Journal: JAMA

Sorted by: date / impact
Abstract

Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection: A Randomized Clinical Trial.

Oldenburg CE, Pinsky BA, Brogdon J, Chen C, ... Arnold BF, Doan T
Importance
Azithromycin has been hypothesized to have activity against SARS-CoV-2.
Objective
To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.
Design, setting, and participants
Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.
Interventions
Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).
Main outcomes and measures
The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.
Results
Among 263 participants who were randomized (median age, 43 years; 174 [66%] women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, -14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, -1% to 9%; P = .16).

Conclusions:
and relevance
Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.
Trial registration
ClinicalTrials.gov Identifier: NCT04332107.



JAMA: 15 Jul 2021; epub ahead of print
Oldenburg CE, Pinsky BA, Brogdon J, Chen C, ... Arnold BF, Doan T
JAMA: 15 Jul 2021; epub ahead of print | PMID: 34269813
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Impact:
Abstract

Diagnosis and Treatment of Alcohol-Associated Liver Disease: A Review.

Singal AK, Mathurin P
Importance
Alcohol-associated liver disease results in cirrhosis in approximately 10% to 20% of patients. In 2017, more than 2 million people had alcohol-associated cirrhosis in the US. Alcohol-associated liver disease is the primary cause of liver-related mortality and the leading indication for liver transplant, representing 40% to 50% of all liver transplant in high-income countries.
Observations
Steatosis, alcoholic hepatitis, and fibrosis are the 3 pathologic findings that are associated with progression to cirrhosis, with highest risk in patients with alcoholic hepatitis. The amount and duration of alcohol consumption, female sex, obesity, and specific genetic polymorphisms such as patatin-like phospholipase domain protein 3, membrane bound O-acyltransferase, and transmembrane 6 superfamily member 2 genes are risk factors for alcohol-associated liver disease progression. Ten-year survival of patients with alcohol-associated liver disease is 88% among those who are abstinent and 73% for those who relapse to alcohol consumption. Symptomatic alcoholic hepatitis is characterized by rapid onset of jaundice and a 30% risk of mortality 1 year after diagnosis. Severe alcoholic hepatitis, defined as a modified discriminant function score greater than or equal to 32 or Model for End-Stage Liver Disease score (starts at 6 and capped at 40; worst = 40) greater than 20, is associated with the development of acute-on-chronic liver failure and multiorgan failure. Corticosteroid therapy is associated with improved 1-month survival from 65% in untreated patients to 80% in treated patients. Early liver transplant may be appropriate in highly select patients with severe alcoholic hepatitis who do not respond to medical therapy. In patients with decompensated cirrhosis, liver transplant should be considered if the Model for End-Stage Liver Disease score remains greater than 17 after 3 months of alcohol abstinence. Between 2014 and 2019, the proportion of patients waiting for liver transplantation who had alcohol-associated liver disease increased from 22% to 40%. Alcohol-associated cirrhosis accounted for approximately 27% of 1.32 million deaths worldwide related to cirrhosis in 2017.

Conclusions:
and relevance
Alcohol-associated liver disease is among the most common liver diseases and more than 2 million people in the US in 2017 had alcohol-associated cirrhosis. Corticosteroid therapy improves survival in select patients with severe alcoholic hepatitis. Liver transplantation is the most effective therapy in patients with decompensated liver disease.



JAMA: 12 Jul 2021; 326:165-176
Singal AK, Mathurin P
JAMA: 12 Jul 2021; 326:165-176 | PMID: 34255003
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Impact:
Abstract

Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women.

