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American Journal of Cardiovascular Drugs

, Volume 19, Issue 1, pp 11–20 | Cite as

FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock

  • Fortunato Senatore
  • Gowraganahalli JagadeeshEmail author
  • Martin Rose
  • Venkateswaran C. Pillai
  • Sudharshan Hariharan
  • Ququan Liu
  • McDowell Tzu-Yun
  • Mohan K. Sapru
  • Mary Ross Southworth
  • Norman Stockbridge
Therapy in Practice
  • 213 Downloads

Abstract

Distributive shock is a subset of shock marked by decreased systemic vascular resistance, organ hypoperfusion and altered oxygen extraction. Despite the use of intravenous fluids and either higher dose of catecholamines or other additional exogenous vasopressors to maintain blood pressure in the target range, the rate of mortality remains higher in patients with septic shock. Therefore, there is clearly an unmet need for additional safe and effective treatments. The use of angiotensin II to raise the mean arterial pressure (MAP) could provide additional therapy and the opportunity to evaluate a catecholamine-sparing effect by decreasing the dose of concomitant catecholamines while maintaining a target MAP. ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3; ClinicalTrials.gov number, NCT02338843) was an adequate and well-controlled trial. The primary endpoint was the rate of MAP response at hour 3 of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or a MAP of at least 75 mmHg. The secondary endpoints were changes from baseline in Sequential Organ Failure Assessment (SOFA) scores (total and cardiovascular). Mortality was an exploratory endpoint. The trial provided substantial evidence of the effectiveness of angiotensin II in raising blood pressure over placebo in patients with distributive shock, while keeping catecholamine levels constant. There was no change in the secondary endpoint of total SOFA scores relative to placebo when catecholamine use was reduced in lieu of angiotensin II treatment. There was a slight decrease in the secondary endpoint of cardiovascular SOFA score relative to placebo during the catecholamine-sparing phase, reflecting the catecholamine-sparing effect. There was a consistent trend in decreased mortality relative to placebo over the 28-day study period. Based on the agreements emanating from the special protocol assessment to assess blood pressure effects, the data from this single study supported approval of angiotensin II by the Food and Drug Administration for marketing in the USA.

Notes

Compliance with Ethical Standards

Funding

No external funds were used in the preparation of this manuscript.

Conflict of interest

Fortunato Senatore, Gowraganahalli Jagadeesh, Martin Rose, Venkateswaran C. Pillai, Sudharshan Hariharan, Ququan Liu, McDowell Tzu-Yun, Mohan K. Sapru, Mary Ross Southworth, and Norman Stockbridge declare that they have no conflicts of interest relevant to the content of this article.

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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  • Fortunato Senatore
    • 1
  • Gowraganahalli Jagadeesh
    • 1
    Email author
  • Martin Rose
    • 1
  • Venkateswaran C. Pillai
    • 2
  • Sudharshan Hariharan
    • 2
  • Ququan Liu
    • 3
  • McDowell Tzu-Yun
    • 1
  • Mohan K. Sapru
    • 4
  • Mary Ross Southworth
    • 1
  • Norman Stockbridge
    • 1
  1. 1.Division of Cardiovascular and Renal ProductsCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  2. 2.Office of Clinical PharmacologyCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  3. 3.Office of BiostatisticsCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA
  4. 4.The Office of Pharmaceutical QualityCenter for Drug Evaluation and Research, Food and Drug AdministrationSilver SpringUSA

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