Cross-Over Trial: How Much Does Dietary Sodium Impact Blood Pressure?

BACKGROUND AND PURPOSE:

• The blood pressure (BP) response to sodium intake can vary widely even within individuals
• Gupta et al. (JAMA, 2023) examined the BP response to dietary sodium within and between individuals

METHODS:

• Prospective, multicenter, observational cohort study
  • CARDIA study: Goal to identify the factors in young adulthood influencing development of CVD
  • Enrollment occurred in 1985 to 1986
• Participants
  • Current study
    • US adults aged 50 to 75
    • Exclusion: Systolic BP outside 90 to 160 mm Hg | Diastolic BP outside 50 to 100 mm Hg
• Exposures
  • Normotension | Controlled hypertension | Uncontrolled hypertension | Untreated hypertension
• Interventions
  • 1-week usual diet
  • 1-week high-sodium diet: 2200 mg/day in addition to daily diet
  • 1-week low sodium diet: 500 mg daily total
• Study design
  • Community cross-over trial
  • 4 study visits: Enrollment | Baseline | End of the first diet week | End of the second diet week
    • Latter 3 occurring over consecutive 1-week intervals
  • Salt sensitive: Defined as ≥5 mm Hg decline in mean arterial pressure between a high-sodium and a low-sodium diet
  • 24-hour urine collections for assessment of dietary adherence
  • Subgroup analysis: Age | Sex | Race | Hypertension | Baseline BP | Diabetes | BMI 
• Primary outcomes
  • Average 24-hour ambulatory systolic and diastolic BP
  • Mean arterial pressure (MAP)
  • Pulse pressure

RESULTS:

• 213 participants
  • Normotension: 25% | Controlled hypertension: 20% | Uncontrolled hypertension: 31% | Untreated hypertension: 25%
  • Median age: 61 years | Female: 65% | Black: 64%
• Median systolic BP measures
  • Usual diet: 125 mm Hg
  • High-sodium: 126 mm Hg
  • Low-sodium: 119 mm Hg
• The median within-individual change MAP between high- and low-sodium diets was not impacted by hypertension status
  • 4 mm Hg (IQR, 0 to 8) | P<0.001
  • 46% met criteria met traditional definition of ‘salt sensitive’ based on ≥5 mm Hg change
• There was a decrease in within-individual MAP in the majority of participants with lower dietary sodium intake
  • Low-sodium MAP decline: 73.4%  
• Mean systolic BP difference between individuals allocated to a high-sodium vs a low-sodium diet
  • 8 mm Hg (95% CI, 4 to 11) | P<0.001
  • Not statistically different between subgroups
• Adverse events were mild

CONCLUSION:

• The majority of older adults who lowered dietary sodium experienced a reduction in mean arterial pressure
• This decline was not associated with hypertension status or use of antihypertensive medication
• The authors state

That none of the classes of antihypertensive medications was consistently associated with the BP response to dietary sodium emphasizes the importance of continued lifestyle modification even among individuals with treated hypertension

Learn More – Primary Sources:

Effect of Dietary Sodium on Blood Pressure: A Crossover Trial

RCT Results: Does Semaglutide Reduce Cardiovascular Events for Patients with Overweight/Obesity without Diabetes?

BACKGROUND AND PURPOSE:

• As a treatment for overweight and obesity, semaglutide, a GLP-1 receptor agonist, can reduce the risk of cardiovascular disease in patients with diabetes
• Lincoff et al. (NEJM, 2023) assessed whether semaglutide also reduces the risk of major adverse cardiovascular events among patients with overweight or obesity and preexisting cardiovascular disease who did not have diabetes

METHODS:

• Multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial
• Participants
  • ≥45 years
  • Preexisting cardiovascular disease
  • BMI ≥27
  • No history of diabetes
• Interventions
  • Once-weekly subcutaneous semaglutide (2.4 mg/dose)
  • Placebo
• Primary outcome
  • Composite: Death from cardiovascular causes | Nonfatal myocardial infarction | Nonfatal stroke

RESULTS:

• Semaglutide: 8803 participants | Placebo: 8801
  • Mean duration of exposure: 34.2 (SD, 13.7) months
  • Mean duration of follow-up: 39.8 (SD, 9.4) months
• Primary cardiovascular end-point events were less common in the semaglutide group
  • Semaglutide: 6.5% | Placebo: 8.0%
  • Hazard ratio 0.80 (95% CI, 0.72 to 0.90) | P<0.001
• Adverse events that led to the permanent discontinuation of treatment occurred in more semaglutide patients than placebo patients
  • Semaglutide: 16.6% | Placebo: 8.2% | P<0.001

CONCLUSION:

• Semaglutide significantly reduced the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke for patients with preexisting cardiovascular disease and overweight or obesity but without diabetes
• The authors state

An important limitation of this trial is that we included only patients with preexisting cardiovascular disease

The effects of semaglutide on primary prevention of cardiovascular events in persons with overweight or obesity but without previous atherosclerotic disease were not studied

Learn More – Primary Sources:

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

GRADE Trial Results: Do Secondary Diabetes Medications Impact Microvascular Complications or Cardiovascular Events?