Goldshtein I, Nevo D, Steinberg DM, Rotem RS, ... Chodick G, Segal Y
Importance
Data on BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) effectiveness and safety in pregnancy are currently lacking because pregnant women were excluded from the phase 3 trial.
Objective
To assess the association between receipt of BNT162b2 mRNA vaccine and risk of SARS-CoV-2 infection among pregnant women.
Design, setting, and participants
This was a retrospective cohort study within the pregnancy registry of a large state-mandated health care organization in Israel. Pregnant women vaccinated with a first dose from December 19, 2020, through February 28, 2021, were 1:1 matched to unvaccinated women by age, gestational age, residential area, population subgroup, parity, and influenza immunization status. Follow-up ended on April 11, 2021.
Exposures
Exposure was defined by receipt of the BNT162b2 mRNA vaccine. To maintain comparability, nonexposed women who were subsequently vaccinated were censored 10 days after their exposure, along with their matched pair.
Main outcomes and measures
The primary outcome was polymerase chain reaction-validated SARS-CoV-2 infection at 28 days or more after the first vaccine dose.
Results
The cohort included 7530 vaccinated and 7530 matched unvaccinated women, 46% and 33% in the second and third trimester, respectively, with a mean age of 31.1 years (SD, 4.9 years). The median follow-up for the primary outcome was 37 days (interquartile range, 21-54 days; range, 0-70). There were 118 SARS-CoV-2 infections in the vaccinated group and 202 in the unvaccinated group. Among infected women, 88 of 105 (83.8%) were symptomatic in the vaccinated group vs 149 of 179 (83.2%) in the unvaccinated group (P ≥ .99). During 28 to 70 days of follow-up, there were 10 infections in the vaccinated group and 46 in the unvaccinated group. The hazards of infection were 0.33% vs 1.64% in the vaccinated and unvaccinated groups, respectively, representing an absolute difference of 1.31% (95% CI, 0.89%-1.74%), with an adjusted hazard ratio of 0.22 (95% CI, 0.11-0.43). Vaccine-related adverse events were reported by 68 patients; none was severe. The most commonly reported symptoms were headache (n = 10, 0.1%), general weakness (n = 8, 0.1%), nonspecified pain (n = 6, <0.1%), and stomachache (n = 5, <0.1%).

Conclusions:
and relevance
In this retrospective cohort study of pregnant women, BNT162b2 mRNA vaccination compared with no vaccination was associated with a significantly lower risk of SARS-CoV-2 infection. Interpretation of study findings is limited by the observational design.



JAMA: 11 Jul 2021; epub ahead of print
Goldshtein I, Nevo D, Steinberg DM, Rotem RS, ... Chodick G, Segal Y
JAMA: 11 Jul 2021; epub ahead of print | PMID: 34251417
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Impact:
Abstract

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Shankar-Hari M, Vale CL, Godolphin PJ, ... Marshall JC, Sterne JAC
Importance
Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.
Objective
To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes.
Data sources
Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts.
Study selection
Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria.
Data extraction and synthesis
In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality.
Main outcomes and measures
The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days.
Results
A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).

Conclusions:
and relevance
In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.
Trial registration
PROSPERO Identifier: CRD42021230155.



JAMA: 05 Jul 2021; epub ahead of print
WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Shankar-Hari M, Vale CL, Godolphin PJ, ... Marshall JC, Sterne JAC
JAMA: 05 Jul 2021; epub ahead of print | PMID: 34228774
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Impact:
Abstract

Diagnosis and Management of Infertility: A Review.

Carson SA, Kallen AN
Importance
In the US, approximately 12.7% of reproductive age women seek treatment for infertility each year. This review summarizes current evidence regarding diagnosis and treatment of infertility.
Observations
Infertility is defined as the failure to achieve pregnancy after 12 months of regular unprotected sexual intercourse. Approximately 85% of infertile couples have an identifiable cause. The most common causes of infertility are ovulatory dysfunction, male factor infertility, and tubal disease. The remaining 15% of infertile couples have \"unexplained infertility.\" Lifestyle and environmental factors, such as smoking and obesity, can adversely affect fertility. Ovulatory disorders account for approximately 25% of infertility diagnoses; 70% of women with anovulation have polycystic ovary syndrome. Infertility can also be a marker of an underlying chronic disease associated with infertility. Clomiphene citrate, aromatase inhibitors such as letrozole, and gonadotropins are used to induce ovulation or for ovarian stimulation during in vitro fertilization (IVF) cycles. Adverse effects of gonadotropins include multiple pregnancy (up to 36% of cycles, depending on specific therapy) and ovarian hyperstimulation syndrome (1%-5% of cycles), consisting of ascites, electrolyte imbalance, and hypercoagulability. For individuals presenting with anovulation, ovulation induction with timed intercourse is often the appropriate initial treatment choice. For couples with unexplained infertility, endometriosis, or mild male factor infertility, an initial 3 to 4 cycles of ovarian stimulation may be pursued; IVF should be considered if these approaches do not result in pregnancy. Because female fecundity declines with age, this factor should guide decision-making. Immediate IVF may be considered as a first-line treatment strategy in women older than 38 to 40 years. IVF is also indicated in cases of severe male factor infertility or untreated bilateral tubal factor.

