- Newer Antipsychotics Compared to Older Antipsychotics
Several economic models suggest that, despite their higher medication costs, risperidone, olanzapine, and clozapine may be more cost-effective than older antipsychotics (e.g., haloperidol) in the treatment of schizophrenia.
Palmer, et al constructed a five-year Markov model to compare the cost of treatment of schizophrenia in the U.S. using olanzapine, haloperidol, or risperidone.94 Results were normalized to 1995 U.S. dollars. For the five-year period of the model, patients treated with olanzapine experienced 6-7 months more time in a disability-free state (Brief Psychiatric Rating Scale (BPRS) score <18) than those treated with haloperidol. The total direct medical costs of treating patients with olanzapine over the five-year period were $1,539 less than for haloperidol and $1,875 less than for risperidone. Patients treated with olanzapine first-line showed a 1.6% reduction in total costs versus haloperidol. Cost savings were due to reduced hospitalization rates, relapse rates and lower suicide rates.
The analysis was robust for variations in the discount rate, the rate and/or costs of suicide attempts, frequency duration and/or cost of hospitalization and/or other medical resource utilization estimates. However, the model was sensitive to drug dosages of olanzapine and risperidone and a decrease in length of stay. Risperidone becomes more cost-effective than olanzapine when the dosages are lowered and raised, respectively. Olanzapine is no longer cost saving when the initial duration of hospitalization is halved. As a result, the model has been criticized for using a dose of olanzapine (10 mg/day) that is lower than generally used in clinical practice, while using a dose of risperidone (6 mg/day) that is much higher than generally used. Furthermore, the high risperidone dosages may aggravate side effects (e.g., extrapyramidal syndrome (EPS)) and limit the real world effectiveness of risperidone in the simulation.
This model was populated using probability estimates obtained from a one-year international comparative trial of olanzapine (10mg/day) versus haloperidol (15mg/day) and a 28-week comparative trial of olanzapine (10mg/day) versus risperidone (6mg/day).41,95 Additional inputs to this model were obtained from the medical literature and an international advisory panel of psychiatrists and health economists. This expert opinion was used to extrapolate clinical data from 1 year or 28 weeks to the 5-year timeline--one of the major limitations of this model. The model examined the cost of treating patients experiencing multiple schizophrenia episodes, while excluding treatment-resistant patients or those experiencing a first-break episode.
A recent historical comparator pilot study by Galvin examined the medical records of 37 patients with schizophrenia, schizoaffective disorder or bipolar disorder one year before and one year after treatment with atypical agents (risperidone and clozapine).96 Based upon patients' detailed medical records, the study estimates an annual total cost savings of $3000 per patient in the community mental health setting when treatment is moved to an atypical agent. There are several limitations inherent to this small-scale community-based study. For example, the entry criteria may have introduced a selection bias by excluding clients who were most intolerant or least responsive to older antipsychotic medications and could not continue their use for one year. Although the study was small, uncontrolled, and retrospective in design, its focus on the community mental health setting is more naturalistic than large-scale clinical trials and set an important example for future research.
