See related AFP article, Top 20 Research Studies of 2024 for Primary Care Physicians.
Clinical question
What is the best oral treatment for mild-to-moderate community-acquired pneumonia?
Bottom line
Continue treating community-acquired pneumonia the way you’re doing it. It’s difficult, given the existing research data, to determine big differences in the clinical impact of the various oral antibiotics used for initial treatment. Using clarithromycin (Biaxin) as the standard, telithromycin (Ketek), azithromycin (Zithromax), amoxicillin/clavulanate, and the quinolones levofloxacin (Levaquin) and nemonoxacin (Taigexyn, available only in a few countries) produce similar benefits with regard to clinical response and mortality. Amoxicillin and penicillin may not work as well. Doxycycline, recommended in some guidelines, was not included in this analysis.
Reference
Kurotschka PK, Bentivegna M, Hulme C, Ebell MH. Identifying the best initial oral antibiotics for adults with community-acquired pneumonia: A network meta-analysis. J Gen Intern Med 2024;39(7):1214-1226.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Self-funded or unfunded
Setting: Various (meta-analysis)
Synopsis
These researchers identified 24 randomized controlled trials of oral treatment in adults with image-confirmed mild-moderate community-acquired pneumonia by searching 2 databases, including Cochrane CENTRAL, as well as the reference lists of practice guidelines and review articles. They included all research written in 1 of 4 languages. Pairs of investigators selected articles for inclusion, abstracted the data, and evaluated the research for risk of bias. Since few studies compared antibiotics directly, the authors used a network meta-analysis to estimate differences in response. No antibiotic produced statistically superior results to clarithromycin. In comparison with clarithromycin, clinical response was best (but still similar to clarithromycin) with nemonoxacin, levofloxacin, and telithromycin. Nemonoxacin, levofloxacin, azithromycin, and amoxicillin/clavulanate led the pack for lower mortality. Penicillin and amoxicillin produced lower clinical response. Half the studies were deemed to be at high risk of bias due to breaches in modern conduct of clinical trials (eg, not masking the participants and evaluators, selected reporting of outcomes, and so forth). There was no evidence of publication bias, but studies of doxycycline, a stalwart treatment of community-acquired pneumonia, were excluded since they were published so long ago.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
Clinical question
Do oral antivirals reduce the likelihood of hospitalization or death for immunocompromised patients with mild to moderate symptomatic COVID-19?
Bottom line
In a mostly vaccinated, immunocompromised population, oral antivirals (molnupiravir or nirmatrelvir-ritonavir) are associated with lower rates of hospitalization and mortality. This is different from the results of recent studies in immunocompetent populations in a similar time frame and with the Omicron variant. The baseline rates of hospitalization were much higher in this immunocompromised population than in contemporary studies of healthy adults, so it makes sense that the absolute benefit of the oral antivirals was also higher.
Reference
Gentry CA, Nguyen PN, Thind SK, Kurdgelashvili G, Williams RJ 2nd. Characteristics and outcomes of US veterans with immunocompromised conditions at high risk of SARS-CoV-2 infection with or without receipt of oral antiviral agents. Clin Infect Dis 2024;78(2):330-337.
Study design: Cohort (retrospective)
Funding source: Government
Setting: Outpatient (any)
Synopsis
To date, there have been no randomized trials of oral antivirals for COVID-19 in immunocompromised patients, so this propensity score–matched analysis provides the best evidence to date. In this Veterans Affairs study, the authors identified 390 immunocompromised patients (based on medication use [89%] or a comorbidity [11%]) who were diagnosed with COVID-19 and received an oral antiviral (molnupiravir or nirmatrelvir-ritonavir). Patients were recruited in early 2022 during the Omicron phase — 75% had received the full initial series of COVID-19 vaccinations and approximately 50% had received a booster. These patients were matched with 390 immunocompromised patients who were also diagnosed with COVID-19 during the study period but did not receive molnupiravir or nirmatrelvir-ritonavir. At 30 days, the composite of hospitalization or death was significantly lower in the treatment groups (5.9% for nirmatrelvir-ritonavir vs 5.8% for molnupiravir vs 14.6% for no treatment; P = .003; number needed to treat = 12). Reductions in the individual outcomes of hospitalization (5.5% to 5.8% vs 11.0%; P = .02) and mortality (0.0% to 0.4% vs 4.9%; P = .0002) were similar for the 2 drugs. The benefit was driven primarily by a reduction in deaths (0.3% vs 4.9%) and was greater with increasing degrees of vaccination.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Does a single intramuscular injection of nirsevimab reduce the likelihood of hospitalization due to respiratory syncytial virus in newborns who do not meet criteria for receiving palivizumab?
Bottom line
In average-risk infants, a single intramuscular dose of nirsevimab reduces the likelihood of hospitalization due to RSV. Although it's not inexpensive, nirsevimab is much less expensive than palivizumab and requires only a single dose.
Reference
Drysdale SB, Cathie K, Flamein F, et al, for the HARMONIE Study Group. Nirsevimab for prevention of hospitalizations due to RSV in infants. N Engl J Med 2023;389(26):2425-2435.
