Saturday, March 19, 2016

Vitamin C Megadose: Ignore it at Your Own Peril

There is an extended dismissing attitude toward vitamin C supplementation in gram doses making the point that it only gets you expensive urine. I don't find this argument neither specially intelligent nor compelling at all. The question is how much of those grams get to do something before going out of your body.

Moreover, I find the labeling of ascorbic acid (AA) as a vitamin misleading.

Index:

Ascorbate Natural History


Source: Figure 1 from Conserved or Lost: Molecular Evolution of the KeyGene GULO in Vertebrate Vitamin C Biosynthesis (adapted)
  1. It seems that ascorbic acid production is ancient. It has been hypothesized that eukaryotes evolved the enzyme now used in animals (GULO gene) early on, giving rise to a related one in fungi (some synthesize the ascorbate analogue D-erythroascorbate) and new ones on plants giving rise to ascorbate production without hydrogen peroxide byproduct due to GULO.
    From Biosynthesis of Ascorbic Acid in Plants: A Renaissance:
    Comparisons between the amino acid sequences of the aldonolactone dehydrogenases (green plants)/oxidases (rat) that produce ascorbate or erythroascorbate (yeast) show 26 to 31% identity.
    From Evolution of alternative biosynthetic pathways for vitamin C following plastid acquisition in photosynthetic eukaryotes:
    Here we present molecular and biochemical evidence demonstrating that GULO was functionally replaced with GLDH in photosynthetic eukaryote lineages following plastid acquisition. GULO has therefore been lost repeatedly throughout eukaryote evolution. The formation of the alternative biosynthetic pathways in photosynthetic eukaryotes uncoupled ascorbate synthesis from hydrogen peroxide production and likely contributed to the rise of ascorbate as a major photoprotective antioxidant.

  2. Nonteleost fishes synthesize ascorbate in their kidneys (some even in their brains) so it isn't a vitamin for them. Nevertheless, there is some effects of supplementation of ascorbic acid under stress.
    From Dietary ascorbic acid may be necessary for enhancing the immune response in Siberian sturgeon (Acipenser baerii), a species capable of ascorbic acid biosynthesis (2006):
    There were no significant differences in renal l-gulono-1, 4-lactone oxidase (GLO) activity between dietary and LPS treatments, but fish exposed to LPS without dietary AA demonstrated an inter-organ transfer of AA from posterior kidney to liver. Our results indicate that dietary AA may be conditionally necessary for Siberian sturgeon to achieve optimal immune response, particularly in early developmental stages, information imperative to developing successful aquaculture programs for sturgeon species.
    Many papers reported that supplementation of dietary vitamin C to the animals with AA biosynthesis capability can raise up the animal's anti-stress ability and immune functions (Pardue and Thaxton, 1985, Bains, 1996, Li et al., 2001, Zhou et al., 2002 and Zhou et al., 2005).

  3. Teleost fishes doesn't make ascorbate so it is a vitamin for them. Nevertheless, we have some special effects at high doses.
    From Optimization of dietary vitamin C in fish and crustacean larvae: a review (1997) (my bolds):
    In studies with European sea basss using diets supplemented with high AA concentrations, positive effects on stress resistance have been observed in salinity stress tests (Merchie et al., 1995b). Also for turbot, cumulative mortalities after challenge with Vibrio anguillarum increased up to 50% for the control, while only 40% mortality occurred in the groups fed vitamin C-enriched diets, providing evidence for an immunostimulatory effect of high AA doses. This lower stress sensitivity was confirmed also for African catfish (Merchie et al., 1995b, 1997b).

  4. It seems kidney production was conserved by amphibians, reptiles and some birds while been transfered to the liver of most mammals and other birds. Nevertheless, supplementation of ascorbic acid under stress still seems beneficial.
    From Ascorbic acid decreases heat shock protein 70 and plasma corticosterone response in broilers (Gallus gallus domesticus) subjected to cyclic heat stress (2004):
    Under stressful environments, physiological requirements for AA may exceed the AA synthesizing ability of chickens (Pardue and Thaxton, 1986). These authors cited several studies that suggest beneficial effects due to heat stress amelioration and acclimation associated with AA supplementation.
    From Vitamin C and infections in animals by Harri Hemilä (excerpt of his dissertation Do vitamins C and E affect respiratory infections?):
    Rawal et al. (1974) reported that survival of mice infected with Pseudomonas aeruginosa was increased by vitamin C supplementation in a dose-dependent fashion. Senatuite and Biziulevicius (1986) reported that in rats infected with Trichinella spiralis the average number of muscle larvae after 3 weeks was 40% lower in the vitamin C administered group. Chaiyotwittayakun et al. (2002) induced mastitis in cows using intramammary infusion of endotoxin, and vitamin C reduced the fall in milk production caused by endotoxin.
    Dr. Hemilä has tackled also experiments with tetanus toxin on animals (I will rewrite my comments about it and the one on humans —first and second— in another blog). Actually it seems that liver ascorbic acid production is increased under stress at least in mammals. From Eight Decades of Scurvy by Irwin Stone:
    This liver metabolite, ascorbate, is produced in an unstressed goat for instance, at the rate of about 13,000 mg per day per 150 pounds body weight (Chatterjee, 1973). A mammalian feedback mechanism increases this daily ascorbate production many fold under stress (Subramanian et al., 1973).
    It seems to happen in ill cats and dogs too.
    It seems that these animals are also prone to increase the value of their urine. From Metabolic interactions between l-ascorbic acid and drugs by Conney et al. (1961):
    The urinary excretion of ascorbic acid increased from control values of about 0.3 mg. per day to values of 17 mg. per day by 6 days after the dose.

  5. Some species of birds and mammals have lost the capacity of ascorbic acid production, so technically it has become a vitamin for us too. Nevertheless, it seems it has some special effects at high doses.
    There has been some research on the effectiveness of enough intramuscular ascorbic acid (100mg/kg twice a day for 7 days) on rabies (guinea pigs) by Dr. Banič (Prevention of rabies by vitamin C, full text) that is still unrefuted: gross estimation of the probability of 17 or less of the 48 guinea pigs in the treatment group dying and 35 or more of the 50 controls dying supposing it being completely by chance —supposing probability of a death being 52/98— is 0.01%.
    We humans (perhaps some but not all Haplorrhini primates) have developed unique adaptations such as not burning it into carbon dioxide and water unlike guinea pigs. Our kidneys work hard to minimize its loses in urine (it seems an ubiquitous mechanism at least in mammals) whenever its concentration drops below a certain threshold. This threshold varies from person to person mostly between 0.9 and 2.0mg/dl.

Reading late Irving Stone's state of the art (at the time) review (its credentials are immaterial since he didn't do the experiments himself, it could do its review incomplete though... good luck finding a more thorough one) on vitamin C is a must.

