A meta-analysis of randomized controlled trials in pulmonary arterial hypertension

Nazzareno Galiè, Alessandra Manes, Luca Negro, Massimiliano Palazzini, Maria Letizia Bacchi-Reggiani, Angelo Branzi, Nazzareno Galiè, Alessandra Manes, Luca Negro, Massimiliano Palazzini, Maria Letizia Bacchi-Reggiani, Angelo Branzi

Abstract

Aims: There is no cure for pulmonary arterial hypertension, but current approved treatment options include prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. The effect on survival of these compounds has not been appropriately assessed in individual trials because of small sample size and short duration. We performed a meta-analysis of all randomized controlled trials with drugs published in this condition.

Methods and results: Trials were searched in the Medline database from January 1990 to October 2008. The primary analysis included only studies with a placebo comparator arm, the sensitivity analysis also included studies comparing two active treatment arms. The main outcome measure was all-cause mortality. Twenty-one trials were included in the primary analysis (3140 patients) and two additional studies (59 patients) were included in the sensitivity analysis. Average duration of the trials was 14.3 weeks. All-cause mortality rate in the control group was 3.8%. Active treatments were associated with a reduction in mortality of 43% (RR 0.57; 95% CI 0.35-0.92; P = 0.023); the sensitivity analysis confirmed a reduction in mortality of 38% (RR 0.62; 95% CI 0.39-1.00; P = 0.048).

Conclusion: The results of this meta-analysis suggest an improvement of survival in the patients treated with the targeted therapies approved for pulmonary arterial hypertension.

Figures

Figure 1
Figure 1
Flow chart of the search strategy and selection of the trials.
Figure 2
Figure 2
Cumulative RR estimate of death in active treatment groups when compared with control groups (RR [95% CI]). P = 0.023 for the overall estimate of the primary analysis by inverse variance method. Studies with no events in both groups (Table 3) were excluded.
Figure 3
Figure 3
Cumulative RR estimate of death in active treatment groups when compared with control groups stratified according to treatment class (inverse variance method). Heterogeneity between groups: P = 0.771. Studies with no events in both groups (Table 3) were excluded. RR, relative risk.
Figure 4
Figure 4
Cumulative RR estimate of death in active treatment groups when compared with control groups stratified by the median of baseline exercise capacity of the studies (inverse variance method). Studies with no events in both groups (Table 3) were excluded. Heterogeneity between groups: P = 0.825. 6MWD, six-minute walk distance; RR, relative risk.
Figure 5
Figure 5
Cumulative RR estimate of hospitalizations in active treatment groups when compared with control groups. P < 0.001 for the overall estimate by inverse variance method. Studies with no events in both groups (Table 3) were excluded. RR, relative risk.

