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Does the Primary Care Physician Gender Wage Gap Differ Based on Compensation Method?

BACKGROUND AND PURPOSE:

  • Female physicians continue to be paid less than their male counterparts
  • Ganguli et al. (Ann Intern Med, 2022) determined how Primary Care Physician (PCP) compensation by gender differs when applying existing productivity-based and alternative compensation models

METHODS:

  • Microsimulation study
    • Data from national clinical registry of 1222 primary care practices (2016 to 2019)
  • Population
    • Male and female PCPs were matched by
      • Specialty | Years since medical school graduation | Practice site | Sessions worked
  • Simulations
    • Productivity-based fee-for-service | Panel size–based capitation
      • Without or with risk adjustment
    • Hybrid payment models
  • Study design
    • Microsimulation inputs included patient and visit characteristics and overhead expenses
  • Primary outcome
    • Net annual, full-time-equivalent compensation for male versus female PCPs under the different simulations

RESULTS:

  • Male PCPs: 881 | Female PCPs: 554
    • Female PCP panels included patients who, on average
      • Were younger
      • Had lower diagnosis-based risk scores
      • Were more often female
      • Were more often uninsured or insured by Medicaid rather than by Medicare
  • Under productivity-based payment
    • Female PCPs earned 21% less than male PCPs
    • Median income difference: $58,829 (IQR, $39,553 to $120,353)
  • Gap was similar under capitation without adjustment
    • Median income difference: $58,723 (IQR, $42,141 to $140,192)
  • Wage gap was larger under capitation risk-adjusted for
    • Age alone
      • Median income difference: $74,695 (IQR, $42,884 to $152,423)
    • Diagnosis-based scores alone (Charlson Comorbidity Index [CCI])
      • Median income difference: $114,792 (IQR, $49,080 to $215,3260)
    • Age-, sex-, and diagnosis-based scores (CCI): Median income difference: $83,438 (IQR, $28,927 to $129,414)
  • The wage gap was small and nonsignificant under capitation risk-adjusted for age and sex
    • Median income difference: $36,631 (IQR, $12,743 to $73,898)

CONCLUSION:

  • Within a productivity-based model, female Primary Care physicians earned 21% less vs male colleagues
  • The authors state

We found that despite female PCPs likely working similar hours to or even more hours than their male counterparts, female PCPs received less compensation under productivity-based payment due to conducting fewer visits

These lower visit rates may be explained by female PCPs spending more time per visit, or being less likely to work with nurse practitioners or physician assistants billing under their NPIs

Learn More – Primary Sources:

How the Gender Wage Gap for Primary Care Physicians Differs by Compensation Approach: A Microsimulation Study

Does the Primary Care Physician Gender Wage Gap Differ Based on Compensation Method?

BACKGROUND AND PURPOSE:

  • Female physicians continue to be paid less than their male counterparts
  • Ganguli et al. (Ann Intern Med, 2022) determined how Primary Care Physician (PCP) compensation by gender differs when applying existing productivity-based and alternative compensation models

METHODS:

  • Microsimulation study
    • Data from national clinical registry of 1222 primary care practices (2016 to 2019)
  • Population
    • Male and female PCPs were matched by
      • Specialty | Years since medical school graduation | Practice site | Sessions worked
  • Simulations
    • Productivity-based fee-for-service | Panel size–based capitation
      • Without or with risk adjustment
    • Hybrid payment models
  • Study design
    • Microsimulation inputs included patient and visit characteristics and overhead expenses
  • Primary outcome
    • Net annual, full-time-equivalent compensation for male versus female PCPs under the different simulations

RESULTS:

  • Male PCPs: 881 | Female PCPs: 554
    • Female PCP panels included patients who, on average
      • Were younger
      • Had lower diagnosis-based risk scores
      • Were more often female
      • Were more often uninsured or insured by Medicaid rather than by Medicare
  • Under productivity-based payment
    • Female PCPs earned 21% less than male PCPs
    • Median income difference: $58,829 (IQR, $39,553 to $120,353)
  • Gap was similar under capitation without adjustment
    • Median income difference: $58,723 (IQR, $42,141 to $140,192)
  • Wage gap was larger under capitation risk-adjusted for
    • Age alone
      • Median income difference: $74,695 (IQR, $42,884 to $152,423)
    • Diagnosis-based scores alone (Charlson Comorbidity Index [CCI])
      • Median income difference: $114,792 (IQR, $49,080 to $215,3260)
    • Age-, sex-, and diagnosis-based scores (CCI): Median income difference: $83,438 (IQR, $28,927 to $129,414)
  • The wage gap was small and nonsignificant under capitation risk-adjusted for age and sex
    • Median income difference: $36,631 (IQR, $12,743 to $73,898)

