Vasopressin in septic shock: an individual patient data meta-analysis of randomised controlled trials
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We performed an individual patient data meta-analysis to investigate the possible benefits and harms of vasopressin therapy in adults with septic shock both overall and in pre-defined subgroups.
Our pre-specified study protocol is published on PROSPERO, CRD42017071698. We identified randomised clinical trials up to January 2019 investigating vasopressin therapy versus any other vasoactive comparator in adults with septic shock. Individual patient data from each trial were compiled. Conventional two-stage meta-analyses were performed as well as one-stage regression models with single treatment covariate interactions for subgroup analyses.
Four trials were included with a total of 1453 patients. For the primary outcomes, there was no effect of vasopressin on 28-day mortality [relative risk (RR) 0.98, 95% CI 0.86–1.12] or serious adverse events (RR 1.02, 95% CI 0.82–1.26). Vasopressin led to more digital ischaemia [absolute risk difference (ARD) 1.7%, 95% CI 0.3%–3.2%] but fewer arrhythmias (ARD − 2.8%, 95% CI − 0.2% to − 5.3%). Mesenteric ischaemia and acute coronary syndrome events were similar between groups. Vasopressin reduced the requirement for renal replacement therapy (RRT) (RR 0.86, 95% CI 0.74–0.99), but this finding was not robust to sensitivity analyses. There were no statistically significant interactions in the pre-defined subgroups (baseline kidney injury severity, baseline lactate, baseline norepinephrine requirement and time to study inclusion).
Vasopressin therapy in septic shock had no effect on 28-day mortality although the confidence intervals are wide. It appears safe but with a different side effect profile from norepinephrine. The finding on reduced RRT should be interpreted cautiously. Future trials should focus on long-term outcomes in select patient groups as well as incorporating cost effectiveness analyses regarding possible reduced RRT use.
KeywordsVasopressin Septic shock Individual patient data Meta-analysis
We are grateful to the investigators and clinical trials groups of all the trials included in this study for providing access to their trial data.
ACG conceived the study. MN, JAR, KRW, SJB, GDP, AJM, DA and ACG designed the protocol. JAR, KRW, LH and ACG provided individual patient data for the analysis. MN performed the analysis and wrote the first draft of the manuscript. All authors contributed to critical revision of the manuscript for important intellectual content and approved the final version. MN and ACG are the guarantors.
ACG is funded by a UK National Institute for Health Research (NIHR) Research Professor award (RP-2015-06-018). GDP is supported as an NIHR Senior Investigator. ACG and GDP are Directors of Research for the Intensive Care Foundation. The VANISH trial was funded by an NIHR Research Professor award (RP-2015-06-018). Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre. The VANCS II trial support was provided by the University of Sao Paulo. The views expressed in this publication are those of the authors and not necessarily those of the NHS, NIHR or the Department of Health.
Compliance with ethical standards
Conflicts of interest
LH reports that outside of this work she has received speaker fees from Amomed Pharma. ACG reports that outside of this work he has received speaker fees from Orion Corporation Orion Pharma and Amomed Pharma. ACG has consulted for Ferring Pharmaceuticals, Tenax Therapeutics, Baxter Healthcare, Bristol-Myers Squibb and GSK and received grant support from Orion Corporation Orion Pharma, Tenax Therapeutics and HCA International with funds paid to his institution. JAR reports patents owned by the University of British Columbia (UBC) that are related to the use of PCSK9 inhibitor(s) in sepsis and related to the use of vasopressin in septic shock. JAR is an inventor on these patents. JAR was a founder, Director and shareholder in Cyon Therapeutics Inc. JAR is a shareholder in Molecular You Corp. JAR reports receiving consulting fees in the last 3 years from: Asahi Kesai Pharmaceuticals of America (AKPA) (developing recombinant thrombomodulin in sepsis), SIB Therapeutics LLC (developing a sepsis drug), Ferring Pharmaceuticals (manufactures vasopressin and developing selepressin). JAR is no longer actively consulting for the following: La Jolla Pharmaceuticals (developing angiotensin II; JAR chaired the DSMB of a trial of angiotensin II from 2015 to 2017), Cubist Pharmaceuticals (now owned by Merck; formerly was Trius Pharmaceuticals; developing antibiotics), Grifols (sells albumin), CytoVale Inc. (developing a sepsis diagnostic), PAR Pharma (sells prepared bags of vasopressin). JAR reports having received an investigator-initiated grant from Grifols (entitled “Is HBP a mechanism of albumin’s efficacy in human septic shock?”) that was provided to and administered by University of British Columbia.
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