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Original Research: Pulmonary Vascular Disease |

Effect of Pulmonary Arterial Hypertension-Specific Therapies on Health-Related Quality of LifePulmonary Hypertension and Quality of Life Therapy and Health-Related Quality of Life: A Systematic Review FREE TO VIEW

Gilles Rival, MD; Yves Lacasse, MD; Sylvie Martin, MSc; Sébastien Bonnet, PhD; Steeve Provencher, MD
Author and Funding Information

From the Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec (Drs Rival, Lacasse, Bonnet, and Provencher and Ms Martin), Quebec, QC, Canada; and the Service de Pneumologie, Centre Hospitalier Universitaire de Besançon (Dr Rival), Besançon, France.

CORRESPONDENCE TO: Steeve Provencher, MD, Pulmonary Hypertension Research Group, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725, Chemin Sainte-Foy, Québec, QC, G1V 4G5, Canada; e-mail: Steve.provencher@criucpq.ulaval.ca


FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

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


Chest. 2014;146(3):686-708. doi:10.1378/chest.13-2634
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BACKGROUND:  Health-related quality of life (HRQoL) is severely impaired in pulmonary arterial hypertension (PAH). We aimed to assess the effect of PAH-specific therapies on HRQoL.

METHODS:  A literature search was performed in MEDLINE and Embase databases (January 1990 to September 2013) to retrieve prospective placebo-controlled randomized trials of at least 6 weeks duration reporting the effect of PAH-specific therapies on HRQoL in adult patients with PAH. The articles were independently reviewed, and the validity of the trials was assessed using the Cochrane’s Risk of Bias Tool.

RESULTS:  The literature search identified 1,172 titles. Seventeen articles reporting on 14 trials were retrieved, all of which were associated with a low risk of bias. The median study duration of the different trials was 12 weeks. Most patients had idiopathic PAH or PAH associated with connective tissue disease. A variety of HRQoL questionnaires were used in these trials, and most were generic. HRQoL results were most commonly minimally detailed, and some pivotal trials did not even assess HRQoL. Nevertheless, these trials consistently demonstrated statistically significant improvements in HRQoL with PAH-specific therapies, especially for the physical domains. In most cases, however, these improvements were smaller than the minimal important difference in HRQoL previously reported in PAH.

CONCLUSION:  This review shows that PAH-specific therapies improve HRQoL in PAH. However, it remains difficult to draw any firm conclusion about the clinical significance of these improvements. Further work is mandatory to validate PAH-specific questionnaires that are responsive to clinical changes as well as to establish their interpretability.

Figures in this Article

Pulmonary arterial hypertension (PAH) is a progressive but fatal vascular disease characterized by a pathologic increase in pulmonary vascular resistance.1 PAH may be idiopathic, heritable, or associated with connective tissue disease, congenital systemic-to-pulmonary shunts, portal hypertension, HIV infection, and anorexigen exposure.2 The clinical consequences of these pulmonary vascular changes include dyspnea, exercise intolerance, right-sided heart dysfunction, loss of health-related quality of life (HRQoL), and ultimately death.1 Over the last two decades, PAH-specific therapies have been developed3 and led to improvements in pulmonary hemodynamics, exercise capacity, and survival.4 However, despite newly developed therapies, most patients display persistent exercise intolerance, and long-term prognosis remains poor.1,59

Thus, in addition to better survival and exercise capacity, these drugs are intended to improve patients’ HRQoL. As a result, many randomized controlled trials (RCTs) included HRQoL as a secondary or exploratory end point. However, the heterogeneity of the HRQoL measures and the small sample size of each of these individual RCTs precluded any firm conclusions about the effects of treatment on HRQoL in PAH. The aim of this systematic review was to assess the effect of recently developed therapies on HRQoL in PAH.

Literature Search

We performed a literature search using MEDLINE and Embase databases (January 1990 to September 2013) to identify randomized placebo-controlled trials published in any language evaluating PAH-specific therapies. Search strategy combined the following terms: (“pulmonary hypertension” OR “pulmonary arterial hypertension”) AND (therapy OR therapies OR treatment OR treatments OR therapeutics) AND (“quality of life” OR “exercise tolerance” OR “exercise capacity” OR “daily living” OR “daily life activities”) AND (trial OR trials OR controlled OR randomized) NOT (children OR child OR infant OR neonates OR neonatal OR pediatric)) OR (“Hypertension, Pulmonary/drug therapy”[Medical Subject Headings (Mesh)] OR “Hypertension, Pulmonary/therapy”[Mesh]) AND (“Quality of Life”[Mesh] OR “Activities of Daily Living”[Mesh] OR “Exercise Tolerance”[Mesh]) AND (Clinical Trial OR Randomized Controlled Trial). We also searched for additional articles from the reference list of relevant articles obtained from the electronic search. In addition, the gray literature was explored by hand searching the conference abstracts of the American Heart Association, American College of Cardiology, European Society of Cardiology, American Thoracic Society, American College of Chest Physicians, European Respiratory Society, and British Thoracic Society from January 1999 to September 2013.

