2024 NEJM Journal Watch Audio General Medicine: January Week 4

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

Upper Gastrointestinal Bleeding in Patients Using Aspirin for Primary Prevention of Adverse Cardiovascular Events

In 2018, the ASPREE and ARRIVE trials showed that taking aspirin for primary prevention did not lower risk for adverse cardiovascular events but did impart bleeding risks (https://www.jwatch.org/na47530 and N Engl J Med 2018; 379:1509; https://www.jwatch.org/na47429 and Lancet 2018; 392:1036). Now, in a U.S. study in The American Journal of Medicine (https://doi.org/10.1016/j.amjmed.2023.08.010), researchers examined whether upper gastrointestinal (UGI) bleeding associated with primary preventive aspirin decreased between 2016 and 2020, an interval that spans those 2018 reports. Using nationwide administrative data, 535,000 middle-aged and older patients (age, ≥45) who presented to an emergency department with UGI bleeding were identified.

Key findings were:

• From 2016 to 2020, the annual age- and sex-adjusted incidence rate of UGI bleeding among patients using primary preventive aspirin increased from 7.5 to 10 per 100,000 people.

• The highest rates and greatest increase were in people older than 75 (from 20.4 to 31.6 per 100,000 people).

• The percentage of all patients with UGI bleeding who were using primary preventive aspirin increased between 2016 and 2020.

• Among patients with UGI bleeding, using primary preventive aspirin was associated with higher odds of hospital admission, endoscopic intervention, and blood transfusion.

These data were collected just before publication of the latest U.S. Preventive Services Task Force guidelines that recommend against primary aspirin prophylaxis for people older than 60 (https://www.jwatch.org/na54890 and JAMA 2022; 327:1577). Still, evidence from clinical trials already had indicated against use of aspirin for this purpose during this study’s time frame. The worrisome trend of increasing UGI bleeding should remind us to ask patients about aspirin use for primary prevention and to discourage its use for this purpose in people who are 60 or older.

Rahul B. Ganatra, MD, MPH

Conservative Management or Surgery for Uncomplicated Symptomatic Gallstones?

About half of patients with an initial episode of gallstone pain develop recurrent biliary colic. Patients with uncomplicated symptomatic gallstones often are advised to undergo laparoscopic cholecystectomy, but among those who do, as many as 40% report continued pain and abdominal symptoms. Does surgery provide better overall symptom relief than conservative management?

For a study in The BMJ (https://doi.org/10.1136/bmj-2023-075383), researchers in the U.K. recruited 400 patients with uncomplicated symptomatic gallstone disease (i.e., biliary colic or uncomplicated acute cholecystitis) and randomized them to cholecystectomy or conservative management (i.e., observation, analgesics, and dietary advice). Eighteen months after randomization, 67% of patients assigned to cholecystectomy and 25% of patients assigned to conservative management had undergone surgery, with median waits of 4.5 and 8.1 months, respectively. Bodily pain scores (the primary outcome), quality of life, and complications did not differ significantly between the two groups. Gallstone-specific symptoms were somewhat better in the cholecystectomy group compared with the conservative management group, but conservative care was less expensive.

This study did not specify how many patients had a history of acute cholecystitis (as opposed to just biliary colic) and how many were recruited as inpatients, nor were the analyses stratified by these potentially important variables. Still, it suggests that through 18 months, conservative care might provide equivalent symptom relief to cholecystectomy for patients with uncomplicated symptomatic gallstones. Given the similar outcomes in both groups, the authors suggest that patients considering cholecystectomy be fully advised on the risks, benefits, and alternatives to surgery and that guidelines recommending surgery for most uncomplicated symptomatic gallstones be reconsidered.

Bruce Soloway, MD

Esophageal Symptoms Can Be Associated with Chronic Opioid Use

When we think about gastrointestinal side effects of opioids, we often focus on constipation or impaired gastric emptying. But opioids also have effects on esophageal motility. In a meta-analysis in The American Journal of Gastroenterology (https://doi.org/10.14309/ajg.0000000000002410), researchers identified nine studies in which high-resolution esophageal manometry was performed in chronic opioid users and nonusers referred for symptoms such as dysphagia, reflux, and esophageal-related chest pain. Findings were categorized according to the Chicago Classification, an increasingly used system for describing esophageal motility disorders (https://doi.org/10.1111/nmo.14058).

