See related AFP article, Top 20 Research Studies of 2022 for Primary Care Physicians.
Clinical question
What is the impact of low-density lipoprotein cholesterol reduction on the individual risks of myocardial infarction, stroke, and overall mortality?
Bottom line
Reducing LDL levels with statins provides only a small reduction in the person's likelihood of dying (0.8% reduction) or experiencing myocardial infarction (1.3%) or stroke (0.4%). Too often we are given relative risk reductions or a bundling together of these outcomes with other lesser outcomes, which leads to an inflated sense of importance attributed to cholesterol treatment. In addition, the authors also found a small and inconsistent relationship between more aggressive lowering of LDL cholesterol and these outcomes, which is contrary to what many (U.S.) guidelines would have us believe.
Reference
Byrne P, Demasi M, Jones M, et al. Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment: a systematic review and meta-analysis. JAMA Intern Med. 2022;182(5):474-481.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Unknown/not stated
Setting: Outpatient (any)
Synopsis
These authors followed PRISMA guidelines to report the results of their meta-analysis evaluating the relationship between low-density lipoprotein (LDL) cholesterol lowering and individual, patient-oriented outcomes. By searching two databases (1987 through June 2021), the authors identified 21 studies of primary and secondary prevention. Overall risk of bias in the studies was low. As compared with placebo in 19 studies (n = 132,763), statin treatment produced a 0.8% overall reduction (95% CI, 0.4% to 1.2%) in the likelihood of death due to any cause over the course of the study (which was typically three years to six years). The likelihood of a heart attack decreased 1.3% (0.9% to 1.7%) in 18 studies of 121,190 participants, and stroke was decreased by 0.4% (0.2% to 0.6%) in 128,086 patients. For primary prevention, these attributable risk reductions were lower—0.6%, 0.7%, and 0.3%—and for secondary prevention, these risk reductions were a little higher—0.9%, 2.2%, and 0.7%. An inconsistent relationship occurred across the studies between the degree of LDL lowering and prevention of the outcome. Statistical heterogeneity was found among the studies, which likely means that differences occurred among the study populations. The authors caution against calculating numbers needed to treat because of this heterogeneity, but I'm going to do it anyway: 88 to 250 people need to be treated for one additional person to be alive at the end of several years.
Allen F. Shaughnessy, PharmD, MMedED
Professor of Family Medicine
Tufts University
Boston, Mass.
Clinical question
Does supplemental vitamin D reduce the risk of fracture in older adults?
Bottom line
Vitamin D level is a very good marker of ill health but a terrible treatment target. This large study showed definitively that supplemental vitamin D does not reduce the risk of fracture, even in persons with low baseline vitamin D levels or a previous fracture.
Reference
LeBoff MS, Chou SH, Ratliff KA, et al. Supplemental vitamin D and incident fractures in midlife and older adults. N Engl J Med. 2022;387(4):299-309.
Study design: Randomized controlled trial (double-blinded)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
This study randomized 25,871 men 50 years and older and women 55 years and older in a 2 x 2 factorial design to receive 2,000 IU vitamin D per day or placebo and 1,000 mg omega-3 fatty acid per day or placebo. Patients were not selected on the basis of their fracture risk or vitamin D levels; participants with a history of cancer, cardiovascular disease, or hypercalcemia were excluded. The primary goal of the VITAL trial was to evaluate the effect of these supplements on cancer and cardiovascular outcomes. Fractures were assessed based on patient self-report in an annual survey and confirmed by medical record review. The mean age of participants was 57 years, 51% were women, and 20% were Black. Approximately 25% of patients had a baseline vitamin D level of less than 24 ng per mL and 1.5% had a value of less than 12 ng per mL. About 42% in each group were taking supplemental vitamin D, which they agreed to limit to no more than 800 mg per day during the study. A total of 1991 fractures occurred in 1551 patients, with no difference in total, nonvertebral, hip, or "osteoporotic" fractures (hip + wrist + humerus + spine). The authors did a series of prespecified subgroup analyses and found no benefit in patients who were taking none of their own supplemental vitamin D or calcium in the placebo group. In patients with a previous fragility fracture, the mean 25-hydroxyvitamin D level was 30.7 ng per mL at baseline, and there was no difference in fracture rates in different quartiles of vitamin D levels, including in patients with vitamin D levels of less than 24.0 ng per mL (hazard ratio [HR] 1.04; 95% CI, 0.80 to 1.36) and of less than 12 ng per mL (HR 1.03; 0.36 to 2.95). There were no differences among groups with regard to renal stones or episodes of hypercalcemia or other adverse events.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
For patients who are currently taking an antidepressant and are doing well, what is the likelihood of relapse after discontinuation of their medication?
Bottom line
Primary care patients who discontinued antidepressant medications were significantly more likely to experience relapse of their depression (NNTH = 6) than those who continued to take their antidepressants. The glass half-full interpretation is that 44% of primary care patients with depression who discontinue their antidepressant medication when they are doing well continue to do well.
Reference
Lewis G, Marston L, Duffy L, et al. Maintenance or discontinuation of antidepressants in primary care. N Engl J Med. 2021;385(14):1257-1267.
Study design: Randomized controlled trial (double-blinded)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (primary care)
Synopsis
These researchers identified primary care patients who had at least two episodes of depression or who had been taking antidepressants for at least two years. All patients felt well enough to consider discontinuing their medication; those with current depressive symptoms were excluded. The patients who had been taking been taking citalopram 20 mg, fluoxetine 20 mg, sertraline 100 mg, or mirtazapine 30 mg for at least nine months were randomized to either continue their medication or to discontinue their medication over a two-month period by substituting placebo. At baseline, the mean age of participants was 54 years, 73% were women, 95% were white, approximately half were taking citalopram, and approximately three-quarters had been taking an antidepressant for more than three years. The primary outcome was relapse of depression, defined as a two-week spell of feeling sad, miserable, or depressed or being unable to enjoy or take an interest in things as much as usual, accompanied by at least one other depressive symptom. After one year, this outcome occurred significantly more often in the placebo group (56% vs. 39%; hazard ratio [HR] 2.06; 95% CI, 1.56 to 2.70; number needed to treat to harm [NNTH] = 6). Depressive and anxiety symptoms were, on average, more severe in the discontinuation group. In addition, more patients in the discontinuation group stopped taking their placebo (48% vs. 30%; HR 2.28; 1.68 to 3.08) and more resumed antidepressant medications (39% vs. 20%). The mean scores on the 7-item Generalized Anxiety Disorder Questionnaire and the 9-question Patient Health Questionnaire were also significantly higher in the discontinuation group.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
What is the treatment efficacy and tolerability of combination therapy compared with monotherapy for acute severe depression and recurrent depression in adults?
