2012 CADTH Symposium

Using Mixed Treatment Comparisons to

compare Oral Treatments for Pulmonary Arterial

Hypertension and Inform Policy Decisions by a

Public Drug Plan

April 2012

2

Objective of this Presentation

To provide an overview of the novel use of a

CADTH-developed statistical technique to assist

the Non-Insured Drug Benefits (NIHB) Drug Plan

in a formulary listing decision

3

Non-Insured Health Benefits (NIHB)

Who are we? • Part of the First Nations & Inuit Health Branch (FNIHB) of

Health Canada

• Federally funded public health benefits plan for 846,024

eligible First Nations and Inuit across Canada (2010-11)

• NIHB covers a range of prescription and over-the-counter

drugs, dental treatments, medical supplies and equipment

and medical transportation to First Nations and Inuit when

not otherwise insured

• $1.03B in expenditures in FY2010/11

• Participating member of CDR and a member of DPAC,

FWG, OUWG & PDF

4

Pulmonary Arterial Hypertension (PAH)

• Life-threatening, progressive condition with poor

prognosis if left unmanaged

• Decreased blood flow in pulmonary circulation

resulting in increased Pulmonary Vascular

Resistance leading to right heart failure and

ultimately death

• Can be idiopathic (rarely) or secondary to systemic

conditions (such as connective tissue disease,

congenital heart disease, lupus or drug-induced)

• More common in females than males (1.7-3.5 to 1)

with a mean age of diagnosis of 36

5

Classification of PAH Severity

Rubin LJ. ACCP Evidence-Based

Clinical Practice Guidelines.

Introduction. Chest. 2004;126:7S-10S.

6

Treatment Algorithm for PAH

Vasodilator challenge (CCB, prostacyclin, or

adenosine)

Treatment options

• PDE-5 Inhibitors (oral)

• ETRAs (oral)

• prostaglandin analogs

(IV/SC)

Heart or

Heart-Lung transplant

Research Area

Calcium Channel

Blocker (CCB)

7

8

Comparison of PAH therapies

PAH drug

NIHB

Listing

Status*

Approved Daily

Dose Annual Cost (Approx.)

PDE-5 Inhibitors

Sildenafil (Revatio) Exception

20mg 3x a day $11,000-$13,000 (name brand)

$7,000-9,000 (generic)

Tadalafil (Adcirca) 40mg daily $8,700-$11,000

Endothelin receptor antagonists (ETRA)

Bosentan (Tracleer) Exception

125mg 2x a day $47,000-$52,000

Ambrisentan (Volibris) 10mg daily $43,800-51,500

Prostacyclin analogues

Epoprostenol (Flolan)

Exception

Varies based on

patient weight

and drug delivery

rate (ng/kg/min)

$35,000-$70,000 (depending

on dose) Treprostenil (Remodulin)

Iloprost (N/A in Canada)

*Prior to recent listing decision

on oral agents

9

PAH Treatment Guidelines

UK/Ireland

(2008)

Stable WHO Class II/III vs Unstable WHO Class IV

•Class II/III: bosentan or prostenoids (prostacyclin analogues)

•Class IV: epoprostenol only

European

Society of

Cardiology

(2009)

WHO Class II vs Class III vs Class IV

•Class II: sildenafil OR bosentan/ambrisentan

•Class III: sildenafil OR bosentan/ambrisentan OR epoprostenol

•Class IV: epoprostenol only

American

College of

Cardiology /

American Heart

Association

(2009)

Lower risk (WHO II/III) vs Higher risk (WHO IV)

•Lower risk: 1st line – PDE-5 inhibitors OR ETRAs

2nd line – Epoprostenol OR Treprostenil

•Higher risk: 1st line – Epoprostenol OR Treprostenil

2nd line – PDE-5 Inhibitors OR ETRAs

10

Research / Policy Question

• What is the optimal treatment strategy for

patients with PAH based on clinical status,

efficacy, safety and comparative cost?

Part 1: Patients with NYHA Class 2-3 or WHO Class II/III PAH treated

with PDE-5 inhibitor/ETRA (oral)

Part 2: Patients with NYHA Class 3-4 or WHO Class III/IV PAH treated

with prostacyclin analogues (IV/SC)

11

Drug Expert Committee Recommendation Date

Sildenafil

(Revatio®)

CEDAC: List similar to bosentan for

WHO Class III

Feb

2007

Tadalafil

(Adcirca®)

CEDAC: List similar to sildenafil if cost

remains comparable

July

2010

Bosentan

(Tracleer®)

NIHB P&T: Do not list, review on a case-

by-case basis

Mar

2002

Ambrisentan

(Volibris®)

CEDAC: List for at least WHO class III

after failing or if contraindicated to

sildenafil

Feb

2009

Previous Committee Recommendations

12

Which outcome to compare between trials?