Compared with opioid nonusers, opioid users had a significantly higher prevalence (odds ratios, ≈5.0) of distal esophageal spasm, esophagogastric junction outflow obstruction, and type III achalasia (a subtype with both inadequate lower esophagogastric relaxation after swallowing and spastic nonperistaltic esophageal contractions). Opioid use was not associated with achalasia types I and II.

These results suggest that when chronic opioid users present with symptoms such as dysphagia and esophageal chest pain, the opioids often are the cause — or at least a contributing factor. We have several treatment options for chronic opioid users who have constipation, but the only satisfactory way to treat opioid-related esophageal symptoms is to discontinue the opioids.

Allan S. Brett, MD

Risks Associated with Cannabis Use During Pregnancy

The association between cannabis use and adverse pregnancy outcomes has been difficult to study given problems in accurately assessing cannabis use and in controlling for common confounding variables. A prospective study in JAMA (https://doi.org/10.1001/jama.2023.21146) was designed to obviate some of those difficulties by employing frequent urine immunoassays of 11-nor-9-carboxy-Δ9-tetrahydrocannabinol throughout pregnancy and by controlling for a wide range of clinical and demographic variables (including nicotine and other drug use, as assessed by urine assays). About 9300 pregnant people — 6.6% of whom used cannabis sometime during pregnancy — were enrolled.

A composite outcome of small-for-gestational-age birth, premature birth for medical indications (as opposed to spontaneous rupture of membranes or spontaneous labor), stillbirth, or hypertensive disorders of pregnancy was significantly more common among people who used cannabis at any time during pregnancy (relative risk, 1.27) compared with those who had no exposure. When stratified for cannabis use in the first trimester or ongoing use throughout the pregnancy, only use throughout pregnancy was associated with adverse outcomes.

These results might help clinicians counsel pregnant patients about risks associated with continuing cannabis use throughout pregnancy as well as the benefits of stopping cannabis use after the first trimester. The validity of this study is strengthened by extensive control for other behaviors and characteristics that tend to be markedly different in users and nonusers of cannabis.

Thomas L. Schwenk, MD

Do Statins Mitigate Risk for Venous Thromboembolism with Hormone Therapy?

Studies conducted >20 years ago showed that statins mitigated risk for venous thromboembolism (VTE) in postmenopausal women receiving hormone therapy (HT). To revisit this issue, researchers used U.S. claims data from 2007 to 2019 and conducted a case-control study comparing 20,000 women (mean age, 58) with VTE and 200,000 age-matched women without VTE. HT exposure included both estrogen alone and estrogen/progesterone, and both oral and nonoral preparations. Findings appear in JAMA Network Open (https://doi.org/10.1001/jamanetworkopen.2023.48213).

In adjusted analyses, the odds ratio for VTE was 1.53 for HT exposure alone compared with no exposure to HT or statin. When HT and statins were used together, VTE risk was lower — roughly midway between risk with HT use alone and risk with neither statin nor HT use.

If this association is causal, the absolute effect is likely less than 1 VTE prevented per 1000 HT users annually (according to my informal estimates from randomized-trial data on VTE risk in oral HT users). Nevertheless, the findings might provide some reassurance to women who are considering HT and already taking a statin.

Thomas L. Schwenk, MD & Allan S. Brett, MD

Hyponatremia from Thiazide Diuretics

Although thiazide-induced hyponatremia traditionally has been considered to be very uncommon, clinical experience suggests otherwise. In a retrospective cohort study in the Annals of Internal Medicine (https://doi.org/10.7326/M23-1989), investigators used a Danish national registry to assess the frequency of new hyponatremia (Na level, <130 mmol/L) among patients who initiated antihypertensive therapy with a thiazide diuretic or a combined thiazide–renin-angiotensin system (RAS) inhibitor. The control group was patients who initiated either a calcium-channel blocker or a RAS inhibitor alone. Two-year cumulative incidence outcomes were reported.

Incidence of hyponatremia was significantly higher among 50,000 patients who initiated antihypertensive therapy with thiazide diuretics or combined thiazide-RAS inhibitors than among 130,000 control patients who initiated nonthiazide antihypertensives (≈3.5% vs ≈2.0%). Hospitalization with hyponatremia also was significantly more common in patients who took thiazides than in control patients (≈2.5% vs ≈1.5%). Hyponatremia was more common in patients with ≥3 medical comorbidities (>10%) and in patients older than 60. Risk increased progressively with age (incidence for patients in their 60s, 70s, and 80s: 4%, 6%, and >10%, respectively).

This study confirms what many of us have observed clinically: Hyponatremia occurs somewhat frequently in patients who take thiazide diuretics, and it occurs more commonly as patients age. These researchers only examined a 2-year interval after thiazide initiation, but my colleagues and I occasionally have seen long-term thiazide users who developed hyponatremia after years of having normal serum sodium levels. Patients who use thiazides likely deserve lab monitoring, and this study might make us think twice before starting a thiazide in a patient with advanced age or multiple medical comorbidities.

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

Patients with Asthma Who Take Biologics Often Can Reduce ICS Doses

Three to ten percent of patients with asthma have severe disease, and the majority of those have type 2 or eosinophilic phenotypes. Biologics such as benralizumab (an anti–interleukin-5 receptor-α monoclonal antibody) can be very effective for preventing exacerbations and possibly reducing inhaled corticosteroid (ICS) exposure.

In a 32-week industry-funded international study published in The Lancet (https://doi.org/10.1016/S0140-6736(23)02284-5), researchers randomized 208 adults whose severe eosinophilic asthma was well controlled on benralizumab to continue high-dose ICS–formoterol therapy or to gradually taper it to only as-needed use. Patients in the dose-reduction group initially used their ICS/formoterol as both maintenance and rescue therapy (MART); 92% were able to reduce their high-dose ICS, and 62% were able to transition to only as-needed use, without worsening asthma control during an additional 16-week maintenance period.

We frequently step up ICS dosing in patients with uncontrolled asthma but then forget to step back down. Dose-response curves for ICS are steep, with most benefit realized at low doses. Guidelines recommend reducing ICS dosing in patients whose asthma is well controlled for 3 months (https://www.nhlbi.nih.gov/health-topics/asthma-management-guidelines-2020-updates). MART is a great way to step down in patients whose asthma is well controlled on biologics — or for any well-controlled patient. With available U.S. formulations, I would recommend the following sequence for stepping down inhaled therapy:

• High dose: Budesonide/formoterol (160/4.5) at 2 puffs twice daily

• Medium dose: Budesonide/formoterol (160/4.5) at 1 puff twice daily plus 1 puff as needed for symptoms

• Low dose: Budesonide/formoterol (80/4.5) at 1 puff twice daily plus 1 puff as needed for symptoms

• Reliever only: Budesonide/formoterol (80/4.5) at 1 puff as needed for symptoms.

David J. Amrol, MD

Holding Off on Intubation for Airway Protection After a Toxic Ingestion

Many patients who present to the emergency department with decreased level of consciousness after a toxic ingestion are intubated for “airway protection” to lower risk for aspiration. In situations where relatively rapid clearance occurs and alertness improves, intubation might be unnecessary.

In a study in JAMA (https://doi.org/10.1001/jama.2023.24391), French investigators randomized 225 patients with acute poisoning and decreased level of consciousness (Glasgow Coma Scale https://www.mdcalc.com/calc/64/Glasgow-coma-scale-score-gcs, <9) to one of two groups. In one group, intubation was withheld unless seizure, respiratory distress, vomiting, or shock developed. In the other group, intubation was optional and at the emergency medicine physician’s discretion. Patients were monitored closely for 4 hours after randomization and then all were treated with usual care. Patients were excluded if they had ingested a single agent with an easily accessible reversal medication (e.g., opioid) or a cardiotropic drug (e.g., calcium-channel blocker). Two thirds of patients had alcohol intoxication, one third had ingested benzodiazepines, and some patients had more than one toxin identified.

Patients in the withhold-intubation group were significantly less likely than those in the physician-discretion group to be intubated (16% vs 58%). They also were less likely to be admitted to the intensive care unit (ICU) and had shorter median ICU length of stay (LOS). No patient died, and incidence of pneumonia was similar in both groups.

We should have a higher threshold for intubating patients for airway protection after acute ingestion, particularly alcohol intoxication. This is distinct from intubation to support ventilation, which often is required when the toxin also depresses respiratory drive.

Patricia Kritek, MD

Pheochromocytoma: A Contemporary Case Series

In recent years, pheochromocytomas are detected increasingly in patients with incidentally discovered adrenal masses, rather than in patients with classic adrenergic symptoms. A report in The Journal of Clinical Endocrinology & Metabolism (https://doi.org/10.1210/clinem/dgad401) describes 167 patients with pheochromocytoma who were evaluated and treated at a U.K. referral center between 2010 and 2022. Findings were as follows:

• After excluding 20 patients whose pheochromocytomas were detected by screening (because of family history), 69% of cases were diagnosed in patients with adrenal incidentalomas, 28% in patients with adrenergic symptoms/uncontrolled hypertension, and 3% in patients with acute cardiomyopathy.

• 40% of patients whose pheochromocytomas were incidentalomas described adrenergic symptoms in retrospect, and 36% had known hypertension.

• Patients with incidentalomas were much older than those who presented because of adrenergic symptoms/uncontrolled hypertension (median ages, 62 vs 42).

• Median metanephrine levels were much higher in patients with adrenergic symptoms/uncontrolled hypertension than in those with incidentalomas (≈15-fold vs 5-fold elevation above upper limit of normal).

• On unenhanced computed tomography (CT), no pheochromocytoma was a homogeneous lesion with unenhanced density ≤10 Hounsfield units (HU).

• Four patients had metastatic lesions at presentation.

This case series provides a good contemporary overview of pheochromocytoma. Two guidelines published in 2023 recommend that patients with adrenal incidentalomas generally should undergo evaluation for pheochromocytoma; the exception is the asymptomatic patient whose CT-identified lesion is typical for a benign adenoma — i.e., homogeneous, unenhanced density ≤10 HU (https://doi.org/10.1093/ejendo/lvad066; https://doi.org/10.1097/JU.0000000000003644).

Allan S. Brett, MD

Easily Calculated Score Estimates Risks for Dementia & Stroke

Dementia and stroke often have devastating consequences, so patients want to know what they can do to protect themselves against these diseases. A team of clinicians in partnership with patients developed a Brain Care Score (BCS) based on modifiable risk factors identified in past epidemiological studies.

In the BCS, weights are assigned to four physical components (i.e., blood pressure, glycosylated hemoglobin, cholesterol, and body-mass index), to five lifestyle elements (i.e., nutrition, alcohol intake, smoking, aerobic activities, and sleep), and to three social factors (i.e., stress, relationships, and purpose in life). Lower scores on the BCS (range, 0-19) predict higher risk (https://www.frontiersin.org/files/Articles/1291020/fneur-14-1291020-HTML/image_m/fneur-14-1291020-g001.jpg).

The team then validated whether the BCS predicted new dementia or stroke in the U.K. Biobank cohort, which consisted of 398,900 people (age range at baseline, 40-69). Details appear in Frontiers in Neurology (https://doi.org/10.3389/fneur.2023.1291020). During average follow-up of nearly 13 years, new dementia or stroke occurred in ≈3% of the cohort. The BCS identified people who were at highest risk for these outcomes. For example, among those who were younger than 50 at baseline, a 5-point higher score predicted 59% lower risk for dementia and 48% lower risk for stroke.

This score could be computed automatically from information already in electronic health records and used to identify risk factors and to engage patients in modifying those risk factors. Whether such scoring would actually lead to lower incidences of dementia and stroke remains to be seen.

Anthony L. Komaroff, MD

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.

Access additional content, included with your subscription, at jwatch.org.

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. The planning committee members reported that they had nothing to disclose.

Acknowledgements

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.75 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.75 CE contact hours.

Lecture ID:

JW350202

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.

More Details - Certification & Accreditation