Angiotensin II was found to increase blood pressure and reduce catecholamine requirements in patients with vasodilatory shock, according to the results of a randomized double-blind placebo-control trial published in the New England Journal of Medicine.1
When vasodilatory shock does not respond to treatment with intravenous fluid resuscitation, vasopressors are often effective. Among patients who remain hypotensive even after high-dose vasopressor therapy, the 30-day all-cause mortality rate is greater than 50%.2,3 Catecholamines and vasopressin, the 2 classes of vasopressors that are currently available, have “narrow therapeutic windows owing to substantial toxic effects at high doses,” the researchers wrote.
“However, when hypotension occurs, human physiology engages a third system, which is represented by hormones in the renin-angiotensin-aldosterone system (RAAS),” the researchers noted.
Earlier findings have demonstrated the vasopressor effects of modified bovine angiotensin II in patients with shock, and results of a pilot study showed that the use of human angiotensin II increased mean arterial pressure in such patients and led to significant reductions in norepinephrine dosing.4-6
Expanding on these results, the phase 3 Angiotensin II for the Treatment of High-Output Shock (ATHOS-3; ClinicalTrials.gov identifier: NCT02338843) trial examined the effects of adjunctive angiotensin II in adult patients with vasodilatory shock that was unresponsive to fluid resuscitation or catecholamine administration. Patients were assigned to receive either LJPC-501, which is a synthetic human angiotensin II (n=163), or a saline placebo (n=158).
After the initial administration, infusions were adjusted during the first 3 hours to increase mean arterial pressure to a minimum of 75 mm Hg, whereas background vasopressor doses were held constant. Further adjustments were made after the first 3 hours until hour 48, when the study infusion was discontinued according to protocol. The primary end point was a mean arterial pressure of at least 75 mm Hg at hour 3, or an increase from baseline of at least 10 mm Hg, without an increase in background vasopressor dosage.
The findings revealed the following observations:
- The primary end point was reached by 69.9% of patients in the angiotensin II group vs 23.4% of patients in the placebo group (odds ratio, 7.95; 95% CI, 4.76-13.3; P <.001).
- A greater mean improvement in the cardiovascular Sequential Organ Failure Assessment was seen in the angiotensin II group at 48 hours compared with placebo (−1.75 vs −1.28; P =.01).
- The rate of serious adverse events was 60.7% in the angiotensin II group vs 67.1% in the placebo group.
- The rate of all-cause mortality at 28 days was 46.0% in the angiotensin II group vs 53.8% in the placebo group (hazard ratio, 0.78; 95% CI, 0.57-1.07; P =.12).
Previous data have indicated that naturally occurring vasoactive substances are synergistic, and “multimodal therapy may leverage this synergy to allow lower doses with potentially fewer toxic effects,” the researchers noted.7.8
“The observed increases in mean arterial pressure with angiotensin II, with concomitant reductions in catecholamine requirements, support this view.”
- Khanna A, English SW, Wang XS, et al; the ATHOS-3 Investigators. Angiotensin II for the treatment of vasodilatory shock [published online May 21, 2017]. N Engl J Med. doi:10.1056/NEJMoa1704154
- Brown SM, Lanspa MJ, Jones JP, et al. Survival after shock requiring high-dose vasopressor therapy. Chest. 2013;143(3):664-671. doi:10.1378/chest.12-1106
- Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. 2014;5(1):4-11. doi:10.4161/viru.27372
- Derrick JR, Anderson JR, Roland BJ. Adjunctive use of a biologic pressor agent, angiotensin, in management of shock. Circulation. 1962;25:263-267.
- Antonucci E, Gleeson PJ, Annoni F, et al. Angiotensin II in refractory septic shock. Shock. 2017;47:560-566. doi:10.1097/SHK.0000000000000807
- Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous Angiotensin II for the Treatment of High-Output Shock (ATHOS trial): a pilot study. Crit Care. 2014;18(5):534. doi:10.1186/s13054-014-0534-9
- Inoue T, Mi Z, Gillespie DG, Jackson EK. Cyclooxygenase inhibition reveals synergistic action of vasoconstrictors on mesangial cell growth. Eur J Pharmacol. 1998;361:285-291. doi:10.1016/S0014-2999(98)00720-1
- Struthers AD, Pai S, Seidelin PH, Coutie WJ, Morton JJ. Evidence in humans for a postsynaptic interaction between noradrenaline and angiotensin II with regard to systolic but not diastolic blood pressure. J Hypertens. 1987;5:671-676.