Study design: Randomized controlled trial (nonblinded)
Funding source: Industry
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
Nirsevimab is a monoclonal antibody against respiratory syncytial virus (RSV) that has recently been approved in the United States, Canada, and Europe. This study at 235 sites in France, Germany, and the United Kingdom identified 8058 infants born at 29 weeks' or later gestation who were not eligible for palivizumab, which is currently recommended for children at high risk of RSV complications and requires a monthly injection. The patients were recruited during their first winter and randomized to receive nirsevimab (50 mg if they weighed less than 5 kg and 100 mg if they weighed 5 kg or more) or usual care, in open-label fashion. The authors state that the vast majority of time the admitting physician was not an investigator, although they may well have been told of the medication by the parents. The primary outcome was hospitalization for lower respiratory infection with a positive test result for RSV, which occurred in 11 infants in the nirsevimab group and 60 in the usual care group (0.3% vs 1.5%; P < .001; number needed to treat [NNT] = 83). Severe RSV infection also occurred less often in the nirsevimab group (0.12% vs 0.47%; P = .004; NNT = 286). All subgroups by age, weight, sex, gestational age, and timing of randomization had similar benefits. Serious adverse events were rare and were similar between groups. According to the American Academy of Pediatrics, the cost of nirsevimab is approximately $495 for the one dose.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Is antibiotic treatment more effective than placebo in resolving symptoms of acute sinusitis in children?
Bottom line
Though this study was a meta-analysis, the data largely come from a single study, which showed a substantial benefit, after a few weeks, to using amoxicillin with or without clavulanate to treat children with symptoms of acute sinusitis.
Reference
Conway SJ, Mueller GD, Shaikh N. Antibiotics for acute sinusitis in children: A meta-analysis. Pediatrics 2024;153(5):e2023064244.
Study design: Randomized controlled trial (double-blinded)
Funding source: Government
Setting: Various (meta-analysis)
Synopsis
The authors searched 2 databases (though, curiously, not Cochrane CENTRAL) and identified 6 studies that compared an antibiotic, usually amoxicillin or amoxicillin/clavulanic acid (co-amoxiclav), with placebo in children at least one year of age with at least 10 days of symptoms of acute sinusitis. All but one study was conducted after the Haemophilus influenzae type b (Hib) vaccine was in widespread use. Treatment failure, defined in most studies as either worsening while using the treatment or a lack of improvement after 2 or so weeks of treatment, was significantly less common in patients who received an antibiotic, with 77% responding to treatment, than in patients who received a placebo (59% responding to treatment; number needed to treat = 6). Diarrhea was about twice as common with treatment. The number of the studies is too small to differentiate between different antibiotics or low-dose versus high-dose treatment. A single study was much larger than the rest combined and contributed most to the outcome. There was significant heterogeneity among the studies, which was removed when a low-quality study was removed from the analysis.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
Clinical question
Is benzyl benzoate 25% or permethrin 5% more effective for the topical treatment of scabies in adolescents and adults?
Bottom line
Benzyl benzoate 25% was significantly more effective than permethrin 5% (NNT = 2). It was also associated with more skin irritation, but this adverse event was generally mild to moderate and transient.
Reference
Meyersburg D, Hoellwerth M, Brandlmaier M, et al. Comparison of topical permethrin 5% vs. benzyl benzoate 25% treatment in scabies: a double-blinded randomized controlled trial. Br J Dermatol 2024;190(4):486-491.
Study design: Randomized controlled trial (double-blinded)
Funding source: Self-funded or unfunded
Allocation: Uncertain
Setting: Outpatient (any)
Synopsis
Researchers at one institution in Austria recruited 110 patients, 12 years and older, with dermoscopically diagnosed scabies. Patients with crusted scabies and those who had been treated in the previous 3 weeks were excluded. The patients' mean age was 28 years, 22% had been treated with topical permethrin, and 12% had been treated with oral ivermectin in the previous 3 months (the dosage of the latter, however, was often judged to have been inadequate). The patients were randomized to receive topical benzyl benzoate 25% or permethrin 5% daily for 3 days in a double-blind fashion. The primary outcome — absence of mites at 3 to 4 weeks after treatment — occurred significantly more often in the benzyl benzoate group (87% vs 27%; P < .001; number needed to treat [NNT] = 2). However, mild to moderate burning or stinging was reported more often by the benzyl benzoate group (43% vs 6%; P < .001; number needed to treat to harm = 3). The skin adverse events were short-lived and resolved spontaneously. Benzyl benzoate is widely available over the counter and is inexpensive.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Do oral or vaginal probiotics (or both) reduce the likelihood of recurrence in premenopausal adult women with frequent urinary tract infections?
Bottom line
Lactobacillus-containing probiotics (orally, vaginally, or both) reduce the incidence of recurrent UTI and prolong the time to the next UTI in premenopausal women with frequent UTIs. Vaginal probiotics (with or without oral probiotics) outperform oral probiotics alone. Vaginal probiotics alone provide a similar benefit to oral plus vaginal supplementation and would seem to be the least invasive and least costly option.
Reference
Gupta V, Mastromarino P, Garg R. Effectiveness of prophylactic oral and/or vaginal probiotic supplementation in the prevention of recurrent urinary tract infections: A randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2024;78(5):1154-1161.
