2021 NEJM Journal Watch Audio General Medicine: November Week 1

Educational Objectives

After hearing and assimilating this program, the listener will be better able to:

1. Increase his/her basic knowledge of important advances in medicine;
2. Identify a broad range of clinical research reported in the medical literature;
3. Synthesize research findings through one-on-one interviews with authors, editorialists, or experts in the field;
4. Integrate new treatments reviewed in the summaries into current practice;
5. Challenge oneself with thoughtful, clinically relevant questions.

Summary

SGLT-2 Inhibitors vs GLP-1 Receptor Agonists for Patients with Diabetes

Among the glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors, several drugs in each class have been shown to improve cardiac outcomes — myocardial infarction (MI), stroke, hospitalization for heart failure (HF), and cardiovascular-related mortality. Current guidelines recommend using either agent for patients with type 2 diabetes and cardiovascular disease (CVD; https://doi.org/10.2337/dc21-S010). Using Medicare and two commercial insurance databases, investigators compared ≈180,000 propensity score–matched patients — stratified by CVD status — who initiated either an SGLT-2 inhibitor (i.e., canagliflozin, dapagliflozin or empagliflozin) or a GLP-1 receptor agonist (i.e., albiglutide, dulaglutide, exenatide, or liraglutide); median follow-up was 7 months. Findings appear on the website of the Annals of Internal Medicine (https://doi.org/10.7326/M21-0893).

Patients who received SGLT-2 inhibitors were significantly less likely to be hospitalized for HF than were patients who received GLP-1 receptor agonists — both patients with CVD (1.2% vs 1.7% annually) and without CVD (0.13% vs 0.19% annually). SGLT-2 patients with CVD also had significantly lower risk for MI or stroke than did GLP-1 patients with CVD (2.1% vs 2.4% annually).

This cohort study offers strength in its size, its propensity-matched adjustment based on more than 100 potential confounders, and its findings of statistically significantly improved outcomes with SGLT-2 inhibitors. From a population health standpoint, these differences are important; but from the standpoint of an individual patient, these outcome differences equate to numbers needed to treat with an SGLT-2 inhibitor (compared with a GLP-1 receptor agonist) of 200 to 400 patients with CVD and nearly 1700 patients without CVD to benefit 1 patient during 1 year — a benefit that is unlikely to be enough to strongly recommend one agent over the other.

Daniel D. Dressler, MD, MSc, MHM, FACP

Fixed vs Age-Adapted Glomerular Filtration Rate Thresholds for Diagnosing Chronic Kidney Disease

An estimated glomerular filtration rate (eGFR) of <60 mL/minute/1.73 m² is accepted widely as indicating substantial (i.e., stage 3) chronic kidney disease (CKD). However, this fixed threshold might be associated with overdiagnosing CKD in older people because of age-related physiological loss of GFR. In a population-based study from Alberta, the results of which appear on the website of JAMA Internal Medicine (https://doi.org/10.1001/jamainternmed.2021.4813), researchers in Canada compared outcomes of adults with incident CKD using two definitions: A fixed eGFR threshold of <60 mL/minute/1.73 m² and age-adapted eGFR thresholds of 75, 60, and 45 mL/minute/1.73 m² for ages <40, 40 to 64, and ≥65, respectively.

The main findings were:

• Overall, the incidence rate for CKD was much higher with the fixed threshold than with the age-adapted thresholds; the difference was particularly striking in older people (i.e., 2356 vs 714 new cases per 100,000 person-years in people 65 or older). However, in people younger than 40, the incidence rate was much lower with the fixed threshold than with the age-adapted threshold (i.e., 14 vs 91 new cases per 100,000 person-years).

• Calculated risks for kidney failure and death at 5 years were lower using the fixed threshold definition (2% and 22%) than when using the age-adapted definition (3% and 25%).

• About 75% of people with CKD defined by the fixed threshold were 65 or older, had eGFRs between 45 and 59 mL/minute/1.73 m², and had no or mild proteinuria; absolute risks for kidney failure and death for these people were similar to risks in those without CKD.

