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Tom Perry MD's avatar

This posting reminds me of a woman, about age 65, once referred to me (a general internist) in desparation by her family doctor. Having enjoyed power and respect as an elementary school teacher in charge of her own classroom, she had little tolerance for doctors telling her what to do. Also, she had been unable to tolerate heart-rate controlling drugs (various beta-blockers, calcium channel antagonists) and was unwilling to try any others.

When I met her, she could barely walk from waiting room to examining room, and turned out to be (quietly) in frank pulmonary edema with very fast heart rate and ECG proof of atrial fibrillation, but no valvular disease. At my suggestion to try digoxin, in which I thought I might interest her as an "entirely different older drug that few people still know how to use", my friendly South Africa-trained cardiologist colleague agreed to admit her to a CCU - perhaps the first time in recent memory that anyone was admitted to be "digitalized."

This treatment worked like hot damn to slow her heart rate, bringing her out of pulmonary edema and back to independent function. She was never willing to try anything else, and insisted that digoxin had saved her life (I agreed). Over some years she never lost her crustiness, but she did lose a great deal of weight and at least 10 years later was thriving. This was almost certainly not an accident, iin my opinion.

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Robert Campbell MD's avatar

Your detailed objective reviews of the literature are priceless. For digoxin your observation that studies with unfavorable outcomes have common characteristics. They are prospective with the digoxin arm having sicker patients and the dosages used were too high. The outcome,then as expected is sicker patients developing dig toxicity. I have noticed this pattern of science unfortunately in our current FDA approval process. HHS terminated the FDA Unapproved Drug Initiative in November 2020 for multiple reasons one being the pattern of older drugs being shown in a bad light in comparison to newer patented alternatives. Indeed digoxin would fall in to this category of drugs in use prior to June 25, 1938 when the FDA was created by Congress. HHS found this element of the FDA Modernization Act resulted in exclusion of generics in lieu of costly alternatives. I first noticed this pattern when a new and very expensive expensive IV anti emetic medication Zoltan was introduced and the tried and true anti emetic droperidol was given a black box warning for prolonged QT syndrome. More recently strange biases emerged with the COVID pandemic. Early in the pandemic there were two fraudulent studies published in the Lancet and NEJM. These were touted by NIH and CDC government public health officials as the end of HCQ as a treatment for COVID on the very day the articles appeared on the pre print server with no peer review.. One demonstrated the inexpensive medication HCQ did not demonstrate efficacy and the other demonstrated unexpected severe toxicities. Both studies were retracted for fraudulent data. Indeed one week of peer review revealed the studies were entirely falsified. At the time Prodromos at U Illinois reviewed all the HCQ literature presumably searching for any patterns of bias or worse yet fraud. Of the 43 published reports 25 reported efficacy for HCQ 15 showed no improvement and 3 demonstrated negative efficacy. Fortunately no additional fraudulent papers were found. Their conclusions were that HCQ was consistently effective in unbiased studies. 11 studies treated early by design and they all demonstrated efficacy. The studies with no benefit or negative efficacy were studies where treatment was given late in doses that were known to be toxic and late in the disease that is more than 48 hours after hospital admission with most already in the ICU on ventilators. HCQ total drug treatment acquisition costs were $20 with Remdesivir costing $3100. My point here is there may be times where unexplained biases in the literature can be explained. I now analyze the potential for financial biases in the medical industrial complex before I conduct literature reviews routinely. Freedom of Information documents reveal from 2010-2020 $350M in royalty payments were received by NIH employees. Remarkably there is no requirement for disclosure revealing who paid how much to whom. We know NIH employees Fauci received 23 royalty payments and NIH Director Collins received 14 royalty payments and Clifford Lane 8 royalty payments in this period. We are not permitted to know how much was paid and which companies or drugs were subject to royalty payments. I have formally recommended all such payments be fully disclosed. I know you work very hard with your reviews. The presence of royalty payments to key officials is pertinent to implicit biases in study design. The NIH awards $30B per year to roughly 56,000 researchers per year. The refusal of NIH to provide transparency on $350M in royalty payments to its employees makes me suspicious of NIH studies having a higher rate of unintentional or intentional biases in study design.

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