key: cord-0925644-bv6y6lad
authors: Alabed, Samer; Shahin, Yousef; Garg, Pankaj; Alandejani, Faisal; Johns, Christopher S.; Lewis, Robert A.; Condliffe, Robin; Wild, James M.; Kiely, David G.; Swift, Andrew J.
title: Cardiac-MRI Predicts Clinical Worsening and Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis
date: 2020-09-30
journal: JACC Cardiovasc Imaging
DOI: 10.1016/j.jcmg.2020.08.013
sha: 69dfc1240430d751e3d81cc70f4a334e5ca9862c
doc_id: 925644
cord_uid: bv6y6lad

OBJECTIVES: This meta-analysis evaluates assessment of pulmonary arterial hypertension (PAH), with a focus on clinical worsening and mortality. BACKGROUND: Cardiac magnetic resonance (CMR) has prognostic value in the assessment of patients with PAH. However, there are limited data on the prediction of clinical worsening, an important composite endpoint used in PAH therapy trials. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Science databases were searched in May 2020. All CMR studies assessing clinical worsening and the prognosis of patients with PAH were included. Pooled hazard ratios of univariate regression analyses for CMR measurements, for prediction of clinical worsening and mortality, were calculated. RESULTS: Twenty-two studies with 1,938 participants were included in the meta-analysis. There were 18 clinical worsening events and 8 deaths per 100 patient-years. The pooled hazard ratios show that every 1% decrease in right ventricular (RV) ejection fraction is associated with a 4.9% increase in the risk of clinical worsening over 22 months of follow-up and a 2.2% increase in the risk of death over 54 months. For every 1 ml/m(2) increase in RV end-systolic volume index or RV end-diastolic volume index, the risk of clinical worsening increases by 1.3% and 0.7%, respectively, and the risk of mortality increases by 0.9% and 1%. Every 1 ml/m(2) decrease in left ventricular end-systolic volume index or left ventricular end-diastolic volume index increased the risk of death by 2.1% and 2.3%. Left ventricular parameters were not associated with clinical worsening. CONCLUSIONS: This review confirms CMR as a powerful prognostic marker in PAH in a large cohort of patients. In addition to confirming previous observations that RV function and RV and left ventricular volumes predict mortality, RV function and volumes also predict clinical worsening. This study provides a strong rationale for considering CMR as a clinically relevant endpoint for trials of PAH therapies.

is characterized by remodeling of the distal pulmonary arteries, leading to an increase in pulmonary vasculature resistance, reduced compliance, and elevated pulmonary artery pressure (1) (2) (3) . Untreated, PAH has high morbidity and mortality that are closely linked to right ventricular (RV) dysfunction (2) . A new diagnosis of PAH increases the risk of death at 1 year fivefold (4) . However, over the last 20 years, treatment advancements have led to an increase in median survival from 3 to 7 years (4-6), although development of new therapies is needed.

Recently, clinical studies of PAH therapies have moved from assessing exercise capacity and pulmonary hemodynamics to using composite endpoints. One such approach uses the time to clinical worsening. Clinical worsening events include hospitalization, disease progression, and unsatisfactory longterm clinical response, in addition to mortality (7) . However, given the large number of patients required and the expense of conducting such event-driven studies, cardiac magnetic resonance (CMR) has recently been explored as a primary endpoint to evaluate PAH therapies (8) .

CMR is the gold standard method of measuring RV function, volumes, and mass, and it is an established prognostic and therapy response tool (1, 9, 10) . In 2015, a meta-analysis assessed the prognostic value of CMR measurements in 5 studies with 332 participants (9) ; however, no data were reported on clinical worsening. Since then, multiple new studies assessing clinical worsening in addition to mortality have been published in PAH.

The current meta-analysis also includes unpublished supplemental data on CMR metrics from 16 previously published studies, which allowed us to provide new data on the utility of CMR to predict clinical worsening in addition to mortality. The goal of the current study therefore was to review the evidence for CMR metrics to predict clinical worsening and mortality in patients with PAH.

The review was prospectively registered with The International Prospective Register of Systematic Reviews on December 12, 2019 (ID: CRD42019160296).

The Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines were followed (11) .

Ethical approval was not required for this metaanalysis because it was based on published literature and did not recruit patients.

Studies of all forms of PAH (including idiopathic PAH [IPAH] , heritable, drug-and toxin-induced PAH, and PAH associated with connective tissue disease [CTD]; congenital heart disease; HIV infection; and portal hypertension) were considered for inclusion in the meta-analysis. For studies including patients with different forms of pulmonary hypertension (PH), data from these studies were incorporated only if the PAH cohort was separately described or the PAH participants formed at least one-half of the study population. To obtain additional data on patients with PAH, which may have been collected but not published, authors were contacted and supplemental data requested. Case reports or small cases series of <10 participants were excluded. Data collected included any clinically relevant outcomes such as hospitalization due to heart failure, disease progression, unsatisfactory long-term clinical response, and death. To allow for analysis, only studies that reported Cox regression hazard ratios expressed per unit of measurement were included. One study reporting dichotomized hazard ratios was excluded because raw hazard ratios could not be obtained after contacting the study author. All studies were performed at PH referral centers and are therefore at risk for referral bias. The Values are median (range), n (%), mean AE SD, or n, unless otherwise indicated. *Only patients with pulmonary arterial hypertension (PAH) were included in the analysis.

