Hospital Pharmacy - July/August 2018 - 231

231

Baker and Levien
and administration of high-dose vasopressors for at least
6 hours but no longer than 48 hours. Exclusion criteria
included burns covering more than 20% of total body surface area (BSA), acute coronary syndrome, bronchospasm, liver failure, mesenteric ischemia, active bleeding,
abdominal aortic aneurysm, or absolute neutrophil count
less than 1000/mm3 or receiving venoarterial extracorporeal membrane oxygenation or treatment with high-dose
glucocorticoids. Study baseline characteristics included
in the prescribing information and the New Drug Application for angiotensin II were as follows: 61% were
male; 80% were white, 10% black, and 4% Asian; and
48% were 65 years and older.
Intervention: Patients were randomly assigned (1:1) to
receive angiotensin II or saline placebo. The starting infusion rate was equivalent to angiotensin II 20 ng/kg/min and
was adjusted during the first 3 hours to increase mean arterial pressure to at least 75 mm Hg. The maximum rate of
administration of study drug or placebo was 200 ng/kg/
min. Dose of standard-of-care vasopressors were held constant during the 3-hour adjustment phase, unless there was
a safety concern. However, if the dose of the vasopressor
had to be adjusted during the first 3 hours, the patient was
classified as a nonresponder to study drug. After 3 hours 15
minutes, the study drug and other vasopressors could be
adjusted to maintain a target mean arterial pressure between
65 and 75 mm Hg. The infusion rate of angiotensin II could
be adjusted between 3 hours 15 minutes and 48 hours to a
rate equivalent to a dose of 1.25 to 40 ng/kg/min. After 48
hours, the study infusion was discontinued per the protocol-specified tapering process. If background vasopressor
dose was subsequently increased to more than 0.1 µg/kg/
min of norepinephrine or equivalent, or if the patient
became unstable, study medication could be resumed for
up to 7 days; however, the study drug could not be restarted
if it had been discontinued for more than 3 hours.

Results

** Cardiovascular Sequential Organ Failure Assessment
(SOFA) score at 48 hours was greater in the angiotensin II group than in the placebo group (−1.75 vs −1.28;
P = .01). However, there were no differences in the
other SOFA score components or in total SOFA score.

Other End Point(s)
** Mean change in norepinephrine-equivalent dose from
baseline to hour 3 was −0.03 with angiotensin II and
+0.03 with placebo (P < .001).
** All-cause mortality at day 7 was 29% in the angiotensin II group and 35% in the placebo group (hazard
ratio, 0.78; 95% CI, 0.53-1.16; P = .22).
** All-cause mortality at day 28 was 46% in the angiotensin II group and 54% in the placebo group (hazard
ratio, 0.78; 95% CI, 0.57-1.07; P = .12).
Comments: Randomization was in blocks, with stratification based on mean arterial pressure at screening (less
than 65 mm Hg or 65 mm Hg or greater) and Acute
Physiology and Chronic Health Evaluation II (APACHE
II) score (30 or less, 31 to 40, or 41 or higher [on a scale
of 0 to 71, with higher scores indicating greater disease
severity]). The primary efficacy analysis used the modified intention-to-treat population (all patients who began
receiving angiotensin II or placebo). Statistical analysis
for the secondary efficacy end points was conducted using
a hierarchical order. Missing data were imputed using the
last-observation-carried-forward method for clinical efficacy; in patients with missing values owing to death,
treatment was considered to have failed.
The study was conducted in 9 countries in North America,
Australasia, and Europe. The combined patient data show
angiotensin II efficacy was similar in men and women;
white and nonwhite patients; and patients older and
younger than age 65 years.6
Limitations: The study had a relatively small sample size and
limited duration of exposure to the angiotensin II infusion.

Primary End Point(s)
** Proportion of patients achieving response at hour 3,
with response defined as mean arterial pressure at
least 75 mm Hg or an increase in mean arterial pressure from baseline of at least 10 mm Hg, without an
increase in the background vasopressor dose: 69.9%
with angiotensin II and 23.4% with placebo (P <.001;
odds ratio, 7.95; 95% confidence interval [CI],
4.76-13.3).

Secondary End Point(s)
** Mean arterial pressure increased by 12.5 mm Hg with
angiotensin II and 2.9 mm Hg with placebo (P < .001).

Contraindications, Warnings, and
Precautions
Contraindications
The product labeling states there are no known contraindications to use of angiotensin II.1 Though not stated in the product
labeling, hypersensitivity reactions to angiotensin II or any of
its inactive ingredients (eg, mannitol) should be considered.

Warnings and Precautions
A higher incidence of arterial and venous thrombotic and thromboembolic events was observed in patients who received

Table of Contents for the Digital Edition of Hospital Pharmacy - July/August 2018