Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Why the Ivermectin Evidence is Pathetic

In a pandemic, which has killed almost a million Americans, you might expect that people would try to figure out the most effective treatment, rather than scam their fellow Americans, but you would be wrong.

There are some doctors, who do not understand the difference between good research and garbage, and are promoting bad research because they really really believe – and they were right lucky about steroids before the evidence was clear. Therefore they must be right about everything.

Except, reality does not care what you believe.

They believed in steroids before there was good evidence that steroids work, but their belief was based on wishful thinking and willful ignorance, not on good science. That they were right was purely coincidence. We have seen doctors kill tens of thousands of patients with antiarrhythmic drugs, because the drugs were widely prescribed without high quality evidence of safety and efficacy.

CAST – The Cardiac Arrhythmia Suppression Trial (the high quality evidence that was agreed to in order to prove which drug saved more lives) showed that the doctors fooled themselves, and killed their patients, by believing in something that only appeared to be an improvement in outcomes. Tens of thousands of deaths were not an improvement in outcomes.

If we have a story that seems to make sense, it is much easier to convince ourselves that we are not killing patients. After all, we mean well. At least some of us do. This is an example of misleading ourselves with a narrative fallacy. C A S T and Narrative Fallacy. Rudyard Kipling called these Just So Stories.

Dr. Pierre Kory (president of the Frontline COVID-19 Critical Care Alliance – FLCCC, which is different from the extreme quackery of America’s Frontline Doctors) may be a true believer, but if Dr. Kory really believes ivermectin works, he should be demanding large scale randomized double blinded placebo controlled research, rather than making excuses for low quality research.

Dr. Kory’s claims are so bad that even PolitiFact can’t find any truth in Dr. Kory’s claim – and PolitiFact tries to be as fair to every claim as possible.

What about the science? The promoters of ivermectin have claimed that the odds are over 2 trillion to 1 that the results of the latest meta-analysis are due to chance low quality research methods. Their research methods are almost as bad as their math.

Dr. David Gorski has written a long article that goes into detail about the problems with this latest paper. Ivermectin is the new hydroxychloroquine, take 2. Read the whole article, but here is a sample:

In fairness, the authors don’t actually say that meta-analyses of crappy studies do make good evidence, at least not in the paper. However, ivermectin advocates touting the study fans are certainly making that claim, and Dr. Kory sure did seem to me to imply the same in his interview with Bret Weinstein. In any event, one large, well-designed rigorous double-blind clinical trial for prevention, along with one large, well-designed rigorous clinical trial for treatment, could trump this entire meta-analysis.

Indeed, Gideon Meyerowitz-Katz did a reanalysis of the studies analyzed by the BIRD Group that shows that if you leave out the two studies that are as yet only preprints, are very small, and actually appear to have been miscategorized as higher quality than they are, the results are very different:

This basically shows that without those two studies, the analysis demonstrates no benefit for ivermectin at all compared to placebo, with a confidence interval that includes everything from a big benefit to a large harm from the drug.

If the study really had a 2 trillion to 1 chance of the results being by chance alone, it would not rely of such low quality research (preprints, tiny studies, studies without placebos, studies that are not double blinded, . . .).

There is no good reason to look at any research on treatment for COVID-19 that is not randomized placebo controlled and double blinded.

There are millions of patients to study, so the only reasons to avoid using the highest quality of research is a lack of confidence in the treatment.

As with promoters of alternative medicine, the actions of the promoters of ivermectin do not demonstrate confidence that what they are selling will survive high quality research.

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Happy Darwin and Lincoln Day 2021

https://www.smithsonianmag.com/history/how-lincoln-and-darwin-shaped-the-modern-world-45447280/


Where would we be without these two revolutionary thinkers? Both Charles Darwin and Abraham Lincoln were born on the same day – February 12, 1809.


We are in a pandemic, which is starting to look much less ominous, in large part, due to the genetic modification of mRNA (messenger RiboNucleic Acid), which was completely unknown to Darwin and Lincoln. So why bring it up?