Study design: Randomized controlled trial (double-blinded)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
This study from India identified 174 women aged 18 to 45 years who had experienced at least 3 uncomplicated urinary tract infections (UTIs) in the past year. The women's mean age was 36 years, and the mean number of UTIs in the previous year was slightly more than 5. The women were randomized into 1 of 4 groups: oral and vaginal placebos, oral probiotic and vaginal placebo, oral placebo and vaginal probiotic, or both oral and vaginal probiotics. The oral probiotic was 112.5 billion live lyophilized lactic acid bacteria and bifidobacteria; the vaginal probiotic contained 1 billion units of 3 lactobacilli strains. The groups were balanced at the start of the study, and analysis appears to have been by intention to treat. At 4 months, a symptomatic UTI had occurred in 70% in the placebo-only group, 61% in the oral probiotic group, 41% in the vaginal probiotic group, and 32% in the group that received both. The differences between placebo only and the active treatments were statistically significant for the vaginal and vaginal plus oral probiotic groups. Results at 12 months were similar, with rates of UTI of 95%, 77%, 61%, and 55%, respectively. Patients were asked to rate their degree of improvement and most in the vaginal and vaginal plus oral probiotic groups rated themselves as "much improved." No adverse events were reported (which suggests they didn't look very hard, since even the placebo groups in every trial report adverse events).
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Does titrated low-dose amitriptyline improve symptoms in adults with irritable bowel syndrome who have failed first-line therapies?
Bottom line
In this study, composed largely of adults with IBS-D and IBS-M with at least moderate severity despite first-line therapy, titrated low dose amitriptyline was more effective than placebo in improving symptoms.
Reference
Ford AC, Wright-Hughes A, Alderson SL, et al, for ATLANTIS trialists. 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. Lancet 2023;402(10414):1773-1785.
Study design: Randomized controlled trial (double-blinded)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (primary care)
Synopsis
These researchers recruited adults with irritable bowel syndrome (IBS) from primary care practices in the United Kingdom. To be included, the participants could have IBS of any subtype but had to have failed first-line treatments (diet, lifestyle, antispasmodics, laxatives, or antidiarrheals) and have at least moderate severity on the IBS Severity Scoring System (IBS-SSS). The researchers randomized the patients to receive titrated low-dose amitriptyline (n = 232) or matching placebo (n = 231). More than 80% of the participants had IBS with diarrhea (IBS-D) or with mixed diarrhea and constipation (IBS-M). The initial dose of amitriptyline was 10 mg every evening and the dose was increased over 3 weeks to a maximum of 30 mg. The researchers built in many overdose safeguards, such as assessing depression and suicidality and limiting the number of pills given to participants. Over the 6 months of the study, in addition to completing the IBS-SSS, the participants were asked “Have you had adequate relief of your IBS symptoms?” At the end of 6 months, a worrisome 23% discontinued their trial medication (20% of the amitriptyline-treated patients and 26% of placebo-treated patients) — the most common reason being adverse events. After 6 months, participants in both groups improved, but the amitriptyline-treated participants had a greater degree of improvement: 27 points better in their intention-to-treat analysis; the authors report, however, that 35 points is the minimum clinically important difference. More important, 61% of the amitriptyline-treated group reported meaningful improvement compared with 45% of those receiving placebo (number needed to treat = 7; 95% CI 4 - 16). These findings are consistent with guidelines from the American College of Gastroenterology and the British Society of Gastroenterology. The authors also provide a patient guide to self-titration of amitriptyline. Finally, this paper was recognized as a distinguished paper at the 2023 meeting of the North American Primary Care Research Group.
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Is it safe to watch patients with symptomatic gallstone disease without complications?
Bottom line
Patients with uncomplicated gallstones can be managed over time with analgesia and monitoring, though approximately 25% will eventually undergo cholecystectomy over the next 18 months. Still, there appears to be no need to rush to surgery without evidence of common bile duct blockage or acute pancreatitis.
Reference
Ahmed I, Hudson J, Innes K, et al, for the C-GALL Study Group. Effectiveness of conservative management versus laparoscopic cholecystectomy in the prevention of recurrent symptoms and complications in adults with uncomplicated symptomatic gallstone disease (C-GALL trial): pragmatic, multicentre randomised controlled trial. BMJ 2023;383:e075383.
Study design: Randomized controlled trial (nonblinded)
Funding source: Government
Allocation: Concealed
Setting: Inpatient (ward only)
Synopsis
These British researchers enrolled 434 adults with uncomplicated symptomatic gallstone disease referred to secondary care. The patients received, using concealed allocation, either conservative management or laparoscopic cholecystectomy. Patients were excluded if they had evidence or history of common bile duct gallstones, acute pancreatitis, obstructive jaundice, or infection. A total of 67% of the participants assigned to surgery over the next 18 months and 25% of the participants assigned to conservative management ended up in surgery. The intention-to-treat analysis, in which patients were evaluated in their original group (despite crossover to the other group), showed that pain scores over the 18 months were similar in both groups. In addition, quality of life, measured by quality-adjusted life years, was similar in both groups. In the United Kingdom, initial assignment to the conservative approach saved £1033 ($1334; €1205) over time after accounting for health sources use over 18 months.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
Clinical question
Which of the new treatments for patients with type 2 diabetes affect mortality, cardiovascular outcomes, and renal outcomes?
Bottom line
Of the new treatments for people with type 2 diabetes, SGLT2 inhibitors and GLP1 agonists outperform DPP4 inhibitors and long-acting insulins as monotherapy or combination therapy in adults with T2DM, reducing all-cause mortality, major cardiovascular events, chronic kidney disease, and heart failure. SGLT2 inhibitors and GLP1 agonists are also less likely to cause severe hypoglycemia.
