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Infamous Vitamin C Study May Rely on Fraudulent Data
— Statistician alleges data in study led by Paul Marik, MD, were fabricated
by Kristina Fiore, Director of Enterprise & Investigative Reporting, MedPage Today March 25, 2022
The data underpinning an infamous study of vitamin C for sepsis may be fraudulent, according to an analysis by an Australian physician and statistician that’s making waves among hospitalists and intensivists.
Kyle Sheldrick, MBBS, who is completing his PhD at the University of New South Wales, alleges that the pre- and post- comparison groups involved in the 94-patient study were too similar to be realistic.
“This is extreme,” Sheldrick told MedPage Today in an interview. “This is probably the most obviously fake data I have seen. … These groups are more similar than would be probable.”
The paper, led by Paul Marik, MD — a controversial figure during the COVID-19 pandemic who recently left his position at Eastern Virginia Medical School (EVMS) — has been the subject of much debate in the intensive care community since it was published in 2017. If clinicians could prevent death from sepsis with a simple regimen of hydrocortisone, ascorbic acid (vitamin C), and thiamine (the procedure was dubbed the HAT protocol), many lives easily could be saved.
“Obviously this paper sparked interest around the globe, but it’s hard to express how much excitement there was locally,” Bryan Carmody, MD, a pediatric nephrologist at EVMS, told MedPage Today. “I remember speaking to several faculty members who predicted that Dr. Marik might one day win the Nobel Prize.”
But many were skeptical from the beginning. “The effect size seemed just impossible,” said Nick Mark, MD, an ICU physician at Swedish Medical Center in Seattle. “It seemed too good to be true.”
Several larger and more methodologically robust studies followed, and to date, none of at least nine randomized trials — notably, the VITAMINS and VICTAS trials — has shown a similar reduction in mortality, raising suspicions even further, Mark said.
When Sheldrick posted his analysis earlier this week, it finally clicked:
“This was under our noses for 5 years,” Mark said. “This isn’t just a mistake. We know things can be done unethically, but to actually fake it? That it’s not just flawed, but perhaps actually fraudulent?”
Sheldrick told MedPage Today the key problem with the Marik paper is “probably the most common sign of fraud that we see, which is overly similar groups at baseline.”
Read the rest here:
https://www.medpagetoday.com/special-reports/exclusives/97865?trw=no
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January 17, 2020
Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic ShockThe VITAMINS Randomized Clinical Trial
Tomoko Fujii, MD, PhD1,2; Nora Luethi, MD1,3; Paul J. Young, MBChB, PhD4,5; et alDaniel R. Frei, BSc, MBChB6; Glenn M. Eastwood, PhD1,7; Craig J. French, MB, BS1,8,9; Adam M. Deane, MB, BS, PhD10; Yahya Shehabi, MB, BS, PhD11,12; Ludhmila A. Hajjar, MD, PhD13; Gisele Oliveira, MD13; Andrew A. Udy, MBChB, PhD1,14; Neil Orford, MB, BS, PhD1,15,16; Samantha J. Edney, BSN4; Anna L. Hunt, BN, PGDipHSM, PGDipClinRes4; Harriet L. Judd, BSN, PGDipHC4; Laurent Bitker, MD7,17; Luca Cioccari, MD1,7,18; Thummaporn Naorungroj, MD7,19; Fumitaka Yanase, MD1,7; Samantha Bates, BN, PGDipCritCare8; Forbes McGain, MB, BS, PhD8; Elizabeth P. Hudson, MD20; Wisam Al-Bassam, MBChB11; Dhiraj Bhatia Dwivedi, BScNsg, MBA11; Chloe Peppin, BN, PGDipCritCare11; Phoebe McCracken, MPH14; Judit Orosz, MD14; Michael Bailey, PhD1,9; Rinaldo Bellomo, MD, PhD1,7,9; for the VITAMINS Trial Investigators
Author AffiliationsArticle Information
JAMA. 2020;323(5):423-431. doi:10.1001/jama.2019.22176
Key Points
Question Does treatment with vitamin C, hydrocortisone, and thiamine lead to a more rapid resolution of septic shock compared with hydrocortisone alone?
Findings In this randomized clinical trial that included 216 patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days (122.1 hours vs 124.6 hours, respectively).
Meaning The findings suggest that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
Abstract
Importance It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock.
Objective To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.
Design, Setting, and Participants Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019.
Interventions Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.
Main Outcomes and Measures The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality.
Results Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was –0.6 hours (95% CI, –8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.
Conclusions and Relevance In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
Trial Registration ClinicalTrials.gov Identifier: NCT03333278
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There was no significant difference in time alive and free of vasopressors up to day 7 (168 hours) after randomization between the intervention group and the control group (median, 122.1 hours [IQR, 76.3-145.4 hours] vs 124.6 hours [IQR, 82.1-147.0 hours], respectively; median of all paired differences between groups, –0.6 hours [95% CI, –8.3 to 7.2 hours]; P = .83) (Table 2).
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In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
Section Editor: Derek C. Angus, MD, MPH, Associate Editor, JAMA (angusdc@upmc.edu).
https://jamanetwork.com/journals/jama/fullarticle/2759414
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