Bottom line
This review found that combination therapy using a reuptake inhibitor (i.e., a selective serotonin reuptake inhibitor, serotonin–noradrenaline reuptake inhibitor, or tricyclic antidepressant) with an antagonist of presynaptic alpha2-autoreceptors (mirtazapine or trazodone) is more effective than monotherapy for first-line treatment of acute severe depression and for those patients who are initially nonresponders to monotherapy. Dropout rates due to adverse events were similar for both combination therapy and monotherapy.
Reference
Henssler J, Alexander D, Schwarzer G, et al. Combining antidepressants vs antidepressant monotherapy for treatment of patients with acute depression. A systematic review and meta-analysis. JAMA Psychiatry. 2022;79(4):300-312.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Industry + foundation
Setting: Various (meta-analysis)
Synopsis
The optimal management of an initial episode of acute severe depression and nonresponsive depression in adults remains uncertain. These investigators thoroughly searched, without language restrictions, multiple databases, including MEDLINE, PsycINFO, Embase, and the Cochrane Central Register of Controlled Trials for randomized trials that compared antidepressant monotherapy with a combination of two antidepressants. Eligible trials included both first-line antidepressant treatment trials and trials that included patients resistant to improvement with initial therapy. In studies that included nonresponders, monotherapy (control group) patients received either continued monotherapy with the same antidepressant at the same or higher dose or monotherapy with a different antidepressant. Two individuals independently evaluated individual trials for study eligibility and risk of bias using the Cochrane scoring tool. Disagreements were resolved by consensus agreement. The primary outcome was treatment efficacy measured as the standardized mean difference (SMD). Of the 39 individual trials, 15 were classified as "low risk of bias." Heterogeneity was minimal when restricted to studies with low risk of bias and an analysis for publication bias found minimal risk for altering the results.
Overall, combination therapy provided superior efficacy than monotherapy for both first-line treatment and among nonresponders (SMD 0.31; 95% CI, 0.19 to 0.44). Results were similar when restricting the analyses to only studies with low risk of bias. The combination of a monoamine reuptake inhibitor with an antagonist of presynaptic alpha2-autoreceptors (i.e., mirtazapine or trazodone) is associated with superior efficacy compared with monotherapy for both first-line treatment and for nonresponding patients. Combination therapy with bupropion was not associated with superior outcomes compared with monotherapy for first-line treatment but was superior to monotherapy for nonresponding patients. Dropout rates due to adverse events were similar for both types of therapy.
David C. Slawson, MD
Professor and Chair of Family Medicine Atrium Health
Charlotte, NC
Clinical question
Is treatment with medication effective for patients with panic disorder?
Bottom line
In a body of evidence plagued by poorly designed studies of short duration, SSRIs show the best balance of effectiveness vs. risk. This analysis did not give us a comparison of medication with psychotherapy, although a meta-analysis of limited research was unable to document a benefit of one over the other.
Reference
Chawla N, Anothaisintawee T, Charoenrungrueangchai K, et al. Drug treatment for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials. BMJ. 2022;376:e066084.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Self-funded or unfunded
Setting: Outpatient (specialty)
Synopsis
These researchers identified randomized controlled trials that evaluated medicines to treat panic disorder (with or without agoraphobia) by searching three databases as well as reference lists of identified studies and meta-analyses. They included 87 studies published in any language that included a total of 12,800 participants and 12 drug classes, with two researchers independently selecting studies for inclusion and abstracting the data. Alas, only one study was at low risk of bias, and all studies were of short duration (12 weeks or less). All the other studies suffered from issues of randomization, allocation concealment (which could affect outcomes), or risk of a selective reporting of outcomes (many studies were conducted before registration of study protocols was a standard practice). The authors used network meta-analysis, a method of comparing different drug treatments when they were not studied in head-to-head trials. Evaluating the effect on remission, which was defined as no panic attacks for at least one week by the end of the study, all drug classes studied were more effective than placebo, with benzodiazepines, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs), in that order, as the top three best treatments for remission. All three drug classes were associated with an increased likelihood of adverse effects, with SSRIs having the least likelihood. Among the SSRIs, sertraline and escitalopram were associated with high remission and low risk of adverse events.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, Mass.
Clinical question
Are hypnotic agents safe and effective in managing insomnia in adults?
Bottom line
In this network meta-analysis, agents for managing insomnia in adults come with significant trade-offs of effectiveness and tolerability. Because only half the studies were at low risk of bias, the recommendations from guidelines from the U.S. Departments of Defense and Veterans Administration and the American College of Physicians to reserve hypnotic agents as second-line therapy seems wise.
Overuse alert: This POEM aligns with the Canadian Geriatric Society’s Choosing Wisely Canada recommendation: Do not use benzodiazepines or other sedative hypnotics in older adults as first choice for insomnia, agitation, or delirium. Choosing Wisely Canada’s primary care and hospital toolkits provide tools to reduce unnecessary benzodiazepine use in older adults.
Reference
De Crescenzo F, D'Alo GL, Ostinelli EG, et al. Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis. Lancet. 2022;400(10347):170-184.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Government
Setting: Various (meta-analysis)
Synopsis
This team searched multiple databases and residencies to identify randomized trials of pharmacologic agents or placebo as monotherapy in managing insomnia in adults. The authors also conducted a network meta-analysis only on double-blind trials. Ultimately, they included 170 randomized trials (47,950 participants), of which 154 (44,089) were double blind. The included trials assessed the effectiveness and tolerability of pharmacological treatments in the acute management of insomnia (median two weeks), as well as the long-term management of insomnia (median 25 weeks). The studies evaluated a wide range of agents, including benzodiazepines, nonbenzodiazepines, lemborexant, doxepin, melatonin, doxylamine, and suvorexant. Of the 170 trials, 82 (48.3%) trials were rated at low risk of bias, 33 (19.4%) at unclear risk, and 55 (32.4%) at high risk. Because the studies used a variety of different outcome measures, the authors did a bunch of statistical gymnastics to estimate standardized effect sizes for each agent’s effectiveness and tolerability. The data presented by the authors are voluminous and generally demonstrate significant trade-offs between effectiveness and tolerability.
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Is a fixed-dose combination of albuterol and budesonide as a rescue medication more effective than albuterol alone in patients with moderate to severe asthma who are taking long-term inhaled corticosteroids?
Bottom line
A fixed-dose combination inhaler using a total dose of 180 mcg albuterol and 160 mcg budesonide as a rescue inhaler yielded a significant reduction in exacerbations and a reduction in the need for systemic corticosteroids.
Reference
Papi A, Chipps BE, Beasley R, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022;386(22):2071-2083.