Conclusions:
and relevance
Approximately 1 in 8 women aged 15 to 49 years receive infertility services. Although success rates vary by age and diagnosis, accurate diagnosis and effective therapy along with shared decision-making can facilitate achievement of fertility goals in many couples treated for infertility.



JAMA: 05 Jul 2021; 326:65-76
Carson SA, Kallen AN
JAMA: 05 Jul 2021; 326:65-76 | PMID: 34228062
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Impact:
Abstract

Frequency of Thrombocytopenia and Platelet Factor 4/Heparin Antibodies in Patients With Cerebral Venous Sinus Thrombosis Prior to the COVID-19 Pandemic.

Sánchez van Kammen M, Heldner MR, Brodard J, Scutelnic A, ... Arnold M, Coutinho JM
Importance
Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism.
Objective
To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic.
Design, setting, and participants
This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies.
Exposures
Diagnosis of cerebral venous sinus thrombosis.
Main outcomes and measures
Frequencies of admission thrombocytopenia (platelet count <150 ×103/μL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples).
Results
Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/μL) in 52 (6.0%), moderate (50-99 ×103/μL) in 17 (2.0%), and severe (<50 ×103/μL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies.

Conclusions:
and relevance
In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.



JAMA: 01 Jul 2021; epub ahead of print
Sánchez van Kammen M, Heldner MR, Brodard J, Scutelnic A, ... Arnold M, Coutinho JM
JAMA: 01 Jul 2021; epub ahead of print | PMID: 34213527
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Impact:
Abstract

Trends in Prevalence of Diabetes and Control of Risk Factors in Diabetes Among US Adults, 1999-2018.

