Ang II: A Real Addition to the Critical Care Armamentarium or Just Another “Me Too” Vasopressor?

First, let me start by apologizing for the 7 month delay between blog posts.  It turns out that keeping up a blog is more work than I anticipated, and I have failed in keeping it up to date – epic failure.

So, in my first blog post in more than half a year, I thought I would write some comments on Angiotensin II (Ang II).  As many have seen, this new vasopressor made a bit of a splash with a NEJM publication in May of this year.

In the two decades I have been practicing medicine, we have essentially been limited to catecholamine vasopressors.  And, as much as we like to talk about the different effects of catecholamine pressors on different catecholamine receptors, the fact remains they are all still catecholamines.  About a decade ago, there was considerable buzz for vasopressin, which does raise blood pressure and save some catecholamine exposure in many hypotensive patients.  Unfortunately, more recent studies of vasopressin have failed to demonstrate improvements in patient outcomes.  The VAsopressin in Septic Shock Trial (VASST) randomized almost 800 critically ill patients with septic shock receiving norepinephrine infusions to blinded administration of vasopressin or more norepinephrine.  Disappointingly, despite reducing the amount of norepinephrine that patients received, vasopressin did not significantly improve overall 28 or 90 day mortality.  A number of subsequent analyses provided some provocative, hypothesis-generating data, including that vasopressin may be more effective in patients with less severe (defined as norepinephrine infusion of 5 to 15 mg/min) shock (VASST – Table 4), those with septic-shock induced renal failure (Vasopressin in Renal Failure – ICM), or in patients also receiving steroids (Vasopressin and Steroids – CCM).  I don’t believe the effect of vasopressin in the subgroup of patients with less severe shock has ever been prospectively tested.  And, while the interaction of vasopressin and steroids is still being investigated (Vasopressin and Steroids Pilot – CCM), the beneficial effect of vasopressin on renal function in patients in shock is less provocative after the VANISH study was found to be overall negative (VANISH).  The VANISH study investigated the effect of early vasopressin compared to norepinephrine (ideally as the initial vasopressor) in a factorial design with a comparison of steroids or placebo.  The primary endpoint was kidney-failure free days up to 28 days after randomization, which did not differ between the two groups.  Patients treated with vasopressin did have slightly less renal replacement therapy, which has made some question whether the 400 patients enrolled just left the trial underpowered, although overall mortality also did not differ between the groups.

Despite what some may consider that long diatribe on vasopressin above, I do still use it in my practice, albeit a lot less and mostly to just spare my refractory shock patients from very high levels of catecholamines. It does, however, temper some of my excitement over Angiotensin II (Ang II).  Ang II has a physiologic basis for raising blood pressure, and it is naturally occurring in nature and humans.  Ang II is an integral part of the renin-angiotensin-aldosterone system (RAAS), which plays a significant role in the regulation of blood pressure.  Pre-clinical studies have shown that Ang II raises blood pressure of patients on pressors, and like vasopressin, allows for reduction in catecholamine doses.  This led to the multicenter, international ATHOS-3 study of Ang II in patients with catecholamine resistant vasodilatory shock, where Ang II (or blinded placebo) was added to catecholamine pressors (ATHOS-3).  While technically not a study restricted to patients with septic shock, more than 80% of the 320 patients enrolled had a septic shock diagnosis.  As expected, Ang II significantly increased the mean arterial blood pressure at 3 hours (time during which open label norepi dosage was to remain constant), and in 69.9% of patients (compared to only 23.4% of the placebo patients) raised the MAP to either 75 mmHg or increased it by 10 mmHg (P<0.001; OR 7.95).  In fact, in some patients, it raised blood pressure so well that catecholamines could be turned off and the Ang II had to be stopped and restarted at a lower dose. It lowered the cardiovascular SOFA score, although interestingly did not significantly lower the overall SOFA score.

While these results are exciting, and “positive” enough that the company, La Jolla Pharmaceuticals, is moving forward with submitting a new drug application with the FDA and requesting FDA approval, they are also a bit disappointing.  Overall, 7 day (maybe too soon) and 28 day all-cause mortality were not significantly different between Ang II and placebo.  Now, maybe this was just due to lack of power – a sample size of 320 is moderate in size, but not huge, and the p-value for 28-day mortality was 0.12 with a hazard ratio of 0.78 favoring Ang II.  However, I think we are going to need further prospective studies, with relevant clinical outcomes including mortality (likely even 90 or 180 day mortality), lengths of stay, and even long term clinical outcomes, as the primary endpoints to better discern Ang II’s true place in the treatment of septic shock.  If it is unable to improve these clinical outcomes, then it still provides a new class of vasopressor medication, but its use may very well be limited to limiting catecholamine exposure to patients with severe, catecholamine resistant refractory shock.  However, on the other hand, IF future studies are able to demonstrate an improvement in clinical outcomes beyond MAP and catecholamine dose, then Ang II might become THE vasopressor of choice in patients with vasodilatory shock.  Regardless, it is nice to potentially have a new vasopressor agent, in a novel class, available for the treatment of our refractory shock patients, and I anxiously await further data to understand if Ang II represents a minor or major advance in our care of these patients.

Todd

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