Cardiac effort: a tool to reduce variability and enrich enrollment for patients: who will increase 6-minute walk distance in pulmonary arterial hypertension trials?

SESSION TITLE: Novel Insights into Diagnosis of PH SESSION TYPE: Original Investigations PRESENTED ON: 10/08/2023 09:30 am - 10:30 am PURPOSE: 6-minute walk test (6MWT) remains an important endpoint in clinical trials. Intrinsic variability has made detecting clinical improvement difficult, especially when walks are longer. We previously showed Cardiac Effort (CE, number of heart beats/6-minute walk distance (6MWD)) is more reproducible than 6MWD and more sensitive to therapy intensification. Here, we assessed whether CE could predict whether a PAH patient adding therapy would improve 6MWD. Specifically, we hypothesize that those with higher CE would be more likely to walk further after intensifying therapy. METHODS: This was a prospective single center study with IRB approval. PAH patients performed 6MWT according to ATS guidelines without a mask. MC10 Biostamp nPoint recorded continuous heart rate, and CE was calculated for each walk. Stable patients on vasodilator therapy for >90 days completed two 6MWT within 4 weeks to test reproducibility. Treatment intensification (TI) patients had a clinical indication to add vasodilator therapy and completed 6MWT at baseline and 12 weeks later. Continuous variables are reported as mean ± standard deviation. RESULTS: 90 patients (61 female) with PAH (52 stable and 38 treatment intensification) completed paired 6MWT. Baseline 6MWD and CE in the stable group was 417m ±94 and 1.8 beats/m ±0.5, while it was 314m ±124 and 2.8 beats/m ±1.7 for TI. In the stables, there was no difference between baseline CE in males vs. females. In the TI group, males had a lower baseline CE, 2.0 beats/m ±1.1 vs 3.2 beats/m ±1.8, p=0.03; this was attributable to males having a longer baseline walk, 374m ±96 vs. 279m ±127. The stable group had a 1m ±29 difference between walks. Expressed as a %, the standard deviation for change in CE (in stables) was smaller than SD for change in 6WMD (5 vs. 7%). In the TI group, 6MWD increased by 34 m ±57; expressed as % change, CE decreased 11% ±25. There was no difference in change in CE or 6MWD at follow up in males vs females. We tested the idea that a ‘threshold’ CE of 1.5 might be useful as an enrollment criteria (to exclude those without sufficient effort during 6MWT). Using a CE of <1.5 beats/m in the stables, Bland Altman comparing the two 6MWD showed a bias of -15 m with 95% CI (-68, 39), while those with CE ≥1.5 showed a bias of 10 m with tighter 95% CI (-37, 56). The group for whom we had made a clinical decision to intensify therapy had a greater mean CE 2.8 beats/m and all were ≥1.5; 23/38 improved by ≥30 m. CONCLUSIONS: CE has less variability than 6MWD in repeat measurements, and higher CE was associated with a clinical decision to intensify therapy. CLINICAL IMPLICATIONS: Incorporating CE as an inclusion criteria (CE ≥1.5 beats/m) into future clinical trials could help decrease the intrinsic variability in 6MWD and enrich for patients most likely to increase walk with additional effective therapy. DISCLOSURES: No relevant relationships by Deborah Haight Speaker/Speaker's Bureau relationship with United Therapeutics Please note: May 2020 - present by Daniel Lachant, value=Honoraria Removed 12/05/2022 by Daniel Lachant, source=Web Response Speaker relationship with Bayer Please note: 2019 - present Added 12/05/2022 by Daniel Lachant, source=Web Response, value=Consulting fee Speaker relationship with United Therapeutics Please note: 2019 - Present Added 12/05/2022 by Daniel Lachant, source=Web Response, value=Grant Support No relevant relationships by Michael Lachant Principal Investigator relationship with United Therapeutics Please note: years, > $100K Added 04/01/2023 by R. James White, value=Grant/Research Removed 04/01/2023 by R. James White, source=Web Response Research relationship with United Therapeutics Please note: 1/1/2005-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research Research relationship with Merck Please note: 1/1/2016-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Merck Please note: 1/1/2013-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Consulting fee Research relationship with Bayer Please note: 1/1/2015-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research Research relationship with Gossamer Please note: 1/1/2019-4/1/2023 Added 04/01/2023 by R. James White, source=Web Response, value=Grant/Research Support