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry
Allocation: Uncertain
Setting: Outpatient (any)
Synopsis
These researchers identified participants four years and older with at least one severe asthma exacerbation (defined as hospitalization, an emergency department visit requiring systemic corticosteroids, or an exacerbation requiring at least three days of systemic corticosteroids) in the previous year. The 3,132 patients were randomized to receive one of three types of rescue inhaler, each given as two actuations (doses shown are per actuation): (1) albuterol 90 mcg plus budesonide 80 mcg, (2) albuterol 90 mcg plus budesonide 40 mcg, or (3) albuterol 90 mcg. Children four to 11 years of age were randomized to receive only the lower dose combination or albuterol only. Groups were balanced at baseline with a mean age of 49 years, and only 6% of participants were younger than 18 years. Analysis was by intention to treat, but allocation concealment was not described, either in this publication or in a previous publication describing the methods (BMJ Open Resp Res. 2021;8:e001077). Patients were followed up for 24 weeks, with approximately 10% not completing the trial in each group. Patients in the higher-dose budesonide group had significantly fewer severe exacerbations than those in the albuterol-only group (hazard ratio [HR] 0.74; 95% CI, 0.62 to 0.89). Fewer severe exacerbations also occurred in the low-dose budesonide group than in the albuterol-only group, but this difference was smaller and not statistically significant (HR 0.84; 0.71 to 1.0). The annualized rate of severe exacerbations was 0.43 in the high-dose budesonide group compared with 0.58 in the albuterol-only group, which is approximately one fewer severe exacerbation per year for every seven patients treated. Patients in the high-dose combination group also took fewer systemic steroids (84 mg vs. 130 mg per year).
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
In Black and Latinx adults with moderate to severe asthma, does adding an extra puff of glucocorticoid inhaler whenever a short-acting beta-agonist inhaler is needed reduce exacerbations compared with usual care?
Bottom line
Instead of telling patients with moderate to severe asthma to just use their SABA when they have symptoms, you should have them accompany the SABA with a puff of their corticosteroid. You may have to customize the ratio of puffs for each patient. For example, if someone uses a 160-mcg beclomethasone inhaler, they should use only one puff for every two puffs of SABA.
Reference
Israel E, Cardet JC, Carroll JK, et al. Reliever-triggered inhaled glucocorticoid in Black and Latinx adults with asthma. N Engl J Med. 2022;386(16):1505-1518.
Study design: Randomized controlled trial (nonblinded)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
These researchers recruited 1,201 Black and Latinx adults with moderate to severe, poorly controlled asthma who were already prescribed an inhaled corticosteroid. The mean age of participants was 48 years, 85% were women, and 72% had at least one asthma exacerbation in the previous year. Exacerbations were defined as an emergency department or urgent care visit, hospitalization, or a course of systemic glucocorticoids. All patients continued usual care, which was a daily inhaled glucocorticoid with (72%) or without (28%) a long-acting beta-agonist, supplemented by as-needed use of a short-acting beta-agonist (SABA) "reliever" inhaler. Those patients randomized to the intervention group were instructed to also use additional glucocorticoid inhaler puffs whenever they used their reliever (beclomethasone 80 mcg, one puff per each puff of their reliever, or five puffs if using a nebulizer as the reliever). Groups were balanced at the beginning the unmasked study, allocation was concealed, and analysis was by intention to treat. After a median of 14.9 months, the annual rate of exacerbations was lower in the intervention group (0.69 vs. 0.82; hazard ratio 0.85; 95% CI, 0.72 to 0.999). That is approximately one fewer exacerbation for every eight patients who received usual care plus the intervention compared with usual care alone. Asthma control scores increased by 1 to 2 points more in the intervention group, which is less than the minimal clinically important difference of 3 points for this score. Participants in the intervention group used approximately one more steroid inhaler per year than did patients in the usual care group. No difference in serious adverse events occurred between groups.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
Is there an association between gastric cancer and the use of proton pump inhibitors?
Bottom line
This is the strongest evidence to date that there is a small but clinically significant increase in the risk of gastric cancer for patients taking a PPI (number needed to treat to harm = 1191 over 10 years). Physicians initiating anti-acid therapy for patients should begin with an H2RA, and if prescribing a PPI, should use the lowest dose and duration possible. Another recent study in the same journal using data from a Korean registry produced similar findings (Gut. 2021;70:2066-2075; doi:10.1136/gutjnl-2020-323845).
This POEM aligns with the Choosing Wisely Canada recommendation that advises not to maintain long-term PPI therapy for gastrointestinal symptoms without stopping at least once per year in most patients. Choosing Wisely Canada’s toolkit provides tools for deprescribing PPIs.
Reference
Abrahami D, McDonald EG, Schnitzer ME, et al. Proton pump inhibitors and risk of gastric cancer: population-based cohort study. Gut. 2022;71(1):16-24.
Study design: Cohort (retrospective)
Funding source: Government
Setting: Population-based
Synopsis
Proton pump inhibitors (PPIs) cause hypergastrinemia, which can lead to hyperplasia of the gastric mucosa, and several previous studies have shown an association between PPI use and gastric cancer. This study is the largest and most methodologically sound; it addresses several potential sources of confounding better than previous studies. The authors identified more than 1.1 million people who had received a new prescription for a PPI between 1990 and 2018 and another 220,825 people who had received a new prescription for a histamine-2 receptor antagonist (H2RA) during the same period. This is a better comparison group than the general population because it avoids confounding by indication (PPI users may have different risk factors and health habits than non-users). People with a familial syndrome associated with gastric cancer, people with previous gastric cancer, and those who had less than one year of follow-up were excluded, leaving 973,281 PPI patients and 198,306 H2RA patients. The authors matched patients using propensity scores that incorporated a large array of potential confounders, including age, comorbidities, tobacco and alcohol use, and medications. In the fully adjusted model, the authors found a significantly increased risk of gastric cancer in PPI users compared with H2RA users (hazard ratio [HR] = 1.45; 95% CI, 1.06 to 1.98; number needed to treat to harm = 2,121 after five years and 1,191 after 10 years). The Kaplan-Meier survival analysis showed that the risk increased linearly with the duration of PPI use. Greater doses were associated with increased risk: HR = 1.22 for less than 14,600 mg cumulative omeprazole dose equivalents; HR = 1.81 for 14,600 mg to 28,199 mg dose equivalents; and HR = 2.03 for 29,200 mg and higher dose equivalents (although the confidence intervals overlap).
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, Ga.
Clinical question
How should clinicians evaluate and manage persons with suspected gastroesophageal reflux disease?