This is going to be more about Darwin, than Lincoln, but both are just introductions to the topic of genetics. Darwin’s explanation of the way evolution works, along with the repeatedly overlooked Gregor Mendel’s explanation of the way inheritance works, led to the field of genetics. Genetics allowed scientists to take the genome of SARS-CoV-2 (Severe Acute Respiratory Syndrome – CoronaVirus – 2 [the first SARS was in 2003 – 2004]), provided by researchers in China, and design a safe and effective vaccine in 2 days.


Only two days? It must be cheap. Right?


Moderna, the company that created one of these vaccines, has been working on mRNA vaccines for a decade, so there is much more than two days that went into the creation of this vaccine. Pfizer/BioNTech makes the other mRNA vaccine.


It is important to understand the speed, because the virus (SARS-CoV-2) appears to be mutating to variants that might not be protected against by the current vaccines. Both vaccines are currently used under EUA (Emergency Use Authorization) from the FDA (Food and Drug Administration), but both vaccines should be able to receive regular approval from the FDA in the next few months. Once the vaccines have full approval, modifications for variants should be similar to approval for influenza variants, which happen every year, because influenza also mutates frequently. This does not mean that the vaccines will be less safe, because the process of protecting the body is what requires approval and we already have evidence from millions of vaccinated people that this process is safe and effective.


There have been tens of millions of vaccinations and the most serious adverse event has been anaphylaxis (a treatable allergic reaction that can rarely cause a fatal drop in blood pressure and/or a fatal airway obstruction). There is good research on about 6 million of the first people vaccinated, showing that the rate of anaphylaxis is 11.1 cases per million doses for the Pfizer/BioNTech vaccine and 2.5 cases per millions doses for the Moderna vaccine.


Everybody who developed anaphylaxis appears to have been discharged to home, following treatment for anaphylaxis, so there do not appear to have been any cases of long term adverse effects from any of these vaccinations. For comparison, the disease, COVID-19 (COronaVIrus Disease first identified in 2019) has a fatality rate of somewhere around 1%, which is millions of times more deadly than a vaccine that is not deadly. If you are worried that the vaccine is deadly, the disease is millions of times worse.


Maybe you are not worried about death, but about living with side effects. Then the case for getting vaccinated is even stronger. About 15% of people who get COVID-19 have significant and long term complications. Again, this is millions of times more of a problem with infection than with vaccination.


Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine — United States, December 14–23, 2020


Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine — United States, December 21, 2020–January 10, 2021


The second shot is reported to cause flu like symptoms (fever, muscle aches, et cetera) beginning about half a day after the vaccination, but treatable with ibuprofen. Plan on not doing anything the day after your second vaccination shot. This is also reported to be much worse in younger people, than in older people, so an 80 year old may not have any side effects, while the healthy 30 year old may feel miserable that night or the next day.


This should not be a difficult decision. These vaccines are safe – especially when compared to the infection they protect against. These vaccines are both over 90% effective at preventing illness (development of symptoms).


While anti-vaxers, anti-maskers, and other conspiracy theorists have been trying to discourage vaccination, there are a few things to consider:


Vaccines save millions of lives every year. Most of those are the lives of children. If the anti-vaxers get their way, millions more children will die every year.


Vaccines are probably the safest and the most effective medical intervention available.


Why do anti-vaxers claim that vaccines are not safe? Why do anti-vaxers claim that vaccines don’t work? There is no research supporting their claims.


At anti-vax events, the sale of dangerous chemicals to “treat” autism is common. These chemicals are not approved by the FDA for this purpose. These “treatments” are dangerous scams. Why are anti-vaxers so comfortable with poisoning children?


Anti-vaxers failed to stop worldwide vaccination against smallpox. The success of vaccines means we no longer vaccinate our children against smallpox. Success for vaccines is eradicating disease, so that vaccines are not needed. They put themselves out of business.


Success for anti-vaxers is a lot of dead children, a lot more disabled children, a lot of disabled adults, and a lot of dead adults – COVID-19 does produce a lot of dead/disabled adults.