CONCLUSION:

  • Within a productivity-based model, female Primary Care physicians earned 21% less vs male colleagues
  • The authors state

We found that despite female PCPs likely working similar hours to or even more hours than their male counterparts, female PCPs received less compensation under productivity-based payment due to conducting fewer visits

These lower visit rates may be explained by female PCPs spending more time per visit, or being less likely to work with nurse practitioners or physician assistants billing under their NPIs

Learn More – Primary Sources:

How the Gender Wage Gap for Primary Care Physicians Differs by Compensation Approach: A Microsimulation Study

Meta-Analysis: Do Daily Multivitamins Have Beneficial Effects on Cognitive Health in Older Adults?

BACKGROUND AND PURPOSE:

  • Vyas et al. (American Journal of Clinical Nutrition, 2024) assessed the effects of multivitamin-mineral (MVM) supplementation on cognitive change

METHODS:

  • 2×2 factorial trial and meta-analysis
    • COcoa Supplement and Multivitamin Outcomes Study (COSMOS)
  • Participants
    • US adults aged ≥60 years who completed all cognitive tests administered at baseline
  • Interventions
    • Cocoa extract [500 mg flavanols/day]
    • Daily multivitamin-mineral supplement
    • Placebo
  • Primary outcomes
    • Cardiovascular disease
    • Cancer
  • Meta-analysis inclusion criteria
    • Non-overlapping participants across three COSMOS cognitive sub-studies
    • Meta-Analysis review of patients from different substudies
      • COSMOS-Clinic: n=573 | COSMOS-Mind: n=2158 | COSMOS-Web: n=2472

RESULTS:

  • 573 participants from COSMOS-Clinic study
  • Compared to placebo, there was a modest nonsignificant benefit of MVM on global cognition over 2 years
    • Mean difference (MD) 0.06 (95% CI, -0.003 to 0.13) standard deviation units
  • MVM was associated with better episodic memory
    • MD 0.12 (95% CI, 0.002 to 0.23) standard deviation units
  • There was no difference in executive function/attention with MVM
    • MD 0.04 (95% CI, –0.04 to 0.11) standard deviation units
  • Meta-analysis showed a benefit of MVM on
    • Global cognition: MD 0.07 (95% CI, 0.03 to 0.11) | P=0.0009
    • Episodic memory: MD 0.06 (95% CI, 0.03 to 0.10) | P=0.0007
  • The effect on global cognition was equivalent to reducing cognitive aging by 2 years

CONCLUSION:

  • Daily MVM supplementation in older adults had a beneficial effect on episodic memory after 2 years
  • Meta-analysis revealed that daily MVM supplements are beneficial for both global cognition and episodic memory
  • The authors state

These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults

Learn More – Primary Sources:

Effect of multivitamin-mineral supplementation versus placebo on cognitive function: Results from the clinic sub-cohort of the COSMOS randomized clinical trial and meta-analysis of three cognitive studies within COSMOS

Do Regular Primary Care Visits Reduce Medicare Costs and Acute Care Utilization?

BACKGROUND AND PURPOSE:

  • Sonmez et al. (JAMA Network Open, 2023) examined the association between Medicare savings and primary care visit patterns

METHODS:

  • Retrospective cohort study
  • Population
    • A 5% sample of traditional Medicare claims from 2016 to 2019
    • Claims included in this sample came from participants with
      • ≥3 primary care visits with ≥180 days between the first and the last visit | Who were not enrolled in Medicare Advantage | Who did not have end-stage kidney disease | Who were not institutionalized
  • Exposures
    • Primary care visit patterns
      • Visit frequency | Regularity | Continuity of care (saw the most responsible primary care clinician or organization vs other primary care clinicians or organizations)
  • Primary outcomes
    • Savings in Medicare expenditures
    • Risk-adjusted Medicare expenditures | Number of emergency department (ED) visits | Hospitalizations

RESULTS:

