nothing you don't already know:
NEW & NOTEWORTHY Active forms of vitamin D and lumisterol can inhibit
SARS-CoV-2 replication machinery enzymes, which indicates that novel
vitamin D and lumisterol metabolites are candidates for antiviral drug
research.
https://journals.physiology.org/doi/full/10.1152/ajpendo.00174.2021
<https://forum.cigar.com/home/leaving?allowTrusted=1&target=https%3A%2F%2Fjournals.physiology.org%2Fdoi%2Ffull%2F10.1152%2Fajpendo.00174.2021>
On Wed, Sep 8, 2021 at 7:41 PM Domingo Pichardo <dmarc-noreply@xxxxxxxxxxxxx>
wrote:
Therapeutic Advances:
Meta-analysis of 15 trials found that ivermectin reduced risk of death
compared with no ivermectin (average risk ratio 0.38, 95% confidence
interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence).
This result was confirmed in a trial sequential analysis using the same
DerSimonian–Laird method that underpinned the unadjusted analysis. This was
also robust against a trial sequential analysis using the
Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin
prophylaxis reduced COVID-19 infection by an average 86% (95% confidence
interval 79%–91%). Secondary outcomes provided less certain evidence.
Low-certainty evidence suggested that there may be no benefit with
ivermectin for “need for mechanical ventilation,” whereas effect estimates
for “improvement” and “deterioration” clearly favored ivermectin use.
Severe adverse events were rare among treatment trials and evidence of no
difference was assessed as low certainty. Evidence on other secondary
outcomes was very low certainty.
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths
are possible using ivermectin. Using ivermectin early in the clinical
course may reduce numbers progressing to severe disease. The apparent
safety and low cost suggest that ivermectin is likely to have a significant
impact on the SARS-CoV-2 pandemic globally.
*Keywords: *ivermectin, prophylaxis, treatment, COVID-19, SARS-CoV-2
.
Just consider all the lives and suffering we could have avoided if only
money and power were not the Gods we worship!
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths
are possible using ivermectin. Using ivermectin early in the clinical
course may reduce numbers progressing to severe disease. The apparent
safety and low cost suggest that ivermectin is likely to have a significant
impact on the SARS-CoV-2 pandemic globally.
Ivermectin for Prevention and Treatment of COVID-19 Infection: A
Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform
Clinical Guidelines
Andrew Bryant
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Bryant%20A%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
MSc,1,* Theresa A. Lawrie
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Lawrie%20TA%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
MBBCh, PhD,2 Therese Dowswell
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Dowswell%20T%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
PhD,2 Edmund J. Fordham
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Fordham%20EJ%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
PhD,2 Scott Mitchell
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Mitchell%20S%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
MBChB, MRCS,3 Sarah R. Hill
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Hill%20SR%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
PhD,1 and Tony C. Tham
<https://www.ncbi.nlm.nih.gov/pubmed/?term=Tham%20TC%5BAuthor%5D&cauthor=true&cauthor_uid=34145166>,
MD, FRCP4
Author information
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#> Copyright and
License information
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#> Disclaimer
<https://www.ncbi.nlm.nih.gov/pmc/about/disclaimer/>
This article has been cited by
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/citedby/> other
articles in PMC.
Go to: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#>
Background:
Repurposed medicines may have a role against the SARS-CoV-2 virus. The
antiparasitic ivermectin, with antiviral and anti-inflammatory properties,
has now been tested in numerous clinical trials.
Areas of uncertainty:
We assessed the efficacy of ivermectin treatment in reducing mortality, in
secondary outcomes, and in chemoprophylaxis, among people with, or at high
risk of, COVID-19 infection.
Data sources:
We searched bibliographic databases up to April 25, 2021. Two review
authors sifted for studies, extracted data, and assessed risk of bias.
Meta-analyses were conducted and certainty of the evidence was assessed
using the GRADE approach and additionally in trial sequential analyses for
mortality. Twenty-four randomized controlled trials involving 3406
participants met review inclusion.
Therapeutic Advances:
Meta-analysis of 15 trials found that ivermectin reduced risk of death
compared with no ivermectin (average risk ratio 0.38, 95% confidence
interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence).
This result was confirmed in a trial sequential analysis using the same
DerSimonian–Laird method that underpinned the unadjusted analysis. This was
also robust against a trial sequential analysis using the
Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin
prophylaxis reduced COVID-19 infection by an average 86% (95% confidence
interval 79%–91%). Secondary outcomes provided less certain evidence.