Outcomes measure Pros/Cons

Improved quality of life and

prolonged survival.

• Best possible outcome to evaluate benefit

• Rarely reported due to short duration of pivotal

DB RCTs (12-16 wks)

Improvement in dyspnea

symptoms (∆ in NYHA/WHO)

• Clinical measure of symptom improvement

• Secondary outcomes of pivotal DB, RCTs

Prevention (or reversal) of the

progression of disease

leading to ↓ hospitalization

and ↓ need for lung or heart-

lung transplantation

• Clinical measure of symptom improvement

• Secondary outcomes of pivotal DB, RCTs

↑ in Functional Capacity via

exercise endurance. Distance

walked in 6 minutes (6-MWD)

• Surrogate outcome of improvement and survival

• Used as primary outcome in all pivotal DB, RCTs.

• Commonly used due to ease of administration

and objective nature of measurement

13

• Mixed Treatment Comparisons (MTC, Indirect Treatment

Comparisons, Network Meta-Analysis) are meta-analytic

methods for comparing the effectiveness of various

treatments where studies directly comparing the

treatments do not exist

Mixed Treatment Comparisons (MTC)

B

C A

For instance, with three

treatments (A, B & C), if

there were similar studies

comparing A & B and B & C

but none comparing A & C,

MTC could be used to

compare treatments A & C

MTC

Existing

Studies

Existing

Studies

14

PAH Network Pattern

Placebo

Sildenafil 20mg

Tadalafil 40mg

Bosentan 125mg

Ambrisentan 10mg

15

Methodology

• Searches were conducted to identify RCTs evaluating oral

treatments for PAH. 10 studies were identified

• Data were extracted from each journal articles separately by

HC staff (AP & HB), resolving any differences afterwards

• Two studies excluded as they were for sitaxsentan (Thelin),

which was discontinued in 2011

• Study characteristics (population, duration, etc.) were

compared to see if studies were similar enough to apply MTC

methodology

• One study was excluded from the analysis as it was found to be

an outlier in terms of study characteristics

16

Methodology (2)

• MTC was applied to outcome data for included studies using WinBUGS code supplied by CADTH for comparing a continuous outcome across studies with either arm-level or trial-level data and random effects

• Automatically generated initial values were used, convergence was near instant over 3 chains with a large number of repetitions run

• Mean differences were compared to test for differences in treatment effects for the approved strength of each drug

• A sensitivity analysis was conducted by trying a few different options for the analysis (including the EARLY trial, only using arms for approved strengths, etc.) to see if that affected the results (no change)

Drug Study Vs. n % Female Mean Age PAH Class Duration

Sildenafil Galiè 2005 Placebo 278 70%-81% 47-51 55% Type 3 12 wks

Tadalafil Galiè 2009 Placebo 405 75%-84% 53-55 65% Type 3 16 wks

Bosentan Channick

2001

Placebo 32 81%-100% 47-52 100% Type 3 12 wks

Rubin 2002 Placebo 213 77%-81% 47-50 90% Type 3 12 wks

Galiè 2008

(EARLY)

Placebo 177 63%-76% 44-45 100% Type 2 24 wks

Galiè 2006 Placebo 54 59%-62% 37-44 100% Type 3 16 wks

Ambrisentan Galiè 2008

(ARIES 1)

Placebo 202 79%-88% 48-53 55% Type 3 12 wks

ARIES 2 Placebo 192 68%-81% 50-52 50% Type 3 12 wks

Study Characteristics

Excluded

(Study Characteristics)

18

Is using MTC justified?

• All RCTs were DB placebo-controlled: no comparative

trials

• 6-MWD same objective measure used as primary

outcome in all RCTs (secondary in one RCT)

• RCTs all similar in duration: 12-16 weeks

• Similar patients in DB RCTs: Similar age/sex distribution,

class 2-3 idiopathic (primary) or secondary to conditions

such as connective tissue disease, HIV, or congenital

diseases

19

Results: All Strengths, 6-MWD (m gained)

-20

-10

0

10

20

30

40

50

60

70

80

20mg 40mg 80mg 2.5mg 10mg 20mg 40mg 125mg250mg 2.5mg 5mg 10mg

Sildenafil Tadalafil Bosentan AmbrisentanMet

res

Gai

ned

in 6

-Min

ute

Wal

k Te

st (

vs. P

lace

bo

) w

ith

95

% C

on

fid

ence

Itn

erva

l

Multiple Treatment Comparisons: Pulmonary Arterial Hypertension

20

Results: Approved Doses Only, 6-MWD (m gained)