All of these data coupled with both its low toxicity and clinical experience by Drs. Klenner, Cathcart and Levy point toward ascorbic acid supplementation at high doses as a therapy to be considered plausible on humans and so to be refuted, not ignored.


Ascorbic acid route administration


Of course achieving an equivalent serum value should produce equivalent outcomes whichever the route of administration. But.

Peak plasma concentration on oral (circles) versus intravenous (triangles) delivery
Source: Vitamin C Pharmacokinetics: Implications for Oral and Intravenous Use
First, peak plasma concentration is going to be quite dissimilar due to the faster absorption  through the intravenous route than the oral one.

Moreover. From Pharmacokinetics of Vitamin C: insights into the oral and intravenous administration of ascorbate:
Model-derived overprediction of plasma ascorbate concentrations with respect to the observed ones in several different literature reports could be the result of incomplete absorption of administered vitamin C at daily doses higher than 200 mg (1.1 mmol). Otherwise, it could also be a result of inappropriate timing of actual measurements.
About oral absorption we have for example the paper by Hornig et alter stating:
A male non-smoking volunteer increased his daily intake of ascorbic acid continuously by ingesting in a single, oral dose 1, 2, 3, 4 and 5 g crystalline ascorbic acid.
The urinary excretion of unmetabolized unlabelled ascorbic acid per day was taken as index for the absorption of ascorbic acid. It decreased from 75% (1 g), 44.0% (2 g), 39% (3g), 28% (4 g) to 20% (5 g) of the ingested ascorbic acid.
These data are about a healthy individual. Clinical experience of Dr. Cathcart points toward quite different dynamics under illness

What's my point? There is no use to mix intravenously|intramuscularly delivered trials with orally delivered ones when assessing ascorbate efficacy.

Finally, there is my concern about the subcutaneous delivery route.


Subcutaneous route and poliomyelitis


Late Dr. Klenner's put the blame of the fail of vitamin C curing poliomyelitis in monkeys on Dr. Sabin unsuccessful replication of Dr. Jungeblut's results. From The Use of Vitamin C as an Antibiotic:
One of the most unfortunate mistakes in all of the research on poliomyelitis was Sabin’s UN-SCIENTIFIC attempt to confirm Jungeblut’s work with vitamin C against the Polio virus in monkeys. Jungeblut in infecting his Rhesus monkeys used the mild ‘droplet method’ and then administered vitamin C by needle in varying amounts up to 400 mgm/day. Even this method did not give him absolute control over the degree of infection that would result. However, his antibiotic (vitamin C) remained relatively constant. With almost infinitesimal amounts, as we at present recognize, he was able to demonstrate in one series that the non-paralytic survivors was six times as great as in the controls. On the other hand, Sabin, in infecting his monkeys did not follow the procedure given by Jungeblut who’s experiments he was attempting to repeat, but instead employed a more forceful method of inoculation which obviously resulted in sickness of maximum severity. Sabin further refused to follow Jungeblut’s suggestion as to the dose of vitamin C to be used. By Sabin’s actual report the amount given was rarely more than 35 per cent of that used by his associate. Sabin makes this significant statement (1939)7, “One monkey was given 400 mgm of vitamin C for one day at the suggestion of Jungeblut who felt that large doses was necessary to effect a change in the course of the disease.” Yet on the basis of Sabin’s work the negative value of vitamin C in the treatment of virus diseases has been for years accepted as final.
This has been the core of every critique henceforward to this day by those on an orthomolecular path such as Andrew W. Saul or Steve Hickey. I would like to point out majkinetor's critique:
It was Dr. Jungeblut who found a inverted U-shape response curve as a function of vitamin C dose in his first 1937 paper:
Source: Table I of Vitamin C Therapy and Prophylaxis in Experimental Polimyelitis showing higher effect with 5mg than with 10-50mg, no effect at all with 100-700mg


I think that we could blame subcutaneous route (instead of intraperitoneal, intravenous or intramuscular one) while not falsified, since Jungeblut says on the third page of his first 1937 paper:
The doses of vitamin C covered a range from 700 mg. to 5 mg. and were mostly administered by the subcutaneous route.

I would like to know if increasing doses of subcutaneous vitamin C injections could give rise to blocked absorption of it. Dr. Klenner observed "Induration (only when intramuscular injections are given too close to the surface)" so perhaps using the subcutaneous route impeded good absorption of high doses in Dr. Jungeblut's experiment. It would explain the no-effect of higher doses found by Dr. Jungeblut commented on his first paper. If true using subcutaneous route would be the original cause of vitamin C megadoses blackout for more than 70 years already. It wouldn't be posterior failed replication by Dr. Sabin.

Since then I have only found one somewhat similar inverse U-shape response with vitamin C injection using the subcutaneous route for tetanus toxin by Ghosh and Guha in 1938 commented upon by Dr. Hemilä. From their paper: "One m. l. d. of the toxin was injected, and ascorbic acid (100 mg.) in saline (1 c.c.) was injected within one minute after the injection of the toxin, and on a site remote from that of the toxin injection." Using two sites I think that discards intraperitoneal route (used successfully by Dey in rats). Since the minimum lethal dose is defined by subcutaneous route in the tetanus toxin case and they weren't more specific I have to conclude that Gosh and Guha used the subcutaneous route both for the toxin and the vitamin C.


Liposomal vitamin C


Source: Wikipedia

One delivery method that differs substantially in the route of absorption is the encapsulation in liposomes. Liposomes are tiny, soluble particles with a lipid bilayer encompassing a substance we want to protect in order to deliver it either directly to cells if we inject them intravenously or to the lymphatic system if we take them orally as pointed out by studentroland.

Oral liposomal vitamin C is absorbed directly to the lymphatic system not longer inside liposomes. In Dr. Levy's words:
Liposomes predominately get taken up by the lymphatic system in the gut, not the portal circulation. There is no significant "one-pass" liver metabolism that takes place with a quality liposome preparation.
On the other hand, the liposomes, especially in the case of those containing vitamin C, rapidly load up the immune cells in the lymphatics of the gut, achieving high intracellular levels of this nutrient.
Colloquially speaking, one could say this "supercharges" the immune system cells.

Those lymphocytes in the thoracic duct and upwards (such as natural killer cells) will be exposed to higher vitamin C concentrations than the one measured in blood. If true it would explain why Dr. Levy gets results with lower doses than predicted by the dynamic flow model (IVC = intravenous vitamin C):
In a nutshell, I found that liposome encapsulated vitamin C, taken orally, was roughly 10 times more effectively clinically in resolving infectious diseases than the IVC.
Nevertheless I am unaware of any either animal or human trial using liposomal encapsulated vitamin C.