BACKGROUND AND PURPOSE:

• The metabolic results of the GRADE trial were recently published, with researchers finding that glargine and liraglutide were more effective than glimepiride and sitagliptin in maintaining glycemic targets when combined with metformin for type 2 diabetes
• The GRADE Study Research Group (NEJM, 2022) presents the effects of these therapies on prespecified secondary outcomes, including microvascular complications and cardiovascular events

METHODS:

• Multicenter, parallel-group, comparative-effectiveness clinical trial
• Participants
  • Adults with type 2 diabetes receiving metformin
• Interventions
  • Insulin glargine U-100 (referred to as glargine)
  • Glimepiride (a sulfonylurea)
  • Liraglutide (a glucagon-like peptide-1 receptor agonist)
  • Sitagliptin (a dipeptidyl peptidase 4 inhibitor)
• Study design
  • Hazard ratios (HR) are presented with 95% confidence limits that are not adjusted for multiple comparisons
• Secondary outcomes
  • Hypertension and dyslipidemia
  • Renal: Confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area
  • Diabetic peripheral neuropathy
    • Assessed with the Michigan Neuropathy Screening Instrument
  • Cardiovascular events
    • Major adverse cardiovascular events (MACE) | Hospitalization for heart failure | Aggregate outcome of any cardiovascular event
  • Death

RESULTS:

• 5047 participants
  • Mean follow-up: 5.0 years
• There were no material differences among the interventions with respect to
  • The development of hypertension or dyslipidemia
  • Microvascular outcomes
• Mean overall rates of renal outcomes
  • Moderately increased albuminuria levels: 2.6 events per 100 participant-years
  • Severely increased albuminuria levels: 1.1 events per 100 participant-years
  • Renal impairment: 2.9 events per 100 participant-years
  • Diabetic peripheral neuropathy: 16.7 events per 100 participant-years
• The treatment groups did not differ in
  • MACE
    • Overall rate 1.0 events per 100 participant-years
  • Hospitalization for heart failure
    • Overall rate 0.4 events per 100 participant-years
  • Death from cardiovascular causes
    • Overall rate: 0.3 events per 100 participant-years
  • All deaths
    • Overall rate 0.6 events per 100 participant-years
• There were small differences in the rates of any cardiovascular disease
  • Glargine: 1.9 events per 100 participant-years
  • Glimepiride: 1.9 events per 100 participant-years
  • Liraglutide: 1.4 events per 100 participant-years
  • Sitagliptin: 2.0 events per 100 participant-years
• When one treatment was compared with the combined results of the other three treatments, the HRs for any cardiovascular disease were
  • Glargine: HR 1.1 (95% CI, 0.9 to 1.3)
  • Glimepiride: HR 1.1 (95% CI, 0.9 to 1.4)
  • Liraglutide: HR 0.7 (95% CI, 0.6 to 0.9)
  • Sitagliptin: HR 1.2 (95% CI, 1.0 to 1.5)
• Comparing liraglutide vs the other 3 groups combined demonstrated a reduced risk of any cardiovascular disease
  • HR 0.71 (95% CI, 0.56 to 0.90)

CONCLUSION:

• There were no major differences in microvascular complications and death among the groups receiving the four secondary diabetes treatment medications
• There may have been some small difference in the incidence of any cardiovascular disease between the groups
• The authors state

The absence of the expected effect of lower glycemia on microvascular complications has been noted in some trials, including studies of diabetes prevention, and this absence has been ascribed to inadequate separation of glycemic levels over time, insufficient trial duration, threshold effects, or inadequate power

Any or all of these factors, including the small separation in glycemia might have been operative in our trial

Learn More – Primary Sources:

Glycemia Reduction in Type 2 Diabetes — Microvascular and Cardiovascular Outcomes

Meta-Analysis: Pain Management in the ED: How Do Nonoral Acetaminophen, NSAIDs, and Opioids Compare?

BACKGROUND AND PURPOSE:

• Qureshi et al. (BMJ Emergency Medicine Journal, 2023) used meta-analysis to evaluate the level of analgesia provided by paracetamol (IVP) alone compared with NSAIDs (intravenous or intramuscular), or opioids (intravenous) alone in adults with acute pain in the emergency department setting

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Randomize trials
  • Studies that assessed adults in the ED with moderate to severe pain managed with paracetamol, NSAIDs, or opioids
  • Studies in which orally administered medications were excluded
• Primary outcome
  • Pain reduction at 30 min (T30) post analgesia delivery
• Secondary outcomes
  • Pain reduction at T60, T90 and T120
  • The need for rescue analgesia
  • Adverse events

RESULTS:

• 27 trials | 5427 patients (25 trials | 5006 patients in the meta-analysis)

Pain Reduction

• There was no significant difference in pain reduction at T30 between
  • IVP vs opioids: mean difference (MD) −0.13 (95% CI, −1.49 to 1.22)
  • IVP vs NSAIDs: MD −0.27 (95% CI, −1.0 to 1.54)
• There was no significant difference in pain reduction at T60
  • IVP vs opioids: MD −0.09 (95% CI, −2.69 to 2.52)
  • IVP vs NSAIDs: MD 0.51 (95% CI, 0.11 to 0.91)

Rescue Analgesia

• The need for rescue analgesia at T30 was significantly higher in the IVP group compared with the NSAID group
  • Risk ratio (RR) 1.50 (95% CI, 1.23 to 1.83)
• There was no difference in need for rescue analgesia at T30 for the IVP group vs the opioid group
  • RR 1.07 (95% CI, 0.67 to 1.70)

Adverse Events

• Adverse events were fewer in the IVP group compared to opioids
  • RR 0.50 (95% CI, 0.40 to 0.62)
• There was no difference for the IVP group compared to the NSAID group
  • RR 1.30 (95% CI, 0.78 to 2.15)

CONCLUSION:

• After 30 minutes, intravenous paracetamol provides the same amount of pain relief as opioids or NSAIDs for patient with moderate to severe pain in the ED
• The authors state

Patients treated with NSAIDs had lower risk of rescue analgesia, and opioids cause more AEs, suggesting NSAIDs as the first-choice analgesia and IVP as a suitable alternative

Learn More – Primary Sources:

Comparison of intravenous paracetamol (acetaminophen) to intravenously or intramuscularly administered non-steroidal anti-inflammatory drugs (NSAIDs) or opioids for patients presenting with moderate to severe acute pain conditions to the ED: systematic review and meta-analysis

Does Concurrent Use of Hormonal Contraception and NSAIDs Increase the Risk of Venous Thromboembolism?