Inclusion Criteria for Studies

Only prospective placebo-controlled RCTs of > 6 weeks duration evaluating the effect of PAH-specific therapies in adult patients with PAH from January 1990 to September 2013 and evaluating HRQoL using questionnaires were included. Studies recruiting both treatment-naive and treated patients at baseline were considered as evaluating monotherapy, unless subgroup analyses allowed the assessment of the effect of PAH-specific therapy in addition to baseline therapy (add-on combination therapy) on HRQoL. Studies involving overlapping cohorts of patients, pediatric populations, and studies evaluating patients without PAH and nonpharmacologic interventions were excluded.

Study Selection and Assessment of Risk of Bias

The retrieved articles were independently reviewed and were considered eligible if the two reviewers (G. R., S. P.) independently decided that they met the inclusion criteria described previously. Disagreements were resolved by consensus or by consulting a third reviewer (Y. L.). Throughout this process, the reviewers were blinded to authors’ names, journal, and year of publication of the articles. If studies that had been reported in multiple articles were identified, the analysis was limited to the largest cohort, unless the necessary data had appeared only in another article. A log of reasons for rejection of citations identified from the searches was kept. The agreement between the two primary reviewers was measured using the quadratic weighted κ statistic.10

Validity of trials was independently assessed by two reviewers (G. R., S. P.) using the Cochrane’s Risk of Bias Tool11 that assesses sequence generation, allocation concealment, blinding, and incomplete outcome data. Studies were classified into “low risk,” “unclear,” or “high risk” of bias. Only low-risk studies were considered. Disagreement between reviewers was resolved by consensus.

Data Extraction and Synthesis

Two reviewers (G. R., S. P.) abstracted information from the original articles selected for inclusion in the review. The abstracted information included the following: (1) the baseline characteristics of the participants, (2) the number of included patients, (3) the active drugs and the comparator, (4) the duration of the study, and (5) the HRQoL measures and their associated results. In each trial and for each outcome, whenever possible, the difference in HRQoL measure from baseline and the end of study between active drugs and placebo was assessed. Results from the studies for which the treatment effect could not be computed were represented as a “0” (no significant difference), “+,” or “−” (statistically significant difference between groups favoring the treatment group or the control group, respectively).12 Unless otherwise specified in the primary studies included in the overview, statistical significance was set at the .05 level. Whether statistical analysis was properly corrected for multiple comparisons was assessed.

General Characteristics of Included Studies

The literature search identified 1,172 titles (Fig 1). Seventeen articles1329 reporting on 14 trials1317,19,2126,28,29 were retrieved by the two independent authors, with an excellent agreement (quadratic weighted κ statistic at 0.8867). Of those 17 articles, three represented subgroup analyses of patients with PAH associated with connective tissue disease,18,20,27 whereas three were specifically reporting HRQoL data23,25,28 from previous pivotal RCTs.3032 Included articles are described in Table 1. The study duration of the different trials ranged from 6 to up to 104 weeks (median, 12 weeks). Most patients had idiopathic PAH or PAH associated with connective tissue disease. Eleven articles compared PAH monotherapy to placebo,1321,23,27 two articles compared the addition of a second therapy vs placebo over baseline monotherapy (add-on combination),22,26 and four articles recruited both treatment-naïve patients and patients on baseline monotherapy.24,25,28,29 The HRQoL questionnaires used in RCTs are described in Table 2.3347 The generic Medical Outcomes Study 36-item Short Form (SF-36) questionnaire43 was most commonly used either alone (n = 7) or in combination with the EuroQol 5D (EQ-5D) (n = 2).39,40 Other instruments included the Medical Outcomes Study 12-item Short Form (SF-12)42 (n = 1), the Nottingham Health Profile35 (NHP) ( n = 1), the Minnesota Living with Heart Failure Questionnaire37 (MLHFQ) (n = 4), the Living with Pulmonary Hypertension Questionnaire46 (LPHQ) (n = 1), and the Chronic Heart Failure Questionnaire33 (CHFQ) (n = 2). All included studies had a low risk of bias (Table 3).