Toxicity

The only real danger of vitamin C megadosing I have found is for those with a defect in their G6PD enzyme gene.
He was also prescribed a course of high dose intravenous ascorbic acid, 40 g three times weekly, supplemented by 20-40 g ascorbic acid daily by mouth. This proceeded uneventfully for about a month with no obvious evidence of either haemolysis or regression of lymphadenopathy. The intravenous dose was increased to 80 g, and next day the patient became breathless and feverish and noticed that his urine was black.
As Dr. Humphries wrote:
Hemolysis can occur in the rare disorder called glucose 6 phosphatase dehydrogenase deficiency (G6PD deficiency) if mega doses of vitamin C are given- yet there are cases of even those people tolerating vitamin C when they are deficient. Mind you, there are no drugs in the Physicians Desk Reference (PDR) without far more common risks and definitely more side effects than vitamin C. The risk of hemolysis while taking vitamin C, could be blown out of proportion. “The texts and websites that mention this possible effect often assert that vitamin C can cause problems for G6PD deficient persons when consumed “in high doses.” Search of the medical and scientific literature finds that vitamin C may cause red blood cell rupture (erythrocyte hemolysis) in G6PD deficient adults after massive intravenous infusions (40 to 100 grams within a few hours, or in extremely large oral doses.) There are no reports of this hemolysis problem when oral intake by G6PD deficient persons is less than 6 grams per day in G6PD deficient adults or in healthy adults at any dose.LINK HERE
Moreover, we have the experience of the Riordan Clinic with intravenous vitamin C:
Hemolysis has been reported in patients with G6PD deficiency when given high-dose IVC (Campbell, et al., 1975). The G6PD level should be assessed before beginning IVC. (At the Riordan Clinic, G6PD readings have yielded five cases of abnormally low levels. Subsequent IVC at 25 grams or less showed no hemolysis or adverse effects.)
About the possible kidney stones danger on men from some epidemiological studies, first of all I have to point out that they are unlikely to grow in a week of vitamin C treatment. Second, we have late Dr. Cathcart clinical experience:
It is my experience that ascorbic acid probably prevents most kidney stones. I have had a few patients who had had kidney stones before starting bowel tolerance doses who have subsequently had no more difficulty with them. Acute and chronic urinary tract infections are often eliminated; this fact may remove one of the causes of kidney stones. Six patients have had mild pain on urination; five of these patients were over fifty and none had stones.
 Dr. Humphries also comments about it:
Kidney stones are a theoretical possibility yet have never been shown to be a true risk in the use of vitamin C.
Apart from the G6PD deficiency, I don't think probable that a short course of intravenous vitamin C is going to drive any long-term harm when they have not been observed in any of the patients of Dr. Hoffer's study, some of them more than 6 cycles, each cycle 4 weeks, each week three treatments of 0.6g/kg. It is going to be even less likely when using either regular oral or liposomal encapsulated vitamin C.

As a matter of fact an overdose on regular oral vitamin C is near impossible. From wikipedia (my bolds):
Vitamin C is water-soluble, with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine. It exhibits remarkably low toxicity. The LD50 (the dose that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per kilogram of body weight when given by forced gavage (orally). The mechanism of death from such doses (1.2% of body weight, or 0.84 kg for a 70 kg human) is unknown, but may be more mechanical than chemical.[103]
It seems they die due to electrolytes loss. You may die of too much water ingestion too.


Human Evidence on Intravenous|Intramuscular Vitamin C

There is already enough evidence pointing toward a deficiency of vitamin C under critical illness. Long et alter write in the abstract of Ascorbic Acid Dynamics in the Seriously Ill and Injured from 2003 (my bolds, TPN = total parenteral nutrition, that is, intravenously delivered, SEM = standard error of the mean):
Materials and Methods. Ascorbic acid levels were determined in 12 critically injured patients and 2 patients with severe surgical infections. Each patient received TPN supplemented with increasing doses of ascorbic acid over a 6-day period. Therapeutic responses were determined by plasma and urine measurements using high-pressure liquid chromatography.
Results. The initial mean ± SEM baseline plasma ascorbic acid concentration was depressed (0.11 ± 0.03mg/dl) and unresponsive following 2 days on 300 mg/day supplementation (0.14 ± 0.03; P =‬ 1.0) and only approached low normal plasma levels following 2 days on 1000 mg/day (0.32 ± 0.08; P = 0.36). A significant increase was noted following 2 days on 3000 mg/day (1.2 ± 0.03; P = 0.005).
Conclusion. We confirmed extremely low plasma levels of ascorbic acid following trauma and infection. Maximal early repletion of this vitamin requires rapid pool filling early in the post-injury period using supraphysiologic doses for 3 or more days.
This advice is acknowledge by Dr. Berger (PN = parenteral nutrition, that is, intravenously delivered) in his 2009 paper:
It has repeatedly been shown that shocked surgical, trauma, and septic patients have a drastic reduction of circulating plasma ascorbate concentrations. These low concentrations require 3-g doses/d to restore normal plasma ascorbate concentrations.10
The problem is that in Long et alter 3 out of 10 patients were lower than 1.1 mg/dl of vitamin C in plasma (0.34, 0.45, 0.53) after at least two days at 3g/day of intravenous vitamin C. Actually these three received 300mg two days, 1g the next two days and 3g the last two days. Moreover, 2 out of these 10 patients received 3g/day from the beginning and during 6 days. They got their vitamin C urine excretion measured too. Long et alter wrote (my bolds):
Baseline plasma levels were below normal values for both patients but were increased to normal levels after 1 day on 3000 mg/day. In spite of the high plasma levels on these megadoses for 5 days, it appeared that the ascorbic acid body pools were not filled in 1 or 2 days, as not all the ascorbic acid infused at 3000 mg/day was excreted until the fourth and fifth days.
I hope you see the stupidity of the expensive urine argument. I see no reason for decreasing the vitamin C dose without checking blood plasma levels first. Least of all decreasing it in less than 5 days.

From these data it should not be any surprise at all when we find positive results at doses of at least 3g/day for at least five days. What I find quite shocking is the reticence toward its use in gram doses in every and each one of the ICUs around the world given its very low toxicity.

I will review those data I have found about intravenous|intramuscular vitamin C interventions both in non randomized and randomized trials.


Non randomized interventions

Late Dr. Klenner used vitamin C to treat his poliomyelitis patients as he describes in The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C. Since it is not clear both how many cases had bulbar involvement nor how many of Dr. Klenner's patients had a previous tonsillectomy (I presume less than under other physicians' care), I don't think any inference may be done about vitamin C efficiency in this case. I feel  more bold in another case commented upon by Dr. Klenner.

So. First a more or less controlled case series by Dr. Klenner. Second an ICU intervention at Vanderbilt hospital.