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US Rep. Stephen Lynch tests postive for COVID despite receiving two doses of vaccine

The increase in the number of cases of disease remains the same for 10 days after the first vaccine shot, then things dramatically change for the better for those who received the vaccine.
https://www.fda.gov/media/144245/download



If the mRNA (messenger RiboNucleic Acid) vaccines really work, how is it possible for someone to get COVID-19 after receiving both the first and second shot of the Pfizer/BioNTech vaccine?


The results of the research submitted to the FDA (Food and Drug Administration) for an EUA (Emergency Use Authorization) show that the vaccine is much more effective than was expected. Originally, the efficacy goal for a vaccine was to prevent at least 50% of disease. The Pfizer/BioNTech vaccine research shows that it prevents 95%.


For participants without evidence of SARS-CoV-2 infection prior to 7 days after Dose 2, VE [Vaccine Efficacy] against confirmed COVID-19 occurring at least 7 days after Dose 2 was 95.0%. The case split was 8 COVID-19 cases in the BNT162b2 group compared to 162 COVID-19 cases in the placebo group (Table 6).


Link to research – Efficacy Results – Primary Endpoint (Evaluable Efficacy Population)


95.0% is more precise than anyone should be using, even if it is mathematically correct to calculate it that way. The paper does admit this: “The 95% credible interval for the vaccine efficacy was 90.3% to 97.6%, . . .” As more people are vaccinated, the numbers reported will more accurately represent the true protection from disease.


Here is where things start to get complicated. Protection from “disease”, in the case of vaccine approval, means not developing symptoms. Symptoms are what the person experiences – cough, shortness of breath, weakness, aches, et cetera. Signs are things that the person might not feel, such as an elevated heart rate or hypoxia (hypoxia is a low oxygen saturation). Hypoxia is a particular problem with COVID-19, since many patients have been hypoxic, but have not experienced any difficulty breathing or other respiratory symptoms. It is easy to miss hypoxia in COVID-19 patients, if we are not measuring oxygen saturation.


If the person does not have any symptoms, does that mean that the person is not infected? No.


Is that a problem? Probably not. It would be best, if the vaccines provide sterilizing immunity – immunity that prevents the transmission of infection. Often an infection is asymptomatic, so the person is not aware of being infected. Measuring the rate of infection requires frequently testing everyone, but that was not the goal of this research. The goal was for the vaccine to decrease the spread of disease (an infection that is causing symptoms), when compared with placebo. We do not yet know if any COVID-19 vaccines prevent transmission of infection. The Pfizer/BioNTech vaccines, which is what US Rep. Stephen Lynch received two doses of, prevents development of symptoms 95% better than placebo (not receiving any active vaccine doses). That also means that a small percentage (5%) of the people who are vaccinated will be expected to become symptomatic.


A statement from the South Boson congressman’s office says Lynch isn’t displaying any symptoms of COVID-19.


Link to article in MassLive


Since he is not reported to be experiencing any symptoms, Rep. Lynch is still considered to be asymptomatic, therefore probably in the 95% protected from disease (symptoms). It is possible that Rep. Lynch would have developed an asymptomatic infection, if he were not vaccinated, but we do not know. At 65 years old, Rep. Lynch is not expected to develop an asymptomatic infection. That is much more likely to occur in much younger people, but there are no guarantees.


Why did the researchers only look at symptoms? Because it would be a lot more work, and money, and could discourage people from volunteering for the study, since participants would have to get tested for COVID-19 every few days to determine if they had infection, rather than only getting tested after developing symptoms. Is it possible that more people became infected in the vaccine group, than in the placebo group? Yes, but it is unlikely and more infections in the vaccine group, with 95% less disease, would not indicate that vaccination is a problem. Why?