Wang L, Li X, Wang Z, Bancks MP, ... Wang H, Zhong VW
Importance
Understanding population-wide trends in prevalence and control of diabetes is critical to planning public health approaches for prevention and management of the disease.
Objective
To determine trends in prevalence of diabetes and control of risk factors in diabetes among US adults between 1999-2000 and 2017-2018.
Design, setting, and participants
Ten cycles of cross-sectional National Health and Nutrition Examination Survey (NHANES) data between 1999-2000 and 2017-2018 were included. The study samples were weighted to be representative of the noninstitutionalized civilian resident US population. Adults aged 18 years or older were included, except pregnant women.
Exposures
Survey cycle.
Main outcomes and measures
Diabetes was defined by self-report of diabetes diagnosis, fasting plasma glucose level of 126 mg/dL or more, or hemoglobin A1c (HbA1c) level of 6.5% or more. Three risk factor control goals were individualized HbA1c targets, blood pressure less than 130/80 mm Hg, and low-density lipoprotein cholesterol level less than 100 mg/dL. Prevalence of diabetes and proportion of adults with diagnosed diabetes who achieved risk factor control goals, overall and by sociodemographic variables, were estimated.
Results
Among the 28 143 participants included (weighted mean age, 48.2 years; 49.3% men), the estimated age-standardized prevalence of diabetes increased significantly from 9.8% (95% CI, 8.6%-11.1%) in 1999-2000 to 14.3% (95% CI, 12.9%-15.8%) in 2017-2018 (P for trend < .001). From 1999-2002 to 2015-2018, the estimated age-standardized proportion of adults with diagnosed diabetes who achieved blood pressure less than 130/80 mm Hg (P for trend = .007) and low-density lipoprotein cholesterol level less than 100 mg/dL (P for trend < .001) increased significantly, but not individualized HbA1c targets (P for trend = .51). In 2015-2018, 66.8% (95% CI, 63.2%-70.4%), 48.2% (95% CI, 44.6%-51.8%), and 59.7% (95% CI, 54.2%-65.2%) of adults with diagnosed diabetes achieved individualized HbA1c targets, blood pressure less than 130/80 mm Hg, and low-density lipoprotein cholesterol level less than 100 mg/dL, respectively. Only 21.2% of these adults (95% CI, 15.5%-26.8%) achieved all 3. During the entire study period, these 3 goals were significantly less likely to be achieved among young adults aged 18 to 44 years (vs older adults ≥65 years: estimated proportion, 7.4% vs 21.7%; adjusted odds ratio, 0.32 [95% CI, 0.16-0.63]), non-Hispanic Black adults (vs non-Hispanic White adults: estimated age-standardized proportion, 12.5% vs 20.6%; adjusted odds ratio, 0.60 [95% CI, 0.40-0.90]), and Mexican American adults (vs non-Hispanic White adults: estimated age-standardized proportion, 10.9% vs 20.6%; adjusted odds ratio, 0.48 [95% CI, 0.31-0.77]).

Conclusions:
and relevance
Based on NHANES data from US adults, the estimated prevalence of diabetes increased significantly between 1999-2000 and 2017-2018. Only an estimated 21% of adults with diagnosed diabetes achieved all 3 risk factor control goals in 2015-2018.



JAMA: 24 Jun 2021; epub ahead of print
Wang L, Li X, Wang Z, Bancks MP, ... Wang H, Zhong VW
JAMA: 24 Jun 2021; epub ahead of print | PMID: 34170288
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Impact:
Abstract

Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers.

Angel Y, Spitzer A, Henig O, Saiag E, ... Padova H, Ben-Ami R
Importance
Randomized clinical trials have provided estimates of the effectiveness of the BNT162b2 vaccine against symptomatic SARS-CoV-2 infection, but its effect on asymptomatic infections remains unclear.
Objective
To estimate the association of vaccination with the Pfizer-BioNTech BNT162b2 vaccine with symptomatic and asymptomatic SARS-CoV-2 infections among health care workers.
Design, setting, and participants
This was a single-center, retrospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. Data were collected on symptomatic and asymptomatic SARS-CoV-2 infections confirmed via polymerase chain reaction (PCR) tests in health care workers undergoing regular screening with nasopharyngeal swabs between December 20, 2020, and February 25, 2021. Logistic regression was used to calculate incidence rate ratios (IRRs) comparing the incidence of infection between fully vaccinated and unvaccinated participants, controlling for demographics and the number of PCR tests performed.
Exposures
Vaccination with the BNT162b2 vaccine vs unvaccinated status was ascertained from the employee health database. Full vaccination was defined as more than 7 days after receipt of the second vaccine dose.
Main outcomes and measures
The primary outcome was the regression-adjusted IRR for symptomatic and asymptomatic SARS-CoV-2 infection of fully vaccinated vs unvaccinated health care workers. The secondary outcomes included IRRs for partially vaccinated health care workers (days 7-28 after first dose) and for those considered as late fully vaccinated (>21 days after second dose).
Results
A total of 6710 health care workers (mean [SD] age, 44.3 [12.5] years; 4465 [66.5%] women) were followed up for a median period of 63 days; 5953 health care workers (88.7%) received at least 1 dose of the BNT162b2 vaccine, 5517 (82.2%) received 2 doses, and 757 (11.3%) were not vaccinated. Vaccination was associated with older age compared with those who were not vaccinated (mean age, 44.8 vs 40.7 years, respectively) and male sex (31.4% vs 17.7%). Symptomatic SARS-CoV-2 infection occurred in 8 fully vaccinated health care workers and 38 unvaccinated health care workers (incidence rate, 4.7 vs 149.8 per 100 000 person-days, respectively, adjusted IRR, 0.03 [95% CI, 0.01-0.06]). Asymptomatic SARS-CoV-2 infection occurred in 19 fully vaccinated health care workers and 17 unvaccinated health care workers (incidence rate, 11.3 vs 67.0 per 100 000 person-days, respectively, adjusted IRR, 0.14 [95% CI, 0.07-0.31]). The results were qualitatively unchanged by the propensity score sensitivity analysis.

