Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock After Cardiac Surgery (VANCS trial), by Ludhmila Hajjar et al .
Back in the time, there was a group of people who dedicated their lives pursuing a way to transform common things into gold! They were known as alchemists. The modern alchemists are just regular guys who went to college and became doctors and researchers. We are always pursuing a miracle cure, a miracle drug, a miracle something. Statins? Vitamins? Acetylcysteine? They might, or have to, work for some disease. Is like having the perfect drug, without a disease. How can people still prescribe cough syrup? Who doesn’t love to experience new things? Or perhaps, new drugs? We all love the idea of discovering a world-changing/life-saving drug. Today, is no different. We will discuss the VANCS trial , recently published on Anesthesiology. A single center trial, conducted by 32 authors, and maybe the door-man and the cab driver, which evaluated the use of norepinephrine vs vasopressin in vasoplegic shock after cardiac surgery.
Why and how
If there is one specific population you can be sure will experience vasoplegic shock, patients after cardiopulmonary bypass would be it! And, if there is one thing intensivists have pleasure with, is titrating vasoactive drugs. Now, we have a match made in heaven. When we think about shock, norepinephrine sounds like Elvis Presley on Christmas Eve! But, it has been speculated for a while that vasopressin could be an alternative to norepinephrine, and the idea of a drug acting on a different pathway than adrenergic drugs do, sounds really interesting. Although, even strong physiological backgrounds can be misleading. The VANCS trial is all about this discussion, it evaluated how vasopressin performed against norepinephrine in vasoplegic shock after cardiac surgery. Indeed, it is a really important question. Despite that little voice inside my head saying that maybe vasopressin is our new obsession in finding a way to transform death into gold.
The authors planned a single center (not going to change the world, again), randomized, double-blind, controlled trial, enrolling patients undergoing elective cardiac surgery (valve replacement, CABG, or repair surgery with cardiopulmonary bypass). Patients were randomized if: requirement of vasopressors for vasodilatory shock within 48h after cardiopulmonary bypass weaning. Vasodilatory shock was defined as: refractory hypotension (MAP<65mmHg) + cardiac index >2.2l/min/m2. They were randomized to an 1:1 ratio to receive vasopressin (0.01-0.06U/min) or norepinephrine (10-60mcg/min), both drugs were titrated to a MAP ≥65mmHg; if the target MAP was not reached, open label norepinephrine was started. During the vasopressor weaning phase, the open label norepinephrine was discontinued first. A sample size of 300 was needed to show a difference of 30% in the primary outcome, with power of 80%, alpha of 5%, accounting for a 5% follow up loss, and expecting a incidence of 55% of the primary outcome in the norepinephrine group. The outcome? Soon, my friend…
The primary outcomes were days alive and free of organ dysfunction at 28 days, BUT (this is a big and fat but), months passed by, and after the trial was alread en route, due the lack of outcome data, the primary outcomes were changed to a “more appropriated endpoint for cardiac surgery patients”. The new glowing outcomes were a composite of mortality or severe postoperative complications (stroke, reoperation, acute renal failure, deep sternal wound infection, or need for mechanical ventilation >48h). It was said that, at the time the outcomes were changed, the data hadn’t been analyzed yet. Well… Who knows? It’s kinda funny to make such a huge discover about which endpoint would be appropriated in the middle of the trial. It reminds me the time I decided to go to France for vacation but I was already flying to Chile…It happens all the time! Not only that, I was thought that your sample size calculation should be based on you primary endpoint, now what? Oh boy, those alchemists are surrounded by mysticism. Another supernatural thing happened when a modified intention to treat analysis were done, excluding, after randomization, of course, 25 patients who were already receiving vasopressors.
Here we have the baseline characteristics of patients:
The results were positive, after all. Vasopressin reduced the primary endpoint compared to norepinephrine. The positive results were driven mostly by a decrease in acute renal failure.
Well, the only real difference was the incidence of acute renal failure. Ok, renal failure is a big deal, BUT (that but again) the norepinephrine group had more patients with chronic renal failure AND more patients using angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB), 70% vs 53%. If you look carefully, there is a beautiful table (on the supplement, of course) and a tiny phrase saying that there was no difference in the primary outcome (including renal failure) after adjusting for ACEI/ARB use. Ok, it might be a math trick, but…
This isn’t personal, I’m not saying that this is a crappy study, because it’s not, however, what has been seen, cannot be unseen. It was a single center study and the outcomes were changed during the enrrolement phase. Again, we’ll have to wait until a multicenter trial gives us a new, and more solid, perspective. To wrap it up, a few considerations:
1-The primary outcome issue: C’mon!
2-Modified intention to treat: when you try to turn something ugly into something beautiful.
3-Cancer (neoplasm) was an exclusion criteria: 21 patients excluded, although 18 patients appeared in the final analysis. Needs clarification.
4-The possible disappointment when, after adjusting for ACEI/ARB use, things might not be so clear as they thought it would be.
5-Not even a smell of mortality benefit.
6-Even if we consider this study as undoubtedly positive, is vasopressin cost effective? Remember that acute renal failure is not equal to dialysis.
The Goldfinger Conclusion
Unfortunately, this is not a practice changing article. Perhaps vasopressin can turn people into gold, like Shirley Eaton (007: Goldfinger). We don’t know yet. But we’ll, or they’ll, keep searching. Maybe the solutions are with our friends alchemists, and a mix of vasopressin, statins and acetylcysteine will do the trick.
1. Ludhmila Abrahao Hajjar, M.D., Ph.D., Jean Louis Vincent, M.D., Ph.D., Filomena Regina Barbosa Gomes Galas, M.D., Ph.D., Andrew Rhodes, M.D., Ph.D., Giovanni Landoni, M.D., Eduardo Atsushi Osawa, M.D., Ph.D., Renato Rosa Melo, M.D., Marcia Rodrigues Sundin, M.D., Solimar Miranda Grande, M.D., Fabio A. Gaiotto, M.D., Ph.D., Pablo Maria Pomerantzeff, M.D., Ph.D., Luis Oliveira Dallan, M.D., Ph.D., Rafael Alves Franco, M.D., Rosana Ely Nakamura, M.D., Luiz Augusto Lisboa, M.D., Ph.D., Juliano Pinheiro de Almeida, M.D., Ph.D., Aline Muller Gerent, M.D., Dayenne Hianae Souza, M.D., Maria Alice Gaiane, M.D., Julia Tizue Fukushima, M.Sc., Clarice Lee Park, M.D., Cristiane Zambolim, M.D., Graziela Santos Rocha Ferreira, M.D., Tânia Mara Strabelli, M.D., Ph.D., Felipe Lourenco Fernandes, M.D., Ligia Camara, R.N., Suely Zeferino, R.N., Valter Garcia Santos, R.Ph., Marilde Albuquerque Piccioni, M.D., Ph.D., Fabio Biscegli Jatene, M.D., Ph.D., Jose Otavio Costa Auler, Jr., M.D., Ph.D., Roberto Kalil Filho, M.D., Ph.D.; Vasopressin versus Norepinephrine in Patients with Vasoplegic Shock after Cardiac Surgery: The VANCS Randomized Controlled Trial. Anesthesiology 2017;126(1):85-93. doi: 10.1097/ALN.0000000000001434.