de-diffusion of medical treatments: atypical antipsychotics the treatment of mental illness robert...

De-diffusion of medical treatments:

Atypical antipsychotics the treatment of mental

illness

Robert Rosenheck MDYale Medical School

Global Antipsychotic Market Achieved $10.2B In Sales in

2003

$0

$2

$4

$6

$8

$10

$12

$14

$16

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2006(est.)

$ B

illions

Source: IMS

Global Antipsychotic Market Sales(MAT Q1 by Yr)

Primary 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.

CATIE Schizophrenia Trial Design

1460 patients with SCZ

ComorbidityOther meds

Participants who discontinue Phase 2 choose one of the

following open-label treatments

•ARIPIPRAZOLE

•FLUPHENAZINE DECANOATE

•PERPHENAZINE

•RISPERIDONE

•OLANZAPINE

•ZIPRASIDONE

•QUETIAPINE

•2 of the antipsychotics above

Phase 3Phase 1*

R

OLANZAPINE

QUETIAPINE

RISPERIDONE

ZIPRASIDONE

PERPHENAZINE

Double-blind, random treatment assignment.

Phase 2

CLOZAPINE(open-label)

OLANZAPINE, QUETIAPINE or RISPERIDONE

OLANZAPINE, QUETIAPINE or RISPERIDONE

ZIPRASIDONE

R

R

No one assigned to same drug as in Phase 1

Participants who discontinue Phase 1 choose either the

clozapine or the ziprasidone randomization pathways

*Phase 1A: participants with TD do not get randomized to perphenazine; phase 1B: participants who fail perphenazine will be randomized to an atypical (olanzapine, quetiapine, or risperidone) before they are eligible for phase 2.

Stroup TS et al. Schizophr Bull. 2003;29:15-31.

•CLOZAPINE

Primary Outcome Measure:All-Cause Treatment Discontinuation

All-Cause Discontinuation

Efficacy Tolerability

Clinician Input Patient Input

0

0.2

0.4

0.6

0.8

1

0 3 6 9 12 15 18

OlanzapinePerphenazine

QuetiapineRisperidone

Ziprasidone

Pro

port

ion

of P

atie

nts

with

ou

t Eve

nt

Time to Discontinuation for Any Cause (mo)

Time to Discontinuation for Any Reason

P<0.001 for olanzapine vs quetiapineP=0.002 for olanzapine vs risperidone

Overall p-value = 0.004*

OLZ (n=330)

QUET (n=329)

RISP (n=333)

PER (n=257)

ZPR (n=183)

Discontinued 210 (64%) 269 (82%) 245 (74%) 192 (75%) 145 (79%)

Kaplan-Meier Median (mos) [95%CI]

9.2 [6.9, 12.1]

4.6 [3.9, 5.5]

4.8 [4.0, 6.1]

5.6 [4.5, 6.3]

3.5 [3.1, 5.4]

Hazard ratios for Olanzapine --- 0.63 < 0.001*

0.75 0.002*

0.78 0.021

0.76 0.028

Treatment-Emergent Adverse Events Assessment

OLZ (n=336)

QUET (n=337)

RISP (n=341)

PER (n=261)

ZPR (n=185)

P-value

Any Serious AE 10% 9% 10% 11% 10% 0.47

Suicide attempt 1% 1% <1% <1% <1% 0.99

Suicide ideation <1% <1% 1% 1% 1% 0.49

Any Moderate or Severe AE by Systematic Inquiry

70% 65% 68% 65% 64% 0.14

Insomnia 16% 18% 24% 25% 30% <0.001

Hypersomnia / Sleepiness 31% 31% 28% 28% 24% 0.18

Urinary Hesitancy / Dry Mouth / Constipation 24% 31% 25% 22% 20% <0.001

Sex Drive/ Sexual Arousal/ Sexual Orgasm 27% 20% 27% 25% 19% 0.59

Gynecomastia / Galactorrhea 2% 2% 4% 2% 3% 0.15

Menstrual Irregularities 12% 6% 18% 11% 14% 0.17

Incontinence / Nocturia 5% 4% 7% 2% 5% 0.04

Sialorrhea 4% 4% 7% 5% 6% 0.20

Orthostatic Faintness 9% 11% 11% 11% 13% 0.08

Skin Rash 7% 6% 6% 3% 5% 0.18

Any Moderate or Severe Spontaneously Reported AE

36% 34% 36% 30% 35% 0.10

Treatment-Emergent Neurologic Effects

Assessment

OLZ (n=336)

QUET (n=337)

RISP (n=341)

PER (n=261)

ZPR (n=185)

P-value

AIMS Severity Index ≥2

(2=mild incapacitation)

14% 13% 16% 17% 14% 0.23

Barnes: Global Clinical Assessment ≥ 3 (3=moderate Akathisia)

5% 5% 7% 7% 9% 0.24

Simpson-Angus: EPS Mean Scale Score ≥ 1

(1=mild or slight symptoms)

8% 4% 8% 6% 4% 0.47

Anticholinergic Agents added 8% 3% 9% 10% 8% 0.01

Weight change from Baseline to Last Observation

Assessment

Statistic

OLZ (n=336)