In the final analysis of the evaluable efficacy population (7 days), four participants had severe COVID-19 disease at least 7 days after Dose 2 (one subject who received BNT162b2 and three participants who received placebo). The vaccine recipient who had severe COVID-19 disease met the severe case definition because oxygen saturation at the COVID-19 illness visit was 93% on room air. The subject was not hospitalized, did not seek further medical care, and did not have risk factors for severe disease. The three placebo recipients who had severe COVID19 disease met the severe case definition for the following reasons: one subject had an oxygen saturation of 92% on room air without other severe disease criteria, one subject was hospitalized for noninvasive positive pressure ventilation with bilateral pneumonia, and one subject had an oxygen saturation of 92% and ICU admission for heart block. One of these placebo recipients with severe disease also had a body mass index > 30 kg/m2 as a risk factor, while the other two participants did not have any risk factors for severe disease. The vaccine efficacy of this secondary efficacy endpoint is shown in Table 11.



The worst outcome, among those vaccinated, was an oxygen saturation that dropped to 93%. It does not describe if symptoms resulted in testing, or if it was due to an exposure, or something else, but the reason this person is categorized as severe disease is an oxygen saturation of 93%. One of the three patients in the placebo group was also considered to have severe disease is for a similar oxygen saturation (92%), which is essentially the same as 93% for treatment purposes.


Has the protection provided by vaccine decreased since the EUA approval for the vaccine? No. There have not been any reports of decreasing efficacy of either mRNA vaccine. Any reasonable person, who does not have a medical reason for not getting vaccinated (severe allergies seems to be the only consideration), should receive both shots of vaccine.


You can develop immunity naturally, with about a 1% chance of death and about a 15% chance of severe disease (depending on age, co-morbidities, …), or you can obtain immunity by vaccination, with the possibility of some side effects, which are reported to be less severe for older people.


The only reason Rep. Lynch found out that he was infected was testing after a member of his staff tested positive for COVID-19. He is not reporting any symptoms. A vaccine that prevents symptoms, even if it allows infection, is still a successful vaccine. Preventing disease and preventing death are both very important benefits of vaccines.


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What to Look for in Today’s Pfizer/BioNTech FDA Advisory Committee Meeting

The 9 AM December 10 meeting is available by video conference at this link. Since we are seeing record rates of infection, there should be a lot more cases of infection, with the same difference in numbers between the placebo group and the vaccine candidate group. There are two important questions.

We may not be be able to answer either one, yet. How long does the vaccine candidate protect recipients. We know there are cases of people developing COVID-19 after recovering from an earlier case. Since there are no coronaviruses that have provided long term immunity, how often will we need to get vaccinated? Every six months? Every year? Every other year?

Usually, reinfection results in a less serious infection, but there is already evidence that this may not be the case with COVID-19.

The patient had two positive tests for SARS-CoV-2, the first on April 18, 2020, and the second on June 5, 2020, separated by two negative tests done during follow-up in May, 2020. Genomic analysis of SARS-CoV-2 showed genetically significant differences between each variant associated with each instance of infection. The second infection was symptomatically more severe than the first.

Genomic evidence for reinfection with SARS-CoV-2: a case study

He was reinfected two months later and the second infection was more severe.

The other important thing that we may not be able to know depends on the amount of information obtained by the study. Did the study require tracking of the close contacts of the participants to see if there is a difference in infection rate?

If there is no difference, that means the vaccine candidate does not prevent transmission, even though it prevents the vaccinated people from becoming noticeably sick. This would still be an effective vaccine, but would require a higher rate of vaccination to control the pandemic.

The higher the rate of vaccination needed, the more likely it is that the anti-vaxers will keep the pandemic from being stopped for years, if not forever. Anti-vaxers have prevented the eradication of polio, so we have to continue to vaccinate our children against polio. Successful vaccines put themselves out of business. Anti-vaxers require vaccination for ever.

Fortunately, anti-vaxers failed to protect smallpox, so we no longer have to vaccinate children against smallpox.

Vaccines are probably the safest and most effective medical intervention available, but anti-vaxers oppose that.

Vaccines save millions of lives every year – mostly the lives of children – but anti-vaxers oppose that.

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Update on the Moderna Vaccine Candidate

Today Moderna issued another press release to update the information available on their vaccine candidate. The results are consistent with the previously released results and will be followed by a much more detailed release of information at an FDA advisory panel meeting, expected to be on December 17, 2020.

