InFocus: Ivermectin Unacceptable for COVID-19 : Emergency Medicine News

COVID-19, ivermectin, best practice:

Ivermectin use for COVID-19 infections is controversial, but no benefit has been proven, and no U.S. medical organization supports it use. The lay public and some clinicians, especially from other countries, have suggested that it may be helpful, but it is currently not recommended to prevent or treat COVID-19 infections.

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The COVID-19 pandemic has raised multiple questions that confront and confuse physicians. A variety of treatments have evolved for this basically untreatable infection, and numerous prevention strategies and therapies have overwhelmed practicing emergency physicians.

It is difficult to stay current and nearly impossible to keep up with medications and treatments that have never been used before, and deciding on the best intervention is difficult. Patients demand interventions of questionable value or that may be downright harmful, but they have nonetheless been searching for the miraculous cure adopted by some physicians or advocated in the lay press.

This infection can be fatal, so it is not surprising that patients peruse the internet and conclude that an intervention should be tried on their loved one, even though there is no scientific basis that it will help. Emotions run high, and the physician is called upon to try an unproven intervention with the hope that it will cure a dying relative.

Some patients even pay lawyers to press their case, and physicians always fear that a lawsuit could be filed from those demanding that an intervention be used despite no proof that it will be helpful and even less that it will not harm the patient. The media have reported several cases of patients hiring lawyers to force hospitals to administer ivermectin, spawning problems not previously faced by clinicians.

What about ivermectin? It’s a medication that has no formal recommendations in the United States, and some have promised that it is helpful with essentially no scientific backup. A review of the recent literature is in order.

Toxic Effects from Ivermectin Use Associated with Prevention and Treatment of COVID-19

Temple C, et al.

New Engl J Med.

2021;385(23):2197

https://bit.ly/3pPSKtD

This article reported the Oregon Poison Center’s experience with ivermectin for treating COVID-19 infection. Ivermectin, basically a veterinary therapy, has been approved by the Food & Drug Administration for some human intestinal parasites, and it has been shown to decrease coronavirus replication in vitro. But ivermectin has shown no clinical benefit in preventing or treating COVID-19 infections in most randomized controlled trials, yet it is supported by some clinicians in this country.

The Oregon Poison Center received 21 calls concerning the use of ivermectin for preventing and treating COVID-19 infections. Half of the callers were men, with a wide range of ages, from 20 to 81. Most of the callers had purchased veterinary formulations of the drug, but three had received a prescription from a physician or veterinarian.

The amount of ivermectin used was not known for certain, but most callers developed symptoms within two hours after one large first-time dose. About half gradually developed symptoms after several days to weeks of repeated doses. Six of the 21 patients were hospitalized because of toxic effects from ivermectin, and all of them had used the drug for prevention. None died, but four required ICU care. Symptoms included GI distress, confusion, ataxia, and weakness. One patient had a seizure.

Comment: Ivermectin is a broad-spectrum antiparasitic agent used to treat a few uncommon intestinal parasites in humans, but it is primarily an animal medication. The drug was awarded a Nobel Prize in 2015. The FDA approved it for intestinal parasites, but it is not approved for COVID-19 prevention or treatment in humans. The FDA has cautioned about the potential risks if used for COVID-19 infection.

The National Institutes of Health has likewise cautioned about using ivermectin for COVID-19 infections. It is generally safe and well tolerated when used for approved indications. The veterinary formulation is available over the counter, and that is the formulation often taken by humans, occasionally in megadoses. The increase in ivermectin prescriptions has been astronomical despite the lack of evidence to support it for COVID-19 prevention or treatment. About 3600 ivermectin prescriptions were written each week before the pandemic, but more than 88,000 prescriptions were recorded the week of Aug. 13, 2021, a 24-fold increase. (CDC Health Alert Network. Aug. 26, 2021; https://bit.ly/39uMhvs.)

Ivermectin is available on the internet, and some individuals ingest topical formulations and animal products. Ivermectin is basically a neuro toxin. It activates and opens chloride channels that allow the increased entry of negative ions into cells, resulting in hyperpolarized cell membranes. It also interacts with inhibitory GABA receptors in the brain. Initial toxicity produces gastrointestinal effects, such as abdominal pain, nausea, vomiting, and diarrhea, but the drug also causes blurred vision, headache, dizziness, altered mental status, confusion, loss of coordination and balance, and seizures when taken in large amounts.

Treatment of ivermectin overdose is supportive and includes IV fluids for hypotension and benzodiazepines for seizures. Liver toxicity has occurred, and some have suggested treating elevated liver enzymes with standard doses of N-acetylcysteine. A good review of ivermectin use for COVID-19 infections can be found from the CDC Health Alert Network. (Aug. 26, 2021; https://bit.ly/39uMhvs.)

The public, lay literature, and some physicians are fans of ivermectin despite no proof that it is helpful. As Leon Gussow, MD, said in EMN, “We live in strange times.” (2021;43[11]:1; https://bit.ly/31kYjXn.)

Ivermectin proponents are likely focused on it because COVID-19 infections are essentially untreatable, and the scope of infections is gargantuan. Daily infection rates are rapidly increasing without significant hope of being contained. The entire world is seemingly infected, and the virus is easily spread with minimal contact.

Vaccinations are helpful, but newer strains are appearing, and even newer variants will likely be seen soon. Numerous potentially helpful interventions are on the horizon, and two oral medications are supported by the NIH. (See table.)

Ivermectin for the Treatment of COVID-19: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Roman Y, et al.

Clin Infect Dis.

June 28, 2021

https://bit.ly/34k1i3R

This review article assessed published potential benefits and harms of ivermectin in patients with COVID-19 infections. The authors reviewed randomized controlled trials on ivermectin found by five search engines, such as PubMed, Medline, and the Cochrane Library, published through March 2021. They noted that researchers in March 2020 showed that ivermectin was active against coronavirus in cell cultures by dramatically reducing viral RNA, but ivermectin concentrations were 50 times the normal maximum concentrations achieved with a standard single dose of ivermectin.

This information, as well as theoretical considerations, misinformation, reports of self-medication, and ready access to ivermectin, precipitated the use of the drug to treat COVID-19 infections, primarily in low-income countries. The governments of Peru and Bolivia actually added ivermectin to national protocols to treat COVID-19. Therapy was initiated despite lack of approval by any formal organizations, such as the FDA, the Infectious Diseases Society of America, and the World Health Organization. The published literature was also evaluated for several parameters, including risk of bias, errors in subject randomization, and missing data.

Most of the patients had only mild to moderate infections. The outcomes evaluated were all-cause mortality rates, length of hospital stay, adverse events, viral clearance of respiratory samples, overall clinical improvement, and need for mechanical ventilation. The authors concluded that ivermectin did not reduce any primary or secondary outcomes and did not positively influence mortality rates, length of stay, viral clearance, or the need for mechanical ventilation in patients with mild to moderate COVID-19 infections. They said ivermectin “is not a viable option for treating patients with COVID-19, and should be used only within clinical trials.”

The standard literature overwhelmingly concluded no proven value of ivermectin for preventing or treating COVID-19. The FDA said ivermectin is not safe or effective for preventing or treating COVID-19 infections and detailed why it should not be used. (Dec. 10, 2021; https://bit.ly/3p0lNdF.)

The Controversy

Several groups espouse an opposite view on ivermectin, and it is wise for emergency physicians to know the controversy surrounding this drug. A group of clinicians called the Front Line COVID-19 Critical Care (FLCCC) Alliance said the evidence on ivermectin demonstrated “a strong signal of therapeutic efficacy,” and recommended that ivermectin “should be systematically and globally adopted” for preventing and treating COVID-19. (FLCCC Alliance; https://bit.ly/3HytcHs.)

The alliance lobbies for ivermectin use, and its article was provisionally accepted for publication in Frontiers in Pharmacology in January 2020 but subsequently rejected and removed from the journal’s website. The editor of Frontiers said, “The article made a series of strong, unsupported claims based on studies with insufficient statistical significance, and at times, without the use of control groups. Further, the authors promoted their own specific ivermectin-based treatment which is inappropriate for a review article and against our editorial policies.” (March 2, 2021; https://bit.ly/34iNtmd.)

The FLCCC Alliance, whose founders include Paul Marik, MD, who is known for a debated vitamin C sepsis protocol, published the paper on its website. (Jan. 16, 2021; https://bit.ly/3HytcHs.) Dr. Marik also filed suit against Sentara Healthcare on Nov. 8, 2021, after the health care network banned the use of ivermectin and other therapies at Sentara Norfolk (VA) General Hospital where Dr. Marik practices. (https://bit.ly/3ztCG43.) Dr. Marik had been using the MATH+ protocol, which consists of methylprednisolone, ascorbic acid, thiamine, and heparin plus ivermectin, statin, zinc, vitamin D, famotidine, and melatonin.

Scientific American called the FLCCC Alliance a “fringe group” and noted that “the doses and schedules that the FLCCC posts on its [website] [https://bit.ly/3HrnqHE] are not consistent with those typically advised for humans.” The magazine said the alliance did not respond to requests for comment, including on whether it earns money through these services. (Sept. 29, 2021; https://bit.ly/3FSJjzm.)

An exhaustive review by the Cochrane Library found 14 studies with 1678 participants comparing ivermectin with no treatment, placebo, or standard of care. The studies were small, and few were considered high quality. They concluded that “based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat people with COVID-19 in the inpatient and outpatient settings and to prevent a SARS-CoV-2 infection in people after having high-risk exposure. … Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID-19 outside of well-designed randomized controlled trials.” (Cochrane Database Syst Rev. 2021;2021[7]:CD015017; https://bit.ly/3ztzc1t.)

Despite some disagreement in the medical literature, ivermectin is not currently supported for preventing or treating COVID-19 infections and should not be used.

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read his past columns athttp://bit.ly/EMN-InFocus.

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NIH Recommendation on Ivermectin

“There is insufficient evidence for the COVID-19 Treatment Guidelines Panel … to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin in the treatment of COVID-19.”

“Despite … in vitro activity, no clinical trials have reported a clinical benefit for ivermectin in patients with these viruses.”

Source: National Institutes of Health. Feb. 11, 2021; https://bit.ly/3eTY7lp.

COVID-19 Guidelines on Therapies for High-Risk, Nonhospitalized Patients with Mild to Moderate COVID-19

The Food and Drug Administration recently issued Emergency Use Authorizations for two oral antiviral agents, ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir (Lagevrio) to treat nonhospitalized patients with mild to moderate COVID-19 at high risk of progressing to serious disease.

The current outpatient treatment recommendations are (in order of preference):

• Paxlovid∗ (nirmatrelvir 300 mg plus ritonavir 100 mg) orally twice daily for five days or
• Sotrovimab 500 mg, administered as a single intravenous (IV) infusion or
• Remdesivir 200 mg IV on day 1, followed by remdesivir 100 mg IV on days 2 and 3 or
• Molnupiravir 800 mg orally twice daily for five days.

These recommendations were current as of Dec. 30, 2021. No clinical trials currently compare the efficacy of these four therapies. https://bit.ly/3EZ3RVF.

∗Paxlovid has multiple drug-drug interactions. Review patient’s medication list to assess risk of interactions. Not recommended if GFR is less than 30 mL/min.

Source: National Institutes of Health. Dec. 30, 2021; https://bit.ly/32Kf0g4