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

Disclosures

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

In This Article

Assessment of Effectiveness

The use of an increasing number of vasopressors in refractory distributive shock poses a risk of end-organ damage due to excess vasoconstriction. In the setting of adequately improving the mean arterial blood pressure to clinical target levels, the safety database from the ATHOS-3 trial did not demonstrate end-organ damage for subjects with refractory shock treated with angiotensin II relative to placebo.

None of the drugs labeled in the USA for distributive shock were approved with data indicating that they reduced mortality. We have not required sponsors to show a benefit other than an increase in blood pressure to support approval of drugs to treat hypotension in the setting of shock. We have accepted the belief prevalent in the medical community that treatment of hypotension in patients with shock will improve tissue perfusion to allow needed time for specific treatment of the underlying cause of shock, and thereby decrease death and serious morbidity, although this hypothesis has never been rigorously evaluated. However, given the high rate of death in patients with septic shock despite treatment, there is clearly an unmet need for additional safe and effective treatments.

Although the sponsor conducted only one controlled trial, the trial was adequate to demonstrate effectiveness in raising mean arterial blood pressure. Several of the criteria for finding effectiveness based on one study that are described in FDA's 1998 guidance, "Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products", are present here. The ATHOS-3 trial was a well-conducted, placebo-controlled, superiority trial with no important flaws in conduct or imbalances in the study arms. The difference between the study arms for the primary endpoint, the MAP response rate, was large and favored angiotensin II. Despite the lack of a confirmed benefit for any outcome other than MAP, the benefits of angiotensin II were determined to outweigh its risks in the studied population. This study population is representative of patients in the USA with distributive shock, so the results of ATHOS-3 can be extrapolated to US patients.

In the ATHOS-3 trial, subjects received study drug against a background of other vasopressors. However, data from outside the ATHOS-3 trial indicate that angiotensin II also raised blood pressure in subjects who had not received other vasopressors, including patients with distributive shock.[13] Consequently, the regulatory decision to approve Giapreza® did not restrict use to subjects who were on maximum levels of catecholamines. Given that Giapreza® was administered in a controlled clinical setting, the dose was titrated to effect that was achieved in less than 5 min. No formal drug interaction studies or pharmacokinetic studies in patients with renal impairment or hepatic impairment were conducted. No specific distribution, metabolism and excretion studies were conducted using Giapreza®. Age and gender did not influence the pharmacokinetics of angiotensin II as observed in the phase 3 study.

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