Reference
Drake T, Landsteiner A, Langsetmo L, et al. Newer pharmacologic treatments in adults with type 2 diabetes: a systematic review and network meta-analysis for the American College of Physicians. Ann Intern Med 2024 May;177(5):618-632.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Self-funded or unfunded
Setting: Various (meta-analysis)
Synopsis
These researchers searched 4 databases and identified 84 randomized studies of the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) agonists, dipeptidyl peptidase-4 (DPP4) inhibitors, and long-acting insulins as monotherapy or combination therapy in adults with type 2 diabetes mellitus (T2DM). These are large studies of middle-aged adults with long-standing (mean 8.8 years) T2DM and co-morbidities, such as hypertension or tobacco use, who were evaluated for a mean of almost 2 years. Data were abstracted by one investigator and verified by a second, and 2 reviewers independently assessed the risk of bias. The authors used direct and indirect comparisons of the treatments via network meta-analysis. Based on high certainty of evidence, SGLT2 inhibitors and GLP1 agonists reduce all-cause mortality and major adverse cardiovascular events compared with usual care. SGLT2 inhibitors reduce the progression of chronic kidney disease and heart failure hospitalizations and GLP1 agonists reduce stroke. Both SGLT2 inhibitors and GLP1 agonists outperform insulin with regard to all-cause mortality. Long-acting insulins and DPP4 inhibitors are not more effective than usual care to prevent bad outcomes. The risk of severe hypoglycemia is lower with SGLT2 inhibitors and GLP1 agonists.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
Clinical question
Does continuous glucose monitoring offer a benefit over traditional glucose self-monitoring in patients with type 2 diabetes?
Bottom line
In relatively short-term studies, glucose monitoring devices have only a small effect on HbA1c and do not affect body composition, lipids, or blood pressure. Real-time (continuous) glucose monitors, such as Dexcom G6 and G5, Medtrum Touch Care Nano, and Medtronic Guardian models, may cause psychological stress in users. Intermittent glucose monitors, such as FreeStyle Libre, are better accepted by patients. Note: Both types of devices increase the risk of adverse effects.
Reference
Seidu S, Kunutsor SK, Ajjan RA, Choudhary P. Efficacy and safety of continuous glucose monitoring and intermittently scanned continuous glucose monitoring in patients with type 2 diabetes: a systematic review and meta-analysis of interventional evidence. Diabetes Care 2024;47(1):169-179.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Government
Setting: Various (meta-analysis)
Synopsis
The researchers searched 4 databases, including Cochrane CENTRAL, and reference lists of retrieved articles to find randomized studies in any language of continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) devices, identifying 26 studies of 2783 patients. Following PRISMA guidelines, 2 authors selected articles for inclusion and one author abstracted the data, which were checked by another author. Most studies were relatively short term (8 to 12 weeks in duration). CGM had a small effect on reducing HbA1c levels (0.19% [percent, not percentage points] lower) but had no effect, over the short term, on body composition, blood pressure, or lipid levels. However, in the 3 studies that evaluated it, user satisfaction was lower with the use of the device and adverse effects were higher (relative risk [RR] 1.22; 95% CI 1.01 - 1.47). isCGM devices, on average, decreased HbA1c by 0.31% but also had no effect on body composition, blood pressure, or lipid levels. User satisfaction was improved with these devices, but adverse events were also more likely (RR 1.30; 1.05 - 1.62).
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
Clinical question
Which drugs are the most effective for achieving weight loss in overweight or obese adults?
Bottom line
In this analysis, phentermine-topiramate and GLP-1 receptor agonists were the most effective drugs for achieving weight loss in overweight or obese adults.
Reference
Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. Lancet 2024;403(10434):e21-e31.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Foundation
Setting: Various (meta-analysis)
Synopsis
These authors searched databases, registries, and reference lists to identify randomized trials of drugs to promote weight loss in overweight or obese adults, regardless of comorbidities. The trials had to be at least 12 weeks long, published in English, and could not systematically recruit adults with psychological conditions. The authors chose 5% weight reduction as the minimal important difference, which is consistent with other studies and recommendations. They included 132 unique trials with 48,209 adults. The participants were generally young (median 47 years of age), 76% were female, and the average body mass index was 35.3 kg/m². The median study duration was 24 weeks. The authors reported the included studies had issues related to study deviations, missing outcome data, and missing adverse event data. To determine the comparative effectiveness of the different drugs, the authors performed a network meta-analysis. All the drugs (combined with lifestyle modifications) were more effective than lifestyle interventions alone at achieving weight loss. The combination of phentermine-topiramate was the most effective at inducing at least a 5% weight loss (odds ratio [OR] 8.02; 95% CI 5.24 - 12.27; mean weight loss 7.98%), followed by the GLP-1 receptor agonists (OR 6.33; 5.00 - 8·00; mean weight loss 5.79%). Naltrexone-bupropion, phentermine-topiramate, GLP-1 receptor agonists, and orlistat had the greatest likelihoods of discontinuation due to adverse effects (ORs 2.69, 2.40, 2.22, and 1.71, respectively). After conducting additional post hoc analyses, the authors conclude that semaglutide, a GLP-1 receptor agonist, was the most effective at achieving at least a 5% weight loss (OR 9.82) and a similar rate of adverse events as other drugs. However, post hoc analyses are fraught with peril and probably best used to generate hypotheses. What happened with the SGLT2 inhibitors? In this analysis, they were in the middle of the pack: slightly more effective than lifestyle modification at achieving at least 5% weight loss (2.07% weight loss from baseline; OR 2.88) with a comparable likelihood of discontinuation due to adverse effects (OR 1.42). Unlike many network meta-analyses researchers, these authors provided additional data on the incremental effects of the various drugs (compared with lifestyle modification) on weight loss and drug discontinuations. The following table translates these data into numbers needed to treat (NNT) and numbers needed to treat to harm (NNTH). Note: These data simulate direct comparisons and are not based on actual head-to-head data.
