TITLE: Combination Therapy for Pulmonary Arterial Hypertension: A Review of the Clinical Effectiveness

Transcription

1 TITLE: Combination Therapy for Pulmonary Arterial Hypertension: A Review of the Clinical Effectiveness DATE: 01 December 2011 CONTEXT AND POLICY ISSUES Pulmonary arterial hypertension (PAH) is a chronic condition characterized by progressive increase in pulmonary vascular resistance which leads to right heart failure and premature death. 1 The pathology includes pulmonary artery vasoconstriction, smooth muscle cell and endothelial cell proliferation, and pulmonary thrombosis. Symptoms of PAH, such as breathlessness, fatigue, chest pain, fainting and edema, worsen as the disease progresses. 1 PAH may be classified as idiopathic, or familial, or may be associated with the following: connective tissue disease, congenital systemic to pulmonary shunts, portal hypertension, HIV infection, drugs and toxins, or other causes. 1 The management of PAH includes supportive treatments, such as anticoagulants, diuretics, digoxin, calcium channel blockers and oxygen. 1 In patients with more advanced disease, three different classes of medications are available to manage the pulmonary hypertension. 1 The drug class and generic name of the Canadian drug products considered in this report are listed below. Table 1: Drug Class and Generic Name Drug Class Prostanglandins Phosphodiesteriase type 5 (PDE-5) inhibitors Endothelin receptor antagonists Generic Name epoprostentol sildenafil bosentan treprostinil tadalafil ambrisentan For patients that do not respond to monotherapy, those who show a suboptimal response or who deteriorate while on a single agent, combination therapy may be considered. 2 This report will review the clinical effectiveness of combination therapy compared with monotherapy or placebo, to support policy decisions on the management of PAH. It is an update to the Rapid Response Report: Summary of Abstracts titled, Combination Therapy for Pulmonary Arterial Hypertension: Clinical Effectiveness, completed on January 18, Disclaimer: The Rapid Response Service is an information service for those involved in planning and providing health care in Canada. Rapid responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. Rapid responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

2 RESEARCH QUESTIONS 1. What is the clinical effectiveness of combination therapy with PDE-5 inhibitors (sildenafil or tadalafil) and endothelin receptor antagonists (bosentan or ambrisentan) in patients with pulmonary arterial hypertension? 2. What is the clinical effectiveness of combination therapy with PDE-5 inhibitors (sildenafil or tadalafil) and prostaglandins (epoprostenol or treprostinil) for patients with pulmonary arterial hypertension? 3. What is the clinical effectiveness of combination therapy with endothelin receptor antagonists (bosentan or ambrisentan) and prostaglandins (epoprostenol or treprostinil) for patients with pulmonary arterial hypertenesion? KEY MESSAGE The clinical effectiveness of combination therapy in patients with PAH is unclear due to the limited quantity and quality of RCTs. METHODS Literature Search Strategy Updating a previous CADTH report, a limited literature search was conducted on key resources including PubMed, The Cochrane Library (2011, Issue 10), University of York Centre for Reviews and Dissemination (CRD) databases, Canadian and major international health technology agencies, as well as a focused Internet search. Methodological filters were applied to limit retrieval to health technology assessments (HTAs), systematic reviews, meta-analyses, randomized controlled trials (RCTs). Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2011 and November 4, Reference lists of relevant articles were hand searched. Selection Criteria and Methods One reviewer screened the titles and abstracts of the retrieved publications and evaluated the full-text publications for the final article selection, according to the selection criteria presented in Table 2. Table 2: Selection Criteria Population Adult patients with pulmonary arterial hypertension Intervention 1. PDE-5 inhibitors (sildenafil or tadalafil) plus endothelin receptor antagonists (bosentan or ambrisentan) 2. PDE-5 inhibitors (sildenafil or tadalafil) plus prostaglandins (epoprostenol or treprostinil) 3. Endothelin receptor antagonists (bosentan or ambrisentan) plus prostaglandins (epoprostenol or treprostinil) Comparator Individual therapy (any one drug listed above) or placebo Outcomes Six-minute walk test (6MWT), mortality, quality of life measures Combination Therapy for Pulmonary Arterial Hypertension 2