Figure Jump LinkFigure 1  Study flowchart. HRQoL = health-related quality of life; PAH = pulmonary arterial hypertension; RCT = randomized controlled trial.Grahic Jump Location
Table Graphic Jump Location
TABLE 1  ] Characteristics of Included Articles

6MWD = 6-min walk distance; AIR = Aerosolized Iloprost Randomized; ARIES = Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study; CHD = congenital heart disease; CHFQ = Chronic Heart Failure Questionnaire; CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension; EARLY = Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients; EQ-5D = EuroQol 5D; ERA = endothelin receptor antagonist; HRQoL = health-related quality of life; IPAH = idiopathic pulmonary arterial hypertension; LPHQ = Living With Pulmonary Hypertension Questionnaire; MLHFQ = Minnesota Living With Heart Failure Questionnaire; NHP = Nottingham Health Profile; PAH = pulmonary arterial hypertension; PACES = Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil; PATENT = Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; PDA = patent ductus arteriosus; PDE5 = phosphodiesterase type 5 inhibitor; PHIRST = Pulmonary Arterial Hypertension and Response to Tadalafil; SERAPHIN = Study With an Endothelin Receptor Antagonist in Pulmonary Hypertension to Improve Clinical Outcome; SF-12 = Medical Outcomes Study 12-item Short Form; SF-36 = Medical Outcomes Study 36-item Short Form; STRIDE = Sitaxsentan to Relieve Impaired Exercise; TSG = Treprostinil Study Group; SUPER = Sildenafil Use in Pulmonary Arterial Hypertension; TRIUMPH = Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension; VSD = ventricular septal defect; WHO = World Health Organization.

a 

Exercise duration on treadmill (Naughton protocol).

b 

Reported HRQoL measures were evaluated after 6 mo of therapy. However, overall mean duration of treatment was 85, 100, and 104 wk for the placebo and macitentan 3 mg and 10 mg groups, respectively.

Table Graphic Jump Location
TABLE 2  ] List of HRQoL Questionnaires Used in Included Studies

MCID = minimal clinically important difference; VAS = visual analog scale. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3  ] Risk of Bias Evaluation

Cochrane’s Risk of Bias Tool11 assesses (1) sequence generation: whether the study was truly randomized; (2) allocation concealment: whether sequence generation was properly protected; (3) blinding: whether the trial was described as double-blinded; and (4) incomplete outcome data: whether a detailed follow-up of all the patients was provided. 6MWT = 6-min walk test; QoL = quality of life.

Effect of PAH Monotherapy on HRQoL
Endothelin Receptor Antagonists:

HRQoL assessed using the SF-36 questionnaire was a secondary end point in five RCTs evaluating endothelin receptor antagonists (Table 4). In the Sitaxsentan to Relieve Impaired Exercise (STRIDE)-1 study, no differences in HRQoL were observed in patients receiving sitaxsentan (either 100 mg or 300 mg) compared with placebo.19 In a post hoc subgroup analysis of PAH associated with connective tissue disease,20,27 improvements in physical functioning and role physical domains were observed. Similarly, significant improvements in the physical functioning scale were observed at 12 weeks for combined ambrisentan doses (2.5 and 5 mg) in the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study (ARIES)-2. In ARIES-1, similar trends were reported without statistical significance.21 Conversely, none of the eight domains of SF-36 was significantly improved in patients with World Health Organization functional class II PAH treated with bosentan in the Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients (EARLY).24 Nonetheless, 57% of patients treated with bosentan improved their SF-36 health transition index at 24 weeks compared with 38% of patients on placebo (P = .02). In the Study With and Endothelin Receptor Antagonist in Pulmonary Hypertension to Improve Clinical Outcome (SERAPHIN), both doses of macitentan (3 mg and 10 mg) improved the physical and mental component scores at 6 months, as well as seven out of eight domains of the SF-36 questionnaires.28 Macitentan also significantly delayed time to first occurrence of a five point or more decrease in the physical score component (hazard ratio [HR], 0.70; 95% CI, 0.54-0.92; P = .008; and HR, 0.65; 95% CI, 0.50-0.85; P = .001 for the 3-mg and 10-mg doses, respectively), whereas it tended to delay the occurrence of a ≥ 5-point decrease in the mental score (HR, 0.81; 95% CI, 0.63-1.03; P = .085; and HR, 0.79; 95% CI, 0.61-1.01; P = .053 for the 3-mg and 10-mg doses, respectively). Thus, except for macitentan, the effect of endothelin receptor antagonists on HRQoL remains largely unknown.