| Drug | NNT 5% or greater weight loss | NNT 10% or greater weight loss | NNTH discontinuation |
| Phentermine-topiramate | 2 | 3 | 18 |
| GLP-1 agonists | 3 | 3 | 20 |
| Naltrexone-bupropion | 3 | 4 | 15 |
| Orlistat | 5 | 9 | 34 |
| Metformin | 6 | NS | NS |
| SGLT2 inhibitors | 5 | NS | NS |
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
In obese patients with established cardiovascular disease (but not diabetes), does semaglutide improve cardiovascular outcomes?
Bottom line
For obese patients with established cardiovascular disease who do not have diabetes, semaglutide decreases the risk of nonfatal MI (NNT = 100) but not cardiovascular mortality (2.5% vs 3.0%, P = .07) over 40 months of follow-up. It is interesting that the title of this industry-sponsored study says nothing of the fact that this was a group of patients with established heart disease. Perhaps they hope that we will fall prey to indication creep and give it to anyone who is obese?
Reference
Lincoff AM, Brown-Frandsen K, Colhoun HM, et al, for the SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med 2023; 389(24):2221-2232.
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Setting: Outpatient (any)
Synopsis
These researchers identified adults who were 45 years and older with a body mass index of at least 27 kg/m2, had established cardiovascular disease, and who did not have diabetes mellitus. The 17,604 patients were randomized to receive a once-weekly semaglutide subcutaneous injection, beginning at 0.24 mg and escalating to a maximum tolerated dose of up 2.4 mg over 16 weeks, or to placebo. At baseline, the groups were nearly identical, with a mean age of 62 years, 72% were men, 84% were white, and they had a mean body mass index of 33 kg/m2. Approximately two-thirds of patients had a previous myocardial infarction (MI), 18% had a stroke, 4% had peripheral arterial disease, and 8% had 2 or more of these previous events. Patients were treated for a mean of 34 months and were followed up for a mean of 40 months, with more patients in the semaglutide group discontinuing the study drug (16% vs 8%). The primary composite of cardiovascular death, nonfatal MI, or nonfatal stroke occurred less often in the treatment group (6.5% vs 8.0%; P < .001; number needed to treat [NNT] = 67 over 40 months). With regard to individual endpoints, nonfatal MI was the only endpoint that decreased significantly (2.7% vs 3.7%; P < .05; NNT = 100 over 40 months). Although cardiovascular mortality was not significantly decreased (2.5% vs 3.0%; P = .07), all-cause mortality was (4.3% vs 5.2%; P < .05; NNT = 111 over 40 months). Since the authors didn't adjust for multiple comparisons and all-cause mortality was a secondary outcome, the statistical significance should be taken with a grain of salt. Patients in the semaglutide group also lost approximately 9% of their body weight, compared with essentially no change in the placebo group.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Do sodium-glucose cotransporter-2 inhibitors improve outcomes in frail adults or elderly adults with type 2 diabetes mellitus and heart failure?
Bottom line
Overall, in this analysis that pooled data from disparate study designs, SGLT2 inhibitors have little effect on glycemic control or all-cause mortality but decrease cardiovascular deaths in elderly or frail adults with T2DM plus heart failure.
Reference
Aldafas R, Crabtree T, Alkharaiji M, Vinogradova Y, Idris I. Sodium-glucose cotransporter-2 inhibitors (SGLT2) in frail or older people with type 2 diabetes and heart failure: a systematic review and meta-analysis. Age Ageing 2024;53(1):afad254.
Study design: Meta-analysis (other)
Funding source: Self-funded or unfunded
Setting: Various (meta-analysis)
Synopsis
These authors searched multiple databases and registries to identify randomized trials and observational studies that compared sodium-glucose cotransporter-2 (SGLT2) inhibitors with either a placebo or another glucose-lowering agent in adults who are frail or 65 years or older. The participants had to have type 2 diabetes mellitus (T2DM) plus heart failure, and the studies had to be published in English. The authors used validated tools to assess the methodologic quality of the included studies. Overall, they identified 22 reports from 20 studies (77,083 participants, of which 57% were male). Ten of the studies were randomized trials, 7 were observational studies, and 3 were secondary analyses. Seventeen of the studies (19 reports) provided data suitable for pooling. The authors of this meta-analysis report the randomized trials were generally at low risk of bias, but half the studies lacked adequate masking of participants and study personnel, half the studies lacked clarity about the masking of outcomes, and several had other areas of uncertainty. Overall, there was no significant difference in glycemic control, however, the data were significantly heterogeneous (I2 = 66%). One trial found the SGLT2 inhibitors resulted in significantly worse glycemic control; removing this study resolved the heterogeneity (I2 = 0%) and the net effect was that the SGLT2 inhibitors were associated with a small but statistically significant improvement in glycemic control (0.24% reduction in glycohemoglobin). The SGLT2 inhibitors were also associated with fewer deaths from any cause (relative risk [RR] = 0.84; 95% CI 0.69 - 0.95), though there was no significant difference in the randomized trials. However, the SGLT2 inhibitors were associated with fewer cardiac deaths (RR = 0.80; 0.69 - 0.94) and these findings were consistent independent of study design. The SGLT2 inhibitors were also associated with fewer hospitalizations for heart failure (RR = 0.69; 0.59 - 0.81) and these data were consistent across study designs. Finally, the SGLT2 inhibitors were not associated with reducing other outcomes, such as acute coronary events, cerebrovascular events, worsening of renal function, heart failure, or diabetic ketoacidosis.
