ATHOS-3: Angiotensin II for Vasodilatory Shock (2017)

“The administration of angiotensin II to patients with vasodilatory shock resulted in a higher mean arterial pressure and a lower dose of norepinephrine than the administration of placebo.”

  • The ATHOS-3 Investigators

1. Publication Details

  • Trial Title: Angiotensin II for the Treatment of Vasodilatory Shock
  • Citation: Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017;377(5):419-430. DOI: 10.1056/NEJMoa1704154
  • Published: August 3, 2017, in The New England Journal of Medicine
  • Author: Ashish Khanna, M.D.
  • Funding: La Jolla Pharmaceutical Company.

2. Keywords

  • Vasodilatory Shock, Septic Shock, Angiotensin II, Vasopressors, Catecholamine Resistance, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with catecholamine-resistant vasodilatory shock (Population), does an infusion of synthetic angiotensin II (Intervention) compared to placebo (Comparison) increase the mean arterial pressure (MAP) response at 3 hours (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Vasodilatory shock is characterized by severe hypotension despite fluid resuscitation, requiring vasopressors like norepinephrine. Some patients develop resistance to these catecholamine vasopressors, which is associated with very high mortality. Angiotensin II is a potent, naturally occurring vasoconstrictor that works through a different pathway (the renin-angiotensin-aldosterone system) and was a promising therapeutic option for these refractory patients.
  • Knowledge Gap: While physiologically plausible, there was no high-quality evidence from a large randomized trial to determine if angiotensin II was effective and safe in this critically ill population.
  • Proposed Hypothesis: The authors hypothesized that angiotensin II would be superior to placebo in increasing blood pressure in patients with catecholamine-resistant vasodilatory shock.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 75 intensive care units (ICUs) in 9 countries.
  • Trial Period: Enrollment ran from May 2015 to January 2017.
  • Population:
    • Inclusion Criteria: Adult patients with vasodilatory shock (sepsis was the cause in >80%) who remained hypotensive despite receiving high doses of standard vasopressors (norepinephrine equivalent >0.2 mcg/kg/min).
    • Exclusion Criteria: Included patients with burns >20% of body surface area or those with acute coronary syndrome.
  • Intervention: Patients received a continuous intravenous infusion of synthetic human angiotensin II, with the dose titrated to achieve a target MAP of ≥75 mm Hg.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: In both groups, standard-of-care vasopressors could be adjusted to maintain the target MAP. All other aspects of ICU care were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 300 patients would provide 90% power to detect a 35% absolute difference in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: The proportion of patients who achieved a target MAP response, defined as a MAP of ≥75 mm Hg or a ≥10 mm Hg increase from baseline at hour 3, without an increase in standard vasopressor dose.
    • Secondary Outcomes: Included 28-day mortality, change in cardiovascular SOFA score, and total vasopressor requirements.

