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#424 Hotcakes: Transfusion in Acute MI, COVID-19 Rebound after Paxlovid, Every-other-day Iron Revisited, Oral Phenylephrine Doesn’t Work, and Stop Correcting Serum Calcium

January 29, 2024 | By

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Join us as we review recent practice-changing articles on transfusion thresholds in acute MI, COVID-19 rebound after treatment with ritonavir-boosted nirmatrelvir (PaxlovidTM), the prevalence of iron deficiency, as well as the debut of our new “corrections and omissions” section, in which we cover important knowledge updates on oral iron dosing and correcting serum calcium. And, find out why oral phenylephrine does not work and what you should prescribe instead for upper respiratory symptoms. Fill your brain hole with a delicious stack of hotcakes! Featuring Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), and Matt Watto (@doctorwatto).

Show Segments

  • 00:00 Introduction and Calcium Puns
  • 03:11 Iron Deficiency and Iron Supplementation
  • 12:20 Corrected Calcium
  • 18:09 Virologic Rebound after nirmatrelvir/ritonavir (Paxlovid™)
  • 32:09 Phenylephrine and its Ineffectiveness
  • 37:00 Restrictive vs. Liberal Transfusion Strategy in MI (MINT trial)
  • 49:20 Outro

Hot take #1: Prevalence of Iron Deficiency (Rahul) 

Weyand AC, Chaitoff A, Freed GL, Sholzberg M, Choi SW, McGann PT. Prevalence of iron deficiency and iron-deficiency anemia in us females aged 12-21 years, 2003-2020. JAMA. 2023;329(24):2191-2193.

Summary: This study, from a June 2023 issue of JAMA, used NHANES data to answer a simple but neglected question: what is the prevalence of iron deficiency, with or without anemia, among young women in the United States? The authors (which include Angela Weyland, the “Shematologist” on Twitter, and Curbsiders Digest own Alex Chaitoff) found that using a ferritin cutoff of 25 ng/mL, 40% of young women were iron deficient, and using a cutoff of 50 ng/mL, 75% of women were! Despite this, only 6% of women in the sample were anemic. Furthermore, among iron-deficient young women, about 85% had a normal hemoglobin.

Bottom line: Iron deficiency is incredibly common among young women, and because many iron-deficient women are not anemic, hemoglobin alone is probably not an adequate screening tool for iron deficiency.  

Corrections and Omissions

#1: Oral Iron Supplementation: Dealer’s choice (Watto)

Breu, Tony. Substack https://tonybreu.substack.com/p/the-unbrindled-enthusiasm-for-qod 

Summary: Our friend, the great Dr. Tony Breu, recently discussed the phenomenon of alternate day oral iron dosing and what he called “The Curbsiders Effect” in a recent SubStack post. We’re covering it here because it seems the hepcidin hypothesis has been proven wrong (or at least too simplistic), and daily iron seems to work just as well (and be just as well tolerated) as alternate day iron dosing. 

We’ve discussed the hepcidin theory and practicality of alternate day iron dosing on multiple Curbsiders episodes #36 ACP 2017 Recap, #84 Anemia, Iron Def., IV iron. In 2015, Moretti et al reported in Blood that serum hepcidin increases for 24 hours after a dose of oral iron and speculated that every other day dosing might be superior. In 2017, Stoffel et al studied one daily vs twice daily vs alternate day dosing of oral iron in 60 iron deficient, mildly anemic women. They concluded that alternate day iron dosing is optimal for absorption because fractional and total iron absorption were higher with alternate day dosing. However, hemoglobin and ferritin levels as well as the incidence of nausea and abdominal pain were not significantly different in both groups! Fast forward to 2023, Siebenthal et al performed a placebo controlled RCT of daily vs alternate day oral iron and found no difference in hemoglobin or ferritin after 90 doses. Additionally, Tony’s SubStack post cites four other RCTs from the 2020s that failed to show consistent superiority of alternate day dosing for iron deficiency, even for its GI side effects!

Bottom line: The hepcidin hypothesis is either wrong or too simplistic. Prescribe either daily or alternate day dosing of oral iron, whichever your patient will take and tolerate. 

#2: Uncorrected Calcium is Good Enough (Watto)

Thanks to Andrew (Last Name withheld) from MUSC for this correction.

Kenny CM, Murphy CE, Boyce DS, Ashley DM, Jahanmir J. Things We Do for No Reason™: Calculating a “Corrected Calcium” Level. J Hosp Med. 2021 Aug;16(8):499-501. doi: 10.12788/jhm.3619. PMID: 34197298; PMCID: PMC8340960. 

Summary: On episode #281 Hypercalcemia, we discussed the use of “corrected calcium”, which was, even then, of questionable utility. Payne’s formula (see below) is still widely used to correct total serum calcium:

Corrected Calcium (mg/dL) = Measured Total Calcium (mg/dL) + 0.8 × [4.0−Albumin (g/dL)]

The formula was developed by studying 200 patients in a single center. Unfortunately, in multiple retrospective studies, this and other commonly used formulas for “corrected calcium” were inferior to uncorrected serum calcium when compared to the gold standard, ionized calcium aka “free calcium”. Further, these formulas perform worse as hypoalbuminemia worsens! Uncorrected total calcium correlates to Ionized calcium (iCa) about 70-80% of the time. iCa should be used when serious disorders of calcium metabolism are suspected. However, iCa is tricky to collect because it requires rapid processing to avoid pH changes in the sample and is also sensitive to temperature and air exposure. It should be stored anaerobically and if processing is delayed more than 30 minutes placed in an ice slurry. 

Bottom line: Use the uncorrected calcium or ionized “free” calcium measurement when deciding whether or not to treat calcium disorders.

Further reading


Hotcake #1: COVID19 rebound after Paxlovid™ (Paul)

Edelstein GE et al. 2023. SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study. Annals of Internal Medicine 176: 1577-1585.

What was the research question? Does treatment with nirmatrelvir-ritonavir (Paxlovid™) impact the frequency of virologic rebound in acute COVID-19 infection?

Why is this study important? Paxlovid remains a recommended COVID treatment for high-risk patients despite drug interactions and concerns about post-treatment viral rebound. If nirmatrelvir-ritonavir increases the rate of virologic rebound, this could have important implications for who we treat, the duration of treatment, and how we monitor them after treatment.  

How was the study done? In this prospective cohort study, enrolled patients with COVID19 had repeated assessments of viral load, viral culture, and symptoms. Patients self-collected nasal swabs that were picked up by courier 3 times a week for two weeks and weekly thereafter until viral load tests were persistently negative. Outcomes were compared between people who received Paxlovid and people who did not. The primary outcome was virologic rebound, which was defined as either 1) a positive SARS-CoV2 viral culture after a prior negative result, or 2) sustained elevated viral load, a surrogate for elevated transmission risk. 

Who were the patients? Patients came from the POSITIVES cohort study within the Mass General Brigham health care system in Boston. They were all outpatients with acute COVID-19 infection and had not recently used other antiviral therapies (including monoclonal antibodies). After exclusions, a total of 127 were included. Treated patients were older, had received more COVID vaccines, and were more likely to be immunosuppressed.  No one died in either group.

Top-line results: This was a positive study: virologic rebound occurred in approximately 20% of patients taking nirmatrelvir-ritonavir, compared with 2% of those not taking this therapy. This difference persisted after stratification for demographics and clinical factors, and rebound was associated with prolonged shedding of replication-competent virus (14 vs 3 days).

Learning points & limitations: Because patients who received Paxlovid were very different from patients who did not, residual confounding is a concern in this cohort study. However, a sensitivity analysis indicating that rebound was more likely when Paxlovid was started within 2 days of symptom onset may suggest a causal relationship because early treatment may blunt the initial immune response and lead to delayed viral clearance. The authors also studied symptom rebound and found that this was not a reliable indicator of virologic rebound. With the price tag of a 5-day course of $1,390, longer treatment would be a significant financial burden for many people.

Bottom line/Hotcakes rating: 4/5

Further reading:


Hot take #2: Stop using oral phenylephrine (Watto) 

Summary: Despite limited evidence, over-the-counter (OTC) cough and cold medicines are a >$10 billion per year industry (per Statista) featuring combinations of antihistamines, antitussives, analgesics, and decongestants. Phenylephrine, the decongestant found in most OTC products in the US, has poor oral bioavailability (inactivated by gut & liver) and does not affect nasal congestion when taken orally (Kanfer, 1993; Hatton, 2007; Meltzer, 2015)! An FDA advisory committee recently recommended that oral phenylephrine be removed from the OTC monograph of drugs “generally regarded as safe and effective”. If the FDA follows this recommendation, oral phenylephrine might be removed from the market! 

Bottom line: Prescribe topical therapies for nasal congestion instead of oral phenylephrine and recognize that the evidence is limited for most other OTC remedies (guaifenesin, benzonatate, etc.). This piece by C&EN nicely summarizes things while also throwing shade at benzonatate and guaifenesin.


Hotcake #2: The MINT Trial (Rahul)

Carson JL, Brooks MM, Hébert PC, et al. Restrictive or liberal transfusion strategy in myocardial infarction and anemia. N Engl J Med. 2023;389(26):2446-2456.

What was the research question? For patients with acute MI and anemia, should we use a liberal (for Hgb <10) or restrictive (for Hgb <7) transfusion strategy to reduce death and MI at 30 days? 

Why is this study important? The 2023 AABB guidelines on blood transfusions in hospitalized patients don’t take a stance on whether a liberal or restrictive transfusion strategy is better for patients with acute MI and anemia due to a lack of evidence. But, in response to this study, UpToDate now recommends a liberal transfusion strategy in this setting!

How was the study done? In this multicenter, open-label randomized superiority trial, adults hospitalized with acute MI and a hemoglobin less than 10 were randomized 1:1 to a restrictive or liberal transfusion strategy. The primary outcome, all-cause death or recurrent MI at 30 days, was assessed by phone and review of medical records. 

Who were the patients? 3,500 older adults (mean age 72), mostly in the US, Canada, and France were randomized an average of 3 days after their index MI, by which time 30% of them had already been revascularized, and about a third of them had already received an average of 2-3 units of pRBCs. 55% of patients had a Type 2 MI (demand ischemia); 40% had type 1 (vessel occlusion). Mean pre-randomization hemoglobin was 8.6 in both groups, and by day 3, mean hgb was 10.5 in the liberal group and 8.9 in the restrictive group (it took 3.5x more transfusions in the liberal group to achieve this!).

Top-line results: At 30 days, death or MI occurred in 16.9% of patients in the restrictive group, and 14.5% of patients in the liberal group (RR 1.15, 0.99 – 1.34, p=0.07), which was less than the 20% difference the study was powered to detect. Among patients with type I MI, a benefit of the liberal strategy was seen: RR: 1.32 (1.04 – 1.67), absolute risk reduction: 4.4%, NNT = 23 over 30 days. 

Learning points & limitations: This was a negative trial with respect to the primary outcome, however, at least 3 sources of chance and bias could have made this a false negative. First, the study was effectively underpowered because of the possibility that a higher threshold only helps in a Type I MI (heterogeneity of treatment effect). Second, 30% of patients in both groups were revascularized before randomization, and about a third of patients in both groups received an average of 2-3 units of pRBCs before randomization. Third, there was differential adherence to the protocol: 2.6% of the restrictive group discontinued vs. 13.7% of liberal group, mostly due to volume overload and transfusion reactions. These sources of bias towards a null finding could be why the UpToDate authors now recommend a liberal strategy in patients with acute MI. For my part, these results make me more likely to transfuse liberally in patients with Type I MI before revascularization.

Bottom line/Hotcakes rating: 4/5

Further reading:


Links

Links are included in the show notes above.


Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

  1. Recall the prevalence of virologic rebound after Paxlovid treatment 
  2. Discuss the limitations of phenylephrine, corrected serum calcium, and every-other-day iron dosing
  3. Evaluate the possibility of benefit of a liberal transfusion strategy in acute MI and anemia

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Ganatra RB, Williams PN, Watto MF. “#424 Hotcakes: Transfusion in acute MI, COVID rebound after treatment, every-other-day iron revisited, oral phenylephrine doesn’t work, and stop correcting serum calcium”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, January 29, 2024.

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Episode Credits

Written, Produced, and Hosted by: Rahul Ganatra MD, MPH; Paul Williams, MD, FACP, Matthew Watto MD, FACP
Cover Art: Matthew Watto MD, FACP
Reviewer: Rahul Ganatra MD, MPH
Technical Production: Pod Paste
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP

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