GIAPREZA Concentrate for solution for infusion Ref.[51552] Active ingredients: Angiotensin II

Pharmacotherapeutic group: Cardiac therapy, other cardiac stimulants
ATC code: C01CX09

Mechanism of action and pharmacodynamic effects

Angiotensin II raises blood pressure by vasoconstriction; increased aldosterone release via direct action of angiotensin II on the vessel wall is mediated by binding to the G-protein-coupled angiotensin II receptor type 1 on vascular smooth muscle cells which stimulates Ca²⁺/calmodulindependent phosphorylation of myosin and causes smooth muscle contraction.

GIAPREZA is titrated to effect for each individual patient. In the ATHOS-3 trial, the median time to increase blood pressure was approximately 5 minutes. The effect on blood pressure is sustained for at least the first three hours of continuous intravenous infusion. Due to the short half-life of GIAPREZA (less than one minute), an abrupt withdrawal of angiotensin may lead to rebound hypotension (see section 4.4). Therefore, once underlying shock is sufficiently improved, a slow down-titration is recommended by gradual decrements of up to 15 ng/kg per minute, as needed, based on blood pressure (see sections 4.2 and 4.4).

Clinical efficacy and safety

The Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) was a Phase 3 randomised, placebo-controlled, double-blind, international, multi-centre safety and efficacy study in which 321 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomised 1:1 to GIAPREZA or placebo. Doses of GIAPREZA or placebo were titrated to a target mean arterial pressure (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 were titrated to maintain MAP between 65 and 70 mmHg while reducing doses of other vasopressors.

For their inclusion in the study, patients had to have clinical features of high-output shock defined as a cardiac index >2.3 l/min/m² or the sum of central venous oxygen saturation >70% with central venous pressure (CVP) >8 mmHg. Patients also had to have catecholamine refractory hypotension (CRH) defined as requiring a total sum vasopressor dose of >0.2 mcg/kg/min for 6 to 48 hours, to maintain a mean arterial pressure (MAP) between 55-70 mmHg and receiving at least 25 ml/kg of crystalloid or colloid equivalent over the previous 24-hour period and be adequately volume resuscitated in the opinion of the treating investigator.

Of the 321 patients treated in the Phase 3 study, 195 patients were male (60.7%), 257 (80%) patients were White, 33 (10%) were Black, and 31 (10%) were Other. Median age was 64 years (range: 22-89 years). Patients requiring high doses of steroids, patients with a history of asthma or bronchospasm who were not mechanically ventilated, and patients with Raynaud’s syndrome were excluded. Patients with active bleeding, mesenteric ischaemia, liver failure and MELD score of ≥30, CV SOFA score ≤3 and patients with extensive burns were also excluded. 91% of subjects had septic shock; the remaining subjects had other forms of distributive shock such as neurogenic shock. Patients with cardiogenic shock were excluded (see section 4.4).

At the time of study drug administration, 97% of subjects were receiving norepinephrine, 67% vasopressin, 15% phenylephrine, 13% epinephrine, and 2% dopamine. 83% of subjects had received two or more vasopressors and 47% three or more vasopressors prior to study drug administration. Patients were not necessarily on maximum doses of other vasopressors at the time of randomisation. Of the 321 patients, 227 (71%) were receiving a baseline norepinephrine equivalent dose (NED) <0.5 mcg/kg/min, 73 patients (23%) were receiving baseline NED ≥0.5 to <1 mcg/kg/min and 21 (6%) patients were receiving high doses of vasopressors (NED ≥1.0 mcg/kg/min). The effect of GIAPREZA when added to maximum doses of other vasopressors is unknown.

The primary endpoint was the percentage of subjects who achieved either a MAP ≥75 mmHg or a ≥10 mmHg increase in MAP without an increase in baseline vasopressor therapy at 3 hours.

The primary endpoint was achieved by 70% of patients randomised to GIAPREZA compared to 23% of placebo subjects; p<0.0001 (a treatment effect of 47%). The treatment effect was consistent in high risk subsets of patients with low baseline MAP or high APACHE II score, which were stratification variables (Table 3).

Table 3. Primary efficacy endpoints: MAP response at hour 3 (mITT population and subgroups):

mITT = modified intent-to-treat population

In the GIAPREZA-treated group, the median time to reach the target MAP endpoint was 5 minutes. The effect on MAP was sustained for at least the first three hours of treatment. The median dose of GIAPREZA was 10 ng/kg/min at 30 minutes. Of the 114 responders at Hour 3, only 2 (1.8%) received more than 80 ng/kg/min.

Mortality through day 28 was 46% on GIAPREZA and 54% on placebo (hazard ratio 0.78; 95% confidence interval 0.57-1.07).

The effect of GIAPREZA on morbidity and mortality has not been determined in appropriate studies.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with GIAPREZA in one or more subsets of the paediatric population for the treatment of hypotension in children who remain hypotensive despite fluid and vasopressor therapy.