CURRICULUM IN CARDIOLOGY - JOURNAL CLUB

Year : 2017  |  Volume : 3  |  Issue : 2  |  Page : 103-105

The Angiotensin II for the treatment of high-output Shock-3 Trial (Athos-3)

Nirmal Ghati
Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India

Correspondence Address:
Nirmal Ghati
6/2/4, Ramkali Mukherjee Lane, Kolkata - 700 050, West Bengal
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jpcs.jpcs_29_17

Introduction

• Shock is a life-threatening condition with severe organ hypoperfusion. There are four major types – vasodilatory, cardiac, hypovolemic, and obstructive
• Vasodilatory shock is the most common type and represents approximately two-thirds of all patients with shock ^[1],[2]
• Fluid resuscitation and vasopressors are main treatment to maintain blood pressure and organ perfusion
• There are two classes of conventional vasopressors – catecholamine (norepinephrine, adrenaline, and dopamine) and vasopressin. All the agents have a narrow therapeutic window with significant side effects at higher doses
• Approximately 6%–7% patients have vasopressor-resistant shock – requiring higher doses of vasopressors ^[3]
• Although there is no absolute definition for vasopressor resistant shock, most of the literature used >0.5 μg/kg/min norepinephrine or equivalent vasopressor dose as the cutoff for vasopressor-resistant shock ^[3]
• Vasopressor-resistant shock indicates poor prognosis with very high mortality rate (48%–94%), but none of the newer treatment options (glucocorticoids, methylene blue, and high volume hemofiltration) showed fruitful results in recent trials ^[3]
• Angiotensin II, a component of renin -angiotensin-aldosterone system, was tested successfully in patients with shock almost 50 years back ^[4],[5] but surprisingly abandoned for a long period of time
• Recently, the ATHOS trial, a small randomized control trial of twenty patients of vasodilatory shock, showed a significant reduction of background norepinephrine dose with intravenous angiotensin II versus placebo (27.6 ± 29.3 mcg/min vs. 7.4 ± 12.4 mcg/min, P = 0.06)^[6]
• In shock, angiotensin II increases blood pressure rapidly by direct vasoconstriction, increases in sympathetic discharge, and increases in adrenal medullary catecholamine release. Slow and persistent rise in blood pressure is due to direct renal vasoconstriction, increased renal sodium reabsorption, and renal sympathetic tone.

Study Objectives

• Primary Objective: To compare the effect of Angiotensin II infusion on mean arterial pressure (MAP) in patients with vasopressor resistant shock.
• Secondary Objective:



• To compare change in Sequential Organ Failure Assessment (SOFA) scores
• To establish the safety and tolerability of angiotensin II.

Study Design

• It was a multisite, randomized, double-blind, placebo-controlled Phase III study
• The study was conducted in 75 intensive care units across nine countries in North America, Australasia, and Western Europe
• The study sponsor was La Jolla Pharmaceutical Company
• It was started in May 2015 and ended in January 2017.

• Adult patients (>18 years) with resistant shock requiring a total catecholamine dose of >0.2 mcg/kg/min to maintain a MAP between 55 and 70 mmHg
• Clinical features of high-output shock (ScvO₂>70% and central venous pressure >8 mmHg or cardiac index = >2.3 L/min/1.73 m ²)
• Patients who were adequately fluid resuscitated and had an arterial line, central venous access, and indwelling urinary catheter.

Methods

• After screening and obtaining informed consent, background vasopressors were titrated to a target MAP of 65 mmHg and then the patients were randomized in 1:1 ratio to receive synthetic human angiotensin II or saline placebo
• Then, the study was conducted in three stages:
• Stage I (0–3 h): Angiotensin II and placebo infusions were initiated at a rate = 20 ng/kg/min and dose adjusted to achieve a MAP ≥75 mmHg. In this stage, doses of background vasopressors were held constant and could not be increased except for safety reasons. If these doses were increased, the patient was designated as nonresponder
• Stage II (3–48 h): In this period, the study drug or placebo and other vasopressors were adjusted to maintain a target MAP between 65 and 75 mmHg. If vasopressin was being used, it was weaned off first if possible. Then, standard-of-care vasopressors were titrated until the sum of the norepinephrine and epinephrine dose was as low as 0.03 μg/kg/min
• Stage III (48 h–7 days): At 48 h, the study infusion was discontinued according to a protocol-specified tapering process. If tapering was not possible due to worsening of patient's condition, study medication or placebo was resumed for up to 7 days. However, once the study medication or placebo was discontinued for >3 h, it could not be restarted.