Bottom line
The American College of Gastroenterology has updated its guideline for the diagnosis and management of GERD. The paper has several useful tables and algorithms that may be of use to primary care clinicians.
This POEM aligns with the Choosing Wisely Canada recommendation that advises not to maintain long-term PPI therapy for gastrointestinal symptoms without stopping at least once per year in most patients. Choosing Wisely Canada’s toolkit provides tools for deprescribing PPIs.
Reference
Katz PO, Dunbar KB, Schnoll-Sussman FH, et ak. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2022;117(1):27-56.
Study design: Practice guideline
Funding source: Unknown/not stated
Setting: Various (guideline)
Synopsis
The American College of Gastroenterology convened a panel to update its 2013 guideline on managing people with gastroesophageal reflux disease (GERD). Although the paper does not describe how the panel was selected, the panel members all appear to be gastroenterologists. The panel members identified specific questions, and a research librarian performed a literature search on each question. The panel members assessed the quality of the underlying research to guide their recommendations. The panel made many specific recommendations and identified key concepts, some of which are relevant to primary care clinicians. A few of these are summarized below. Additionally, the panel recommends searching for non-GERD causes of extraesophageal symptoms (cough, asthma, etc.) before ascribing them to GERD, and, after that, in the absence of GERD symptoms, patients should undergo reflux testing before taking a proton pump inhibitor (PPI). Finally, the panel recognizes that some patients require long-term PPI therapy and some harms have been associated with this treatment. The panel suggests advising patients that PPIs are the most effective medical treatment for GERD and that the studies reporting an association between the long-term use of PPIs and harms such as pneumonia, gastric cancer, and so forth are flawed; they do not establish a cause-and-effect relationship between PPIs and the adverse conditions. The panel states that the benefits of PPIs outweigh their theoretical risks.
Table: Select Summary of recommendations relevant to primary care.
| Recommendation | Quality of Evidence | Strength of Recommendation |
| An 8-week trial of empiric PPIs in persons with classic symptoms and no alarm symptoms | Moderate | Strong |
| Attempt to discontinue PPIs after a successful 8-week trial | Low | Conditional |
| Endoscopy is the preferred initial test in persons with dysphagia, alarm symptoms, and with multiple risk factors for Barrett's esophagus | Low | Conditional |
| Persons with suspected GERD but unremarkable endoscopy should have reflux monitoring off therapy | Low | Strong |
| Overweight or obese persons with GERD should attempt weight loss | Moderate | Strong |
| Avoid meals within 2 to 3 hours before bedtime | Low | Conditional |
| Avoid tobacco and trigger foods | Low | Conditional |
| Elevate the head of the bed | Low | Conditional |
| Use PPIs over histamine receptor antagonists in persons with erosive esophagitis | High | Strong |
| Administer PPIs 30 minutes to 60 minutes before a meal rather than at bedtime | Moderate | Strong |
| In the absence of Barrett's or erosive esophagitis, attempt to discontinue PPIs in persons whose symptoms have resolved | Low | Conditional |
| Don't use prokinetic agents in the absence of objective evidence for gastroparesis | Low | Strong |
| Administer sucralfate only to pregnant women | Low | Strong |
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
What is the best way to manage irritable bowel syndrome?
Bottom line
This high-quality evidence-based guideline provides sound advice for the evaluation and management of IBS in primary care.
Reference
Vasant DH, Paine PA, Black CJ, et al. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut. 2021;70(7):1214-1240.
Study design: Practice guideline
Funding source: Foundation
Setting: Outpatient (any)
Synopsis
These guidelines from the British Society of Gastroenterology were created by a multidisciplinary panel that included primary care physicians, psychologists, dietitians, and gastroenterologists. Treatment recommendations were based on systematic reviews, and all other recommendations were based on a comprehensive review of the literature. There are dozens of recommendations; I'll outline the highlights. The guidelines advocate a pragmatic definition of irritable bowel syndrome (IBS) as at least six months of abdominal pain or discomfort, in association with altered bowel habits, in the absence of alarm signs or symptoms. Initial evaluation in primary care should include a complete blood count, C-reactive protein or sedimentation rate, and serology for celiac disease. For patients younger than 45 years who present with diarrhea, order a fecal calprotectin test to rule out inflammatory bowel disease. Screen for colorectal cancer in accordance with national guidelines; colonoscopy is recommended only for patients with alarm signs and symptoms or who are at increased risk for microscopic colitis (female, at least 50 years of age, with comorbid autoimmune disease; weight loss; diarrhea for less than 12 months; or severe, nocturnal, or watery diarrhea). Consider testing for bile acid diarrhea in patients with nocturnal diarrhea or prior cholecystectomy. The guidelines recommend against testing for pancreatic insufficiency, small intestinal bacterial overgrowth, or carbohydrate intolerance if the symptoms are typical for IBS. First-line treatment recommendations include exercise and gradually increasing doses of soluble fiber (e.g., ispaghula) but not insoluble fiber (e.g., wheat bran). Consider probiotics, although the guideline doesn't recommend a specific species or dose. Consider loperamide for diarrheal symptoms; antispasmodics and peppermint oil for global symptoms, as well as abdominal pain and cramping; and polyethylene glycol for constipation. (Note that a recent POEM found no benefit to peppermint oil in a well-designed trial.) Second-line drugs in primary care include tricyclic antidepressants and selective serotonin reuptake inhibitors. Other drug classes, such as medications targeting 5-HT-3 and 5-HT-4 receptors, should be prescribed after evaluation by a gastroenterologist.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
What is the natural history of prediabetes in adults older than 60 years?
Bottom line
In this cohort study, older persons with prediabetes were more likely to become normoglycemic than to develop diabetes or to die.
Reference
Veronese N, Noale M, Sinclair A, et al. Risk of progression to diabetes and mortality in older people with prediabetes: the English Longitudinal Study on ageing. Age Ageing. 2022;51(2):afab222.