6. Key Results

  • Enrollment and Baseline: 321 patients were randomized (163 to angiotensin II and 158 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: A significantly higher proportion of patients in the angiotensin II group achieved the primary outcome: 114 of 163 patients (69.9%) in the angiotensin II group had a MAP response, compared with 37 of 158 patients (23.4%) in the placebo group (p<0.001).
  • Secondary Outcomes: There was no significant difference in 28-day mortality between the groups (46% in the angiotensin II group vs. 54% in the placebo group; p=0.12). However, patients in the angiotensin II group had a greater improvement in their cardiovascular SOFA score.
  • Adverse Events: The overall incidence of adverse events was similar between the groups. However, there was a higher incidence of deep-vein thrombosis in the angiotensin II group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who achieved a MAP response between the two groups.
  • Key Statistic(s) Reported: Odds Ratio (OR) for a MAP response: 7.95 (95% CI, 4.76 to 13.3; P-value: <0.001).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Response in Intervention Group) / (Odds of Response in Control Group).
      • Calculation: The paper reports the result as 7.95.
      • Clinical Meaning: The OR of 7.95 means that the odds of having a blood pressure response were nearly 8 times higher in the angiotensin II group compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 4.76 to 13.3.
      • Clinical Meaning: Since this entire range is well above the line of no effect (1.0), it confirms that the result is highly statistically significant.
    • P-value: The p-value of <0.001 indicates the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Increase (for achieving MAP response):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 69.9% – 23.4% = 46.5%.
      • Clinical Meaning: For every 100 patients treated with angiotensin II, about 47 additional patients achieved the target blood pressure response.
    • Number Needed to Treat (NNT) (to achieve MAP response):
      • Formula: NNT = 1 / ARI
      • Calculation: NNT = 1 / 0.465 = 2.15, which is rounded down to 2.
      • Clinical Meaning: You would only need to treat 2 patients with angiotensin II to achieve one additional blood pressure response.
  • Subgroup Analyses: The effect was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The multicenter, randomized, double-blind, placebo-controlled design is the gold standard for minimizing bias.
  • Generalizability: The inclusion of 75 diverse ICUs across nine countries increases the external validity of the findings.
  • Statistical Power: The study was adequately powered for its primary outcome.
  • Patient-Centered Outcomes: While the primary outcome was physiological, the study did track and report on important patient-centered outcomes like mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The primary outcome was a physiological marker (blood pressure response) rather than a patient-centered outcome like mortality. A change in a number does not always translate to patient benefit.
  • External Validity (Generalizability): The study population was a highly selected group of patients with refractory shock, so the findings may not apply to all patients with septic shock.
  • Other: The trial was funded by the pharmaceutical company that manufactures angiotensin II, which represents a potential conflict of interest.

10. Conclusion of the Authors

  • The administration of angiotensin II to patients with catecholamine-resistant vasodilatory shock effectively increased blood pressure and allowed for a reduction in the dose of standard vasopressors.

11. To Summarize

  • Impact on Current Practice: This trial led to the FDA approval of angiotensin II and introduced a new therapeutic option for the management of refractory vasodilatory shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients with vasodilatory shock who remain hypotensive despite high doses of standard catecholamine vasopressors.
    • Actionable Intervention: Angiotensin II can be considered as an adjunctive vasopressor to help achieve the target MAP and potentially reduce the dose of other vasopressors.
  • What This Trial Does NOT Mean: This trial does NOT mean that angiotensin II improves survival. The study was not powered for mortality and showed no significant difference in this key patient-centered outcome.
  • Implementation Caveats: Clinicians should be aware of the potential increased risk of thromboembolic events and should ensure appropriate VTE prophylaxis is in place.

12. Context and Related Studies

  • Building on Previous Evidence: The ATHOS-3 trial (2017) was the pivotal registration trial for angiotensin II, building on a strong physiological rationale and smaller, earlier studies.
  • Influence on Subsequent Research: The trial has spurred further research into the role of the renin-angiotensin-aldosterone system in septic shock and the potential for personalized vasopressor therapy.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The key unresolved question is whether angiotensin II provides a true survival benefit. The trend towards lower mortality was not statistically significant, and the trial was not designed to answer this question definitively.
  • Future Directions: A larger trial powered specifically to detect a difference in mortality would be needed to clarify the role of angiotensin II in improving patient-centered outcomes.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a common and often fatal clinical problem (refractory shock) for which new therapeutic options were needed.
  • Methods: The multicenter, double-blind RCT design was of high quality. The main methodological point for discussion is the choice of a physiological primary outcome (MAP response) rather than a patient-centered outcome like mortality. While a MAP response is important, it is a surrogate marker.
  • Results: The study reported a large and statistically significant effect on its primary outcome. The lack of a significant mortality benefit, despite a trend in that direction, is a critical finding that must be considered when interpreting the results.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the primary outcome data. The trial provides strong evidence that angiotensin II is an effective vasopressor. However, its role in improving patient-centered outcomes remains unproven. Its applicability is limited to the specific, highly refractory patient population studied.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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