable across treatment groups, except that patients taking aripiprazole had longer therapy than those taking olanzapine (49.0 vs 43.4 days; P &lt; 0.001) (Table V). Before propensity score match-ing, the mean starting dose of aripiprazole was 11.2 mg/d; the mean maximum dose was 12.4 mg/d. Most of the other atypical antipsychotics had low starting doses </p></li><li><p>April 2009 839</p><p>E. Kim et al.</p><p>Patients treated with atypical antipsychotics from 2003 through 2006 (the rst episode of atypical antipsychotic treatment was used for the analysis)</p><p>(N = 198,919)</p><p>Patients(1) aged 1865 years;</p><p>(2) not treated with clozapine;(3) without mail-order prescription; and</p><p>(4) 6 months preindex and 3 months postindex with continuous enrollment(n = 61,901)</p><p>Patients(1) without long-term care (nursing home or hospice); and</p><p>(2) without psychiatric hospitalization at index date or 7 days after index (n = 59,755)</p><p>Patients(1) with bipolar disorder; and</p><p>(2) without schizophrenia(n = 13,774)</p><p>Study Sample(1) total preindex mood stabilizer supply 30 days; and</p><p>(2) mood stabilizer claim during atypical antipsychotic treatment or within 30 days before atypical antipsychotic index date</p><p>(n = 6162)</p><p>Aripiprazole(n = 840)</p><p>Ziprasidone(n = 446)</p><p>Olanzapine(n = 1101)</p><p>Quetiapine(n = 2501)</p><p>Risperidone(n = 1274)</p><p>Figure 1. Flow of patients through the study of mood stabilizer plus atypical antipsychotics for bipolar disorder.</p></li><li><p>840 Volume 31 Number 4</p><p>Clinical Therapeutics</p><p>Table I. Baseline characteristics before and after propensity score matching for aripiprazole versus ziprasidone among patients being treated for bipolar disorder. Values are no. (%) unless otherwise indicated.</p><p> Before Propensity Score Match* After Propensity Score Match</p><p> Aripiprazole Ziprasidone Aripiprazole Ziprasidone Variable (n = 840) (n = 446) P (n = 431) (n = 431) P </p><p>Age, mean (SD), y 37.9 (11.5) 37.5 (10.9) 0.61 37.8 (11.5) 37.5 (11.0) 0.64Men 557 (66.3) 328...</p></li></ul>

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