3 Study Designs HTAs, systematic reviews, meta-analyses, randomized controlled trials (RCTs) Exclusion Criteria Studies were excluded if they did not meet the selection criteria, were duplicate publications, or were published prior to Critical Appraisal of Individual Studies RCTs were assessed to determine if allocation to treatment groups was concealed from participants. Randomization, blinding, follow up, and intention to treat (ITT) analysis of data was also assessed. SUMMARY OF EVIDENCE: Quantity of Research Available The electronic database, grey literature and hand search identified 38 reports of which 13 were reviewed in full text. Eight reports met the inclusion criteria including one HTA 1 and seven reports on five RCTs. 2-8 Two RCTs 3,4 evaluated combination therapy with PDE-5 inhibitors and endothelin antagonists, one RCT 6 evaluated prostaglandins plus PDE-5 inhibitors, one RCT 7 evaluated prostaglandins combined with either an PDE-5 inhibitor or endothelin antagonist, and one RCT 8 evaluated prostaglandins plus endothelin antagonists. Two of the RCTs 6,8 were included in the HTA. Data from these RCTs was extracted primarily from the HTA 1 but was also supplemented with information from the published study reports. 6,8 The scope of the HTA 1 was more broad than this report, thus, only two of the 20 RCTs in the HTA 1 met the selection criteria. No systematic reviews or meta-analyses were found that met the inclusion criteria. Appendix 1 describes the PRISMA flowchart of the included studies in this report. Summary of Study Characteristics Details on the study characteristics are found in Appendix 2. All RCTs were double blind, multicenter studies conducted primarily in North American and European countries. 3,4,6-8 Population The patients enrolled had idiopathic or familial PAH, or PAH related to connective tissue disease or other causes (Appendix 2). The mean age of participants ranged from 45 to 54 years per study. One RCT 4 was comprised entirely of patients in World Health Organization (WHO) functional class II (slight limitation of physical activity), and in all other studies the majority of patients were functional class III (marked limitation of physical activity). 3,6-8 The number of patients on combination versus monotherapy ranged from 29 to 267 (median 216) per study. Combination Therapy for Pulmonary Arterial Hypertension 3

4 Interventions Table 3 presents the interventions tested in the selected studies. Table 3: Interventions Tested in the Selected Studies Research Question Combination therapy Monotherapy Reference 1 tadalafil bosentan bosentan 3 1 bosentan sildenafil sildenafil 4 2 sildenafil epoprostenol epoprostenol 6 2 & 3 treprostinil bosentan or sildenafil bosentan or sildenafil 7 3 bosentan epoprostenol epoprostenol 8 In the Humbert et. al. study, 8 patients were randomized to combination therapy (bosentan plus epoprostenol), or monotherapy (placebo plus epoprostenol). In four RCTs, patients who were on pre-existing therapy of either bosentan, sildenafil or epoprostenol, were randomized to receive either a second drug (tadalafil, 3 bosentan, 4 sildenafil, 6 or treprostinil 7 ) or placebo. In two RCTs, 3,4 patients on pre-existing therapy were a subgroup of the overall study population. No studies were found that evaluated the effectiveness of ambrisentan. The treprostinil inhalation product used in one RCT 7 is not available in Canada. Outcome measures The RCTs reported the outcomes of interest which included health related quality of life (HRQL), 6,7 mortality, 4,6-8 and exercise capacity (i.e., 6MWT). 3,4,6-8 Summary of Critical Appraisal Details on the critical appraisal of the included studies are presented in Appendix 3. Allocation concealment was adequate for two 4,6 of five RCTs. Methods of blinding participants were not reported in any study. All studies blinded participants to the second drug or placebo, which was allocated to patients randomly. The primary therapy, however, was not blinded. It is not clear of knowledge of the primary therapy potentially biased the results. Withdrawals ranged from 4% to 16%, and ITT analysis was inconsistently used. In two RCTs the study population of interest was a subgroup. 3,4 The subgroup analyses were pre-planned, and randomization was stratified appropriately. Randomization was stratified by pre-existing therapy for PAH, so patients already on therapy were allocated equally between the placebo and the new drug treatment groups. This stratification is important to help distribute prognostic factors equally between groups and improve the validity of the subgroup results. Summary of Findings Mortality Mortality data for combination therapy versus monotherapy was reported for four studies (Appendix 4). 4,6-8 The number of deaths were lower in the combination therapy group than in the Combination Therapy for Pulmonary Arterial Hypertension 4

