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Original Research: Pulmonary Vascular Disease |

Comparative Effectiveness and Safety of Drug Therapy for Pulmonary Arterial HypertensionDrug Therapy for Pulmonary Arterial Hypertension: A Systematic Review and Meta-analysis FREE TO VIEW

Remy R. Coeytaux, MD, PhD; Kristine M. Schmit, MD, MPH; Bryan D. Kraft, MD; Andrzej S. Kosinski, PhD; Alicea M. Mingo, MD, MPH; Lisa M. Vann, MD; Daniel L. Gilstrap, MD; C. William Hargett, MD; Brooke Heidenfelder, PhD; Rowena J. Dolor, MD, MHS; Douglas C. McCrory, MD, MHS
Author and Funding Information

From the Department of Community and Family Medicine (Drs Coeytaux and Schmit), the Division of Pulmonary Medicine (Drs Kraft, Gilstrap, and Hargett), and the Department of Biostatistics and Bioinformatics (Dr Kosinski), Duke University School of Medicine; the Duke Evidence-based Practice Center (Drs Coeytaux, Heidenfelder, Dolor, and McCrory), Duke Clinical Research Institute, Duke University; the United States Navy (Dr Mingo); the Division of Hospital Medicine (Dr Vann), and the Division of General Internal Medicine (Drs Dolor and McCrory), Department of Medicine, Duke University Medical Center; and the Center for Health Services Research in Primary Care (Drs Dolor and McCrory), Department of Veterans Affairs, Durham, NC.

Correspondence to: Remy R. Coeytaux, MD, PhD, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC, 27705; e-mail: remy.coeytaux@dm.duke.edu


Funding/Support: This project was funded under the Agency for Healthcare Research and Quality, US Department of Health and Human Services [Contract No. 290-2007-10066-I].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(5):1055-1063. doi:10.1378/chest.13-1864
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Background:  Current treatments for pulmonary arterial hypertension (PAH) have been shown to improve dyspnea, 6-min walk distance (6MWD), and pulmonary hemodynamics, but few studies were designed to compare treatment regimens or assess the impact of treatment on mortality.

Methods:  We conducted a systematic review to evaluate the comparative effectiveness and safety of monotherapy or combination therapy for PAH using endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids. We searched English-language publications of comparative studies that reported intermediate or long-term outcomes associated with drug therapy for PAH. Two investigators abstracted data and rated study quality and applicability.

Results:  We identified 28 randomized controlled trials involving 3,613 patients. We found no studies that randomized treatment-naive patients to monotherapy vs combination therapy. There was insufficient statistical power to detect a mortality difference associated with treatment. All drug classes demonstrated increases in 6MWD when compared with placebo, and combination therapy showed improved 6MWD compared with monotherapy. For hospitalization, the OR was lower in patients taking endothelin receptor antagonists or phosphodiesterase-5 inhibitors compared with placebo (OR, 0.34 and 0.48, respectively).

Conclusions:  Although no studies were powered to detect a mortality reduction, monotherapy was associated with improved 6MWD and reduced hospitalization rates. Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy.

Figures in this Article

Pulmonary arterial hypertension (PAH) is a rare disease characterized by increased pulmonary vascular resistance leading to right ventricular pressure-volume overload and ultimately right-sided heart failure and premature death.1 The goals of medical treatment of PAH are to improve patients’ symptoms and slow the rate of disease progression. Currently, there are three main classes of medications2 used to treat PAH: endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin analogs, each of which has been shown to improve dyspnea, 6-min walk distance (6MWD), pulmonary hemodynamics, and functional class. It is unknown whether combination drug therapy (using two or more drugs with different mechanisms of action) will improve these clinical indexes or be cost effective, because few studies have been powered to detect an effect on mortality or have compared the effectiveness or safety of two or more medications. The aim of this systematic review is to evaluate the intermediate and long-term comparative effectiveness and safety of monotherapy vs combination therapy for PAH using endothelin receptor antagonists, phosphodiesterase inhibitors, or prostanoids.

This article summarizes key methods and findings from a comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality.3 Further details of the topic refinement, literature search, methods, and conclusions can be found in the full report.

Literature Search

We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from 1995 through August 2012. We identified English-language clinical studies relating to the comparative effectiveness and safety of monotherapy and combination therapy in the treatment of PAH.