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
In patients with preserved ejection fraction following an acute myocardial infarction (AMI), does long-term use of a beta-blocker reduce the likelihood of death or new AMI?
Bottom line
For patients with AMI and preserved ejection fraction, the use of a beta-blocker for a median of 3.5 years did not reduce the likelihood of death or a new AMI.
Reference
Yndigegn T, Lindahl B, Mars K, et al, for the REDUCE-AMI Investigators. Beta-blockers after myocardial infarction and preserved ejection fraction. N Engl J Med 2024;390(15):1372-1381.
Study design: Randomized controlled trial (nonblinded)
Funding source: Government
Allocation: Concealed
Setting: Inpatient (any location) with outpatient follow-up
Synopsis
This trial recruited adults within 7 days of AMI who had an ejection fraction of at least 50% based on angiography or echocardiography and at least one ≥ 50% obstructed coronary artery. At baseline, these 5020 patients, predominantly from Sweden and New Zealand, had a median age of 65 years, 22% were female, and 55.4% had single vessel disease. At the time of discharge, 97% were taking aspirin, 80% were taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 99% were using a statin. Groups were balanced at baseline and analysis was by intention to treat. The patients were randomized to receive a beta-blocker (62.2% received metoprolol, 37.8% received bisoprolol) or no beta-blocker. Ultimately, only 9.8% in the no beta-blocker group took one. Patients were followed up for a median of 3.5 years. There was no difference in the likelihood of death or AMI between groups (7.9% beta-blocker vs 8.3% no beta-blocker; P = .64). There was also no difference in secondary endpoints, including all-cause mortality, cardiovascular mortality, AMI, and hospitalization for atrial fibrillation or heart failure. The number of hospitalizations for potential adverse effects of beta-blockers was not increased.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
What is the best subsequent strategy to attain smoking cessation in adults following initial treatment failure with varenicline or combined nicotine replacement therapy?
Bottom line
For patients who failed to attain smoking abstinence at 6 weeks after initial treatment with varenicline, increasing the dosing of varenicline (from 2 mg to 3 mg daily) resulted in a significantly higher quit rate than continuing to use the same dosage for a longer period. Switching to CNRT was not effective for attaining smoking abstinence. For similar patients who failed on initial treatment with CNRT, an increased dosage of CNRT (from 21-mg patch to 42-mg patch plus lozenges) or switching to varenicline resulted in a significantly higher quit rate than continuing to use the same dosage of CNRT.
Reference
Cinciripini PM, Green CE, Shete S, et al. Smoking cessation after initial treatment failure with varenicline or nicotine replacement. A randomized clinical trial. JAMA 2024;331(20):1722-1731.
Study design: Randomized controlled trial (double-blinded)
Funding source: Foundation
Allocation: Concealed
Setting: Outpatient (primary care)
Synopsis
These investigators identified 490 adult smokers, aged 18 to 75 years, who smoked 5 or more cigarettes per day. The study participants randomly received (concealed allocation) assignment in phase 1 to receive either the standard dosage titration of varenicline or combined nicotine replacement therapy (CRNT; 21-mg patch plus at least six 2-mg lozenges per day) for weeks 1 to 6. In phase 2 (weeks 7 to 12), patients who met abstainer criteria (n = 142) continued their assigned medication. Nonabstainers (n = 348) were randomly assigned to (1) continue their phase 1 medication dosage, (2) increase their phase 1 medication dosage, or (3) switch to the alternate phase 1 medication for another 6 weeks. The increased varenicline dosage consisted of taking an extra 1-mg tablet (3 mg total daily dosage) with the evening dose, and the increased CNRT dose consisted of an additional 21-mg nicotine patch (42 mg total daily) plus continuing lozenges. Masking of patients, physicians, and study personnel occurred via inactive matched placebos using the same dosing regimen. Smoking abstinence was confirmed by self-report of no smoking in previous 7 days plus expired carbon monoxide of less than 6 ppm at week 12.
The analysis was by intention to treat. Of the nonabstainers who were initially treated with standard-dose varenicline, confirmed abstinence occurred significantly more among often patients who increased their varenicline dosage compared with either switching to CNRT or continuing their initial varenicline dose (20% vs 0% and 3%, respectively). Of the nonabstainers who were initially treated with CNRT, confirmed abstinence occurred significantly more often among patients who either switched to varenicline or increased the CNRT dosage compared with continuing the initial CNRT dosage (14% and 14% vs 8%, respectively).
David C. Slawson, MD
Professor
University of Virginia School of Medicine
Charlotte, NC
Clinical question
For smokers who want to quit, do electronic nicotine-delivery systems increase the likelihood of abstinence at 6 months?
Bottom line
Adult smokers who are given e-cigarettes are significantly more likely to be abstinent at 6 months (NNT = 6 - 8). In this study, the cost of e-cigarettes was paid by the study, so in the real world where patients have to buy their own e-cigarettes the results may be less favorable.
