Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial

Abstract

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy. Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS. Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours. Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13–58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios ( r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo ( P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) ( P = 0.048 for the interaction). Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes. Clinical trial registered with www.clinicaltrials.gov (NCT 02338843).

The Effect of Angiotensin II Infusion on Markers of Organ Function in Invasively Ventilated COVID-19 Patients

“…ANGII has been previously reported as bene cial in patients with markedly abnormal renal function at randomization [9]. Our ndings of a >95% probability of decreasing renal of replacement therapy use in COVID-19 patients with abnormal renal function at admission support such previous ndings.…”

“…This is the rst controlled evaluation of ANGII as adjunctive treatment in ventilated patients with COVID-19 pneumonia. However, a recent case series had shown evidence of increased PaO 2 /FiO 2 over time [9]. Our ndings con rm this effect on oxygenation.…”

“…34/int/2020), was registered on ClinicalTrials.gov (NCT04318366). Full description of patient management and clinical protocols at San Raffaele were previously published [9,10].…”

“…[8]. Moreover, in patients receiving renal replacement therapy (RRT) at randomization, ANG II increased the likelihood of recovery to RRT independence [9]. Its physiological effect on oxygenation in patients with COVID-19 was recently assessed in an uncontrolled case series [10] which reported an improvement of PaO2/FiO2 ratio with ANGII.…”

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

“…In this issue of the Journal , Bellomo and colleagues (pp. 1253–1261 ) demonstrate an important early step in this journey ( 3 ). In a secondary analysis of the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial ( 4 ), they examine how biologic measures along the proposed mechanistic pathway for angiotensin II infusion modify the effect of the treatment on outcomes, posing the question, “Can bedside measurement of serum renin levels identify which patients will benefit from treatment with angiotensin II?”…”