The silence of the evidence: ivermectin (ab)use in North Macedonia
Written by: Jelena Kalinić, biologist, science journalist
Note: no media outlet wanted to publish this article in its entirety. Those who wanted to publish the article, did great cuts to the scientific part of the article. The text was created in October 2021 and I decided to publish an unedited version of the text, the article in its entirety on my blog.
Author: Jelena Kalinić
Fake studies against hard evidence
North Macedonia officially approved ivermectin for COVID-19 treatment in December 2020 and it is one of the few countries with this approach for COVID-19 treatment. In some countries, off-label use is allowed and health organizations of those countries (ministries of health) have approved the use of ivermectin in COVID-19 therapy. In Serbia, for example, this drug is not approved for use in COVID-19, and doctors who prescribed it to patients and advised taking it in the Viber group go to the court of honor of the Medical Chamber of Serbia.
North Macedonia is, according to Worldometers on September 27, 2021 at the top of the world list in terms of the number of COVID-19 deaths per million inhabitants, along with Peru, Hungary, Bosnia and Herzegovina and Montenegro. Total number of deaths per 1M is also high in Czechia and Slovakia where ivermectin is also approved for COVID-19. Excess death - difference between the observed numbers of deaths (any cause) in specific time periods and expected numbers of deaths in the same time periods – are also very high in North Macedonia.
There is just a little difference between Bosnia, where ivermectin is not approved for COVID-19 treatment, and North Macedonia, where it is approved. Total number of deaths per 1M is also high in Czechia and Slovakia where ivermectin is also approved for COVID-19.
North Macedonia also has one of the highest rates of excess deaths (Source: Economist):
Statistics show that ivermectin doesn't reduce mortality significantly, compared to countries where this medicine is not approved in COVID-19 treatment.
If ivermectin had an effect on COVID-19, we would see that the death rate per 100,000 and the excess mortality in Northern Macedonia is lower than in Bosnia and Herzegovina, which did not use ivermectin. But it is not so.
What is ivermectin?
Ivermectin is an antiparasitic that is mainly used in Europe for the treatment of certain parasitic diseases in veterinary practice. It is allowed for human use in cases of severe parasitosis, a condition not common in Europe. If it occurs in Europe - these are mostly cases of immigrants coming from those parts of the world where there are these diseases or, less frequently, among tourists who have recently been to these areas, mainly Africa and Asia. The U.S. Food and Drug Administration (FDA) has approved ivermectin tablets for the treatment of people with intestinal strongyloidiasis and onchocerciasis, two conditions caused by parasitic worms.
Onchocerciasis or river blindness is an infection with Onchocerca volvulus worm and is manifested by itchy subcutaneous nodules in which the parasite develops, while strongyloidosis is caused by the nematode Strongyloides stercoralis. This should be noted in order to better understand the seriousness of parasitic diseases which are treated with ivermectin. These are life-threatening conditions, and the therapy and dosage of ivermectin is precisely determined and does not last long - it goes with the optimal doses depending on the patient's body weight in the short term.
In 2015, William C. Campbell shared the Nobel Prize in Physiology or Medicine for the discovery of ivermectin. But, Nobel Prize for ivermectin intended for treatment of parasitic infections doesn’t prove its efficacy on COVID-19. Unfortunately, the Nobel Prize link is being used to present ivermectin as a treatment for COVID-19 by circles that spread disinformation.
“Ivermectin has been given to humans 3.7 billion times in the past 30 years. It’s totally safe and has been called a miracle drug. Its creators won a Nobel Prize in Medicine for inventing it, and the WHO puts it on a list of ‘must have drugs’.” – reads one of the ivermectin for COVID-19 treatment posts.
Ivermectin is not easy to obtain for human use. In the time before the pandemic, it was prescribed only for severe parasitosis, and is usually not a drug in stock in Europe because there is no need for it. Even in the case of parasitosis, it is not easy to find and get it, except in countries affected by such diseases. The World Health Organization had not advised ivermectin use for COVID-19. This organization rather recommended in early 2021 that this substance should not be used to treat COVID-19 until evidence is obtained whether or not it is effective. Ivermectin also has unpleasant side effects. In the Al Jazeera Balkans talk-show Kontekst, doctor-radiologist Aleksandar Ivković from Serbia mentions cases of patients with COVID-19 who took ivermectin on their own and in whom side effects of hallucinations were recorded.
