2012 CADTH Symposium. April 2012

Transcription

1 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 2

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 ( ) 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 3

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 ( to 1) with a mean age of diagnosis of 36 4

5 Classification of PAH Severity Rubin LJ. ACCP Evidence-Based Clinical Practice Guidelines. Introduction. Chest. 2004;126:7S-10S. 5

6 Treatment Algorithm for PAH Vasodilator challenge (CCB, prostacyclin, or adenosine) Research Area Treatment options PDE-5 Inhibitors (oral) ETRAs (oral) prostaglandin analogs (IV/SC) Calcium Channel Blocker (CCB) Heart or Heart-Lung transplant 6

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8 PAH drug PDE-5 Inhibitors Sildenafil (Revatio) Comparison of PAH therapies NIHB Listing Status* Exception Approved Daily Dose 20mg 3x a day Annual Cost (Approx.) $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) 125mg 2x a day $47,000-$52,000 Exception Ambrisentan (Volibris) 10mg daily $43,800-51,500 Prostacyclin analogues Epoprostenol (Flolan) Treprostenil (Remodulin) Iloprost (N/A in Canada) Exception Varies based on patient weight and drug delivery rate (ng/kg/min) $35,000-$70,000 (depending on dose) *Prior to recent listing decision on oral agents 8

9 PAH Treatment Guidelines UK/Ireland (2008) European Society of Cardiology (2009) American College of Cardiology / American Heart Association (2009) Stable WHO Class II/III vs Unstable WHO Class IV Class II/III: bosentan or prostenoids (prostacyclin analogues) Class IV: epoprostenol only 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 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 9

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) 10

11 Drug Expert Committee Recommendation Date Sildenafil (Revatio ) Previous Committee Recommendations CEDAC: List similar to bosentan for WHO Class III Feb 2007 Tadalafil (Adcirca ) Bosentan (Tracleer ) Ambrisentan (Volibris ) CEDAC: List similar to sildenafil if cost remains comparable NIHB P&T: Do not list, review on a caseby-case basis CEDAC: List for at least WHO class III after failing or if contraindicated to sildenafil July 2010 Mar 2002 Feb

12 Which outcome to compare between trials? Outcomes measure Improved quality of life and prolonged survival. Improvement in dyspnea symptoms ( in NYHA/WHO) Prevention (or reversal) of the progression of disease leading to hospitalization and need for lung or heartlung transplantation in Functional Capacity via exercise endurance. Distance walked in 6 minutes (6-MWD) Pros/Cons Best possible outcome to evaluate benefit Rarely reported due to short duration of pivotal DB RCTs (12-16 wks) Clinical measure of symptom improvement Secondary outcomes of pivotal DB, RCTs Clinical measure of symptom improvement Secondary outcomes of pivotal DB, RCTs 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 12

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 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 Mixed Treatment Comparisons (MTC) Existing Studies A B MTC Existing Studies C 13

14 PAH Network Pattern Sildenafil 20mg Tadalafil 40mg Placebo Ambrisentan 10mg Bosentan 125mg 14

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 15

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) 16

17 Study Characteristics Drug Study Vs. n % Female Mean Age PAH Class Duration Sildenafil Galiè 2005 Placebo %-81% % Type 3 12 wks Tadalafil Galiè 2009 Placebo %-84% % Type 3 16 wks Bosentan Channick 2001 Placebo 32 81%-100% % Type 3 12 wks Rubin 2002 Placebo %-81% % Type 3 12 wks Galiè 2008 (EARLY) Placebo %-76% % Type 2 24 wks Galiè 2006 Placebo 54 59%-62% % Type 3 16 wks Ambrisentan Galiè 2008 (ARIES 1) Placebo %-88% % Type 3 12 wks ARIES 2 Placebo %-81% % Type 3 12 wks 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: 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 18

19 Metres Gained in 6-Minute Walk Test (vs. Placebo) with 95% Confidence Itnerval 80 Results: All Strengths, 6-MWD (m gained) Multiple Treatment Comparisons: Pulmonary Arterial Hypertension mg 40mg 80mg 2.5mg 10mg 20mg 40mg 125mg250mg 2.5mg 5mg 10mg Sildenafil Tadalafil Bosentan Ambrisentan 19

20 Metres Gained in 6-Minute Walk Test (vs. Placebo) with 95% Confidence Itnerval Results: Approved Doses Only, 6-MWD (m gained) 80 Multiple Treatment Comparisons: PAH Therapies - Approved Doses Only* Sildenafil Tadalafil Bosentan Ambrisentan 20mg 40mg 125mg 10mg 20

21 Mean Differences in 6-MWD (m gained) Treatment vs Point Estimate* 95% Confidence Interval (CI)** Tadalafil 40mg Bosentan 125mg Ambrisentan 10mg Bosentan 125mg Ambrisentan 10mg Ambrisentan 10mg Sildenafil 20mg Sildenafil 20mg Sildenafil 20mg Tadalafil 40mg Tadalafil 40mg Bosentan 125mg *Positive = First treatment better **All 95% CIs contain 0, so no differences are statistically signficant 21

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 22

23 P&T Committee Recommendations Oct 2011 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 23

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 24

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 25

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; 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): Galié N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009;119: 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: Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. NEJM 2002;346: Galié N, Beghetti M, Gatzoulis MA et al. Bosentan therapy in patient with Eisenmenger Syndrome. Circulation 2006; 114: 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: 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:

27 Comment & Questions 27