ATHOS-3

Angiotensin II for the Treatment of Vasodilatory Shock

Khanna A. NEJM May 21 2017. doi:10.1056/NEJMoa1704154

Clinical Question

  • In patients with refractory vasodilatory shock does the addition of angiotensin II improve blood pressure compared with standard vasopressor therapy?

Background

  • ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) was conducted in an attempt to assess a third class of vasopressor for vasodilatory shock
  • It is known that patients who have refractory shock have high mortality (50% 30 day all- cause mortality) and we currently only have catecholamines (such as noradrenaline) and vasopressin in the armamentarium to support blood pressure
  • AT II activates AT1a and AT1b receptors to increase intracellular Calcium in smooth muscle and activate the myosin contractile mechanism, thus promoting vasoconstriction. Exogenous administration of AT II augments the endogenous renin-angiotensin-aldosterone system.

Design

  • Randomised controlled trial
  • 1:1 assignment
  • Block randomisation
  • Allocation concealment through a central Web-based system
  • Stratification according to MAP (<65mmHg or >65mmHg) and APACHE II score (<30, 31-40 or >40)
  • Blinded: staff and patients
  • Infusions of angiotensin II and placebo were in identical bags

Setting

  • 75 Intensive Care Units across 9 countries (North America, Australasia, Europe)
  • Trial conducted May 2015 – January 2017

Population

  • Inclusion:
    • >18 years
    • Require a total sum catecholamine dose of >0.2mcg/kg/min for a minimum of 6 hours and a maximum of 48 hours to maintain a MAP 55-70mmHg
    • Clinical features consistent with high-output shock (1 of ScvO2 >70% and CVP >8mmHg OR CI >2.3 L/min/BSA)
    • Patient had urinary catheter, CVC and A-line in situ
    • Received at least 25 ml/kg of crystalloid or colloid over previous 24 hours
  • Exclusion:
    • Burns > TBSA 20%
    • Acute coronary syndrome
    • Bronchospasm
    • Liver Failure
    • Mesenteric Ischemia
    • Active bleeding
    • AAA
    • Neutrophil count < 1000 cm3
    • VA ECMO
    • High dose glucocorticoids
  • Participant numbers:
    • 404 eligible, 344 randomised (172 placebo, 172 angiotensin II)
    • 158 received placebo (13 withdrawn, 1 re-randomised to angiotensin II ) and 163 received angiotensin II (10 withdrawn) and were analysed by a modified intention to treat analysis
  • Comparison of baseline demographics;(ATII vs Placebo)
    • Age: 63 vs 65 years
    • Men; 56.2% vs 65.2%
    • APACHE II;  27 vs 29

Intervention

  • Patients on high dose vasopressors were commenced on 20ng/kg/min of ATII. The dose was adjusted over the first 3 hours to increase the MAP to at least 75mmHg. During the adjustment period the dose of vasopresors was held constant and could not be increased except for safety reasons. If the dose was increased the patient was deemed as not having had a response to the study intervention. The maximum rate of administration of the study medication during the first 3 hours was equivalent to a dose of 200ng/kg/min
  • Between 3-48 hours the dose of angiotensin II or placebo could be adjusted to a dose of 1.25-40ng/kg/min

Control

  • Patients on high dose vasopressors were commenced on placebo. The ‘dose’ of placebo was up-titrated over the next 3 hours. If the dose of the background vasopressors increased then the patient was deemed as a non-responder

Outcome

  • Primary outcome:
    • At  hour 3, the number of patients in whom MAP increased to 75mmHg OR 10mmHg higher than baseline, without an increase in baseline vasopressors, was higher in the ATII group
      • 69.9% vs 23.4%
      • OR 7.95; 95% CI 4.76-13.3; P < 0.001
      • Fragility Index: 57
      • Mean doses of background vasopressors were consistently less in the ATII group
  • Secondary outcome:
    • Cardiovascular component of the SOFA score at 48 was improved in ATII group: -1.75 vs -1.28, P=0.01
    • Total SOFA score at 48 hours: No difference
    • All-cause mortality was lower (not statistically significant) at day 7 in the ATII group:
      • 47/163 (28.8%) vs 55/158 (34.8%)
      • HR 0.78 95% CI 0.53- 1.16, P=0.22
    • All-cause mortality was lower (not statistically significant) at day 28 in the ATII group:
      • 75/163 (46%) vs85/158 (53.8%)
      • HR 0.78; 95% CI 0.57-1.07, P=0.12
    • Adverse Events (ATII vs Placebo)
      • Serious adverse events (60.7% vs 67.1%)
      • Adverse event-related drug discontinuation (14.1% vs 21.5%)
      • All adverse events (87.1% vs 91.8%)

Authors’ Conclusions

  • Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors

Strengths

  • Strong internal validity: allocation concealment, baseline balance, modified intention to treat analysis, block stratified randomisation, blinding, complete follow-up (for primary outcome measure)
  • Multi-centre improves the external validity
  • The drug was tested in a patient group that had already trialed conventional therapy, so this was a particularly sick cohort of patients

Weaknesses

  • Primary outcome measure was not clinically meaningful
  • The trial was not powered to detect mortality differences and did not measure other key ICU outcomes such as ICU length of stay, need for renal replacement therapy

The Bottom Line

  • Angiotensin II increases blood pressure in patients with vasodilatory shock
  • Numerically patients were less likely to have adverse events and die compared with the control group
  • This trial is likely to make angiotensin II available (the trial was conducted in consultation with the FDA)
  • Angiotensin II is coming to an ICU near you
  • Future trials assessing clinically meaningful outcomes are needed to assess it’s exact role in this patient group

External Links

Metadata

Summary author: Celia Bradford
Summary date: May 30 2017
Peer-review editor: Adrian Wong

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