Compared with age-adapted eGFR thresholds, a fixed eGFR threshold of <60 mL/minute/1.73 m² results in overdiagnosis of CKD in older people and underdiagnosis in younger people. Correspondingly, adopting age-adapted thresholds for diagnosing CKD might prevent overtreatment in older people (e.g., unnecessary testing and referrals to nephrologists) and undertreatment in younger people with CKD (e.g., missing opportunities to prevent CKD progression).

Paul S. Mueller, MD, MPH, FACP

Use of Race in Estimating Glomerular Filtration Rate

Estimation of the glomerular filtration rate (GFR) generally is based on serum creatinine, age, and sex — and incorporates an adjustment for race (Black or non-Black). Recently, however, race-based adjustment has been questioned, and in two new studies in the New England Journal of Medicine, researchers have addressed this issue.

In the first study (https://doi.org/10.1056/NEJMoa2103753), researchers compared directly measured GFR (using urinary ¹²⁵I-iothalomate clearance) and estimated GFR (eGFR) in 1248 adults with chronic kidney disease of varying severity; 37% of participants self-identified as Black and 63% as non-Black. When race was omitted from the calculation of creatinine-based eGFR, the eGFR was less accurate than when race was included; the same pattern was found when genetic ancestry was substituted for race. However, when serum cystatin C was used to calculate eGFR (instead of serum creatinine), adjustment for race was not necessary to achieve acceptable accuracy.

In the second study (https://doi.org/10.1056/NEJMoa2102953), researchers used data from several preexisting datasets to examine the accuracy of equations for estimating GFR — with or without race, and with incorporation of creatinine, cystatin C, or both. They found that equations based on age, sex, and both serum creatinine and cystatin C — with race omitted — were reasonably accurate for both Black and non-Black populations.

The growing acknowledgement of race as a socially constructed category has led to controversy about inclusion of race in predictive algorithms for GFR, pulmonary function, and other entities. Ideally, new calculators and algorithms would replace racial categories with biological variables that improve predictive accuracy. For eGFR, these two studies point to use of cystatin C (a small protein that is filtered in the glomerulus) as one such variable. However, it remains unclear whether widespread use of cystatin C would improve clinical outcomes — and reduce racial disparities in those outcomes — in patients with chronic kidney disease.

Allan S. Brett, MD

Guideline Watch: 2021 Update to the CHEST VTE Treatment Guidelines

The ninth edition of the CHEST Clinical Practice Guidelines for managing venous thromboembolism (VTE) — sponsored by the American College of Chest Physicians and published in 2012 and updated in 2016 — now has a second update on the website of Chest (https://doi.org/10.1016/j.chest.2021.07.055), which addresses 14 clinical questions and offers 32 guidance statements for clinicians who manage patients with VTE. The 2012 guideline (https://doi.org/10.1378/chest.11-2301) and the 2016 update (www.jwatch.org/na40157) both are publicly available.

Key Recommendations

Patients with isolated subsegmental pulmonary embolism (PE):

• Rule out proximal deep vein thrombosis (e.g., with ultrasonography). If risk for recurrent VTE is low, surveillance is recommended over anticoagulation. If risk for recurrent VTE is high, anticoagulation is recommended. (Weak recommendation, low-certainty evidence)

Patients with incidentally discovered asymptomatic PE (other than isolated subsegmental PE):

• Same initial and long-term anticoagulation that patients with symptomatic PE receive should be used. (Weak recommendation, moderate-certainty evidence)

Patients with cancer-associated VTE:

• Direct-acting oral anticoagulants (DOACs; i.e., apixaban, edoxaban, or rivaroxaban) should be used for the treatment phase of therapy (strong recommendation, moderate-certainty evidence). Caveat: For patients with luminal gastrointestinal malignancies, apixaban or low-molecular-weight heparin is preferred to reduce bleeding risk.

Patients with antiphospholipid syndrome:

• Warfarin (target international normalized ratio, 2.5) is recommended over DOAC therapy during the treatment phase for VTE. (Weak recommendation, low-certainty evidence)

Catheter-assisted mechanical thrombectomy:

• Recommended for patients with PE and hypotension who also have high bleeding risk, failed systemic thrombolysis, or shock that is likely to lead to death before systemic thrombolysis can take effect. (Weak recommendation, low-certainty evidence)

Initial anticoagulation setting:

• Outpatient treatment is recommended over hospitalization in patients with low-risk PE, if access to medications and outpatient care is available. (Strong recommendation, low-certainty evidence)

Treatment-phase anticoagulants:

• DOACs are recommended over warfarin. (Strong recommendation, moderate-certainty evidence)

Extended-phase therapy (beyond 3 months) for VTE:

• Extended anticoagulation should be offered to patients with unprovoked VTE — i.e., with no major or minor transient risk factors. Risk for recurrent VTE, risk for bleeding, and patients’ values and preferences should be considered in decisions about extended anticoagulation therapy. (Strong recommendation, moderate-certainty evidence)

• Low-dose apixaban or rivaroxaban is recommended over full doses of these agents. (Weak recommendation, very low-certainty evidence)

• Aspirin is recommended for patients who are stopping anticoagulation. (Weak recommendation, low-certainty evidence)

Although much of the guidance in this update already is prevalent in clinical practice, some of the updated recommendations might help forge greater consistency among providers who care for patients with VTE.

Daniel D. Dressler, MD, MSc, MHM, FACP

No Benefit to Routine Use of Probiotics in Patients Receiving Mechanical Ventilation

Quality-improvement interventions have led to lower rates of ventilator-associated pneumonia (VAP) in many intensive care units (ICUs), but it remains a common nosocomial infection associated with prolonged length of stay. Studies have suggested that probiotics might be a helpful addition to other preventive strategies. An international team of investigators randomized 2650 patients from 44 ICUs who were receiving mechanical ventilation (and expected to require support for ≥72 hours) to receive enteral Lactobacillus rhamnosus GG or placebo twice daily. More than 80% of patients were receiving antibiotics at enrollment, including 60% of patients who were admitted with pneumonia. Diagnosis of VAP required a new, progressive, or persistent opacity on chest radiograph and two of the following: Fever or hypothermia, white blood cell count <3000/μL or >10,000/μL, or purulent sputum. Details appear in the September 21, 2021 issue of JAMA (https://doi.org/10.1001/jama.2021.13355).

Rates of VAP were similar between groups, including in prespecified subgroups. No differences were noted in duration of mechanical ventilation, ICU length of stay, new diarrhea, or Clostridioides difficile infection. In 11 patients, all in the intervention group, blood cultures contained L. rhamnosus GG.

Although the hypothesis that restoration of gut flora would protect against many nosocomial complications in the ICU is physiologically plausible, routine use of probiotics doesn’t appear to affect outcomes. This large trial demonstrates that probiotics should not be included in standard VAP prevention strategies.

Patricia Kritek, MD, EdM

Baricitinib for Severe COVID-19

The Janus kinase (Jak) inhibitor, baricitinib, was proposed as a treatment for patients with COVID-19 because of its anti-inflammatory and potential antiviral effects. In an early trial, baricitinib shortened time to recovery when added to remdesivir in patients hospitalized with COVID-19, but this study excluded people who were receiving corticosteroids (which are now standard of care for hospitalized patients who require oxygen; https://www.jwatch.org/na52968). Now, a manufacturer-sponsored study on the website of The Lancet: Respiratory Medicine (https://doi.org/10.1016/S2213-2600(21)00331-3) provides data on baricitinib’s role during the corticosteroid era.

More than 1500 patients hospitalized with COVID-19 who had ≥1 elevated inflammatory marker were randomized to baricitinib or placebo; patients who required invasive mechanical ventilation were excluded. Approximately 79% of enrollees were receiving systemic corticosteroids; ≈19% were receiving remdesivir. Incidence of the composite primary endpoint (i.e., progression to high-flow oxygen, noninvasive or invasive mechanical ventilation, or death) was 28% with baricitinib and 30% with placebo — a nonsignificant difference. However, 28-day mortality was significantly lower with baricitinib than with placebo (8% vs 13%). The benefit of baricitinib was most evident among patients who required high-flow oxygen or noninvasive ventilation at baseline. Incidence of serious adverse events was similar in both groups.

Based largely on this trial, guidelines from the NIH (https://www.covid19treatmentguidelines.nih.gov) and the Infectious Diseases Society of America (https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management) recommend baricitinib plus dexamethasone in select patients with severe COVID-19. Interleukin-6 blockade (also in combination with dexamethasone) is similarly recommended, but we don’t know yet whether a Jak inhibitor (like baricitinib) or an interleukin-6 blocker (like tocilizumab) is better. For now, the choice is largely influenced by drug availability and other institutional considerations.

Rajesh T. Gandhi, MD

Azithromycin for COVID-19 Outpatients: No Benefit

Because azithromycin has antiviral and anti-inflammatory properties (in addition to its established antibacterial effect), some clinicians advocated using it for COVID-19 early in the pandemic. Since then, several randomized trials have shown no clinical benefit, but some clinicians still might be prescribing it.

For outpatients, the most recently published randomized trial (ATOMIC2) involved 295 adult U.K. outpatients (mean age, 46) with strongly suspected or documented COVID-19. Patients received either azithromycin (500 mg daily for 14 days) or standard care. The primary outcome — hospitalization or death at 28 days — was similar in the two groups (10.3% vs 11.6%; P=0.8). One person in each group died. In the subgroup of patients who had positive polymerase chain reaction (PCR) tests for SARS-CoV-2 (about half the study population), the primary outcome occurred with equal frequency in the azithromycin and the standard-care groups (14.7%). Details appear in the October 2021 issue of The Lancet: Respiratory Medicine (https://doi.org/10.1016/S2213-2600(21)00263-0).

Two other randomized trials involving azithromycin for outpatients were published recently:

• In a U.S. trial (ACTION) in the August 10, 2021 issue of JAMA (https://doi.org/10.1001/jama.2021.11517), 263 adults (median age, 43) who had tested positive for SARS-CoV-2 received a single 1200-mg dose of azithromycin or placebo. The primary outcome — total resolution of symptoms by day 14 after enrollment — occurred in identical proportions in the two groups (50%), and no differences in incidence of hospitalization or death were noted.

• In another U.K. trial (PRINCIPLE) in the March 20, 2021 issue of The Lancet (https://doi.org/10.1016/S0140-6736(21)00461-X), about 1300 patients with strongly suspected or documented COVID-19 received azithromycin (500 mg daily for 3 days) or usual care; patients in this trial were older than those in the trials discussed above (mean age, 61), and most had comorbidities. All outcomes (including resolution of symptoms, hospitalization, and death) occurred with similar frequency in the two groups.

Each of these trials has certain limitations, but taken together, they make a convincing case: Azithromycin has no meaningful effect on clinical course for outpatients with COVID-19.

Allan S. Brett, MD

COVID Vaccines: Latest Recommendations and Performance

THIS INTERVIEW HAS NO ACCOMPANYING SUMMARY OR TRANSCRIPT.

These summaries are presented to facilitate your understanding of ongoing medical research. They aren’t intended for use as the sole basis for clinical treatment nor as a substitute for reading the original research. Journal Watch is a registered trademark of the Massachusetts Medical Society, publishers of the New England Journal of Medicine.

Readings

Disclosures

In adherence to the ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. Dr. John Mascola and the planning committee members reported having no financial conflicts of interest.

Acknowledgements

CME/CE INFO

Accreditation:

Lecture ID:

JW322101

Qualifies for:

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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