Journal of the Practice of Cardiovascular Sciences

: 2017  |  Volume : 3  |  Issue : 2  |  Page : 103--105

The Angiotensin II for the treatment of high-output Shock-3 Trial (Athos-3)

Nirmal Ghati 
 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Nirmal Ghati
6/2/4, Ramkali Mukherjee Lane, Kolkata - 700 050, West Bengal

How to cite this article:
Ghati N. The Angiotensin II for the treatment of high-output Shock-3 Trial (Athos-3).J Pract Cardiovasc Sci 2017;3:103-105

How to cite this URL:
Ghati N. The Angiotensin II for the treatment of high-output Shock-3 Trial (Athos-3). J Pract Cardiovasc Sci [serial online] 2017 [cited 2023 May 28 ];3:103-105
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Full Text

Article: Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017.


Shock is a life-threatening condition with severe organ hypoperfusion. There are four major types – vasodilatory, cardiac, hypovolemic, and obstructiveVasodilatory shock is the most common type and represents approximately two-thirds of all patients with shock [1],[2]Fluid resuscitation and vasopressors are main treatment to maintain blood pressure and organ perfusionThere are two classes of conventional vasopressors – catecholamine (norepinephrine, adrenaline, and dopamine) and vasopressin. All the agents have a narrow therapeutic window with significant side effects at higher dosesApproximately 6%–7% patients have vasopressor-resistant shock – requiring higher doses of vasopressors [3]Although there is no absolute definition for vasopressor resistant shock, most of the literature used >0.5 μg/kg/min norepinephrine or equivalent vasopressor dose as the cutoff for vasopressor-resistant shock [3]Vasopressor-resistant shock indicates poor prognosis with very high mortality rate (48%–94%), but none of the newer treatment options (glucocorticoids, methylene blue, and high volume hemofiltration) showed fruitful results in recent trials [3]Angiotensin II, a component of renin -angiotensin-aldosterone system, was tested successfully in patients with shock almost 50 years back [4],[5] but surprisingly abandoned for a long period of timeRecently, the ATHOS trial, a small randomized control trial of twenty patients of vasodilatory shock, showed a significant reduction of background norepinephrine dose with intravenous angiotensin II versus placebo (27.6 ± 29.3 mcg/min vs. 7.4 ± 12.4 mcg/min, P = 0.06)[6]In shock, angiotensin II increases blood pressure rapidly by direct vasoconstriction, increases in sympathetic discharge, and increases in adrenal medullary catecholamine release. Slow and persistent rise in blood pressure is due to direct renal vasoconstriction, increased renal sodium reabsorption, and renal sympathetic tone.

 Study Objectives

Primary Objective: To compare the effect of Angiotensin II infusion on mean arterial pressure (MAP) in patients with vasopressor resistant shock.Secondary Objective:

To compare change in Sequential Organ Failure Assessment (SOFA) scoresTo establish the safety and tolerability of angiotensin II.

 Study Design

It was a multisite, randomized, double-blind, placebo-controlled Phase III studyThe study was conducted in 75 intensive care units across nine countries in North America, Australasia, and Western EuropeThe study sponsor was La Jolla Pharmaceutical CompanyIt was started in May 2015 and ended in January 2017.

Inclusion criteria

Adult patients (>18 years) with resistant shock requiring a total catecholamine dose of >0.2 mcg/kg/min to maintain a MAP between 55 and 70 mmHgClinical features of high-output shock (ScvO2>70% and central venous pressure >8 mmHg or cardiac index = >2.3 L/min/1.73 m 2)Patients who were adequately fluid resuscitated and had an arterial line, central venous access, and indwelling urinary catheter.

Exclusion criteria

Patients with burns covering >20% of the total body surface area, acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding, abdominal aortic aneurysm, an absolute neutrophil count of <1000/dl or who were receiving venoarterial extracorporeal membrane oxygenation or treatment with high-dose glucocorticoids.


After screening and obtaining informed consent, background vasopressors were titrated to a target MAP of 65 mmHg and then the patients were randomized in 1:1 ratio to receive synthetic human angiotensin II or saline placeboThen, the study was conducted in three stages:Stage I (0–3 h): Angiotensin II and placebo infusions were initiated at a rate = 20 ng/kg/min and dose adjusted to achieve a MAP ≥75 mmHg. In this stage, doses of background vasopressors were held constant and could not be increased except for safety reasons. If these doses were increased, the patient was designated as nonresponderStage II (3–48 h): In this period, the study drug or placebo and other vasopressors were adjusted to maintain a target MAP between 65 and 75 mmHg. If vasopressin was being used, it was weaned off first if possible. Then, standard-of-care vasopressors were titrated until the sum of the norepinephrine and epinephrine dose was as low as 0.03 μg/kg/minStage III (48 h–7 days): At 48 h, the study infusion was discontinued according to a protocol-specified tapering process. If tapering was not possible due to worsening of patient's condition, study medication or placebo was resumed for up to 7 days. However, once the study medication or placebo was discontinued for >3 h, it could not be restarted.