QUET (n=337)

RISP (n=341)

PER (n=261)

ZPR (n=185)

P-value

Weight Gain > 7% (%) 30% 16% 14% 12% 7% <0.001

Weight: Change (lbs) Mean (S.E.) Median Range

9.4 (0.9) 7

-14, 42

1.1 (0.9) 1

-25, 25

0.8 (0.9) 0

-24, 24

-2.0 (1.1) -1

-29, 22

-1.6 (1.1) -2

-24, 18

<0.001

Weight Change / Treatment Duration (lbs/month)

Mean (S.E.) Median Range

2.0 (0.3) 0.8

-1.4, 9.5

0.5 (0.2) 0.1

-4.4, 6.3

0.4 (0.3) 0.0

-4.6, 5.7

-0.2 (0.2) -0.1

-4.9, 4.0

-0.3 (0.3) -0.3

-5.3, 5.9

<0.001

CATIE Cost Effectiveness Analysis (CEA) Study Design

Comparison of Initiation Strategies (Intent-to-Treat including all follow-up data)

Comparison of “fail first” strategies with different starting agents.

Secondary analysis “on initially assigned treatment” excluded observations after first medication change (as in NEJM paper).

CATIE multi-phase algorithm assured balanced treatment after first discontinuation.

98% received atypicals Balance across atypicals.

CATIE Cost-Effectiveness (2)

EFFECTIVENESS

Methods: Measuring Effectiveness

1) PANSS Total Score: “Gold standard” for symptom comparison: paired comparisons between groups.

2) Primary Outcome Measure: Health State Utility Assessment in Quality Adjusted Life Years [QALYs]: following Gold, 1996.

Measurement is based on the PANSS-based health states and measures of side effects using methods developed by Lenert et al. 2004 (societal preferences);

3) An aggregate health status measure weighted by patient importance ratings (patient preferences);

4) Visual Analogue Scale: subjective patient global rating of overall health from 0 (worst possible health) to 100 (perfect health)

5) Lehman QOL question (How would you rate your life overall (1-7, delighted to terrible).

PANSS TOTAL SCORE (LS Means from Mixed Models

(Adj for site, baseline, exacerbation)

30

40

50

60

70

80

Baseline 1 mo. 3 mo. 6 mo. 9 mo. 12 mo. 15 mo. 18 mo.

PA

NS

S

Olanzapine PerphenazineQuetiapine RisperidoneZiprasidone

Olanzapine<risperidone, quetiapine (with Hochberg adjustment for multiple comparisons)

Quality Adjusted Life Years (LS Means from Mixed Models (Adj for site, baseline, exacerbation)

(all group p<.0001; time p<.0001)

0.00

0.20

0.40

0.60

0.80


QA

LYs


Perphenazine>risperidone (with Hochberg adjustment for multiple comparisons)

Visual Analogue Scale: 0-100 [death - perfect health] (LS Means from Mixed

Models (Adj for site, baseline, exacerbation)(all

group p= ns, time p<.0002)

0

15

30

45

60

75


Mo

nth

ly e

xp

en

dit

ure

s

Olanzapine Perphenazine

Quetiapine Risperidone

Lehman QOLS (1-7: Terrible to Delighted) (LS Means from Mixed

Models (Adj for site, baseline, exacerbation)(all

group p=ns, time p<.01)

1.0

2.0

3.0

4.0

5.0

Baseline 6 mo. 12 mo. 18 mo.

De

ligh

ted

- T

err

ible


Quetiapine Risperidone

Patient Preference Weighted Index (PPWI) (LS Means from Mixed Models (Adj for site,

baseline, exacerbation)(all p=ns, time p<.0001)

-0.4

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

0.4

0.5

Baseline 6 mo. 12 mo. 18 mo.

PP

WI


CATIE Cost-Effectiveness Results (1)

COST

Service Use and Cost Measures

Service Use (Service Use and Resources Form [SURF])

Outpatient Mental health Medical

Inpatient Mental Health Substance Abuse Medical

Nursing home Residential

Medication records Criminal justice, public

support, productivity

Cost Outpatient All residential Inpatient All health care Experimental medications

2003 Medicaid Discount rates and mandated company rebates

VA discount (40%) Sensitivity analysis of price

discounts (as funded vs Medicaid vs. VA).

Ancillary medication (discounted cost to privately insured Market Scan ® patients).

Monthly Costs: All medication costs (experimental drugs and concomitant medications)(actual prices, with

discounts)(mean=$499/month)(ITT)

$0

$100

$200

$300

$400

$500

$600

$700

Baseli

ne

1 mo.

2 mo.

3 mo.

4 mo.

5 mo.

6 mo.

7 mo.

8 mo.

9 mo.

10 m

o.

11 m

o.

12 m

o.

13 m

o.

14 m

o.

15 m

o.

16 m

o.

17 m

o.

18 m

o.