Table Graphic Jump Location
TABLE 4  ] HRQoL Questionnaires and ERAs

Treatment effect: 0 = no significant difference; + = statistically significant difference between groups favoring the treatment group; − = statistically significant difference between groups favoring the control group. DNS = data not shown; NS = not significant. See Table 1 legend for expansion of other abbreviations.

a 

Among patients with PAH associated with connective tissue disease treated with sitaxsentan 100 mg or 300 mg, significant improvements in Physical function (P = .042) and Role physical (P = .01) were observed compared with placebo.20 These results were confirmed by Mychaskiw et al27 in the sitaxsentan 100-mg group and for only the Physical component scores and the Role physical.

b 

An analysis of covariance models adjusted for baseline value was used to compare treatment groups. Whether statistical analysis was properly corrected for multiple comparisons was not described.

c 

P value for combined ambrisentan groups (2.5 and 5 mg). Improvements in physical function were noted for both 2.5-mg (P = .005) and 5-mg (P = .040) dose groups. Similar trends were observed without statistical significance for ambrisentan 5 and 10 mg. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the eight SF-36 domains) was not described. However, multiple comparisons for efficacy end points were controlled with a fixed sequence procedure in each study. Thus, HRQoL measures were analyzed because at least one ambrisentan dose was significant for the primary end point and time to clinical worsening showed an effect at α < 0.04.

d 

SF-36 health transition indexes were compared with relative risks (bosentan vs placebo), and the treatment effect was tested with Fisher exact test. A higher proportion of patients on bosentan (57%) vs placebo (38%) improved their SF-36 health transition index at 24 wk (P = .02). Importantly, HRQoL was an exploratory end point only.

e 

Differences in separation between cumulative distribution functions were assessed using Kolmogorov-Smirnov tests. Whether statistical analysis was properly corrected for multiple comparisons was not described.

f 

Reported HRQoL measures were evaluated after 6 months of therapy. Importantly, HRQoL was an exploratory end point only, and whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the eight SF-36 domains) was not described.

Phosphodiesterase Type 5 Inhibitors and Soluble Guanylate Cyclase Stimulators:

In their crossover trial, Sastry et al17 documented significant improvement in dyspnea and fatigue as well as a trend for an improved emotional function assessed by the CHFQ during the 6-week treatment with sildenafil (Table 5). The effect of sildenafil on HRQoL was further evaluated in the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER)-1 study,23 in which improvements in physical functioning, general health, and vitality domains of the SF-36 were observed at 12 weeks when the 20-, 40-, and 80-mg doses were pooled. Statistically significant improvements were also seen in the EQ-5D utility index score. In the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) trial,25,30 tadalafil 40 mg was associated with statistically significant improvements in six of the eight domains of the SF-36 questionnaire and all sections of EQ-5D.25 Improvements in the US and UK population-based EQ-5D utility index scores were significant in all tadalafil treatment groups, with the largest improvement seen with tadalafil 40 mg. However, a significant improvement on the EQ-5D current health state score was found only for tadalafil 40 mg (P < .05; effect size, 0.35).25,30 More recently, the EQ-5D score did not differ significantly between riociguat and the placebo group, whereas exploratory analyses suggested improvements in HRQoL assessed using the LPHQ.29,48 Hence, phosphodiesterase type 5 inhibitors consistently showed improvements in HRQoL measures.

Table Graphic Jump Location
TABLE 5  ] HRQoL Questionnaires and Phosphodiesterase Type-5 Inhibitors and Soluble Guanylate Cyclize Stimulators

See Table 1 and 4 legends for expansion of abbreviations.

a 

Results are presented as mean (SD). Changes between baseline and the end of the study were analyzed using paired t test; a value of P < .05 was considered significant. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the three CHFQ domains) was not described.

b 

HRQoL domains were analyzed using an unadjusted t test performed at the two-sided α-level of 0.05. Data are presented of mean changes from baseline (SD) for pooled doses. No adjustment of significance values for multiple testing was performed.

c 

Improvements in physical functioning and general health domains of the SF-36 were also observed for the each of 20-, 40-, and 80-mg individual doses.

d 

An effect size between 0.3 and 0.5 and > 0.5 represents a moderate and an important improvement of HRQoL, respectively.

e 

Analysis of covariance was used to evaluate changes from baseline to week 16 for SF-36 and EQ-5D measures. No adjustment of significance values for multiple testing was performed.

f 

The physical functioning, vitality, social functioning, and mental health domains were also improved in the 20-mg group.

g 

Data for the maximum 2.5-mg tid dose.

h 

On the basis of the prespecified hierarchical testing procedure, the analysis of the scores on the LPHQ was considered to be exploratory only.