BACKGROUND AND PURPOSE:

• The use of hormonal contraception and NSAIDs are individual risk factors for venous thromboembolism (VTE)
• Meaidi et al. (BMJ, 2023) assess the incidence of VTE in women using hormonal contraception and NSAIDs simultaneously

METHODS:

• Nationwide cohort study
  • National Danish registry | Personal ID numbers
• Population
  • All 15 to 49-year-old women living in Denmark between 1996 and 2017
  • Exclusion: Venous or arterial thrombotic event | Cancer | Thrombophilia | Hysterectomy | Bilateral oophorectomy | Sterilization | Infertility
• Exposures
  • Concurrent use of hormonal contraception and NSAIDs
  • Examples of NSAIDs include ibuprofen, diclofenac, and naproxen
• Study design
  • High-risk hormonal contraceptives
    • Combined estrogen and progestin patch
    • Vaginal ring
    • Tablets:  50 µg ethinyl estradiol | Progestins (desogestrel, gestodene, drospirenone) | Anti-androgen: cyproterone
  • Medium-risk hormonal contraception
    • All other combined oral contraceptives
    • Medroxyprogesterone injection
  • Low/no risk hormonal contraceptives
    • Progestin-only tablets
    • Implants
    • Hormonal IUDs
• Primary outcome
  • A first-time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism

RESULTS:

• 2.0 million women | 21.0 million person-years of follow-up
  • VTE events: 8710
• Compared with non-use of NSAIDs, use of NSAIDs was associated with a higher adjusted incidence rate ratio (aIRR) of VTE in women
  • Not using hormonal contraception
    • aIRR 7.2 (95% CI, 6.0 to 8.5)
  • Using high risk hormonal contraception
    • aIRR 11.0 (95% CI, 9.6 to 12.6)
  • Using medium risk hormonal contraception
    • aIRR 7.9 (95% CI, 5.9 to 10.6)
  • Using low/no risk hormonal contraception
    • aIRR 4.5 (95% CI, 2.6 to 8.1)
• Number of extra VTE events over the first week of NSAID treatment compared with non-use of NSAIDs
  • Not using hormonal contraception
    • 4 (95% CI, 3 to 5) per 100,000 women
  • Using high risk hormonal contraception
    • 23 (95% CI, 19 to 27) per 100,000 women
  • Using medium risk hormonal contraception
    • 11 (95% CI, 7 to 15) per 100,000 women
  • Using low/no risk hormonal contraception
    • 3 (95% CI, 0 to 5) per 100,000 women

CONCLUSION:

• Reproductive-age women who used NSAIDs were more likely to develop VTE than non-users
• The number of VTE events was significantly higher in women using NSAIDs with high/moderate risk hormonal contraception vs low-risk contraception or no hormonal contraception use
• The authors state

Despite the high incidence rate ratios, the absolute risk of venous thromboembolic event in the first week after NSAID purchase remained low even in users of high risk hormonal contraception (0.02%)

• A related editorial states

Among individual NSAIDs, the association was strongest for the older COX-2 inhibitor diclofenac (12-fold increased risk in women not using hormonal contraception)

These data add to existing evidence and concerns about the cardiovascular safety of diclofenac

Learn More – Primary Sources:

Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study

Editorial: NSAIDs, hormonal contraception, and venous thromboembolism

Should 37°C be Considered the Benchmark for ‘Normal’ Oral Temperature?

BACKGROUND AND PURPOSE:

• The “normal” oral temperature of 37°C was established in 1851 based on a population mean
• Ley et al. (JAMA Internal Medicine, 2023) determined normal oral temperature ranges by age, sex, height, weight, and time of day

METHODS:

• Cross-sectional study
  • Temperature values from all adult outpatient encounters at Stanford Health Care
  • Application of LIMIT (Laboratory Information Mining for Individualized Thresholds), a machine learning algorithm that filters data sets to generate a ‘normal’ distribution
• Population
  • All adult outpatient encounters that included temperature measurements in a large medical care system
• Exposures
  • Primary diagnoses | Medications | Age | Sex | Height | Weight | Time of day | Month
• Study design
  • LIMIT removed overrepresented primary diagnoses in the temperature distribution tails leaving diagnoses unrelated to temperature
  • Mixed-effects model used to
    • Identify independent factors associated with normal oral temperature
    • Generate normal temperature ranges
• Primary outcome
  • Normal temperature ranges by exposure

RESULTS:

• 618,306 patient encounters with temperature data
  • Removed by LIMIT: 35.9%
  • Encounters removed were primarily linked to infectious diseases and type 2 diabetes
• 396,195 included patient encounters | 126,705 patients
  • Mean age: 52.7 (SD, 15.9) years | Women: 57.35%
• After running LIMIT, the mean temperature was 36.64°C (SD, 0.35°C)
  • Central 95% of these temperatures were between 35.95°C and 37.33°C
• Age, sex, height, weight, and time of day accounted for variability in temperature
  • Overall: 6.86%
  • Per patient: 25.52%
• Mean normal oral temperature did not reach 37°C for any subgroup
• The upper 99^th percentile ranged from
  • 36.81ºC (a tall man with underweight aged 80 years at 8:00 am)
  • 37.88ºC (a short woman with obesity aged 20 years at 2:00 pm)

CONCLUSION:

• The mean usual or “normal” oral temperature is 36.64°C
• Body temperature varies as expected by age, weight, sex, and time of day
• The authors state

Given that body temperature is a rough marker of metabolic rate, it is reasonable to conclude that metabolic rate has decreased over time

Reasons for such a decrease in metabolic rate remain speculative but likely include a reduction in inflammation, due in part to reduced chronic infections, improved dental care, and access to anti-inflammatory medications such as statins and nonsteroidal anti-inflammatory drugs

Learn More – Primary Sources:

Defining Usual Oral Temperature Ranges in Outpatients Using an Unsupervised Learning Algorithm

Meta-Analysis: Do Cholinesterase Inhibitors Improve Psychotic Symptoms in Patients with Neurodegenerative Disorders?

