treatment demand and drug related deaths: results and hints from the vedette study patrizia schifano...

Treatment demand and drug related deaths:

results and hints from the VEdeTTE study

Patrizia SchifanoEMCDDA - 2006 Annual expert

meeting

Lisbon

ObjectivesObjectivesObjectivesObjectives

the effectviness of treatments

offered in public treatment centers

in preventing overdose mortality

among heroin users in Italy

The VEdeTTE Study has been designed to evaluate

ObjectivesObjectivesObjectivesObjectives

to describe treatment offer

tipologylenghttherapeutic aim

and differences among services

and….

to evaluate retantion in treatment according to type of treatment

and….

Design:Design:Design:Design:

National Multicenter Longitudinal Prospective Study:

Target population: heroin users seeking for treatment, >18 yrs old

115 (out of 554) PTCs (NHS)

Enrollment and follow-up: October 1998 - March 2000

Vital status ascertainment: March 2001

Study population: 10454 subjects

The cohortThe cohortThe cohortThe cohort

86% males 12% new clients Average age: 31 yrs 80% intravenous users 41% had previous overdose episodes 8.2% HIV positive (33.6 MV)

The TreatmentsThe TreatmentsThe TreatmentsThe Treatments

Pharmacological therapies

residential communitysemi-residential communityemergency center

Therapeutic community

psychoterapysupportcounsellingorientation and work fellowship

Psychosocial therapies

methadone detoxification

naltrexonedetoxification with syntomaticnot-substitutive syntomatic

methadone maintenance

The TreatmentsThe TreatmentsThe TreatmentsThe Treatments

Total time in treatment: 10,208 p-yrs (78%)

Total time out of treatment: 2,914 p-yrs (22%)

Median lenght of follow-up: 547 days (99%)

Average number of treatments per person: 3.1

The TreatmentsThe TreatmentsThe TreatmentsThe Treatments

Methadone Maintenance

Detoxification Methadone

Psychosocial Therapies

Other Pharmacological

Ntrt

Nsubjects

Average n per

person

Median

lenght (days)

Therapeutic Community 1830

11311

10684

5931

1876

1.2 192.5

2.3 28.0

1.7 120.06837

4764

1274

1563

3582 1.7

1.5

30.0

32.0

The sequence of treatments: starting with MMT ……………. 

The sequence of treatments: starting with MMT ……………. 

2nd treatment %

MMT 6,3

MD 74,7

TC 1,7

Other 12,2

No treatment 5,1

MMT 40,6

MD 12,9

TC 0,9

Other 25,8

No treatment 19,8

concluded(33.2%)

drop-out(20.4%)

MMT

N=4412

MD

N=1718

2nd treatment %

MMT 34,5

MD 34,6

TC 1,7

Other 26,6

No treatment 5,6

MMT 23,1

MD 47,0

TC 1,1

Other 21,5

No treatment 7,3

concluded(66.7%)

drop-out(20.4%)

The sequence of treatments: starting with MD.……………. 

The sequence of treatments: starting with MD.……………. 

Dose

Average: 40.9 mg/dayMedian: 39.7 mg/day

19% of subjects >60mg/day

Methadone Manteinance Methadone Manteinance

Mortality analysisMortality analysis

Study population: 10258

Observed deaths: 189

• 36.8% overdose

• 20.0% AIDS

• 15.8% violent causes

Males

Females

Rate /1000 p-y 95% CI

12.7

8.4

12.0

4.9 – 20.5

4.7 – 12.2

5.4 – 18.6

Mortality analysisMortality analysis

Total

in treatment

out of treatment

SMR 95% CI

3.9

22.8

9.9

5.7 – 7.8

8.6 – 11.4

Mortality analysisMortality analysis

total

16.7-27.4

Mortality and treatmentMortality and treatment

Study period: 18 months Deaths: 100 (53% of the total) Overdose deaths: 41 (59% of the total)

