413 - Ivermectin and COVID, COVID Booster Follow-up, Diabetes Screening
Take 3 – Practical Practice Pointers©
From the Literature – Another Cautionary Tale
1) The Story of Ivermectin and the Importance of Critical Appraisal
Ivermectin has continued to be a controversial agent for both prevention and treatment of COVID-19. It was promoted early in the pandemic by the group Front Line COVID-19 Critical Care Alliance, though they have not updated their review since January 2021. Four systematic reviews (Hill, et al., Bryant, et al., Roman et al., and Popp, et al.) of ivermectin’s effect on mild-moderate COVID-19 have been published recently that differ in their conclusions and illustrate a need to remain critical of our information sources at a time when they are multiplying rapidly.
The Hill systematic review and meta-analysis looked at the treatment of COVID-19 only. It included 24 RCTs and 3328 subjects (search date May 2021) and assessed all-cause mortality as the primary outcome in addition to viral clearance, inflammatory markers, and clinical recovery. The research team identified 25% of their studies as having a high-risk of bias for the primary outcome, but curiously, this group did not include a study that was subsequently retracted by the pre-print service it was published on for “ethical concerns” and possible fictitious data. Hill found a significant benefit on all-cause mortality attributable to ivermectin, but because much of this effect was due to the retracted study, a re-analysis is planned.
Bryant, et al. (search date April 2021) looked at ivermectin for both treatment and prevention of COVID-19 in a systematic review involving 22 studies and 2668 subjects for the treatment outcomes and 3 studies with 738 participants for the prevention outcomes. This was a detailed systematic review that had no obvious methodologic flaws but is criticized for its decision to include low-quality studies, and active comparator studies. It also included the retracted study noted above. The analysis found a benefit to ivermectin that was robust to several sensitivity analyses intended to account for risk of bias and heterogeneity.
Both Hill, et al. and Bryant, et al. included studies that compared ivermectin to other studied agents – other antibiotics, antivirals, hydroxychloroquine, etc. Roman, et al. was a carefully done systematic review that included only 10 studies (1173 subjects) because of strict inclusion criteria that narrowed the field to studies with placebo or usual care controls and only focused on studies of treatment of COVID-19. This review found no mortality or length-of-stay benefit to ivermectin.
The official Cochrane systematic review by Popp, et al. was also more restrictive about study quality and control arms. It used the strict Cochrane methodology and limited the studies to those with placebo or usual care controls. Fourteen studies with 1678 participants failed to find any convincing effects of ivermectin in the treatment of COVID-19. This review noted there were another 49 trials in various stages of completion, so we will continue to get data on this question for some time.
Validity matters. Carefully done trials with the appropriate controls are the answer to understanding the benefit of interventions. In the early pandemic, it is only natural that we would search for any promising therapy to counter the devastating effects of a new, rapidly-spreading virus. However, at some point, continuing to include low-quality studies or studies with inappropriate comparators in systematic reviews is asking to be misdirected. These sorts of biases increase the likelihood that the benefit of an intervention is overestimated. If we want the real answer, we must test the hypotheses in the best ways we know how, then act according to the answers we get. In this case, we have no justification for the use of ivermectin outside of a clinical trial.
- Hill A, Garratt A, Levi J, Falconer J, Ellis L, McCann K, et al. A correction has been published: Meta-analysis of randomized trials of ivermectin to treat SARS-CoV-2 infection. Open Forum Infectious Diseases [Internet]. 2021 Jul 6 [cited 2021 Aug 16];(ofab358). Link
- Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, et al. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. American Journal of Therapeutics. 2021 Aug;28(4):e434. Link
- Popp M, Stegemann M, Metzendorf M-I, Gould S, Kranke P, Meybohm P, et al. Ivermectin for preventing and treating COVID-19. Cochrane Database Syst Rev. 2021 Jul 28;7:CD015017. Link
- Roman YM, Burela PA, Pasupuleti V, Piscoya A, Vidal JE, Hernandez AV. Ivermectin for the Treatment of Coronavirus Disease 2019: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clinical Infectious Diseases [Internet]. 2021 Jun 28 [cited 2021 Aug 23];(ciab591). Link
A Question From a Colleague, and Then Some Additional Questions
2) COVID-Vaccine Booster Dose Follow-up
With the new recommendations regarding a COVID booster vaccine for those who are immunocompromised, what is the guidance regarding the mixing of vaccine products?
On August 20th the CDC updated their guidance regarding this.
- For people who received either Pfizer-BioNTech or Moderna’s COVID-19 vaccine series, a third dose of the same mRNA vaccine should be used.
- A person should not receive more than three mRNA vaccine doses.
- If the mRNA vaccine product given for the first two doses is not available or is unknown, either mRNA COVID-19 vaccine product may be administered.
What should immunocompromised people who received the J&J/Janssen vaccine do?
The FDA’s recent EUA amendment only applies to mRNA COVID-19 vaccines, as does CDC’s recommendation. There is not enough data at this time to determine whether immunocompromised people who received the Johnson & Johnson’s Janssen COVID-19 vaccine also have an improved antibody response following an additional dose of the same vaccine.
One More Question:
Can people who received Johnson & Johnson’s Janssen (J&J/Janssen) COVID-19 Vaccine get a booster dose of an mRNA vaccine?
No, there aren’t enough data currently to support getting an mRNA vaccine dose (either Pfizer-BioNTech or Moderna) if someone has gotten a J&J/Janssen vaccine. People who got the J&J/Janssen vaccine will likely need a booster dose, and more data are expected in the coming weeks. With those data in hand, CDC will keep the public informed with a timely plan for J&J/Janssen booster shots.
To emphasize, the booster guidance applies only to mRNA vaccines, only to the third dose, and that the same product is preferred but if that product isn’t available or you don’t know which one was given, you can use the product you have. And we know this whole area is evolving rapidly, so stay tuned for regular updates.
From the US Preventive Services Task Force (USPSTF)
3) Screening for Diabetes Overweight/Obese Adults
According to the CDC 2020 National Diabetes Statistics Report, an estimated 13% of all US adults (18 years or older) have diabetes, and 35% meet criteria for prediabetes. Of persons with diabetes, 21% were not aware of or did not report having diabetes, and only 15% of those with prediabetes reported being told by a health professional that they had this condition. Overweight and obesity are the strongest risk factors for developing prediabetes and type 2 diabetes in adults. The most recent national data indicate that more than 2/3 of US adults have either overweight or obesity.
The USPSTF recently updated its 2015 guidance on screening for type 2 diabetes and prediabetes in overweight and obese adults. The specific recommendation is:
- For adults age 35 – 70 who have overweight (BMI > 25) or obesity (BMI > 30) , screen for prediabetes and type 2 diabetes, and offer or refer patients with prediabetes to effective prevention interventions. Grade B
This recommendation lowers the age to start screening from 40 to 35. Based on the available studies, the USPSTF concluded with moderate certainty that this approach to screening will have a moderate net benefit.
The guidance states that clinicians should consider screening at an even earlier age in persons from groups with disproportionately high incidence and prevalence (American Indian/Alaska Native, Asian American, Black, Hispanic/Latino, or Native Hawaiian/Pacific Islanders) or in persons who have a family history of diabetes, a history of gestational diabetes, or a history of polycystic ovarian syndrome. Data suggest that a BMI of > 23 may be an appropriate cut point in Asian Americans.
Lifestyle interventions that focus on diet, physical activity, or both and metformin have demonstrated efficacy in preventing or delaying progression to diabetes in persons with prediabetes. However, metformin has not been approved for this specific indication by the FDA and has not been shown to improve blood pressure or lipid levels.
Evidence on the optimal screening interval for adults with an initial normal glucose test result is limited. Cohort and modeling studies suggest that screening every 3 years may be a reasonable approach for adults with a normal initial screening test.
The USPSTF recommendations are similar to the American Diabetes Association (ADA) 2021 Standards of Medical Care in Diabetes advice to screen all adults 45 and older for diabetes regardless of body-mass index (BMI), and to screen adults younger than 45 if they have a BMI of 25 or higher and at least one additional diabetes risk factor.
The data in the first paragraph above is simply stunning, yet because it has literally become the norm it is often not viewed as the healthcare concern that it is. And sadly, the US is not alone. The World Health Organization indicates that an escalating global epidemic of overweight and obesity – “globesity” – is taking over many parts of the world, paradoxically coexisting with undernutrition. Of course, part of our challenge is that our own culture often seems to be working against us, yet we are called to do what we can to identify those at risk and teach, encourage, and model healthy lifestyle choices. And awareness raising through screening can be an important step in this process.
Mark and John
Carilion Clinic Department of Family and Community Medicine
Feel free to forward Take 3 to your colleagues. Glad to add them to the distribution list.