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Hospitalization Risk in Patients with Schizophrenia Treated with Dose-Equivalent Antipsychotics
Daisy Ng-Mak, PhD; Andrew Messali, PharmD, PhD; Ahong Huang, MS; Li Wang, PhD; and Antony Loebel, MD

Hospitalization Risk in Patients with Schizophrenia Treated with Dose-Equivalent Antipsychotics

Daisy Ng-Mak, PhD; Andrew Messali, PharmD, PhD; Ahong Huang, MS; Li Wang, PhD; and Antony Loebel, MD
This study compared the risk of hospitalization among adults with schizophrenia being treated with equivalent dose ranges of lurasidone versus aripiprazole, olanzapine, quetiapine, or risperidone. Administrative claims data for this analysis came from the IBM MarketScan Commercial, Medicare Supplemental, and Multi-State Medicaid databases between January 2011 and June 2017. The study included adults with schizophrenia who initiated treatment with an antipsychotic and were continuously enrolled for 360 days prior to and following the date of the initial antipsychotic prescription. Risk of all-cause and schizophrenia-related hospitalization among patients who received lurasidone monotherapy versus aripiprazole, olanzapine, quetiapine, or risperidone in equivalent dose ranges were assessed. Marginal structural models that accounted for preindex characteristics, changes in antipsychotic treatment, and time-varying covariates assessed differences between lurasidone and other second-generation antipsychotics on all-cause and schizophrenia-related hospitalizations. A sensitivity analysis was conducted without the dose-equivalence requirement. A total of 20,212 patients met the study inclusion criteria. Compared with those treated with lurasidone monotherapy, the adjusted risk of all-cause hospitalization was significantly higher among patients treated with olanzapine (adjusted rate ratio [aRR], 1.49; P = .04), quetiapine (aRR, 1.64; P = .01), or risperidone (aRR, 1.47; P = .04), but not aripiprazole (aRR, 1.24; P = .28). A similar, non-statistically significant pattern of adjusted risks of schizophrenia-related hospitalizations was observed. A sensitivity analysis without the dose-equivalence requirement produced consistent results. As hospitalization is a major cost driver of direct healthcare cost, lurasidone may be a cost-saving treatment option for patients with schizophrenia.
Am J Manag Care. 2019;25:-S0

Schizophrenia is a debilitating, chronic mental illness that affects approximately 0.3% to 1.0% of the US population.1,2 Symptoms can be divided into “positive,” such as delusions and hallucinations, and “negative,” such as lack of emotion and social withdrawal.1 Because of the severity of the symptoms, most individuals with schizophrenia are unable to engage in paid employment, maintain marriage/partner relationships, or live independently.3

In the United States, the economic burden of schizophrenia in 2013 was estimated at $155.7 billion, including $37.7 billion in direct healthcare costs.4 Inpatient costs were the largest driver of direct healthcare costs, accounting for $15.2 billion (40.3%) of the direct costs.4 Different types of healthcare expenditures have different clinical implications in schizophrenia.5 Inpatient and emergency department (ED) use may reflect symptomatic relapses, while higher rates of outpatient visits and greater use of antipsychotic medications may reflect greater engagement in treatment.5 Increased adherence with antipsychotics has been linked with reduced inpatient costs6,7 and improved long-term functioning.8

Antipsychotics are the primary treatment for acute schizophrenia9,10 and are recommended in the stable phase because they substantially reduce the risk of relapse.10 Second-generation antipsychotics (SGAs) are preferred over first-generation antipsychotics (FGAs) for acute schizophrenia because of a reduced risk of developing extrapyramidal symptoms.9 Meta-analyses summarizing the results of randomized controlled trials of patients who are taking antipsychotics have reported substantial variations in extrapyramidal symptoms, prolactin elevation, sedation, and weight gain.11,12 The metabolic burden associated with commonly used SGAs has been classified as substantial for olanzapine and clozapine, intermediate for quetiapine and risperidone, and neutral to low for aripiprazole, lurasidone, and ziprasidone.13 A patient’s past experience with antipsychotics, particularly tolerability issues, should be considered before prescribing a particular treatment.9 Study results have shown that patients prefer efficacious antipsychotics with less risk of weight gain and hyperglycemia.14

Comparative Effectiveness Study Challenges

Patient preferences, adherence, real-world dosing, and other factors can affect the efficacy of treatment in usual clinical care and potentially limit the generalizability of clinical trial results to real-world effectiveness.

When designing comparative effectiveness studies using real-world data, the Agency for Healthcare Research and Quality (AHRQ) recommends, “When appropriate and possible, comparisons should be made for exposure and comparison groups at various clinically equivalent dose levels.”15 Studying medication effects across different dosage strengths is an important consideration when designing head-to-head clinical trials16-18; however, it is often ignored in studies using real-world data where treatment effects are studied without considering the consequences of dosage strength. Comparisons between medications used at different doses could make a lower-dosed medication appear more tolerable and a higher-dosed medication appear more efficacious. In addition, comparisons among different dose levels could result in confounding by severity, as higher doses are more likely to be given to patients with greater disease severity.15

An additional challenge for comparative effectiveness research in schizophrenia is the high frequency of antipsychotic treatment switching. As such, an intent-to-treat (ITT) analysis of antipsychotic treatment in real-world clinical practice is often inappropriate. Many comparative effectiveness studies using administrative claims have used an ITT approach,19-23 in which patients are classified according to their first prescribed antipsychotic, and outcomes are observed regardless of whether patients discontinue or switch to a different antipsychotic treatment. However, in clinical trials using ITT, adherence to the treatment protocol is closely monitored and data are no longer collected from a patient if treatment is discontinued.

To address these challenges in real-world studies, some investigators have used treatment episodes, rather than patients, as the unit of analysis.24-26 Recent studies have gone a step further and used marginal structural models (MSMs),27-29 which account for treatment switching, incorporate time-varying covariates, and appear to more accurately estimate causal treatment effects.30 Marginal structural modeling is a multistep analytic procedure which uses weighted repeated measures and takes into consideration time-varying treatment effects. To accomplish this, weights are calculated and assigned to each observation to balance background characteristics across treatment groups. Consistent estimates of treatment effects can be generated.31

The objective of this study was to compare the risk of hospitalization among patients with schizophrenia treated with equivalent doses of lurasidone versus aripiprazole, olanzapine, quetiapine, or risperidone using an MSM that accounted for changes in treatment and covariates over time.


Study Design and Database

This retrospective database study used administrative claims data from the IBM MarketScan Commercial Claims and Encounters Database, MarketScan Medicare Supplemental and Coordination of Benefits Database, and Multi-State Medicaid Database.32 The databases contained adjudicated inpatient, outpatient, and pharmacy claims data that were deidentified per the Health Insurance Portability and Accountability Act of 1996.32,33 For this study, all the administrative claims were dated between January 1, 2011, and June 30, 2017.

Patient Inclusion/Exclusion Criteria

All patients were required to have at least 1 diagnosis of schizophrenia (International Classification of Disease, 9th Revision, Clinical Modification [ICD-9-CM]: 295.x; or ICD-10-CM: F20.x; for both, x can be any value). Patients were also required to initiate an oral SGA (lurasidone, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, paliperidone, olanzapine, quetiapine, risperidone, or ziprasidone) or an oral FGA (chlorpromazine, fluphenazine, haloperidol, loxapine, prochlorperazine, perphenazine, pimozide, thioridazine, thiothixene, or trifluoperazine) following their first diagnosis for schizophrenia. Patients were required to be at least 18 years of age on the index date, defined as the date of the first antipsychotic prescription. Continuous enrollment in a health plan with medical and pharmacy benefits was required for 360 days before (preindex period) and after (postindex period) the index date. Finally, patients could not have been treated with any antipsychotics during the preindex period.

Treatment Categorization

This study compared hospitalization rates among patients treated with monotherapy lurasidone versus aripiprazole, olanzapine, quetiapine, or risperidone. These 5 SGAs were the focus because they were the most commonly used, accounting for more than 75% of all antipsychotic monotherapy use in our dataset. The daily dose associated with each antipsychotic claim was estimated by multiplying the dose strength (in milligrams) with the quantity of tablets or capsules supplied, then dividing by the estimated number of days the quantity should last (days supplied). In the primary analysis, dosing was restricted to a maximum daily dose equivalent to 80 mg of lurasidone.34 The dose of each medication equivalent to 80 mg of lurasidone was determined using published estimates of doses equivalent to 100 mg of chlorpromazine.34 The rationale for using lurasidone 80 mg per day as a threshold of dose equivalence was based on its inclusion in the initially approved dose range for schizophrenia and as the most common dose used in real-world settings. Lurasidone was initially approved in 2010 with a recommended dose range of 40 mg to 80 mg in adult patients with schizophrenia; this dose was updated to 40 mg to 160 mg in 2013.35 In clinical practice, the majority of adult patients with schizophrenia are treated with 40 mg to 80 mg of lurasidone.26,36 The median daily dose is reported for each antipsychotic with and without this dose-equivalence requirement in Table 1.

The 360-day postindex period was divided into twelve 30-day intervals (“months”), such that each patient contributed 12 patient-months to our dataset. Monotherapy was defined as treatment for at least 75% of days (≥22 days) with a single antipsychotic during a 30-day interval. The comparison groups included monotherapy lurasidone, aripiprazole, olanzapine, quetiapine, or risperidone, at a dose equivalent to 80 mg per day or less of lurasidone. Patient-months that did not meet these criteria were classified as “other.” The “other” group was included because the statistical model (described below) required all patient-months to be classified and could include combination therapy, monotherapy with FGAs or SGAs other than those listed above, monotherapy with equivalent doses above 80 mg per day of lurasidone, and no antipsychotic treatment.

A sensitivity analysis that did not involve dose-equivalence comparison was conducted. In this analysis, lurasidone, aripiprazole, olanzapine, quetiapine, and risperidone monotherapy patient-months were classified as such, regardless of the daily dose. Patient-months classified as “other” in this analysis included the same treatments as in the primary analysis, with the exception of monotherapy doses above 80 mg per day of lurasidone.

Outcome Variables

All-cause hospitalizations were identified using any hospital claim, regardless of associated diagnostic codes. Schizophrenia-related hospitalizations were those in which the hospital claim contained a diagnosis of schizophrenia (ICD-9-CM: 295.x or ICD-10-CM: F20.x) in any position. Rates of all-cause and schizophrenia-related hospitalization associated with lurasidone monotherapy patient-months were compared with rates of all-cause and schizophrenia-related hospitalization associated with aripiprazole, olanzapine, quetiapine, and risperidone monotherapy patient-months.

Statistical Methods

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