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Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial.

ABSTRACT: BACKGROUND:Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring???5 ng kg-1 min-1 angiotensin II at 30 min (??5 ng kg-1 min-1 subgroup) to maintain mean arterial pressure (MAP)???75 mmHg versus patients receiving?>?5 ng kg-1 min-1 angiotensin II at 30 min (>?5 ng kg-1 min-1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used. RESULTS:The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg-1 min-1 at treatment initiation to???5 ng kg-1 min-1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the?>?5 ng kg-1 min-1 subgroup (84/163). Patients in the???5 ng kg-1 min-1 subgroup were more likely to have a MAP response at 3 h versus those in the?>?5 ng kg-1 min-1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63-19.7], P??5 ng kg-1 min-1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28-0.72], P?=?0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The???5 ng kg-1 min-1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the?>?5 ng kg-1 min-1 subgroup. CONCLUSIONS:This prespecified analysis showed that down-titration to???5 ng kg-1 min-1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency.

SUBMITTER: Ham KR

PROVIDER: S-EPMC6546778 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial.

Ham Kealy R KR Boldt David W DW McCurdy Michael T MT Busse Laurence W LW Favory Raphael R Gong Michelle N MN Khanna Ashish K AK Chock Stefan N SN Zeng Feng F Chawla Lakhmir S LS Tidmarsh George F GF Ostermann Marlies M

Annals of intensive care 20190603 1

<h4>Background</h4>Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg-1 min-1 angiotensin II at 30 min (≤ 5 ng kg-1 min-1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg-1 min-1 angiotensin II at 30 min (> 5 ng kg-1</s ...[more]

PMID: 31161442

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Project description:BackgroundIn patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study.MethodsWe measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes.ResultsMedian baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P < 0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P < 0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P < 0.0001), lower ANG II levels (P < 0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P < 0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses.ConclusionsPatients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction.Trial registrationClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Project description:BackgroundHigh dose vasopressors portend poor outcome in vasodilatory shock. We aimed to evaluate the impact of baseline vasopressor dose on outcomes in patients treated with angiotensin II (AT II).MethodsExploratory post-hoc analysis of the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial data. The ATHOS-3 trial randomized 321 patients with vasodilatory shock, who remained hypotensive (mean arterial pressure of 55-70 mmHg) despite receiving standard of care vasopressor support at a norepinephrine-equivalent dose (NED) > 0.2 µg/kg/min, to receive AT II or placebo, both in addition to standard of care vasopressors. Patients were grouped into low (≤ 0.25 µg/kg/min; n = 104) or high (> 0.25 µg/kg/min; n = 217) NED at the time of study drug initiation. The primary outcome was the difference in 28-day survival between the AT II and placebo subgroups in those with a baseline NED ≤ 0.25 µg/kg/min at the time of study drug initiation.ResultsOf 321 patients, the median baseline NED in the low-NED subgroup was similar in the AT II (n = 56) and placebo (n = 48) groups (median of each arm 0.21 µg/kg/min, p = 0.45). In the high-NED subgroup, the median baseline NEDs were also similar (0.47 µg/kg/min AT II group, n = 107 vs. 0.45 µg/kg/min placebo group, n = 110, p = 0.75). After adjusting for severity of illness, those randomized to AT II in the low-NED subgroup were half as likely to die at 28-days compared to placebo (HR 0.509; 95% CI 0.274-0.945, p = 0.03). No differences in 28-day survival between AT II and placebo groups were found in the high-NED subgroup (HR 0.933; 95% CI 0.644-1.350, p = 0.71). Serious adverse events were less frequent in the low-NED AT II subgroup compared to the placebo low-NED subgroup, though differences were not statistically significant, and were comparable in the high-NED subgroups.ConclusionsThis exploratory post-hoc analysis of phase 3 clinical trial data suggests a potential benefit of AT II introduction at lower doses of other vasopressor agents. These data may inform design of a prospective trial.Trial registrationThe ATHOS-3 trial was registered in the clinicaltrials.gov repository (no. NCT02338843). Registered 14 January 2015.

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Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial.

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Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial.

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