Angiotensin II
Ang II, angiotensin II acetate, LJPC-501, [Asp1]angiotensin II, 5-isoleucine angiotensin II
Angiotensin II is the endogenous octapeptide at the business end of the renin-angiotensin system, the hormone that ACE inhibitors and sartans exist to block. Since 2017 it has also been a licensed intravenous vasopressor for vasodilatory shock, on the reasoning that a patient failing on catecholamines might respond to a pressor acting through an entirely different receptor. The registration trial met a blood-pressure endpoint but did not demonstrate a survival benefit.
Mechanism
Angiotensin II is generated in the circulation when renin, released from the juxtaglomerular apparatus in response to reduced renal perfusion or sympathetic stimulation, cleaves angiotensinogen to angiotensin I, which angiotensin-converting enzyme then trims to the active octapeptide Asp-Arg-Val-Tyr-Ile-His-Pro-Phe. It acts at two G-protein-coupled receptors. AT1, which mediates essentially all the classical actions, couples through Gq to phospholipase C, generating inositol trisphosphate and diacylglycerol, releasing intracellular calcium and producing potent vascular smooth muscle contraction. AT1 activation also stimulates aldosterone release from the adrenal zona glomerulosa, vasopressin release from the posterior pituitary, proximal tubular sodium reabsorption, thirst, and facilitation of noradrenaline release from sympathetic nerve terminals. AT2 signalling is largely counter-regulatory, promoting vasodilation and antiproliferative effects. Degradation by aminopeptidases and ACE2 is rapid, giving a circulating half-life well under a minute.
The therapeutic rationale in vasodilatory shock rests on two observations. First, catecholamines and vasopressin act through adrenergic and V1 receptors respectively; adding a third, mechanistically independent pressor allows the doses of each to be reduced, potentially limiting catecholamine toxicity. Second, in septic and post-cardiopulmonary-bypass shock, ACE activity in the pulmonary endothelium falls, so the angiotensin I to angiotensin II ratio rises and endogenous angiotensin II generation is relatively deficient, which makes exogenous replacement a physiologically coherent, not merely additive, intervention.
What the research shows
ATHOS-3 is the pivotal trial. It randomised 321 patients with vasodilatory shock who remained hypotensive despite high-dose vasopressors (a noradrenaline-equivalent dose greater than 0.2 µg/kg/min) to angiotensin II or placebo. The primary endpoint (a mean arterial pressure response at three hours, defined as an increase of at least 10 mmHg or a rise to at least 75 mmHg without an increase in background vasopressors) was achieved by 69.9% of the angiotensin II group versus 23.4% of the placebo group (p<0.001), an absolute difference of about 46 percentage points. That is an unusually large effect for a critical care intervention. Improvement in the cardiovascular component of the SOFA score at 48 hours also favoured angiotensin II. Mortality at 28 days was 46% versus 54%, a difference that did not reach statistical significance in a trial not powered for it. Serious adverse event rates were broadly similar between groups, with more thromboembolic events reported in the angiotensin II arm.
A phase 2 pilot (Chawla and colleagues, 2014) had previously shown in 20 patients that angiotensin II substantially reduced the noradrenaline dose required to maintain target blood pressure, the catecholamine-sparing effect that defines its intended role and that formed the rationale for the phase 3 programme.
Post hoc and secondary analyses of ATHOS-3 have generated hypotheses rather than answers. Subgroups reported to derive greater benefit include patients with acute kidney injury requiring renal replacement therapy and those with high baseline renin or a high angiotensin I to angiotensin II ratio, consistent with the idea that the drug replaces a genuine deficiency in a subset of patients. Another exploratory analysis suggested earlier initiation at lower background vasopressor doses might be advantageous. All of these are post hoc, hypothesis-generating findings from a single trial and none has been prospectively confirmed. No trial has yet demonstrated a mortality benefit for angiotensin II in shock.
Evidence assessment
Mixed evidence
Downgraded from 'strong' in the draft on audit. Angiotensin II does hold FDA and EMA approval for vasodilatory shock, and the pivotal trial is real and well conducted (ATHOS-3, PMID 28528561, verified), as is the phase 2 pilot (PMID 25286986, verified). But elsewhere in this set 'strong' denotes replicated randomised evidence, and angiotensin II fails that test on two counts. The approval rests on a single adequately powered phase 3 trial with no replication. And the primary endpoint was a physiological surrogate (mean arterial pressure response at three hours), which angiotensin II met convincingly, whereas 28-day mortality did not reach statistical significance in a trial not powered to detect it. One unreplicated trial on a surrogate endpoint, with no demonstrated mortality benefit and a thromboembolic signal, is mixed rather than strong. The evidence that it raises blood pressure and spares catecholamines is genuinely solid; the evidence that it saves lives does not exist yet. A third 'study' in the draft (a purported 2025 systematic review with no PMID, no DOI, 'Multiple authors' and a journal given only as 'Critical care literature') could not be shown to exist and has been deleted outright.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Angiotensin II for the treatment of vasodilatory shock Preclinical only
The primary endpoint of mean arterial pressure response at 3 hours was met by 69.9% of angiotensin II patients versus 23.4% on placebo (p<0.001). Cardiovascular SOFA score at 48 hours improved more with angiotensin II. Mortality at 28 days was 46% versus 54%, not statistically significant. Serious adverse events were broadly similar, with more thromboembolic events in the angiotensin II arm.
Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study Preclinical only
Angiotensin II substantially reduced the noradrenaline dose required to maintain target mean arterial pressure, with the placebo group requiring significantly higher catecholamine doses at hour one. Hypertension was the most common adverse effect, in one-fifth of treated patients; 30-day mortality was comparable between groups. Established the catecholamine-sparing effect that formed the rationale for the phase 3 programme.
Safety
The predictable risk of any potent vasoconstrictor is excessive vasoconstriction: digital, mesenteric and myocardial ischaemia are theoretical and reported concerns. In ATHOS-3, the most notable imbalance was in thromboembolic events. Deep vein thrombosis and arterial thrombosis were more frequent in the angiotensin II arm, with the trial's adverse event tabulation and the resulting product labelling reporting roughly 13% of angiotensin II patients versus 5% of placebo patients experiencing a thrombotic or embolic event. This is consistent with angiotensin II's known prothrombotic effects through plasminogen activator inhibitor-1 induction and platelet activation. Thromboprophylaxis is recommended in the labelling. Tachyarrhythmias, peripheral ischaemia, delirium, acidosis and hyperglycaemia have been reported.
Because angiotensin II is degraded within seconds, the infusion is titrated minute by minute against an arterial line and hypertension is easily corrected by reducing the rate. There is a theoretical interaction with ACE inhibitors, which reduce the conversion of angiotensin I and might increase sensitivity to exogenous angiotensin II, and with angiotensin receptor blockers, which would be expected to blunt the response.
This is a critical care infusion with no application outside an intensive care unit, and any use of angiotensin II by any other route or setting has no evidence base whatsoever. It is worth noting that angiotensin II is also the peptide that most of modern cardiovascular medicine is designed to suppress. ACE inhibitors, angiotensin receptor blockers and aldosterone antagonists all exist because sustained angiotensin II signalling drives hypertension, cardiac hypertrophy, fibrosis and renal injury. Its therapeutic use is confined to the narrow situation of catecholamine-refractory shock precisely because chronic exposure is harmful.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Prescription-only medicine, intensive care use. Angiotensin II acetate holds a Great Britain marketing authorisation, carried over from the EU centralised authorisation granted in August 2019, for increasing blood pressure in adults with refractory hypotension resulting from septic or other distributive shock who remain hypotensive despite adequate volume restitution and application of catecholamines and other available vasopressor therapies. Uptake in the NHS has been limited and it has not been endorsed for routine use by all UK health technology bodies. |
| United States | FDA-approved (December 2017) to increase blood pressure in adults with septic or other distributive shock. Intravenous infusion, intensive care setting only. |
| WADA (sport) | Not listed on the WADA Prohibited List. Angiotensin II is an endogenous hormone with no plausible ergogenic application and is not named in any prohibited class; it is an intensive care vasopressor administered by continuous infusion with arterial line monitoring. |
Questions
The two situations are opposites. Chronic, inappropriate angiotensin II signalling drives hypertension, cardiac hypertrophy, fibrosis and renal damage, which is why ACE inhibitors and sartans are cornerstone therapies. Vasodilatory shock is the reverse problem: profound pathological vasodilation with a relative deficiency of angiotensin II, because pulmonary endothelial ACE activity falls in sepsis. Giving it back for hours in an intensive care unit is a different proposition entirely from years of excess signalling.
That has not been shown. ATHOS-3 met its primary endpoint of blood pressure response convincingly (69.9% versus 23.4%), but 28-day mortality was 46% versus 54%, which did not reach significance in a trial that was not powered to detect a mortality difference. The honest position is that angiotensin II reliably raises blood pressure and spares catecholamine doses, and whether that translates into more survivors remains an open question.
Because the circulating half-life is well under a minute. Blood pressure responds within a minute or two of a rate change and falls back just as fast when the infusion is reduced. That makes the drug highly controllable at the bedside with an arterial line, but it also means it can only ever be used as a continuous infusion in a monitored setting.
In ATHOS-3, thromboembolic events, including deep vein thrombosis and arterial thrombosis, were more frequent in the angiotensin II arm than with placebo. This is biologically plausible: angiotensin II induces plasminogen activator inhibitor-1, which impairs fibrinolysis, and promotes platelet activation. The product labelling accordingly recommends concurrent venous thromboembolism prophylaxis.