Mo

nth

ly e

xp

en

dit

ure

s

OLANZAPINE PERPHENAZINEQUETIAPINE RISPERIDONEZIPRASIDONE

$200/mo $2,400/yr

Monthly service use: All inpatient days (mental health and medical/surgical)(mean=0.70/month)(ITT)(p=ns)

0

1

2

3

Mo

nth

ly in

pa

tie

nt

da

ys


Monthly Costs: All inpatient (mental health and medical/surgical)costs (mean=$363/month)(ITT)(p=ns)

$0

$500

$1,000

$1,500

$2,000

Mo

nth

ly e

xp

en

dit

ure

s


Quetiapine RisperidoneZiprasidone

Monthly Costs: All outpatient (mental health and

medical/surgical)costs (mean=$372/month)(ITT)(p=ns)

$0

$100

$200

$300

$400

$500

$600

$700

Mo

nth

ly e

xp

en

dit

ure

s


Monthly health costs (IP and OP) excluding medications (mean=$1,047/month)(ITT)(p=ns)

$0

$700

$1,400

$2,100

$2,800

Mo

nth

ly e

xp

en

dit

ure

s


Monthly Costs: All healthcare costs including medications (mean=$1,544/month)(actual drug

prices with discounts)(ITT)(p=P<O,Q,R,P)(APA).

$0

$700

$1,400

$2,100

$2,800

Mo

nth

ly e

xp

en

dit

ure

s


`

Other “no difference” findings Neurocognitive functioning Quality of Life Violent behavior Family burden Employment

Critiques 1) low follow-up rates, 2) “short” study duration to address TD risk, 3) sample characteristics (“too chronic”), 4) the choice of outcome measures (QALYs), 5) exclusion of patients with tardive dyskinesia

from assignment to perphenazine, 6) choice of study drugs and doses, 7) reliance on intention-to-treat analysis, and 8) differences in pre-study treatment 9) doesn’t address latest entrants to the

market.

Tardive Dyskinesia (TD) RiskIncidence vs Health

Outcomes

Six Dimensions of Sensitivity analysis i) severity, ii)duration, iii)treatment with SGAs, iv)QOL, iv)QALYs v) Annual cost

ICERs for TD If ,as per CATIE cost difference is $2,400-

$3,600-$6,000 cost/case of TD yields the following matrix:

Diff in CATIE CATIE TotalEffect low/long-term risperidone

Diff. in Annualized Heatlh Cost vs Perph. $2,400 $6,216Difference in Risk of TD cases 4.6% $52,174 $135,130Assume all cases are severe 0.14 $372,671 $965,217Asssume 2/3 mild (QALY loss= 0.07) 0.093 $561,010 $1,453,015Assume 15% of cases last < 3 months 0.85 $660,012 $1,709,430

Antipsychotic Formulary Policy Revisited

Virtual current policy: only use SGAs Greater cost No greater effectiveness Greater risk of weight gain/metabolic syndrome/

diabetes Less risk of EPS/TD than moderate/high dose

haloperidol, but not intermediate or high potency FGAs (perphenazine, loxitane, thiothixene)

Risperidone, least expensive SGA will be coming off patent and will be even less expensive.

Two Aspects of Formulary Policy

What is the most cost effective sequence of treatments?

How do we create incentives to follow it? No marketing for generics even if

they are SGAs.

Four groups of APS drugs Risperidone or any FGA Clozapine (2 or 3 failures)

Generic available Weight gain risk is of concern and

some patients may not tolerate the required blood monitoring

Aripiprazole, ziprasidone or quetiapine

Olanzapine: greatest weight gain

Monitoring Form Data (N=609): Diagnosis and Treatment

Treatment of: Schizophrenia 19.2% Bipolar disorder 27.6% Other affective 22.8% PTSD 19.7% Other 31.9%

Treatment proposed: Aripirazole 14.6% Olanzapine 19.9% Quetiapine 56.0% Ziprasidone 6.7% Consta 2.6%

Monitoring Form Data (N=609): Reason for new medication Patient preference 28.9% Efficacy 34.8% Sleep 29.7% Less EPS 13.8% Less TD risk 9.7% Less sedation 5.1% Treatment of TD 0.8% Other 24.8%

Monitoring Form Data (N=609):Previous Drugs, Health Status

Failed previous drugs due to lack of efficacy Risp (4.3%), Perph 0.7%) Haloperidol

(2.4%),Aripip (1.3%), Quet (1.6%), Zip (1.3%), Cloz (0.3) Don’t know (26.8)

Failed previous drugs due to intolerability Risp (6.9%), Perph (1.8%), Halop. (2.5%) Aripip

(1.1%), Quet (3.4%), Cloz (0.5%) Age=54.2 Wt=196, Ht = 5’9”, BMI=31.0 AIMS = 0.8 (possible TD=1)

Monitoring Form Data (N=609):Co-Morbidity

TD 4.6% EPS 4.4% Akithesia 3.4% Diabetes 14.6% Hyperlipidemia27.1% Obesity 20.5% Hypertension 34.0%- ASCVD 9.5%

Conclusion The results of the CATIE

schizophrenia trial provide no support for the hypothesis that any second generation antipsychotic is more cost-effective than perphenazine in chronic schizophrenia.

This study has important implications for practice and policy.

de-diffusion of medical treatments: atypical antipsychotics the treatment of mental illness robert...

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