1.- Acute Viral Haemorrhagic Encephalitis at Annie Penn Memorial Hospital

Dr. Klenner wrote about seven cases admittted to his hospital from 1950 until 1957 in his paper An ‘Insidious’ Virus. All of them were younger than 4 years old (I think that nullifies the tonsillectomy issue concern) and shared similar symptoms described too at his expanding paper The Clinical Evaluation and Treatment of a Deadly Syndrome Caused by an Insidious Virus:
Two important stages are recognized in this deadly syndrome: Stage (A)—(1) There is a history of having had “the flu” which lasted forty-eight to ninety-six hours, complicated by extreme physical or mental stress; (2) a mild cold, similar to an allergic rhinitis, which lingered on for several weeks but did not incapacitate the individual. Stage (B)—This stage, which is always sudden, will present itself in at least six forms: (1) convulsive seizure; (2) extreme excitability resembling delirium tremens if an adult and with dancing of the eyeballs if a child; (3) severe chill; (4) strangling in the course of normal eating or drinking; (5) collapse; (6) stupor.
He treated 2 of those 7 patients and they survived. The other 5 were attended by other physicians who didn't start any treatment until a diagnosis were made but all of them died before that. If we suppose that Dr. Klenner's clinical judgment was correct then we may estimate the probability of these results being brought by sheer chance alone: (2/7)2∙(5/7)5 = 1.5%.

Perhaps Dr. Klenner judgment was incorrect but these data would at least spark curiosity in any scientific  mind.


2.- Vanderbilt University Medical Center Study

This study was based on a new protocol intervention implemented at the ICU of this trauma hospital. It compares the results of the first year of the protocol with a retrospective cohort of the previous year.

They cite the paper by Long et alter and abide to its minimum dose but use a longer duration. From the paper Impact of High-Dose Antioxidants on Outcomes in Acutely Injured Patients by Dr. Collier et alter from 2008 (my bolds, AO = antioxidants, OR = odds ratio):
Beginning October 1, 2005, we implemented a high dose AO protocol for acutely injured patients. The protocol consisted of ascorbic acid (Hospira, Lake Forest, IL) 1000 mg intravenously in 100 mL NS every 8 hours, α -tocopherol (dl-α-tocopherol acetate, PCCA, Houston, TX) 1,000 IU (1 mL) via naso- or orogastric tube every 8 hours, and selenium (selenious acid, American Regent, Shirley, NY) 200 μg intravenously in 100 mL NS once daily. Ascorbic acid was administered as a bolus over 1 hour (0600-1400-2200 time schedule) and selenium as a bolus over 2 hours (1000 time schedule), although both were permitted to be changed to an enteral dosage form once enteral access was established. The course of treatment was 7 days or until hospital discharge, whichever came first.
The unadjusted relative risk indicates that patients receiving AO have a 30% less risk of dying during their hospitalization (OR 0.70, 95% confidence interval (CI), 0.56-0.88). After adjusting for age, gender, and probability of survival, AO exposure was associated with an even stronger protective effect (OR 0.32, 95% CI 0.22-0.46).
Expected Survivors had a probability of survival >50% (TRISS >0.50) and Expected Deaths had a probability of survival of <50% (TRISS <0.50). For the Expected Survivors group, there appeared to be no benefit to AO treatment (OR 1.0, 95% CI 0.70-1.4, P = .98), whereas the treatment effect was even greater in the Expected Deaths group (OR 0.24, 95% CI 0.15-0.37, P < .001), adjusted and unadjusted.
There has been a letter from Dr. Hemilä pointing out an error in the decimal point placement for several number needed to treat (NNT) given elsewhere in the article and confirmed by the authors. The overall unadjusted NNT is 42.7. The adjusted one is 17.10. Both the adjusted and unadjusted NNT for the Expected Deaths group should be 2.13, that is, the estimated relative risk ratio (RR) is 0.47 in this group.

The Expected Deaths group happening to get a better result is from a post hoc analysis. Nevertheless it is important to look for a plausible reason other than pure chance since we are not looking at a non effective intervention we must repartition creatively in order to let it look positive, it was already a positive one on the whole population. I think we have a reason for the higher effectiveness on the more seriously wounded patients:
Intravenously delivered vitamin C and selenium were switched to orally delivered ones (enteral) whenever possible. All the mortality benefit has come to happen only in the Expected Deaths group so it seems that the number of days on parenteral nutrition when analyzing the outcomes should be taken into account, moreover when we have seen that blood concentrations of vitamin C is going to be quite different for intravenous route with respect to oral one.


Randomized trials

I will proceed from the paper by Miller & Hill selecting those two cited with intravenously delivered doses of vitamin C of at least 1g/day and adding the only one after its publication that I am aware of.


1.- Cohort of critically ill surgical patients


Dr. Nathens et alter, Randomized, Prospective Trial of Antioxidant Supplementation in Critically Ill Surgical Patients. Not blinded. Treatment included 1g of vitamin C every 8 hours for the shorter of ICU stay duration or 28 days. They comment on the Results Section:
Five hundred ninety-five patients were enrolled and analyzed, 91% of whom were victims of trauma. The relative risk of pulmonary morbidity was 0.81 (95% confidence interval 0.60–1.1) in patients receiving antioxidant supplementation. Multiple organ failure was significantly less likely to occur in patients receiving antioxidants than in patients receiving standard care, with a relative risk of 0.43 (95% confidence interval 0.19–0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay.
This trial was focused on pulmonary morbidity and excluded those highly likely to die as stated in the Protocol Section:
Patients with isolated or severe (Glasgow Coma Scale score = 6 or less) head injury, brain death, anticipated survival less than 48 hours, burns over more than 20% body surface area, sickle cell anemia, need for anticoagulation with coumadin while in the ICU, and chronic renal failure (creatinine > 2.5 mg/dL) were excluded from the trial.
There were 5 deaths of 301 patients under treatment versus 9 deaths of 294 patients under standard care. Nathens et alter comment:
The relative risk of death in the treatment group was 0.55 (95% CI 0.17–1.88). Similar benefits were also evident when ICU mortality and hospital mortality were examined.

One sided-like probability of vitamin C (at the same time that standard care) treatment giving rise to this or better (worse) result by chance alone is 7.4%.

They also measured average plasma concentration of vitamin C in a subset of patients.


2.- Cohort of critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients

Berger et alter, Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Blinded. Treatment included 2.7g of vitamin C the first two days, 1.1g day for another rest 3 days (plus 500mg of vitamin C per day as standard care in ICU stay). Why on earth did they cut so short the 2.7+0.5=3.2g/day intervention? Berger et alter say:
Vitamin C is strongly depressed in critical illness, and doses of 3 g per day are required to normalize plasma concentrations [47].
This reference is the paper by Long et alter. This is depressing. As I have pointed out before 3g for two days let 3 out of 10 people with low plasma levels of vitamin C. They are confusing the mean value with the population distribution. Moreover, with such a short high dose duration most of them aren't going to get replenished their body pools either. There is no reason whatsoever for such a short intervention when they were aware of the results obtained by Dr. Nathens et alter too, their reference 38. I haven't been able to find a justification to use a shorter and lower dose vitamin C intervention. I would bet they didn't read fully the paper by Long et alter. They seem not to have measures plasma vitamin C concentration.