The new cases are more than double the 95 cases from the November 16 press release. The total is now 196 symptomatic cases – 185 in the placebo group and 11 in the mRNA-1273 group – efficacy of 94.1%. There were 30 severe cases, including 1 death, in the placebo group and no severe cases in the mRNA-1273 group.

We do not know how many asymptomatic cases are in either group, so this route of transmission by vaccinated people is still a possibility.

Another part of the press release raises different questions.

Efficacy was consistent across age, race and ethnicity, and gender demographics. The 196 COVID-19 cases included 33 older adults (ages 65+) and 42 participants identifying as being from diverse communities (including 29 Hispanic or LatinX, 6 Black or African Americans, 4 Asian Americans and 3 multiracial participants).

But . . .

The study includes more than 11,000 participants from communities of color, representing 37% of the study population, which is similar to the diversity of the U.S. at large.

The minority rate in the study is stated to match the 37% minority rate of America, but the symptomatic infection rate among American minorities in the study is 42 out of 196 (21.4%), but according to a meta-analysis of over 18 million patients in the Lancet, the symptomatic infection rate among minorities is significantly higher than 37%:

Patients from ethnic minority groups are disproportionately affected by Coronavirus disease (COVID-19). We performed a systematic review and meta-analysis to explore the relationship between ethnicity and clinical outcomes in COVID-19.

How is this study of randomized volunteers, who are allegedly representative of the American population, producing symptomatic infection rates that are much less than half of what is expected among minorities?

The November 18 Pfizer/BioNTech vaccine candidate press release only states:

Efficacy was consistent across age, gender, race and ethnicity demographics.

I did not find any details of the actual numbers in the press release, nor in any of the links. The Moderna press release has a similar statement, even though the numbers provided disagree with that statement: “Efficacy was consistent across age, race and ethnicity, and gender demographics.” Is the Pfizer/BioNTech statement more trustworthy, because it does not provide any numbers? No, but this is something that needs to be addressed for all of the vaccine candidates.

What are the Pfizer/BioNTech numbers for minorities? The FDA meeting for Pfizer/BioNTech is scheduled for December 10, so we should learn a lot more from that open to the public by video FDA meeting.

Why does the Moderna press release list such disproportionate numbers, but not mention that they are disproportionate? There is no reason to expect that a placebo would provide this kind of disproportionate protection.

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Why 90% vs. 62% for the Efficacy of the AstraZeneca Vaccine Candidate?

 

There was a press release from AstraZeneca at 7 AM today. It includes two different dosing methods with two dramatically different rates of efficacy. One group received half a dose, followed by a month later by a full dose. The other group received a full dose, followed by a month later by another full dose.

 

One dosing regimen (n=2,741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8,895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. All results were statistically significant (p<=0.0001). More data will continue to accumulate and additional analysis will be conducted, refining the efficacy reading and establishing the duration of protection.

 

Usually, the result of the differences in dosing is to use the lowest effective dose, in order to minimize any side effects, which are usually dose related. A higher dose is expected to be more effective, but also to have more side effects.

 

The part people are having a hard time explaining is that the 90% efficacy is in the smaller dose group. This does not seem to make medical sense, but this is what people who understand statistics expect.

 

Why?

 

Daniel Kahneman explains this in his excellent book, Thinking, Fast and Slow. He uses the following example as an introduction:

 

A study of the incidence of kidney cancer in the 3,141 counties of the United States reveals a remarkable pattern. The counties in which the incidence of kidney cancer is lowest are mostly rural, sparsely populated, and located in traditionally Republican states in the Midwest, the South, and the West. What do you make of this?

 

This is known informally as the Law of Small Numbers. Intuitively, we can come up with many different explanations about a healthy rural lifestyle, or something else. Kahneman follows that with the statistics on counties with the highest incidence of kidney cancer, which are also mostly rural, sparsely populated, and located in traditionally Republican states in the Midwest, the South, and the West.

 

The important factor is not lifestyle, not politics, and not geography. The important factor is that these are all sparsely populated counties, which means that the number of cases of kidney cancer will be disproportionately affected by the addition/subtraction of a tiny number of cases.

