Critical Care Commentary

Life after angiotensin II


 

Hypotension is an often-underestimated adversary. Even brief periods of intraoperative mean arterial pressure (MAP) <65 mm Hg increase the odds of both myocardial ischemia and acute kidney injury in the postoperative period. The threshold may be even higher in the postoperative critically ill population (Khanna, et al. Crit Care Med. 2018;46(1):71). Hypotension that is refractory to high-dose vasopressors is associated with an all-cause mortality of 50% to 80%.

The vasopressor toolbox centers around escalating doses of catecholamines with or without the addition of vasopressin. High-dose catecholamines, albeit a frequent choice, is associated with adverse cardiac events (Schmittinger, et al. Intensive Care Med. 2012;38[6]:950) and is an independent predictor of ICU mortality (Sviri, et al. J Crit Care. 2014;29[1]:157).

The evidence behind angiotensin II

Angiotensin II (AT II) is a naturally occurring hormone in the renin-angiotensin-aldosterone (RAA) system that modulates blood pressure through direct arterial vasoconstriction and direct stimulation of the kidneys and adrenal cortex to release vasopressin and aldosterone, respectively.

Positive results from the recent phase 3 trial for AT II have offered hope that this agent would add the needed balance to the current scarcity of vasopressor options (Khanna, et al. N Engl J Med. 2017;377[5]:419). AT II would provide the missing piece in the jigsaw that would allow the intensivist to manage refractory hypotension, while keeping a multimodal vasopressor dosing regimen within therapeutic limits.

Dr. Jonathan Chow

Irvine Page and coworkers are credited with most of the initial work on AT II, which they did nearly 70 years ago. Anecdotal use in humans has been reported since the early 1960s (Del Greco, et al. JAMA 1961;178:994). After a prolonged period of quiescence, the Angiotensin II in High-Output Shock (ATHOS) pilot study, which was done in 2014 as a single-center “proof of concept” study of 20 patients, reinvigorated clinical enthusiasm for this agent (Chawla, et al. Crit Care. 2014;18[5]:534). ATHOS demonstrated the effectiveness of AT II at decreasing norepinephrine (NE) requirements of patients in vasodilatory shock (mean NE dose in AT II group 7.4 ug/min vs 27.6 ug/min in placebo, P=.06). These promising results were followed by ATHOS-3, a phase 3, double-blind, multicenter randomized controlled trial of stable human synthetic AT II. This trial was conducted under a special protocol assessment agreement with the US Food and Drug Administration (FDA). A total of 344 patients with predefined criteria for vasodilatory shock were randomized to AT II or placebo as the intention-to-treat population. The primary end-point was a response in MAP by hour 3 of AT II initiation; response was defined as either a MAP rise to 75 mm Hg or an increase in MAP ≥ 10 mm Hg. The primary end-point was reached more frequently in the AT II group than in the placebo group (69.9% AT II vs 23.4% placebo, OR 7.95, 95% CI 4.76-13.3, P<.001). The AT II group had significantly lower cardiovascular sequential organ failure assessment (SOFA) scores at 48 hours and achieved a consistent decrease in background vasopressor doses. Post-hoc data analysis found that the highest benefit was in patients who were AT II deficient (high ratio of AT I:AT II) (Wunderink, et al. Intensive Care Med Exp. 2017;5(Suppl 2):44). The patients who were AT II depleted and received placebo had a higher hazard ratio of death (HR 1.77, 95% CI 1.10-2.85, P=.019), while those who were AT II depleted and received AT II had a decreased risk of mortality (HR 0.64, 95% CI 0.41-1.00, P=.047). The data suggest not only that AT II levels may be predictive of mortality in vasodilatory shock but also that exogenous AT II administration may favorably modulate mortality in this population. Further, a subset data analysis of severely ill patients (APACHE II scores > 30) showed that those who received AT II and standard vasopressors had a significantly lower 28-day mortality compared with patients who only received standard vasopressors (Szerlip, et al. Crit Care Med. 2018;46[1]:3). Considering that the endothelial cells in the lungs and kidneys are locations where AT I is hydrolyzed by angiotensin-converting enzyme (ACE) into AT II, patients receiving ACE-inhibitors and individuals with pulmonary or renal disease are at greatest risk for AT II deficiency. As such, the use of AT II in the extra-corporeal membrane oxygenation (ECMO), post cardiopulmonary bypass, acute respiratory distress syndrome (ARDS), and renal failure populations are of future interest.

Is there a downside?

Appropriate caution is necessary when interpreting these outcomes. One criticism that ATHOS-3 received was the use of a MAP goal of 75 mm Hg, a higher value than currently recommended by clinical guidelines, in the first 3 hours of AT II administration. Because this was a phase 3 trial, both the safety and efficacy of the drug were examined. These goals are difficult to accomplish if simultaneously manipulating other variables. Therefore, to isolate the effects of drug efficacy and safety, a higher MAP goal (75 mm Hg) was established to minimize any effect from varying background vasopressor doses during the first 3 hours of the study.

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