Study Selection and Data Abstraction

Using prespecified inclusion and exclusion criteria, titles and abstracts were examined for potential relevance by two independent reviewers. Inclusion criteria were patients with PAH; pharmacotherapy with calcium channel blockers, prostanoids (epoprostenol, treprostinil, iloprost), endothelin antagonists (bosentan, ambrisentan), or phosphodiesterase inhibitors (sildenafil, tadalafil); comparison of one pharmacotherapy vs another (or vs placebo or standard therapy) or monotherapy vs combination therapy; reporting of intermediate or long-term outcomes or adverse effects of pharmacotherapies; randomized controlled trial (RCT) or observational study with an appropriate comparator; and English-language, peer-reviewed publication. Included articles then underwent full-text screening by two additional independent reviewers to determine eligibility. Any disagreements were resolved by discussion or by a third-party arbitrator.

We collected data on demographics, interventions, outcomes, and adverse events. We evaluated the quality of individual studies using the general approach described in the US Agency for Healthcare Research and Quality’s “Methods Guide for Effectiveness and Comparative Effectiveness Reviews.”4 Studies were rated as good, fair, or poor based on their adherence to well-accepted standard methodologies and adequate reporting.

Data Synthesis

We conducted meta-analyses for comparisons when two or more studies reported the same outcome. We used random effects models to quantitatively synthesize the available evidence and to calculate summary estimates. When meta-analysis was not appropriate, studies were summarized and presented in tabular form. For analyses that included four or more studies, we used graphical displays and test statistics (Q and I2 statistics) to assess heterogeneity, recognizing these may be limited because of the small number of studies. We present summary estimates and CIs in our data synthesis.

We use the term “background treatment” when patients were taking a preexisting medication prior to randomization to a second drug. Thus, the trial of iloprost plus bosentan vs bosentan alone (ie, the Combination Therapy of Bosentan and Aerosolised Iloprost in Idiopathic Pulmonary Arterial Hypertension [COMBI] trial5) would be described as a trial of iloprost with bosentan background therapy and would be construed to examine the efficacy of combination vs monotherapy; it is also relevant to the efficacy of iloprost. We assumed independent and additive effects of the experimental drug relative to any or all of the other background therapies received by the patients enrolled in the trial (including other PAH-specific drugs, supplemental oxygen, vasodilators, and so forth).

Literature Review

Searches of PubMed, the Cochrane Database of Systematic Reviews, and EMBASE yielded 28 RCTs (represented by 36 articles), involving a total of 3,613 patients, that evaluated the comparative effectiveness and safety of monotherapy or combination therapy for PAH (Figure 1).530 Of the 28 included RCTs, 18 (64%) were rated good quality, nine (32%) fair quality, and one (4%) was poor quality. Studies were conducted in a variety of centers and countries; most studies were multicenter trials, three were single-center trials, and four did not report the number of centers. Mean ages of patients ranged from 28 to 50 years. Twenty studies enrolled patients with PAH, four studies enrolled patients with PAH associated with systemic sclerosis (formerly scleroderma),7,12,21 and two studies enrolled patients with Eisenmenger syndrome.10,23 Two studies enrolled patients with PAH in addition to patients with category III or IV pulmonary hypertension.17,18

Figure Jump LinkFigure 1. Literature flow diagram. KQ = key question; PAH = pulmonary arterial hypertension; RCT = randomized controlled trial.Grahic Jump Location

Twenty-two studies compared a single drug (monotherapy) with either placebo or standard therapy, and one was a head-to-head comparison of bosentan and sildenafil. The remaining five studies compared combination therapy with monotherapy.

Detailed Analysis of Drug Therapies

We report on the outcomes of mortality, 6MWD, hospitalization, hemodynamic measures (ie, pulmonary vascular resistance, mean pulmonary arterial pressure, cardiac index), and commonly reported adverse reactions. The comparative analyses of pharmacotherapies are head-to-head comparisons by individual drug; monotherapy vs placebo or standard therapy by individual drug; monotherapy vs placebo or standard therapy by drug class; and combination therapy vs monotherapy by individual drug.