Prostanoids:

Barst et al13 first showed that the four domains of the CHFQ and two of the six dimensions of the NHP were improved by IV epoprostenol (Table 6).13 Inhaled iloprost was also associated with significant improvement on the EQ-5D visual-analog scale, whereas no changes were observed for the mean EQ-5D health-state or the SF-12.14 Subcutaneous treprostinil was associated with significant improvement in the physical dimension score of the MLHFQ,15 and subgroup analysis suggested this improvement was of similar magnitude in PAH associated with connective tissue disease (P = .075).15,18 Conversely, no treatment effect on HRQoL was observed after 3, 6, 9, and 12 months of treatment with beraprost.16 Consequently, IV epoprostenol, subcutaneous treprostinil, and inhaled iloprost have been associated with statistically significant changes in HRQoL.

Table Graphic Jump Location
TABLE 6  ] HRQoL Questionnaires and Prostanoids

See Table 1, 2, and 4 legends for expansion of abbreviations.

a 

For the CHFQ, positive values for changes indicate improvements over baseline values, whereas negative values for changes indicate improvements over baseline values for the NHP.

b 

The Hodges-Lehmann estimate is used to estimate the true median changes from baseline. A CI that does not contain zero indicates statistical significance. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the CHFQ and NPH domains) was not described.

c 

HRQoL scores were compared between treatment groups using the Wilcoxon rank sum test without imputation. Data are presented as mean changes (SD). Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the MLHFQ domains) was not described.

d 

Analysis of covariance was used to compare score at baseline and at the end of study. Data are presented as mean changes (SD).

HRQoL and Combination Therapies

In the Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil (PACES)-1,22 positive changes were observed in patients randomized to sildenafil in addition to epoprostenol in six of eight domains of SF-36 compared with epoprostenol alone (Table 7). Similarly, in the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study, the addition of inhaled treprostinil over concomitant bosentan or sildenafil resulted in improved global and physical scores of the MLHFQ.26

Table Graphic Jump Location
TABLE 7  ] HRQoL Questionnaires and Combination Therapy

See Table 1 and 4 legends for expansion of abbreviations.

a 

Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the eight SF-36 domains) was not described.

b 

Using Hodges-Lehmann estimates. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the MLHFQ domains) was not described.

The present systematic review confirms that the effects of PAH-specific therapies on HRQoL have been assessed in most of the recent RCTs. These trials consistently demonstrated statistically significant improvements in HRQoL with PAH-specific therapies, especially for the physical domains. However, a variety of HRQoL questionnaires were used in these trials, and most were generic. More importantly, it remains difficult to draw any firm conclusion about the clinical significance of these improvements, given that changes in HRQoL with therapy were often poorly described, the results often being presented as P values only. In addition, for most questionnaires, the minimal important difference (MID) in scores in the setting of PAH is unknown.

HRQoL is the most complex measure of patient-reported outcomes. It refers to an individual’s satisfaction with the physical, social, and psychologic domains of life, insofar as they affect or are affected by health.49 As a result, HRQoL instruments are designed to capture the impact of impairment on an individual’s perceived well-being. Only recently has HRQoL been a specific focus of study in PAH. Preliminary evaluations have identified profound impairment in HRQoL of patients with PAH, at least as severe as those reported in studies of patients with other severely debilitating and life-threatening conditions.50 It has usually been extrapolated that improvement in functional status would automatically lead to a better HRQoL.47,5053 Given the poor correlation between the impairment of HRQoL and the severity of PAH, the measurement of physiologic and laboratory parameters cannot be used as a surrogate outcome for HRQoL.54 Indeed, individual differences in perceptions and expectations may lead to dramatic differences in HRQoL that are not fully captured without validated HRQoL questionnaires. Thus, from a patient’s perspective, and increasingly from the perspective of regulatory agencies,46 the assessment of treatment-related changes in HRQoL is important, particularly in PAH, where current treatments may cause side effects and may require invasive, cumbersome, and at times painful modes of administration.55

Improved outcomes with expanding treatment options have expanded the goals of therapy from increasing survival to improving HRQoL, following the paradigm set by other conditions. As a result, HRQoL has been used as a secondary1317,19,21,22,26,2931 or exploratory24,28 end point in most placebo-controlled RCTs evaluating PAH-specific therapies. Many trials documented statistically significant improvements in HRQoL using the SF-36 questionnaire,2023,25,28 the MLHFQ,15,26 the CHFQ,13,17 and the EQ-5D23,25 questionnaire. In most trials, however, whether statistical analysis was properly corrected for multiple comparisons (eg, each of the eight SF-36 questionnaire domains) was not described. In our review, most of the changes in HRQoL we found in the domains related to physical functioning. Moreover, these improvements were most commonly smaller than the MID in HRQoL previously reported in PAH.45 The MID is the smallest change in a health-related outcome measure that, in association with minimal toxicity and cost, is large enough to trigger a change in management.34 In an attempt to provide a metric for interpreting the level of change in HRQoL in PAH and to allow clinicians to make meaningful interpretations of results, the MID for the physical functioning, role-physical, social functioning, and vitality domains of the SF-36 questionnaires were estimated between 13 and 25 using distribution-based methods.45 These estimates were very close to those previously reported in other chronic lung diseases56 and would suggest that PAH-specific therapies may not be associated with clinically meaningful changes in HRQoL. It is noteworthy, however, that nearly all knowledge about HRQoL in PAH has been gathered through the use of instruments initially designed for left-sided heart diseases (CHFQ,33 MLHFQ37) and generic questionnaires (NHP,35 SF-36,43 SF-12,42 EQ-5D39,40). Tools that were not designed to measure PAH-related HRQoL may not accurately capture the PAH experience. In addition, generic instruments generally provide less sensitivity to treatment-induced changes in the unique qualities of individual diseases. Many studies may also have been inadequately powered to detect significant differences in HRQoL. Finally, most studies were of short duration, whereas HRQoL is a dynamic process, and adaptation may occur over a period of months to years. As a result, the MID for HRQoL questionnaires remains largely unknown in PAH. Additional research is thus needed to determine the absolute change in HRQoL scores that translate into significant change in PAH patients’ perception of well-being, especially in the trial setting.

In an attempt to cope with the lack of disease-specific HRQoL questionnaires for PAH, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) questionnaire and its utility index were developed.57 This questionnaire has a good internal consistency and reproducibility and has been validated in many countries. Similarly, the MLHFQ has been modified and validated for PAH.47,54 The LPHQ (ie, modified MLHFQ) tool was shown to be a responsive measure of HRQoL changes with treatment as well as to be predictive of subsequent clinical worsening.47,53 Nevertheless, whether this questionnaire fully captures the perspective of the patient with PAH and unique variables important to patients with PAH rather than only describing certain aspects similar to chronic heart failure remains unknown. Moreover, the CAMPHOR questionnaire and the LPHQ have not yet been widely used in prospective RCTs yet. Assessing the responsiveness of these instruments in clinical studies will rely in part on future trial designs.

Despite being an important patient-centered outcome in clinical trials,58 pivotal RCTs evaluating sitaxsentan,59 bosentan,6062 treprostinil,63,64 imatinib,65 and combination therapy,6668 as well as the phase 2 RCT evaluating selexipag,69 did not assess or report HRQoL. Even when assessed, the reporting of HRQoL data has generally been poor. Except for the few articles specifically reporting treatment-induced changes in HRQoL from previous RCTs,23,25 little information is provided other than whether a statistically significant difference was detected. In many cases, the magnitude of changes observed and the specific domains affected are not even described. Until now, lack of consensus on which measures to use and how results should be reported has made it difficult to compare HRQoL results across different trials. This lack of details precluded systematic analysis of the effect size of PAH-specific therapies on HRQoL or assessment of whether these effects are homogeneous among patients with diverse PAH types and severity. Further work is thus needed to begin standardizing the reporting and interpretation of HRQoL in RCTs for PAH.70

Most recent RCTs evaluating the efficacy of PAH-specific therapies used HRQoL as a secondary end point and demonstrated statistically significant improvements, especially in the physical domains of generic instruments. These improvements were generally smaller than the MID previously reported in PAH. Moreover, many pivotal trials did not assess HRQoL. More commonly, HRQoL results were only minimally detailed. Therefore, it remains difficult to draw any firm conclusion about the effects of current PAH-specific therapies on HRQoL. Further work is thus mandatory to validate PAH-specific questionnaires that are responsive to clinical changes as well as to determine their interpretability.

