Peptide education
Angiotensin II
Angiotensin 2 · Ang II · Giapreza
Angiotensin II is a peptide hormone that helps regulate blood pressure. The US prescription product Giapreza is given by intravenous infusion to raise blood pressure in adults with septic or other distributive shock.
In ATHOS-3, 69.9% of patients receiving angiotensin II reached the defined blood-pressure response at 3 hours, compared with 23.4% receiving placebo. Both groups continued background vasopressor treatment.
Overview
Quick answer
A rapid rise in blood pressure can be important during shock, but it is not the same as evidence that a treatment improves survival. ATHOS-3 measured both outcomes and showed a clear difference in the early pressure endpoint, not a statistically significant difference in day-28 mortality.
What is angiotensin II?
It is an eight-residue peptide in the body's blood-pressure control system. It constricts blood vessels and stimulates aldosterone release. Giapreza is a prescription intravenous formulation of the peptide.
What is Giapreza approved to do?
The US label describes it as a vasoconstrictor to increase blood pressure in adults with septic or other distributive shock.
What did the main trial measure?
ATHOS-3 measured whether mean arterial pressure rose by at least 10 mm Hg or reached at least 75 mm Hg at 3 hours without an increase in background vasopressors. More treated patients reached that target than placebo patients.
What is the main safety concern?
Arterial and venous clotting events were more common with Giapreza than placebo in ATHOS-3. The label calls for concurrent venous thromboembolism prophylaxis during treatment.
Evidence
Evidence snapshot
Giapreza is a vasoconstrictor indicated to increase blood pressure in adults with septic or other distributive shock.
Among 321 patients who received study treatment, those proportions met the predefined 3-hour blood-pressure endpoint with angiotensin II or placebo, respectively, on background vasopressors.
Death by day 28 occurred in 46% of the angiotensin II group and 54% of the placebo group. The trial did not show a statistically significant difference.
The label reports arterial or venous thrombotic and thromboembolic events in 13% of Giapreza-treated patients versus 5% of placebo patients in ATHOS-3.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Angiotensin II can raise blood pressure in distributive shock. | In ATHOS-3, patients remained hypotensive despite fluids and substantial vasopressor support. Angiotensin II improved the prespecified 3-hour mean arterial pressure response compared with placebo. | Angiotensin II constricts blood vessels through type 1 receptor signaling. | Supported for the blood-pressure endpoint in the studied shock population and reflected in the adult Giapreza label. |
| A higher blood pressure proves better survival. | ATHOS-3 did not find a statistically significant difference in mortality by day 28, despite a larger early blood-pressure response. | Blood-pressure response and survival are separate outcomes. | |
| Clot risk is irrelevant in monitored hospital care. | In the label's ATHOS-3 safety analysis, thrombotic or thromboembolic events occurred in 13% of Giapreza patients and 5% of placebo patients. | Clot risk remains important. The label calls for concurrent venous thromboembolism prophylaxis. |
Bottom line
Main takeaway
Giapreza is a hospital medicine that narrows blood vessels to raise blood pressure in adults with certain forms of shock.
The pressure response was measured after 3 hours in patients already receiving other vasopressors. A survival advantage was not established.
The primary endpoint combined an absolute mean arterial pressure target or an increase from baseline with no increase in background vasopressors. Thromboembolic events were more frequent in the treated group.
Identity
What it is
Angiotensin II is an eight-amino-acid peptide in the renin-angiotensin system. It activates receptors that affect vascular tone and aldosterone release.
Distributive shock can cause dangerously low blood pressure despite fluids and other vasopressors. ATHOS-3 evaluated an additional angiotensin II infusion in this setting.
Use context
Routes, doses, and cycle patterns
Giapreza is administered as a continuous intravenous infusion. Its dose is weight-based and adjusted to blood pressure during shock care.