 Study Endpoints


Response at 3 h: MAP of 75 mmHg or higher or an increase in MAP from baseline of at least 10 mmHg - without an increase in the dose of background vasopressors.


Changes in the cardiovascular SOFA score between baseline measurement and 48 hChanges in total SOFA score between baseline measurement and 48 h.


Serious adverse events, adverse event-related drug discontinuations, all adverse events, and all-cause mortality at 7 and 28 days.


The primary efficacy analysis was based on the modified intention-to-treat populationWilcoxon rank-sum test or analysis of variance was used for continuous or ordinal variablesChi-square or Fisher's exact test was used for discrete variablesTwo-tailed alpha level of 0.05 was used to test the hypothesis of treatment differenceLogistic regression analysis was used to identify baseline factors that may have influenced the primary endpointTime-to-event data including mortality were compared by a log-rank test and were characterized by Kaplan–Meier estimatesHazard rates were estimated from the proportional hazards model.


A total of 321 patients were recruited in the modified intention to treat model (163 patients received angiotensin II and 158 patients received placebo)The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio: 7.95; 95% confidence interval [CI]: 4.76–13.3; P < 0.001)At 48 h, the mean improvement in the cardiovascular SOFA score was greater in the angiotensin II group than in the placebo group (−1.75 vs. −1.28, P = 0.01)There was no significant improvement in total SOFA score in the angiotensin II group (1.05 vs. 1.04, P = 0.49)Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group.Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio: 0.78; 95% CI: 0.57–1.07; P = 0.12).


Unlike other new therapies, angiotensin II more closely mimicked natural physiologic responses to shockThe concomitant reductions in catecholamine requirements support the concept of synergistic action of vasoactive drugsNo serious adverse effect of angiotensin II was reported in this trialIn the study, angiotensin II was not associated with higher mortalityHowever, there was no improvement in multiorgan failure (total SOFA score) by angiotensin II which points against any mortality benefitIf we see the mechanism of action, angiotensin II is a pure vasopressor agent. Hence, it may not be an appropriate standalone drug for the treatment of septic shock, in which cardiac contractility can be suppressed.

 Positive Points

ATHOS-3 trial was a well-structured randomized controlled trialIt had an international multicenter trial design that involved large varieties of populationsThe study groups were well matched with respect to baseline disease characteristics and demographicsThe patients were severely ill, as indicated by high APACHE II scores and elevated baseline vasopressor dosesMoreover, a significant proportion of the patients in this trial had septic shock - the most severe type of vasodilatory shock we face in our daily practice.


The sponsor (La Jolla Pharmaceutical Company) had significant contribution in protocol design, data analysis, and manuscript writing. Hence, a potential conflict of interest cannot be ruled outThe reason behind a low cutoff for vasopressor resistance was not explained in the trial. Was it to get a positive efficacy result?Moreover, in patients with baseline norepinephrine dose >0.5 μg/kg/min, odd ratio for positive response was 0.40 which points against any real effectiveness of angiotensin II in severe vasopressor-resistant shockAlthough it was a blinded study, the significant blood pressure response to angiotensin II may have allowed treating clinicians to correctly guess the treatment assignment in some casesSample size was relatively small, so the possibility of clinically important side effects cannot be fully excludedThe follow-up was only for 28 days, which is insufficient to evaluate any long-term effects of angiotensin II therapyIt was not a head-to-head comparison trial. Hence, we cannot say at this moment that angiotensin II is better than other conventional vasopressor agentsThe safety and efficacy of angiotensin II in patients with distributive shock and low cardiac output were not tested in this studyAbove all, the trial was not sufficiently powered to detect any mortality benefit of angiotensin II.


Angiotensin II may be useful in the treatment of catecholamine-resistant vasodilatory shockSignificant short- and long-term adverse effects should be ruled out in the future trials before adding the drug in the conventional management planGiven the lack of mortality benefits and total organ function improvement, its commercial potential could be debatableIn the future, larger and longer trial will answer the question whether we have got a perfect vasopressor with mortality benefit or not.

There are no conflicts of interest.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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