Add-on Vasopressin May Lower AF Risk in Distributive Shock

Patrice Wendling

May 14, 2018

Patients in distributive shock appear to have a lower risk for atrial fibrillation when vasopressin is added to catecholamine vasopressors, but its effect on other outcomes are mixed, according to a new systematic review and meta-analysis.

Based on pooled data from 13 studies at low risk of bias, the addition of vasopressin was associated with a 33% reduction in the risk for atrial fibrillation compared with catecholamines alone (risk ratio [RR], 0.77; 95% CI, 0.67 - 0.88).

In absolute terms, 68 fewer people per 1000 patients (95% CI, 36 - 98) will experience atrial fibrillation when vasopressin is added to catecholamines.

The finding was driven by the 2017 VANCS study, which carried 74.8% of the weight and was one of two trials in the analysis to evaluate vasoplegic shock after cardiac surgery, senior author, Emilie Belley-Côté, MD, McMaster University, Hamilton, Ontario, Canada, and her colleagues reported May 8 in JAMA.

"Clinicians may need to revisit their practice and start using vasopressin more frequently or earlier," Belley-Côté told | Medscape Cardiology. "It's a bit early, but the evidence in our review definitely differs from what was in the previous Surviving Septic campaign; so I do expect these findings to impact recommendations."

New Surviving Sepsis guidelines are expected in 2020, but the current version makes only a weak recommendation to add vasopressin to norepinephrine to raise mean arterial pressure to target or to reduce catecholamine use, citing only moderate-quality evidence in favor of vasopressin.

The meta-analysis is the first on this topic to examine atrial fibrillation as an outcome and one of few reviews to compare vasopressin plus catecholamines against the current standard, catecholamines alone, the authors note.

Using the GRADE system, investigators analyzed data from 3088 patients (mean age, 61.1 years; 45.3% women) in 23 studies. Of these, 22 studies, including the 2016 VANISH trial, included patients with septic shock; 15 trials were not blinded; and 5 were published only as abstracts.

Overall, 13 trials studied vasopressin, 9 terlipressin, 1 selepressin, and 1 pituitrin. One three-group study compared vasopressin vs terlipressin vs norepinephrine alone.

The crude rate of atrial fibrillation was 73% in the post–cardiac surgery population and 13% in the sepsis studies. Despite this difference, the relative effect of vasopressin was similar in sensitivity analyses of patients after cardiac surgery (RR, 0.77; 95% CI, 0.67 - 0.88) and those with sepsis (RR, 0.76; 95% CI, 0.55 - 1.05).

"What vasopressin really ends up being more than anything is a catecholamine-sparing agent when you look across the trials," first author, William F. McIntyre, MD, McMaster University, said in an interview. "Catecholamines are adrenergic; atrial fibrillation is an arrhythmia that the arrhythmogenesis and speed and intensity of the arrhythmia are all driven by catecholamines."

Secondary Outcomes

Mortality data available from 17 studies showed a significant 11% reduction in mortality with the addition of vasopressin to catecholamines (RR, 0.89; 95% CI, 0.82 - 0.97). The association was no longer significant, however, when the analysis was limited to the two trials at low risk of bias (RR, 0.96; 95% CI, 0.84 - 1.11).

"I don't think we can make a strong recommendation to use vasopressin to decrease mortality; however, it is quite reassuring because I've heard worries about vasopressin and the risk of mesenteric ischemia," Belley-Côté said. "And there is definitely no increase in mortality and, if anything, the effect may be neutral."

The analysis found no significant difference with the use of vasopressin in the risk for myocardial injury, ventricular arrhythmia, stroke, or hospital and ICU length of stay.

Vasopressin was associated with a nonsignificant 26% reduced risk for renal replacement therapy in six trials that reported the outcome, and a significant 30% reduction when the analysis was limited to two trials at low risk of bias (RR, 0.70; 95% CI, 0.53 - 0.92).

Renal protection related to reduced activation of the renin-aldosterone-angiotensin system is one of the hypothesized benefits of vasopressin in distributive shock, the authors note. For clinicians targeting mean arterial pressure, maintaining adequate blood flow while mitigating excessive vasoconstriction, a likely mechanism of digital ischemia, is also important.

Post hoc analyses of nine studies in 1963 patients, however, showed more than a twofold increased risk for digital ischemia with vasopressin use (RR, 2.38; 95% CI, 1.37 - 4.12), which translated into an absolute increase of 24 cases/1000 patients treated with vasopressin (95% CI, 6 - 55).

The finding is challenging to interpret because data were not available, despite additional attempts to clarify, on whether these events simply required more monitoring or stopping the drug or led to amputation, McIntyre said.

The quality of reporting for many studies was not sufficient to permit definitive judgments about risk of bias in all domains, and subgroup analyses were limited by the study-level nature of the data, the authors note.

Overall, the findings further emphasize the need to understand the long-term clinical implications of atrial fibrillation in distributive shock, McIntyre said. The mindset is often that atrial fibrillation is driven by the sepsis or "secondary," but it also may be paroxysmal. The distinction has consequences in terms of treatment, particularly the need for long-term anticoagulation.

"We know that up to half of patients who survive sepsis and other related hospitalizations are going to have atrial fibrillation again detected in the next couple of years," he said. "The question is, Is that going to translate into a long-term risk of stroke? — and that's what we're trying to figure out with some of the other studies in our program."

Belley-Côté reported receiving grant funding from the Canadian Institutes of Health Research. McIntyre reported receiving grant funding from the Canadian Stroke Prevention Intervention Network and being a trainee member of the Cardiac Arrhythmia Network of Canada.

JAMA. 2018;319:1889-1990. Abstract

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