Angiotensin II for the Treatment of Vasodilatory Shock, by Ashish Khanna et al .
I wish I had either the literary touch of Alexandre Dumas or the amazing mind of Rinaldo Bellomo. The first wrote an incredible book, the second, among other things, wrote an editorial about the article we’re gonna discuss today with an amazing metaphor about The Three Muusleteers and the so called pressors triumvirate: epinephrine, norepinephrine and vasopressin. However, in this blog, we replace the lack in literacy with bad jokes and personal offenses. Ok, focus now! [Clears throat] Most of the time, we see our hands tied up while watching our patients tumbling down the septic shock role. I mean, we give them early antibiotics, fluids, source control, sometimes dialysis, and we’re always aware to not screw things up. But once these things are done, we see ourselves relying on the pressors triumvirate. Ok, if you are the science kinda guy, you still might have some drugs in your pocket for refractory shock, like glibenclamide, methylene blue and glucose-insulin-potassium. Either way, you’re doomed. It’s hard to keep things up when you’re sick, specially arterial pressure. That being said, some guys who never skipped physiology lessons published the ATHOS 3 Trial (Angiotensin II for the Treatment of Vasodilatory Shock). So, without further delays, here we go!
Of course, running a major multicenter trial is easier said than done, and unfortunately, money talks. The trial protocol was designed by a committee and the sponsor (La Jolla Pharmaceutical Company), to make things worse, the data were analyzed by the sponsor, which also had direct participation in the manuscript writing! [Breath in, breathe out] No more comments. The inclusion criteria were: patients > 18 y/o, with vasodilatory shock (CI>2.3 L/min/m2 or SvO2 >70% + CVP>8mmHg with a MAP 55-70mmHg) despite fluids and high-dose pressors (0.2 μg/kg/min of norepinephrine or equivalent), for 6 to 48h. Exclusion criteria were: burns >20% BSA, acute coronary syndrome, bronchospasm, liver failure, AAA, treatment with high dose corticoids, neutrophil <1000/ml, or VA ECMO. I can bet that every time someone measures CVP, a well-intentioned physician is willing to give the patient some fluids, and of course an angel dies. Despite the CVP, there is another thing that bothers me: why the cutoff of 0.2 μg/kg/min of norepinephrine? One of the references the authors cited defined high-dose vasopressor (HDV) as ≥1 mg/kg/min of norepinephrine equivalent. Also, the most used definition for refractory shock (assuming HDV and refractory shock are the same thing) is ≥0.5 mg/kg/min of norepinephrine or equivalent. So, deciding to use a cutoff of 0.2, doesn’t fit. Ok, it is easier to recruit patients with the chosen cutoff, but calling it HDV is rather premature.
Mental marturbation aside, this multicenter, double-blind, placebo-controlled trial, used stratified (MAP, APACHE II) block randomization in a 1:1 ratio to either placebo or synthetic human angiotensin II (LJPC-501). So, although it is a “blind study”, we know that is impossible, we’re comparing a drug that is supposed to increase MAP against placebo, that is suppose to, well, visually looks like the intervention drug. Again, it’s interesting to see that 23% of patients receiving placebo had a positive MAP response (see results section). Just remember, this is a phase-3 trial, they are looking for efficacy and safety.
Once the patient was recruited, infusions of the study drug were initiated, and during the first 3 hours titrated to a MAP ≥75mmHg. During this phase, all pressors were held constant (except for safety reasons), and if the doses were increased, patient was designated as non-responder. From 3 to 48h the study drug/placebo and other pressors could be titrated as needed. After 48h, the study drug/placebo were withdrawn.
The primary endpoint was MAP ≥75mmHg or an increase in MAP ≥10mmHg from baseline. A sample size of 150/arm was needed, with power of 90% and two-sided alpha of 5%. Secondary endpoints were hierarchically analyzed. Safety was also evaluated.
A total of 404 patients were screened, and 344 randomized. The table below shows the patients characteristics.
Both groups were balanced regarding important characteristics. I was amazed to see that almost half patients had their cardiac index measured, and I really hope they performed a dynamic fluid responsiveness test in those patients. Almost 50% of patients were receiving an equivalent norepinephrine dose <0.35, while almost 30% were receiving doses ≥0.5, also, almost 70% of all patients used vasopressin during 6h before randomization (thais is A LOT!). More patients in the intervention group achieved the primary outcome (69.9% vs. 23.4%, P<0.001; odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3). The intervention group had greater increase in MAP than placebo group during the first 3h (12.5 mm Hg vs. 2.9 mm Hg; P<0.001). Also, the authors highlighted that intervention group had greater improvement in cardiovascular SOFA at 48h (−1.75 vs. −1.28, P=0.01). Another interesting finding was that elevated vasopressor dose was a negative predictor of response (odds ratio, 0.40; 95% CI, 0.21 to 0.77; P = 0.006), only 50% of patients receiving norepinephrine dose >0.5 μg/kg/min responded to the intervention. There were no difference in adverse events between groups. The graphs and table below show the results.
Well, what the data showed us. First, the drug do increase MAP when compared to placebo. This might seem little obvious, but since it’s a P3 trial looking for efficacy, all we’re left to say is: job well done! Regarding to the difference in CV SOFA at 48h, well, it seems they’re measuring the same thing. See, the CV SOFA is nothing more than a categorization of a continuous variable (MAP) adding the use and dose of pressors in the equation. And since the intervention drug is not listed as a pressor in the CV SOFA, it seems a little obvious that patients in the intervention group would have better CV SOFA at 48h (just take a look at the graphs above). Another purpose of this study was to evaluate safety, and although around 90% of patients experience some form of adverse events, there were no difference between groups. An important reminder is that if you take a look at the adverse events table at the study, you will see that almost every adverse event imaginable is listed, and it should be. Again, P3 study.
So, it seems that we’re about to see some changes in our arsenal against shock, the triumvirate will become a…well, I think the word is tetravirate, but I’m not sure. Anyway… I really don’t know what is gonna happen, but I can guess: The LJPC-501 will soon hit the market…and I suppose they won’t sell it cheap, then, it will be advertised as an alternative for refractory shock (and if we choose the 0.5 of norepinephrine as a cutoff, things might not be crystal clear), to justify the price, however, as time goes by, people will be using it to treat shock like we use norepinephrine today. I’m not a pessimist, I really hope once the drug is available, trials will begin to pop-up, maybe some investigator-driven trials, new evidences, and so on. Can you imagine all the potential discoveries? Until then, let’s wait and hope for the best.
1. Khanna A, English SW, Wang XS et al. Angiotensin II for the Treatment of Vasodilatory Shock. N Engl J Med. 2017
2. Bellomo R, Hilton A. The ATHOS-3 trial, angiotensin II and The Three Musketeers. Critical Care and Resuscitation. March 2017
3. Brown SM, Lanspa MJ, Jones JP et al. Survival After Shock Requiring High-Dose Vasopressor Therapy Chest. 2013; 143(3):664-671.
4. Benbenishty J, Weissman C, Sprung CL, Brodsky-Israeli M, Weiss Y. Characteristics of patients receiving vasopressors Heart & Lung: The Journal of Acute and Critical Care. 2011; 40(3):247-252.