The Trouble with Studies and endpoints, or vit C vs Sepsis

So, I after digging into the study and finding the very significant decrease in mortality for the vitamin C group, I went searching for articles on this study, hoping I could find a comment by Marik, the doc who claims such great results at VA Medical School. Perhaps saying “ I disagree with your conclusion” or something. And I did find a related article at NPR.

It explains that the author’s of the study did not at all feel like there was no difference in the Vitamin C vs placebo, they were in fact quite excited about the results. But it appears that they have been hoisted on their own petard, so to speak. Or at least the petard of researchers. It appears there is a rule for getting research published that says that whatever your primary endpoint stated up front is, that is what you must emphasize. What they say is that they chose the wrong endpoints. Especially considering that death, or lack thereof, is possibly the ultimate endpoint.


https://www.npr.org/sections/health-shots/2019/10/01/766029397/mixed-results-for-a-test-of-vitamin-c-for-sepsis

Somebody said...

'Tantalizing' Results For A Test Of Vitamin C For Sepsis
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October 1, 201911:02 AM ET


Could the leading cause of death in hospitals be curtailed with a safe and inexpensive treatment that includes vitamin C?
That question has been on the minds of intensive care doctors since the spring of 2017, when a well-known physician asserted that he was saving the lives of most of his patients with sepsis by using a treatment based on intravenous vitamin C.
Scientists from around the world have jumped on this claim to support or refute it because, if it worked, it would save millions of lives. The biggest study published to date now comes to a vexing conclusion. If you read the study summary, vitamin C didn't help the patients. But if you dig deep into the paper, you will find that the people who got the treatment were much more likely to survive.
Confusing? Absolutely. The rub comes from the way the study, published Tuesday in the American Medical Association journal, JAMA, was designed.
Sepsis is the body's overreaction to a severe infection, leading to multiple organ failure and, frequently, death. Though many people haven't heard of sepsis, the Centers for Disease Control and Prevention says it afflicts more than 1.7 million Americans a year and kills more than 250,000, making it one of the top 10 causes of death.
Over the years, scientists have stumbled across clues that vitamin C might be effective against sepsis. For one thing, people with sepsis tend to have surprisingly low levels of vitamin C in their blood. In 2014, Dr. Alpha "Berry" Fowler published a paper involving just 24 patients, hinting that vitamin C was a benefit. In particular, Fowler noted that a measure of organ failure, known as a mSOFA score, improved far more in the patients who had received vitamin C.
That study was far too small to draw any real conclusions. But Dr. Paul Marik at the Eastern Virginia Medical School in Norfolk read the study and was intrigued. When Marik encountered a sepsis patient who seemed on the verge of death, he decided to give her vitamin C. He added thiamine (a B vitamin) and a dose of steroids to her treatment. And, much to his surprise, the woman quickly recovered.
Marik then started using it regularly in his intensive care unit. He reported in 2017 that the mortality rate for sepsis in his ICU had plummeted after he switched to this treatment. That paper led some ICU doctors to start using the so-called Marik protocol, figuring that it was quite safe and possibly effective. In the meantime, researchers geared up to do careful studies to see whether the treatment really worked.
Meanwhile, Fowler, at Virginia Commonwealth University, pressed on with his own research. He rounded up a group of colleagues to further explore the role of vitamin C in one set of sepsis patients — those who became extremely ill after they developed an associated disease called acute respiratory distress syndrome.
Fowler's team studied 167 patients, half of whom received the vitamin C treatment and half of whom received a placebo. They chose as the mark of success the same endpoints he had used in his study of 24 patients.
The result: no difference in these scores at all. The bottom line was that vitamin C "did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury," the study says.
Here's the twist. The researchers also looked at 46 other "secondary" endpoints. And one in particular stands out: 28 days following treatment, 25 of the 84 patients treated with vitamin C died, compared with 38 of the 83 patients given the placebo. That's a big difference, with the mortality rate dropping from 46% to 30%.
If death had been the primary endpoint of the study, this result would have been highly significant. The conclusion would strongly support the hypothesis that vitamin C is an effective treatment of sepsis.
But there's a catch. Since Fowler and his colleagues looked at 46 secondary endpoints, it's likely that something would randomly pop up as statistically significant. It's as though they had 46 bites at the apple to find something meaningful. To guard against that, statisticians have strict rules for analyzing multiple comparisons. And when those rules are followed, the death numbers in the JAMA paper don't pass that test.
What patients really care about, of course, is not their mSOFA scores and blood test results, but whether they live or die. Fowler tells NPR that he now rues his decision to select an endpoint that seemed more likely to show a benefit (as it did in his study of 24 patients). "So many sepsis studies have failed that used mortality as a primary endpoint," he says. He and his colleagues worried that if the result was not dramatic, "vitamin C probably would have fallen on its face."
Though he's now bound by the rules of experimental design to downplay the mortality results, he personally feels a sense of success. "We're all whooping and hollering because of what we found," he says.