  • 504,471 beneficiaries
    • Mean age: 74.26 (SD, 10.41) years | Women: 59.16%
  • Compared to the irregular noncontinuous group, the group with a regular and highly continuous pattern was associated with
    • Greater savings
      • 175.87% (95% CI, 167.40 to 184.33) | P<0.001
    • Lower risk-adjusted expenditures
      • −16.61% (95% CI, –16.73 to –16.48) | P<0.001
    • Fewer risk-adjusted ED visits
      • −40.49% (95% CI, –40.55 to −40.43) | P<0.001
    • Fewer risk-adjusted hospitalizations
      • −53.32% (95% CI, –53.49 to –53.14) | P<0.001
  • Regular visits with higher continuity were associated with the highest savings
    • Savings increased with increasing visit frequencies
    • Peak savings were observed at higher visit frequencies as clinical complexity increased
  • As regularity and continuity decreased, the association between savings and visit frequencies progressively inverted

CONCLUSION:

  • Medicare savings were maximized when primary care visits were frequent, regular, and continuous regardless of demographics and clinical characteristics
  • The authors state

Proactive approaches to primary care, defined by temporally regular visits with a continuity-of-care clinician at a frequency optimized for clinical complexity, may offer benefits to payers, clinicians, and patients by decreasing expenditures, reducing ED visits, and reducing hospitalizations

Learn More – Primary Sources:

Primary Care Continuity, Frequency, and Regularity Associated With Medicare Savings

RCT Results: Oral Orforglipron for the Treatment of Obesity

BACKGROUND AND PURPOSE:

  • Glucagon-like peptide-1 (GLP-1) receptor agonists appear to be effective for the treatment of obesity, but injection as a mode of delivery may prevent patient uptake
  • Wharton et al. (NEJM, 2023) evaluated the efficacy and safety of oral orforglipron in adults with obesity or with overweight plus at least one weight-related coexisting condition

METHODS:

  • Phase 2, randomized, double-blind trial
  • Participants
    • Obesity or overweight and ≥1 weight-related coexisting condition
    • Exclusion: Diabetes
  • Intervention
    • 36 weeks of orforglipron at one of four doses: 12 mg | 24 mg | 36 mg | 45 mg
    • Placebo
  • Primary outcome
    • Percentage change from baseline in body weight at week 26
  • Secondary outcome
    • Percentage change from baseline in body weight at week 36

RESULTS:

  • 242 participants
    • Mean body weight at baseline: 108.7 kg | Mean BMI: 37.9
  • At week 26, the mean change from baseline in body weight was higher in all orforglipron dose cohorts
  • The mean change in body weight increased linearly with increasing dose
    • Orforglipron 12 mg: −8.6 (95% CI, −10.2 to −6.9)
    • Orforglipron 45 mg: −12.6 (95% CI, −14.1 to −11.1)
    • Placebo: −2.0 (95% CI, −3.6 to −0.4)
  • The mean change from baseline was higher in all orforglipron dose cohorts at week 36
  • A weight reduction of at least 10% by week 36 occurred in more participants in the orforglipron groups
    • Orforglipron 12 mg: 46% (95% CI, 32 to 61)
    • Orforglipron 45 mg: 69% (95% CI, 57 to 81)
    • Placebo: 9% (95% CI, 1 to 17)
  • The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures
  • Adverse events
    • Most common adverse events: Mild to moderate gastrointestinal events
    • Typically occurred during dose escalation
    • Discontinuation of orforglipron occurred in 10% to 17% of participants across dose cohort
  • The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class

CONCLUSION:

  • Compared to placebo, the daily use of oral orforglipron was associated with greater weight loss in participants with obesity and overweight with similar outcomes to injectables
  • The safety profile of orforglipron is similar to that of other GLP-1 receptor agonists
  • The authors state

Daily oral orforglipron was associated with weight reduction and related benefits that appeared to be similar to the efficacy outcomes observed with injectable GLP-1 receptor agonists that have already been approved for weight management

Learn More – Primary Sources:

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

Meta-Analysis: Metformin for PCOS Weight Management

BACKGROUND AND PURPOSE:

  • Melin et al. (European Journal of Endocrinology, 2023) examined the effectiveness of metformin and lifestyle modification for the management of PCOS

METHODS:

  • Systematic review and meta-analysis
  • Inclusion criteria
    • Randomized controlled trials
    • Studies that assessed the effectiveness of metformin and lifestyle compared to placebo for the management of hormonal and clinical features of PCOS
  • Primary outcomes
    • Outcomes related to weight management and insulin sensitivity

