Remote evaluation of risk and physiological response to therapeutic escalation and clinical worsening in patients with pulmonary hypertension

Background International guidelines for the treatment of patients with pulmonary arterial hypertension (PAH) recommend the use of risk stratification to optimise therapy to achieve and maintain a low-risk profile. However, recommended methods require hospital-based investigations. We sought to develop a method for daily, remote risk evaluation. Methods Consecutive patients (n=5820) with pulmonary hypertension (PH) were identified from the ASPIRE registry and stepwise Cox regression applied to identify parameters associated with survival. A physiological risk score was applied to all patients and survival assessed by the Kaplan-Meier method. Physical activity was measured in patients with PAH implanted with insertable cardiac monitors (ICM, n=80) to provide a remote measure of exercise capacity. In patients with PAH and implanted pulmonary artery pressure (PAP) monitor and ICM (n=28) we undertook a time-stratified bidirectional case–crossover study to determine the physiology of therapeutic escalation (TE) and clinical worsening and a remote physiological risk score applied to the data. Results Age, male sex, PH aetiology, WHO functional class (FC), incremental shuttle walk-distance (ISWD), heart rate reserve (HRR) and total pulmonary resistance (TPR) as independent predictors of survival. Mortality increased with each decile of baseline physiological risk (p<0.001). In patients with PAH, thresholds of physiological risk were used to classify patients into low-, intermediate-low-, intermediate-high-, and high-risk groups for one-year mortality, which were well matched to COMPERA-2.0 score-stratified groups (Cohen’s weighted Kappa 0.61). ICM-measured physical activity decreased with indicators of increased clinical risk (WHO-FC, NT-proBNP, ISWD, COMPERA-2.0, p<0.0001). Following TE, remote monitored mean PAP and TPR were reduced, and cardiac output (CO) and physical activity increased at days seven, four, 22 and 42 respectively (p<0.05). Clinical worsening events (CWE) were preceded by an increased remote monitored mean PAP and TPR and reduced CO and physical activity (p<0.05). Change in remote physiological risk score identifiable six days after TE and twelve days prior to a CWE (p<0.05). Conclusion Remote risk evaluation may facilitate personalised medicine and proactive management. The physiological risk score accurately stratifies patients with PH and may be applied to remote monitoring data for early evaluation of clinical efficacy and detection of clinical worsening. ### Competing Interest Statement Disclosures: AMKR: Research funding: Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z), Medical Research Council (UK) Experimental Medicine Award (MR/W026279/1), NIHR Biomedical Research Center Sheffield, Contribution in kind: Medtronic, Abbott, Endotronix, Novartis, Janssen. Research support and consulting: NXT Biomedical, Endotronix, SoniVie, Neptune, Gradient. MT: Research funding: NIHR Biomedical Research Center Cambridge, NIHR HTA. Personal support: GCK and Jansen. DSMB: ComCov, FluCov. PDM: personal support: Abbott. JTM, SB, HZ, JP, CA, JT, DNN, CB, CP, CR, SR, JA, AR, LW, JD, RL, FV, CD, NH, IA, KD, AJS, JH, AH, AC, TB, SKWH, JMSW, AART, RC, CE, DGK: none. ### Funding Statement Wellcome Trust Clinical Research Career Development Fellowship (AR: 206632/Z/17/Z; AS: 205188/Z/16/Z, PDM: 214567/Z/18/Z), BHF Intermediate Fellowship (AART: FS/18/13/33281), MRC Confidence in Concepts (AR), Medtronic External Research Program Award (AR), Donald Heath Research Fellowship (JM), MRC Experimental Medicine grant (MR/W026279/1) (AR/JM/MT/DGK), NIHR Applied Research Collaboration North East and North Cumbria (TB: NIHR2001), National Institute for Health Research (SKWH: NIHR302746; JMSW: NIHR301614). The research was carried out at the National Institute for Health and Care Research (NIHR) Sheffield and Cambridge cardiorespiratory Biomedical Research Centres. AR is grateful to Richard Hughes, whose generous philanthropic support has helped to make this work possible. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was provided by NHS research ethics committees (ASPIRE:22/EE/0011; FIT-PH: 19/YH/0354; National Cohort Study of Idiopathic and Heritable Pulmonary Arterial Hypertension: 13/EE/0203). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors