Presentation on theme: "Scott Stroup, MD, MPH University of North Carolina at Chapel Hill"— Presentation transcript:
1Scott Stroup, MD, MPH University of North Carolina at Chapel Hill Comparative Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia: Findings to Date from the NIMH-CATIE Schizophrenia TrialScott Stroup, MD, MPHUniversity of North Carolina at Chapel Hill
2Research program to evaluate the effectiveness of antipsychotic medications for schizophrenia and Alzheimer’s disease in “real-world” settings
3Determinants of drug effectiveness Staying on the drug is critical EfficacyTolerabilityDecision to stay on the drugClinician InputPatient Input
4The approach to extrapyramidal side effects is a key methodologic issue in comparative studies of first- and second-generation antipsychotic drugs.
5New Antipsychotics vs Haloperidol ‘Pooled’ Data on use of anticholinergics Use of Anticholinergic MedicationOlanzapine pooledr=.35*; n=2694(3 studies)Quetiapine pooledr=.38*; n=758Risperidone pooledr=.12*; n=1938(7 studies)Greater UseLesser UseThe newer atypicals are associated with less EPS than haloperidolr (95% CI)*Statistically significant.Modified from Leucht S, et al. Schizophr Res. 1999;35:51-68.
6Atypical antipsychotics in the treatment of schizophrenia: metaregression analysis (Geddes et al for the National Schizophrenia National (UK) Schizophrenia Guideline Development Group 2000)Result: When the dose was <12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects.Conclusion: There is no clear evidence that atypicals are more effective or better tolerated than conventional antipsychotics. Therefore, conventional antipsychotics should usually be used in the initial treatment of schizophreniaGeddes and colleagues looked at symptoms, side effects, and rate of drop out and came up with the conclusions on the slide.Of course, this conclusion is drawn in the UK, which has a very different health system than the U.S. But when stewardship of public dollars are concerned people seem to take a different view of whether the marginal benefits of atypicals justify the costs and trade-offs required due to potentially huge expenditures.An accompanying editorial from Canada, in a setting where the costs of drugs are paid for through public funds, reported that patients almost always choose atypicals when given the opportunity.Geddes was highly criticized by the drug companies and by some consumer advocates.
7Effectiveness and cost of olanzapine and haloperidol: A randomized clinical trial Rosenheck et al. JAMA 2003All patients assigned haloperidol also received benztropine to minimize EPS.
8Olanzapine vs. Haloperidol; Rosenheck et al, 2003 Figure 2. Symptom outcomes (PANSS total scores) among patients assigned to clozapine or standard antipsychotic treatment , stratified by whether they continued to take clozapine or a standard medication (completers), or crossed over to the other treatment (crossovers).Note: Crossovers from clozapine to standard treatment occurred at months (median 2.5 months). Crossovers from haloperidol to clozapine occurred at months (median 4.8 months).Mixed model analysis: ns
9Mixed model analysis: ns Olz. N:159121108939092Hal. N:150115105948385
10Side Effects of Atypical Antipsychotics: Shift in Risk Perception Prior Safety ConcernsCurrent Safety ConcernsDiabetesNeurologic Side EffectsWeight GainEPS + TDHyperGlycemiaCVDInsulinResistanceSide Effects of Atypical Antipsychotics: Shift in Risk PerceptionWeight GainInsulinResistanceHyper-lipidemiaEPSQTcDyslipidemiaCVDQTcHyper-glycemia
11Chronic Schizophrenia: Key Recommendations of the Schizophrenia Patient Outcomes Research Team (PORT)No clear statement of preference of SGAs over FGAs in acute or maintenance treatmentClozapine the treatment of choice for treatment-refractory positive symptoms; clozapine also recommended for hostility and suicidalityLehman AF et al. Schizophr Bull. 2004;30:
12Rationale for CATIE Published studies have significant limitations: Predominantly short-term studies designed for regulatory approval and labeling languageComparators are either placebo or a single active agent (usually haloperidol)Results have limited generalizability because they lack representative patient samples, clinical settings and treatment conditionsExisting studies do not address critical clinical and policy questionsSponsored by pharmaceutical companiesClinical experience and case reports are not an adequate substitute for dataExisting data largely from studies sponsored by drug companies for regulatory and marketing purposes- these typically focus on short-term efficacy and involve carefully selected patients who have no concurrent medical illnesses or substance use disorders and are conducted in rarified settings, like inpatient research units where medication compliance is ensured, that do not resemble usual practice. In other words, there is little data to inform us about the real-world effectiveness of these trials.