Reference
Auer R, Schoeni A, Humair JP, et al. Electronic nicotine-delivery systems for smoking cessation. N Engl J Med 2024;390(7):601-610.
Study design: Randomized controlled trial (nonblinded)
Funding source: Government
Allocation: Concealed
Setting: Population-based
Synopsis
Swiss adults who smoked at least 5 cigarettes per day and were interested in quitting were randomized into 2 groups. The control group received smoking cessation counseling, including cognitive behavioral therapy, motivational interviewing, and shared decision-making for the use of drugs that support smoking cessation, including nicotine replacement therapy and smoking cessation medications. They also received $50 vouchers that could be used for any purpose. The intervention group received all of that plus 2 e-cigarette starter kits, replacement coils, and e-liquids containing from 0 to 19.6 mg of nicotine (participants could choose the dose of nicotine they preferred). At baseline, the groups were similar: a median age of 38 years, 47% were female, the median age that they started smoking was 16 years, and they smoked a median of 15 cigarettes per day. Allocation to groups was concealed but otherwise it was an open-label trial. A total of 1246 participants were randomized, and analysis was by intention to treat. The primary outcome was biochemically verified continuous abstinence from tobacco from the target quit date to 6 months. This occurred significantly more often in the intervention group (28.9% vs 16.3%; absolute difference 12.6%; 95% CI 8% - 17.2%; number needed to treat [NNT] = 8). However, abstinence from any nicotine use was higher in the control group (33.7% vs 20.1%; NNT = 8). Not all patients underwent biochemical verification — if you believe the patients, the quit rates were even higher (38.1% vs 23.4%; NNT = 7). Abstinence that was not continuous but had been present for the last 7 days with biochemical verification was also greater with the intervention (39.4% vs 21.3%; NNT = 6). More patients in the intervention group reported absence of cough (41% vs 34%) and phlegm (62% vs 51%), though the differing response rates between the 2 groups could have biased these results. Serious adverse events were uncommon and similar between groups.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
What medications are safe and effective for the treatment of alcohol use disorder?
Bottom line
This updated systematic review found that, in conjunction with psychosocial interventions, oral naltrexone (50 mg/day) and oral acamprosate have the strongest evidence for the effective treatment of alcohol use disorder.
Reference
McPheeters M, O'Connor EA, Riley S, et al. Pharmacotherapy for alcohol use disorder. A systematic review and meta-analysis. JAMA 2023;330(17):1653-1665.
Study design: Systematic review
Funding source: Government
Setting: Various (meta-analysis)
Synopsis
These investigators searched multiple databases — including PubMed, the Cochrane Library, PsycINFO, and EMBASE — for English-language studies of adults, 18 years or older, that evaluated the efficacy of pharmacotherapy for alcohol use disorder. Eligible studies included randomized trials that compared active therapy for at least 12 weeks with placebo or another medication in an outpatient setting. Two investigators independently assessed articles for inclusion and risk of bias using a standardized scoring tool. Disagreements were resolved by consensus discussion with a third reviewer. A total of 156 articles described the results of 118 randomized controlled trials of various pharmacotherapies. Of these, 37 were new since a previous systematic review was published in 2014.
Overall, the strength of evidence best supported acamprosate and oral naltrexone (50 mg/day) for reducing the risk of returning to any drinking (number needed to treat [NNT] = 11 and 18, respectively). Oral naltrexone was also associated with a significantly reduced risk of return to heavy drinking (NNT = 11). Injectable naltrexone was not associated with lower rates of return to any drinking or heavy drinking but was significantly more effective than placebo in reducing the percentage of drinking days and heavy drinking days. Acamprosate was not significantly better than placebo for reducing the risk of return to heavy drinking. Summary evidence did not support a benefit of disulfiram or gabapentin compared with placebo. Compared with placebo, topiramate was only significantly associated with a reduction in the mean percentage of drinking days and number of drinks per day. Similarly, the data for the effectiveness of baclofen were graded as having low strength of evidence. The most commonly reported adverse events for acamprosate were gastrointestinal problems (e.g., nausea, diarrhea); for naltrexone, the most commonly reported adverse events were anxiety and dizziness. None of the trials reported evidence that any pharmacotherapies significantly affected other patient-oriented outcomes, such as quality of life, motor vehicle accidents and injuries, and mortality. The authors provided no formal evaluation of publication bias or heterogeneity/homogeneity of results.
David C. Slawson, MD
Professor
University of Virginia School of Medicine
Charlotte, NC
Clinical question
Does cognitive behavioral therapy improve fatigue in patients with long COVID?
Bottom line
For patients with severe fatigue at least 3 months after COVID-19 infection, CBT offers significant improvement in symptoms over care as usual.
Reference
Kuut TA, Müller F, Csorba I, et al. Efficacy of cognitive-behavioral therapy targeting severe fatigue following coronavirus disease 2019: Results of a randomized controlled trial. Clin Infect Dis 2023;77(5):687-695.