5 monotherapy group in two RCTs, 6,7 and higher in two RCTs. 1,4 None of the studies showed a statistically significant difference between groups on the incidence of mortality. Figure 1. Mortality Review: Comparison: Outcome: PAH 01 Combination therapy versus Monotherapy 01 Mortality Study Combination therapy Monotherapy RR (random) or sub-category n/n n/n 95% CI Galie /14 0/15 Simonneau /134 7/133 McLaughlin /115 1/120 Humbert /22 0/ Favours combination Favours monotherapy In the fifth study (Galie ) three deaths were reported (1 placebo, 2 tadalafil), but it was not known if these patients were part of the subgroup of patients who received combination therapy. Six Minute Walk Test (6MWT) All five studies reported results of the 6MWT (Appendix 5). The distance walked improved more in the combination therapy than in the monotherapy group in four RCTs 3,4,6,7 however the differences were statistically significantly different in only two of these RCTs. 6,7 The clinical importance of the between-group differences detected (ranging from 5 meters to 26 meters) is not clear. Health-related Quality of Life (HRQL) Quality of life was measured in two RCTs using the Short Form 36 6 and the Minnesota Living with Heart Failure (MLWHF) questionnaires (Appendix 6). 7 Both studies reported statistically significant increases in HRQL favoring combination therapy. The differences in HRQL between groups reported for the SF-36 domains 6 did not exceed the minimal important difference as defined by Gilbert et.al. 9 Limitations Overall the quality and quantity of RCTs evaluating the clinical effectiveness of combination therapy versus monotherapy or placebo in patients with PAH were limited. There were insufficient data to draw any conclusions on specific combinations of drugs. Allocation concealment was unclear in three of five studies. Studies with unclear allocation concealment have a higher risk of reporting biased results. Three of the studies had a small sample size. 3,4,8 None of the studies had an adequate follow up time or sample size to evaluate mortality. Follow up time was limited to three to six months. The population of interest was a subgroup in two RCTs. 3,4 The 6MWT is a surrogate measure, and the clinical importance of the differences detected between groups is unclear. Two of five RCTs reported on HRQL. The generalizability of findings was limited for the McLaughlin et.al. RCT 7 which used inhaled treprotinil, a product not available in Canada. Galie et. al tested several doses of tadalafil, of which only the 40 mg dose is approved in Canada. Combination Therapy for Pulmonary Arterial Hypertension 5

6 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: The clinical effectiveness of combination therapy in patients with PAH is unclear due to the limited quantity and quality of RCTs. Five RCTs were identified that evaluated the efficacy of combination therapy with prostaglandins, endothelin receptor antagonists or PDE-5 inhibitors compared to monotherapy with one of these agents. Improvements in exercise function measured by the 6MWT were noted with combination therapy. The improvement was statistically significant in two of five studies, but the clinical significance of the findings remains unclear. No statistically significant difference in mortality was detected between combination and monotherapy. Changes in HRQL favored combination therapy in two studies reporting this outcome. Most studies had limitations, such as sample size (less than75 patients in three RCTs), unclear allocation concealment, follow up durations that ranged from three to six months), or were based on subgroup analyses. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: Combination Therapy for Pulmonary Arterial Hypertension 6