BACKGROUND AND PURPOSE:

• d’Angremont et al. (JAMA Neurology, 2023) assessed the use of cholinesterase inhibitors (ChEIs) for treatment of individual neuropsychiatric symptoms in patients Alzheimer disease (AD), Parkinson disease (PD), and dementia with Lewy bodies (DLB)

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Randomized controlled trials
  • Studies that including at least 1 donepezil, rivastigmine, or galantamine treatment arm in patients with AD, PD, or DLB, compared to placebo, and measured at least one neuropsychiatric symptom, such as hallucinations and/or delusions
• Study design
  • A 2-stage meta-analysis was performed using random-effects models
    • First stage: Data is collected from each study separately and analyzed individually
    • Second stage: The summarized or aggregated data from each study is combined to perform a meta-analysis
• Primary outcomes
  • Hallucinations and delusions
• Secondary outcomes
  • All other individual neuropsychiatric subdomains
  • The total neuropsychiatric score

RESULTS:

• 17 RCTs | 6649 individuals
  • Women: 62.6% | Mean age: 75.0 (SD, 8.2) years
  • AD: 12 | PS: 5
• ChEI treatment was associated with a reduction in delusions and hallucinations
  • Delusions
    • AD: SMD −0.08 (95% CI, −0.14 to −0.03) | P=0.006
    • PD: SMD −0.14 (95% CI, −0.26 to −0.01) | P=0.04
  • Hallucinations
    • AD: SMD −0.09 (95% CI, −0.14 to −0.04) | P=0.003
    • PD: SMD −0.08 (95% CI, −0.13 to −0.03) | P=0.01

CONCLUSION:

• ChEI treatment improves hallucinations and delusions in patients with neurodegenerative disease, but effect sizes are small
• The authors state

Psychotic symptoms appear to significantly increase the disease burden for patients and caregivers, and alternative treatment with, for instance, antipsychotic medication has been associated with serious adverse effects

Therefore, our data may provide an extra reason to consider ChEI treatment as a first-line pharmacotherapy for psychotic symptoms in people with AD and PD

Learn More – Primary Sources:

Cholinesterase Inhibitors for Treatment of Psychotic Symptoms in Alzheimer Disease and Parkinson Disease: A Meta-analysis

How Does a New Sepsis Prediction Model Compare to Other Sepsis Determinations Models?

BACKGROUND AND PURPOSE:

• There are multiple established sepsis determination models such as SIRS, qSOFA, and SOFA
• A new prediction model, the Sepsis Prediction Model (SPM), a proprietary decision support tool created by Epic Systems, has not yet been evaluated against the established models
• Schertz et al. (JAMA Network Open, 2023) assessed the validity and timeliness of the SPM compared with SIRS, qSOFA, and SOFA

METHODS:

• Retrospective cohort study
  • 5 US Hospitals within a single system
  • Between June 2019 and December 2020
• Population
  • Adults admitted to US acute care hospitals
• Exposures
  • Sepsis prediction models (SIRS, qSOFA, and SOFA, and SPM)
• Study design
  • Time zero was defined as 15 minutes prior to qualifying antimicrobial or blood culture order
  • Sepsis was defined as receipt of 4 or more days of antimicrobials | Blood cultures collected within ±48 hours of initial antimicrobial | ≥1 organ dysfunction
• Primary outcomes
  • The ability of each of the prediction models to classify sepsis admissions
  • The timeliness of each tool with respect to time zero

RESULTS:

• 60,507 total admissions
  • Met sepsis criteria: 2.7%
• Within the vendor recommended predicting sepsis score (PSS) of 5 to 8, the SPM had the highest balanced accuracy for classifying a sepsis admission with a score of ≥8
• The greatest sensitivity for determining sepsis was achieved with change in SOFA score of ≥2
• Median time to score positivity from time zero varied widely among the different tests
  • At a PSS of ≥8: 68.00 (IQR, 6.75 to 605.75) minutes
  • SIRS: 7.00 (IQR, −105.00 to 08.00) minutes
  • qSOFA: 74.00 (IQR, −22.25 to 599.25) minutes
  • SOFA: 28.00 (IQR, −108.50 to 134.00) minutes

CONCLUSION:

• The balanced accuracy at predicting sepsis was higher for SPM, especially at a higher threshold PSS
• However, SIRS and SOFA both far outperformed SPM for timeliness
• The authors state

In the case of sepsis, prioritization of timely treatment is paramount, given the potentially severe consequences when the diagnosis is missed or delayed

Learn More – Primary Sources:

Sepsis Prediction Model for Determining Sepsis vs SIRS, qSOFA, and SOFA

Does ChatGPT Accurately Cite Scientific Sources?