Conclusions:
and relevance
Among health care workers at a single center in Tel Aviv, Israel, receipt of the BNT162b2 vaccine compared with no vaccine was associated with a significantly lower incidence of symptomatic and asymptomatic SARS-CoV-2 infection more than 7 days after the second dose. Findings are limited by the observational design.



JAMA: 21 Jun 2021; 325:2457-2465
Angel Y, Spitzer A, Henig O, Saiag E, ... Padova H, Ben-Ami R
JAMA: 21 Jun 2021; 325:2457-2465 | PMID: 33956048
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Impact:
Abstract

Triple vs Dual Inhaler Therapy and Asthma Outcomes in Moderate to Severe Asthma: A Systematic Review and Meta-analysis.

Kim LHY, Saleh C, Whalen-Browne A, O\'Byrne PM, Chu DK
Importance
The benefits and harms of adding long-acting muscarinic antagonists (LAMAs) to inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs) for moderate to severe asthma remain unclear.
Objective
To systematically synthesize the outcomes and adverse events associated with triple therapy (ICS, LABA, and LAMA) vs dual therapy (ICS plus LABA) in children and adults with persistent uncontrolled asthma.
Data sources
MEDLINE, Embase, CENTRAL, ICTRP, FDA, and EMA databases from November 2017, to December 8, 2020, without language restriction.
Study selection
Two investigators independently selected randomized clinical trials (RCTs) comparing triple vs dual therapy in patients with moderate to severe asthma.
Data extraction and synthesis
Two reviewers independently extracted data and assessed risk of bias. Random-effects meta-analyses, including individual patient-level exacerbation data, were used. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach was used to assess certainty (quality) of the evidence.
Main outcomes and measures
Severe exacerbations, asthma control (measured using the Asthma Control Questionnaire [ACQ-7], a 7-item list with each item ranging from 0 [totally controlled] to 6 [severely uncontrolled]; minimal important difference, 0.5), quality of life (measured using the Asthma-related Quality of Life [AQLQ] tool; score range, 1 [severely impaired] to 7 [no impairment]; minimal important difference, 0.5), mortality, and adverse events.
Results
Twenty RCTs using 3 LAMA types that enrolled 11 894 children and adults (mean age, 52 years [range, 9-71 years]; 57.7% female) were included. High-certainty evidence showed that triple therapy vs dual therapy was significantly associated with a reduction in severe exacerbation risk (9 trials [9932 patients]; 22.7% vs 27.4%; risk ratio, 0.83 [95% CI, 0.77 to 0.90]) and an improvement in asthma control (14 trials [11 230 patients]; standardized mean difference [SMD], -0.06 [95% CI, -0.10 to -0.02]; mean difference in ACQ-7 scale, -0.04 [95% CI, -0.07 to -0.01]). There were no significant differences in asthma-related quality of life (7 trials [5247 patients]; SMD, 0.05 [95% CI, -0.03 to 0.13]; mean difference in AQLQ score, 0.05 [95% CI, -0.03 to 0.13]; moderate-certainty evidence) or mortality (17 trials [11 595 patients]; 0.12% vs 0.12%; risk ratio, 0.96 [95% CI, 0.33 to 2.75]; high-certainty evidence) between dual and triple therapy. Triple therapy was significantly associated with increased dry mouth and dysphonia (10 trials [7395 patients]; 3.0% vs 1.8%; risk ratio, 1.65 [95% CI, 1.14 to 2.38]; high-certainty evidence), but treatment-related and serious adverse events were not significantly different between groups (moderate-certainty evidence).

