Establishing minimally important differences for cardiac MRI end-points in pulmonary arterial hypertension

Graphical Abstract Summary of cardiac magnetic resonance (CMR) absolute change minimally important differences (MIDs) for how a patient “feels” benchmarked to the emPHasis-10 (E-10) quality of life questionnaire, “functions” benchmarked to the incremental shuttle walk test or “survives” benchmarked to 1-year mortality post-follow-up. RVEF: right ventricular ejection fraction; RVEDV: right ventricular end-diastolic volume; RVESV: right ventricular end-systolic volume. Background Cardiac magnetic resonance (CMR) is the gold standard technique to assess biventricular volumes and function, and is increasingly being considered as an end-point in clinical studies. Currently, with the exception of right ventricular (RV) stroke volume and RV end-diastolic volume, there is only limited data on minimally important differences (MIDs) reported for CMR metrics. Our study aimed to identify MIDs for CMR metrics based on US Food and Drug Administration recommendations for a clinical outcome measure that should reflect how a patient “feels, functions or survives”. Methods Consecutive treatment-naïve patients with pulmonary arterial hypertension (PAH) between 2010 and 2022 who had two CMR scans (at baseline prior to treatment and 12 months following treatment) were identified from the ASPIRE registry. All patients were followed up for 1 additional year after the second scan. For both scans, cardiac measurements were obtained from a validated fully automated segmentation tool. The MID in CMR metrics was determined using two distribution-based (0.5sd and minimal detectable change) and two anchor-based (change difference and generalised linear model regression) methods benchmarked to how a patient “feels” (emPHasis-10 quality of life questionnaire), “functions” (incremental shuttle walk test) or “survives” for 1-year mortality to changes in CMR measurements. Results 254 patients with PAH were included (mean±sd age 53±16 years, 79% female and 66% categorised as intermediate risk based on the 2022 European Society of Cardiology/European Respiratory Society risk score). We identified a 5% absolute increase in RV ejection fraction and a 17 mL decrease in RV end-diastolic or end-systolic volumes as the MIDs for improvement. Conversely, a 5% decrease in RV ejection fraction and a 10 mL increase in RV volumes were associated with worsening. Conclusions This study establishes clinically relevant CMR MIDs for how a patient “feels, functions or survives” in response to PAH treatment. These findings provide further support for the use of CMR as a clinically relevant clinical outcome measure and will aid trial size calculations for studies using CMR. Extract In patients with pulmonary arterial hypertension (PAH), symptoms and survival are determined primarily by right ventricular (RV) function. In PAH, a progressive pulmonary vasculopathy results in elevation of mean pulmonary arterial pressure (mPAP) and an increase in RV afterload [1]. With disease progression and chronically elevated mPAP, the right ventricle undergoes remodelling, resulting in either adaptation and maintenance of output [2] or maladaptation, RV failure and consequently reduced survival [3]. Cardiac magnetic resonance (CMR) is the gold standard for assessing the right ventricle and shows potential in the assessment of PAH [4]. Impairments of RV function and associated increases in RV volumes can be detected and quantified by CMR, enabling prediction of clinical worsening and mortality [5] and aiding risk stratification [6]. In addition, CMR is sensitive to improvements in RV function following PAH therapy [7–10] and detects a larger treatment effect than the 6-min walk test (6MWT) [11]. In this context, CMR is an important tool for risk stratification and monitoring of disease and treatment response in PAH [4]. Tweetable abstract Changes in key cardiac MRI metrics reflect changes in how a patient “feels, functions or survives” in pulmonary arterial hypertension https://bit.ly/3IE21Ow Plain language summary Pulmonary arterial hypertension (PAH) is a disease of the vessels of the lung that causes their narrowing and stiffening. As a result, the heart pumping blood into these diseased lung vessels has to work harder and eventually gets worn out. PAH can affect patients' ability to function in daily activities and impact their quality of life. It also reduces their life expectancy dramatically. Patients are, therefore, often monitored and undergo several investigations to adapt treatment according to their situation. These investigations include a survey of how a patient feels (the emPHasis-10 questionnaire), functions (walking test) and how well the heart is coping with the disease (MRI of the heart). Until now, it is unclear how changes on MRI of the heart reflect changes in how a patient feels and functions. Our study identified patients that had the emPHasis-10 questionnaire, walking test and MRI of the heart at both the time of PAH diagnosis and one year later. This allowed us to compare how the changes in the different tests relate to each other. And because previous research identified thresholds for important changes in the emPHasis-10 questionnaire and the walking tests, we were able to use these tests as a benchmark for changes in the MRI of the heart. Our study identified thresholds for change on heart MRI that might indicate whether a patient has improved or worsened. This finding might have implications for how patients are monitored in clinical practice and future research on PAH treatments.