0

10

20

30

40

50

60

70

80

Sildenafil Tadalafil Bosentan Ambrisentan

20mg 40mg 125mg 10mg

Met

res

Gai

ned

in 6

-Min

ute

Wal

k Te

st (

vs. P

lace

bo

) w

ith

95

% C

on

fid

ence

Itn

erva

l

Multiple Treatment Comparisons: PAH Therapies - Approved Doses Only*

21

Mean Differences in 6-MWD (m gained)

Treatment vs Point Estimate* 95% Confidence Interval (CI)**

Tadalafil 40mg

Sildenafil 20mg -12.0 -38.3 14.5

Bosentan 125mg

Sildenafil 20mg 7.2 -14.7 29.4

Ambrisentan 10mg

Sildenafil 20mg 5.8 -24.4 35.8

Bosentan 125mg

Tadalafil 40mg 19.1 -2.2 40.8

Ambrisentan 10mg

Tadalafil 40mg 17.8 -11.7 47.2

Ambrisentan 10mg

Bosentan 125mg -1.4 -27.1 24.4

*Positive = First treatment “better”

**All 95% CIs contain 0, so no

differences are statistically signficant

22

Results

• No evidence of a significant difference between any

of the approved doses of the examined treatments for

PAH

• Results were presented to the NIHB Pharmacy &

Therapeutics Committee as part of the review of oral

treatments for PAH

• Noting the caveat that MTC is just one more tool in the

comparison of different treatments; a complete review

cannot rely only on MTC, but also on reviewing evidence,

safety data and cost comparisons

23

PDE-5 Inhibitors: sildenafil/tadalafil : List with Criteria

List for patients with WHO class III PAH, either idiopathic or associated with

connective tissue disease and confirmed by right heart catheterization, who have

failed to respond to calcium channel blockers (CCBs) and/or other supportive

measures or are non-vasoreactive to CCBs or have contraindications to these

agents

ETRAs: bosentan/ambrisentan: List with Criteria (after sildenafil or tadalafil)

List for patients with WHO class III PAH, either idiopathic or associated with

connective tissue disease and confirmed by right heart catheterization, who have

failed to respond to sildenafil OR tadalafil or have contraindications to

sildenafil OR tadalafil

P&T Committee Recommendations – Oct 2011

24

Conclusion

• Mixed Treatment Comparison (MTC) methods are

useful tools in class reviews where head-to-head

studies have not been conducted but the studies

available measured the same outcome and have

similar enough study characteristics

• In the analysis of oral drugs for PAH, MTC analysis

showed no evidence of a difference in treatment

effects between drugs. This result was highly

valuable to NIHB’s drug review process

25

Recommendations to CADTH

• Next area of research could be expanding MTC to

adjust for differences in individual study

characteristics (“Bayesian Network Meta-

Regression”?)

• Fully-commented code (complete descriptions of

functions, input data structures, etc.) will make code

easier for other agencies to use

26

References

1. NIHB Annual Report 2010/2011, Program Analysis Division, First Nations & Inuit Health Branch, Health Canada

2. Wells GA, Sultan SA, Chen L, Khan M, Coyle D. Indirect Evidence: Indirect Treatment Comparisons in Meta-

Analysis. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2009.

3. National Pulmonary Hypertension Centers of the UK/Ireland

4. American College of Cardiology/ American Heart Association (ACC/AHA)

5. European Society of Cardiology (ESC)

6. Galié N, Ghofrani HA, Torbicki et al. Sildenafil citrate therapy for pulmonary arterial hypertension. NEJM

2005;353(20):2148-57

7. Galié N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation

2009;119: 2894-2903

8. Channick RN, Simmoneau G, Sitbon O et al. Effects of the dual endothelin-receptor antiagonist bosentan in

patients with pulmonary hypertension: a randomized placebo-controlled study. Lancet 2001; 358: 1119-23

9. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. NEJM

2002;346:896-903

10. Galié N, Beghetti M, Gatzoulis MA et al. Bosentan therapy in patient with Eisenmenger Syndrome. Circulation

2006; 114:48-54

11. Galié N, Rubin LJ, Hoeper MM et al. Treatment of patients with mildly symptomatic pulmonary arterial

hypertension with bosentan (EARLY study): a double-blind, randomized trial. Lancet 2008; 371:2093-2100

12. Galié N, Olschewski H, Ouditz RJ et al. Ambrisentan for the Treatment of Pulmonary Arterial Hypertension:

Rsults of the ambrisentan in pulmonary arterial hypertension randomized, double-blind, placebo-controlled,

multicenter, efficacy (ARIES) study 1 and 2. Circulation 2008; 117:3010-9

27

Comment & Questions