The U.S. Centers for Disease Control and Prevention (CDC) and Food and Drug Administration (FDA), put out advisories in August 2021 warning against using ivermectin to treat COVID-19. February 2021 guidelines from the National Institutes of Health (NIH) say there is not enough evidence “either for or against” recommending the drug. In March 2021, WHO advised that ivermectin should only be used to treat COVID-19 within clinical trials. The next WHO study on potential drugs for COVID-19 (Solidarity PLOS) did not include ivermectin in the studies at all.
How did the buzz about ivermectin come about?
“There is no good evidence indicating that ivermectin is effective at treating or preventing COVID-19.“ says in e-mail correspondence with me David H. Gorski, physician and managing editor-author of the Science-Based Medicine website.
“In the summer, I believe, of 2020, an Australian group published an article showing that ivermectin has antiviral activity in cell culture. The problem was that the antiviral activity was only observed at a concentration of the drug something like 100 times higher than what can be achieved in the plasma from normal doses of ivermectin in humans“, explains Gorski. Ivermectin is pretty safe at normal dosages used in humans to treat, for example, river blindness. “The problem is that people are taking doses way higher than the recommended safe doses. Some are even buying the horse version of the drug, which comes in a paste and is given at a much higher dose than in humans. It is, after all, intended for horses, not humans, which is why the dose is so much higher”, continues Gorski.
The problem is that, although it appears to have antiviral activity in cell culture, it only blocks the virus at concentrations that aren’t achievable at a safe dose. Chemist Derek Lowe in an article for Science explicitly explains why high doses of ivermectin, which could destroy the coronavirus, are not feasible.
Macedonian media outlets (Kanal 5 here, Deutsche Welle here, Glas Mk here) reported this: “Ivermectin, according to the latest WHO study from November 18, 2020, has been shown to be the only drug that is effective in all three stages of COVID disease: the incubation period, lighter and more severe symptomatology.“
In late December 2020, ivermectin passed all stages of approval in the country’s Ministry of Health and the Drug Agency MALMED (which approves drugs and vaccines), and the Commission for Protection against Infectious Diseases (Governmental body which gives recommendations), of which the Ministry of Health is a member, gave permission for its use. On 31 December, MALMED issued the necessary approvals for ivermectin, and Macedonian government published statement on this. In January 2021, the protocol for the treatment in North Macedonia was issued.
"In high-risk groups of workers who have a high risk of getting sick, people who have been in contact with confirmed sick contact and, normally, people who are sick. The three groups of citizens, ie patients, have different indications and different dosages, so it is important that the drug is given under the control of a doctor. I believe that in the next two weeks it will be available in our country. "-said Venko Filipče, former Minister of Health for Kanal 5 on 8th January 2021. In the same article mysterious “WHO study from 18th November” was mentioned.
However, there had been no 18 November WHO study. The WHO Office for North Macedonia confirmed that the WHO has not approved the use of ivermectin for COVID-19. “The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive. Until more data is available, WHO recommends that the drug only be used to treat COVID-19 within clinical trials. This applies to patients with any disease severity“, wrote Dr Jihane Tawilah, who is the WHO Representative in North Macedonia, in an email to me. Asked to comment on the alleged 18 November study, Tawilah wrote, “There are many false news in the media.”
She included an official statement from WHO on ivermectin, which said: „A guideline development group was convened in response to the increased international attention on ivermectin as a potential treatment for COVID-19. This group is an independent, international panel of experts, which includes clinical care experts in multiple specialties and also include an ethicist and patient-partners. The group reviewed pooled data from 16 randomized controlled trials (total enrolled 2,407), including both inpatients and outpatients with COVID-19. They determined that the evidence on whether ivermectin reduces mortality, need for mechanical ventilation, need for hospital admission and time to clinical improvement in COVID-19 patients is of “very low certainty” due to the small sizes and methodological limitations of available trial data, including small number of events. The panel did not look at the use of ivermectin to prevent COVID-19, which is outside of scope of the current guidelines.”
So where does the existence of the alleged study come from? It is possible that someone misunderstood something; that it was not a WHO study at all, but some other study, which the media misreported. It is also possible that someone deliberately disseminated the disinformation..