7 REFERENCES 1. Chen YF, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JS, et al. Clinical and costeffectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation. Health Technol Assess [Internet] Oct [cited 2011 Nov 9];13(49): Available from: (copy and paste link into URL bar). 2. Barst RJ, Oudiz RJ, Beardsworth A, Brundage BH, Simonneau G, Ghofrani HA, et al. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transplant Jun;30(6): Galiè N, Brundage BH, Ghofrani HA, Oudiz RJ, Simonneau G, Safdar Z, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation [Internet] Jun 9 [cited 2011 Nov 16];119(22): Available from: 4. Galiè N, Rubin L, Hoeper M, Jansa P, Al-Hiti H, Meyer G, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet Jun 21;371(9630): Rubin LJ, Simonneau G, Hoeper MM, Jansa P, Kusic-Pajic A, Galiè N. improves hemodynamics in patients receiving background sildenafil treatment: esults from early, a randomized, double-blind, placebocontrolled study in patients with mildly symptomatic pulmonary arterial hypertension [abstract]. Chest [Internet] [cited 2011 Nov 16];132(4 Suppl S):487S. Available from: 6. Simonneau G, Rubin LJ, Galie N, Barst RJ, Fleming TR, Frost AE, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med Oct 21;149(8): McLaughlin VV, Benza RL, Rubin LJ, Channick RN, Voswinckel R, Tapson VF, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol May 4;55(18): Humbert M, Barst RJ, Robbins IM, Channick RN, Galiè N, Boonstra A, et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J [Internet] Sep [cited 2011 Nov 9];24(3): Available from: 9. Gilbert C, Brown MC, Cappelleri JC, Carlsson M, McKenna SP. Estimating a minimally important difference in pulmonary arterial hypertension following treatment with sildenafil. Chest [Internet] Jan [cited 2011 Nov 25];135(1): Available from: Combination Therapy for Pulmonary Arterial Hypertension 7

8 APPENDIX 1: Selection of Included Studies 33 citations identified from electronic literature search and screened 25 citations excluded 8 potentially relevant articles retrieved for scrutiny (full text, if available) 5 potentially relevant reports retrieved from other sources (grey literature, hand search) 13 potentially relevant reports 5 reports excluded: -non-randomized study (2) -duplicate (1) -other (review articles, editorials)(2) 8 reports included in review (5 unique RCTs) Combination Therapy for Pulmonary Arterial Hypertension 8

9 APPENDIX 2: Characteristics of Included Studies Author, Publication, Year, Country International Study Design, Length of Followup Patient Characteristics, Sample Size (n), Mean age, FC PDE-5 inhibitors endothelin antagonists Galiè ,3 DB RCT Subgroup Galiè ,5 International 16 weeks DB RCT Subgroup 6 months PAH* Total N=406 Combination therapy subgroup N=216 Age: 51 years FC: II (34%) III (64%) IV (1%) PAH* Total N=185 Combination subgroup N=29 Age: 45 years FC II: 100% Prostaglandins PDE-5 inhibitors Simonneau DB RCT PAH [PPAH (79%), CTD International 16 weeks (21%)] N=267 Age: 48 years FC: II (26%) III (67%) IV (5%) Intervention Comparator Key Clinical Outcomes Tadalafil 2.5 mg, or 10 mg or 20 mg or 40 mg daily PO (max. 125 mg BID) PO 62.5 mg BID titrated to 125 mg BID Sildenafil PO (dose NR) Sildenafil 20 mg TID titrated to 80 mg TID PO Epoprostenol IV (individual optimal dose) Prostaglandins PDE-5 inhibitors or endothelin antagonists McLaughlin US, Austria, Germany DB RCT 12 weeks PAH N=235 Age: 54 years FC: III (98%) IV (2%) Treprostinil 18 µg QID titrated to 54 µg QID IH 125 mg daily or sildenafil 20 mg TID PO Placebo (max. 125 mg BID) PO Placebo Sildenafil PO (dose NR) Placebo Epoprostenol IV (individual optimal dose) Placebo 125 mg daily or sildenafil 20 mg TID PO 6MWT 6MWT, mortality 6MWT, HRQL, mortality 6MWT, HRQL, mortality Combination Therapy for Pulmonary Arterial Hypertension 9

10 Author, Publication, Year, Country Study Design, Length of Followup Patient Characteristics, Sample Size (n), Mean age, FC Prostaglandins endothelin antagonists Humbert ,8 DB RCT PPAH or CTD US, France, Italy, Netherlands 16 weeks N=33 Age: 46 years FC: III (76%) IV (24%) Intervention Comparator Key Clinical Outcomes 62.5 BID titrated to 125 mg BID PO Epoprostenol titrated to target dose of 12 to 16 ng/kg/min IV Placebo Epoprostenol titrated to target dose of 12 to 16 ng/kg/min IV 6MWT, mortality 6MWT=six-minute walk test; BID=twice daily; DB=double blind; CTD= pulmonary arterial hypertension associated with connective tissue disease; FC=functional class (WHO or NYHA); HRQL=health-related quality of life; IH=inhalation; IV=intravenous; PAH=pulmonary arterial hypertension; PDE-5=phosphodiesterase type 5 inhibitors; PPAH=primary pulmonary arterial hypertension; PO=oral; QID=four times daily; RCT=randomized controlled trial; TID=three times per day *PAH included idiopathic PAH, familial PAH or PAH associated with HIV infection, anorexigen use, congenital defects, connective tissue or autoimmune diseases. PAH included idiopathic PAH, familial PAH or PAH associated with anorexigen use, congenital defects, connective tissue diseases. PAH included idiopathic PAH, familial PAH or PAH associated with anorexigen use, HIV infection, collagen vascular disease. Combination Therapy for Pulmonary Arterial Hypertension 10

11 Appendix 3. Critical Appraisal of Included Studies Study, % Strengths withdrawals Galiè Randomization stratified by bosentan use (subgroup) Withdrawals: 16% -Blinded Galiè ,5 Withdrawals: 12% Simonneau ,6 Withdrawals: 4% McLaughlin Withdrawals: 10% Humbert Withdrawals: 15% -Randomization stratified by sildenafil use (subgroup) -Allocation concealment adequate -Blinded -Allocation concealment adequate -Blinded -Blinded -Adequately powered for primary outcome (6MWT) -Compared initiation of combination therapy versus monotherapy (rather than comparing the addition of a second drug to ongoing therapy) -Blinded Weaknesses 6MWT=six minute walk test; HRQL=health related quality of life; ITT=intention to treat -Subgroup analysis -Sample size (n=37 patients received Health Canada approved dose of tadalafil) -Limited subgroup data available -Allocation concealment unclear -Subgroup analysis -Sample size lacks statistical power (n=29) -Incomplete subgroup data available - 6MWT and HRQL outcomes were not based on ITT principle (more patients in placebo group excluded from analyses) -Randomization and allocation concealment methods not described -Randomization and allocation concealment methods not described -Sample size underpowered to detect differences (n=33 patients) -ITT analysis not used for 6MWT Combination Therapy for Pulmonary Arterial Hypertension 11