13Practical Clinical Trials Designed to answer questions faced by clinicians and policy makersCompare clinically relevant alternative interventionsInclude a representative population of study participantsConduct studies at representative practice settingsSimulate actual treatment conditionsCollect data on a broad range of health outcomes that are clinically meaningfulTunis et al JAMA 2003, March et al AJP 2005
14How Does a Practical Clinical Trial Differ from a Traditional Clinical Trial? Traditional Clinical TrialsPractical Clinical TrialsPopulationExclusiveInclusiveSettingRecruitment relies on patients coming to academic health centers.Recruitment relies on community practice settings, including private practices and state facilities.DesignTreatment vs. PlaceboTreatment vs. TreatmentDurationWeeksMonthsOutcomeSymptoms (efficacy)Symptoms and Function (effectiveness)Courtesy Tom Insel, MD
16CATIE: Broad Inclusion & Minimal Exclusion Criteria DSM-IV schizophrenia, years oldNot first-episode or treatment resistantConcomitant medications, medical illnesses, substance use disorders allowedConducted at 57 geographically, demographically and organizationally diverse sitesIn order to enroll a broad array of patients representing those who are actually seen in clinics, we developed minimal inclusion and exclusion criteria:Stroup TS et al. Schizophr Bull. 2003;29:15-31.
17Primary Questions Addressed by CATIE Schizophrenia Trial How do the second generation antipsychotics compare with a representative first generation antipsychotic?What is the comparative effectiveness of the second generation antipsychotic drugs?Are the second generation antipsychotics cost-effective?Stroup TS et al. Schizophr Bull. 2003;29:15-31.
18CATIE Schizophrenia Trial: Overview Participants1460 people with schizophreniaTrial durationSubjects participate for 18 monthsDesignPractical trial that is a hybrid of efficacy and effectiveness trial designsStroup TS et al. Schizophr Bull. 2003;29:15-31.
19CATIE Schizophrenia Trial Design Phase 1*ROLANZAPINEQUETIAPINERISPERIDONEZIPRASIDONEPERPHENAZINEDouble-blind, random treatment assignment.Phase 2Phase 3Participants who discontinue Phase 1 choose either the clozapine or the ziprasidone randomization pathwaysParticipants who discontinue Phase 2 choose one of the following open-label treatmentsARIPIPRAZOLECLOZAPINECLOZAPINE(open-label)FLUPHENAZINE DECANOATE1460 patients with SCZComorbidityOther medsROLANZAPINE, QUETIAPINE or RISPERIDONEOLANZAPINEPERPHENAZINEZIPRASIDONEQUETIAPINEROLANZAPINE, QUETIAPINE or RISPERIDONERISPERIDONEZIPRASIDONENo one assigned to same drug as in Phase 12 of the antipsychotics above*Phase 1A: participants with TD (N=231) do not get randomized to perphenazine; phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before eligibility for phase 2.Stroup TS et al. Schizophr Bull. 2003;29:15-31.
21Stroup TS et al. Schizophr Bull. 2003;29:15-31. Secondary OutcomesSymptom measuresSafetyService use and costsNeurocognitionTreatment adherenceComorbidityQuality of LifeSubstance useViolencePsychiatric studies usually have “cumbersome and lengthy follow-up interviews.” We are doing perhaps more of these than is desirable because of our and our funding agency’s desire to use this effort to obtain lots of data and to have available some evidence of our primary outcome’s validity. For efficacy we are using the usual rating scales. We have familiar monthly ratings of side effects and questions about other possible adverse events. We have a neurocognitive battery. We have multiple measures of treatment adherence. And we have a monthly interview about service use that will be used in cost-effectiveness and cost-benefit analyses.Stroup TS et al. Schizophr Bull. 2003;29:15-31.
22CATIE Phase 1: Double-Blinded and Randomized Olanzapine 7.5–30 mg/dayPerphenazine 8–32 mg/day1460 Patientswith SchizophreniaRandomizedQuetiapine 200–800 mg/dayRisperidone 1.5–6 mg/dayZiprasidone 40–160 mg/day *Persons with TD not assigned to perphenazine* Ziprasidone added after 40% sample enrolledStroup TS et al. Schizophr Bull. 2003;29:15-31.
24Prevalence of Metabolic Syndrome in CATIE Schizophrenia Study Participants at Baseline vs. the General Adult Population (NHANES Data)CATIE (N = 689)*NHANES (N = 687)*CATIE = Clinical Antipsychotic Trials in Intervention Effectiveness; NHANES = National Health and Nutrition Examination Survey *P = CATIE vs NHANES.McEvoy et al. Schizophrenia Research 2005
25Substance Use in CATIE Subjects (Alcohol and Illicit Drugs) Source of data: Marvin Swartz, MD; unpublished data.
26Phase I Randomization and Treatment Intent-to-treat (ITT) patients received at least one dose of study medication.Dose and efficacy assessments are reported for the ITT patients. Safety assessments are reported for all randomized patients.
27Time to Discontinuation for Any Reason Overall p-value = 0.004*P<0.001 for olanzapine vs quetiapineP=0.002 for olanzapine vs risperidoneThe Kaplan Meier median is the time by which half of the patients have discontinuedThe hazard ratio for olanzapine vs. quetiapine is 0.63: at any given time, patients on olanzapine are 63% less likely to discontinue treatment compared to patients on quetiapine.The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.