- Risperidone Compared to Haloperidol
The pharmacoeconomic evidence of risperidone versus typical antipsychotics indicates that the costs incurred for treatment with risperidone approximately equal those incurred for treatment with haloperidol. Results from these studies suggest that risperidone, despite its higher acquisition cost, does not significantly increase overall treatment costs compared to conventional antipsychotics and is at least as effective. However, several considerations raised by Zito suggest that experimental design and reporting of data from the large multi-center trials of risperidone compared to haloperidol favored clinical and economic outcomes for the atypical agent.50 On the other hand, economic analyses that assume equal compliance rates or effectiveness for risperidone and haloperidol may underestimate potential cost savings with risperidone.97,98
Janssen Pharmaceuticals, the manufacturer of risperidone, is currently sponsoring a multicenter, randomized clinical trial across 21 investigative sites in the U.S. The trial, named the Risperidone Outcomes Study of Effectiveness (ROSE), compares treatment with risperidone to 13 conventional agents in patients with schizophrenia or schizoaffective disorder. The trial examines clinical, quality of life, and economic outcomes in a typical U.S. clinical practice setting. Clinical outcomes include changes in psychiatric symptoms, side effects, health-related quality of life, drug satisfaction, therapy switching, rehospitalization for relapse and use of psychiatric services. Economic outcomes focus on the costs of mental health-specific care. 99
In 1997, Mahmoud et al. presented a cost analysis of the ROSE trial at the 36th Annual Meeting of the American College of Neuropsychopharmacology. Estimates of national average costs were used to calculate mean costs per patient. The intent-to-treat analysis favored conventional agents over risperidone in total, acute care, outpatient and medication costs. Intent-to-treat analyses included patients having prolonged drug-free periods, polypharmacy, or crossing over to receive alternative treatment; patients who remained in the treatment arm (50% of those randomized to risperidone and 61% of those randomized to conventional agents) may have received multiple or concurrent antipsychotic agents.100 Total costs for treatment with risperidone were $1,963 higher than for treatment with conventional agents, but the results were not judged to be statistically significant. When patients switching therapies were excluded from analysis yields, risperidone was cost saving compared to conventional agents in total, acute care and outpatient treatment costs. Although the total costs differed between the types of analysis, mean positive and negative scores on the PANSS showed greater improvement at one year with risperidone than with conventional agents in both types of analyses. Further publication of trial data was not found at the time of this study.
Davies et al. developed a robust decision-analytic model to compare treatment with risperidone or haloperidol over a two-year period in patients with chronic schizophrenia.101 The authors constructed a decision tree that considered ten possible clinical scenarios. The expected cost per favorable outcome was $11,395 (1993 Australian dollars) less for risperidone than haloperidol over the two year period (cost per patient treated was $2,783 less for risperidone than haloperidol). Direct costs included cost of drugs, general practitioner visits, psychiatrist visits, hospitalization, social worker consultations, lab tests and hotel accommodation. Probability estimates (e.g., efficacy, tolerability, and drop-out rate) were derived from meta-analysis of clinical trials and expert opinion. The model was robust to sensitivity analysis and the break-even point for treatments to be of equal cost was an 11.8% difference in effectiveness. Using baseline assumptions, risperidone was found to be 20% more effective than haloperidol. It should be noted that costs, reported in Australian dollars, may not necessarily be applicable to the U.S. setting.
Glazer & Ereshefsky developed a US-based decision-analytic model which is less robust than the one described above.98The model estimated which of three possible treatment paths would have the lowest total direct costs during the first year after discharge from a hospital for a 29-year old male with a history of relapse and rehospitalization for schizophrenia. While compliance rates were varied for each of the three treatment options (65% for risperidone 6mg/day, 50% for oral haloperidol 15mg/day, and 80% for depot haloperidol decanoate, 150 mg/month), clinical outcomes probabilities were assumed the same for each treatment. Total direct treatment costs were less for depot haloperidol decanoate than for continuing oral haloperidol, and both were less than for treatment with risperidone. Sensitivity analysis showed that when the compliance rates for risperidone were increased to 80% and assuming 25% discount on the cost of medication, total one-year direct costs with risperidone were $1,862 less than with oral haloperidol and $705 less than haloperidol decanoate.
We have reviewed 11 historical comparator studies which examine the costs of treatment one year before and one to two years after treatment with risperidone. The pretreatment costs may have included treatment with haloperidol or other typical antipscyhotic agents. Costs were obtained from regional medical claims databases or unspecified sources. In most cases (5 of 7 ITT analyses82,10284-86,88,103 and 4 of 4 completer analyses84,89,93,104,105) risperidone resulted in overall cost savings (range, $308 to $2596 in U.S., 1993-1997 dollars). The historical comparator studies that used intent-to-treat analyses (i.e., including cross-over and treatment-resistant patients, etc.) found that the reduction in costs with risperidone was generally smaller than that observed in studies that included only treatment successes. Furthermore, these studies generally find that savings are more significant in the second year of therapy (cost savings may approach 50%), suggesting that long-term comparative economic studies are needed to demonstrate the true cost-effectiveness of antipsychotic treatment.
Only two of the historical comparator studies found that treatment with risperidone increased total costs over treatment with haloperidol when crossover patients were included.84,88 However, in neither of these cases, did treatment costs increase by more than 3%. That one of these studies found inpatient costs to be 10% higher after treatment is misleading.54 In this study, inpatient costs included all inpatient care in hospitals, skilled nursing facilities, psychiatric facilities and department of correction facilities. After initiation of risperidone, acute inpatient care costs actually decreased, while other inpatient costs increased. Furthermore, in both of these studies, there was a very low rate of acute inpatient care before initiation of treatment. Therefore, substantial cost savings could not be achieved.54
A more recent retrospective study conducted by Schiller et al. compared treatment with risperidone to conventional therapies in a community mental health setting.106 This study used a quasiexperimental mixed-model analysis and obtained outcomes and service utilization data from outpatient charts and databases. Results found no difference in clinical outcomes, measured by Global Assessment of Functioning (GAF) scores, but a trend towards higher total costs for risperidone. The $370 increase in total costs with risperidone was attributed mainly to higher medication costs and medication-related outpatient visits, but only the difference in medication costs was statistically significant. Mental health service costs and lab costs were obtained from county year-end (1994) cost reports of San Francisco community mental health services. Medication costs were average wholesale prices. One limitation of this study is the comparability of the two groups. The risperidone group was selected based upon a change in medication, whereas the comparison group was not. The authors note that a higher service utilization in the risperidone group in the pre-risperidone period may have produced possible selection bias. The authors suggest that given the possible selection bias, restricting use of risperidone based upon an increase in costs is not justified.
Nightengale (1995) conducted a small naturalistic retrospective cohort study which estimated the monthly costs for risperidone (n=28) compared to haloperidol (n=24) inpatients with schizophrenia, schizoaffective disorder or major depression with psychotic features. 97 The study found no significant differences in length of follow-up, length of stay, or hospitalization rates between the two treatment groups. The haloperidol cohort used significantly fewer physician services than did the risperidone cohort (every 127 days versus every 75 days). However, haloperidol patients were more likely to be admitted to day hospitals. Although the difference in monthly costs per patient between the risperidone and haloperidol groups were not judged by the authors to be significant ($1,636 versus $1,759, p=0.04693), the total monthly cost per patient was considerably lower in the risperidone cohort ($123.24 less per patient than haloperidol). Although the setting of care is realistic, the 100% compliance rate assumed by the authors for both medications is not. Considering that compliance with risperidone may be greater than with haloperidol in reality, the study may have underestimated cost savings with risperidone.
- Olanzapine Compared to Haloperidol
Studies comparing olanzapine to haloperidol provide solid evidence that olanzapine is more cost-effective than haloperidol.
Several prospective economic analyses have been conducted as "piggy back" studies to an international comparative trial of olanzapine versus haloperidol.95 This trial enrolled patients with schizophrenia, schizophreniform disorder or schizoaffective disorder were followed during a 6-week acute phase (n=551, olanzapine; n=266, haloperidol) and 46-week maintenance phase (n=270, olanzapine; n=74, haloperidol). Clinical and resource utilization data were collected in 174 clinical centers in 17 countries, 66 of which were in the US. Although prospective studies such as these are ideal, the analyses were limited because economic data were not collected for patients after they withdrew. Several economic models imputed missing values to determine incremental cost-effectiveness. Several of the analyses are published in full94,107-110, while others have only appeared as abstracts or presentations (Dutch and German analyses)111,112 Overall, the prospective analyses indicate that olanzapine is associated with lower total costs than haloperidol and possibly risperidone in moderately to severely ill patients with chronic schizophrenia.
In a basic cost analysis, Hamilton et al. used resource utilization data from an international trial to estimate direct medical costs for those patients who completed treatment with olanzapine or haloperidol.108 Olanzapine showed a trend toward greater efficacy compared to haloperidol in the acute phase based upon the BPRS scale. This trend did not attain statistical significance in the maintenance phase according to BPRS, PANSS and QLS scores. Total costs were significantly lower for olanzapine in the acute phase ($388 lower over 6 weeks) but not in the maintenance phase ($636 lower over 46 weeks). These results are considered conservative because patients who discontinued therapy were not considered. It should be noted that significantly fewer patients treated with haloperidol completed the acute phase of treatment than did patients treated with olanzapine (43% versus 64%).
Subsequently, Obenchain et al. developed a mixed effects linear model to estimate cost-effectiveness of olanzapine compared to haloperidol over the one-year study period of the international trial. 107 The model used homogenous variance components and imputed missing values for patients who discontinued treatment early. Total direct medical expenditures per patient were estimated to be $10,301 lower for patients treated with olanzapine than haloperidol (p<0.0001). Patients taking olanzapine experienced on average 18.3 more symptom-free days than those taking haloperidol (symptom-free = BPRS score <18 on items 0 to 6). The incremental cost-effectiveness ratio estimated annual savings of $563 per symptom-free day gained. Mean annual hospitalization costs were $10,856 less with olanzapine (p=0.007). Bootstrap analysis was highly stable for the finding that olanzapine is associated with greater efficacy and lower costs. However, results were somewhat sensitive to drug costs, which were based upon dosages of 10mg/day for olanzapine and 15mg/day for haloperidol. If recalculated on the basis of the cost of olanzapine at 20 mg/day, the annual savings are reduced to $7,542 per patient.
Two retrospective historical comparator studies compared costs for six months before and after treatment with olanzapine.113,114 Results of both studies showed that total medical costs did not increase (and may have decreased) despite an increase in medication costs. As discussed earlier, these studies have significant limitations including potential selection artifacts and historical bias. 53
- Quetiapine Compared to Usual Care
In light of the previously published, and often poorly designed, cost-effectiveness literature on risperidone and olanzapine, the manufacturers of quetiapine are conducting a well-designed naturalistic comparative pharmacoeconomic trial. Hong et al. have described the design of a multicenter, open-label, randomized, comparative, effectiveness trial for treatment with quetiapine or "usual care" in revolving door patients.115. The primary objective of the trial is to compare the rates ofrehospitalization due to psychiatric, medical, or social consequences of schizophrenia or schizoaffective disorder for revolving door patients treated with quetiapine or usual care. In this study, "usual care" is defined as treatment with any first-line oral or depot antipsychotic -- including atypicals, excluding clozapine -- commercially available at the time of the trial in the United States. (Clozapine is excluded from the study because it is not a first-line antipsychotic and clozapine-treated cohorts are biased towards treatment-resistance and chronicity.) The study will also assess the use of inpatient and outpatient health services, quality of life (SF-36, BASIS-32), and outcomes such as efficacy, safety, compliance, and patient satisfaction. The trial duration is 53 weeks.
The study design for this trial focused on a subpopulation of patients with the greatest potential for cost savings by treatment with quetiapine or usual care. The appropriate minimal threshold for revolving-door status was calculated from hospitalization rates and inpatient payments obtained from MedStat MarketScan databases (1/91-12/92) and Medi-Cal data (7/91-6/93). Analysis of medical claims databases indicated that patients with schizophrenia with an annual hospitalization rate of at least 1.0 (=10% of total sample) generate about 50% of inpatient costs. Therefore the minimal threshold for revolving-door status was defined as 1.0 admission per year. It was estimated that 182 patients would be necessary for each arm of the trial to detect a 15% difference in rehospitalization rates, the value expected to result in significant reduction in hospitalization costs.