12 Appendix 4. Mortality Study Treatment Death n/n (%) Cause of death PDE-5 inhibitors endothelin antagonists Galiè ,5 Sildenafil 1/14 (7) Fall with subsequent headache and sudden death Sildenafil 0/15 Prostaglandins PDE-5 inhibitors Simonneau 1,6 * Sildenafil Epoprostenol RR (95% CI) NE 1/134 (<1) NR 0.14 (0.02 to 1.12) Epoprostentol 7/133 (5) Renal failure and aggravated PH; aggravated PH; hemoptysis; aggravated PH and cardiac arrest; right heart failure and hypotension; right heart failure (2) Prostaglandins PDE-5 inhibitors or endothelin antagonists McLaughlin 7 Treprostinil or Sildenafil 0/115 NE or Sildenafil 1/120 (<1) NR Prostaglandins endothelin antagonists Humbert 1 Epoprostentol 3/22 (14) worsening PAH; acute cardiopulmonary failure; pneumonia and progressing right heart failure Epoprostentol 0/11 CI=confidence interval; n=number of patients; NE=not estimable; NR=not reported; PAH=pulmonary arterial hypertension; PDE-5=phosphodiesterase type 5 inhibitors; PH=pulmonary hypertension; RR=relative risk * A discrepancy was noted between the data reported in the systematic review (SR) and the published study report, which may be due to different data sources. The mortality data in Appendix 4 is from the SR, which used data from Pfizer s submission to NICE and other unpublished data from the manufacturer. In the published report 6 no deaths were reported in the combination therapy group. NE Combination Therapy for Pulmonary Arterial Hypertension 12

13 Appendix 5. 6MWT Change from Baseline Study Treatment groups Mean/Median Change from Baseline PDE-5 inhibitors endothelin antagonists Galiè Tadalafil 40 mg Mean change 40 m (95% CI 23 to 57) 19 m ( 95% CI 1 to 37) Mean/Median Difference (95% CI) p value Mean difference 23 m (-2 to 48 m) p=0.09 Galiè Sildenafil NR Median difference NR 5.0 m (-43 to 54 m) * Prostaglandins PDE-5 inhibitors Simonneau 1,6 Sildenafil Epoprostenol Mean change 29.8 m Epoprostenol 1.0 m Prostaglandins PDE-5 inhibitors or endothelin antagonists McLaughlin 7 Treprostinil or Sildenafil Median change 22 m (IQR -8 to 54) Subgroup N=165 Subgroup N=70 or Sildenafil 3 m (IQR -26 to 32) Mean difference 26 m (11 to 41 m) Median difference 20 m (8 to 33 m) P<0.01 Treprostinil bosentan NR 25 m (10 to 40 m) p<0.001 Treprostinil sildenafil NR 9 m, (95%CI: NR) p= NS Sildentafil Prostaglandins PDE-5 inhibitors or endothelin antagonists Humbert 1 Epoprostentol Median change 68 m Epoprostentol 74 m NS difference between groups (data not shown) 6MWT=six minute walk test; CI=confidence interval; IQR=interquartile range; M=meters; MD=mean difference; NR=not reported; NS=not statistically significant; PDE-5=phosphodiesterase type 5 inhibitors * p value not reported. The 95% CI confidence interval includes zero, therefore the differences between groups is not statistically significant. p value not reported. The 95% CI confidence interval does not include zero, therefore the differences between groups is statistically significant. Combination Therapy for Pulmonary Arterial Hypertension 13

14 Appendix 6. Health-related Quality of Life Study Instrument Results Simonneau 1 SF-36 Combination therapy group had greater improvement in physical functioning, role limitations, due to physical problems, bodily pain, general health, vitality, social functioning and mental health than monotherapy group. No statistically significant difference between groups on role limitation due to emotional problems McLaughlin 7 MLWHF Median difference for combination versus mono-therapy Global score: -4 (p=0.03) Physical: -2 (p=0.04) MLWHF=Minnesota Living with Heart Failure questionnaire [score range 0 to 105, higher scores indicate worse HRQL]. SF-36=Short Form Health Survey 36 [score range 0 to 100; positive changes indicate improvement] Combination Therapy for Pulmonary Arterial Hypertension 14