Conclusions:
and relevance
Among children (aged 6 to 18 years) and adults with moderate to severe asthma, triple therapy, compared with dual therapy, was significantly associated with fewer severe asthma exacerbations and modest improvements in asthma control without significant differences in quality of life or mortality.



JAMA: 21 Jun 2021; 325:2466-2479
Kim LHY, Saleh C, Whalen-Browne A, O'Byrne PM, Chu DK
JAMA: 21 Jun 2021; 325:2466-2479 | PMID: 34009257
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Impact:
Abstract

Transcatheter Treatment of Valvular Heart Disease: A Review.

Davidson LJ, Davidson CJ
Importance
More than 40 million people are living with either mitral or aortic valve disease worldwide, and more than 180 000 heart valve replacement surgeries are performed each year in the US. Transcatheter valve repair has emerged as an important therapeutic option for patients who are candidates for heart valve replacement.
Observations
All transcatheter valve therapies involve a multidisciplinary team of interventional cardiologists, cardiothoracic surgeons, radiologists, echocardiographers, nurses, and social workers, termed the heart team, to determine the optimal approach for managing each patient. Transcatheter aortic valve implantation (TAVI) is an aortic valve replacement procedure that is performed percutaneously and is currently approved for patients with severe, symptomatic aortic stenosis in all surgical risk categories. The TAVI procedure can be performed using a balloon-expandable or self-expanding valve. In a low-risk cohort of patients (PARTNER [Placement of Aortic Transcatheter Valves] 3 trial), the rates of death from any cause, stroke, or rehospitalization were 8.5% for patients receiving TAVI and 15.1% for patients undergoing surgical aortic valve replacement. Decision-making regarding therapy choice should be based on individual anatomy (including the number of leaflets, annular size, and peripheral arterial anatomy), comorbidities (including concomitant coronary artery disease and aortopathies), and patient preference guide. A mitral transcatheter edge-to-edge repair device is approved by the US Food and Drug Administration for high-risk patients with degenerative and functional mitral regurgitation that has excellent safety and efficacy in these populations. In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation) trial, the annualized rate of all hospitalizations for heart failure was 35.8% among patients who underwent transcatheter edge-to-edge repair and received medical therapy compared with 67.9% among patients in the medical therapy alone group. Transcatheter tricuspid valve repair and replacement trials are ongoing and show promise for the treatment of patients with tricuspid regurgitation, which previously had limited therapeutic options. Multimodality imaging, which includes transthoracic echocardiography, transesophageal echocardiography, computed tomography, and intracardiac echocardiography, is important for preprocedural planning, device selection, and optimal outcomes.

Conclusions:
and relevance
Approximately 78 000 TAVI procedures and 10 000 transcatheter mitral valve repairs take place yearly in the US to treat patients with severe, symptomatic aortic stenosis and mitral regurgitation, respectively. Transcatheter valve therapies have expanded therapeutic options for patients, including for those who previously had no viable surgical options.



JAMA: 21 Jun 2021; 325:2480-2494
Davidson LJ, Davidson CJ
JAMA: 21 Jun 2021; 325:2480-2494 | PMID: 34156404
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Impact:
Abstract

Chronic Pelvic Pain in Women: A Review.

