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

Shock is characterized by inadequate organ perfusion, which, if not rapidly corrected, leads to multiorgan failure and death [1]. International guidelines recommend catecholamines as first-line vasopressor agents [2, 3]. Outcomes remain unacceptable because approximately half of patients with vasodilatory shock do not survive beyond 28 days [4‐7]. Additionally, treatment with norepinephrine may cause immunosuppression and seriously complicate the clinical course in patients with septic shock, the most common form of shock [8, 9]. High-dose catecholamines are associated with worse outcomes and adverse events in patients who require higher doses to achieve targeted hemodynamic parameters [9, 10]. An alternative noncatecholamine agent, vasopressin [3], is effective in some patients and may allow the lowering of catecholamine dose, but it has not been shown to improve survival [3]. Further, fewer than 50% of patients in shock generate a blood pressure response to treatment with vasopressin [11], and vasopressin may cause cardiac toxicity, heart failure, and mesenteric ischemia at higher doses [3, 12].

Angiotensin II is a naturally occurring peptide with strong vasopressor activity [13]. A pilot study indicated that the addition of synthetic human angiotensin II to catecholamine and vasopressin therapy maintained mean arterial pressure (MAP) in patients with vasodilatory shock, while allowing for a reduction in catecholamine dosing [14]. In addition, the pilot study noted that 20% of treated patients were exquisitely sensitive to angiotensin II. Given the risk of higher-dose catecholamines, the ability to approach or restore normal hemodynamic function with low doses of systemic vasopressor(s) is an important clinical goal.

Following the pilot study, the randomized, double-blind, phase 3 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) trial (ClinicalTrials.gov, NCT02338843) demonstrated that angiotensin II significantly increased MAP and provided a catecholamine-sparing effect versus placebo in patients with catecholamine-resistant vasodilatory shock [15]. In this study, patients receiving a stable dose of vasopressor were treated with a starting dose of 20 ng kg⁻¹ min⁻¹ angiotensin II that could be adjusted every 5 min to achieve a MAP of ≥ 75 mmHg by hour 3. By 30 min, the angiotensin II dose had been down-titrated from 20 to ≤ 5 ng kg⁻¹ min⁻¹ for 79 of 163 (48%) patients in the treatment arm; analyses comparing this population with those with a dose of > 5 ng kg⁻¹ min⁻¹ at 30 min were prespecified. In a study by Fliser et al. [16], dosing with 1.5 ng kg⁻¹ min⁻¹ of angiotensin II resulted in serum levels of ~ 50 pg/mL, just beyond the upper physiologic range for angiotensin II; therefore, administration of 1.5 to 5 ng kg⁻¹ min⁻¹ angiotensin II is expected to result in serum levels of angiotensin II that approximate physiologic levels in a normotensive individual [16, 17]. Doses of > 5 ng kg⁻¹ min⁻¹ are expected to result in serum levels in the pharmacologic range [16‐18].

We hypothesized that patients most responsive to angiotensin II may have had a defect in angiotensin-converting enzyme function resulting in diminished angiotensin II levels. We further hypothesized that these low angiotensin II levels could be easily corrected to normal physiologic levels by direct exogenous supplementation with the low dose of angiotensin II.

To further characterize the clinical benefit of angiotensin II and to explore these hypotheses, we compared various efficacy and safety parameters in patients receiving angiotensin II in ATHOS-3 who were down-titrated to doses ≤ 5 ng kg⁻¹ min⁻¹ angiotensin II at 30 min versus patients who required > 5 ng kg⁻¹ min⁻¹ angiotensin II at 30 min [15].

Seventy-nine of 163 (48%) patients were down-titrated from an initial angiotensin II dose of 20 ng kg⁻¹ min⁻¹ to a dose of ≤ 5 ng kg⁻¹ min⁻¹ at 30 min following initiation of study drug. This subset of patients was more likely to have a MAP response, increased 28-day survival, and better safety profile when considering grade 3/4 and serious AEs. These data may provide health care practitioners an early indication of which patients are most likely to respond to angiotensin II.