Author contributions: S. P. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. G. R., S. M., and S. P. contributed to data acquisition; G. R., Y. L., S. M., S. B., and S. P. contributed to data analysis and interpretation; G. R., Y. L., and S. P. contributed to the design and supervision of the study; G. R. and S. P. contributed to the concept of the study and the drafting of the manuscript; S. B. contributed to the supervision of the study; and G. R., Y. L., S. M., S. B., and S. P. contributed to the revision of the manuscript

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Bonnet holds a Canadian Research Chair on Vascular Pathologies at Université Laval and is a consultant for Merck & Co, Inc. Dr Provencher is clinician-scientist of the Fonds de la recherche en santé du Québec (FRSQ) and has received research grants from Actelion Pharmaceuticals Ltd, Bayer AG, and GlaxoSmithKline, and has received speaker fees from Actelion Pharmaceuticals Ltd. The Pulmonary Hypertension Research Group is also supported by the “Réseau en Santé Respiratoire” of the FRSQ. Drs Rival and Lacasse and Ms Martin have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

CAMPHOR

Cambridge Pulmonary Hypertension Outcome Review

CHFQ

Chronic Heart Failure Questionnaire

EQ-5D

EuroQol 5D

HR

hazard ratio

HRQoL

health-related quality of life

LPHQ

Living with Pulmonary Hypertension Questionnaire

MID

minimal important difference

MLHFQ

Minnesota Living with Heart Failure Questionnaire

NHP

Nottingham Health Profile

PAH

pulmonary arterial hypertension

RCT

randomized controlled trial

SF-12

Medical Outcomes Study 12-item Short Form

SF-36

Medical Outcomes Study 36-item Short Form

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Simonneau G, Rubin LJ, Galiè N, et al; PACES Study Group. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008;149(8):521-530. [CrossRef] [PubMed]
 
Pepke-Zaba J, Gilbert C, Collings L, Brown MCJ. Sildenafil improves health-related quality of life in patients with pulmonary arterial hypertension. Chest. 2008;133(1):183-189. [CrossRef] [PubMed]
 
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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]
 
Mychaskiw MA, Hwang LJ, Liu X, Teal S, Louie M. The effect of sitaxentan on exercise capacity, hemodynamic function, and health-related quality of life in adults with pulmonary arterial hypertension associated with connective tissue disease [abstract]. Am J Respir Crit Care Med. 2011;183(1):A5887.
 
Mehta S, Channick R, Delcroix M, et al. Macitentan improves health-related quality of life in pulmonary arterial hypertension: results from the randomized controlled SERAPHIN trial [abstract]. Am J Respir Crit Care Med. 2013;187(1):A3269.
 
Ghofrani HA, Galiè N, Grimminger F, et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340. [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 in .Circulation. 2011;124(10):e279]. Circulation. 2009;119(22):2894-2903. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 1  Study flowchart. HRQoL = health-related quality of life; PAH = pulmonary arterial hypertension; RCT = randomized controlled trial.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1  ] Characteristics of Included Articles

6MWD = 6-min walk distance; AIR = Aerosolized Iloprost Randomized; ARIES = Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study; CHD = congenital heart disease; CHFQ = Chronic Heart Failure Questionnaire; CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension; EARLY = Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients; EQ-5D = EuroQol 5D; ERA = endothelin receptor antagonist; HRQoL = health-related quality of life; IPAH = idiopathic pulmonary arterial hypertension; LPHQ = Living With Pulmonary Hypertension Questionnaire; MLHFQ = Minnesota Living With Heart Failure Questionnaire; NHP = Nottingham Health Profile; PAH = pulmonary arterial hypertension; PACES = Pulmonary Arterial Hypertension Combination Study of Epoprostenol and Sildenafil; PATENT = Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; PDA = patent ductus arteriosus; PDE5 = phosphodiesterase type 5 inhibitor; PHIRST = Pulmonary Arterial Hypertension and Response to Tadalafil; SERAPHIN = Study With an Endothelin Receptor Antagonist in Pulmonary Hypertension to Improve Clinical Outcome; SF-12 = Medical Outcomes Study 12-item Short Form; SF-36 = Medical Outcomes Study 36-item Short Form; STRIDE = Sitaxsentan to Relieve Impaired Exercise; TSG = Treprostinil Study Group; SUPER = Sildenafil Use in Pulmonary Arterial Hypertension; TRIUMPH = Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension; VSD = ventricular septal defect; WHO = World Health Organization.

a 

Exercise duration on treadmill (Naughton protocol).

b 

Reported HRQoL measures were evaluated after 6 mo of therapy. However, overall mean duration of treatment was 85, 100, and 104 wk for the placebo and macitentan 3 mg and 10 mg groups, respectively.

Table Graphic Jump Location
TABLE 2  ] List of HRQoL Questionnaires Used in Included Studies

MCID = minimal clinically important difference; VAS = visual analog scale. See Table 1 legend for expansion of other abbreviations.

Table Graphic Jump Location
TABLE 3  ] Risk of Bias Evaluation

Cochrane’s Risk of Bias Tool11 assesses (1) sequence generation: whether the study was truly randomized; (2) allocation concealment: whether sequence generation was properly protected; (3) blinding: whether the trial was described as double-blinded; and (4) incomplete outcome data: whether a detailed follow-up of all the patients was provided. 6MWT = 6-min walk test; QoL = quality of life.