There is less celebration in other quarters. "Despite this rigorous clinical trial, the question remains: does administration of vitamin C in patients with organ dysfunction confer benefit?" write Drs. Emily Brant and Derek Angus at the University of Pittsburgh in an editorial that is published alongside the paper. While the death results are "tantalizing," they note that none of the many clinical measurements normally associated with better outcomes can explain the higher survival rate in vitamin C patients.
"They have to explain how vitamin C would have an impact on mortality through a mechanism that did not affect the organ failure scores," Dr. Steve Goodman at Stanford University writes in an email to NPR. Goodman, who is an expert in experimental design, notes that the Food and Drug Administration has at least once approved a drug (a heart medication called carvedilol) based on improved mortality, even though the drug didn't appear to work based on its primary endpoint. But in his view the mortality result in this new study isn't so convincing.
Fowler has some ideas to explain the results — at least after the fact. One issue is that these patients were far sicker than the patients in his original study of 24 patients. Some were septic for four days before treatment began, unlike the other study in which patients often got the treatment promptly.
One requirement of this study was that the patients must have developed the serious complication of ARDS and had been put on mechanical ventilators.
The findings also don't have a direct bearing on the Marik protocol. That's not simply vitamin C (at a much lower dose than the Fowler study) but also includes corticosteroids and thiamine (vitamin B1). Marik has been treating patients at the first signs of sepsis, when treatment is more likely to be successful.
"One could argue this [new result] doesn't say very much about the Marik protocol," Brant tells NPR.
Marik agrees. He says the vitamin C and corticosteroids have a synergistic effect that is not evident in the new study. While Marik agrees that the study is not definitive, he says it importantly finds no side-effects and it does show a mortality benefit. "You can argue about all the statistical nuances, but that's what the study showed," he said.
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The parts that most jump out at me are: "What patients really care about, of course, is not their mSOFA scores and blood test results, but whether they live or die. Fowler tells NPR that he now rues his decision to select an endpoint that seemed more likely to show a benefit (as it did in his study of 24 patients). "So many sepsis studies have failed that used mortality as a primary endpoint," he says. He and his colleagues worried that if the result was not dramatic, "vitamin C probably would have fallen on its face."
Though he's now bound by the rules of experimental design to downplay the mortality results, he personally feels a sense of success. "We're all whooping and hollering because of what we found," he says.................................................................................................................................................................................The findings also don't have a direct bearing on the Marik protocol. That's not simply vitamin C (at a much lower dose than the Fowler study) but also includes corticosteroids and thiamine (vitamin B1). Marik has been treating patients at the first signs of sepsis, when treatment is more likely to be successful.
"One could argue this [new result] doesn't say very much about the Marik protocol," Brant tells NPR.
Marik agrees. He says the vitamin C and corticosteroids have a synergistic effect that is not evident in the new study. While Marik agrees that the study is not definitive, he says it importantly finds no side-effects and it does show a mortality benefit. "You can argue about all the statistical nuances, but that's what the study showed," he said."
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So here is what I think: if I(or a loved one) am in ICU dying from sepsis which I acquired from my medical procedure- say my RP- or acquired in some other way, I want the freaking IV vitamin C, preferably Marik's protocol combined with riboflavin b2 and hydrocortisone. But, above all else, I want the Vit C along with whatever else more traditional they desire to give me. And I want it until someone actually proves it useless or harmful. Preferably, I would like it before I actually get sepsis or advanced sepsis. Why the heck not? Since it is dirt cheap and has shown about zero harm in any study, why on earth would I not want it, assuming I am not mentally ill? Personally, I could dig a significantly lower risk of death from sepsis as well as 1/2 the time in ICU, call me crazy.
But would you guys not want the VC ( along with whatever else they want to give you) until some of this great evidence is proven otherwise?