Lamvu G, Carrillo J, Ouyang C, Rapkin A
Importance
Chronic pelvic pain (CPP) is a challenging condition that affects an estimated 26% of the world\'s female population. Chronic pelvic pain accounts for 40% of laparoscopies and 12% of hysterectomies in the US annually even though the origin of CPP is not gynecologic in 80% of patients. Both patients and clinicians are often frustrated by a perceived lack of treatments. This review summarizes the evaluation and management of CPP using recommendations from consensus guidelines to facilitate clinical evaluation, treatment, improved care, and more positive patient-clinician interactions.
Observations
Chronic pelvic pain conditions often overlap with nonpelvic pain disorders (eg, fibromyalgia, migraines) and nonpain comorbidities (eg, sleep, mood, cognitive impairment) to contribute to pain severity and disability. Musculoskeletal pain and dysfunction are found in 50% to 90% of patients with CPP. Traumatic experiences and distress have important roles in pain modulation. Complete assessment of the biopsychosocial factors that contribute to CPP requires obtaining a thorough history, educating the patient about pain mechanisms, and extending visit times. Training in trauma-informed care and pelvic musculoskeletal examination are essential to reduce patient anxiety associated with the examination and to avoid missing the origin of myofascial pain. Recommended treatments are usually multimodal and require an interdisciplinary team of clinicians. A single-organ pathological examination should be avoided. Patient involvement, shared decision-making, functional goal setting, and a discussion of expectations for long-term care are important parts of the evaluation process.

Conclusions:
and relevance
Chronic pelvic pain is like other chronic pain syndromes in that biopsychosocial factors interact to contribute and influence pain. To manage this type of pain, clinicians must consider centrally mediated pain factors as well as pelvic and nonpelvic visceral and somatic structures that can generate or contribute to pain.



JAMA: 14 Jun 2021; 325:2381-2391
Lamvu G, Carrillo J, Ouyang C, Rapkin A
JAMA: 14 Jun 2021; 325:2381-2391 | PMID: 34128995
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Abstract

Lower Extremity Peripheral Artery Disease Without Chronic Limb-Threatening Ischemia: A Review.

Polonsky TS, McDermott MM
Importance
Lower extremity peripheral artery disease (PAD) affects approximately 8.5 million people in the US and approximately 230 million worldwide.
Observations
Peripheral artery disease is uncommon before aged 50 years but affects up to 20% of people aged 80 years and older. It can be noninvasively diagnosed with the ankle-brachial index (ABI), a ratio of Doppler-recorded pressures in the dorsalis pedis and/or posterior tibial artery in each leg to brachial artery pressures. An ABI value less than 0.90 is 57% to 79% sensitive and 83% to 99% specific for arterial stenosis of at least 50%. Intermittent claudication, consisting of exertional calf pain that does not begin at rest and that resolves within 10 minutes of rest, is considered the classic symptom of PAD. However, 70% to 90% of people with an ABI value less than 0.90 either report no exertional leg symptoms (ie, asymptomatic) or report leg symptoms with walking that are not consistent with classic claudication. Over time, people with PAD restrict walking activity or slow walking speed to avoid leg symptoms. Thus, although approximately 75% of people with PAD report no change in leg symptoms over time, those with PAD have significantly greater annual declines in 6-minute walk performance compared with those without it. Approximately 11% of people with PAD develop chronic limb-threatening ischemia, the most severe form of PAD. Compared with people without PAD, those with the disease have approximately twice the rate of all-cause mortality, cardiovascular mortality, and major coronary events at 10-year follow-up. High-dose statins and antiplatelet therapy with or without antithrombotic therapy reduced rates of coronary events and stroke in people with PAD. Supervised treadmill exercise improved 6-minute walk distance by 30 to 35 m, consistent with a clinically meaningful change, whereas effective home-based walking exercise interventions improved 6-minute walk by 42 to 53 m. Effective home-based exercise programs require behavioral methods, including monitoring by a coach.

Conclusions:
and relevance
Peripheral artery disease affects approximately 230 million people worldwide and is associated with increased rates of cardiovascular events, lower extremity events, and functional decline compared with that of people without PAD. People with PAD should be treated with the highest dose of statin tolerated, antithrombotic and/or antiplatelet therapy, and exercise.



JAMA: 31 May 2021; 325:2188-2198
Polonsky TS, McDermott MM
JAMA: 31 May 2021; 325:2188-2198 | PMID: 34061140
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Abstract

Diagnosis and Management of Headache: A Review.

