2024 NEJM Journal Watch Audio General Medicine: September Week 1

Educational Objectives

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

1. Increase his/her/their 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

A Breakthrough in HIV Prevention

Globally, about half of all HIV infections occur in women, yet women constitute only a small proportion of at-risk people who are taking pre-exposure prophylaxis (PrEP; https://www.jwatch.org/na57209 and JAMA 2024; 331:930). Now, in a manufacturer-sponsored study (PURPOSE-1) in the New England Journal of Medicine (https://doi.org/10.1056/NEJMoa2407001), investigators evaluated whether twice-yearly lenacapavir (a long-acting HIV capsid inhibitor) is efficacious at preventing HIV.

About 5340 sexually active cisgender women in sub-Saharan Africa were randomized to receive twice-yearly subcutaneous lenacapavir, daily oral FTC-tenofovir alafenamide (FTC/TAF), or daily oral FTC–tenofovir disoproxil fumarate (FTC/TDF). Key findings are as follows:

• HIV incidence in the lenacapavir group (0/100 person-years) was significantly lower than background in the screened population (2.4/100 person-years) and incidence in the FTC/TAF (2.0/100 person-years) and FTC/TDF (1.7/100 person-years) groups.

• HIV incidence did not differ between the FTC/TAF group and background. However, adherence to oral FTC/TAF and FTC/TDF (as measured by drug levels) was low. Most women who acquired HIV were not taking FTC/TAF or FTC/TDF.

In a separate study discussed by the editorialists (https://doi.org/10.1056/NEJMe2408591), investigators reported that the uncommon individuals who acquire HIV while receiving a different long-acting injectable (cabotegravir) might be asymptomatic, exhibit delayed antibody production, and have low or undetectable HIV RNA levels. Some people with this syndrome develop resistance to cabotegravir and other integrase inhibitors.

The striking efficacy of lenacapavir in the PURPOSE-1 trial hopefully portends the dawn of a new era in HIV prevention. If, as expected, lenacapavir successfully prevents HIV in cisgender men and transgender women and men (groups in the PURPOSE-2 trial), the drug likely will be reviewed and approved by the U.S. FDA for PrEP. Thereafter, the global community should waste no time in making it broadly available at an affordable cost. Only then can we end the HIV epidemic in our lifetimes.

Rajesh T. Gandhi, MD

PET-CT for Investigating Fever and Inflammation of Unknown Origin

Total-body computed tomography (CT) often is used to evaluate patients with fever of unknown origin (FUO; defined as temperature >38.3°C on multiple occasions, symptom duration of ≥3 weeks, and no diagnosis after extensive evaluation) and inflammation of unknown origin (IUO; defined as prolonged inflammatory syndrome without fever but with elevated acute-phase reactants such as C-reactive protein). In a meta-analysis in The American Journal of Medicine (https://doi.org/10.1016/j.amjmed.2024.03.017), researchers systematically reviewed 36 studies that involved 3500 patients and evaluated the contributory effect of positron-emission tomography CT (PET-CT) in diagnosing causes of FUO or IUO. PET-CT was defined as contributory if was positive and led to a final diagnosis or if it was completely negative (in accord with a final diagnosis).

Most studies were retrospective and included FUO patients only. Final diagnoses were infectious diseases (29%), noninfectious inflammatory conditions (27%), cancers (15%), or other conditions (5%); the remaining 24% resolved without diagnosis. The pooled contribution of PET-CT was 75%; the pooled contribution of total-body CT was 68%. Sensitivity and specificity for PET-CT were 86% and 60%; sensitivity and specificity for total-body CT were 63% and 84%.

PET-CT contributed to establishing diagnoses in three quarters of patients with FUO and IUO — better than the result for total-body CT. PET-CT also had higher sensitivity but lower specificity than total-body CT. Notably, prior research has shown that negative PET-CT is associated with spontaneous resolution of FUO (https://doi.org/10.1007/s11739-022-03171-x). Whether total-body CT or PET-CT should be the first imaging modality for these patients remains to be determined.

Paul S. Mueller, MD, MPH, FACP

Positive Catheter Tip Culture Without Bloodstream Infection — To Treat or Not to Treat?

Central venous catheter tips often are colonized with pathogenic organisms that can cause bloodstream infections (BSI). After a catheter is removed for suspected infection, a positive tip culture often tempts the clinician to start antimicrobial treatment — even if simultaneously drawn blood cultures do not yield the same pathogen.

To evaluate this practice, researchers in France retrospectively identified critically ill patients without BSI but with potentially pathogenic microorganisms isolated from removed intravascular catheters. Details appear in Intensive Care Medicine (https://doi.org/10.1007/s00134-024-07498-1). One hundred fifty patients who received active antimicrobial treatment against the isolated pathogen within 48 hours were matched to 150 patients without this early treatment; 37% of the latter group eventually were treated (median delay, 4 days). Fifteen patients in each group developed subsequent infections between 48 hours and 30 days after catheter removal; 30-day mortality was ≈20% in each group.

This study suggests that detection of potential pathogens on a removed catheter tip probably does not warrant systemic antimicrobial therapy if simultaneously drawn blood cultures do not grow the same pathogen — a finding relevant to antibiotic stewardship. However, whether this ultimately holds true for highly pathogenic organisms (specifically, Staphylococcus aureus) remains to be confirmed, as the study was insufficiently powered to address this issue. In any case, the results underline the importance of drawing blood cultures if a catheter-related infection is suspected and not just sending the tips for culture.

Thomas Glück, MD

Which Oral Antibiotics Are Associated Most Strongly with Serious Cutaneous Drug Reactions?

Serious cutaneous adverse drug reactions (cADRs) can lead to life-threatening conditions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome. Diagnosing these rare syndromes can be challenging, as most reactions are delayed, and relative risks for severe cADRs associated with various antibiotic classes are not well understood. To evaluate this risk, researchers in Canada used a large database that contained 20 years of outpatient antibiotic prescribing in older patients (age, ≥66). Each patient who received oral antibiotics within 60 days of emergency department (ED) presentation or hospitalization for a serious cADR was compared with one to four age- and sex-matched controls who received antibiotics in the same 60-day period but who didn’t have cADRs. Findings appear in JAMA (https://doi.org/10.1001/jama.2024.11437).

Almost 22,000 patients (0.7% of older patients who received outpatient antibiotic prescriptions) experienced serious cADRs. Median antibiotic course was 7 days, and median interval to presentation for serious cADRs was 14 days. Sulfonamides and cephalosporins were associated most strongly with serious cADRs, with adjusted odds ratios of 2.9 and 2.6, respectively, compared with macrolides. Excess risks for serious cADRs also were noted for nitrofurantoin, penicillins, and fluoroquinolones (adjusted ORs: 2.2, 1.4, and 1.3, respectively). Among 2850 patients hospitalized with serious cADRs, overall mortality was 5%, but it was as high as 20% for patients who developed SJS/TEN.

This study highlights that serious cADRs occur with many oral antibiotics, particularly sulfonamides and cephalosporins. The authors estimate that for every 1000 antibiotic prescriptions, 2 serious cADRs will occur, which will require ED visits or hospitalizations. Although that small absolute risk might not be relevant when a patient has strong indications for an antibiotic, it joins the many other potential harms resulting from inappropriate antibiotic prescribing.

David S. Weisman, DO, FACP

Comparing Cardiovascular and Kidney Outcomes with Tirzepatide vs GLP‑1 Agonists

Studies suggest that tirzepatide results in more weight loss than do the glucagon-like peptide-1 (GLP‑1) receptor agonists (e.g., https://www.jwatch.org/na53795 and N Engl J Med 2021; 385:503). In a new retrospective cohort study in JAMA Network Open (https://doi.org/10.1001/jamanetworkopen.2024.27258), researchers used administrative databases to compare the relative effects of the two drug classes on cardiovascular and kidney diseases. About 140,000 patients with type 2 diabetes who recently initiated one of the two drugs were evaluated. Patients with severe chronic kidney disease or recent cardiovascular events were excluded.

Adjusted analyses showed that during a median follow-up of ≈1 year, tirzepatide was associated with significantly lower risk for all-cause mortality (hazard ratio, 0.58), major adverse cardiovascular events (HR, 0.80), acute kidney injury (HR, 0.78), and major adverse kidney events (HR, 0.54) than were GLP‑1 agonists. Intermediate markers also favored tirzepatide for weight loss and lower glycosylated hemoglobin levels.

These observations for tirzepatide are interesting but preliminary, given the known caveats for retrospective studies that incorporate administrative data (i.e., inaccuracy of coding, modest effect sizes for the upper limit of confidence intervals, residual confounding, and lack of detailed clinical assessments). Head-to-head, prospective, longer-duration trials to examine cardiovascular and renal outcomes would be desirable to inform choices about these drugs.

Thomas L. Schwenk, MD

Rate of Ambulatory Follow-up After Cardiovascular-Related Hospitalization

Patients discharged after acute myocardial infarction (MI), or heart failure (HF) are at considerable risk for postdischarge adverse events and hospital readmissions. In 2012 and 2013, the U.S. Centers for Medicare & Medicaid Services (CMS) introduced Hospital Readmission Reduction and Transitional Care Management programs to incentivize providers financially to improve postdischarge outcomes.

To evaluate trends in postdischarge visits with cardiologists or primary care providers (PCPs) within 30 days, researchers conducted a retrospective study of all Medicare fee-for-service patients who were hospitalized between 2010 and 2019. Details appear in the Annals of Internal Medicine (https://doi.org/10.7326/M23-3475).

By the end of the study period, outpatient follow-up visits with either cardiologists or PCPs had improved from 71% to 80% for MI patients and from 64% to 71% for HF patients. Follow-up with cardiologists specifically improved for both MI (from 48% to 61%) and HF (from 35% to 48%) patients. Although rates of follow-up visits increased in all demographic and socioeconomic groups, follow-up rates were lower for Blacks, Hispanics, and Asian/Pacific Islanders compared with their white counterparts — and this gap widened over time. Patients with Medicaid dual eligibility and those from the most disadvantaged counties also lagged in improvement.

These results suggest that CMS’s financial incentive programs have helped improve 30-day outpatient follow-up after cardiovascular hospitalizations. However, a substantial percentage of patients still were not seen by clinicians within 30 days, and these numbers were worse for minority and socially disadvantaged patients. Hopefully, new CMS initiatives like ACO Reach (https://www.cms.gov/priorities/innovation/innovation-models/aco-reach), which put a strong emphasis on health equity and on underserved Medicare beneficiaries, will have a meaningful effect.

Aaron J. Calderon, MD, FACP, SFHM

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.

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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. Rajesh Gandhi reported receiving grant or research support from the NIH; sitting on the editorial boards of UpToDate, ID Images, and NEJM Journal Watch Infectious Diseases; and holding leadership positions in the Department of Health and Human Services, Antiretroviral Guidelines for Adults and Adolescents (Scientific Member), HIV Medicine Association (Past Chair), International Antiviral Society–USA (Chair, Guidelines Committee), NIH COVID-19 Treatment Guidelines (Scientific Member) and Infectious Diseases Society of America COVID-19 Treatment Guidelines. The planning committee members reported that they had nothing to disclose.

Acknowledgements

CME/CE INFO

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