Mortality

Mortality was reported in 20 RCTs. An OR for mortality could not be calculated from two studies in which no deaths were reported, leaving 18 studies (14 monotherapy and four combination therapy) involving 3,077 patients eligible for inclusion in the meta-analysis. Figure 2 shows the forest plot of the mortality OR for each of these 18 studies, stratified by drug class. Only one monotherapy study comparing IV epoprostenol with standard therapy20 demonstrated a statistically significant reduction in mortality (OR, 0.05 during the 12-week trial; 95% CI, 0.00-0.83). Meta-analysis by drug class revealed a decreased incidence of death after 8 to 16 weeks of prostanoid treatment compared with placebo or standard therapy (OR, 0.52; 95% CI, 0.29-0.95) but not after treatment with endothelin receptor antagonists (OR, 0.60; 95% CI, 0.23-1.59) or phosphodiesterase inhibitors (OR, 0.30; 95% CI, 0.08-1.11). There was little evidence of statistical heterogeneity among the six endothelin receptor antagonist studies (Q = 3.33 for 5 degrees of freedom [df], I2 = 0, P = .65) or among the four phosphodiesterase inhibitor studies or eight prostanoid studies (Q = 3.11 for 3 df, I2 = 3%, P = .38; and Q = 6.75 for 7 df, I2 = 0, P = .46, respectively).

Figure Jump LinkFigure 2. Forest plot of effects of therapy on mortality. Parentheses indicate background therapy. Aer = aerosolized; Bos = bosentan; Epo = epoprostenol; ERA = endothelin receptor antagonist; PDE5 = phosphodiesterase type 5 inhibitor; SC = subcutaneous; Sil = sildenafil; Trep = treprostinil.Grahic Jump Location

Three studies representing 566 patients evaluated mortality with combination therapy vs monotherapy. The therapies differed between studies: sildenafil plus IV epoprostenol vs IV epoprostenol plus placebo, bosentan plus IV epoprostenol vs IV epoprostenol plus placebo, and bosentan or sildenafil plus aerosolized treprostinil vs bosentan or sildenafil plus placebo. Treatment duration ranged from 12 to 16 weeks. The individual ORs ranged from 0.06 to 2.80, with a summary OR of 0.37 (95% CI, 0.04-3.32). The comparative efficacy of combination therapy vs monotherapy for reducing mortality is inconclusive given the small number of trials, the wide CIs, and the observation that the CI includes 1.0.

6-Min Walk Distance

6MWD was reported in 19 RCTs representing 2,790 patients. These trials compared the effects of monotherapy or combination therapy after 8 to 16 weeks of treatment.58,11,12,14,16,17,19,21,2427,30 One study was a head-to-head comparison of bosentan vs sildenafil showing no statistically significant difference in 6MWD in an intention-to-treat analysis.9 The remaining 18 studies were included in a meta-analysis comparing monotherapy with placebo/standard therapy or combination therapy (Fig 3).

Figure Jump LinkFigure 3. Forest plot of effects of therapy on 6-min walk distance. Parentheses indicate background therapy. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

The analysis revealed a statistically significant improvement in 6MWD associated with each of the three drug classes. Endothelin receptor antagonists improved 6MWD by 31.8 m (95% CI, 12.0-51.7), whereas phosphodiesterase inhibitors and prostanoids increased 6MWD by 38.9 m (95% CI, 22.0-55.9) and 27.9 m (95% CI, 10.3-45.4), respectively. There was moderate heterogeneity among these studies, with Q = 7.68 for 5 df, I2 = 34.89, P = .17 for endothelin receptor antagonists; Q = 10.09 for 3 df, I2 = 70.28, P = .018 for phosphodiesterase inhibitors; and Q = 11.02 for 6 df, I2 = 45.57, P = .088 for prostanoids.

Three studies evaluated changes in 6MWD in 363 patients receiving combination therapy vs monotherapy. One study evaluated the efficacy of adding sildenafil to background epoprostenol therapy, and two studies evaluated the efficacy of adding iloprost to background bosentan therapy. The summary estimate of the difference in means for these studies was 23.9 (95% CI, 8.0-39.9), suggesting that combination therapy produces a moderate improvement in 6MWD compared with monotherapy.

Hospitalization

Hospitalization was reported in nine RCTs representing 1,918 patients; these studies compared the effects of monotherapy with combination therapy after 8 to 16 weeks of treatment.8,14,16,19,24,25,29,30 Meta-analysis revealed a statistically significant reduction in hospitalization associated with endothelin receptor antagonists (OR, 0.34; 95% CI, 0.17-0.69) and phosphodiesterase inhibitors (OR, 0.48; 95% CI, 0.25-0.91), whereas data on prostanoids were inconclusive (OR, 0.42; 95% CI, 0.06-3.08) (Fig 4). There was little evidence of statistical heterogeneity among the four studies involving endothelin receptor antagonists (Q = 2.34 for 3 df, I2 = 0, P = .51).

Figure Jump LinkFigure 4. Forest plot of effects of therapy on hospitalization. Hosp = hospitalization. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location

Three studies16,19,29 evaluated hospital admissions due to worsening PAH symptoms in 566 patients receiving combination therapy vs monotherapy. The summary estimate of the ORs for these studies was 0.64 (95% CI, 0.31-1.36), indicating that there is insufficient evidence to conclude whether combination therapy and monotherapy differ in their effects on hospitalization incidence during the first 8 to 16 weeks of treatment.

Hemodynamic Measures

Modest improvements in pulmonary vascular resistance (as assessed by right-sided heart catheterization at 8 to 16 weeks after initiating treatment) were associated with endothelin receptor antagonists (mean change, −218 mm Hg/L/min; 95% CI, −424 to −11), the phosphodiesterase inhibitor sildenafil (mean change, −225 mm Hg/L/min; CI, −340 to −110), and prostanoids (mean change, −256 mm Hg/L/min; 95% CI, −440 to −72) when compared with placebo or standard therapy. Meta-analysis also revealed significant improvement in mean pulmonary artery pressure for phospodiesterase inhibitors and prostanoids. The summary change in mean arterial pressures was −2.7 mm Hg (95% CI, −5.6 to 0.3) for endothelin receptor antagonists, −3.6 mm Hg (95% CI, −5.2 to −2.0) for sildenafil, and −3.8 mm Hg (95% CI, −6.1 to −1.5) for prostanoids.

Adverse Events

Adverse events during the first 8 to 16 weeks after initiation of treatment were reported in 21 RCTs. The incidence of jaw pain was sixfold higher among patients treated with any prostanoid (OR, 6.68; 95% CI, 2.28-19.62) and fourfold higher among patients treated with inhaled iloprost (OR, 4.32; 95% CI, 1.67-11.17), compared with placebo or standard therapy. There was no association between endothelin receptor antagonists or phosphodiesterase inhibitors and jaw pain. The incidence of headache was twice as high among patients treated with phosphodiesterase inhibitors (OR, 1.98; 95% CI, 1.18-3.32) or inhaled prostanoids (OR, 2.35; 95% CI, 1.50-3.70) when compared with placebo or standard therapy. The incidence of cough was higher among patients treated with an inhaled prostanoid compared with placebo or standard therapy (OR, 2.42; 95% CI, 1.66-3.53). There was no association between endothelin receptor antagonists or phosphodiesterase inhibitors and cough.

Our review found inconclusive evidence regarding mortality reduction for 11 of the 12 drug treatment comparisons, with prostanoids vs placebo or standard therapy being the only one demonstrating a statistically significant improvement in mortality. Few deaths were observed in these limited-duration studies, leading to wide CIs and lack of statistical power to detect a difference. However, a consistent direction of effect and demonstrated improvements in other outcomes, including functional and hemodynamic measures, suggest that a mortality reduction might exist. The findings from the three combination therapy studies that reported on mortality are similar to a meta-analysis by Fox et al,31 which found no significant change in mortality with combination therapy compared with monotherapy for PAH.

Increases in 6MWD ranging from 27.9 m (95% CI, 10.3-45.4) to 39.9 m (95% CI, 21.4-58.4) were observed in trials of all drug classes when compared with placebo or standard therapy; however, comparisons between agents are inconclusive. The magnitude of these statistically significant improvements in 6MWD associated with treatment are very close to a published estimate of 33 m for the minimal important difference for the 6MWD in patients with PAH32 as well an estimated threshold change in 6MWD of 41.8 m that has been shown to be associated with a reduction in clinical events.33 Combination therapy also showed improved 6MWD compared with monotherapy (OR, 23.9; 95% CI, 8.0-39.9), but the diversity of treatment regimens and the small number of combination therapy trials again make comparisons between specific regimens inconclusive.