Preliminary assessments indicate patients had had two hospitalizations in the past two years, one hospitalization and one admission to a crisis shelter for conditions related to schizophrenia or schizoaffective disorder in the past year, or at least three admissions to a crisis shelter in the past year. Settings included U.S. clinical settings associated with community mental health centers, state psychiatric facilities, private psychiatric hospitals, university hospitals, and VA hospitals. No further publication of these trial results was found at the time of this study.
- Risperidone Compared to Olanzapine
Current inconsistencies regarding the dosages in the risperidone Compared to olanzapine studies render the evidence inconclusive as to which agent is more cost-effective.
Grainger et al. presented preliminary results of a resource utilization and quality of life analysis of the 28-week clinical trial comparing risperidone and olanzapine.116 In the 91 evaluated patients, mean total direct medical costs were $493 lower per patient with olanzapine than risperidone (p<0.01). This figure was statistically significant after controlling for hospitalization status at baseline and length of hospitalization prior to randomization. Mean medication costs were significantly higher for olanzapine than risperidone (+$655). However, mean inpatient and outpatient costs per patient were significantly lower for olanzapine (-$318 and -$829, respectively). These preliminary results must be interpreted with caution, because of the small sample size and because the study is not yet published in full. Furthermore, costs for nonresponders and discontinuers were not assessed beyond the acute treatment phase. Finally, the study has been criticized because it uses doses for risperidone that are higher (6 mg/day) and doses of olanzapine that are lower (10 mg/day) than is customary in clinical practice.53
A more recent short-term comparative study used more realistic dosages for risperidone and olanzapine (4.8 and 12.5 mg/day, respectively). Risperidone was potentially more effective and as safe as olanzapine and it was suggested that treatment costs would be lower with risperidone. 117
- Clozapine Compared to Typical Antipsychotics for Treatment Refractory Schizophrenia
Collectively, the results of the numerous following studies together provide strong evidence of clozapine's superior cost-effectiveness relative to older, typical antipsychotics for treatment-resistant schizophrenia.
Clozapine, the first atypical antipsychotic, has been studied extensively for treatment-resistant schizophrenia. The side effects common to traditional antipsychotics are not found with clozapine (EPS, tardive dyskinesia, etc.). However, the risk of agranulocytosis is greater with clozapine and it is reserved for treatment-refractory cases. Generally the higher acquisition cost with clozapine is offset by a reduction in hospital days. Overall, studies demonstrate that clozapine is no more costly, and more effective than conventional therapy in patients with treatment-resistant schizophrenia.
Rosenheck et al. completed the only prospective, randomized double-blind comparative study evaluating the cost-effectiveness of clozapine (n=205, 552mg/day) versus haloperidol (n=218, 28mg/day).118 Patients were older males with treatment refractory schizophrenia and a history of high inpatient service utilization (30-364 days in previous year). An intent-to-treat analysis showed no significant cost savings associated with treatment with clozapine (total health costs were $2,441 less and societal costs were $2,773 less for clozapine than haloperidol). Outpatient treatment and medication costs were substantially more costly for the clozapine group than for the haloperidol group. These costs were offset by fewer hospital days in the clozapine group (24.3 fewer hospital days). Treatment with clozapine was also associated with significantly better clinical outcomes. The clozapine group showed improvements in PANSS scores relative to the haloperidol group, as well as significantly higher scores on QOL and EPS assessment scales. Overall, clozapine was cost neutral, but more clinically effective than haloperidol. This study was considered to be a more definitive cost-effectiveness analysis than previous studies.