Robbins MS
Importance
Approximately 90% of people in the US experience headache during their lifetime. Migraine is the second leading cause of years lived with disability worldwide.
Observations
Primary headache disorders are defined as headaches that are unrelated to an underlying medical condition and are categorized into 4 groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies evaluating prevalence in more than 100 000 people reported that tension-type headache affected 38% of the population, while migraine affected 12% and was the most disabling. Secondary headache disorders are defined as headaches due to an underlying medical condition and are classified according to whether they are due to vascular, neoplastic, infectious, or intracranial pressure/volume causes. Patients presenting with headache should be evaluated to determine whether their headache is most likely a primary or a secondary headache disorder. They should be evaluated for symptoms or signs that suggest an urgent medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence of cancer or immunosuppression, and provocation by physical activities or postural changes. Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs, and combination products that include caffeine. Patients not responsive to these treatments may require migraine-specific treatments including triptans (5-HT1B/D agonists), which eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients with or at high risk for cardiovascular disease should avoid triptans because of vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the inflammatory neuropeptide calcitonin gene-related peptide, such as rimegepant or ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT1F agonist, lasmiditan, is also available for acute migraine treatment and appears safe in patients with cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics, antidepressants, calcitonin gene-related peptide monoclonal antibodies, and onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo.

Conclusions:
and relevance
Headache disorders affect approximately 90% of people during their lifetime. Among primary headache disorders, migraine is most debilitating and can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, gepants, and lasmiditan.



JAMA: 10 May 2021; 325:1874-1885
Robbins MS
JAMA: 10 May 2021; 325:1874-1885 | PMID: 33974014
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Abstract

Diagnosis and Management of Stable Angina: A Review.

Joshi PH, de Lemos JA
Importance
Nearly 10 million US adults experience stable angina, which occurs when myocardial oxygen supply does not meet demand, resulting in myocardial ischemia. Stable angina is associated with an average annual risk of 3% to 4% for myocardial infarction or death. Diagnostic tests and medical therapies for stable angina have evolved over the last decade with a better understanding of the optimal use of coronary revascularization.
Observations
Coronary computed tomographic angiography is a first-line diagnostic test in the evaluation of patients with stable angina due to higher sensitivity and comparable specificity compared with imaging-based stress testing. Moreover, coronary computed tomographic angiography allows detection of nonobstructive atherosclerosis that would not be identified with other noninvasive imaging modalities, improving risk assessment and potentially triggering more appropriate allocation of preventive therapies. Novel therapies treating lipids (proprotein convertase subtilisin/kexin type 9 inhibitors, ezetimibe, and icosapent ethyl) and type 2 diabetes (sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists) have improved cardiovascular outcomes in patients with stable ischemic heart disease when added to usual care. Randomized clinical trials showed no improvement in the rates of mortality or myocardial infarction with revascularization (largely by percutaneous coronary intervention) compared with optimal medical therapy alone, even in the setting of moderate to severe ischemia. In contrast, revascularization provides a meaningful benefit on angina and quality of life compared with antianginal therapies. Measures of the effect of angina on a patient\'s quality of life should be integrated into the clinic encounter to assist with the decision to proceed with revascularization.

Conclusions:
and relevance
For patients with stable angina, emphasis should be placed on optimizing lifestyle factors and preventive medications such as lipid-lowering and antiplatelet agents to reduce the risk for cardiovascular events and death. Antianginal medications, such as β-blockers, nitrates, or calcium channel blockers, should be initiated to improve angina symptoms. Revascularization with percutaneous coronary intervention should be reserved for patients in whom angina symptoms negatively influence quality of life, generally after a trial of antianginal medical therapy. Shared decision-making with an informed patient is important for effective treatment of stable angina.



JAMA: 03 May 2021; 325:1765-1778
Joshi PH, de Lemos JA
JAMA: 03 May 2021; 325:1765-1778 | PMID: 33944871
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Impact:

This program is still in alpha version.