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

Fortunato Senatore; Gowraganahalli Jagadeesh; Martin Rose; Venkateswaran C. Pillai; Sudharshan Hariharan; Ququan Liu; McDowell Tzu-Yun; Mohan K. Sapru; Mary Ross Southworth; Norman Stockbridge


Am J Cardiovasc Drugs. 2019;19(1):11-20. 

In This Article

Abstract and Introduction


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 catecholaminesparing 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.


Distributive shock occurs in nearly 200,000 US adults yearly. It is often fatal despite intensive monitoring and treatment. It occurs despite normal cardiac function and a euvolemic state.[1] The cause of distributive shock is systemic inflammation that renders blood vessels unresponsive to endogenous vasoconstrictors. This causes redistribution of blood flow from the arterial system to the venous system resulting in adverse consequences for organ perfusion. The hemodynamic profile in distributive shock includes increased cardiac output, normal or decreased filling pressures, and a decreased systemic vascular resistance (SVR).[2] By far the most frequent cause of distributive shock is sepsis. Other causes include pancreatitis, burns, toxic shock syndrome, anaphylaxis, adrenal insufficiency, reaction to drugs/toxins, heavy metal poisoning, hepatic insufficiency, and damage to the central nervous system.

The management of shock is based on a multitude of metrics, including heart rate, blood pressure, arterial oxygen saturation, respiratory rate, temperature, urinary output, and hemodynamic measurements of cardiac status.[3] The "Surviving Sepsis Campaign Bundle: 2018" guidelines recommend fluid resuscitation and consideration of vasopressors within the first hour of the recognition of shock.[4] When rapid fluid replacement fails to restore adequate perfusion pressure (e.g., mean arterial pressure [MAP] to > 65 mmHg), exogenous vasopressors are introduced (catecholamines and non-catecholamines). The most widely used catecholamines include epinephrine and norepinephrine. These are neuromodulators of the sympathetic nervous system that have a direct effect on vascular smooth muscle cells. Dopamine, phenylephrine, and vasopressin are also used. The latter of these is a non-catecholamine vasoconstrictor that also promotes renal fluid retention and has been approved by the US Food and Drug Administration (FDA) to increase blood pressure in patients with severe hypotension. A compilation of drugs used to treat septic shock is listed in Table 1.

Most patients will respond to either volume replacement or vasopressors. However, approximately 6% of critically ill patients will develop refractory shock. Norepinephrine doses exceeding 0.1 μg/kg/min or rescue therapy with vasopressin is generally associated with mortality rates greater than 50%, whereas 94% of patients requiring doses above 100 μg/min of norepinephrine or epinephrine die.[5] The greater the number of vasopressors required, the higher the death rate; use of three pressors infused at full dose is associated with a mortality rate of 92%.[6]

Septic shock that is refractory to catecholamine treatment is a life-threatening condition with significant mortality. This condition represents an important unmet medical need as the currently available vasopressor therapies only leverage the vasopressin and adrenergic systems.[3] A third possible leverage point is the renin-angiotensin-aldosterone system, a homeostatic system that regulates blood pressure and fluid and electrolyte balance.[7] Angiotensin II, the principal hormone of the system, is a potent vasoconstrictor,[7] and might be able to reverse the vasoplegia associated with septic shock.[8] This is the therapeutic context addressed in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3) trial of angiotensin II.

Use of angiotensin II as a pressor dates back to 1941, and there are reports of administration to healthy subjects for up to 11 days.[8,9] Several reports of clinical use of angiotensin II to treat severe hypotension in septic shock have been published.[3,8,10–13] Based on a literature search, 31,281 subjects in 1124 studies have received angiotensin II (0.05–3780 ng/kg/min).[8] Hypertensin®, a modified bovine angiotensin II, was approved for treatment of shock and circulatory collapse by the US FDA in 1962, but the sponsor (Ciba-Geigy) subsequently withdrew the marketing application for reasons unrelated to safety.

The new drug application (NDA) for angiotensin II (Giapreza®) was submitted by La Jolla Pharmaceutical company, San Diego, CA (the Applicant), in June 2017 and approved by the agency on December 21, 2017. The standard time between NDA submission and approval is 12 months. The rapidity of this NDA review and subsequent approval was based on its Priority Review status, high submission quality, ease of review based on a small sample size relative to a standard cardiovascular clinical outcome phase 3 trial, and timely and high-quality responses from the Applicant to information requests from the review team.