There were 14 deaths of 102 patients under treatment versus 9 deaths of 94 patients under standard care (RR 1.43). One sided-like probability of vitamin C (at the same time that placebo) treatment giving rise to this or worse (better) result by chance alone is 8.4%.

They acknowledge "more severe brain injuries in the AOX group" (the intervention one) too.

So. I hope any competent mind grasp why these negative intervention doesn't falsify any other one with longer intervention at 3g/day of intravenous vitamin C.


3.- Phase I study in patients with severe sepsis

Fowler et alter, Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. Blinded. Treatment included three groups:
Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8).
Lo-AscA would be 3g/day for a 60kg person. Intervention lasted 4 days. Near enough.

28-days-mortality was 62.5% under placebo, 38.1% under Lo-AscA and 50.6% under Hi-AscA. One sided-like probability of vitamin C (at the same time that standard care) treatment giving rise to this or better (worse) result by chance alone is 14.6%.

Foster et alter comment also:
High dose ascorbic acid patients exhibited significantly faster declines in the regression slopes of delta daily total SOFA scores over time compared to placebo (-0.043 vs. 0.003, p < 0.01) (Figure 2). Placebo patients exhibited a gradual rise in SOFA scores. Though the cohort size is limited, these data suggest that ascorbic acid infusion significantly attenuates the systemic organ injury associated with sepsis.
This study has been done by the same Virginia Commonwealth University group studying the impact of ascorbic acid on inhibition of Neutrophil Extracellular Trap (NET) formation that I have already commented upon elsewhere. NET formation seems to be the last salvo when fighting viruses like that of influenza A. Inhibiting it with vitamin C seems to give rise to positive results.

Now, the good news: the Phase II trial is coming.


N=1 (or several) Testing

Late Dr. Klenner explains how he discovered the viricidal and antipyretic action of injectable vitamin C in his paper from 1953:
Our interest with vitamin C against the virus organism began ten years ago in a modest rural home. Here a patient who was receiving symptomatic treatment for virus pneumonia had suddenly developed cynosis. He refused hospitalization for supportive oxygen therapy. X-Ray had not been considered because of its dubious value and because the nearest department equipped to give such treatment was 69 miles distant. Two grams of vitamin C was given intramuscularly with the hope that the anaerobic condition existing in the tissues would be relieved by the catalytic action of vitamin C acting as a gas transport aiding cellular respiration. This was an old idea, the important factor being that it worked. Within 30 minutes after giving the drug (which was carried in my medical bag for the treatment of diarrhea in children) the characteristic breathing and slate-like color had cleared. Returning six hours later, at eight in the evening, the patient was found sitting over the edge of his bed enjoying a late dinner. Strangely enough his fever was three degrees less than it was at 2 P.M. that same afternoon. This sudden change in the condition of the patient led us to suspect that vitamin C was playing a role of far greater significance than that of a simple respiratory catalyst. A second injection of one gram of vitamin  was administered, by the same route, on this visit and then subsequently at six hour intervals for the next three days. This patient was clinically well after 36 hours of chemotherapy.

Of course the antipyretic and antihistaminic parts are easy to check when you are ill with a simple discontinuation|rechallenge strategy using either Dr. Cathcart's titrate technique with regular vitamin C or Dr. Levy's approach with 4-6g of liposomal vitamin C. There are those of us who are ready to try it in our children too. I translate my friend Ana's experience with her 17 months old son's fever convulsions using vitamin C mixed in juice:
I started with 250mg when he had 38.4°C. We repeated the same dose every 25 minutes until his bowels "roared" loud and clear. He had saturated with 1000mg. The fever was at 37°C and decreased in some meager 5 minutes to 36.4°C.
His son has suffered fever convulsions only once more since then when on travel having forgotten to carry vitamin C.

Apart of antihistaminic and antipyretic effect, can we ascertain its antiviral and antibacterial effect pointed out by Drs. Klenner and Cathcart? We have no means of discerning if it has a viricidal or bactericidal effect or not. It may happen that all of the tonsillitis, colds and flu-like illnesses I|we have passed using only vitamin C (without symptoms once saturated) were to last just as long without any treatment at all. Since the longest of them was 5 days I am quite certain they didn't last longer. It's been 5 years without any other antipyretic or antibiotic. It's been 5 years without any time off sick.

At this point it is a credibility issue. As far as I|we have been able to check both late Drs. Klenner and Cathcart predicted the results I|we get. I|we will continue to act as if they are correct while waiting for their hypothesis to be falsified.


Conclusion

It seems to me highly unlikely that ascorbic acid at high doses is completely useless under stresses like either viral or bacterial infections on humans when we have plenty of evidence pointing toward a general positive effect on vertebrates. Is it scientifically proven? Not yet. Neither I have found a refutation of promising preliminary evidence like either the guinea pigs one or the scant humans trials. Given its ridiculous toxicity a simple risk|benefit analysis should drive anyone to act.

Of course you can abide to Evidence Based Medicine criteria and put enough blinders on till you don't see any evidence left. Your choice. Good luck.

Sunday, January 3, 2016

Statins and death postponement

Applied statistics belongs to the same field than Magic. Hence it is marvelous whether you are aware of the trick or not.
A. P.

Before anything else. Everyone of us is going to die. I don't think there is any need to play with the information available about statins to give them a bad appearance. They do already have it whenever we do a minimally critical analysis. Hence this post.

I will introduce computing methods that can require some time to understand. Feel free to skip over them.

Prologue


First an example by Vicente.

Suppose your boss is giving an extra payment to all of her employees. Suppose it is being given at different times along the current year. Suppose she gives a different quantity to each one of her employees. Suppose a month has already passed and you have access to the following questions and their answers:
  1. How much is the average extra payment already received by all the employees? Adding all the extra payments already given and dividing by the number of all the employees gives us the average amount received by anyone and it equals 20€.
  2. How much is the average extra payment already received by those who have received it? Let's say 20% of your colleagues has already received the extra payment and the average for them has been of 100€. It is compatible with Point 1 because there are an 80% of employees that have received 0€ at the time being:
    0.2 • 100€ + 0.8 • 0€ = 20€.
  3. How much is the average extra payment going to be? You know the assistant of your boss and he has heard her saying that the average extra payment is going to be of 80€.
The paper I comment in this post answers a question similar to that of Point 1. I think we all consider more useful an answer to Point 3. If there is not enough information available we could settle for an answer to Point 2 though.