Table Graphic Jump Location
TABLE 4  ] HRQoL Questionnaires and ERAs

Treatment effect: 0 = no significant difference; + = statistically significant difference between groups favoring the treatment group; − = statistically significant difference between groups favoring the control group. DNS = data not shown; NS = not significant. See Table 1 legend for expansion of other abbreviations.

a 

Among patients with PAH associated with connective tissue disease treated with sitaxsentan 100 mg or 300 mg, significant improvements in Physical function (P = .042) and Role physical (P = .01) were observed compared with placebo.20 These results were confirmed by Mychaskiw et al27 in the sitaxsentan 100-mg group and for only the Physical component scores and the Role physical.

b 

An analysis of covariance models adjusted for baseline value was used to compare treatment groups. Whether statistical analysis was properly corrected for multiple comparisons was not described.

c 

P value for combined ambrisentan groups (2.5 and 5 mg). Improvements in physical function were noted for both 2.5-mg (P = .005) and 5-mg (P = .040) dose groups. Similar trends were observed without statistical significance for ambrisentan 5 and 10 mg. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the eight SF-36 domains) was not described. However, multiple comparisons for efficacy end points were controlled with a fixed sequence procedure in each study. Thus, HRQoL measures were analyzed because at least one ambrisentan dose was significant for the primary end point and time to clinical worsening showed an effect at α < 0.04.

d 

SF-36 health transition indexes were compared with relative risks (bosentan vs placebo), and the treatment effect was tested with Fisher exact test. A higher proportion of patients on bosentan (57%) vs placebo (38%) improved their SF-36 health transition index at 24 wk (P = .02). Importantly, HRQoL was an exploratory end point only.

e 

Differences in separation between cumulative distribution functions were assessed using Kolmogorov-Smirnov tests. Whether statistical analysis was properly corrected for multiple comparisons was not described.

f 

Reported HRQoL measures were evaluated after 6 months of therapy. Importantly, HRQoL was an exploratory end point only, and whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the eight SF-36 domains) was not described.

Table Graphic Jump Location
TABLE 5  ] HRQoL Questionnaires and Phosphodiesterase Type-5 Inhibitors and Soluble Guanylate Cyclize Stimulators

See Table 1 and 4 legends for expansion of abbreviations.

a 

Results are presented as mean (SD). Changes between baseline and the end of the study were analyzed using paired t test; a value of P < .05 was considered significant. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the three CHFQ domains) was not described.

b 

HRQoL domains were analyzed using an unadjusted t test performed at the two-sided α-level of 0.05. Data are presented of mean changes from baseline (SD) for pooled doses. No adjustment of significance values for multiple testing was performed.

c 

Improvements in physical functioning and general health domains of the SF-36 were also observed for the each of 20-, 40-, and 80-mg individual doses.

d 

An effect size between 0.3 and 0.5 and > 0.5 represents a moderate and an important improvement of HRQoL, respectively.

e 

Analysis of covariance was used to evaluate changes from baseline to week 16 for SF-36 and EQ-5D measures. No adjustment of significance values for multiple testing was performed.

f 

The physical functioning, vitality, social functioning, and mental health domains were also improved in the 20-mg group.

g 

Data for the maximum 2.5-mg tid dose.

h 

On the basis of the prespecified hierarchical testing procedure, the analysis of the scores on the LPHQ was considered to be exploratory only.

Table Graphic Jump Location
TABLE 6  ] HRQoL Questionnaires and Prostanoids

See Table 1, 2, and 4 legends for expansion of abbreviations.

a 

For the CHFQ, positive values for changes indicate improvements over baseline values, whereas negative values for changes indicate improvements over baseline values for the NHP.

b 

The Hodges-Lehmann estimate is used to estimate the true median changes from baseline. A CI that does not contain zero indicates statistical significance. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the CHFQ and NPH domains) was not described.

c 

HRQoL scores were compared between treatment groups using the Wilcoxon rank sum test without imputation. Data are presented as mean changes (SD). Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the MLHFQ domains) was not described.

d 

Analysis of covariance was used to compare score at baseline and at the end of study. Data are presented as mean changes (SD).

Table Graphic Jump Location
TABLE 7  ] HRQoL Questionnaires and Combination Therapy

See Table 1 and 4 legends for expansion of abbreviations.

a 

Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the eight SF-36 domains) was not described.

b 

Using Hodges-Lehmann estimates. Whether statistical analysis was properly corrected for multiple comparisons (eg, for each of the MLHFQ domains) was not described.

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