RESULTS:

  • 32 RCTs
  • There was moderate certainty evidence that metformin vs placebo improved
    • BMI with or without lifestyle change
      • MD −0.53 kg/m2 (95% CI, −0.95 to −0.12) 
      Homeostatic model assessment for insulin resistance
      • MD −0.50 (95% CI, −0.91 to −0.09)
    • Fasting glucose
      • MD −0.13 mmol/L (95% CI, −0.19 to −0.07) 
  • Compared to placebo, there were increased mild gastrointestinal adverse effects with metformin
    • OR 7.67 (95% CI, 2.74 to 21.46)
  • There was low certainty evidence to support metformin improving
    • Reduction of waist-hip ratio
      • MD −0.02 (95% CI, −0.03 to −0.00)
    • Total cholesterol
      • MD −0.24 mmol/L (95% CI, −0.43 to −0.05) 
    • Low-density lipoprotein
      • MD −0.16 mmol/L (95% CI, −0.30 to −0.01) 
    • Triglycerides
      • MD −0.11 mmol/L (95% CI, −0.20 to −0.02) 

CONCLUSION:

  • For individuals with PCOS, metformin can effectively improve weight management, insulin tolerance, and lipids
  • The authors state

Metformin should be considered in adult women with PCOS and BMI ≥25 kg/m2 for prevention of weight gain and management of weight and metabolic disorders

Metformin may be considered in adults with BMI < 25 kg/m2 and adolescents with PCOS, acknowledging more limited evidence

Learn More – Primary Sources:

The impact of metformin with or without lifestyle modification versus placebo on polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials

Are Oral Antiviral Drugs Still Effective at Reducing COVID-19 Deaths in the Omicron Subvariant Era?

BACKGROUND AND PURPOSE:

  • Ritonavir-boosted nirmatrelvir (Paxlovid) and molnupiravir are prescribed to outpatients with mild-to-moderate COVID-19 who are at risk of progression to severe disease
  • Lin et al. (JAMA Network Open, 2023) assessed the association of nirmatrelvir or molnupiravir use with the risks of hospitalization and death among patients infected with new Omicron subvariants

METHODS:

  • Cohort study
  • Population
    • Patients with COVID-19 between April 2022 and February 2023 who were at high risk of progressing to severe disease
    • During this period, Omicron variants evolved from BA.2 to BA.4/BA.5, then to BQ.1/BQ.1.1, and finally to XBB/XBB.1.5
  • Exposures
    • Treatment with ritonavir-boosted nirmatrelvir or molnupiravir
  • Study design
    • Follow-up through 90 days
    • The association of either nirmatrelvir or molnupiravir use with each outcome was measured by the hazard ratio (HR) adjusted for
      • Demographic factors | Socioeconomic status | Date of COVID-19 diagnosis | Coexisting medical conditions | COVID-19 vaccination status | Previous SARS-CoV-2 infection
  • Primary outcome
    • Time to death
  • Secondary outcome
    • Time to either hospitalization or death

RESULTS:

  • 68,867 patients
    • Aged ≥65 years: 42.7% | Men: 38.9% | Non-Hispanic White: 42.7%
  • Treatment with ritonavir-boosted nirmatrelvir or molnupiravir was associated with a reduction in deaths
    • Nirmatrelvir: aHR 0.16 (95% CI, 0.11 to 0.23)
    • Molnupiravir: aHR 0.23 (95% CI, 0.16 to 0.34)
  • Treatment was also associated with a reduction in hospitalizations or death
    • Nirmatrelvir: aHR 0.63 (95% CI, 0.59 to 0.68)
    • Molnupiravir: aHR 0.59 (95% CI, 0.53 to 0.66)
  • These associations were observed across subgroups
    • Age | Race and ethnicity | Date of COVID-19 diagnosis | Vaccination status | Previous infection status | Coexisting conditions

CONCLUSION:

  • Ritonavir-boosted nirmatrelvir or molnupiravir are associated with a reduction in deaths and hospitalizations in patients with Omicron variants of SARS-CoV-2
  • This benefit of treatment existed regardless of age, race and ethnicity, virus strain, vaccination status, previous infection status, or coexisting condition
  • The authors state

Both drugs can, therefore, be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19

Learn More – Primary Sources:

Nirmatrelvir or Molnupiravir Use and Severe Outcomes From Omicron Infections

Is Non-Erosive GERD Linked to an Increased Incidence of Esophageal Adenocarcinoma?