BACKGROUND AND PURPOSE:

• ChatGPT performs well when generating new content, but performs poorly when providing scientific references
• Chen and Chen (JAMA Network Open, 2023) quantified ChatGPT’s citation error rate

METHODS:

• Study design
  • The GPT-3.5 and GPT-4 models were used
  • ChatGPT was asked about specific learning health systems topics followed by citation request
    • E.g., “Machine learning can use EHR data. Provide 8 journal articles for stroke risk prediction models using EHR data”
  • Cited journal articles were verified using Google Scholar
    • To determine a reliable error rate, over 300 article references were produced on the LHS topics
  • The error rate between the GPT-4 and GPT-3.5 models was compared using the Fisher exact test
• Primary outcome
  • Error rate in citing scientific articles

RESULTS:

• When asked to provide citations, the error rate was significantly higher for GPT-3.5, compared to GPT-4 (P<0.001), but both had high error rates
  • GPT-3.5: 98.1% (95% CI, 94.7 to 99.6)
  • GPT-4: 20.6% (95% CI, 15.8 to 26.1)
• Narrower topics tended to have more fake articles than broader topics

CONCLUSION:

• GPT-4 could be used to provide citations regarding new learning health systems education and training materials, provided they are verified by humans
• The authors state

When asked why it returned fake references, ChatGPT explained that the training data may be unreliable, or the model may not be able to distinguish between reliable and unreliable sources

Learn More – Primary Sources:

Accuracy of Chatbots in Citing Journal Articles

FDA Finalizes New Mammography Dense Breast Notification Rule

SUMMARY:

The FDA has updated the mammography regulations and now requires that mammography facilities notify patients about the density of their breasts. The amendments incorporate language that specifies how breast density can influence the accuracy of mammography in addition to recommending a discussion with their healthcare professional. The rule goes into effect September 10, 2024. Currently, the ACOG committee opinion states unequivocally that healthcare professionals comply with all laws, although evidence is lacking as to clinical utility and improved outcomes with additional screening and testing.

Summary of Results to be Provided to Patients (FDA Rule)

Non-Dense Breast

Breast tissue can be either dense or not dense

Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer

Your breast tissue is not dense

Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation

Dense Breast

Breast tissue can be either dense or not dense

Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer

Your breast tissue is dense

In some people with dense tissue, other imaging tests in addition to a mammogram may help find cancers

Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation

ACOG

• The current ACOG Practice Advisory States

While ACOG does not recommend routine use of alternative or adjunctive tests to screening mammography in individuals with dense breasts who are asymptomatic and have no additional risk factors, ACOG recommends that clinicians comply with the new FDA rule and any state laws and federal rules that require disclosure of a patient’s breast density as recorded in a mammogram report

BI-RADS Density Categories (for more on BI-RADS classification, see ‘Related ObG Topics’ Below)

• a. Breasts are almost entirely fatty
  • Prevalence: 10%
  • Mammography considered highly sensitive in this setting (88%)
• b. There are scattered areas of fibroglandular density
  • Prevalence: 43%
  • Still sensitive but decreased from category a (82%)
• c. Breasts are heterogeneously dense
  • Prevalence: 39%
  • Small masses may be obscured
  • Sensitivity drops to 69%
• d. Breasts are extremely dense
  • Prevalence: 8%
  • Significantly lowers sensitivity of mammography (62%)

KEY POINTS:

• Dense breast tissue and screening is more common in younger women
  • Accuracy of mammography for the detection of breast cancer is reduced (less sensitive)
  • In women with heterogeneously and extremely dense breasts, digital mammography appears to be superior to film with respect to efficacy
• Breast cancer risk
  • Dense breast tissue (BI-RADS density categories c and d) is associated with increased breast cancer risk
  • BI-RADS c breast cancer risk: 1.2 relative risk compared to average breast density
  • BI-RADS d breast cancer risk: 2.1 relative risk compared to average breast density
• The FDA also has required reporting language that should be provided to the referring healthcare professional that falls into 4 categories

(A) The breasts are almost entirely fatty

(B) There are scattered areas of fibroglandular density

(C) The breasts are heterogeneously dense, which may obscure small masses

(D) The breasts are extremely dense, which lowers the sensitivity of mammography

Learn More – Primary Sources:

FDA Updates Mammography Regulations to Require Reporting of Breast Density Information and Enhance Facility Oversight (2023)

ACOG Committee Opinion 625: Management of Women With Dense Breasts Diagnosed by Mammography

ACOG Practice Advisory: The U.S. Food and Drug Administration Requires Notification of Breast Density in Mammography Reports

Is Caffeine Consumption Linked to Lower BMI and Risk of Type 2 Diabetes

BACKGROUND AND PURPOSE:

• Coffee consumption has been linked with a lower risk of type 2 diabetes and cardiovascular disease in observational studies
• Larsson et al. (BMJ, 2023) investigate the potential causal effects of long-term plasma caffeine concentrations on adiposity, type 2 diabetes, and major cardiovascular diseases using mendelian randomization to determine causality

METHODS:

• Two sample mendelian randomization study
• Population
  • Primarily European ancestry
  • Participating in cohorts contributing to genome-wide association study consortia
• Exposures
  • Genome-wide association study summary data for associations of two single nucleotide polymorphisms associated with plasma caffeine at the genome-wide significance threshold
    • rs2472297 near the CYP1A2 gene
    • rs4410790 near the AHR gene
• Primary outcomes
  • BMI | Whole body fat mass | Whole body fat-free mass | Type 2 diabetes | Ischemic heart disease | Atrial fibrillation | Heart failure | Stroke

RESULTS:

• 9876 individuals
• Higher genetically predicted plasma caffeine concentrations were associated with lower
  • BMI
    • Beta −0.08 standard deviation (95% CI, −0.10 to −0.06)
    • 1 SD equals about 4.8 kg/m2 in BMI, for every standard deviation increase in plasma caffeine
  • Whole body fat mass
    • Beta −0.06 SD (95% CI, −0.08 to −0.04)
    • 1 SD equals about 9.5 kg | P<0.001
• There was no association with fat-free mass
  • Beta −0.01 SD (95% CI, −0.02 to −0.00)
  • 1 SD equals about 11.5 kg | P=0.17
• Higher genetically predicted plasma caffeine concentrations were associated with a lower risk of type 2 diabetes (two consortia: FinnGen and DIAMANTE)
  • Combined OR 0.81 (95% CI, 0.74 to 0.89) | P<0.001
• Approximately half of the effect of caffeine on type 2 diabetes was estimated to be mediated through BMI reduction
  • 43% (95% CI, 30 to 61)
• There were no strong associations between genetically predicted plasma caffeine concentrations and a risk of any of the studied cardiovascular diseases