Study design: Randomized controlled trial (nonblinded)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
Severe fatigue is a prominent and potentially disabling component of post-acute COVID-19 syndrome, or "long COVID." This trial identified 114 Dutch adults with severe fatigue beginning with COVID-19, or substantially worsened by it, and persisting for 3 months to 12 months following the onset of the acute infection. They were randomized to a mean of 18 weeks of cognitive behavioral therapy (CBT) or care as usual. The groups were balanced at baseline with a mean age of 46 years, 11% had been hospitalized for COVID-19, 99% were unvaccinated, and 73% were female. Analysis was by intention to treat, with only 3 or 4 patients lost to follow-up in each group. The CBT intervention included goal setting, targeting a regular sleep-wake pattern, developing helpful thinking patterns, developing social support, implementing graded increases in activity, and several other components. It was delivered via online modules or telemedicine because of the pandemic. (More details about the intervention can be found in a supplementary appendix to the study.) The primary outcome was the score on the 20-item Checklist Individual Strength (CIS; range 8 - 56), with higher scores indicating worse fatigue. At baseline, this score was 48 points in both groups. Clinical response was evaluated at 19 weeks (end of treatment) and at 26 weeks. The difference in fatigue scores at 19 weeks (-9.3 points; 95% CI -13.2 to -5.3) and 26 weeks (-8.4 points, 95% CI -13.1 to -3.7) both favored CBT and would be considered clinically significant. The percentage of patients no longer having severe fatigue (CIS score < 35 points) was much higher for the CBT group at 26 weeks (63% vs 26%; P < .001; number needed to treat = 3). Other secondary outcomes also favored CBT, and no serious adverse events occurred.
Mark H. Ebell, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Does treatment with monoclonal antibody therapy that targets amyloid improve patient outcomes?
Bottom line
To date, amyloid-targeting antibodies for the treatment of Alzheimer disease have failed to demonstrate clinical meaningful benefits. They are associated with concerning risks of harm, most notably cerebral hemorrhage identified on imaging studies (NNTH = 13). The balance of risk versus benefit demonstrated thus far doesn’t justify the use of these costly (> US$20,000 annually) drugs.
Reference
Ebell MH, Barry HC, Baduni K, Grasso G. Clinically important benefits and harms of monoclonal antibodies targeting amyloid for the treatment of Alzheimer disease: A systematic review and meta-analysis. Ann Fam Med 2024;22(1):50-58..
Study design: Meta-analysis (randomized controlled trials)
Funding source: Unknown/not stated
Setting: Various (meta-analysis)
Synopsis
The authors of this systematic review and meta-analysis of randomized controlled trials sought to determine whether monoclonal antibody medications that target amyloid for the treatment of Alzheimer disease provide clinically meaningful patient-oriented benefits or harms. This is an important question because federal approval of these medications was based on surrogate markers. The authors included 19 studies with 23,202 participants. Inclusion criteria included the enrollment of adults with cognitive impairment, Alzheimer disease of any severity, or a high risk of Alzheimer disease with at least one year duration, and the reporting of an outcome of interest. The authors excluded trials or trial arms that used doses lower than those approved by the US Food and Drug Administration. All studies were industry-funded placebo-controlled trials. Most studies enrolled patients with mild cognitive impairment or mild to moderate Alzheimer disease. Outcomes of interest were well-defined minimum clinically important differences (MCIDs) in the results for any of multiple cognitive scoring tools and potential harms. The drugs used in the trials included in this meta-analysis were solenezumab, aducanumab, and lecanemab, donanemab, and bapineuzumab. Notably, there are no head-to-head trials with other drugs. The summary analysis showed that improvement over placebo was small (standard mean difference [SMD] -0.07; 95% CI -0.10 to 0.04). Although some statistically significant benefits were identified, none were close to reaching an MCID threshold. There was no overall difference between treatment and control groups for all-cause mortality, though bapineuzumab was associated with an increase (relative risk [RR] 1.76; 1.03 - 3.00; number needed to treat to harm [NNTH] = 102). The most frequently reported harms were amyloid-related imaging abnormalities, including edema (ARIA-E) (RR in overall analysis 10.3; 7.4 - 14.3; NNTH = 9), symptomatic ARIA-E (RR for the 3 drugs reporting = 24.3; 9.9 - 59.9; NNTH = 86), and hemorrhage (ARIA-H; RR = 1.74; 1.2 - 2.4; NNTH = 13).
Linda Speer, MD
Professor and Chair, Department of Family Medicine
University of Toledo
Toledo, OH
Clinical question
Does delivery of bad news via telephone increase psychological stress more than in-person communication?
Bottom line
Delivering bad news by telephone does not affect levels of anxiety, depression, or satisfaction with care as compared with delivering the news in person.
Reference
Mueller J, Beck K, Loretz N, et al. The disclosure of bad news over the phone vs. in person and its association with psychological distress: a systematic review and meta-analysis. J Gen Intern Med 2023;38(16):3589-3603.
Study design: Meta-analysis (other)
Funding source: Government
Setting: Various (meta-analysis)
Synopsis
These researchers searched 4 databases and reference lists of screened articles to identify 11 observational and randomized controlled trials that investigated differences in psychological distress of breaking bad news by telephone compared with in person in patients or next of kin. Two authors independently selected articles for inclusion and abstracted the relevant data. Most (7) of the studies evaluated disclosure of malignancy diagnoses; the rest included results of genetic testing, Alzheimer disease, and hypertrophic cardiomyopathy. Overall, the study quality was moderate to good. There was no difference regarding psychological distress when bad news was delivered via telephone in terms of anxiety (3 studies, 285 participants), depression (3 studies, 284 participants), and post-traumatic stress disorder (2 studies, 171 participants). Results were similar for satisfaction with care. In a single study, there was no association between level of trust, which was high, and disclosure of bad news via telephone versus in person..
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, Mass.
Levels of Evidence definitions from Essential Evidence Plus
POEMs are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, please see http://www.essentialevidenceplus.com.