Statins and death postponement


A Danish research group has recently published a paper where they compute how much longer within the trial duration time all of those who take statins live with respect to a control group who don't (they either take placebo, nothing at all or usual care treatment). They compute this gain for every statin with control group trial publishing enough information, that is, including all-cause mortality curves.

Actually it was Dr. Kendrick who first pointed out that lives are not being saved but merely death is slightly posponed. He was unable to publish it in the peer reviewed literature though. Go figure.

Dr. Kendrick has written a post about the paper by Kristensen et alter too and I have commented there a highly condensed version of what I am going to explain here.

I write this post because I have read conclusions about the paper that doesn't follow at all from it (confusing aswer to Question 1 with the one to Question 3). I am going to replicate the method by Kristensen et alter first. Afterwards I am going to extend it to answer what people is really interested in (Question 3). Finally I am going to explain why this last step doesn't make sense.


Method by Kristensen et alter


The question they answer is: what is the average death postponement time all the statin consumers acquire with respect to those not taking them during the trial duration time? Its details are important so I excerpt their paper at its Discussion Section, second paragraph (my bolds):
First, this analysis only estimates the survival gain achieved within the trials’ running time. After termination of the trials, the treated would continue to accrue survival gain as long as there was a difference in cumulative mortality between the treatment arms.
They don't include the word "average" because another different estimator is used.


How do they compute this survival gain? They explain their method in the Web Appendix. I am going to explain it here replicating it for the same LIPID trial. I will include some explanatory graphs.


Kristensen et alter start with the published survival curves for both those under statins and those under placebo:


This plot has a mortality range from 0% to 15%. It has a time range from 0 to 7 years. At 6.1 years mortality under statins arrives to 11% and under placebo to 14.1%.


I perform the following steps from this initial figure:


  1. The area MK between the two mortality curves is computed. I color it magenta. This time we have MK = 17.4 cm2.
  2. An auxiliar area A is computed.  It represents some arbitrary time (t=2 years in this case) for some arbitrary fraction of subjects (10% in this case). I color it yellow. This time we have A = 56'84 cm2.
  3. This auxiliar area is implicitly expanded to a reference area TK by Kristensen et alter in order to represent the 100% of subjects by dividing by its height (10%). I color it cyan. This time we have TK = A/(10%) = 568.4 cm2.
  4. Finally a rule of three is performed. We know the reference area (TK) represents two years (t) for all the subjects. We compute how much average extra life time (mK) during the 6.1 years of duration of the trial is represented by the area between curves (MK) for everyone under statins. This time we have mK = MKt / TK = 17.4 • 2 /  568.4 = 0.06122 years  • 365 days / (1 year) = 22.35 days.
In this same case Kristensen et alter compute an average death postponement for everyone under statins during the duration of the trial of 22.07 days. Close enough. I consider validated my implementation of their method.

Explanation


It is easier to understand what the method is doing if we think in exactly N=100 subjects in each one of the two arms. Every time a subject under placebo dies we measure the time until either the corresponding subject under statins dies too or we reach the trial end at 6.1 years. This way we add for each subject under placebo (dead or alive at trial end) the amount of extra time the corresponding subject under statins has lived till either dead or arriving alive at the trial end.



As time goes by we have:
  • The first two either under statins or placebo die more or less at the same time. Those are the two magenta points surrounding year 1.
  • From the third to the eleventh subject under placebo die before the one under statins. This gives rise to segments of 0.4, 0.9, 1.5, 1.7, 1.6, 1.7, 1.9, 2.2 and 2.3 cm.
  • From the twelfth to the fourteenth subject under placebo die while those under statins are still alive at 6.1 years. This gives rise to segments of 1.7, 1.1 and 0.3 cm.
  • From the fifteenth to the one hundredth there will be no difference in survival because all of them arrive alive to trial end at 6.1 years. I don't plot these points.
How do we estimate the average death postponement for everyone (death or alive) under statins during the 6.1 years of the trial?:
  • We measure how long in centimeters is t = 2 years in the figure to compute the cyan reference piece. This time it measures 6 cm, that is, 3 cm each year. We approximate the cyan reference piece adding 100 times (shown the first 17 segments and ellipsis afterwards) this 6 cm segment: TK = N • 6 = 100•6 = 600 cm.
  • The previous area between curves here is approximated by the sum of extra live of those under statins with respect to those under placebo (I omit the 87 zeros): MK = 0.4 + 0.9 + 1.5 + 1.7 + 1.6 + 1.7 + 1.9 + 2.2 + 2.3 + 1.7 + 1.1 + 0.3 = 17.3 cm (that is, 17.3/3 = 5.77 extra years accrued by all subjects under statins in this 6.1 years).
  • Finally we apply the rule of three in order to compute how much extra live time share belongs to each subject under statins: mK = MKt / TK = 17.3 • 2 / (N • 6) = (17.3/3)/N = 5.77 years / 100 = 0.0577 years • 365 days / (1 year) = 21.05 days.
Dividing by the cyan area is equivalent to change from length to time and concurrently computing an average dividing by the number of subjects under statins.

We should assign a height in centimeters for each subject (line separation is 1 cm in this case) and multiply by it in order to have actual areas (cm2 instead of cm) for approximations MK and TK. It won't impact the result since MK is divided by TK though.

If we would increase the number of subjects from N=100 then the result would approach from 21.05 days to the 22.34 days computed directly with areas.

Finally, it may happen that the trial doesn't have an actual N value. It is clearly seen when trials are stopped early. Since subjects are not recruited at the same time, there will be a lower number of subjects as we look at a more advanced time.

Analysis limitations


The main drawback of the results by Kristensen et alter is the lack of confidence intervals. Without them we can't be sure how much close we are to the real value we are estimating. I don't know if there is enough information in the published trial studies to compute them though.

There are more problems when trying to draw conclusions from these results:
  • Those still alive under placebo when the trial ends make their corresponding subjects under statins contribute with ZERO to the extra life computation (just like those that haven't received the extra payment yet at the prologue).
  • Kristensen et alter doesn't answer the following question: how much extra time is going to live someone when taking statins for 6.1 year (or until death if it happens first)? This will need extrapolations to be made but it is the actual question people think is being addressed.
  • There are doubts about convergence of mortality curves like in the JUPITER trial. There are those that think that sooner or later both curves will cross and subjects under statins will begin to die ealier than subjects under placebo.
    Source: Spanish critique to the JUPITER trial by López & Wright
    Kristensen et alter already talk about this issue (same paragraph than before):
    There are a few studies with long-term follow-up after cardiovascular intervention trials showing that this survival might be substantial,17 but there are also studies showing that mortality becomes similar in the two groups after the trial’s termination.18
    These studies follow both arms when the trial ends and everyone is under statins. It seems that this kind of studies are not very popular though.
  • Not being possible to answer the question people are interested in, I think we should answer the one we can: how much extra time have lived those dead under statins during the trial because of the treatment?
I will try to answer this latter question. Afterwards I will try to do a conservative estimate of the former.