CONCLUSION:

• A genetic prediction of lifelong, higher plasma caffeine concentrations was associated with a lower BMI and lower risk of type 2 diabetes
• The authors state

Approximately half of the effect of caffeine on type 2 diabetes was estimated to be mediated through body mass index reduction 

Learn More – Primary Sources:

Appraisal of the causal effect of plasma caffeine on adiposity, type 2 diabetes, and cardiovascular disease: two sample mendelian randomisation study

Meta-Analysis: Protection Against SARS-CoV-2 From Previous Infection

BACKGROUND AND PURPOSE:

• The COVID-19 Forecasting Team (The Lancet, 2023) systematically synthesized studies to estimate protection from past infection by SARS-CoV-2

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Cohort studies and test-negative case-control studies
  • Compared risk reduction of COVID-19 among individuals with a past SARS-CoV-2 infection vs those without a previous infection
• Study design
  • Primary outcome was based upon variants and time since infection
  • Bayesian meta-regression was used to estimate the pooled estimates of protection
  • Risk-of-bias assessment was evaluated using quality-assessment tools
• Primary outcome
  • Effectiveness of past infection by outcome against infection, symptomatic disease, and severe disease

RESULTS:

• 65 studies (19 countries)
• Protection from infection and any symptomatic disease was
  • High for ancestral, alpha, beta, and delta variants
  • Lower for the omicron BA.1 variant
    • Against re-infection: 45.3% (95% uncertainty interval (UI), 17.3 to 76.1)
    • Against symptomatic disease: 44.0% (95% UI, 26.5 to 65.0)
• For all variants, protection against re-infection declined over time
  • From ancestral, alpha, and delta variants, this protection declined over time, but remained at 78% for 40 weeks
  • Protection against re-infection by the omicron BA.1 variant declined more rapidly | At 40 weeks: 36.1% (95% UI, 24.4 to 51.3)
• For all variants, mean pooled effectiveness against severe disease was greater than 78%
• Protection against severe disease remained high for all variants
  • Ancestral, alpha, and delta variants at 40 weeks: 90.2% (95% UI, 69.7 to 97.5)
  • Omicron BA.1 at 40 weeks: 88.9% (95% UI, 84.7 to 90.9)

CONCLUSION:

• Protection against re-infection was high and remained high for ancestral SARS-CoV-2 variants
  • For Omicron BA.1, this protection waned more quickly, and was around 36% at 40 weeks
• Protection against severe disease was high for all variants, and remained high for all
• The authors state

Our analysis suggests that the level of protection from past infection by variant and over time is at least equivalent if not greater than that provided by two-dose mRNA vaccines

Learn More – Primary Sources:

Past SARS-CoV-2 infection protection against re-infection: a systematic review and meta-analysis

STI Detection Assays: Are Vaginal Swabs Better Than Urine Samples?

BACKGROUND AND PURPOSE:

• Vaginal swabs are recommended for detection of chlamydia, gonorrhea, and/or trichomoniasis, but many commercially available kits use urine samples
• Aaron et al. (Ann Fam Med, 2023) assessed the diagnostic sensitivity of commercially available assays for vaginal swabs vs urine specimens from women

METHODS:

• Systematic review and meta-analysis
• Study inclusion criteria
  • Studies that evaluated commercially available STI assays
  • Data obtained from the same assay on both a urine specimen and a vaginal swab from the same patient
• Study design
  • Pooled estimates of sensitivity were calculated, as well as odds ratios for any difference in performance
• Primary outcome
  • Sensitivity of tests for detecting chlamydia, gonorrhea, and trichomoniasis

RESULTS:

• 28 articles
  • Comparisons for chlamydia: 30 | Gonorrhea: 16 | Trichomoniasis: 9
• Pooled sensitivity estimates were higher for vaginal swabs for all infections (P<0.001 for all)
  • Chlamydia
    • Vaginal swabs: 94.1% (95% CI, 93.2% to 94.9%) | Urine samples: 86.9% (95% CI, 85.6% to 88.0%) 
    • Odds ratio (OR) that vaginal swabs were more sensitive than urine for detection: 2.69 (95% CI, 2.21 to 3.28); P<.001
  • Gonorrhea
    • Vaginal swabs: 96.5% (95% CI, 94.8% to 97.7%) | Urine samples: 90.7% (95% CI, 88.4% to 92.5%) 
    • OR that vaginal swabs were more sensitive than urine for detection: 3.68 (95% CI, 2.19 to 6.18); P<.001
  • Trichomoniasis
    • Vaginal swabs: 98.0% (95% CI, 97.0% to 98.7%) | Urine samples: 95.1% (95% CI, 93.6% to 96.3%) 
    • The difference in sensitivity was not statistically significant: OR of 2.48 (95% CI, 1.50 to 4.08); P=0.15

CONCLUSION:

• Compared to urine samples, vaginal swabs have superior sensitivity for detecting chlamydia and gonorrhea
• There was a small sample size for trichomoniasis
• The authors state

For female screening, the CDC has recommended vaginal swabs as the optimal specimen type for both CT and NG NAATs since 2014

Our data support and reinforce that recommendation by adding analyses of numerous publications since the evidence for the CDC recommendations was generated

We cannot continue to justify the use of urine except for women for whom collection of a vaginal sample is not acceptable

Learn More – Primary Sources:

Vaginal Swab vs Urine for Detection of Chlamydia trachomatis, Neisseria gonorrhoeae, and Trichomonas vaginalis: A Meta-Analysis