The Macedonian fact-checking site Vistinomer wrote that there is no proven efficacy of ivermectin for COVID-19.
As "evidence" that Macedonian health institutions support the use of ivermectin in COVID-19 therapy, an anonymous Word document appeared on the website of the Association of Private Doctors of the Republic of Macedonia - without signature, without stamp, without any authenticity, stating that it is an opinion for the use of ivermectin in COVID-19 made by the expert group of the University Clinic for Pulmonology and Allergology in Skopje. This document, used by Macedonian medical chamber offers a series of studies that support the use of ivermectin for covid, and dates from January 2021. The problem with it is that what is written in the document is completely identical to the article published on Macedonian portal Emiter in August 2020. The author of that article is journalist Marjan Bozinovski. His article only listed studies in which ivermectin was effective - on cell cultures, small samples, and poorely done studies. The Word document is a forgery, by all accounts. In the info section of that document, it is written that the author - the owner of the license, is Nikola Georgievski cyrillic: Никола Георгиевски, see screenshots down), for whom we know nothing. The name is identical to the deceased Macedonian epidemiologist. It was as if a ghost had written and uploaded that document. Doctor Nenad Lazarov, wrote for Kurir that the word document that the medical chamber sends to the family doctors for the use of ivermectin is plagiarism, and that the author of the original text is Marjan Bozinovski, who is not part of this organization.
The approval of ivermectin for COVID-10 in Northern Macedonia appears to have been based on fictitious studies whose origins are unknown, public pressure, and the opinions of several doctors. The decision to officially include ivermectin in COVID-19 therapy protocols in North Macedonia was made based on the opinion of one or very few experts and public pressure, on the basis of rumors and not on highly valid scientific evidence.
There are arguments that show that North Macedonia has imitated Greece, Bulgaria and Turkey in the use of ivermectin for COVID-19. Sloboden Pečat, independent media from North Macedonia, writes the following: "Greece is not the only country in the region where Ivermectin is used as a medicine. In Bulgaria it is already an integral part of hospital protocols. Acibadem City Clinic is a hospital in Sofia, where Ivermectin was officially introduced in the hospital treatment of Covid 19".
What is even more interesting - the media examined the prices and questioned the import of ivermectin, which is not officially approved for human use in North Macedonia, which makes it difficult to procure and import, BUT THEY DID NOT ASK IF IVERMECTIN IS EFFECTIVE AND HOW MUCH FOR TREATMENT O COVID-19!!!
It seems that Europe, ie the EU, has big problems within its borders, because some member states approved ivermectin officially, and in some it was used illegally.
According to Nikola Panovski, a Macedonian microbiologist, the price of ivermectin therapy is 10-25 euros. This price may not seem high, but in a country where GDP is 5, 888 USD (2020) - that's a lot. The City Hospital and the Pulmonary Clinic prescribe it according to the I-MASK protocol, but the Infectious Diseases Clinic does not. Thus, there is no consensus in the medical community in North Macedonia about the use of this drug.
"Hospitals and doctors in clinics decide for themselves whether to prescribe it“, says microbiologist Panovski, who is a proponent of ivermectin use in COVID-19. Interesting thing is that the Pulmonology Clinic included ivermectin in its protocol, and the Infectious Diseases Clinic at the same clinical center did not and never allows it to be prescribed. “The big City hospital in Skopje does not have it in the protocol, but if the patients insist, they will get it. It is used for prevention most often at the beginning of the disease, and less often in the hospital. It is given according to the I MASK protocol, 0.15 to 0.2 mg per kg of body weight. For prevention two days, for therapy 2 to 5 days“ he adds.
This means that in North Macedonia, ivermectin was even given to those who have a milder form of the disease, oras a post-exposure prevention, on the advice of a doctor or at their own request
In a debate show on one of the most watched private commercial TV stations in the country (Kanal 5), broadcast on 24 September 2021, doctors Niko Bekjarovski, director of the University toxicology clinic, and Dejan Dokik, director of the University clinic of pulmonology and allergology, both agreed (after 24th minute) that ivermectin has its place in the treatment of COVID-19. Dokik added that ivermectin is "most effective in the early stages of the disease," which conflicted with Kanal 5's earlier report that ivermectin is effective “in all three stages of the disease." Dokik said the recommendations of the Food and Drug Administration in the USA and the EU’s European Medicines Agency that the drug be used only in clinical studies means they did not completely give up ivermectin as COVID therapy, and that "time will tell if the drug is effective."