Extra time lived by those dead under statins during the trial




This time we focus on a shorter area where we can compute all of the extra time lived by those dead under statins during the trial. The magenta area goes only till the horizontal line with 11% of deaths (mortality under statins during the trial). We have M = 14.05 cm2.

We have a cyan area representing 2 years of life for exactly this 11% of subjects and not the 100%. We have T = 63'8 cm2.

The average time of extra life of those dead under statins (11%) with respect to those under placebo is m = Mt / T = 14.05 • 2 / 63.8 = 0.4404 years • 365 days / (1 year) = 160.8 days (about 5 months).

Explanation


Let's come back to the "N=100 subjects" approximation. Now we are computing only the extra life time achieved by those dead under statins with respect to those under placebo.




As time goes by we will have only the first two groups in this case:
  • The first two either under statins or placebo die more or less at the same time. Those are the two magenta points surrounding year 1.
  • From the third to the eleventh subject under placebo die before the one under statins. This gives rise to segments of 0.4, 0.9, 1.5, 1.7, 1.6, 1.7, 1.9, 2.2 and 2.3 cm.
This time we share the extra life achieved only among the n=11 dead under statins and not among the total number N=100 of subjects in each arm:
  • We have that t = 2 years still measures 6 cm, that is, 3 cm each year. We approximate the cyan reference piece adding n=11 times this 6 cm segment: T = n • 6 = 11•6 = 66 cm.
  • The previous area between curves here is approximated by the sum of extra life of those under statins with respect to those under placebo (zeroes included this time): M = 0 + 0 + 0.4 + 0.9 + 1.5 + 1.7 + 1.6 + 1.7 + 1.9 + 2.2 + 2.3 = 14.2 cm (that is, 14.2/3 = 4.73 extra years accrued by those dead under statins during this 6.1 years).
  • Finally we apply the rule of three in order to compute how much extra life time share belongs to each subject dead under statins: m = Mt / T = 14.2 • 2 / (n • 6) = (14.2/3)/n = 4.73 years / 11 = 0.4303 years • 365 days / (1 year) = 157.06 days.
Dividing by the cyan area is equivalent to change from length to time and concurrently computing an average dividing by the number of subjects dead under statins during the trial.


If we would increase the number of subjects from N=100 then n would increase too and the result would approach from 157.06 days to the 160.8 days computed directly with areas.


Statistics of interest


We may decompose the benefit attained during the trial duration due to taking statins for 6.1 years instead of placebo into:
  • 11% have died after living an average of 160.8 extra days.
  • 14.1%-11%=3.1% are still alive while they would be dead under placebo. This is the absolute risk reduction. There are other two related statistics:
    • Inverting it we get the NNT (Number Needed to Treat): number of subjects under treatment so one of them gets the benefit (still alive at 6.1 years due to treatment), 100/3.1=32.26.
    • The ratio between mortality under treatment and under placebo gives rise to relative risk of dying: 11/14.1 = 78%. If we substract this quantity from the unity we get the relative risk reduction: 1-11/14.1 = 3.1/14.1 = 22%. These pair of statistics are useful to answer the pair of questions about the hypothetical situation where I die within the first 6.1 years due to not taking statins:
      • What would be the probability of still being alive (some months added so I would make it to 6.1 years) if I would have taken them? The answer is the relative risk reduction, that is in this case, 22%.
      • Even more interesting, what would be the probability of me dying within those first 6.1 years anyway? The answer is the relative risk, that is, 1-22%=3'1/14'1=78%.
      I hope you see the tiny efficacy of the treatment with statins even in favorable trials like LIPID.
  • We have 100%-14.1%=85.9% that hasn't get any benefit in added life within these 6.1 years because they would be alive anyways.
We may relate all of these statistics to the NNT. For every 32.26 subjects taking statins for 6.1 years we get:
  • 1 saved,
  • 32.26•11% = 3.55 dead anyways after living an average 160.8 extra days.
  • 32.26•(1-14.1%) = 27.71 survivors independent of treatment.
Collapsing these statistics to the average life extension for everyone on statins (dead or alive at the trial end) is losing a lot of useful information.

Extra time lived by those dead under statins during the trial: Approximation


You can call me lazy. I haven't replicated all of the analysis for each and every one of the trials studied by Kristensen et alter. Instead I have estimated approximately how much extra time have lived those dead under statins during the trial duration time working from their estimation up.


Let's suppose that the area between curves would include not only the magenta one computed by Kristensen et alter but the hypothetical green one (G) of extra live for those extra still alive under statins with respect to placebo at trial end (14.1%-11%=3.1%). Then we could compute the extra time lived by those dead under treatment simply changing the reference area from the 100% height used by Kristensen et alter (TK) to that cyan area taking into account only the 14.1% of subjects: Text = TK • 14.1% . Hence we could get the result we are interested in just by dividing by 14.1%:
mext = (MK+G) • t / T = (MK+G) • t / (TK14.1%).
Since we actually don't know how much the green area would measure, our approximation (mapp) will be actually lower than this value:
mapp = MKt / (TK14.1%) =  mK/(14.1%)< mext.
It is expected to be lower than focusing on only the first 11% of those dead under statins too.

If we check this approximation for the LIPID trial we get the approximation:
mapp = 22.05/0.141 = 156.4 days
We had m=160.8 extra days for those first 11% dead under statins in the previous section. We see that the approximate value is close enough.