BACKGROUND AND PURPOSE:

  • Gastroesophageal reflux disease (GERD) with erosive esophagitis is a risk factor for esophageal adenocarcinoma
  • Holmberg et al. (BMJ, 2023) assessed the incidence rate of esophageal adenocarcinoma among patients with non-erosive GERD compared with the general population

METHODS:

  • Population based cohort study
  • Population
    • Adults undergoing endoscopy in Denmark, Finland, and Sweden from 1987 through 2019
  • Exposures
    • Non-erosive GERD: absence of esophagitis and any other esophageal diagnosis at endoscopy
    • Erosive GERD: presence of esophagitis at endoscopy
  • Study design
    • Follow-up: Up to 31 years
    • Standardized incidence ratios with 95% CIs were calculated by dividing the observed number of esophageal adenocarcinomas in each of the GERD cohorts by the expected number
      • Expected number derived from the general populations in Denmark, Finland, and Sweden of the corresponding age, sex, and calendar period
  • Primary outcome
    • Incidence rate of esophageal adenocarcinoma

RESULTS:

  • Non-erosive GERD: 285,811 patients | Erosive GERD: 200,745 patients
  • Non-erosive GERD: 2,081,051 person-years of follow-up | Erosive GERD: 1,750,249 person-years
  • Incidence of esophageal adenocarcinomas
    • Non-erosive GERD: 228
      • Incidence rate: 11.0 per 100,000 person-years
    • Erosive GERD: 542
      • Incidence rate: 31.0 per 100,000 person-years
  • The incidence of esophageal adenocarcinomas in the non-erosive GERD cohort was similar to that of the general population
    • Standardized incidence ratio 1.04 (95% CI, 0.91 to 1.18)
  • The incidence in the non-erosive GERD cohort did not increase with longer follow-up
    • For 15 to 31 years of follow-up: IR 1.07 (95% CI, 0.65 to 1.65)
  • Erosive GERD cohort had an increased incidence of esophageal adenocarcinomas compared to the general population
    • Effect more pronounced with longer follow-up
    • Standardized incidence ratio 2.36 (95% CI, 2.17 to 2.57)

CONCLUSION:

  • Patients with non-erosive GERD experience esophageal adenocarcinomas at similar rates to patients in the general population
  • The authors state

This finding suggests that patients with confirmed non-erosive GORD are not susceptible to develop oesophageal adenocarcinoma and may not require repeated endoscopic examinations regarding assessment of cancer risk

Learn More – Primary Sources:

Non-erosive gastro-oesophageal reflux disease and incidence of oesophageal adenocarcinoma in three Nordic countries: population based cohort study

GLP-1 Agonist Use for Weight Loss and Gastrointestinal Complications

BACKGROUND AND PURPOSE:

  • Sodhi et al. (JAMA, 2023) examined gastrointestinal adverse events associated with Glucagon-like peptide 1 (GLP-1) agonists used for weight loss in a clinical setting

METHODS:

  • Cohort study
  • Population
    • A random sample of a large health claims database
  • Exposures
    • New users of semaglutide or liraglutide
    • New users of active comparator bupropion-naltrexone (weight loss agent unrelated to GLP-1 agonists)
  • Study design
    • Cox proportional hazards regression model was used to estimate hazard ratios (HR)
    • Adjustments: Age | Sex | Alcohol use | Smoking | Hyperlipidemia | Abdominal surgery in the previous 30 days | Geographic location
  • Primary outcome
    • Incidence of biliary disease | Pancreatitis | Bowel obstruction | Gastroparesis

RESULTS:

  • Liraglutide: 4144 | Semaglutide: 613 | Bupropion-naltrexone: 654
  • Use of GLP-1 agonists compared with bupropion-naltrexone was associated with increased risk of
    • Pancreatitis: Adjusted HR 9.09 (95% CI, 1.25 to 66.00)
    • Bowel obstruction: HR, 4.22 (95% CI, 1.02 to 17.40)
    • Gastroparesis: HR, 3.67 (95% CI, 1.15 to 11.90)
  • Use of GLP-1 agonists did not increase the risk of biliary disease
    • HR 1.50 (95% CI, 0.89 to 2.53)
  • Inclusion of GLP-1 agonists regardless of history of obesity reduced HRs and narrowed CIs but did not change the significance of the results