This is an example of how doctors, experts, spread misinformation on TV and convince the audience that this therapy is useful. When we look at other former Yugoslav countries, it seems as if North Macedonia is in an informational blackout spread by some doctors and the government. In Serbia, Croatia, Montenegro and Bosnia, there have been marginal attempts to introduce ivermectin as a drug for COVID-19, but in none of these countries have governments that approved this drug for covid. In Serbia, the Medical Chamber has started the procedure of sanctioning doctors who in Viber groups gave illegal protocols of ivermectin treatment and helped the illegal purchase of this medicine. Yes - in Serbia it is illegal to prescribe ivermectin to COVID-19 patients, this drug is not allowed for this kind of use.
To understand how complex and strange the situation with ivermectin in Macedonia is, we need to know that in the countries of Yugoslavia (Slovenia, Croatia, Bosnia and Herzegovina, Serbia, Macedonia, Montenegro) ivermectin is not approved for human use as an oral medicine. It is the only one in Croatia approved for topical use. There are no cases of severe human parasitosis in these countries and there is no need for ivermectin, except for animals, in veterinary use.
Thus, the Government of North Macedonia ignored this and approved the drug for COVID-19 therapy based on weak evidence and further lied that the WHO claims that ivermectin is eikasan in these situations. Northern Macedonia then made emergency imports of the drug, from Turkey and Bulgaria. In the other countries mentioned, governments have never approved ivermectin for COVID-19, but this drug could be obtained illegally, through some Viber groups.
The ivmmeta page has appeared on the Internet. com which is very popular among those who believe that ivermectin is a “hidden” drug for COVID-19. To the untrained eye the site looks "scientific" and is presented as a meta-analysis of 66 studies. However, a meta-analysis is not done like this and does not look like this. One also requires a choice of material and does not include all studies, especially not one of poor quality. It is an anonymous site without authors - let's not forget, meta-studies must have authors.
The ivmmeta.com website provides several meta-analyzes of pooled effects. This website presents pooled estimates suggesting significant benefits of ivermectin, leading to confusion among clinicians, patients, and decision makers. The analyzes are misleading and have several limitations. Otherwise, non-Cochane metastudies typically show greater intervention efficiency and have less precision than Cochrane.
For those who do not come from the biomedical profession, Cochrane is an international organization founded to organize medical research to facilitate evidence-based choices about health interventions involving health professionals, patients, and policy makers. Cochrane is investigating the strength of the evidence for or against the application of a health intervention.
Another anonymous site, c19ivermectin, which is very similar to the aforementioned ivmmeta, lists a number of seemingly meta-studies that support ivermectin, as many as 129 of which have been compiled here. However, it is a mixture of all kinds of studies - the authors of this site have included everything they came across, whether it is a preprint, where it was published, what the new evidence is, how good the methodology is - if these studies have had a positive effect. They simply did not put studies with a negative effect. In fact, those who compiled this page did just the opposite of what the study aims at.
These mentioned pages cite as "evidence" some so-called zombie studies that do not actually exist - for example, in those studies it says that they were done in places where no one has any idea that such studies were done.
Conservatives, antivaxers and QAnon are pushing ivermectin fever
In December 2020, the chairman of the U.S. National Security Committee, Ron Johnson, used a Senate hearing to promote marginal theories about COVID-19. Among the witnesses heard was Pierre Kory, a pulmonologist who also works in intensive care, who described ivermectin as a “miracle drug” against COVID-19. Videos of his statements went viral on social media, garnering more than a million views.
A review article by Kory, Paul E. Marik, and others on the efficacy of ivermectin, which was accepted for publication in open-source science publisher Frontiers Media but subsequently rejected because of "a series of strong, unsupported claims based on studies with insufficient statistical significance.”
The use of ivermectin for COVID-19 is advocated by a group calling itself the “Frontline COVID-19 Critical Care Alliance” (FLCCC) and America's Frontline Doctors (AFLD), which say it is at the forefront of the “global movement to move ivermectin into the mainstream”. The attempt went viral on social media, where it was accepted by COVID risk deniers, vaccination opponents and conspiracy theorists. FLCCC pushed mentioned I-MASK protocol. One of the prominent faces of the FLCCC is precisely Marik, who was the co-author of a retracted review in Frontiers Media.
Conservative, not to mention right QAnon currents, push ivermectin. In the US, some doctors even prescribe and recommend ivermectin, contrary to the FDA's and CDC recommendations, but it's interesting to note that these doctors often come from the "red states" and are very close to conservative groups and are favorite among Q anon members. One such example is dermopatologist Ryan Cole from Idaho, who at one event said that Spike protein from vaccines damages organs (which is not true because the evidence for this is based on experiments with very high concentrations of Spike protein, which cannot occur after vaccination). Cole called COVID-19 immunization “needle rape.” It is Cole who belongs to the current that pushes ivermectin and who is championed by the GOP. This shows how ivermectin-vaccines case is highly politicized: conservatives and Qanon as far-right manifestation of political spectrum are mostly against vaccines and pro-ivermectin, while democrats align with the evidence-based medicine that COVID-19 vaccines are effective and safe, while there is lack of evidence that ivermectin helps in COVID-19.
Those who deny science and spread misinformation and distrust of vaccines, embrace ivermectin as a COVID drug hidden from the public. They say the global establishment refuses to admit that there is an inexpensive drug.
For those who are not yet familiar with Social media, so they wonder how things like this are spreading and reaching from the USA to small helpless countries like North Macedonia - the power of social networks is huge and one podcast, like the one done by Joe Rogan, youtube channels, a seemingly irrelevant tweet or status on a FB profile that has been declared a "critical opinion" with little or no investment, can go a long way and become viral.
It is very interesting that the advocates of ivermectin are members of conservative and right-wing currents that are at the same time against vaccines. Why is that so? The answer would require a special article(for that, I recommend this one on Vox), but, in short, it is a cognitive bias/cognitive dissonance when these groups simply cannot accept that vaccines are effective and useful and that they are trying in every way to find an excuse and show that "vaccines are unnecessary and COVID-19 is a minor disease". Therefore, after the failure of hydroxychloroquine, another antiparasitic presented as an "effective drug against COVID-19", the narrative of these groups focused on ivermectin. This is only because mainstream science, as they like to call evidence-based medicine, advises against taking ivermectin, simply because there is no evidence that it is effective. The WHO, CDC, EMA are seen in these circles as traitors and puppets of the rich and politicians who "hide cheap medicine and impose vaccines at the same time". Ivermectin is not effective in these circles because there is hard evidence for it, but it is simply "effective" because professional "treacherous" organizations do not recommend it.
Hierarchy of evidence
Once upon a time, decisions in science and medicine were made based on the opinions of experts and subjective reviews. This was the case until the 1980s, when several examples showed how subjective reviews and opinions of experts are just that - subjective. There is something we call the hierarchy of evidence in medicine, which is described and explained on Oxford’s Centre for Evidence-Based Medicine. At the bottom, as the weakest (level 5) are the opinions of experts and case studies. This is followed by different types of observational studies that can give good indications, but suffer from bias and confounding problems, then randomized placebo-controlled studies as the "gold standard", then meta-analyzes of the study and finally systematic reviews as the highest level (1a) of evidence.
“Current level 1 evidence for ivermectin indicates that there is no evidence of efficacy of this pre-intended pharmaceutical in the prevention and treatment of COVID19. The opinion of the expert cannot challenge this conclusion”, explains Dr Vladica Veličković, associate researcher at the Institute of Public Health, Medical Decision Making, and an expert in health technology assessment at Private University for Health Sciences, Medical Informatics and Technology, Austria.
Conclusion of Cochrane (a global independent network of researchers who support evidence-based medicine) for ivermectin use in COVID-19 is that “the reliable evidence available does not support the use of ivermectin for treatment or prevention of COVID‐19 outside of well‐designed randomized trials”.
"Based on the current very low- to low-certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID-19. The completed studies are small and few are considered high quality." is conclusion of the Cochrane meta-study from July 2021.
Public health decisions, as well as other decisions in medicine, cannot and must not be based on the opinion of lone experts, and especially not on public pressure. It is necessary to do series and series of studies, then meta-analyzes that carefully choose according to strict criteria what the analysis will be included, and finally systematic reviews.