But, unless I am at Virginia Medical School or a few other places, I'm betting it would be an absolute ***** to get my doctors to let me have some in my vein. Unless I am willing and able to threaten law suites, and maybe even then, it might prove impossible. Here is Marik's original 2017 retrospective/before/after study that stimulated the more recent RCTs:
https://www.ncbi.nlm.nih.gov/m/pubmed/27940189/
"Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study
METHODS: In this retrospective before-after clinical study, we compared the outcome and clinical course of consecutive septic patients treated with intravenous vitamin C, hydrocortisone, and thiamine during a 7-month period (treatment group) with a control group treated in our ICU during the preceding 7 months. The primary outcome was hospital survival. A propensity score was generated to adjust the primary outcome.

RESULTS: There were 47 patients in both treatment and control groups, with no significant differences in baseline characteristics between the two groups. The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P < .001). The propensity adjusted odds of mortality in the patients treated with the vitamin C protocol was 0.13 (95% CI, 0.04-0.48; P = .002). The Sepsis-Related Organ Failure Assessment score decreased in all patients in the treatment group, with none developing progressive organ failure...............................................".
https://rebelem.com/the-marik-protocol-have-we-found-a-cure-for-severe-sepsis-and-septic-shock/

"Treatment Group: Treated with standard sepsis care + intravenous vitamin C, hydrocortisone and thiamine within 24 hours of ICU admission
Control Group: Treated with standard sepsis care only.

Standard ICU Care:

Empiric broad spectrum antibiotics giving initially, which were de-escalated according to microbiological data and clinical progress
Conservative physiologic fluid based therapy
Intravenous hydrocortisone 50mg q6hr................

Vitamin C (Marik) Treatment Protocol:

Standard ICU care (see above), plus:
Intravenous vitamin C 1.5g q6hr x4d or until ICU discharge
Hydrocortisone 50mg q6hr x7d or until ICU discharge followed by a taper over 3d
Intravenous thiamine 200mg q12hr x4 or until ICU discharge
Strengths:

No difference in baseline characteristics between groups
Consecutive patients enrolled
The studied interventions were cheap, seemingly safe (we don’t really know the long term outcomes), and readily available.
This was the first study to evaluate the combination of intravenous vitamin C, hydrocortisone, and thiamine

Limitations:

Not a RCT
Small sample size
Only a single center study
Use of non-concurrent controls (i.e., patients were not evaluated during the same timeframe)
PCT is not readily available at every hospital

Discussion:

No patients in the treatment group died from complications related to sepsis, rather their mortality was secondary to complications of their underlying disease" .............................................................................................................................................................................................

So what is sort of mind blowing is that while 19 of 47 control group patients died, of the 4 who died in the treatment group, not a single one actually died of the sepsis, but from their underlying disease. Which is why, until proven otherwise, if I have sepsis, I want the vitamin C.

Post Edited (BillyBob@388) : 12/28/2019 10:23:49 PM (GMT-7)

DjinTonic said...
A fascinating topic, BillyBob, and one about which I have no familiarity. A quick search showed that there have been quite a number of studies on Vit. C and sepsis in 2018-2019, so the question is far from dead and buried. It will probably take prospective studies to settle the outstanding questions of just what is accounting for any benefit: the C itself, the C plus additions, patient status at the start of therapy, particulars of the strains involved, etc. Studies focusing on the mechanism of action of Vit. C in sepsis should help in the design of protocols. But I agree, risk/benefit is certainly on the side of using C here, at least until we have more data.

Djin

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Thanks for your thoughts, Djin! I'd say( as you have probably already figured out), I'm pretty much in the same camp.

The thing is, if this turns out to be correct, it is HUGE. As it is, due to the end points chosen in the last study, about all they can do is call for more studies, but I will volunteer as a guinea pig if I get sick. In fact, I will demand to be one! ;)

Right now, we technically still don't know as proved by RCTs(but I bet Dr. Marik is keeping right on! ). But if correct, HUGE. In the USA, 1.7 million (!) a year get sepsis and 270,000 die of it. Which dwarfs PC deaths. Even a 10% reduction in mortality would save 27,000 lives a year(more than die from PC, right?). This newest study showed a mortality reduction from 46% that died to 29%. So instead of 46 out of 100 patients dying, only 29. How do we figure that? Is that a 37% reduction? Not 10%, but 37%? Good grief! But in Marik's original study(not an RCT), not only did the hospital mortality drop from 40.4% (19 of 47) in the control group to 8.5% (4 of 47) in the treatment(vitamin C) group, in the VC group not a single person died from the actual sepsis! (and Marik did the study after he did a single case study with a woman that was almost certain to die, but- after being treated normally PLUS VC, shocked every one by recovering. Shocked by those results with the one lady, he then did his study with 47 patients, comparing them with another 47 with similar levels of illness. 19(40%) deaths vs 4(8%)!

Such dramatic differences just seem a little extreme to be just chance. But the problem as always is getting the medical profession to jump on this with both feet and prove it one way or the other. With such ridiculous results, they should have had such life saving claims proven or disproved within 6 months or 1 year, IMO. Thousands of lives are at stake. Instead, it's 3 years later and, despite another big drop in mortality, all we have is "more studies are needed". Unless it is me or my loved one, then I am going to fight for the Vitamin C.

Did you ever see the report out of New Zealand of the guy was on his death bed, not expected to live, with Sepsis after flu, whose family had to fight the docs with lawyers(at 2 different hospitals) to get some IV vitamin C? He is alive and healthy today. Not exactly an RCT for sure, no proof there, but a very interesting story that was covered by 60 minutes New Zealand.

Post Edited (BillyBob@388) : 12/29/2019 1:50:04 PM (GMT-7)

Crazy stuff there. I can't say I have seen any RCTs or even less stringent trials of any kind on IV turmeric.

Post Edited (BillyBob@388) : 12/29/2019 3:12:42 PM (GMT-7)

NotBubba said...
There was a reason
https://www.forbes.com/sites/brittmariehermes/2017/08/05/fda-links-naturopathic-turmeric-death-to-contaminated-product/#4320dae02db4

OK, interesting. I almost got caught in something like that just before I retired, but in more traditional medicine. I would do epidural injections of steroids for pain. The hospital I worked in supplied the the equipment and the drugs, as usual. So I started hearing about some contaminated steroid drug that was causing meningitis and paralysis. It was being produced way up north somewhere, but had made it all the way down to Memphis- with some injuries there- which was only about 75 miles north of the hospital where I was working. Scared me to death, until I was able to determine that one of that product had made it to our facility. Thank goodness. I felt terrible for the victims of that contamination, and was so grateful that I was not involved in such. But, I could have easily been involved, but for sheer luck.

No idea, but I take tumeric curcumin capsules. It's one of the more researched phytochemicals for its PCa activity.

Djin

In my previous post I forgot to add: Whether or not IV curcumin is legal or FDA allowed or whether it is some crazy thing that quacks have come up with and are doing, I have no idea and it is not relevant for what is being discussed in this thread. In no far stretch of the imagination can the people be called quacks who are doing these studies on IV Vitamin C being added to the more traditional treatments, in an ICU, of sepsis. Or even called alternative practitioners. These researchers and clinicians are 100% near the top of the traditional MD heap, of the kind of folks any of you are going to encounter if you have the misfortune to need an ER or ICU/CCU. For example, Marik is well known- in a good way- among critical care doctors. And there is nothing quack like about where he did this study: Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, VA

Post Edited (BillyBob@388) : 12/30/2019 12:37:26 PM (GMT-7)

There are several more studies in progress. I am hoping they are good, unbiased studies that will be completed fairly soon, to tell us one way or another that there is a benefit as well as no harm to adding vitamin C to the treatment. One way or another for sure, even though the evidence seems strong right now, at least for reduced mortality, which is pretty important. We would probably have a solid declaration of "very helpful" from the OP study if the authors had simply chosen mortality, days on the ventilator and days in ICU as their primary endpoints, rather than the lab values they chose instead. But as it is, we are stuck with what they apparently are required to emphasize: those primary end points.

And I have learned something new while researching this study, as I had previously about "statistical significance": The whole "primary end point" thing. Apparently it would not matter if the death rates had been reduced to zero, they can't say much about it if that was not their declared up front primary end point.