Study Endpoints

• The primary efficacy analysis was based on the modified intention-to-treat population
• Wilcoxon rank-sum test or analysis of variance was used for continuous or ordinal variables
• Chi-square or Fisher's exact test was used for discrete variables
• Two-tailed alpha level of 0.05 was used to test the hypothesis of treatment difference
• Logistic regression analysis was used to identify baseline factors that may have influenced the primary endpoint
• Time-to-event data including mortality were compared by a log-rank test and were characterized by Kaplan–Meier estimates
• Hazard rates were estimated from the proportional hazards model.

Results

• A total of 321 patients were recruited in the modified intention to treat model (163 patients received angiotensin II and 158 patients received placebo)
• The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio: 7.95; 95% confidence interval [CI]: 4.76–13.3; P < 0.001)
• At 48 h, the mean improvement in the cardiovascular SOFA score was greater in the angiotensin II group than in the placebo group (−1.75 vs. −1.28, P = 0.01)
• There was no significant improvement in total SOFA score in the angiotensin II group (1.05 vs. 1.04, P = 0.49)
• Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group.
• Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio: 0.78; 95% CI: 0.57–1.07; P = 0.12).

Discussion

• Unlike other new therapies, angiotensin II more closely mimicked natural physiologic responses to shock
• The concomitant reductions in catecholamine requirements support the concept of synergistic action of vasoactive drugs
• No serious adverse effect of angiotensin II was reported in this trial
• In the study, angiotensin II was not associated with higher mortality
• However, there was no improvement in multiorgan failure (total SOFA score) by angiotensin II which points against any mortality benefit
• If we see the mechanism of action, angiotensin II is a pure vasopressor agent. Hence, it may not be an appropriate standalone drug for the treatment of septic shock, in which cardiac contractility can be suppressed.

Positive Points

• ATHOS-3 trial was a well-structured randomized controlled trial
• It had an international multicenter trial design that involved large varieties of populations
• The study groups were well matched with respect to baseline disease characteristics and demographics
• The patients were severely ill, as indicated by high APACHE II scores and elevated baseline vasopressor doses
• Moreover, a significant proportion of the patients in this trial had septic shock - the most severe type of vasodilatory shock we face in our daily practice.

• The sponsor (La Jolla Pharmaceutical Company) had significant contribution in protocol design, data analysis, and manuscript writing. Hence, a potential conflict of interest cannot be ruled out
• The reason behind a low cutoff for vasopressor resistance was not explained in the trial. Was it to get a positive efficacy result?
• Moreover, in patients with baseline norepinephrine dose >0.5 μg/kg/min, odd ratio for positive response was 0.40 which points against any real effectiveness of angiotensin II in severe vasopressor-resistant shock
• Although it was a blinded study, the significant blood pressure response to angiotensin II may have allowed treating clinicians to correctly guess the treatment assignment in some cases
• Sample size was relatively small, so the possibility of clinically important side effects cannot be fully excluded
• The follow-up was only for 28 days, which is insufficient to evaluate any long-term effects of angiotensin II therapy
• It was not a head-to-head comparison trial. Hence, we cannot say at this moment that angiotensin II is better than other conventional vasopressor agents
• The safety and efficacy of angiotensin II in patients with distributive shock and low cardiac output were not tested in this study
• Above all, the trial was not sufficiently powered to detect any mortality benefit of angiotensin II.

Conclusion

• Angiotensin II may be useful in the treatment of catecholamine-resistant vasodilatory shock
• Significant short- and long-term adverse effects should be ruled out in the future trials before adding the drug in the conventional management plan
• Given the lack of mortality benefits and total organ function improvement, its commercial potential could be debatable
• In the future, larger and longer trial will answer the question whether we have got a perfect vasopressor with mortality benefit or not.

References

1.	Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377:419-30.   [PUBMED]
2.	Dellinger RP, Trzeciak S. Angiotensin II for the treatment of vasodilatory shock - promise and caution. N Engl J Med 2017;377:486-7.   [PUBMED]
3.	Bassi E, Park M, Azevedo LC. Therapeutic strategies for high-dose vasopressor-dependent shock. Crit Care Res Pract 2013;2013:654708.   [PUBMED]
4.	Derrick JR, Anderson JR, Roland BJ. Adjunctive use of a biologic pressor agent, angiotensin, in management of shock. Circulation 1962;25:263-7.   [PUBMED]
5.	del Greco F, Johnson DC. Clinical experience with angiotensin II in the treatment of shock. JAMA 1961;178:994-9.   [PUBMED]
6.	Chawla LS, Busse L, Brasha-Mitchell E, Davison D, Honiq J, Alotaibi Z, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): A pilot study. Crit Care 2014;18:534.   [PUBMED]