Septic Shock: Different Patients, Different Vasopressors
Dr Richard G. Wunderink presents a patient case and holds panel discussion on guiding treatment by perfusion markers.
GIAPREZA in septic shock
Consider GIAPREZA
sooner—reach target
MAP in more patients1
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Trial Design
ATHOS-3: A landmark trial
in septic shock1-3
GIAPREZA was studied in ATHOS-3, an international, randomized, double-blind, placebo-controlled trial of 321 patients with vasodilatory (distributive) shock who remained hypotensive despite fluid and traditional vasopressor therapy.1,4
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Treatment arms1 GIAPREZA (n=163) plus traditional vasopressors* Placebo (n=158) plus traditional vasopressors* | Primary endpoint1 An increase in MAP at hour 3 of at least 10 mmHg, or a MAP response of ≥75 mmHg, without an increase in baseline vasopressor dosing. |
Secondary endpoints1 - Mean change in cardiovascular SOFA score at hour 48 - Mean change in total SOFA score at hour 48 | |
Select additional endpoint1 All-cause mortality through day 28. |
Traditional vasopressors included norepinephrine, epinephrine, dopamine, phenylephrine, and vasopressin.4
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| Select baseline patient characteristics (N=321)1 | GIAPREZA + traditional vasopressors (n=163) | Placebo + traditional vasopressors (n=158) |
|---|---|---|
| Median MAP, mmHg (IQR) | 66.3 (63.7-69.0) | 66.3 (63.0-68.3) |
| Median APACHE II score (IQR) | 27 (22-33) | 29 (22-34) |
| Cause of shock, sepsis (%) | 127 (77.9%) | 132 (83.5%) |
| Median vasopressor dose (NED), mcg/kg/min (IQR) | 0.33 (0.23-0.56) | 0.34 (0.23-0.56) |
| Vasopressin use during 6 hours before randomization (%) | 113 (69.3%) | 111 (70.3%) |
*Doses of GIAPREZA or placebo were titrated to a target MAP of ≥75 mmHg during the first 3 hours of treatment while doses of other vasopressors were maintained. From hour 3 to hour 48, GIAPREZA or placebo was titrated to maintain a MAP between 65 and 70 mmHg while reducing doses of other vasopressors.4
MAP Stabilization
3x more patients
achieved and sustained target MAP with GIAPREZA added to traditional vasopressors1,4
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Rapid MAP
stabilization in
septic shock4
Median time to reach target MAP was 5 minutes4
Rapid MAP stabilization
helps you quicklydetermine
patient response in the ICU1,4
48% of patients who achieved target MAP reached it within the first 30 minutes of treatment at doses ≤5 ng/kg/min5
The effect on MAP was sustained for at least the first 3 hours of treatment4
Powerful MAP results in a broad range of patients4
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Patients with a history of ACEi and ARB favored GIAPREZA over placebo but interpretation should consider the small sample sizes (9% and 7%, respectively).4
Note: The figure above presents effects in select subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be overinterpreted.4
Patient Survival
Increased patient survival at day 28
with GIAPREZA + traditional vasopressors1,4,6
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A meta-analysis found no difference in mortality rates between angiotensin II and norepinephrine (46.2% vs 54.2%; RR, 0.85 [95% CI, 0.69-1.06])
-2021 SSC Guidelines7,*
Not statistically significant. Mortality through day 28 was an exploratory endpoint in ATHOS-3. The study was not powered to detect a difference in mortality.1
*The SSC released updated global guidelines in October 2021 for clinicians caring for adult patients with sepsis or septic shock.7
There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received GIAPREZA compared to placebo-treated patients in the ATHOS-3 study (13% vs 5%).4
Survival benefit was greatest when initiated with lower vasopressor doses8
In an exploratory post hoc analysis of ATHOS-3, early use of GIAPREZA plus traditional vasopressors was associated with improved survival vs placebo plus traditional vasopressors.8
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For complete Safety Information of GIAPREZA, .
*Early use was defined as initiation of study treatment at a norepinephrine-equivalent vasopressor dose ≤0.25 mcg/kg/min.8
†Delayed use was defined as initiation at a dose >0.25 mcg/kg/min.8
DON’T WAIT—start GIAPREZA sooner to help reduce mortality with lower doses of other vasopressors.8
Running Out of Options: Managing Refractory Septic Shock
Dr Samir S. Awad presents a patient case and holds panel discussion on vasopressor escalation strategy.
VASOPRESSOR LOAD
With GIAPREZA, patients needed lower mean doses of
traditional vasopressors1
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Norepinephrine-equivalent dose (NED) is a standardized way to express the total vasopressor burden a patient is receiving—by converting all vasopressors into an equivalent dose of norepinephrine for comparison.9
GIAPREZA: a catecholamine-sparing agent to target RAAS and increase patient survival6,10,11
In an exploratory post hoc analysis of ATHOS-3, a shock-disrupted RAAS pathway was confirmed as a key contributor to low MAP. The analysis uncovered abnormally high renin levels and ANG I/II ratios, suggesting RAAS dysfunction, which correlated with a much higher risk of mortality.10
255patients studied10
76%had elevated
renin levels10
renin levels10
3xthe upper
limit of normal10,*
limit of normal10,*
High renin levels correlated with10:
↑ ACE inhibitor use
↑ NED needs
↑ ANG I/II ratios
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| GIAPREZA effectively reduced renin and ANG I levels for better outcomes10: | GIAPREZA + traditional vasopressors | Placebo + traditional vasopressors |
|---|---|---|
| Median reduction in serum renin levels, % | 54.3 | 14.1 |
| Median reduction in serum ANG I levels, % | 39.7 | 7.0 |
| 28-day mortality, % [median (IQR)]† | 51 (39-65) | 70 (59-80) |
| Ventilator liberation by day 7 (alive and ventilator-free), % [median (IQR)]† | 28 (18-43) | 14 (8-25) |
| RRT liberation by day 7 (alive and RRT free), % [median (IQR)]† | 43 (25-66) | 12 (5-27) |
| ICU discharge by day 28, % [median (IQR)]† | 44 (32-58) | 22 (14-33) |
*The upper limit of normal was defined as 58.78 pg/mL; the median renin level was 172.7 pg/mL.10
†Values represent outcomes in patients who had renin concentrations above the study population median.10
SAFETY
Safety and tolerability
vs placebo and traditional
vasopressors in ATHOS-31
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| GIAPREZA + traditional vasopressors (n=163) | Placebo + traditional vasopressors (n=158) | |
|---|---|---|
| AEs of any grade, % (n) | 87.1% (142) | 91.8% (145) |
| AEs leading to discontinuation, % (n) | 14.1% (23) | 21.5% (34) |
| Any serious AEs with frequency ≥1% in either study group, % (n) | 60.7% (99) | 67.1% (106) |
Adverse reactions occurring in ≥4% of patients treated with GIAPREZA and ≥1.5% more often than in placebo‑treated patients included thromboembolic events, including arterial and venous thrombosis events (12.9% vs 5.1%), deep vein thrombosis (4.3% vs 0.0%), thrombocytopenia (9.8% vs 7.0%), tachycardia (8.6% vs 5.7%), fungal infection (6.1% vs 1.3%), delirium (5.5% vs 0.6%), acidosis (5.5% vs 0.6%), hyperglycemia (4.3% vs 2.5%), and peripheral ischemia (4.3% vs 2.5%).4
Thromboembolic events
- In ATHOS-3, serious adverse events (SAEs) were reported. The Prescribing Information grouped SAEs and adverse events, including thromboembolic events, as presented under a single category1,4
- The incidence of patients with a grade 3 or 4 (severe or life-threatening) thromboembolic event was 9 (5.5%) events in the GIAPREZA group vs 5 (3.2%) in the placebo group12
- In the GIAPREZA group, 12/25 (48%) thromboembolic events occurred within 5 days of randomization in comparison to 7/8 (87.5%) events in the placebo arm12
Use concurrent venous thromboembolism (VTE) prophylaxis.4
Fewer GIAPREZA-treated
patients experienced AEs and
SAEs vs placebo1
Fewer GIAPREZA-treated patients discontinued treatment vs
placebo due to AEs1
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*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, and other such activities.13
†Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, and taking medications without being bedridden.13
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REP FOR INFO
and support.
ACE=angiotensin-converting enzyme; ACEi=ACE inhibitor; ADL=activities of daily living; ANG=angiotensin; ARB=angiotensin II receptor blocker; APACHE 2=Acute Physiology and Chronic Health Evaluation II; ATHOS-3=Angiotensin II for the Treatment of High-Output Shock; CI=confidence interval; ICU=intensive care unit; IQR=interquartile range; MAP=mean arterial pressure; NE=norepinephrine; NED=NE-equivalent dose; RAAS=renin-angiotensin-aldosterone system; RRT=renal replacement therapy; SOFA=Sequential Organ Failure Assessment; SSC=Surviving Sepsis Campaign.
References:
- Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154
- Andrews L, Benken J, Benedetti E, et al. Effects of angiotensin II in the management of perioperative hypotension in kidney transplant recipients. Clin Transplant. 2022;36(9):e14754. doi:10.1111/ctr.14754
- National Center for Biotechnology Information. PubChem Compound Summary for CID 172198, angiotensin II. Accessed August 21, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/Angiotensin-II-human
- GIAPREZA. Prescribing information. La Jolla Pharmaceutical Company; 2021.
- Ham KR, Boldt DW, McCurdy MT, et al. Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial. Ann Intensive Care. 2019;9(1):63. doi:10.1186/s13613-019-0536-5
- Supplementary appendix to: Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419-430. doi:10.1056/NEJMoa1704154
- Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y
- Wieruszewski PM, Bellomo R, Busse LW, et al. Initiating angiotensin II at lower vasopressor doses in vasodilatory shock: an exploratory post‑hoc analysis of the ATHOS-3 clinical trial. Crit Care. 2023;27(1):175. doi:10.1186/s13054-023-04446-1
- Kotani Y, Di Gioia A, Landoni G, et al. An updated "norepinephrine equivalent" score in intensive care as a marker of shock severity. Crit Care. 2023;27(1):29. doi:10.1186/s13054-023-04322-y
- Bellomo R, Forni LG, Busse LW, et al. Renin and survival in patients given angiotensin II for catecholamine-resistant vasodilatory shock. A clinical trial. Am J Respir Crit Care Med. 2020;202(9):1253-1261. doi:10.1164/rccm.201911-2172OC
- Buckley MS, Barletta JF, Smithburger PL, et al. Catecholamine vasopressor support sparing strategies in vasodilatory shock. Pharmacotherapy. 2019;39(3):382-398. doi:10.1002/phar.2199
- Data on File. Innoviva Specialty Therapeutics; 2023.
- Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. US Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Published May 28, 2009. Updated June 14, 2010. Accessed August 21, 2026. https://evs.nci.nih.gov/
ftp1/ CTCAE/ CTCAE_4.03/ CTCAE_4.03_2010-06-14_ QuickReference_ 8.5x11.pdf
INDICATION
GIAPREZA® (angiotensin II) increases blood pressure in adults with septic or other distributive shock.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions
The safety of GIAPREZA was evaluated in 321 adults with septic or other distributive shock in a randomized, double-blind, placebo-controlled study, ATHOS-3. There was a higher incidence of arterial and venous thrombotic and thromboembolic events in patients who received GIAPREZA compared to placebo-treated patients in the ATHOS-3 study (13% vs. 5%). The major imbalance was in deep venous thromboses. Use concurrent venous thromboembolism (VTE) prophylaxis.
Adverse Reactions
The most common adverse reactions reported in greater than 10% of GIAPREZA-treated patients were thromboembolic events. Adverse reactions occurring in ≥4% of patients treated with GIAPREZA and ≥1.5% more often than placebo-treated patients in the ATHOS-3 study were thromboembolic events (including deep vein thrombosis), thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia.
Drug Interactions
Angiotensin converting enzyme (ACE) inhibitors may increase response to GIAPREZA. Angiotensin II receptor blockers (ARBs) may reduce response to GIAPREZA.
You are encouraged to report negative side effects of prescription drugs to the FDA. To report SUSPECTED ADVERSE REACTIONS, please contact:
Before administering, please see the Full Prescribing Information for GIAPREZA.