CONCLUSION:

  • The use of GLP-1 agonists for weight loss was linked to an increased risk of pancreatitis, gastroparesis, and bowel obstruction
  • The authors state

Given the wide use of these drugs, these adverse events, although rare, must be considered by patients who are contemplating using the drugs for weight loss because the risk-benefit calculus for this group might differ from that of those who use them for diabetes

Learn More – Primary Sources:

Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss

RCT Results: To What Extent Does the Wrong BP Cuff Size Impact the Accuracy of BP Readings?

BACKGROUND AND PURPOSE:

  • The effect of incorrect cuff size has not been systematically measured
  • Ishigami et al. (JAMA Internal Medicine, 2023) determined the effect of using a regular BP cuff vs an appropriately sized BP cuff on automated BP readings

METHODS:

  • Randomized crossover trial
    • Baltimore, MD
  • Participants
    • Adults in the community
  • Interventions
    • 4 sets of triplicate BP measurements
      • Initial 3 sets used an appropriate, too-small, or too-large BP cuff in random order
      • The fourth set always used repeated measurements obtained with an appropriate BP cuff (to determine reproducibility of the reference measurement)
  • Study design
    • 4 cuff sizes: Small | Regular | Large | Extra large
    • Automated BP devices
    • All participants had ≥1 set of BP measurements with the regular cuff regardless of whether size was appropriate based on arm circumference
    • Results were stratified by
      • Systolic BP: ≥130 mm Hg vs <130 mm Hg
      • BMI: ≥30 vs <30
  • Primary outcome
    • The difference in mean BP when measured with a regular BP cuff compared with an appropriate BP cuff
  • Secondary outcome
    • The difference in BP when using too-small or too-large BP cuffs vs an appropriate BP cuff across all cuff sizes

RESULTS:

  • 195 adults
    • Mean age: 54 (SD, 16) years | Male: 34% | Black: 68% | With hypertension: 51%
  • Patients who require a small BP cuff
    • Use of a regular BP cuff resulted in a significant lower BP reading
    • Mean systolic BP difference −3.6 (95% CI, −5.6 to −1.7) mm Hg
  • Patients who require a large or extra-large BP cuff
    • Use of a regular BP cuff resulted in a significant higher BP reading
      • Large: Mean systolic BP difference 4.8 mm Hg (95% CI, 3.0 to 6.6)
      • Extra-large: Mean systolic BP difference 19.5 mm Hg (95% CI, 16.1 to 22.9)
  • BP differences were greater among those requiring larger BP cuffs
  • These results were consistent when stratified by systolic BP and BMI

CONCLUSION:

  • Using the wrong BP cuff size resulted in significantly inaccurate BP readings especially among patients requiring a large or extra-large BP cuff size
  • The authors state

…using a regular BP cuff size for all individuals regardless of arm size resulted in strikingly inaccurate BP readings. A renewed emphasis on individualized BP cuff selection is warranted, particularly in individuals with larger arm sizes 

Learn More – Primary Sources:

Effects of Cuff Size on the Accuracy of Blood Pressure Readings: The Cuff(SZ) Randomized Crossover Trial

Are Direct Oral Anticoagulants or Warfarin a Better Choice for Extended VTE Therapy?

BACKGROUND AND PURPOSE:

  • It is not clear whether warfarin or more recently developed direct oral anticoagulants (DOACs) are the better treatment option for extended VTE therapy
  • Fang et al. (JAMA Network Open, 2023) compared DOACs vs warfarin for anticoagulant treatment beyond 6 months after acute VTE

METHODS:

  • Cohort study
    • Data derived from Kaiser Permanente Virtual Data Warehouse 
    • Sampling time period: January 1, 2010, to December 31, 2018
  • Population
    • ≥18 years
    • Received a diagnosis of incident VTE
    • Completed a 6-month initial treatment for VTE
  • Exposures
    • DOACs
    • Warfarin
  • Study design
    • Follow-up: End of the initial 6-month treatment period until discontinuation of anticoagulation | Occurrence of an outcome event | Health plan disenrollment | End of the study follow-up period
    • Comparison of DOAC and warfarin outcomes performed using multivariable Cox proportional hazards regression
  • Primary outcomes
    • Recurrent VTE | Hospitalizations for hemorrhage | All-cause death