Essock et al. reported results from a prospective randomized open-label study comparing clozapine (n=138, 486mg/day) with standard care (n=89, neuroleptic/psychosocial services).119 Patients were screened in 1991 from Connecticut's State psychiatric hospitals for treatment-resistant schizophrenia (>=2 drug trials) or schizoaffective disorder. The trial lasted two years. Hospitalization (i.e., time to readmission and probability of discharge) was used as a proxy for costs. Preliminary data show decrease in the rate of readmission for those treated with clozapine compared to those treated with typical agents (3% versus 29% at 6 months and 17 versus 41% at 1 year for clozapine versus typical agents). However, the probability of discharge was not significantly better for clozapine than for standard care. BPRS and QOL scores reveal that patients treated with clozapine show significantly reduced side effects and disruptiveness than those treated with conventional antipsychotics. However, clozapine was no more effective than were typical agents in reducing symptoms, improving QOL or probability of life.
Another historical comparator retrospective study compares clozapine (n=133) to conventionals (n=51) one year prior to and two years after therapy in treatment-resistant patients.120 Total costs for the clozapine group were increased in the first year after treatment but decreased in the second year of treatment for both ITT and completer analysis. Cost-reductions were more substantial in completer analysis, but ignoring the cost of drop-outs is misleading.50 The net treatment costs over the three-year period were $1,029 greater for the clozapine group than the neuroleptic group for those patients who completed treatment (for clozapine, n=87 one year before and first year after index date; n=46 in second year). However, assuming a shorter initial hospital stay (14 days), clozapine was found to be more cost-saving (3-year net savings of $15,036).
Another historical comparator study compares the cost of treatment with clozapine (n=86) to conventional therapy (n not stated) five years prior to and one and two years after treatment. Costs and probability estimates were taken from manufacturers' quarterly reports and patient records from a clinical investigation.121 Clozapine patients were participating in a clinical trial in the inpatient setting. Patients receiving conventional therapies were considerably less seriously ill than clozapine patients (which may underestimate the benefit of clozapine). The study found an average cost savings of $20,000 by the second year for patients who completed two years of treatment with clozapine versus patients who were treated with conventional antipsychotics. However, the study did not measure clinical outcomes for the control group. The rehospitalization rate was substantially lower for clozapine versus conventional antipsychotics (27.8% versus 56.2%). Total hospital costs from the five-year period before treatment to one and two years after treatment went from $73,403 to $58,941 to $28,367 with clozapine and $72,121 to $67,934 to $61,518 with conventional therapy, demonstrating substantial cost-savings in the second year.
A small retrospective historical comparator study evaluated clozapine responders with two years of follow-up (n=37) in a university-based ambulatory clinic. Cost data (inpatient and outpatient treatment, housing costs, other costs, and family burden) were available for 47 of the 96 treatment-resistant patients who participated in a clinical study. Outcome measurements were psychopathology, quality of life, global functioning, work function and rehospitalization. Results indicated that a dramatic decrease in the frequency and cost of rehospitalization contributed to a significant decrease in cost of treatment for patients who continued clozapine treatment for at least two years. For the 37 patients who continued clozapine treatment for two years, costs decreased by $22,936 per year per patient. Including drop-outs, there was a savings of $8,702/year/patient. The study is limited by the retrospective collection of cost data, on average three years after the start of treatment with clozapine.122
The results of these numerous studies together provide strong evidence of clozapine's superior cost-effectiveness relative to older, typical antipsychotics in treatment-resistant schizophrenia. Several other uncontrolled historical comparator studies have been conducted on clozapine (Exhibit VII-3).
The retrospective historical comparator studies in Exhibit VII-3 compare one year before and up to 2.5 years after index treatment with clozapine. Overall results showed a decrease in number of patients hospitalized and/or the hospitalization rate. Results varied from cost increases to cost savings. Several studies demonstrate that although total medical costs may initially increase, by the second year of treatment cost savings begin to be realized.
There are many limitations to these studies. For example, few studies include a control group. In addition, completer analyses fail to acknowledge cases which dropped out but incurred high medical costs.50