Study design: Cohort (prospective)
Funding source: Government
Setting: Population-based
Synopsis
These authors analyzed data from the English Longitudinal Study on Ageing, which is a prospective and nationally representative cohort of men and women living in England. The authors categorized 2,027 adults older than 60 years who did not have diabetes at baseline by whether or not they had prediabetes (defined as a glycohemoglobin level between 5.7% and 6.4% or a fasting glucose level between 5.6 and 7.0 mmol per L [100 to 125 mg per dL]). The authors do not report how often the participants were assessed, but the patients were followed up for eight years. The average age of the participants was 70.6 years, and 55% were women. Among the participants classified as normoglycemic at baseline (glycohemoglobin < 5.7%), 2.3% developed diabetes and 9.8% died (incidence rates: 3.5 per 1,000 person years and 13.7 per 1,000 person years, respectively). Among the participants with prediabetes based on glycohemoglobin, 12.9% developed diabetes, 11.6% died (incidence rates: 19.6 per 1,000 person years and 16.8 per 1,000 person years, respectively), and 37.6% became normoglycemic. Of those with prediabetes based on fasting glucose levels, 15.6% developed diabetes, 13.8% died (incidence rates: 23.8 per 1,000 person years and 19.0 per 1,000 person years, respectively), and 58.2% became normoglycemic. After adjusting for age and sex, compared with being normoglycemic, having prediabetes by either parameter or its permutations was associated with a higher risk of developing diabetes (hazard ratio range: 2.94 to 41.0). Additionally, compared with being normoglycemic, having prediabetes based on fasting glucose and the combination of fasting glucose plus glycohemoglobin was associated with an increased risk of death (1.47 and 1.65, respectively). Regardless, older persons with prediabetes are more likely to become normoglycemic than to develop diabetes or die.
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
What is the long-term impact of treating prediabetes on mortality and cardiovascular outcomes?
Bottom line
In patients with prediabetes, neither an intensive lifestyle intervention nor metformin had any impact on the long-term risk of cardiovascular outcomes.
Reference
Goldberg RB, Orchard TJ, Crandall JP, et al, for the Diabetes Prevention Program Research Group. Effects of long-term metformin and lifestyle interventions on cardiovascular events in the diabetes prevention program and its outcome study. Circulation. 2022;145(22):1632-1641.
Study design: Randomized controlled trial (nonblinded)
Funding source: Government
Allocation: Uncertain
Setting: Outpatient (any)
Synopsis
The original Diabetes Prevention Program study randomized 3,234 overweight or obese adults with impaired glucose tolerance ("prediabetes") to receive metformin 850 mg twice daily, an intensive exercise program, or placebo and followed them for three years. The primary outcome was the prevention of a diagnosis of type 2 diabetes mellitus (T2DM), which was reduced by 58% in the lifestyle therapy group and by 31% with metformin compared with placebo. Patients were invited to participate in a long-term open-label follow-up study, and 86% agreed. All patients were offered a less-intensive lifestyle intervention, and those who were originally randomized to receive metformin continued to take it until their glycated hemoglobin level was 7.0% or higher, at which time their physician determined the appropriate drug therapy for T2DM. This article reports long-term cardiovascular and mortality outcomes for each group. Patients in the intervention groups were less likely to have been given a diagnosis of T2DM (55% for metformin and 53% for lifestyle vs. 60% for placebo; P = .001; number needed to treat [NNT] = 17), and the lifestyle therapy group was also less likely to have hyperlipidemia (91% vs. 94%; P = .03; NNT = 33). There was no difference between either intervention group and placebo with regard to the risk of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction. There was also no significant difference in the composite of all three outcomes for the original metformin group vs. the placebo group (hazard ratio [HR] 1.03; 95% CI, 0.78 to 1.37) or for those in the original lifestyle group vs. the placebo group (HR 1.14; 0.87 to 1.50). Subgroup analysis by age, sex, race, or the presence of T2DM found no reduction in risk for any group. There was a trend for women to have more composite endpoint outcomes with intensive lifestyle intervention, but with 24 subgroup comparisons this could just be due to chance. Limitations that the study did not adjust for include differences in medication use among groups, including the use of statins and other cardiovascular or diabetes medications prescribed by their physicians.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
How frequent is hypoglycemia among elderly institutionalized persons with type 2 diabetes mellitus?
Bottom line
In this small study, more than 75% of elderly persons with type 2 diabetes mellitus who were residing in nursing homes had at least one hypoglycemic event during two weeks of monitoring, and nearly 50% experienced severe hypoglycemia. A lower HbA1C level was associated with more frequent events and a longer time spent in a hypoglycemic state.
This POEM aligns with Choosing Wisely Canada recommendations. Choosing Wisely Canada recommends avoiding using medications known to cause hypoglycemia to achieve hemoglobin A1c <7.5% in many adults age 65 and older; moderate control is generally better. Learn more.
Reference
Bouillet B, Tscherter P, Vaillard L, et al. Frequent and severe hypoglycaemia detected with continuous glucose monitoring in older institutionalised patients with diabetes. Age Ageing. 2021;50(6):2088-2093.
Study design: Cohort (prospective)
Funding source: Self-funded or unfunded
Setting: Nursing home/extended care facility
Synopsis
This study, which took place in six nursing homes in France, recruited 42 persons with type 2 diabetes who were older than 65 years and taking medications capable of inducing hypoglycemia (e.g., sulfonylureas, repaglinide, insulin). The researchers defined hypoglycemia as a capillary glucose level of less than 70 mg per dL (3.9 mmol jper L) and severe hypoglycemia as a glucose level of less than 54 mg per dL (3 mmol per L). The participants wore a continuous glucose monitor for up to 14 days. The monitor did not reveal the readings to the participants or the care staff. Most of the participants were women (69%), and their average age was 87.4 years. The care staff identified five hypoglycemic events in four participants through episodic capillary glucose monitoring; the continuous monitoring identified 242 events in 33 (79%) of the participants. Seven participants (17%) spent more than 20% of an entire day in a hypoglycemic state. Nineteen participants (45%) experienced severe hypoglycemia. After adjusting for sex, comorbidities, weight, treatment, and functional status, the authors report that the glycated hemoglobin (HbA1C) level was inversely associated with the number of events and with time spent in hypoglycemia (i.e., a lower HbA1C was associated with more events).
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
Are amitriptyline, duloxetine, and pregabalin effective in decreasing pain in adults with diabetic peripheral neuropathy?
Bottom line
In this study, adults with painful diabetic peripheral neuropathy had similar degrees of improvement with monotherapy using amitriptyline, duloxetine, and pregabalin. However, there was even greater improvement with subsequent combination therapy regardless of initial choice of medication.
Reference
Tesfaye S, Sloan G, Petrie J, et al.; OPTION-DM trial group. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial. Lancet. 2022;400(10353):680-690.
Study design: Cross-over trial (randomized)
Funding source: Government
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
This was a complex study design.. The researchers enrolled 130 adults with diabetes and pain associated with distal symmetrical polyneuropathy for at least three months. In this cross-over trial, the participants were randomly assigned to three, 16-week pathways separated by a two-week washout period: oral amitriptyline supplemented with pregabalin (A-P), pregabalin supplemented with amitriptyline (P-A), and duloxetine supplemented with pregabalin (D-P). Each pathway started with a two-week period in which doses of medication were titrated to the maximum tolerated dose. This was followed by six weeks of maintenance monotherapy. At the end of six weeks, as we would do in clinical practice, those with pain ≤ 3/10 were classified as responders and maintained on monotherapy for 10 weeks. Nonresponders then received the second drug for 10 weeks. During the subsequent 10 weeks, the researchers titrated medication doses to maintain pain levels at ≤ 3/10. At the end of 16 weeks, the researchers stopped all study drugs for a two-week washout period, and then the participants started the next drug combination. Whew!