Mortality by overdose and treatment Mortality by overdose and treatment

Hazard Ratio of overdose mortality for heroin users in treatment, VEdeTTE study

Number of deaths

(41) Person-years Rate

1000 p-y Crude RR Adjusted RR* 95% IC

Out of treatment 31 2913.79 10.64 1.00 1.00 In treatment 10 10207.72 0.98 0.09 0.09 0.04 0.19

In treatment Methadone maintenance 7 5751.28 1.22 0.11 0.10 0.04 0.24 Therapeutic Community 0 1188.94 - - - - - Methadone detoxification 1 1495.72 0.67 0.06 0.07 0.01 0.50 Other pharmacological 1 422.59 2.37 0.22 0.37 0.05 2.76 Psychosocial 1 1349.23 0.74 0.07 0.07 0.01 0.55

* Adjusted for age, gender, psychiatric co-morbidity, HIV status, previous non fatal overdose, route of administration, length of use

Mortality by overdose and treatment Mortality by overdose and treatment

Hazard Ratio of overdose mortality for heroin users out of treatment by treatment andby time since last treatment , VEdeTTE study

Number of deaths (41) Person-years Rate 1000

p-y Crude

RR Adjusted

RR* 95% IC

In treatment 10 10207.72 0.98 1 - - Out treat ment 31 2913.79 10.64 10.86 11.11 5.29 23.35

Out of treatment Methadone maintenance 9 997.68 9.02 9.21 8.26 3.27 20.88

Therapeutic Community 5 231.74 21.58 22.02 23.00 7.63 69.31 Methadone detoxification 7 814.06 8.60 8.78 9.35 3.46 25.26 Other pharmacological 7 612.20 11.43 11.67 12.09 4.48 32.60 Psychosocial 3 250.46 11.98 12.23 22.31 5.88 84.58 Time since last treatment (days)

<=30 13 561.44 23.15 23.64 26.57 11.56 61.10 >30 18 2352.36 7.65 7.81 7.29 3.28 16.22

* Adjusted for age, gender, psychiatric co-morbidity, HIV status, previous non fatal overdose, route of administration, length of use

Is no treatment better than a short-period treatment?

Is no treatment better than a short-period treatment?

in treatment out of treatment

2.67 x 10002.67 x 1000 19.26 x 100019.26 x 1000

out of treatment out of treatment

7.7 x 10007.7 x 1000 7.7 x 10007.7 x 1000

1 month

A

B

Is no treatment better than a short-period treatment?

Is no treatment better than a short-period treatment?

Excess of mortality attributable to being in a short-term treatment in a 2-month period

5.52 deaths x 10000 episodes

Summary of resultsSummary of results

High heterogeneity in treatment offer

Apparent PTC’s preference towards abstinence oriented therapies (70% of patients at their first visit)

Methadone Maintenance offered on avearage at lower doses than those known to be effective (40 mg/day)

a range of specialist drug treatments are protective, substantially reducing the risk of drug related overdose during treatment

the risk of death is substantially higher in the month after treatment discharge or drop out;

leading to an excess of 6 deaths per 10,000 treatment episodes lasting less than one month

What to change if designing a new Vedette studyWhat to change if designing a new Vedette study

Necessisity to simplify information collected on treatment

Is there a better way to collect information on treatment?

18 months of follow-up. Is it a too short period? 100 deaths after 18 months, 189 after 30 months.

Do we have to plan longer studies to evaluate treatments correctly?

Tretaments already ongoing at the start of the study are difficult to be analyzed. Who to enroll? How many?