 

The small sample size is the most likely explanation for the 90% efficacy in the half dose, then full dose group. When more cases of COVID-19 are diagnosed among those who have received the half dose, then the full dose, expect the estimate of benefit to drop closer to 70%. The 70% efficacy is also based on small numbers, but those numbers (including the 90% sample) are more than four times the size of the 90% sample. This is not certain. This is statistical probability. A reasonable person should feel comfortable in placing a wager on the results dropping to near 70%.

 

In other words, the news is worse than expected, although still good news. There is another vaccine candidate that, based on the preliminary numbers, meets the approval criteria of better than 50% efficacy.

 

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What Do the Moderna Vaccine Candidate Press Releases Tell Us?


 

I had thought that the vaccine studies would only be recruiting people up to 55 years old, which was the age limit on the phase 1 studies, but there is significant representation of people over 65 and people with serious comorbidities. This is excellent news.

 

According to one press release from Moderna:

The COVE study includes more than 7,000 Americans over the age of 65. It also includes more than 5,000 Americans who are under the age of 65 but have high-risk chronic diseases that put them at increased risk of severe COVID-19, such as diabetes, severe obesity and cardiac disease.

 

The other important concern I had was the need to store the vaccine at around -80 degrees C, which would limit access for a lot of people, even in America. From another press release, dated 4 minutes earlier, Moderna:

today announced new data showing that mRNA-1273, its COVID-19 vaccine candidate, remains stable at 2° to 8°C (36° to 46°F), the temperature of a standard home or medical refrigerator, for 30 days. Stability testing supports this extension from an earlier estimate of 7 days. mRNA-1273 remains stable at -20° C (-4°F) for up to six months, at refrigerated conditions for up to 30 days and at room temperature for up to 12 hours.

 

There is an excellent analysis of the press release on preliminary efficacy results at STAT News, which has been ahead of the rest of the media in recognizing the serious nature of this pandemic.

 

It is important to remember that a press release, even about something this serious, is a commercial, intended to promote the company’s product. The information provided by Moderna in the press releases has not been peer reviewed. The numbers may change as mistakes are caught and conclusions are examined. That is OK, because there will be thorough analysis of the results before any vaccine candidate is approved for use outside of these experiments.

 

How will we know when a vaccine is safe and effective? I provided my criteria in August, when I wrote about a vaccine approved by President Putin, based on inadequate research:

I want to see recommendation of a vaccine by the people who know the most about vaccines – Paul Offit, Michael Osterholm, Peter Hotez, and Anthony Fauci. They need to be able to see all of the evidence. The only reasonable conclusion about a refusal to share the evidence with any of them is that there is something bad being hidden. These are not politicians. None of these medical experts have shown signs of being influenced by political pressure.

 

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2020 ACLS Repeats the Mistakes of 2015 ACLS

 

 

The International Liaison Committee on Resuscitation (ILCOR) has updated the ACLS (Advanced Cardiac Life Support) recommendations by making excuses for the evidence.

 

We have been using epinephrine for 50 years without evidence of improved outcomes that matter to patients.

 

A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest (Paramedic2) shows that epinephrine does not improve outcomes for prehospital patients.

 

In conclusion, in this randomized trial involving patients with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of survival at 30 days than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group.

 

Rather than limit treatments to those with high quality evidence that they improve outcomes that matter to patients, the recommendation is to keep giving epinephrine, because eventually someone might provide something – anything – to support epinephrine.

 

What about amiodarone?

 

Amiodarone, Lidocaine, or Placebo in Out-of-Hospital Cardiac Arrest (ALPS) showed that amiodarone also does not improve outcomes.

 

Conclusions Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia.

 

If amiodarone was mentioned, I missed it. Both epinephrine and amiodarone had large placebo-controlled research results released showing that the outcomes are worse with epinephrine and worse with amiodarone.

 

There is still no evidence that any ventilation produces better outcomes than compression-only resuscitation, but it looks like the intervention will continue to be recommended.

 

In the absence of evidence of benefit, inadequately tested interventions should be avoided.

 

The goal is to protect the patients, not to protect the interventions.

 

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