CC ¼ case-control; CHD ¼ congenital heart disease; CTD ¼ connective tissue disease; IPAH ¼ idiopathic pulmonary arterial hypertension; mPAP ¼ mean pulmonary artery pressure; NR ¼ not reported; PCS ¼ prospective case series; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension; RCS ¼ retrospective case series; U.K. ¼ United Kingdom; U.S. ¼ United States. Table 2 . There may, however, be sources of heterogeneity that could not be assessed in a meta-regression analysis

where not enough data were available. There were differences in the types of clinical worsening events The meta-analyses of right ventricular (RV) and left ventricular (LV) function and mass showed that RVEF and RVMI are significant prognostic markers. RVEF could predict clinical worsening separate from mortality, whereas RVMI is a nonspecific prognostic marker. Unpublished data are indicated by (þ). CI ¼ confidence interval; other abbreviations as in Figure 1 . Cardiac MRI Prediction of Clinical Worsening and Mortality in Pulmonary Arterial Hypertension -2 0 2 0 : --- RV and LV volumes are significant prognostic markers. A decrease in RV volumes can predict mortality and clinical worsening, whereas an increase in LV volumes indicates an increased risk for death only. Unpublished data are indicated by (þ). LVSVI ¼ left ventricular stroke volume index; RVSVI ¼ right ventricular stroke volume index; other abbreviations as in Figures 1 and 2. also indicate that some studies with extreme negative results have not been published.

To the best of our knowledge, this paper is the largest meta-analysis of CMR imaging in patients with PAH and the first to report on clinical worsening in addition to mortality. We have confirmed that CMR imaging is a powerful prognostic marker in a large cohort of patients from multiple institutions, across several continents and using different imaging platforms. In addition, we have shown that CMR imaging predicts clinical worsening in patients with PAH. Our findings highlight the clinical utility of CMR imaging and support further evaluation of this modality as a clinically meaningful trial endpoint for the assessment of new therapies for PAH (Central Illustration, Table 3 ).

Clinical worsening as a composite endpoint has been shown to predict mortality (34) and has established itself as a primary efficacy endpoint in trials of PAH therapies (7, 35) . Although heart failure and all-cause mortality are included in all PAH trials using a composite clinical worsening endpoint, these trials vary in their inclusion and definition of progression markers, such as change in exercise tolerance or functional capacity (36), and they may use different thresholds to define a meaningful change (37) . Nonetheless, study designs using time to clinical worsening have been increasingly adopted to evaluate PAH therapies. However, such studies require large numbers of participants and a prolonged period of follow-up, usually lasting for several years. As a consequence and given recent events such as the coronavirus disease 2019 pandemic, there has been a focus on considering clinical trial endpoints, which allow the impact of candidate therapies to be assessed over a shorter period and using an endpoint that correlates with clinically meaningful events. STUDY LIMITATIONS. An extensive systematic literature search was performed, and a pre-published protocol was followed. However, a potential limitation of this study is that inclusion was assessed by a single investigator. Any doubt regarding study selection was discussed with another investigator, however. This meta-analysis contains previously unpublished data for participants included in previously published studies. However, this approach has allowed improved data completeness and additional analysis. The included studies including supplemental data are indicated by (þ) in Figures 2 and 3 .

The unpublished univariate hazard ratios are provided in Supplemental Appendix 5. Patients in this study included a cohort with a predominantly intermediate and high risk of 1-year mortality and likely represent a cohort with more severe disease.

Although the results of the meta-analysis suggest that CMR imaging, as performed in expert centers, strongly associates with outcomes, some caution is warranted in its application in less-experienced centers given the limited existence of multicenter studies. In some instances, heterogeneity is high, and greater caution in interpretation is therefore indicated. Finally, only limited data are provided on the potential of CMR metrics such as myocardial strain analysis, right atrial size, pulmonary artery wall stiffness, and four-dimensional flow parameters and the application of artificial intelligence approaches to large imaging datasets, which may add clinical value.

This meta-analysis is the first to study the role of CMR in the prediction of clinical worsening in PAH. We have shown that CMR can predict clinical worsening, in addition to confirming its prognostic role, in a large cohort of patients with PAH. This study provides a strong rationale for considering CMR as a clinical trial endpoint.

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The authors also thank Dr. Maria Sukhanenko for her help with extracting data from a Russian study.

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

worsening is an important composite endpoint used in therapy trials in PAH. In a meta-analysis of 1,938 participants with PAH, we showed that CMR predicts clinical worsening and has prognostic value. In a metaregression, we have also shown that CMR predicts clinical worsening and mortality independent of age, sex, pulmonary hemodynamics, and walking distance. This study provides further data supporting the clinical utility of CMR in patients with PAH.TRANSLATIONAL OUTLOOK: The findings of this meta-analysis provide a strong rationale for future research to consider CMR as a clinically relevant endpoint for therapy trials in PAH.