It seems that post-communist countries are especially vulnerable to misinformation and they also stick to old way of looking at the strength of evidence against the argument of authority, which was abandoned in the late 1980s. Argument of authority (a form of logical fallacy) in North Macedonia, won over scientific evidence.
There is no respect for evidence in the case of those countries that have included ivermectin in the treatment of COVID-19 and in individual cases of recommending this substance, such as Ryan Cole. There is only a complete deviation from the recommendations of the WHO, and the health authorities of more developed countries. There are no official recommendations for taking ivermectin with COVID-19 in the US or most EU countries. The promotion of bad science, low-confidence scientific papers, which is being disseminated from conservative circles in America and Qanon, is reaching out to small countries via social networks like Facebook around the world and acting devastatingly and dangerously.
Emergency situations increase the likelihood of non-compliance with scientific evidence
But what is also tragic is that states that at one point included ivermectin continued to use it even after others like the EMA and the World Health Organization distanced themselves from ivermectin in COVID-19 treatment. The introduction of ivermectin was actually a populist move of health authorities (which are a reflection of the establishment) to please the electorate for the local elections in 2021 and not lose the voters.
However, before criticizing the establishment, one more thing needs to be taken into account, because this is only a partial answer to the question from the beginning of the article about how, for God's sake, this medicine was approved in one state without enough evidence.
In post-communist, post-socialists states, people still trust more the individual expert, rather than abstract evidence of scientific studies and analyses that are incomprehensible to ordinary citizens. They trust those who speak simply, even if it is not true. However, this is a mistake of the logical fallacy called authority's argument, which was overexploited during the COVID-19 pandemic: experts saying incorrect things from the position of authority. In many post-communist countries, corruption and nepotism have led to a large increase in distrust in state institutions, primarily health care, which is reflected in low vaccination rates against COVID-19. Post-socialists states are in vaccination rates below Europe's average (source: Our World in data):
But a seemingly opposite phenomenon has occurred in North Macedonia - that people believed government's decisions that ivermectin is a drug for COVID-19. Of course, what really happened was that the government felt the pulse of the public and what people wanted and pleased them.
In times of uncertainty, such as emergencies like pandemics, people often make wrong decisions based on things that scare them. New study has shown that physicians are also prone to similar mistakes. The absence of scientific guidelines at the beginning of a pandemic due to an unknown virus, such as COVID-19, could influence the perceived legitimacy of the application of non-evidence-based therapeutic approaches.
The results of the study published in Plos One showed that decision-makers, when under pressure from emergencies, such as a pandemic, are more inclined to accept and allow interventions for which scientific evidence is weak or erroneous
Doctors, but as we see health institutions also, in emergency situations play dodge ball: trying to help based on insufficient evidence or not exposing themselves to the risk of an intervention for which there is not enough evidence, but it may be helpful. Institutions must also play between public pressure for a particular intervention for which there is insufficient evidence and uncertainty about the effectiveness (and safety) of that intervention. If they do not include intervention - they will be accused of not wanting to act. If they include, it is a populist move, but, to citizens it looks like government is doing something. However, if such therapy does not help, or does harm, institutions will again be charged, this time for acting beyond evidence. In North Macedonia, even the credible media praised ivermectin and did not delve deeper into the issue of the pros and cons of this substance in the treatment of COVID-19.
But other post-socialist states are no better either. People in these countries have already seen many examples of corruption and negligence in the health sector - from the supply of inadequate ventilators for COVID-19 patients, to tourist and agricultural companies procuring medical equipment. The question is whether it is possible to restore citizens' trust in health care at all.
Scientific, health and quantitative literacy of the general population in Western Balkans region is low, there is distrust in institutions, health care system that fails even in non-emergency situations, insufficient system of screening patients who later come to doctors only in advanced stages of the disease, low GDP, which reflects on the quality of health and education, corruption in health care, political interference in this area - all these are the problems of these countries that are a recipe for tragedy.
This is the story of how the government of one country falsified evidence, lied to its citizens that ivermectin is a cure for COVID-19 and recommended by the WHO, the story of how the country's closure leads to blindness to evidence and fake newsspreading and the story of one big manipulation.