INADEQUATE EVIDENCE TO RECOMMEND IVERMECTIN IN THE
PROPHYLAXIS AND TREATMENT OF COVID-19
Professor Dr. Moy Foong Ming
Professor in Epidemiology
Center of Evidence Based Practise and Clinical
Epidemiology
Department of Social and Preventive Medicine
Faculty of Medicine, University Malaya
22.6.2021
Evidence-based medicine (EBM) is conscious, specific,
reasonable use of modern, best evidences in making decisions about treatment of
patients.
Doctor chooses the best possible solution for his
patients by the use of the best possible evidence to provide the optimum health
care in every aspect.
It is also used to avoid major mistakes in the course
of treatment, by providing better quality health care to the patients,
ultimately to save the lives of patients.
During the current pandemic of COVID-19, clinicians
and researchers are actively exploring various methods of prophylaxis and
treatment of COVID-19.
Besides vaccination for prophylaxis and symptomatic
treatment of the disease, currently there is a very strong voice in advocating
Ivermectin for the prophylaxis and treatment of COVID-19 globally as well as in
our country.
Ivermectin is a broad-spectrum antiparasitic agent
approved by the US Food and Drug Administration (FDA) and is proved to be safe
at the conventional dose of < 200ug/kg, although severe adverse effects
ranging from ataxia to seizures were occasionally reported.
Due to its in-vitro antiviral activity against a broad
range of viruses, it has been used off-label for the treatment of some viral
diseases.
However, regulatory bodies including the US FDA and
the European EMA as well as the Malaysian Ministry of Health concluded that
there was insufficient evidence to support the use of Ivermectin as treatment
of COVID-19.
The WHO also issued guidelines against the routine use
of Ivermectin in the treatment of COVID-19 except in clinical trial settings.
The MOH has initiated a RCT using Ivermectin among the
severe COVID-19 patients which will only complete by September 2021.
The MAECC is actively pursuing Ivermectin to be
included as routine drug in the prophylaxis and treatment of COVID-19. The
MAECC has a large of followers, including clinicians and patients.
There was even a police report launched against the
Ministry of Health for not approving Ivermectin in the treatment of COVID-19.
Most of the justifications in proposing Ivermectin as
prophylaxis and treatment for COVID-19 presented were from randomized controlled
trial (RCTs) or systematic reviews of low quality. Among the RCTs, there are
considerable heterogeneity in the population receiving Ivermectin who were
family contacts of confirmed COVID-19 cases as a prophylactic measure, mild to
moderate infected or severe hospitalized patients using Ivermectin for
treatment.
Applied doses and outcomes of interest were also highly
variable. Additionally, patients in the control groups received different kinds
of comparators ranging from placebo or no intervention to standard care or even
hydroxychloroquine.
The sample sizes of these RCTs were also small. Most
of the RCTs were not registered with the Trial Registration Platform and were in the form of pre-prints, not peer reviewed
nor published in journals.
Registering clinical trials before they begin and
making results peer reviewed overcome publication and selective outcome
reporting biases.
I would like to share a latest high quality RCT
published in the Journal of American Medical Association (JAMA)
(doi:10.1001/jama.2021.3071).
The trial was among 400 patients with mild COVID-19,
with Ivermectin of 300 ug/kg of body weight per day for five days or placebo,
with the primary outcome as the time to resolution of symptoms within a 21 days
follow up period.
The results showed that by day 21, 82% of the Ivermectin
and 79% of the placebo groups had resolved symptoms. The conclusion is that
among the adults with mild COVID-19, a five-day course of Ivermectin, compared
with placebo, did not significantly improve the time to resolution of symptoms.
The findings do not support the use of Ivermectin for treatment of mild
COVID-19.
The highest level of evidence comes from systematic
review with meta-analysis from RCTs, however the quality of evidence generated
depends greatly on the quality of the included RCTs.
There is a latest systematic review and meta-analysis
(doi:10.1097/MJT.0000000000001402) published in the American Journal of
Therapeutics, reported that Ivermectin reduced risk of death computed with no
Ivermectin (average risk ratio of 0.38, 95% confidence interval 0.19-0.73;
n=2438) with moderate-certainty evidence)
However, when we read the full text, it was found that
there are many issues which are of concern.
This review included a total of 24 trials (with 21
RCTs and three quasi-RCT). The included patients were widely variable:
asymptomatic, mild and moderate infected individuals who were outpatients, or
inpatients; severe hospitalized patients were included in the treatment modality; while healthcare workers, health
care worker’s family members and close contact were included for prophylaxis
purpose.
The intervention was Ivermectin with widely variable
doses and treatment duration, while the comparison had either placebo, standard
of care (SOC) only, placebo and SOC, Ritonavir/lopinaviror etc.
The primary outcome was all cause mortality, while the
secondary outcomes were improvement or deterioration of COVID-19 symptoms, but
how these outcomes were derived were unclear.
Among the included trials, only eight were peer
reviewed (published), the rest were from pre-print or communication with researchers.
Although there was mentioned of “most trials were
registered”, the evidence was not presented.
Sources of funding were not reported among ten trials,
with three trials were pharma sponsored and the rest either self-funded or
institution funded.
On the results, sub-group analyses were carried out
for mild to moderate and severe COVID patients separately and the results for
these sub-groups were either not significant or marginally significant with wide
confidence intervals.
However, the authors pooled all sub-groups and
presented the pool results giving “more precise and significant estimates”,
with high heterogeneity (up to 60%).
The authors claimed that the findings indicate with
moderate certainty that Ivermectin treatment in COVID-19 provides a significant
survival benefit from pool estimates for all sub-groups.
Considering all the above, I considered the evidence
to be of low quality and there is insufficient evidence from the review to
recommend Ivermectin as treatment or prophylaxis for COVID-19 infection.
In conclusion, most of the current research related to
Ivermectin in COVID-19 has serious methodological limitations resulting in very
low certainty of the evidence.
Recommendation in using this drug for prophylaxis or
treatment for COVID-19 should be based on trustworthy evidence, with proven
patients’ safety and efficacy.
More RCTs which are well planned and peer reviewed,
without conflict of interest, ethically approved are required.
Source :
https://www.sinchew.com.my/content/content_2498865.html?fbclid=IwAR3EMOaanhUqXvVuEXM2uY59yJDzOcsPWvYrc_mcwbSKKfUjjHtYNpgXOH0