Human studies and product labels
Giapreza US label
- Purpose
- Increase blood pressure in adults with septic or other distributive shock
- Context
- US prescribing information
- Route
- Continuous intravenous infusion
- Amount
- Starting rate 20 ng/kg/min
- Frequency
- Titrated to blood pressure as often as every 5 minutes
- Duration
- Adjusted as shock improves
The label specifies a maximum of 80 ng/kg/min during the first 3 hours and a maintenance maximum of 40 ng/kg/min. It calls for concurrent venous thromboembolism prophylaxis.
ATHOS-3
- Purpose
- Mean arterial pressure response during vasodilatory shock
- Context
- Randomized placebo-controlled study on background vasopressors
- Route
- Continuous intravenous infusion
- Amount
- Titrated study infusion
- Frequency
- Adjusted to blood-pressure targets
- Duration
- Primary response assessed at 3 hours
Patients were already receiving high doses of vasopressors. The primary endpoint required the blood-pressure response without an increase in background vasopressor dose.
What varies
- The rate is expressed in nanograms per kilogram per minute, not milligrams per dose.
- Blood-pressure response and thromboembolic events were measured separately from mortality in the trial and label.
Research
Research evidence
ATHOS-3 found a greater early blood-pressure response with angiotensin II than placebo in patients receiving other vasopressors. Mortality by day 28 was not significantly different. The prescribing information reports a higher rate of thrombotic and thromboembolic events in the angiotensin II group.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| ATHOS-3 | 321 treated adults with vasodilatory shock on high-dose vasopressors | Randomized double-blind placebo-controlled trial | Angiotensin II or placebo added to background vasopressors | At 3 hours, 114 of 163 treated patients and 37 of 158 placebo patients met the prespecified blood-pressure response, or 69.9% versus 23.4%. | The primary endpoint was a short-term blood-pressure measure. Day-28 mortality was not significantly different between groups. | Randomized, pressure endpoint |
| Giapreza prescribing information | Adults with septic or other distributive shock | US prescribing information and trial safety summary | Intravenous vasopressor infusion | The label defines the indication and infusion ranges and reports a higher incidence of thrombotic or thromboembolic events than placebo in ATHOS-3. | The trial involved critically ill patients receiving other therapies. The observed safety rate does not identify the cause of each individual event. | Label and randomized trial context |
Use context
Reported use context
ATHOS-3 added a titrated angiotensin II or placebo infusion to background vasopressor therapy in patients with vasodilatory shock.
Study and label context
Study drug was titrated to a mean arterial pressure target on background vasopressors.
The primary response was assessed at 3 hours without increasing background vasopressors.Cautions
Safety and unknowns
- The label warns about venous and arterial thrombotic and thromboembolic events. In ATHOS-3, the reported rates were 13% with Giapreza and 5% with placebo, with deep-vein thrombosis accounting for the major imbalance.
- Blood pressure must be monitored during infusion and the dose adjusted to the clinical response. The label calls for concurrent venous thromboembolism prophylaxis.
- The label says angiotensin-converting enzyme (ACE) inhibitors may increase the response to Giapreza, while angiotensin II receptor blockers (ARBs) may reduce it.
Product quality
Product identity and quality
Giapreza is a defined intravenous product whose concentration and infusion rate are specified in the prescribing information.
Dose units
The labeled infusion rate is expressed in ng/kg/min and titrated to blood pressure.
Mechanism
How it is proposed to work
Angiotensin II activates a receptor on blood vessels, causing them to narrow. It also promotes aldosterone release, contributing to blood-pressure regulation.
The eight-residue peptide binds angiotensin II type 1 receptors. The pressure effect is a pharmacologic response, while patient outcomes require clinical measurement.
Details
Technical details
Sources
References
- 1.
DailyMed. Giapreza prescribing information
US label for adult distributive shock, intravenous infusion, blood-pressure titration, thrombosis risk and drug interactions.
- 2.
PubMed. Angiotensin II for vasodilatory shock: ATHOS-3
doi:10.1056/NEJMoa1704154 PMID:28528561 NCT02338843
Randomized trial of blood-pressure response to angiotensin II versus placebo on background vasopressors.
- 3.
PubMed. Angiotensin II structure and type 1 receptor signaling
PMID:40509287
Primary molecular study identifying the eight-residue angiotensin II sequence and receptor context.