Does Elinzanetant Improve Sleep and Vasomotor Symptoms Associated with Menopause

BACKGROUND AND PURPOSE:

• Newer nonhormonal medications are being investigated for the treatment of vasomotor symptoms (VMS) and sleep symptoms associated with menopause
• Elinzanetant is a selective NK-1,3 receptor antagonist that may improve sleep and quality of life for women with menopause
• Simon et al. (Menopause, 2023) sought to determine the efficacy and safety of elinzanetant for improving menopause symptoms

METHODS:

• Phase 2b, adaptive, dose-range finding study
• Multicenter, multicountry, double-blind, placebo-controlled
  • 25 sites across the US, UK, and Canada
• Participants
  • Postmenopausal women
  • 40 to 65 years
  • ≥7 moderate-to-severe VMS per day
• Intervention
  • Elinzanetant at 40 mg, 80 mg, 120 mg, or 160 mg once daily
  • Placebo once daily
• Primary outcomes
  • A reduction in mean frequency and severity of moderate-to-severe VMS at weeks 4 to 12
• Secondary outcomes
  • Patient-reported assessments of sleep and quality of life

RESULTS:

• 180 participants
• Compared to placebo, elinzanetant 120 mg and 160 mg achieved reductions in VMS frequency
  • 120 mg at week 4: difference in least squares (LS) means −3.93 (SE, 1.02) | P<0.001
  • 120 mg at week 12: difference in LS means −2.95 (SE, 1.15) | P=0.01
  • 160 mg at week 4:  difference in LS means −2.63 (SE, 1.03) | P=0.01
• Elinzanetant 120 mg reduced nighttime awakenings at weeks 1, 2, 4, and 8 (P = 0.006 to P = 0.049), but not at week 12
  • Elinzanetant 160 mg did not improve sleep compared to placebo
• Both 120 mg and 160 mg doses improve quality of life at 4 and 12 weeks
  • 120 mg at week 4: difference in LS means −3.41 (SE, 0.92) | P<0.001
  • 120 mg at week 12: difference in LS means −4.27 (SE, 1.01) | P<0.001
  • 160 mg at week 4: difference in LS means −3.28 (SE, 0.95) | P<0.001
  • 160 mg at week 12: difference in LS means −4.85 (SE, 1.05) | P<0.001
• All doses were well tolerated

CONCLUSION:

• Elinzanetant at 120 mg or 160 mg daily reduced VMS frequency through 4 to 12 weeks vs placebo
• The authors state

…the 120-mg dose offers clinically important efficacy across a range of menopause-related symptoms with the most favorable benefit/risk profile

The efficacy and safety of elinzanetant 120 mg will be further evaluated in a phase 3 program

Learn More – Primary Sources:

Efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist for vasomotor symptoms: a dose-finding clinical trial (SWITCH-1)

Cochrane 2023: Is Ultrasonography Plus Mammography Superior to Mammography Alone in Average Risk Women?

BACKGROUND AND PURPOSE:

• Glechner et al. (Cochrane Database of Systematic Reviews, 2023) assessed the comparative effectiveness and safety of mammography in combination with breast ultrasonography vs mammography alone for breast cancer screening for women at average risk of breast cancer

METHODS:

• Systematic review and meta-analysis
• Inclusion criteria
  • Randomized controlled trials and controlled non-randomized studies of women at average risk of breast cancer between the ages of 40 and 75
  • Studies were also included if 80% of the population met the age and breast cancer risk inclusion criteria
• Study design
  • GRADE criteria were used to assess quality of evidence
  • Random-effects meta-analysis was used
• Primary outcome
  • Breast cancer detection
  • Breast cancer mortality

RESULTS:

• 8 studies | 209,207 women
  • Follow-up 1 to 3 years | Dense breasts: 48 to 100% of women in included studies
• None of the studies assessed whether mammography screening in combination with ultrasonography led to lower mortality from breast cancer or all-cause mortality
• Screening with a combination of mammography and ultrasonography detects more breast cancer than mammography alone
  • Additional ultrasonography: 5 detected per 1000
  • Mammography alone: 3 detected per 1000
  • Risk ratio (RR) 1.54 (95% CI, 1.22 to 1.94)
  • 1 trial | High-certainty evidence
• The percentage of invasive tumors was similar between the groups
  • Additional ultrasonography: 69.6%
  • Mammography alone: 73.5%
  • RR 0.95 (95% CI, 0.82 to 1.09)
  • Low-certainty evidence
• Positive lymph node status was detected less frequently in women with invasive cancer who underwent mammography screening and ultrasonography
  • Additional ultrasonography: 18%
  • Mammography alone: 34%
  • RR 0.53 (95% Ci, 0.33 to 0.86)
  • Moderate-certainty evidence
• interval carcinomas occurred less frequently in the group screened by mammography and ultrasonography
  • Additional ultrasonography: 5 per 10,000 women
  • Mammography alone: 10 per 10,000 women
  • RR 0.50 (95% CI, 0.29 to 0.89)
  • High-certainty evidence
• False-negative results were less common when ultrasonography was used in addition to mammography
  • Additional ultrasonography: 9%
  • Mammography alone: 23%
  • RR 0.39 (95% CI, 0.23 to 0.66)
  • Moderate-certainty evidence
• False-positive results were more common in the group with additional ultrasonography
  • RR 1.43 (95% CI, 1.37 to 1.50)
  • High-certainty evidence
• Compared to mammography alone, for every 1000 women participating in screening with a combination of mammography and ultrasonography, 27 more women will have a biopsy
  • RR 2.49 (95% CI, 2.28 to 2.72)
  • High-certainty evidence