Low-certainty evidence suggested that there may be no benefit with
ivermectin for “need for mechanical ventilation,” whereas effect estimates
for “improvement” and “deterioration” clearly favored ivermectin use.
Severe adverse events were rare among treatment trials and evidence of no
difference was assessed as low certainty. Evidence on other secondary
outcomes was very low certainty.
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths
are possible using ivermectin. Using ivermectin early in the clinical
course may reduce numbers progressing to severe disease. The apparent
safety and low cost suggest that ivermectin is likely to have a significant
impact on the SARS-CoV-2 pandemic globally.
*Keywords: *ivermectin, prophylaxis, treatment, COVID-19, SARS-CoV-2
Go to: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#>
INTRODUCTION
To date, very few treatments have been demonstrated to reduce the burden
of morbidity and mortality from COVID-19. Although corticosteroids have
been proven to reduce mortality in severe disease,1
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R1> there has been
little convincing evidence on interventions that may prevent disease,
reduce hospitalizations, and reduce the numbers of people progressing to
critical disease and death.
Ivermectin is a well-known medicine that is approved as an antiparasitic
by the World Health Organization and the US Food and Drug Administration.
It is widely used in low- and middle-income countries (LMICs) to treat worm
infections.2 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R2>,3
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R3> Also used for
the treatment of scabies and lice, it is one of the World Health
Organization’s Essential Medicines.4
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R4> With total
doses of ivermectin distributed apparently equaling one-third of the
present world population,5
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R5> ivermectin at
the usual doses (0.2–0.4 mg/kg) is considered extremely safe for use in
humans.6 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R6>,7
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R7> In addition to
its antiparasitic activity, it has been noted to have antiviral and
anti-inflammatory properties, leading to an increasing list of therapeutic
indications.8 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R8>
Since the start of the SARS-CoV-2 pandemic, both observational and
randomized studies have evaluated ivermectin as a treatment for, and as
prophylaxis against, COVID-19 infection. A review by the Front Line
COVID-19 Critical Care Alliance summarized findings from 27 studies on the
effects of ivermectin for the prevention and treatment of COVID-19
infection, concluding that ivermectin “demonstrates a strong signal of
therapeutic efficacy” against COVID-19.9
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R9> Another recent
review found that ivermectin reduced deaths by 75%.10
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R10> Despite these
findings, the National Institutes of Health in the United States recently
stated that “there are insufficient data to recommend either for or against
the use of ivermectin for the treatment of COVID-19,”11
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R11> and the World
Health Organization recommends against its use outside of clinical trials.
12 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R12>
Ivermectin has exhibited antiviral activity against a wide range of RNA
and some DNA viruses, for example, Zika, dengue, yellow fever, and others.
13 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R13> Caly et al
14 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R14> demonstrated
specific action against SARS-CoV-2 in vitro with a suggested host-directed
mechanism of action being the blocking of the nuclear import of viral
proteins14 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R14>,15
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R15> that suppress
normal immune responses. However, the necessary cell culture EC50 may not
be achievable in vivo*.*16
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R16> Other
conjectured mechanisms include inhibition of SARS-CoV-2 3CLPro activity17
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R17>,18
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R18> (a protease
essential for viral replication), a variety of anti-inflammatory effects,
19 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R19> and
competitive *binding* of ivermectin with the viral S protein as shown in
multiple *in silico* studies.20
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R20> The latter
would inhibit viral binding to ACE-2 receptors suppressing infection.
Hemagglutination via viral binding to sialic acid receptors on erythrocytes
is a recently proposed pathologic mechanism21
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R21> that would be
similarly disrupted. Both host-directed and virus-directed mechanisms have
thus been proposed, the clinical mechanism may be multimodal, possibly
dependent on disease stage, and a comprehensive review of mechanisms of
action is warranted.
Developing new medications can take years; therefore, identifying existing
drugs that can be repurposed against COVID-19 that already have an
established safety profile through decades of use could play a critical
role in suppressing or even ending the SARS-CoV-2 pandemic. Using
repurposed medications may be especially important because it could take
months, possibly years, for much of the world's population to get
vaccinated, particularly among LMIC populations.
Currently, ivermectin is commercially available and affordable in many
countries globally.6
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R6> A 2018
application for ivermectin use for scabies gives a direct cost of $2.90 for
100 12-mg tablets.22
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R22> A recent
estimate from Bangladesh23
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R23> reports a
cost of US$0.60—US$1.80 for a 5-day course of ivermectin. For these
reasons, the exploration of ivermectin's potential effectiveness against
SARS-CoV-2 may be of particular importance for settings with limited
resources.24 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R24> If
demonstrated to be effective as a treatment for COVID-19, the
cost-effectiveness of ivermectin should be considered against existing
treatments and prophylaxes.
The aim of this review was to assess the efficacy of ivermectin treatment
among people with COVID-19 infection and as a prophylaxis among people at
higher risk of COVID-19 infection. In addition, we aimed to prepare a brief
economic commentary (BEC) of ivermectin as treatment and as prophylaxis for
COVID-19.25 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R25>
Repurposed medicines may have a role against the SARS-CoV-2 virus. The
antiparasitic ivermectin, with antiviral and anti-inflammatory properties,
has now been tested in numerous clinical trials.
Areas of uncertainty:
We assessed the efficacy of ivermectin treatment in reducing mortality, in
secondary outcomes, and in chemoprophylaxis, among people with, or at high
risk of, COVID-19 infection.
Data sources:
We searched bibliographic databases up to April 25, 2021. Two review
authors sifted for studies, extracted data, and assessed risk of bias.
Meta-analyses were conducted and certainty of the evidence was assessed
using the GRADE approach and additionally in trial sequential analyses for
mortality. Twenty-four randomized controlled trials involving 3406
participants met review inclusion.
Therapeutic Advances:
Meta-analysis of 15 trials found that ivermectin reduced risk of death
compared with no ivermectin (average risk ratio 0.38, 95% confidence
interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence).
This result was confirmed in a trial sequential analysis using the same
DerSimonian–Laird method that underpinned the unadjusted analysis. This was
also robust against a trial sequential analysis using the
Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin
prophylaxis reduced COVID-19 infection by an average 86% (95% confidence
interval 79%–91%). Secondary outcomes provided less certain evidence.
Low-certainty evidence suggested that there may be no benefit with
ivermectin for “need for mechanical ventilation,” whereas effect estimates
for “improvement” and “deterioration” clearly favored ivermectin use.
Severe adverse events were rare among treatment trials and evidence of no
difference was assessed as low certainty. Evidence on other secondary
outcomes was very low certainty.
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths
are possible using ivermectin. Using ivermectin early in the clinical
course may reduce numbers progressing to severe disease. The apparent
safety and low cost suggest that ivermectin is likely to have a significant
impact on the SARS-CoV-2 pandemic globally.
*Keywords: *ivermectin, prophylaxis, treatment, COVID-19, SARS-CoV-2
Go to: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#>
METHODS
The conduct of this review was guided by a protocol that was initially
written using Cochrane's rapid review template and subsequently expanded to
a full protocol for a comprehensive review.26
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R26>
Search strategy and selection criteria
Two reviewers independently searched the electronic databases of Medline,
Embase, CENTRAL, Cochrane COVID-19 Study Register, and Chinese databases
for randomized controlled trials (RCTs) up to April 25, 2021 (see *Appendix
1–3*, *Supplemental digital content 1*, http://links.lww.com/AJT/A95);
current guidance25
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R25> for the BEC
was followed for a supplementary search of economic evaluations. There were
no language restrictions, and translations were planned to be performed
when necessary.
We searched the reference list of included studies, and of two other 2021
literature reviews on ivermectin,9
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R9> as well as the
recent WHO report, which included analyses of ivermectin.12
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R12> We contacted
experts in the field (Drs. Andrew Hill, Pierre Kory, and Paul Marik) for
information on new and emerging trial data. In addition, all trials
registered on clinical trial registries were checked, and trialists of 39
ongoing trials or unclassified studies were contacted to request
information on trial status and data where available. Many preprint
publications and unpublished articles were identified from the preprint
servers MedRχiv and *Research Square*, and the International Clinical
Trials Registry Platform. This is a rapidly expanding evidence base, so the
number of trials are increasing quickly. Reasons for exclusion were
recorded for all studies excluded after full-text review.
Data analysis
We extracted information or data on study design (including methods,
location, sites, funding, study author declaration of interests, and
inclusion/exclusion criteria), setting, participant characteristics
(disease severity, age, gender, comorbidities, smoking, and occupational
risk), and intervention and comparator characteristics (dose and frequency
of ivermectin/comparator). The primary outcome for the intervention
component of the review included death from any cause and presence of
COVID-19 infection (as defined by investigators) for ivermectin
prophylaxis. Secondary outcomes included time to polymerase chain reaction
(PCR) negativity, clinical recovery, length of hospital stay, admission to
hospital (for outpatient treatment), admission to ICU or requiring
mechanical ventilation, duration of mechanical ventilation, and severe or
serious adverse events, as well as post hoc assessments of improvement and
deterioration. All of these data were extracted as measured and reported by
investigators. Numerical data for outcomes of interest were extracted
according to intention to treat.
If there was a conflict between data reported across multiple sources for
a single study (eg, between a published article and a trial registry
record), we contacted the authors for clarification. Assessments were
conducted by 2 reviewers (T.L., T.D., A.B., or G.G.) using the Cochrane RCT
risk-of-bias tool.27
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R27> Discrepancies
were resolved by discussion.
Continuous outcomes were measured as the mean difference and 95%
confidence intervalss (CI), and dichotomous outcomes as risk ratio (RR) and
95% CI.
We did not impute missing data for any of the outcomes. Authors were
contacted for missing outcome data and for clarification on study methods,
where possible, and for trial status for ongoing trials.
We assessed heterogeneity between studies by visual inspection of forest
plots, by estimation of the I2 statistic (I2 ≥60% was considered
substantial heterogeneity),28
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R28> by a formal
statistical test to indicate statistically significant heterogeneity,29
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R29> and, where
possible, by subgroup analyses (see below). If there was evidence of
substantial heterogeneity, the possible reasons for this were investigated
and reported. We assessed reporting biases using funnel plots if more than
10 studies contributed to a meta-analysis.
We meta-analyzed data using the random effects model (DerSimonian and
Laird method)30
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R30> using RevMan
5.4.1 software.27
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R27>,31
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R31> The results
used the inverse variance method for weighting.27
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R27> Some
sensitivity analyses used other methods that are outlined below and some
calculations were performed in *R*32
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R32> through an
interface33 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R33> to
the *netmeta* package.34
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R34> Where
possible, we performed subgroup analyses grouping trials by disease
severity, inpatients versus outpatients, and single dose versus multiple
doses. We performed sensitivity analyses by excluding studies at high risk
of bias. We conducted further post hoc sensitivity analyses using
alternative methods to test the robustness of results in the presence of
zero events in both arms in a number of trials35
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R35> and estimated
odds ratios [and additionally RR for the Mantel–Haenszel (MH) method] using
a fixed effects model. The models incorporate evidence from single-zero
studies without having to resort to continuity corrections. However,
double-zero studies are excluded from the analysis; so, the risk difference
was also assessed using the MH method as this approach can adequately
incorporate trials with double-zero events. This method can also use a
random-effects component. A “treatment-arm” continuity correction was used,
where the values 0.01, 0.1, and 0.25 were added where trials reported zero
events in both arms. It has been shown that a nonfixed continuity
correction is preferable to the usual 0.5.35
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R35> Other methods
are available but were not considered due to difficulty in interpretation,
sensitivity of assumptions, or the fact they are rarely used in practice.
36 <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R36>–40
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R40>
Trial sequential analysis
When a meta-analysis is subjected to repeated statistical evaluation,
there is an exaggerated risk that “naive” point estimates and confidence
intervals will yield spurious inferences. In a meta-analysis, it is
important to minimize the risk of making a false-positive or false-negative
conclusion. There is a trade-off between the risk of observing a
false-positive result (type I error) and the risk of observing a
false-negative result (type II error). Conventional meta-analysis methods
(eg, in RevMan) also do not take into account the amount of available
evidence. Therefore, we examined the reliability and conclusiveness of the
available evidence using trial sequential analyses (TSA).41
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R41>–43
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R43> The
DerSimonian–Laird (DL) method was used because this is most often used in
meta-analytic practice and was also used in the primary meta-analysis.30
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R30>
The TSA was used to calculate the required information size (IS) to
demonstrate or reject a relative reduction in the risk (RRR) of death in
the ivermectin group, as found in the primary meta-analysis. We assumed the
estimated event proportion in the control group from the meta-analysis
because this is the best and most representative available estimate.
Recommended type I and II error rates of 5% and 10% were used, respectively
(power of 90%),43
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R43> powering the
result on the effect observed in the primary meta-analyses. We did not
identify any large COVID-19 trials powered on all-cause mortality, so
powering on some external meaningful difference was not possible. Any small
RRR is meaningful in this context, given the scale of the pandemic, but the
required IS would be unfeasibly high for this analysis if powered on a
small difference. The only reliable data on ivermectin in its repurposed
role for treatment against COVID-19 will be from the primary meta-analysis.
Therefore, assuming it does not widely deviate from other published
systematic reviews, a pragmatic decision was therefore made to power on the
pooled meta-analysis effect estimate for all-cause mortality a priori. This
is more reflective of a true meaningful difference. We used a model
variance-based estimate to correct for heterogeneity. A continuity
correction of 0.01 was used in trials that reported zero events in one or
both arms. The required IS is the sample size required for a reliable and
conclusive meta-analysis and is at least as large as that needed in a
single powered RCT. The heterogeneity corrected required IS was used to
construct sequential monitoring boundaries based on the O'Brien–Fleming
type alpha-spending function for the cumulative z-scores (corresponding to
the cumulative meta-analysis),43
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R43> analogous to
interim monitoring in an RCT, to determine when sufficient evidence had
been accrued. These monitoring boundaries are relatively insensitive to the
number of repeated significance tests. They can be used to further
contextualize the original meta-analysis and enhance our certainty around
its conclusions. We used a two-sided test, so also considered futility
boundaries (to test for no statistically significant difference) and the
possibility that ivermectin could harm. Sensitivity analyses were performed
excluding the trial of Fonseca,44
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R44> which was a
cause of substantial heterogeneity (but retained in the core analysis
because it was at low risk of bias). Its removal dramatically reduced I2 and
D2 (diversity) estimates, thus reducing the model variance-based estimate
to correct for heterogeneity. Two further sensitivity analyses were
performed using 2 alternative random effect models, namely the
Biggerstaff–Tweedie (BT) and Sidik–Jonkman (SJ) methods.43
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R43>
All outcomes have been assessed independently by 2 review authors (T.D.
and A.B.) using the GRADE approach,45
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R45> which ranks
the quality and certainty of the evidence. The results of the TSAs will
also form part of the judgment for the primary all-cause mortality outcome.
The results are presented in a summary of findings table. Any differences
in judgments were resolved by discussion with the wider group. We used
Cochrane Effective Practice and Organisation of Care guidance to interpret
the evidence.46
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R46>
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systema...
Repurposed medicines may have a role against the SARS-CoV-2 virus. The
antiparasitic ivermectin, with antiviral ...
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#R46>
Go to: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#>
Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systema...
Repurposed medicines may have a role against the SARS-CoV-2 virus. The
antiparasitic ivermectin, with antiviral ...
<https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248252/#>
Background:
Repurposed medicines may have a role against the SARS-CoV-2 virus. The
antiparasitic ivermectin, with antiviral and anti-inflammatory properties,
has now been tested in numerous clinical trials.
Areas of uncertainty:
We assessed the efficacy of ivermectin treatment in reducing mortality, in
secondary outcomes, and in chemoprophylaxis, among people with, or at high
risk of, COVID-19 infection.
Data sources:
We searched bibliographic databases up to April 25, 2021. Two review
authors sifted for studies, extracted data, and assessed risk of bias.
Meta-analyses were conducted and certainty of the evidence was assessed
using the GRADE approach and additionally in trial sequential analyses for
mortality. Twenty-four randomized controlled trials involving 3406
participants met review inclusion.
Therapeutic Advances:
Meta-analysis of 15 trials found that ivermectin reduced risk of death
compared with no ivermectin (average risk ratio 0.38, 95% confidence
interval 0.19–0.73; n = 2438; I2 = 49%; moderate-certainty evidence).
This result was confirmed in a trial sequential analysis using the same
DerSimonian–Laird method that underpinned the unadjusted analysis. This was
also robust against a trial sequential analysis using the
Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin
prophylaxis reduced COVID-19 infection by an average 86% (95% confidence
interval 79%–91%). Secondary outcomes provided less certain evidence.
Low-certainty evidence suggested that there may be no benefit with
ivermectin for “need for mechanical ventilation,” whereas effect estimates
for “improvement” and “deterioration” clearly favored ivermectin use.
Severe adverse events were rare among treatment trials and evidence of no
difference was assessed as low certainty. Evidence on other secondary
outcomes was very low certainty.
Conclusions:
Moderate-certainty evidence finds that large reductions in COVID-19 deaths
are possible using ivermectin. Using ivermectin early in the clinical
course may reduce numbers progressing to severe disease. The apparent
safety and low cost suggest that ivermectin is likely to have a significant
impact on the SARS-CoV-2 pandemic globally.
*Keywords: *
A true lover of wisdom has hands too busy to hold on to anything! He
learns by doing and every pebble in the path becomes her teacher! Oink
