Selection of patient-reported outcome measures in pulmonary arterial hypertension clinical trials: a systematic review, meta-analysis and health-related quality of life framework

Abstract

Introduction: Health-related quality of life (HRQoL) in pulmonary arterial hypertension (PAH) is valued as an outcome measure by patients, clinicians and regulators. The selection of patient-reported outcome measures (PROMs) for measurement of HRQoL in PAH clinical trials lacks systematic evaluation of their suitability, accuracy and reliability.

Methods: We report a systematic review (PROSPERO ID: CRD42024484021) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines of PROMs selected in PAH clinical trials. PROM measurement properties were then evaluated according to the 10-step COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and graded by recommendation for use. Finally, HRQoL was modelled into a conceptual framework using patient interviews and surveys.

Results: Screening of 896 records identified 90 randomised controlled trials. 43 trials selected PROMs, of which 20 were sufficiently validated to detect meaningful change. Of these, eight trials were adequately powered, using either EuroQol-five dimensions-five levels (EQ-5D-5L), Short-Form-36 (SF-36) or the Living with Pulmonary Hypertension Questionnaire (LPHQ). The COSMIN evaluation recommended EmPHasis-10 and the LPHQ for use (grade A); whereas, SF-36 and EQ-5D-5L require further study (grade B). A conceptual framework of HRQoL was developed from literature comprising 8045 patients. This framework can be used to visualise the different HRQoL concepts measured by different PROMs.

Conclusion: To improve patient-centred research, greater consistency in PROM selection is required. Three of 90 randomised controlled trials have selected COSMIN-recommended PROMs. Whilst the PROMs evaluated require development across the 10 areas of psychometric property measurement, EmPHasis-10 and the LPHQ can be recommended for use. The ratified conceptual framework can further support PROM selection by identifying the HRQoL concepts they are likely to capture.

Selection of patient-reported outcome measures (PROMs) in pulmonary arterial hypertension (PAH) clinical trials. COSMIN: COnsensus-based standards for the Selection of health-Measurement INstruments; EQ-5D-5L: EuroQol-five dimensions-five levels; HRQoL: health-related quality of life; LPHQ: Living with Pulmonary Hypertension Questionnaire; MCID: minimal clinically important difference; QALY: quality-adjusted life-years, RCT: randomised controlled trial; SF-36: 36-Item Short Form Survey. Image created using BioRender.

FIGURE 1

Health-related quality of life (HRQoL) instruments in pulmonary arterial hypertension (PAH) randomised controlled trials (RCTs) from the systematic review categorised by ability to distinguish meaningful change in the PAH population. 20 of 43 trials selected an instrument with a minimal clinically important difference (MCID) for HRQoL. 56 total instruments are included as 13 trials included more than one instrument, see supplementary table E2 for all RCTs with an HRQoL end-point. No trials reported results in the context of MCID. The Pulmonary Arterial Hypertension Symptoms and Impact Questionnaire (PAH-SYMPACT) MCID evaluation is underway [58]. BDI: Beck's Depression Inventory; CAMPHOR: Cambridge Pulmonary Hypertension Outcome Review; EQ-5D-5L: EuroQol-five dimensions-five levels; DFI: Dyspnoea Fatigue Index; FSS: Fatigue Severity Score; HADS: Hospital Anxiety and Depression Scale; HAP: Human Activity Profile; IPAQ: International Physical Activity Questionnaire; KCCQ: Kansas City Cardiomyopathy Questionnaire; LPHQ: Living with Pulmonary Hypertension Questionnaire; MLWHF: Minnesota Living with Heart Failure; NHP: Nottingham Health Profile; PGA: patient global assessment; PROM: patient-reported outcome measure; SF-36: 36-item Short-Form Survey; SGA: subjective global assessment.

FIGURE 2

Meta-analysis of health-related quality of life (HRQoL) outcomes for riociguat. Patient-reported outcome measure (PROM) instruments: a) Living with Pulmonary Hypertension Questionnaire (LPHQ) and b) EuroQol-five dimensions-five levels (EQ-5D-5L). The 1.5 mg dose in PATENT-1 for LPHQ was excluded as the subgroup was insufficiently powered. Utility index score was not reported with EQ-5D-5L analysis. PROMs delivered at start and week 12 for PATENT-1 and every 2 weeks up to week 8 for the PATENT-2 follow-on study. 12-month follow-up data for EQ-5D-5L from PATENT-2 is not included. No imputation was reported of missing data. PATENT-1 [77] 2.5 mg riociguat, n=254 (World Health Organization Functional Class (WHO FC) III, n=140 (55%) versus WHO FC II, n=108 (43%), p>0.05). PATENT-1 [77] 1.5 mg riociguat, n=63 (WHO FC III, n=39 (62%) versus WHO FC II, n=19 (30%), p<0.0001). PATENT-2 [78] 2.5 mg riociguat, n=231 (WHO FC III, n=127 (55%) versus WHO FC II, n=97 (42%), p>0.05). PATENT-2 [78] 1.5 mg riociguat, n=56 (WHO FC III n= 35 (63%) versus WHO FC II, n=17 (30%), p<0.005). All Fisher's exact test. 6MWD: 6-min walk distance.

FIGURE 3

(Left) Conceptual framework for pulmonary arterial hypertension (PAH) of health-related quality of life (HRQoL) and (right) example of “mapping” of patient-reported outcome measures (PROMs) used in PAH randomised controlled trials onto the conceptual framework. (Left) Framework of patient-reported themes (n=6) and subthemes (n=25) identified by two independent reviewers on the impact of PAH (majority group 1 PAH) on HRQoL. Directly reported concepts are in bold (n=8,045 from supplementary table E6). Concepts may indirectly cross subthemes (cross-loading). For example, treatment burden may impact on the EuroQol-five dimensions-five levels (EQ-5D-5L) item “pain/discomfort” as a reflection of treatment side-effects; however, this is not included within the scope of this analysis. Further PROMs mapped are available in online supplementary figure E4. The Living with Pulmonary Hypertension Questionnaire (LPHQ) is combined with the Minnesota Living with Heart Failure (MLWHF) questionnaire as these instruments are identical. (Right) Conceptual mapping of PROMs to the HRQoL framework (undertaken by six PAH consultants, two PAH clinical fellows, one nurse specialist, one clinical psychologist and one physiotherapist). The LPHQ covers all main themes compared to EQ-5D-5L. PWM: preference-weighted measure.