Patients in the ≤ 5 ng kg⁻¹ min⁻¹ angiotensin II subgroup had lower levels of endogenous baseline angiotensin II than their counterparts in the > 5 ng kg⁻¹ min⁻¹ angiotensin II subgroup. However, the angiotensin II levels for patients with shock are higher than those for normal patients as previous studies have shown levels of angiotensin II in normal adult plasma to range from 5 to 35 pg/mL [19]. The observations seen herein support our hypothesis that patients sensitive to low levels of angiotensin II (≤ 5 ng kg⁻¹ min⁻¹) are more likely to have an angiotensin II insufficiency. Nonetheless, supplementation with exogenous angiotensin II in “angiotensin II insufficient” patients helped rapidly restore MAP and was associated with improved outcomes. The possible reasons underlying sensitivity to exogenous angiotensin II remain unclear, as patients in the ≤ 5 ng kg⁻¹ min⁻¹ subgroup had lower baseline angiotensin II levels but also had higher baseline MAP and lower norepinephrine-equivalent doses at baseline. In addition, no difference existed between the > 5 ng kg⁻¹ min⁻¹ angiotensin II subgroup and the ≤ 5 ng kg⁻¹ min⁻¹ angiotensin II subgroup in characteristics potentially associated with impaired production/function of angiotensin II (such as prior use of angiotensin-converting enzyme inhibitors, use of angiotensin II receptor blockers, or radiographic evidence of ARDS; Table 1). It is conceivable that angiotensin II sensitivity is linked to endothelial injury, which was not rigorously assessed in the current analyses or the ATHOS-3 study. Across the entire cohort, the delivered dose of exogenous angiotensin II would overcome any inherent angiotensin-converting enzyme defects, so it is likely that attenuation of the MAP response to angiotensin II in the > 5 ng kg⁻¹ min⁻¹ subgroup may be influenced by other factors, including down-regulation of angiotensin I/II receptors in conditions such as sepsis and/or biofeedback to the production of vasodilatory peptides [20‐22]. Although our analysis does not account for all possible mechanisms that could account for the differences in MAP response between the two subgroups, patients receiving ≤ 5 ng kg⁻¹ min⁻¹ angiotensin II at 30 min represent a subset of patients who may be more likely to safely recover from shock and who can be identified soon after treatment initiation (at 30 min). This observation may allow clinicians to rapidly identify those patients who may benefit most from the continued use of angiotensin II.

Those patients who required ≤ 5 ng kg⁻¹ min⁻¹ at 30 min had less severe shock (higher baseline MAP) and lower baseline norepinephrine-equivalent doses than those who required > 5 ng kg⁻¹ min⁻¹. Accordingly, the beneficial effect seen in these patients may support the concept of using angiotensin II earlier in the course of disease. Additionally, in prespecified analyses, these patients exhibited improved survival even after adjusting for baseline differences in shock. Again, this would suggest that the use of angiotensin II at an early stage may be reasonable before a patient progresses to more severe refractory shock at very high norepinephrine-equivalent doses.

The study has several limitations. First, even though this was a prespecified analysis, the subgroups were defined by an on-treatment variable that was likely to be related to drug efficacy and was associated with better prognostic characteristics, not all of which are measured and controllable. However, no patients were discontinued from treatment within 30 min, nor was there selection bias, as all patients receiving angiotensin II were included in the analyses. The on-treatment variable of angiotensin II dose was adjusted based on MAP responsiveness, so higher hour 3 response rates in patients who ultimately required lower hour 3 doses of angiotensin II were expected. However, dose adjustment was made based on prespecified, objective, and easily measurable criteria (i.e., MAP), adding validity to the study findings. The observed improvement in day 28 survival in patients receiving ≤ 5 ng kg⁻¹ min⁻¹ of angiotensin II is not directly linked to angiotensin II dose, but it is expected that patients with better prognostic characteristics may be more likely to demonstrate immediate responsiveness. As a result, there were significant imbalances in key disease and previous treatment characteristics between the two groups that confound the interpretation of these analyses. For example, patients receiving ≤ 5 ng kg⁻¹ min⁻¹ angiotensin II had significantly lower baseline norepinephrine-equivalent dose and significantly higher baseline MAP compared with patients in the subgroup receiving > 5 ng kg⁻¹ min⁻¹. To account for the baseline differences, we performed regression analyses adjusting for the baseline characteristics. However, there may be unmeasured characteristics that were unaccounted for.

Despite these limitations, this prespecified analysis of ATHOS-3 showed that, for a significant proportion of patients with vasodilatory shock, a low dose of angiotensin II may be effective and is safe, and may provide an early indication of which patients are more likely to respond to angiotensin II. Larger, prospective studies are needed to understand the reasons underlying the phenomenon of hyper-responsiveness to low doses of angiotensin II and to identify all responders. Such information would be informative for clinical decision-making as well as help improve emergency management of patients with vasodilatory shock.