28Time to Discontinuation for Lack of Efficacy Overall p-value < 0.001*P<0.001 for olanzapine vs quetiapine, risperidone and perphenazineThe Kaplan Meier 25th %ile is the time by which 25% of the patients have discontinued. The median can not be estimated due to low event rates.The hazard ratio for olanzapine vs. quetiapine is 0.41: at any given time, patients on olanzapine are 41% less likely to discontinue treatment for lack of efficacy compared to patients on quetiapine.The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.
29Time to Discontinuation for Intolerability Overall p-value = 0.054Kaplan Meier medians and 25th %ile can not be estimated due to low event ratesThe hazard ratio for risperidone vs. olanzapine is 0.62: at any given time, patients on risperidone are 62% less likely to discontinue treatment for intolerability compared to patients on olanzapine. This difference is not significant since the overall p-value was not less than 0.05.The Hazard ratio is from Cox proportional hazards regression, and is the ratio of the probability of discontinuing the phase at any timepoint for one treatment group vs. another.
30Reasons for Discontinuation Due to Intolerability All Randomized Patients Discontinued for Intolerability 15% Weight/Metabolic 4% Extrapyramidal 4% Sedation 2% Other %
31PANSS Total ScoreP=0.001 for time-by-treatment interactionP=0.065 for ziprasidone cohortInteraction of time × treatment indicates significant variation in treatment effects over time. Improvement was initially greatest with olanzapine but its advantage diminished over time. The number of patients declines over assessment times. Least -square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as estimated data for discontinued patients.
32PANSS Positive ScoreP=0.004 for time-by-treatment interactionP=0.346 for ziprasidone cohortInteraction of time × treatment indicates significant variation in treatment effects over time. The number of patients declines over assessment times. Least -square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as estimated data for discontinued patients.
33PANSS Negative ScoreP=0.177 for time-by-treatment interactionP=0.019 for ziprasidone cohortThe number of patients declines over assessment times. Least -square mean estimates are from a mixed model, which assumes that data are missing at random. Values at later time points are based on the observed data for continuing patients as well as estimated data for discontinued patients.
34Hospitalizations for Exacerbation of Schizophrenia
38Laboratory Chemistry: Change from Baseline to Average of Two Highest Values patients were instructed to fast, nonfasting results were not excludedExposure-adjusted means are the estimated mean values that we would see at the average treatment duration across all groups (8.3 months). They are least squares means from an ANCOVA model adjusting for treatment duration.
39Reasons for Discontinuation Due to Intolerability All Randomized Patients FYI: the percentages of patients discontinued for intolerability differ slightly between this slide and the previous one because this slide is based on all randomized patients, and the previous slide is limited to ITT patients who took at least one dose of study medication.
40Key MessagesCATIE provides important new information on antipsychotic drugs that should greatly assist doctors and patients in making individualized treatment choices.Overall, all the medications were comparably effective but were associated with high rates of discontinuation due to intolerable side effects, failure to adequately control symptoms, or other reasons.
41Key MessagesOlanzapine was somewhat more efficacious than the other drugs but also was associated with significant weight gain and metabolic changes.The older medication perphenazine generally performed as well as the newer medications. The older medication was as well tolerated as the newer drugs and was as effective as three of the newer medications. Contrary to expectations, EPS was not seen more frequently with perphenazine than with the newer drugs.
42Key MessagesTreatments for persons with schizophrenia must be individualized. Doctors and patients must carefully evaluate the tradeoffs between efficacy and side effects in choosing an appropriate medication. What works for one person may not work for another.
44Washington Post New Antipsychotic Drugs Criticized Federal Study Finds No Benefit Over Older, Cheaper Drug September 20, 2005; A01New York Times Study Finds Little Advantage in New Schizophrenia Drugs September 20, 2005 F-1The Wall Street Journal Generic Fares Well in Big Psychiatry Study: Newer Costlier Drugs Have Little Advantage for Schizophrenia September 20, 2005 D-1
45Alliance for Human Research Protection 29 July 2005:“Next Phase in Psychiatry? Or, NIMH Effort to Rescue Bad Drugs”20 September 2005:“Federal Study Finds No Benefit of New Antipsychotic Drugs”
46“Psychiatry hasn’t advanced in thirty years!” Schizophrenia Anonymous-Durham is going retro to celebrate HalloweenOn 9/20, the researchers got their treat: the psychiatric patients got the trick.…while saving Medicaid money and adjusting to those vintage neuroleptics, here’s some music to get you in the mood: “Let’s twist again”
47Tom Toles Sketch, Washington Post, September 23, 2005
48FAQs Are the newer medications better than the older ones? Are the newer drugs all the same?Are the older drugs all the same? Do the results with perphenazine apply to the others?
49FAQs Why were the discontinuation rates so high? Were the doses comparable?Was the study long enough to make comparisons regarding tardive dyskinesia?
50FAQs Should everyone be switched to a cheaper drug? Should we keep everything on the formulary?Why not start with the cheapest drugs?
51FAQsDo we know what to do when someone doesn’t do well on one medication?
52CATIE results still to come Cost-effectiveness evaluationPhase 2 studies:Efficacy pathway: clozapine vs. a second atypicalTolerability pathway: ziprasidone vs. a secondNeurocognitionSubstance use, violence