Strenght points of the Vedette studyStrenght points of the Vedette study

Valuable information about effectiveness of treatments for drug-dependance on more than one outcome

An insight of treatment demand and offer

Mortality follow-up. Easy to be updated

It provides the unique possibility of studying the occurance of outcomes

in the “real world” where:Patients are not randomizedTreatments are not optimal

Resources are limited

Results from A STYSTEMATIC REVIEW OF the OBSERVATIONAL STUDIES ON TREATMENT OF OPIOID DEPENDENCE

Results from A STYSTEMATIC REVIEW OF the OBSERVATIONAL STUDIES ON TREATMENT OF OPIOID DEPENDENCE

Review: Observational studies on treatment for opioid dependence and mortality Outcome: Comparison:

any cause mortality in methadone maintenance vs out of methadone maintenance

Study in MMT out MMT RR (random) Weight or sub-category n/N n/N 95% CI %

Davoli, Italy 1998-2001

27/5751 24/998 15.04 0.20 [0.11, 0.34] Caplehorn, Australia 1970-1991 11/1975 36/2279 11.17 0.35 [0.18, 0.69] Fugelstad, Sweden 1986-1993 7/177 33/330 8.60 0.40 [0.18, 0.88] Appel, USA 1966-1976

93/6118 83/2358 28.72 0.43 [0.32, 0.58] Brugal, Spain 1992-1999

119/5400 887/17649 36.46 0.44 [0.36, 0.53]

Total (95% CI) 19421 23614 100.00 0.37 [0.29, 0.48] Total events: 257 (in MMT), 1063 (out MMT) Test for heterogeneity: Chi² = 7.98, df = 4 (P = 0.09), I² = 49.9% Test for overall effect: Z = 7.44 (P < 0.00001)

0.001 0.01 0.1 1 10 100 1000 Favours treatment Favours control

Outcome:

Overdose mortality Comparison in methadone maintenance vs out of methadone maintenance

Study in MMT out MMT RR (random) Weight or sub-category n/N n/N 95% CI %

Davoli, Italy 1998-2001

7/5751 9/998 19.78 0.13 [0.05, 0.36] Appel, USA1966-1976 2/6118 36/2358 17.62 0.02 [0.01, 0.09] Brugal, Spain1992-1999

11/5400 338/17649 21.30 0.11 [0.06, 0.19] Van Ameijdem, The Netherlands 1989-1995 8/1500 7/466 19.67 0.36 [0.13, 0.97] Buster, The Netherlands. 1986-1998 42/18747 26/10983 21.63 0.95 [0.58, 1.54]

Total (95% CI) Total events: 70 (in MMT), 416 (out MMT) Test for heterogeneity: Chi² = 53.93, df = 4 (P < 0.00001), I² = 92.6% Test for overall effect: Z = 2.66 (P = 0.008)

0.001 0.01 0.1 1 10 100 1000 Favours treatment Favours control

Results from A STYSTEMATIC REVIEW OF the OBSERVATIONAL STUDIES ON TREATMENT OF OPIOID DEPENDENCE

Results from A STYSTEMATIC REVIEW OF the OBSERVATIONAL STUDIES ON TREATMENT OF OPIOID DEPENDENCE

What do you need to implement a study similar to Vedette?What do you need to implement a study similar to Vedette?

1 Ministry1 Ministry

2 coordination centres2 coordination centres

10 researchers10 researchers

13 regions13 regions

119 treatment services119 treatment services

+ di 1000 health operators+ di 1000 health operators

+ di 15000 clients+ di 15000 clients

and and

A strong collaboration among the A strong collaboration among the coordination centres and the servicescoordination centres and the services

It contributed to spread the aweraness of the importance of evidence based practice,

and of quantitative evaluation of treatments

CONCLUSIONCONCLUSION

The Vedette study is still ongoing:

Imputing missing treatment to use all the deaths registered at the last vital status ascertainmentContinuing the analysis of the effect of short-period treatmentsUpdating the follow-up of mortalityDesigning a nested case-control study to better understand the determinants of overdose mortalityOngoing follow-up on treatments on a sub-cohort (one region). . . . . . . . . . . . . . . . . . . . . . .

CONCLUSIONCONCLUSION

Do you think it would be

valuable

feasible

to replicate the Vedette study in other European countries?