References

    1. Galie N, Rubin L. Pulmonary arterial hypertension. Epidemiology, pathobiology, assessment and therapy. J Am Coll Cardiol. 2004;43:S1–S90.
    1. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004;351:1655–1665.
    1. Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(Suppl. 12):S13–S24.
    1. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med. 2004;351:1425–1436.
    1. Rich S. The value of approved therapies for pulmonary arterial hypertension. Am Heart J. 2007;153:889–890.
    1. Farber HW. The status of pulmonary arterial hypertension in 2008. Circulation. 2008;117:2966–2968.
    1. Ghofrani HA, Wilkins MW, Rich S. Uncertainties in the diagnosis and treatment of pulmonary arterial hypertension. Circulation. 2008;118:1195–1201.
    1. Macchia A, Marchioli R, Marfisi R, Scarano M, Levantesi G, Tavazzi L, Tognoni G. A meta-analysis of trials of pulmonary hypertension: a clinical condition looking for drugs and research methodology. Am Heart J. 2007;153:1037–1047.
    1. Langleben D, Christman BW, Barst RJ, Dias VC, Galie N, Higenbottam TW, Kneussl M, Korducki L, Naeije R, Riedel A, Simonneau G, Hirsch AM, Rich S, Robbins IM, Oudiz R, McGoon MD, Badesch DB, Levy RD, Mehta S, Seeger W, Soler M. Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension. Am Heart J. 2002;143:E4.
    1. Singh T, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J. 2006;151:851.e1–851.e5.
    1. Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RMF, Lauer A, Chiossi E, Landzberg M for the Bosentan Randomized Trial of Endothelin Antagonist Therapy. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006;114:48–54.
    1. McLaughlin VV, Oudiz RJ, Frost A, Tapson VF, Murali S, Channick RN, Badesch DB, Barst RJ, Hsu HH, Rubin LJ. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006;174:1257–1263.
    1. Barst RJ, Langleben D, Badesch D, Frost A, Lawrence EC, Shapiro S, Naeije R, Galie N. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006;47:2049–2056.
    1. Hoeper M, Leuchte H, Halank M, Wilkens H, Meyer FJ, Seifarth HJ, Wensel R, Ripken F, Bremen H, Kluge S, Hoeffken G, Behr J. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Resp J. 2006;4:691–694.
    1. Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, Seeger W, Grimminger F. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002;136:515–522.
    1. Ghofrani HA, Wiedemann R, Rose F, Schermuly RT, Olschewski H, Weissmann N, Gunther A, Walmrath D, Seeger W, Grimminger F. Sildenafil for treatment of lung fibrosis and pulmonary hypertension: a randomised controlled trial. Lancet. 2002;360:895–900.
    1. Rubin LJ, Mendoza J, Hood M, McGoon M, Barst R, Williams WB, Diehl JH, Crow J, Long W. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med. 1990;112:485–491.
    1. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group [see comments] N Engl J Med. 1996;334:296–302.
    1. Badesch DB, Tapson VF, McGoon MD, Brundage BH, Rubin LJ, Wigley FM, Rich S, Barst RJ, Barrett PS, Kral KM, Jobsis MM, Loyd JE, Murali S, Frost A, Girgis R, Bourge RC, Ralph DD, Elliott CG, Hill NS, Langleben D, Schilz RJ, McLaughlin VV, Robbins IM, Groves BM, Shapiro S, Medsger TA., Jr Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial [see comments] Ann Intern Med. 2000;132:425–434.
    1. Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119–1123.
    1. Simonneau G, Barst RJ, Galie N, Naeije R, Rich S, Bourge RC, Keogh A, Oudiz R, Frost A, Blackburn SD, Crow JW, Rubin LJ. Continuous Subcutaneous Infusion of Treprostinil, a Prostacyclin Analogue, in Patients with Pulmonary Arterial Hypertension. A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med. 2002;165:800–804.
    1. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, Sitbon O, Torbicki A, Delcroix M, Naeije R, Hoeper M, Chaouat A, Morand S, Besse B, Simonneau G. Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomised, double-blind placebo-controlled trial. J Am Coll Cardiol. 2002;39:1496–1502.
    1. Olschewski H, Simonneau G, Galie N, Higenbottam T, Naeije R, Rubin LJ, Nikkho S, Sitbon O, Speich R, Hoeper M, Behr J, Winkler J, Seeger W for the AIR Study Group. Inhaled iloprost in severe pulmonary hypertension. N Engl J Med. 2002;347:322–329.
    1. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896–903.
    1. Barst RJ, McGoon M, Mc Laughlin VV, Tapson V, Rich S, Rubin L, Wasserman K, Oudiz R, Shapiro S, Robbins I, Channick R, Badesch BD, Rayburn BK, Flinchbaugh R, Sigman J, Arneson K, Jeffs R for the Beraprost Study Group. Beraprost therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2003;41:2125.
    1. Sastry BKS, Narasimhan C, Reddy NK, Raju BS. Clinical efficacy of sildenafil in primary pulmonary hypertension. 1: A randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol. 2004;43:1149–1153.
    1. Humbert M, Barst RJ, Robbins IM, Channick RN, Galie N, Boonstra A, Rubin LJ, Horn EM, Manes A, Simonneau G. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004;24:353–359.
    1. Barst RJ, Langleben D, Frost A, Horn EM, Oudiz R, Shapiro S, McLaughlin V, Hill N, Tapson VF, Robbins IM, Zwicke D, Duncan B, Dixon RA, Frumkin LR. Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004;169:441–447.
    1. Galie N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005;353:2148–2157.
    1. Wilkins MR, Paul GA, Strange JW, Tunariu N, Gin-Sing W, Banya WA, Westwood MA, Stefanidis A, Ng LL, Pennell DJ, Mohiaddin RH, Nihoyannopoulos P, Gibbs JS. Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med. 2005;171:1292–1297.
    1. Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ for the Ambrisentan in Pulmonary Arterial Hypertension RD-BP-CMESAG. Ambrisentan for the treatment of pulmonary arterial hypertension. Results of the Ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, Efficacy (ARIES) Study 1 and 2. Circulation. 2008;117:3010–3019.
    1. Galie' N, Rubin LJ, Hoeper M, Jansa P, Al-Hiti H, Meyer GMB, Chiossi E, Kusic-Pajic A, Simonneau G. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093–2100.
    1. Simonneau G, Rubin L, Galie N, Barst RJ, Fleming T, Frost A, Engel PJ, Kramer MR, Burgess G, Collings L, Cossons N, Sitbon O, Badesch BD For the Pulmonary Arterial Hypertension combination Study of Epoprostenol Sildenafil (PACES) Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension. Ann Intern Med. 2008;149:521–530.
    1. Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43(Suppl. 12):S5–S12.
    1. Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The 6 min walk: a new measure of exercise capacity in patients with chronic failure. Can Med Assoc J. 1985;132:919–923.
    1. Barst R, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski A, Gaine S. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(Suppl. [12 1]):S40–S47.
    1. Petitti DB. Meta-analysis, decision analysis, and cost-effectiveness analysis. London, UK: Oxford University Press; 1994.
    1. Bradburn MJ, Deeks JJ, Berlin JA, Localio AR. Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med. 2007;26:53–77.
    1. Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev. 1987;9:1–30.
    1. Higgins JPT, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med. 2002;21:1539–1558.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera