Deconstructing PPI-Associated Risks with Nearly 8 Billion Data Points and More on COVID-19 GI Symptoms (Video)

Link: 22 minute video —COVID-19 and the GI Tract -What We Know Right Now

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A recent study (C Ma et al. Gastroenterol 2020; 158: 780-82) used cross-sectional data from the National Ambulatory Medical Care Survey (NAMCS) (2006-2015) with a total 7,872,115,883 weighted observations.  They used this data to evaluate medication exposures and outcomes.

Key findings:

  • There was no association between PPI use and dementia, pneumonia, or intestinal infections.  There was a trend towards intestinal infections (AOR 1.48, CI 0.80-2.71) but this did not reach statistical significance. “Sensitivity analysis showed an association between PPI use and C difficile.”
  • There was an association with chronic kidney disease (CKD) (AOR 1.26); however, this was seen with a multitude of drug classes including statins, calcium channel blockers, and beta-blockers.

Discussion:

  • This study notes that a recent large randomized controlled trial found no statistically significant differences between those receiving PPIs and those receiving placebo except for intestinal infections.
  • With regard to CKD, “it is extremely unlikely that all of these medications increase the risk of CKD, and therefore, it is likely that these findings are due to residual confounding.”

My take: With the exception of C difficile/intestinal infections, this study provides further evidence of the safety of PPIs and a lack of association between these medications and purported PPI-related adverse events.  That said, it is still a good idea to limit use for appropriate indications.

Related blog posts:


Also, IOIBD recommendations for IBD patients and COVID-19 have been published.

Here is link as well:

IOIBD (International Organization for the Study of Inflammatory Bowel Disease) Recommendations (#76) for IBD Patients with Regard to COVID-19:

Full link: IOIBD Update on COVID19 for Patients with Crohn’s Disease and Ulcerative Colitis (3/26/20)

 

C difficile three-fer: Overdiagnosis with Multiplex Testing, Fidaxomicin Pediatric Approval, & Changing Incidence

Queen Elizabeth II -picture for the pandemic

JM Cotter et al. (J Pediatr 2020; 218: 157-65) reviewed 1214 C difficile positive results from a total of 6841 C difficile tests 2013-15 & 2015-17). Key findings:

  • In the later era of multiplex tests, there was a much higher rate of C difficile detection (1.7-2.3 times higher) and a much higher rate of detection.
  • However, 31% of the multiplex tests identified another organism which indicates a high likelihood of a false-positive test (C difficile colonization)
  • Many of these “C difficile infections” were detected simply due to ease of test ordering.  In addition, the test results should be viewed with suspicion particularly in low-risk individuals.
  • Nearly one-third of the C difficile infected patients were oncology patients who are known to have high rates of asymptomatic colonization.
  • In patients known to have high risk of asymptomatic colonization (eg. young, oncology, IBD), detection of C difficile infection may lead to anchoring bias resulting in diagnostic delays for other disorders.

My take: We know that we are approaching the diagnosis of C difficile infection the wrong way (see IDSA guidelines below), but it is so quick and easy.

Related blog posts:

  • Clostridium difficile Guidelines The diagnosis of CDI… Molecular tests (eg, nucleic acid amplification tests [NAATs], such as polymerase chain reaction), which do not differentiate colonization and infection, are now the most commonly used test for CDI among US hospitals. NAATs have the potential to misdiagnose patients with colonization as having CDI, particularly when used in patients with low likelihood of CDI. Thus, this guideline strongly reinforces the importance of practicing good diagnostic stewardship and limiting C difficile testing to patients with new-onset, unexplained, and clinically significant (ie, at least 3 unformed stools in a 24-hour period) diarrhea…formed stools should not be tested for C difficile, nor should patients be retested within 7 days of a previous negative C difficile test. In pediatric populations, because of the unclear role of C difficile as a cause of diarrhea in infants, children less than 12 months of age should not be tested…If diagnostic stewardship is not an achievable goal, use of NAAT alone is likely to lead to frequent misdiagnosis of CDI among patients with C difficile colonization. In these cases, NAAT alone should be avoided and a multistep algorithm that incorporates toxin testing is recommended.

From MDEdge Pediatrics: full link: FDA approves fidaxomicin for treatment of C. difficile-associated diarrhea

An excerpt:

Approval [by FDA] was based on results from SUNSHINE, a phase 3, multicenter, investigator-blind, randomized, parallel-group study in 142 pediatric patients aged between 6 months and 18 years with confirmed C. difficile infection who received either fidaxomicin or vancomycin for 10 days. Clinical response 2 days after the conclusion of treatment was similar in both groups (77.6% for fidaxomicin vs. 70.5% for vancomycin), and fidaxomicin had a superior sustained response 30 days after the conclusion of treatment (68.4% vs. 50.0%)…

The fidaxomicin pediatric trial was the first randomized, controlled trial of C. difficile infection treatment in children,” Larry K. Kociolek, MD

AY Guh et al. NEJM 2020; 382: 1320-30. The authors examined the U.S. Burden of CDI by using the Emerging Infections Program (35 counties in 10 states). Key findings:

  • 15,461 cases of CDI in 2011 and 15,5512 in 2017 detected which extrapolates to 476,000 national cases in 2011 and 462,400 national cases in 2017
  • When accounting for increased use of PCR assays, the authors estimate that the C difficile infectious burden decreased by 24% from 2011 to 2017 (due to a drop in health care-associated infections.

My wife has been receiving a lot of compliments for her daily jokes which she decided to post for all of the neighborhood walkers: “If number two pencils are so popular, why are they still number 2?”

What is the Current Standard of Care for PPE and Endoscopy Cases?

CC Thompson et al. Gastointestinal Endoscopy (EPUB), in a letter to the editor, respond to two recent studies on SARS-CoV-2 virus/COVID-19 and provide recommendations for PPE use in this era of COVID-19.

Here’s a link to manuscript: COVID-19 in Endoscopy: Time to do more?

Key points:

  • Reduce non-urgent cases. “We have cut our daily endoscopy volume by over 80% and closed our ambulatory endoscopy practice.”
  • Increase the use of telemedicine. “At present, telemedicine or virtual visits make up 91% of our upcoming clinic appointments.”
  • Physical distancing as advocated recently by WHO throughout a patient’s time in the endoscopy unit is stressed in the papers, with a 6-foot minimum between individuals.
  • Suggests “the need for a separate toilet as part of the isolation to minimize spread of infection due to bioaerosols from the toilet plume”
  • Our hospital system has recently changed policy to mandate that all employees wear surgical masks at all times while in the hospital and attest to their wellness online before reporting to work.
  • We suggest labeling each computer so the same provider uses that computer and chair for the entire day, and separating by at least 6 feet.
  • All endoscopic procedures (upper endoscopy, colonoscopy, EUS, ERCP) are aerosol-generating, referencing studies that show contamination of the endoscopist’s face during routine procedures. This makes all endoscopic procedures high risk from an infectious standpoint, and appropriate PPE is
    recommended… It makes little sense for healthcare providers to perform
    aerosolizing procedures, with patients coughing or passing gas on them, while not wearing an N95 mask or better
  • “It is important to use full PPE for all endoscopic procedures while in a pandemic such as this especially in areas with community spread, because no one is truly low risk given our ongoing difficulties with testing.”
  • “The mask can be reused as long as it is functional, not soiled, and not used in a suspected or COVIDpositive patient. It is important to cover the N95 to prevent soiling.”
  • “A study from China showed that no medical staff working in high-risk departments who wore N95s and practiced strict hand hygiene regardless of patient’s infection status became infected.”
  • “Testing all patients before high-risk procedures such as endoscopy is likely the best approach; however, this will depend on significant expansion of testing capabilities. Hopefully, the development of point-of-care testing with rapid results and increasing testing availability will make this a reality soon”

My take (in part from authors): “We are living through an unprecedented time and are all trying our best to protect our patients and ourselves under suboptimal conditions of limited PPE, limited testing, and limited data. ”  The recommendations in this article are based mainly on expert opinion and may need modifications based on new data and circumstances.

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IOIBD (International Organization for the Study of Iinflammatory Bowel Disease) Recommendations (#76) for IBD Patients with Regard to COVID-19:

Full link: IOIBD Update on COVID19 for Patients with Crohn’s Disease and Ulcerative Colitis (3/26/20)

 

 

How to Do a Colonoscopic Polypectomy & U.S. COVID-19 Tracker

NPR’s website has a good tracker of what is going in each state.  Here’s the link:

NPR: Map: Tracking The Spread Of The Coronavirus In The U.S  One example: on this tracher, in Georgia, March 27, 8:30 am: 1642 reported cases, 56 deaths. (However, Georgia has conducted less than 10,000 tests in a population of more than 10 million).

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A recent review (M Kay, R Wyllie. JPGN 2020; 70: 280-4) provides some practical tips for improving polypectomy technique.

Key points:

The optimal position for the polyp is in the 5-7 o’clock position.

  • Snaring juvenile polyps close to the head rather than close to the colonic wall “allows for easier therapeutic intervention if polypectomy bleeding occurs” (eg. hemoclip) and may lower the risk of complications like perforation
  • Epinephrine volume reduction (for larger polyps) (use 1:10,000 dilution) and saline-assisted polypectomy may facilitate procedure.  Large polyps (>2 cm) could require piecemeal resection; epinephrine reduction may result in a decreased size as well.
  • “Cold snare technique has replaced use of hot biopsy forceps in adults for removal of small sessile polyps”
  • Electrosurgical units (ESUs) -settings are specific to each unit.  Newer ‘smart’ ESUs have suggested default settings, typically lower settings for right colon. “Most endoscopists use pure coagulation current or a combination of coagulation and cutting settings (blended current) for snare polypectomy. Use of pure cutting current without coagulation will result in bleeding.”

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

Pipeline Medications for Ulcerative Colitis (Part 2)

To continue with topic of new medications for ulcerative colitis started yesterday -two more articles:

  • WJ Sandborn et al. Gastroenterol 2020; 158: 537-49
  • S Danese. Gastroenterol 2020; 158: 467-70 (commentary)

The first reference describes a randomized phase 2 study of mirikizumab with 249 patients.  Mirikizumab is a monoclonal antibody to the p19 subunit of IL23. A similar agent, ustekinumab is a monoclonal antibody directed at the p40 subunit of IL23 and IL12; thus mirikuzumab is more selective targeting of IL23. the authors examined response to the study drug at 3 doses: 50 mg, 200 mg, and 600 mg and compared to intravenous placebo.  All patients received dosing at weeks 0, 4, and 8. A subset of patients continued with subcutaneous treatment starting at week 12, with 47 receiving 200 mg every 4 weeks and 46 receiving 200 mg every 12 weeks. 63% of patients in this trial had previous exposure to biologics.

Key findings:

  • At week 12, 15.9% (50 mg), 22.6% (200 mg), and 11.5 % (600 mg) in the treatment groups achieved clinical remission compared to 4.8% of the placebo group
  • Clinical responses occurred in 41.3%, 59.7%, and 49.2% in the respective treatment groups compared to 20.6% in placebo group
  • At week 52, clinical remission was achieved in 46.8% of SC every 4 weeks and 37.0% every 12 weeks.

In the commentary, Danese reviews the pipeline of new drugs emerging for ulcerative colitis.  Full Text Link: New Drugs in the Ulcerative Colitis Pipeline: Prometheus Unbound

A couple of key points:

  • “Like Prometheus, who gave fire to humans and paid with the price of eternal torment, so the gift of new drugs in ulcerative colitis brings the consequence of patients with heterogeneous disease being cycled indiscriminately through similarly modestly effective agents.”
  • “Predictive biomarkers are needed” to optimize treatment and avoid ineffective and potentially harmful treatments

My take: The emergence of new treatments is welcome given the frequent loss of response or lack of response to current therapies.  Two questions: How will we decide which agent(s) is the best one to use? When will pediatric studies be available?

 

 

Pipeline Medications for Ulcerative Colitis (Part 1) & Face Mask Shortages

Before getting to today’s post, I wanted to provide a link on why we are desperately short of face masks in the midst of this crisis: NY Times: How the World’s Richest Country Ran Out of a 75-Cent Face Mask

An excerpt:

The answer to why we’re running out of protective gear involves a very American set of capitalist pathologies — the rise and inevitable lure of low-cost overseas manufacturing, and a strategic failure, at the national level and in the health care industry, to consider seriously the cascading vulnerabilities that flowed from the incentives to reduce costs…

Given the vast global need for masks — in the United States alone, fighting the coronavirus will consume 3.5 billion face masks, according to an estimate by the Department of Health and Human Services — corporate generosity will fall short. People in the mask business say it will take a few months, at a minimum, to significantly expand production…

Hospitals began to run out of masks for the same reason that supermarkets ran out of toilet paper — because their “just-in-time” supply chains, which call for holding as little inventory as possible to meet demand, are built to optimize efficiency, not resiliency.

My take: Conserve, conserve, conserve PPE -supply chains meeting the need is NOT imminent.

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Several articles from Gastroenterology highlight emerging medications for ulcerative colitis (UC).

Two of the studies:

  • WJ Sandborn et al. Gastroenterol 2020; 158: 550-61.
  • WJ Sandborn et al. Gastroenterol 2020; 158: 562-72.

The first study was a phase 2 randomized trial of etrasimod which is an oral selective sphingosine 1-phosphate receptor modulator.  A total of 156 patients were randomized into 3 groups: placebo, 1 mg etrasimod, and 2 mg etrasimod.

Key findings (graphical abstract):

In the second phase 3, double-blind, double-dummy study, Sandborn et al show that, after the initial 2 intravenous doses,  among patients with an initial response subcutaneous vedolizumab (108 mg every 2 weeks) had similar effectiveness to intravenous vedolizumab (300 mg every 8 weeks); both SC and IV vedolizumab resulted in higher clinical remission rates compared to placebo at 52 weeks in the 216 patients: 46.2%, 42.6%, and 14.3% respectively.

Full text link: Efficacy and Safety of Vedolizumab Subcutaneous Formulation in a Randomized Trial of Patients With Ulcerative Colitis

Iron Injectables

At bottom of post, more information on COVID-19.

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At a recent Pharmacy, Nutrition, and Therapeutics (PNT) meeting, one of the topics that we reviewed was injectable iron agents, primarily iron sucrose (Venofer ®) and ferric carboxymaltose (Injectafer®).  Iron dextran is mainly used as a supplement in parenteral nutrition in our patient population.

Also, this topic is reviewed in Practical Gastroenterology Jan 2020 (M Auerbach et al. January 2020 • Volume XLIV, Issue 1: Treatment of Iron Deficiency in Gastroenterology: A New Paradigm

Key points:

  • Venofer® is much less expensive and currently has an FDA indication for children. To provide 1500 mg, Venofer®, 5 doses of 300 mg (~$75/dose)~$375. Injectafer®, 2 doses of 750 mg (~$600/dose) ~1200.  This does not include potential travel and other ancillary costs.
  • Dosing: Injectafer® can give large amounts of iron; in adults, typical dose is 750 mg given 7 days apart (in children 15 mg/kg/dose with 750 mg max).  FDA approved method is to administer over 15 minutes. Venofer® in children is 5-7 mg/kg/dose with 300 mg max per dose.
  • Injectafer® has been associated with hypophosphatemia (in 27%, <2 mg/dL); Hypophosphatemia has also been reported with iron sucrose.  The reported incidence of hypophosphatemia is higher with ferric carboxymaltose vs iron sucrose.
  • Other Adverse Effects
Iron Sucrose (Venofer®) Ferric Carboxy (Injectafer®)
Nausea 8.6% 7.2%
Vomiting 5% 1.7%
Diarrhea 7.2% <1%
Dizziness 6.5% 2%
Hypertension 6.5% 3.8%

Oral vs IV Iron for IBD: Auerbach et al recommends that “iron should only be given orally to IBD patients with inactive disease, mild anemia, and good tolerance of oral iron; in patients with active IBD oral iron should be avoided.”  They state that “oral iron has been shown to exacerbate intestinal inflammation of IBD independent of anemia, and cause luminal changes in microbiota and bacterial metabolism, which may negatively alter the microbiome.” (Has IV iron’s effect on the microbiome been studied/compared to oral iron?)

Safety of intravenous iron: “In a recent meta-analysis, the results of more than 10,000 patients who were treated with intravenous iron were reported. Compared to oral iron, placebo, and even intramuscular iron (which should never be given), while minor infusion reactions were observed with IV iron, there was no increase in serious adverse events compared to any comparator including placebo.”

My take: Injectafer® is likely preferable to Venofer® in the outpatient setting as adequate dosing can be given in 1 or 2 infusions.

Related blog posts:

Trail on Blood Mountain

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition

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Here’s a link to Financial Times COVID-19 Tracker –includes logrithmic charts plotting the rates of reported infection and deaths and allows quick comparison between countries and high-volume locations (eg. Madrid, Lombardia, NY City).  Some figures from March 23, 2100 GMT noted below; unfortunately, the U.S is likely to the world leader in number of reported cases quite soon.

Other relevant tweets: