ATHOS 3: Is Angiotensin II useful in refractory vasodilatory shock?

Khanna A et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-430.

‘All for one, and one for all!’ – motto of Athos, Porthos and Aramis (The Three Musketeers – 1844 novel by Alexandre Dumas)


Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. Angiotensin II (ATII) is part of the native response to shock, causing vasoconstriction, aldosterone release and prompting productive cross-talk between the renin-angiotensin system and the sympathetic as well as the anti-diuretic hormone response to hypotension. In 2014 the ATHOS (Angiotensin II for the Treatment of High Output Shock) trial suggested that ATII was an effective noradrenaline (NA)-sparing agent and that ATII could become in the future the third class of vasopressors (besides catecholamines and vasopressin) in the treatment of vasodilatory shock.

Clinical question:

Is Angiotensin II effective when added to standard vasopressors in patients with refractory vasodilatory shock?


  • Double-blind randomized controlled trial
  • International (75 ICUs, 9 countries from North America, Australasia, and Europe)
  • Vasodilatory shock was defined as: MAP 55-70 mmHg + CI > 2.3 l/min/m2 + CVP > 8 mmHg & scvO2 > 70%
  • Refractoriness was defined as requiring NA > 0.2 mcg/kg/min (or other vasopressor at equivalent dose) for 6-48 hrs
  • 344 patients randomized
  • Treatment protocol: after randomization, for the first 3 hours only the study drug (ATII or placebo) dose could be changed (while the standard vasopressor was kept constant) to achieve a MAP of 65 – 75 mmHg. If the standard vasopressor had to be increased, the patient was considered as non-responder. Between the 3rd and the 48th hour the dose of both the study drug and of the standard vasopressor could be adjusted to achieve a MAP 65 – 75 mmHg

End points:


  • MAP response at hour 3, defined as increase in baseline MAP ³ 10 mmHg OR achieving MAP ³ 75 mmHg
  • Sequential Organ Failure Assessment (SOFA) Score
    • Mean change in Cardiovascular (CV) SOFA at hour 48
    • Mean change in total SOFA at hour 48


  • Mean change in NA dose at hour 3
  • All-cause mortality at day 7
  • All-cause mortality at day 28


  • There was a significantly higher chance of MAP response in ATII group compared to placebo (69.9% vs 23.4%, P<0.001)
  • There was a significant reduction in CV SOFA at hour 48 hours in ATII group compared to placebo (-1.75 ±77 vs – 1.28 ± 1.65, P 0.01)
  • There was no significant difference in mean change in total SOFA at hour 48 hours


  • There was a significant reduction of NA dose at hour 3 in ATII group compared to placebo (- 0.03 ±1 vs + 0.03 ± 0.23, P<0.001)
  • There was no benefit in all-cause mortality at day 7 or at day 28


  • No deaths during the first 3 hours
  • No difference in adverse events between ATII and placebo groups


  • Very impressive increase in MAP when ATII was added to standard vasopressor (see original paper figures)
  • Clinically relevant target population: vasodilatory shock refractory to standard treatment
  • Internal validity: double-blind, randomized, controlled trial
  • External validity: multi-centre, international


  • Is a NA dose of 0.2 mcg/kg/min an appropriate threshold to define refractoriness?
  • Relatively small number of randomized patients, hence study underpowered:
    • To detect difference in mortality
    • to stratify patient and identify if those who are deficient in endogenous ATII activity benefit more from the exogenous one:
      • Patients with ARDS: the lung endothelium is the main source of ACE, the enzyme that converts angiotensin-I in ATII
      • Patients on long term ACE-inhibitors or aldosterone-receptor blockers (ARB)
    • Undeclared potential safety concern: patients with acute coronary syndromes (which not infrequently associates with sepsis in the form of the so-called type 2 myocardial infarction) were excluded from the study. ATII is known to promote endothelial dysfunction and plaque instability and the exogenous administration might not be safe in patients with ACS.
    • Conflict of interest: data analysis was performed by the sponsor (LaJolla Pharmaceutical), who is linked to 6 of the authors (3 are actually LaJolla’s employee).

What to bring home from ATHOS 3?

ATII is a promising option in refractory vasodilatory shock, is effective in increasing the MAP and as a noradrenaline-sparing agent (in this role, it might theoretically be less toxic than vasopressin). Nonetheless, further studies are needed:

  • To confirm efficacy and safety in more independent settings
  • To significantly increase the study population in order to detect a benefit in clinically meaningful end points (including mortality) and to stratify patients (do ARDS, ACE-inhibitor or ARB patients do better?)


Summary by Dr Mattia Baldini

Second Opinion

Here’s what they thought of this paper over at The Bottom Line:


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