Breast Density

• Secondary analysis of J-START trial
  • 19,213 women
  • In women with dense breasts, the combination of mammography and ultrasonography detected 3 more cancer cases per 1000 women screened
    • RR 1.65 (95% CI, 1.0 to 2.72)
    • High-certainty evidence
• Meta-analysis of three cohort studies showed similar findings in women with dense breasts
  • RR 1.78 (95% CI, 1.23 to 2.56)
  • Moderate-certainty evidence
• In women with non-dense breasts, there were more cancer cases detected when adding ultrasound to mammography screening
  • RR 1.93 (95% CI, 1.01 to 3.68)
  • Moderate-certainty evidence
• However, meta-analysis of two cohort studies did not support this finding
  • RR 1.13 (95% CI, 0.85 to 1.49)
  • Low-certainty evidence

CONCLUSION:

• Based on one quality study, adding ultrasonography to mammography results in more screening‐detected breast cancer cases among average risk women
• There were higher false-positives and more biopsies with the addition of ultrasonography
• No studies addressed mortality

The authors state

For women with dense breasts, cohort studies more in line with real‐life clinical practice confirmed this finding, whilst cohort studies for women with non‐dense breasts showed no statistically significant difference between the two screening interventions

Learn More – Primary Sources:

Mammography in combination with breast ultrasonography versus mammography for breast cancer screening in women at average risk

Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-cancer Randomized Trial (J-START): a randomised controlled trial

RCT Results: Does Bariatric-Metabolic Surgery Lead to Better Outcomes in Patients with NASH? 

BACKGROUND AND PURPOSE:

• Observational studies have suggested that non-alcoholic steatohepatitis (NASH) may be significantly improved by bariatric–metabolic surgery
• Verrastro et al. (The Lancet, 2023) compared the efficacy and safety of bariatric-metabolic surgery with lifestyle intervention plus best medical care as a treatment of NASH

METHODS:

• Multicenter, open-label, randomized trial
• Participants
  • 25 to 70 years
  • Obesity, with or without type 2 diabetes
  • Histologically confirmed NASH
• Interventions
  • Lifestyle modification plus best medical care
  • Roux-en-Y gastric bypass
  • Sleeve gastrectomy
• Study design
  • 1:1:1 randomization
  • Obesity: BMI≥30 or 27.5 kg/m2 if Asian descent
  • Hepatopathologists performing biopsies were blinded
  • 80% power, with type I error, set to 0.05 | sample size 77 in each group, with final total of 288 participants to account for 20% attrition rate
• Primary outcome
  • Histological resolution of NASH without worsening of fibrosis at 1-year follow-up

RESULTS:

• Lifestyle modification: 96 patients | Roux-en-Y gastric bypass: 96 | Sleeve gastrectomy: 96
• In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in both surgery groups compared to lifestyle modification (P<0.0001)
  • Lifestyle modification: 16%
  • The Roux-en-Y gastric bypass group: 56%
  • The sleeve gastrectomy group: 57%
• The calculated probability of NASH resolution was also higher in these groups
  • Roux-en-Y gastric bypass group
    • 3.60 times greater (95% CI 2.19 to 5.92) | P<0.0001
  • Sleeve gastrectomy group
    • 3.67 times greater (95% CI, 2.23 to 6.02) | P<0.0001
• In the per protocol analysis, the percentage of participants who met the primary outcome remained higher in the surgery groups (P<0.0001)
  • Lifestyle modification: 19%
  • The Roux-en-Y gastric bypass group: 70%
  • The sleeve gastrectomy group: 70%
• No deaths or life-threatening complications were reported
• Severe adverse events occurred in 6% of bariatric-metabolic surgery participants
  • These individuals did not need re-operations and severe events resolved with medical or endoscopic management

CONCLUSION:

• Treatment of NASH is more effective with bariatric-metabolic surgery than with lifestyle modification and optimized medical therapy
• The authors state

Novel anti-obesity drugs might result in better NASH outcomes than those we observed in the non-surgical group of our study, given their greater weight-loss potential

Future research should compare new anti-obesity drugs with other active drugs or bariatric-metabolic surgery

Learn More – Primary Sources:

Bariatric–metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial

Is the Duration of Proton Pump Inhibitor Use Related to an Increased Dementia Risk?

BACKGROUND AND PURPOSE:

• Northuis et al. (Neurology, 2023) evaluated the associations between current and cumulative PPI use and risk of incident dementia

METHODS:

• Secondary analysis of community-based cohort study
  • Data derived from the Atherosclerosis Risk in Communities (ARIC) Study
• Population
  • Participants in the ARIC study from time of enrollment (1987 to 89) through 2017
• Exposures
  • PPI use
    • Current use at baseline
    • Duration of use prior to baseline: 0 days | 1 day to 2.8 years | 2.8 to 4.4 years | >4.4 years
• Study design
  • ARIC Visit 5 (2011 to 2013) was used as baseline, since this was the first visit in which PPI use was common
  • Cox Proportional Hazards models were used
    • Adjustments: Demographics | Co-morbid conditions | Other medication use
• Primary outcome
  • Incident dementia after visit 5

RESULTS:

• 5,712 dementia-free participants at visit 5
  • Mean age 75.4 (SD, 5.1) years
  • Black: 22% | Female: 58%
  • Median follow-up: 5.5 years
  • Minimum cumulative PPI use: 112 days | Maximum use: 20.3 years
• Incident dementia: 585 cases
• Participants using PPIs at Visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs
  • HR 1.1 (95% CI, 0.9 to 1.3)
• Those who used PPIs for >4.4 cumulative years prior to Visit 5 were at a higher risk of developing dementia during follow-up than those who reported no use
  • HR 1.3 (95% CI, 1.0 to 1.8)
• Associations were not significant for lesser amounts of PPI use

CONCLUSION:

• The use of PPIs for more than 4.4 years was associated with a higher risk of dementia in this population of adults aged 45 and older
• The authors state

Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia

Learn More – Primary Sources:

Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study