If we compute this approximate value for those trials studied by Kristensen et alter we have:
  • Secondary prevention:
    • 4S (4444 subjects, year 1994, statin vs placebo): 27.18/0.123 = 221.0 extra days for the first 8.7% dead under statins during the trial 5.8 years.
    • LIPID (9014 subjects, year 1998, statin vs placebo): 22.05/0.141 = 156.4 ( 160.8) extra days for the first 11% dead under statins during the trial 6.1 years.
    • GISSI-P (4271 subjects, year 2000, statin vs no treatment): 1.76/0.0413 = 42.6 extra days for the first 3.37% dead under statins during the trial 2 years.
    • CORONA (5011 subjects, year 2007, statin vs placebo): 4.09/0.304 = 13.5 extra days for the first 29% dead under statins during the trial 2.7 years.
    • GISSI-HF (4631 subjects, year 2008, statin vs placebo): -9.51/0.288 = -33.0 → 33.0 extra days for the first 28.1% dead under placebo during the trial 4.4 years.
  • Primary prevention:
    • High risk of bias (clearly explained by the Therapeutics Initiative):
      • ASCOT-LLA (19342 subjects, year 2003, statin vs placebo): 1.99/0.041 = 48.5 extra days for the first 3.6% dead under statins during the trial 3.5 years.
      • CARDS (2838 subjects, year 2004, statin vs placebo): 18.66/0.058 = 321.7 extra days for the first 4.3% dead under statins during the trial 4.8 years.
      • MEGA (7832 subjects, year 2006, statin vs no treatment): 4.42/0.0166 = 266.3 extra days for the first 1.11% dead under statins during the trial 5 years.
      • JUPITER (17802 subjects, year 2008, statin vs placebo): 7.26/0.0277 = 262.1 extra days for the first 2.22% dead under statins during the trial 4 years —the median duration was 1.9 years.
    • Low risk of bias:
      • WOSCOPS (6595 subjects, 44% smokers, year 1995, statin vs placebo): 9.33/0.041 = 227.6 extra days for the first 3.2% dead under statins during the trial 5 years.
      • ALLHAT-LLT (10355 hypertensive subjects, year 2002, statin vs usual care): -4.96/0.153 = -32.4 → 32.4 extra days for the first 15.3% dead under usual care (14.9% dead under statins) during the trial 6 years.
Yes, negative number means there was a tendency to die first under statins. In this case we divide by the maximum mortality of both arms. That happened under statins in GISSI-HF. It happened under usual care in ALLHAT-LLT:


Source: ALLHAT-LLT


ALLHAT-LLT was the only big trial independently funded. That's no small fact but if you think it doesn't matter who funds the research you should start reading about trial 329. Aferwords you may read about Vioxx (another article about it). Finally much more information available in some books such as Deadly Medicines and Organised Chrime, Doctoring Data or Bad Pharma.

Due to Vioxx and after 2004 there was some regulations changes in USA and EU too. Internationally there has been similar pressures such as mandatory registration of trials before recruiting subjects in order to be publishable afterwards. Do these facts have any impact in trial results? Judge by yourself:

Source: Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms (via Vicente)

There are other clues pointing out to potential data massage as stated by Sir Richard Thompson et alter:
Furthermore, the rate of adverse effects in the statin and placebo arms of all the trials has been almost identical. Exact comparison between trials is not possible, due to lack of complete data, and various measures of adverse effects are used, in different ways.
A common source of bias taken into account by the Therapeutics Initiative in its meta-analysis is stopping trials early because it introduces a robust relative risk of about 0.71 with respect to those driven toward completion. This practice has been highly critized some time ago so ignorance about it should be already scarce. Doing as if nothing happens and using data from such a trial in a meta-analysis completely invalidates its conclusions. I can only think of two possible reasons to do so: either malice or incompetence in statistics.

Given all of these details, what trials should be more reliable? I have already highlighted them in bolds:
  • Secondary prevention: tentatively GISSI-HF  and CORONA, just because they have been published after 2004. I haven't checked either if they were stopped early or if they published intention to treat analysis (source of bias in the MEGA trial) though.
  • Primary prevention: ALLHAT-LLT, because it was funded independently from Big Pharma.

Extrapolated life-long life extension due to statins


We are going to do an extrapolation toward the future in order to estimate how much those taking statins would live with respect to not taking them. We are going to suppose both no further benefit and no further damage from them. This supposition would be somewhat more plausible when subjects stop treatment after completion of the trial.

The conservative (supposing not further benefit nor harm) approach would be that both 1-0.11=89% survivors on placebo at 5.2 years and 89% survivors on statin at 6.1 year started dying exactly at the same rate. I have measured (red segment over the magenta area) something like 2.4 cm • year/(3 cm) • 365 days/(1 year) = 292 days between those two survival curves when they arrive at 11% (similar method as Dr. Kendrick's). That would be the conservative estimation of death postponement for all of those 89% still alive under treatment at 5.2 years. That way the conservative average gain for anyone under treatment would be:
0.11 x 160.8 + (1-0.11) x 292 = 277.6 days.
Of course it gets really interesting when focusing on the big study not funded by Big Pharma (ALLHAT-LLT) though. I dare you to do a reasonable extrapolation given their two mortality curves already shown.

Analysis limitations


I think the previous method used to extrapolate outcomes is minimally plausible whenever the treatment duration time is shorter enough than the outcome measurement time. This happens in treatments like chemotherapy (tamoxifen included). That's not the case here where treatment is supposed to be even chronic. Even if all statin trials gave consistent results, I don't think it would be a good idea to try to extrapolate.

Source: Stats Land

There are some secondary effects of statins that are going to increase as time goes by such as worse blood glucose control. It is going to be a matter of time that it brings about its consequences.

Source: Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms
I think that in statins case focus should be on all of those statistics shown earlier and not on extrapolations.

Conclusion


Is there intelligent life outside the blood cholesterol hypothesis? You bet.

Take a look at the graph (and full post) of Ivor Cummings:

Source: Atherosclerosis Root Cause Diagram with References

Perhaps reducing blood cholesterol levels and doing nothing else can give you some extra months without a heart attack. There are those who think that considering such a meager, shubby, negligible approach just one to be ignored in order to keep searching is being a cholesterol/statin denier. Sorry, being engineers doesn't make us stupid. I don't think focusing on cholesterol is a too bright approach.

[Added on January 14]
You should take a look at Zahc's take on the cholesterol issue on his slide show.

There are those who have checked the efficacy of a low carb diet plus vitamin D supplemenation in suppressing coronary events in complying (secondary prevention) patients.

My numbers at June 23:
  • Total cholesterol: 316 mg/dl.
  • HDL cholesterol: 91 mg/dl.
  • Tryglycerides: 76 mg/dl.
I am not betting my health on the advice of those focusing on cholesterol and issuing inconsistent guidelines. I am not waiting till more evidence is accrued. I have done a benefit-risk analysis and proceed with a low carb diet and vitamin D (plus K2) supplementation.

You can do as you wish. And if you are going to discontinue statins better abide to Dr. Graveline's advice: do it slowly.

[Added on January 14]
As pointed out by Mie the peer reviewed paper talking about the risk of abrupt statin discontinuation is the one by Drs. Endres & Laufs.

Epilogue


A police officer sees a drunken man intently searching the ground near a lamppost and asks him the goal of his quest. The inebriate replies that he is looking for his car keys, and the officer helps for a few minutes without success then he asks whether the man is certain that he dropped the keys near the lamppost.
“No,” is the reply, “I lost the keys somewhere across the street.” “Why look here?” asks the surprised and irritated officer. “The light is much better here,” the intoxicated man responds with aplomb.

I don't think they are going to find the cure for cardiovascular disease while they stubbornly keep looking for it where the money shines: plain cholesterol reduction.