‘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.
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
- 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
Here’s what they thought of this paper over at The Bottom Line: http://www.thebottomline.org.uk/summaries/icm/athos-3/