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ATHOS-3: Angiotensin II may increase BP in patients with vasodilatory shock
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BP increased in patients with vasodilatory shock who were treated with angiotensin II after not responding to high doses of conventional vasopressors, according to a study in The New England Journal of Medicine.
“All these years, we had only norepinephrine and vasopressin available to maintain a [BP] when the patient was struggling with low [BP] in the ICU, but we never had angiotensin, even though physiologically, naturally speaking, the human body is dependent on angiotensin,” Ashish Khanna, MD, an intensivist and anesthesiologist at Cleveland Clinic’s Center for Critical Care and lead investigator on the ATHOS-3 trial, said in an interview with Cardiology Today. “Even you and me, at this point in time, have some angiotensin being secreted. That’s why we’re able to maintain a [BP]. I compare it to a jigsaw puzzle, where we had two pieces of the puzzle. We never had the third one available to us, and that’s why now that we have proven that angiotensin II is safe and [effective] in maintaining [BP]. The critical care physician will have all three pieces of the jigsaw puzzle easily and early available, and they will be better able to maintain [BP] in these patients. By using angiotensin at an early stage, we will be able to avoid high and potentially toxic doses of conventional vasopressors.”
In the ATHOS-3 trial, researchers analyzed data from 321 patients (median age, 64 years; 61% men) with vasodilatory shock who did not respond to high dose of conventional vasopressors, which was defined as more than 0.2 µg/kg per minute of norepinephrine or a comparable dose of another vasopressor. Patients were assigned to angiotensin II (n = 163) or placebo (n = 158). Shock was caused by sepsis in most patients (80.7%).
The primary endpoint was response regarding mean arterial pressure at 3 hours. Response was defined as mean arterial pressure of 75 mm Hg or higher, or an increase in mean arterial pressure of at least 10 mm Hg from baseline without an increase in background vasopressor dose. Fluctuations in the CV Sequential Organ Failure Assessment score, in which higher scores signify increased severity of organ dysfunction, and total score from baseline to 48 hours were the secondary efficacy endpoints.
More patients assigned angiotensin II achieved the primary endpoint (69.9%) compared with those assigned placebo (23.4%; OR = 7.95; 95% CI, 4.76-13.3). At 48 hours, CV Sequential Organ Failure Assessment score improvement was greater in the angiotensin II group (–1.75) vs. the placebo group (–1.28; P = .01).
Researchers observed serious adverse events in 60.7% of patients in the angiotensin II group vs. 67.1% of patients the placebo group. By day 28, death occurred in 46% of patients assigned angiotensin II vs. 53.8% of patients assigned placebo (HR = 0.78; 95% CI, 0.57-1.07). Results remained similar after age and sex adjustment.
“Once this new drug, angiotensin II, gets approved by the FDA, one area of exploration would be to look at different subsets of patient populations,” Khanna told Cardiology Today. “We would be specifically interested in finding out what subset of the patient population is a hyper-responder or is exquisitely responsive to angiotensin II, and once we can figure that out, then there will come a time where a patient comes into the ICU with septic shock or refractory shock, and you’re able to have the clinician find out fairly quickly whether I should give my patient norepinephrine, angiotensin or vasopressin first and understand which patient is exquisitely responsive.” – by Darlene Dobkowski
Disclosure: The study was funded by La Jolla Pharmaceutical Co. Khanna reports receiving grant support from La Jolla Pharmaceutical during the conduct of the study and outside the submitted work. Please see the full study for a list of the other researchers’ relevant financial disclosures.
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