An index of the initial blood pressure response to angiotensin II treatment and its association with clinical outcomes in vasodilatory shock

Abstract

Background: No standardized index exists to assess cardiovascular responsiveness to angiotensin-II. We hypothesized that a standardized index of initial blood pressure response to angiotensin-II treatment would be associated with clinical outcomes.

Methods: Using data from the Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we developed an Angiotensin-II Initial MAP Response Index of Treatment Effect (AIMRITE) defined as (MAP at hr1 - MAP at baseline)/study drug dose. We assessed AIMRITE continuously and, based on observed distributions, we additionally categorized patients as "responsive" or "resistant", with responsiveness defined by an AIMRITE ≥ 0.90 mmHg/ng/kg/min. The primary clinical outcome was 28-day mortality. Secondary outcomes included days alive and vasopressor- or ventilator- or renal replacement therapy-free at day-7. Biological outcomes included baseline renin, angiotensin-II, and renin/angiotensin-II ratio, and their change at hr3.

Results: Of 158 placebo patients, as expected, 157 (99%) had AIMRITE < 0.90 mmHg/ng/kg/min (median AIMRITE 0.02; IQR - 0.03-0.10). In contrast, 163 patients assigned to angiotensin-II had a median AIMRITE of 1.43 mmHg/ng/kg/min (IQR 0.35-2.83). Of these, 97 (60%) were responsive (median AIMRITE 2.55; IQR 1.66-4.12) and 66 (40%) were resistant (median AIMRITE 0.24; IQR 0.10-0.52). Each 1.0-unit increase in AIMRITE was associated with a 16% lower hazard of death (HR: 0.84 per-mmHg/ng/kg/min [95% CI 0.74-0.95], p = 0.0062). Responsive patients had half the mortality hazard than resistant patients (HR: 0.50 [95% CI 0.32-0.78], p = 0.0026) and placebo patients (HR 0.58 [95% CI 0.40-0.86], p = 0.0064). Resistant patients had a similar mortality hazard to placebo (HR 1.17 [95% CI 0.80-1.72], p = 0.41). Compared to resistant patients, responsive patients had lower baseline renin and renin/angiotensin-II ratio, but a greater decrease in both at hr3. When stratified by baseline renin level, mortality was highest in placebo patients with high renin (69%) and angiotensin-II resistant patients with low renin (61%).

Conclusions: Among patients with catecholamine-refractory vasodilatory shock treated with angiotensin-II, the AIMRITE was associated with mortality at day-28. Responsive angiotensin-II patients had higher survival versus both angiotensin-II resistant patients and those treated with placebo plus standard vasopressors. This index may serve as a prognostic indicator and early identifier of patients most likely to benefit from angiotensin-II.

Trial registration: ClinicalTrials.gov NCT02338843.

Keywords: Angiotensin II; Norepinephrine; Renin-angiotensin system; Septic; Shock.

Fig. 1

Distributions of Initial MAP Response by Treatment Assignment and AIMRITE Phenotype A Violin plots of initial MAP response at hr₁ indexed to study-drug dose, stratified by treatment assignment. Dotted lines indicate thresholds used for assignment in categorical analyses. Dots correspond to individual patients. Highlighted solid and broken lines indicate the median and interquartile range, respectively. B Distribution of study drug dose among Ang-II and Placebo patients (LEFT), and within Ang-II patients, among responsive vs. resistant patients (RIGHT). Dots correspond to individual patients. Box height represents interquartile range, error bars the range. The black dotted line at 20 ng/kg/min indicates the study drug dose at which all infusions were initiated at baseline. C Spaghetti plot for MAP at baseline and hour 1 in Ang-II versus Placebo patients. Each dot represents an individual patient’s MAP at the indicated timepoint with lines connecting measurements from the same patient. In the overlaid box and whisker plot, Box height represents interquartile range, error bars the 2.5th and 97.5th percentiles. D Shows the same, but within the Ang-II patients for the responsive versus resistant groups. Abbreviations: AIMRITE: Angiotensin-II Initial MAP Response Index of Treatment Effect; Ang-II: angiotensin-II; MAP: mean arterial pressure

Fig. 2

Illustrative Examples of AIMRITE Calculation and Interpretation Boxed text outlines how AIMRITE is calculated and subsequently interpreted. Four hypothetical patients are then displayed, from most to least responsive, demonstrating how large changes in MAP relative to the angiotensin-II dose produce high (responsive) AIMRITE values. While the threshold of 0.90 mmHg/ng/kg/min was used in categorical analysis, AIMRITE is a continuous variable and should be understood to reflect a spectrum of sensitivity to angiotensin-II rather than a binary test for responsiveness. Abbreviations: AIMRITE – Angiotensin-II Initial MAP Response Index of Treatment Effect; Ang-II: angiotensin-II; MAP: mean arterial pressure

Fig. 3

Association of Survival to Day 28 with Initial MAP Response to Angiotensin-II Treatment (A) Survival plots for angiotensin-II responsive (green) vs. resistant (red) vs. placebo (blue) patients. Adjusted HRs show the indicated comparison from the primary analysis multivariable model. (B) Day-28 mortality probability plot shows the predicted probability of death as a function of the AIMRITE (modeled non-parametrically as a continuous variable). The vertical dotted line indicates the 95th percentile of AIMRITE among subjects. Shaded areas indicate 95% confidence bands. Boxed text displays the effect estimates from the Cox models with a linear predictor for comparison. Abbreviations: Ang-II: angiotensin-II, AIMRITE: angiotensin-II initial MAP response index of treatment effect, MAP: mean arterial pressure, HR: hazard ratio

Fig. 4

Initial MAP Response to Angiotensin-II Treatment and Renin Levels (Top row) Baseline renin level (left column), angiotensin-II level (middle column), and renin/angiotensin-II ratio (right column) according to initial treatment response. Y-axis is on log2-scale. Bars indicate median, boxes IQR, whiskers data range. Brackets indicate specific group comparisons. (Middle row) Shows the same for the change in log-renin at hour 3. (Bottom row) Shows change in the indicated biomarker stratified by whether the baseline plasma renin level was > 172.7 pg/mL. Bar height indicates the mean value, error bars, SEM. Brackets indicate specific group comparisons. Abbreviations: A-II + : angiotensin-II responsive group, A-II: angiotensin-II resistant group, PBO: placebo group, SEM: standard error of the mean

Fig. 5

Mortality Stratified by Initial MAP Response to Angiotensin-II Treatment and Renin Levels Survival curves stratified by baseline renin and treatment responsiveness. Raw 28-day mortality is displayed at the bottom right of the plot, with the cell color corresponding to the indicated group’s survival curve. The stratified HR from the proportional hazard model is displayed below the plot. Abbreviations: Ang-II: angiotensin-II, HR: hazard ratio, 95%CI 95% confidence interval