Renin, Angiotensin II, and the Journey to Evidence-based Individual Treatment Effects

Casey, Jonathan D; Semler, Matthew W.

doi:10.1164/rccm.202007-2731ed

Cited by 4 publications

(3 citation statements)

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“…One challenge in identifying effective therapeutics for a broadly defined syndrome like acute HRF is heterogeneity in treatment response and prognosis [ 6 ]. Defining reliable subsets of patients with high likelihood of disease-related events or differential treatment responses (often termed subphenotypes) can help target clinical care and trial enrollment to patients most likely to benefit [ 7 , 8 ]. Previous efforts to identify subphenotypes of respiratory failure have largely centered on acute respiratory distress syndrome (ARDS), which represents less than a quarter of patients on mechanical ventilation, and two-thirds of patients with acute HRF [ 9 – 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Reliably diagnosing ARDS is also challenging, largely driven by variability in the interpretation and sensitivity of the chest radiograph [ 13 – 17 ]. As such, characterizing subphenotypes of acute HRF is a newly identified research priority by the National Heart, Lung, and Blood Institute with potential to expand inclusion criteria for trials [ 8 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of persistent and resolving subphenotypes of acute hypoxemic respiratory failure in two independent cohorts

et al. 2021

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Background Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Defining subphenotypes with distinct prognoses or biologic features can improve therapeutic trials, but prior work has focused on ARDS, which excludes many acute HRF patients. We aimed to characterize persistent and resolving subphenotypes in the broader HRF population. Methods In this secondary analysis of 2 independent prospective ICU cohorts, we included adults with acute HRF, defined by invasive mechanical ventilation and PaO2-to-FIO2 ratio ≤ 300 on cohort enrollment (n = 768 in the discovery cohort and n = 1715 in the validation cohort). We classified patients as persistent HRF if still requiring mechanical ventilation with PaO2-to-FIO2 ratio ≤ 300 on day 3 following ICU admission, or resolving HRF if otherwise. We estimated relative risk of 28-day hospital mortality associated with persistent HRF, compared to resolving HRF, using generalized linear models. We also estimated fold difference in circulating biomarkers of inflammation and endothelial activation on cohort enrollment among persistent HRF compared to resolving HRF. Finally, we stratified our analyses by ARDS to understand whether this was driving differences between persistent and resolving HRF. Results Over 50% developed persistent HRF in both the discovery (n = 386) and validation (n = 1032) cohorts. Persistent HRF was associated with higher risk of death relative to resolving HRF in both the discovery (1.68-fold, 95% CI 1.11, 2.54) and validation cohorts (1.93-fold, 95% CI 1.50, 2.47), after adjustment for age, sex, chronic respiratory illness, and acute illness severity on enrollment (APACHE-III in discovery, APACHE-II in validation). Patients with persistent HRF displayed higher biomarkers of inflammation (interleukin-6, interleukin-8) and endothelial dysfunction (angiopoietin-2) than resolving HRF after adjustment. Only half of persistent HRF patients had ARDS, yet exhibited higher mortality and biomarkers than resolving HRF regardless of whether they qualified for ARDS. Conclusion Patients with persistent HRF are common and have higher mortality and elevated circulating markers of lung injury compared to resolving HRF, and yet only a subset are captured by ARDS definitions. Persistent HRF may represent a clinically important, inclusive target for future therapeutic trials in HRF.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of persistent and resolving subphenotypes of acute hypoxemic respiratory failure in two independent cohorts

et al. 2021

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“…Finally, we note that a previous criticism of the ATHOS-3 trial had been the higher prevalence of ARDS in the placebo group [ 47 ]. We now show that in that subset of ATHOS-3 patients with ARDS at enrollment, angiotensin-II met the trial’s primary efficacy endpoint and was associated with improved oxygenation.…”

Section: Discussionmentioning

confidence: 85%

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock

Leisman,

Handisides,

Chawla

et al. 2023

Ann. Intensive Care

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Background The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. Methods Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. Results Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2–161.5], p = 0.0028). Similarly, oxygenation index decreased by − 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus − 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI − 8.6 to − 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5–47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. Conclusions In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. Trial Registration: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

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Angiotensin II: A Review of Current Literature

Alam

Sovic

Gill

et al. 2022

Journal of Cardiothoracic and Vascular Anesthesia

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Renin, Angiotensin II, and the Journey to Evidence-based Individual Treatment Effects

Cited by 4 publications

References 10 publications

Identification of persistent and resolving subphenotypes of acute hypoxemic respiratory failure in two independent cohorts

Identification of persistent and resolving subphenotypes of acute hypoxemic respiratory failure in two independent cohorts

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock

Angiotensin II: A Review of Current Literature

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