Treatment with monotherapy or combination therapy was associated with a statistically significant decrease in hospitalization rates for endothelin receptor antagonists (OR, 0.34) and phosphodiesterase-5 inhibitors (OR, 0.48) and with nonstatistically significant trends for prostanoids (OR, 0.42) and combination therapy compared with monotherapy (OR, 0.64). In studies using right-sided heart catheterization to evaluate response to therapy, the results were inconsistent and largely inconclusive. We found modest reductions in pulmonary vascular resistance, mean pulmonary artery pressure, and cardiac index associated with prostanoids, whereas the evidence was largely inconclusive for endothelin receptor antagonists and phosphodiesterase inhibitors. The clinical significance of the magnitude of the observed changes is unclear in these intermediate outcomes associated with prostanoids. In studies reporting adverse effects, we found a strong association between treatment with inhaled prostanoids and the incidence of both jaw pain and cough.

As with all meta-analyses, there is the potential for bias due to analyzing published studies, which are more likely to have positive results. We investigated this possibility by creating a funnel plot that included 17 of the 28 RCTs that met eligibility criteria and that reported 6MWD as an outcome at 8 to 16 weeks after randomization to treatment. Visual inspection of this funnel plot (Fig 5) suggests an absence of publication bias. Our analysis of the 6MWD outcome was hindered by the inconsistent ways studies reported treatment effect (mean vs median, SD vs SE); we addressed this by converting medians to means and interquartile ranges to SEs, but this required us to make assumptions about normal distribution of data. Study populations were not comparable from study to study, in part because sicker patients are more likely to be receiving prostanoid therapy, so the data on the efficacy of oral therapies may appear to be more favorable because they were studied in patients who were less sick. There is also a paucity of evidence in the published literature to help interpret the clinical significance of the magnitude of effects observed for most outcomes. The evidence base was also limited by nonstandardized and nonsystematic reporting of adverse events.

Figure Jump LinkFigure 5. Funnel plot of estimates of differences of 6-min walk distance between active therapy and control. Parentheses indicate background therapy. Std diff = standard difference.Grahic Jump Location

Although no studies were powered to detect a mortality reduction, meta-analysis revealed improved mortality associated with prostanoid therapy, and monotherapy was associated with improved 6MWD and reduced hospitalization rates. Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy. These findings are generally consistent with current guideline recommendations for monotherapy as initial treatment, with combination treatment reserved for patients who have an inadequate clinical response to monotherapy.34,35

Author contributions: Dr Coeytaux is the guarantor of the entire manuscript.

Dr Coeytaux: contributed to the study conception and design; data acquisition, analysis, and interpretation; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Schmit: contributed to the study conception and design; data acquisition, analysis, and interpretation; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Kraft: contributed to the study conception and design; data acquisition, analysis, and interpretation; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Kosinski: contributed to the data analysis and interpretation, critical revision of the manuscript for important intellectual content, and final approval of the version to be published.

Dr Mingo: contributed to the study conception and design; data acquisition, analysis, and interpretation; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Vann: contributed to the study conception and design; data acquisition, analysis, and interpretation; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Gilstrap: contributed to the study conception and design; data acquisition, analysis, and interpretation; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Hargett: contributed to the data analysis and interpretation, critical revision of the manuscript for important intellectual content, and final approval of the version to be published.

Dr Heidenfelder: contributed to the study conception and design; data acquisition, analysis, and interpretation; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr Dolor: contributed to the study conception and design; data acquisition, analysis, and interpretation; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Dr McCrory: contributed to the study conception and design; data acquisition, analysis, and interpretation; drafting of the manuscript; critical revision of the manuscript for important intellectual content; and final approval of the version to be published.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The topic of this article was nominated by the American College of Chest Physicians and selected by the Agency for Healthcare Research and Quality (AHRQ) for systematic review by an Evidence-based Practice Center. A representative from AHRQ served as a contracting officer’s technical representative, provided technical assistance during the conduct of the full evidence report, and provided comments on draft versions of the full evidence report. AHRQ did not directly participate in the literature search; determination of study eligibility criteria; data analysis or interpretation; or preparation, review, or approval of the manuscript for publication. The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for Healthcare Research and Quality or the US Department of Health and Human Services.

Other contributions: We thank Megan von Isenburg, MSLS, for help with the literature search and retrieval; Rachael Posey, MSLS, and Megan Chobot, MSLS, for project coordination; and Liz Wing, MA, for editorial assistance.

6MWD

6-min walk distance

df

degrees of freedom

PAH

pulmonary arterial hypertension

RCT

randomized controlled trial

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Hiremath J, Thanikachalam S, Parikh K, et al; TRUST Study Group. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010;29(2):137-149. [CrossRef] [PubMed]
 
McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915-1922. [CrossRef] [PubMed]
 
Jing ZC, Yu ZX, Shen JY, et al; Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension (EVALUATION) Study Group. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183(12):1723-1729. [CrossRef] [PubMed]
 
Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol. 2011;108(8):1177-1182. [CrossRef] [PubMed]
 
Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(5):428-433. [CrossRef] [PubMed]
 
Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126(3):349-356. [CrossRef] [PubMed]
 
Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263. [CrossRef] [PubMed]
 
Galiè N, Hoeper MM, Humbert M, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Literature flow diagram. KQ = key question; PAH = pulmonary arterial hypertension; RCT = randomized controlled trial.Grahic Jump Location
Figure Jump LinkFigure 2. Forest plot of effects of therapy on mortality. Parentheses indicate background therapy. Aer = aerosolized; Bos = bosentan; Epo = epoprostenol; ERA = endothelin receptor antagonist; PDE5 = phosphodiesterase type 5 inhibitor; SC = subcutaneous; Sil = sildenafil; Trep = treprostinil.Grahic Jump Location
Figure Jump LinkFigure 3. Forest plot of effects of therapy on 6-min walk distance. Parentheses indicate background therapy. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4. Forest plot of effects of therapy on hospitalization. Hosp = hospitalization. See Figure 2 legend for expansion of other abbreviations.Grahic Jump Location
Figure Jump LinkFigure 5. Funnel plot of estimates of differences of 6-min walk distance between active therapy and control. Parentheses indicate background therapy. Std diff = standard difference.Grahic Jump Location

Tables

References

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Mukhopadhyay S, Nathani S, Yusuf J, Shrimal D, Tyagi S. Clinical efficacy of phosphodiesterase-5 inhibitor tadalafil in Eisenmenger syndrome—a randomized, placebo-controlled, double-blind crossover study. Congenit Heart Dis. 2011;6(5):424-431. [CrossRef] [PubMed]
 
Galiè N, Brundage BH, Ghofrani HA, et al; Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group. Tadalafil therapy for pulmonary arterial hypertension [published correction appears inCirculation. 2011; 124(10):e279]. Circulation. 2009;119(22):2894-2903. [CrossRef] [PubMed]
 
Galiè N, Olschewski H, Oudiz RJ, et al; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. 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(23):3010-3019. [CrossRef] [PubMed]
 
Simonneau G, Barst RJ, Galie N, et al; Treprostinil Study Group. 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(6):800-804. [CrossRef] [PubMed]
 
McLaughlin VV, Gaine SP, Barst RJ, et al; Treprostinil Study Group. Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension. J Cardiovasc Pharmacol. 2003;41(2):293-299. [CrossRef] [PubMed]
 
Hiremath J, Thanikachalam S, Parikh K, et al; TRUST Study Group. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant. 2010;29(2):137-149. [CrossRef] [PubMed]
 
McLaughlin VV, Benza RL, Rubin LJ, et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010;55(18):1915-1922. [CrossRef] [PubMed]
 
Jing ZC, Yu ZX, Shen JY, et al; Efficacy and Safety of Vardenafil in the Treatment of Pulmonary Arterial Hypertension (EVALUATION) Study Group. Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med. 2011;183(12):1723-1729. [CrossRef] [PubMed]
 
Fox BD, Shimony A, Langleben D. Meta-analysis of monotherapy versus combination therapy for pulmonary arterial hypertension. Am J Cardiol. 2011;108(8):1177-1182. [CrossRef] [PubMed]
 
Mathai SC, Puhan MA, Lam D, Wise RA. The minimal important difference in the 6-minute walk test for patients with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(5):428-433. [CrossRef] [PubMed]
 
Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation. 2012;126(3):349-356. [CrossRef] [PubMed]
 
Galiè N, Hoeper MM, Humbert M, et al; Task Force for Diagnosis and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC); European Respiratory Society (ERS); International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J. 2009;34(6):1219-1263. [CrossRef] [PubMed]
 
Galiè N, Hoeper MM, Humbert M, et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30(20):2493-2537. [CrossRef] [PubMed]
 
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