RESULTS:

  • 18,495 patients
    • DOAC: 11.5% | Warfarin: 88.5%
    • Aged ≥75 years: 29.6% | Women: 48.5%
    • Predominant DOAC was dabigatran
  • Unadjusted event rates were lower for patients receiving DOAC therapy than warfarin therapy for (per 100 person-years)
    • Recurrent VTE
      • DOACs: 2.92 (95% CI, 2.29 to 3.54)
      • Warfarin: 4.14 (95% CI, 3.90 to 4.38)
    • Hospitalizations for hemorrhage
      • DOACs: 1.02 (95% CI, 0.66 to 1.39]
      • Warfarin: 1.81 (95% CI, 1.66 to 1.97)
    • All-cause death
      • DOACs: 3.79 (95% CI, 3.09 to 4.49)
      • Warfarin: 5.40 (95% CI, 5.13 to 5.66)
  • After adjustment, DOAC treatment was associated with a lower risk of recurrent VTE
    • Adjusted hazard ratio (aHR) 0.66 (95% CI, 0.52 to 0.82)
  • There were no significant differences between the groups in the risk of
    • Hospitalization for hemorrhage: aHR 0.79 (95% CI, 0.54 to 1.17)
    • All-cause death: aHR 0.96 (95% CI, 0.78 to 1.19)

CONCLUSION:

  • Patients who continued anticoagulation treatment beyond 6 months experienced a lower risk of recurrent VTE with DOACs vs warfarin
  • The authors state

Our study contributes to the growing evidence supporting the use of DOACs for both initial and extended treatment of VTE in terms of clinical outcomes as well as treatment satisfaction

Learn More – Primary Sources:

Clinical Outcomes of Direct Oral Anticoagulants vs Warfarin for Extended Treatment of Venous Thromboembolism

RCT Results: Does a Low-Dose Tricyclic Antidepressant Improve Irritable Bowel Syndrome?

BACKGROUND AND PURPOSE:

  • When first-line treatments for irritable bowel syndrome (IBS) are ineffective, guidelines suggest low-dose tricyclic antidepressants as a second-line treatment
  • Despite most IBS cases being managed in primary care, very few primary care practitioners prescribe tricyclic antidepressants for IBS
  • Ford et al. (The Lancet, 2023) examines the impact of amitriptyline on IBS at 6 months

METHODS:

  • Randomized, double-blind, placebo-controlled trial
    • Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment (ATLANTIS)
  • Participants
    • ≥18 years
    • Rome IV IBS Criteria: Recurrent abdominal pain, on average, at least 1 day per week associated with stool changes
    • Ongoing symptoms despite first-line treatment
    • Normal full blood count and C-reactive protein | Negative celiac serology | No evidence of suicidal ideation
  • Interventions
    • Low-dose oral amitriptyline (10 mg once daily) for 6 months
    • Placebo
  • Study design
    • Amitriptyline dose titration occurred over 3 weeks (up to 30 mg daily)
    • Participants, their general practitioners, investigators, and  analysis team were all masked to allocation throughout the trial
    • Analysis by intention-to-treat
    • Safety analyses were conducted with all participants who took at least one dose of the trial drug
  • Primary outcome
    • IBS- Severity Scoring System (SSS) score at 6 months

RESULTS:

  • Low-dose amitriptyline: 232 participants | Placebo: 231
    • Mean age: 48.5 (SD, 16.1) years | Female: 68%
  • There was a significant improvement in IBS-SSS score at 6 months among the low-dose amitriptyline
    • Difference: –27.0 (95% CI, –46.9 to –7.10) | P=0.0079
  • Discontinuation due to adverse events before 6 months
    • Low-dose amitriptyline: 13% | Placebo: 9%
  • There were 5 serious adverse reactions
    • Amitriptyline group: 2 | Placebo: 3

CONCLUSION:

  • As a second-line treatment, low-dose amitriptyline, 10 mg to 30 mg daily, significantly improved IBS symptoms at 6 months vs placebo
  • Treatment was well-tolerated
  • The authors state

General practitioners should offer low-dose amitriptyline to patients with IBS in whom first-line therapies are ineffective, with appropriate support to guide patient-led dose titration, such as the self-titration document we developed

Management guidelines should be updated to reflect these findings 

Learn More – Primary Sources:

Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial

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