Most (84%) of the participants had type 2 diabetes and were White (94%). Although 130 started the first pathway, only 97 and 84 began a second and third pathway, respectively. At the end of six weeks of monotherapy, the proportion of responders was similar for amitriptyline (37%), duloxetine (32%), and pregabalin (34%). At the end of 16 weeks, the proportion of responders was similar for A-P (48%), D-P (43%), and P-A (47%). Additionally, the authors found that at the end of each evaluation period, the participants had similar degrees of improvement in pain regardless of agent. Finally, most adverse events were mild and similar across all three paths, with the three exceptions summarized (bolded) in the table.
| A-P | P-A | D-P | P value | |
|---|---|---|---|---|
| Dizziness | 12% | 16% | 24% | 0.036 |
| Nausea | 5% | 23% | 7% | 0.0011 |
| Dry mouth | 32% | 8% | 17% | 0.0003 |
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
How do patients interpret word-based and number-based probability estimates, and how do they prefer to receive estimates of risk?
Bottom line
In general, people grossly overestimate probabilities conveyed by the words we use. People translate "rare" as 10%, on average, which is 100-fold higher than its intended meaning when used for medication risk labeling. The interpretation of "common"—an average 59%—is much closer, in my mind, to "almost always" than the accepted definition of 1% to 10%. Patients may prefer hearing the actual numbers, if you can provide them. I suspect, though, that numbers will be misinterpreted given the general state of innumeracy in most of us (imagine, perhaps, your own difference in interpretation if I had written "100-fold" instead of "two orders of magnitude" in the synopsis).
Reference
Andreadis K, Chan E, Park M, et al. Imprecision and preferences in interpretation of verbal probabilities in health: a systematic review. J Gen Intern Med. 2021;36(12):3820-3829.
Study design: Systematic review
Funding source: Government
Setting: Other
Synopsis
These researchers followed PRISMA guidelines to search several databases to find English-language experimental and quasi-experimental studies that evaluated different formats (numerical vs. word-based) for presenting health-related quantitative information to patients. Two researchers selected the studies, and three researchers abstracted the studies. The review included 33 studies that evaluated the way probabilities were presented and the resultant interpretation. There is a lot to unpack in this report, but here are the main points. One person's "rare" occurrence is another person's "common" occurrence. "Rare," defined by the European Commission (EC) labeling guidelines as between 0.1% and 0.01%, was defined as two orders of magnitude higher by study patients (average 10%; range 7% to 21%). "Common," defined by the EC as a risk of 1% to 10%, was thought to mean an average of 59% (range 34% to 70.5%) by patients. In studies asking for preference, a majority of patients prefer numbers rather than word-based estimates of risk.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, Mass.
Clinical question
Is there any benefit to extending varenicline (Chantix) therapy beyond 12 weeks, or to combining varenicline with nicotine replacement therapy, for increasing smoking cessation?
Bottom line
OVERUSE ALERT: This study found no additional benefit with varenicline plus NRT vs. varenicline monotherapy, or with varenicline treatment for 24 weeks vs. 12 weeks for increasing smoking cessation rates. These results were not affected by sex, race, treatment site, or level of tobacco dependence.
Reference
Baker TB, Piper ME, Smith SS, et al. Effects of combined varenicline with nicotine patch and of extended treatment duration on smoking cessation. A randomized clinical trial. JAMA. 2021;326(15):1485-1493.
Study design: Randomized controlled trial (double-blinded)
Funding source: Industry + government
Allocation: Concealed
Setting: Outpatient (any)
Synopsis
Evidence remains unclear whether combining varenicline with nicotine replacement therapy (NRT) or extending its use beyond three months increases smoking cessation rates. These investigators identified 1,251 adults, 18 years or older, who smoked at least five cigarettes per day during the last six months, with an exhaled carbon monoxide (CO) level of 5 ppm or greater. Consenting participants who expressed a desire to quit smoking randomly received (concealed) assignment to one of four treatment groups: (1) varenicline monotherapy for 12 weeks; (2) varenicline plus patch NRT for 12 weeks; (3) varenicline monotherapy for 24 weeks; or (4) varenicline plus patch NRT for 24 weeks. Varenicline treatment (using a standard dosing titration schedule) began one week before the target quit date and nicotine patch treatment (one 14-mg patch per day) started two weeks before the target quit date. All participants received 24 weeks of varenicline pills and 26 weeks of nicotine patches (active and placebo-matched medications). All patients also received six 15-minute counseling sessions focused on instructions, support, and coping skills to improve motivation to quit. The primary outcome was self-reported seven-day abstinence biochemically confirmed with exhaled CO level measured by individuals masked to treatment group assignments. Complete follow up occurred for 70.4% of patients at 52 weeks. Individuals who did not complete follow-up were analyzed according to randomization group (intention to treat) and were assumed to be still smoking.
Approximately 25% of patients met the criteria for biochemically confirmed abstinence at the 52-week follow-up, with no significant differences in quit rates among the four treatment groups. Additional secondary analyses found no significant effect of any prespecified covariates including sex, race, treatment site, or level of tobacco dependence (based on the Fagerstrom Test for Nicotine Dependence score).
David C. Slawson, MD
Professor and Chair of Family Medicine Atrium Health
Charlotte, NC
Clinical question
What common medicines have serious interactions with cannabidiol?
Bottom line
CBD, a nonintoxicating phytocannabinoid, is widely available and may interact with other medications. Although a number of interactions have been documented, their likelihood and impact have not yet been described. Consider asking patients about their CBD use before prescribing another psychoactive medicine, and ask whether they have experienced any unexpected adverse effects with other medications.
Reference
Balachandran P, Elsohly M, Hill KP. Cannabidiol interactions with medications, illicit substances, and alcohol: a comprehensive review. J Gen Intern Med. 2021;36(7):2074-2084.
Study design: Systematic review
Funding source: Self-funded or unfunded
Setting: Not applicable
Synopsis
These authors searched three databases, including a drug-interaction database, to identify drug interactions with cannabidiol (CBD). In addition to affecting the brain, CBD also affects other organs and systems, including the liver. The list of interactions is large, and this synopsis presents only the common medicines with significant interactions. CBD inhibits the hepatic enzyme CYP2D6 and may increase the blood levels of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, beta-blockers, and opioids. CBD will increase serum levels of lamotrigine (Lamictal), but other anticonvulsants will decrease serum levels of CBD.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
Clinical question
How do ibuprofen, ketorolac, and diclofenac compare for the treatment of acute, nonradicular low back pain in adults?
Bottom line
This study found no differences among ibuprofen, ketorolac, and diclofenac in the primary outcome of overall clinical improvement at five days in adults presenting to the emergency department with acute, nonradicular low back pain. Some of the secondary outcomes favored ketorolac, however, leaving open the possibility that ketorolac is superior to ibuprofen and/or diclofenac. As the saying goes, "Absence of proof is not proof of absence."
Reference
Irizarry E, Restivo A, Salama M, et al. A randomized controlled trial of ibuprofen versus ketorolac versus diclofenac for acute, nonradicular low back pain. Acad Emerg Med. 2021;28(11):1228:1235.
Study design: Randomized controlled trial (double-blinded)
Funding source: Self-funded or unfunded
Allocation: Concealed
Setting: Emergency department
Synopsis
Although nonsteroidal anti-inflammatory drugs (NSAIDs) are the recommended first-line treatment for acute low back pain, there is no clear evidence for recommending one oral NSAID over another. These investigators identified adults, 18 to 65 years of age, who presented to an emergency department with acute low back pain. Eligibility criteria included pain between the lower border of the scapulae and the upper gluteal folds without any radicular symptoms that lasted less than two weeks, or a history of direct trauma to the back within the last month. Patients (N = 198) randomly received (concealed allocation assignment) ibuprofen (600 mg every eight hours, as needed), ketorolac (10 mg every eight hours, as needed), or diclofenac (50 mg every eight hours, as needed). Study participants masked to treatment group assignment self-rated overall symptoms, including pain and function, using a validated 24-item low back pain scoring tool. Complete follow-up occurred for 86% of patients at five days.
Using intention-to-treat analysis, no significant group differences occurred in the primary outcome of an improved pain and function score. A number of secondary outcomes were assessed, some of which significantly favored ketorolac. The investigators, however, appropriately conclude that the current study found no clear evidence to recommend one of these NSAIDs over either of the others.
David C. Slawson, MD
Professor and Chair of Family Medicine Atrium Health
Charlotte, NC
Clinical question
What is the best topical treatment for patients with mild to moderate acne vulgaris?
Bottom line
For patients with mild to moderate acne, this network meta-analysis suggests starting with either adapalene plus BPO, clindamycin plus BPO, or adapalene alone. Patients who do not tolerate either BPO-containing combination are likely to better tolerate adapalene alone.
Reference
Stuart B, Maund E, Wilcox C, et al. Topical preparations for the treatment of mild-to-moderate acne vulgaris: systematic review and network meta-analysis. Br J Dermatol. 2021;185(3):512-525.
Study design: Meta-analysis (randomized controlled trials)
Funding source: Government
Setting: Outpatient (any)
Synopsis
This interdisciplinary team of UK researchers began by asking patients with acne what was most important to them in a study of acne treatments. The patients stated that self-reported improvement was more important than investigator-reported outcomes. Thus, the primary outcomes of this study were the proportion of patients who reported moderate or better improvement, and the proportion who withdrew from the study or stopped using the study medication due to adverse events. This network meta-analysis searched carefully and identified 40 randomized trials evaluating 12 topical agents or topical combinations in 18,089 patients; 79% of the studies were from North America or Europe. Only studies that reported acne severity and in which fewer than half of patients had severe acne were included. The studies were a mix of active drug vs. vehicle cream or active drug vs. a different active drug. A network meta-analysis reports both a meta-analysis of direct comparisons, as well as a meta-analysis of both direct and indirect comparisons. The authors found that adapalene plus benzoyl peroxide (BPO) was most effective compared with vehicle cream based on meta-analyses of both direct and indirect comparisons (odds ratio [OR] 3.65; 95% CI, 2.58 to 5.15), with clindamycin plus BPO coming in second (OR 2.98; 2.22 to 4.01) and adapalene third (OR 2.44; 1.66 to 3.60). Limiting the analysis to only studies that made a direct comparison with vehicle cream had similar findings (the technical term for this is "coherence"), which gives us greater confidence in the overall results. With regard to withdrawals due to adverse events, adapalene plus BPO had the highest rate (OR 2.93; 1.69 to 5.08), followed by BPO alone (OR 1.59; 0.98 to 2.57) and clindamycin plus BPO (OR 1.44; 0.75 to 2.72). Although absolute probabilities and numbers needed to treat or harm are not reported, the researchers state that withdrawals due to adverse events were uncommon.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
Does a booster of the Pfizer/BioNTech BNT162b2 mRNA vaccine reduce mortality due to COVID-19?
Bottom line
Previous studies found a reduction in severe and symptomatic disease in patients who received a Pfizer-BioNTech vaccine booster. This study adds that mortality is also reduced by approximately 90%.
Reference
Arbel R, Hammerman A, Sergienko R, et al. BNT162b2 vaccine booster and mortality due to covid-19. N Engl J Med. 2021;385(26):2413-2420.
Study design: Cohort (retrospective)
Funding source: Government
Setting: Population-based
Synopsis
In response to the rising number of cases of the delta variant of COVID-19 and the reduced vaccine efficacy over time, on July 30, 2021, the Israeli Ministry of Health recommended a third dose of the Pfizer/BioNTech vaccine for people 50 years and older who had received their second dose at least five months earlier. (This study predates the Omicron wave.) This observational study of 843,208 persons compared the outcomes in persons who received a third dose (booster) and those who were vaccinated but did not receive the booster. People with a previous COVID-19 infection and those who had a confirmed case before the booster had time to become effective were excluded. People who chose to receive a booster were, on average, older (69 vs. 65 years of age), more likely to be Jewish (89% vs. 68%), and had a higher socioeconomic status than those who did not; there were no clinically significant differences between groups with regard to comorbidities. The authors adjusted the analysis for the socioeconomic and demographic differences. The primary outcome of death due to COVID-19 occurred much less often in the boosted group (0.16 vs. 2.98 deaths per 100,000 persons per day; adjusted hazard ratio 0.10; 95% CI, 0.07 to 0.14). It is possible that those seeking a booster were also more likely to engage in other protective health behaviors.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
What is the benefit of a fourth dose of the Pfizer-BioNTech mRNA COVID-19 vaccine for people 60 years and older?
Bottom line
A fourth dose of the Pfizer-BioNTech COVID-19 vaccine provides a benefit for people 60 years and older, with lower rates of infection, hospitalization, and death in the period immediately following vaccination. The durability of that benefit is unknown.
Reference
Magen O, Waxman JG, Makov-Assif M, et al. Fourth dose of BNT162b2 mRNA Covid-19 vaccine in a nationwide setting. N Engl J Med. 2022;386(17):1603-1614.
Study design: Cohort (prospective)
Funding source: Foundation
Setting: Population-based
Synopsis
This study in a large Israeli health system identified 182,122 people 60 years or older who had received a fourth dose of the Pfizer-BioNTech mRNA vaccine against COVID-19 (BNT162b2). The people had all received their third dose at least four months previously, and none had a previous confirmed COVID-19 infection. Each person was matched with a person who had not yet received their fourth dose (the matching was based on demographics, area of residency, number of chronic conditions, and the number of hospitalizations in the previous three years). Each pair was followed up for up to 30 days; if the control person received a fourth dose during that period, both members of the pair were dropped. The groups were very similar at baseline, with a median age of 72 years, 53% were women, and they had similar numbers of comorbidities and hospitalizations. Vaccine efficacy between seven days and 30 days was 45% against infection, 55% against symptomatic infection, 68% against hospitalization, 62% against severe COVID-19, and 74% against death. Among those with a COVID-19 infection during days 7 to 30, the likelihood of hospitalization was 2.0% in the four-dose group and 3.4% in the three-dose group. Similarly, the likelihood of death among those infected with COVID-19 was 0.17% in the four-dose group and 0.39% in the three-dose group. I calculated the numbers needed to immunize as 34 to prevent one infection between days 7 and 30, 673 to prevent one hospitalization, and 5,228 to prevent one death. Those numbers will be smaller (i.e., more favorable) over a longer time horizon. A second study in the same journal confirmed these benefits and also found that although protection against infection waned relatively quickly, protection against severe disease did not.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
Other than vaccination, what public health measures are effective in controlling the spread of COVID-19?
Bottom line
The paucity of high-quality data suggests we need better studies to determine which measures are truly effective. However, it appears that several personal and social protective measures, including handwashing, mask wearing, and physical distancing, are associated with reductions in COVID-19 incidence.
Reference
Talic S, Shah S, Wild H, et al. Effectiveness of public health measures in reducing the incidence of covid-19, SARS-CoV-2 transmission, and covid-19 mortality: systematic review and meta-analysis. BMJ. 2021;375:e068302.
Study design: Meta-analysis (other)
Funding source: Self-funded or unfunded
Setting: Various (meta-analysis)
Synopsis
These authors searched multiple databases, including the World Health Organization’s preprint database, to identify studies that evaluated the effectiveness of individual public health measures (other than vaccinations) to prevent COVID-19. They did not describe “snowballing” to identify any studies that escaped their initial search and did not include studies that evaluated multiple interventions. The authors independently evaluated studies for inclusion and assessed the methodologic quality of the individual studies. Ultimately, they identified 72 studies, 35 of which reported data on individual interventions (only one was a randomized trial). Overall, three of the 35 studies were of good methodologic quality, with major confounding as the most common source of serious or critical bias. In three low-quality studies (n = 10,345 participants), handwashing was associated with a nonsignificant decrease in COVID-19 infection (relative risk [RR] 0.47; 95% CI, 0.19 to 1.12). Six low-quality studies (n = 389,228 participants) evaluated mask wearing. Persons who wore masks were less likely to contract COVID-19 (RR 0.47; 0.29 to 0.75), although these data varied greatly among the studies. The authors also report, based on several large natural experiments (in 200 countries and 15 states), that mask wearing was associated with lower rates of COVID-19 transmission and COVID-19 mortality, although they could not pool the available data. They identified a single low-quality study that reported that disinfecting surfaces was associated with a lower risk of secondary COVID-19 transmission (RR 0.23; 0.07 to 0.84). Five low-quality studies (n = 108,933 participants) reported that physical distancing was associated with a lower incidence of COVID-19 (RR 0.75; 0.59 to 0.95), but these data were also quite variable across the studies. Three low-quality studies each found that physical distancing was associated with less COVID-19 transmission.
Two lower-quality studies evaluated school closures: one reported a lower rate of COVID-19 incidence and the other found no effect. Additionally, among three natural experiments of school closures, two studies found a significant decrease in COVID-19 transmission. The other reported a small increase in COVID-19 among the parents and found that teachers in lower secondary schools were twice as likely to become infected as teachers in upper secondary schools. Because of methodologic heterogeneity, the authors did not pool data for several other interventions. All the studies assessing stay-at-home or isolation measures, quarantine measures, business closures, and lockdown were associated with decreased COVID-19 incidence, transmission, or mortality. Finally, the results from two low-quality studies of border closures were inconsistent: increased COVID-19 incidence in one and decreased incidence in the other. Overall, these results suggest that better data are needed to determine which measures, other than vaccination, are truly effective.
Henry C. Barry, MD, MS
Professor
Michigan State University
East Lansing, MI
Clinical question
How protective are previous infection, vaccination, or both against symptomatic COVID-19 infection and against severe infection?
Bottom line
Three doses of vaccine with or without previous infection or two doses of vaccine plus previous infection both conferred excellent protection against serious disease in the first part of the Omicron wave. A limitation of this study is that the authors did not report results for the BA.4 and BA.5 variants now sweeping the globe. So, stay tuned.
Reference
Altarawneh HN, Chemaitelly H, Ayoub HH, et al. Effects of previous infection and vaccination on symptomatic omicron infections. N Engl J Med. 2022;387(1):21-34.
Study design: Case-control
Funding source: Foundation
Setting: Population-based
Synopsis
This study was done in Qatar, which has a diverse, young population that includes many guest workers from south and east Asia. Only 9% are older than 50 years. This study looked at symptomatic COVID-19 infections between December 23, 2021, and February 21, 2022. They used a case-control, test-negative design, matching each confirmed person with symptomatic COVID-19 with a control person who had not been infected. The researchers evaluated the following for protection during the initial omicron wave with the BA.1 and BA.2 variants: infection with a variant prior to the omicron wave, two doses of mRNA vaccine, three doses of mRNA vaccine, and hybrid immunity in patients with two or three doses of vaccine and a previous infection. For those who received two doses, the median interval from the second dose to PCR test was 268 days, while that interval was only 42 days for patients who received a third dose. Protection from symptomatic infection was 50.8% for previous infection without vaccine, 0% for two doses of vaccine (mostly given at least six months ago) and no previous infection, 55.5% for two doses of vaccine and previous infection, 54.0% for three doses of vaccine, and 76.3% for three doses of vaccine plus a previous infection. The authors did not evaluate four doses of vaccine. The good news is that protection against severe, critical, or fatal COVID-19 was much better: 71.6% for previous infection only, 73.5% for two doses and no previous infection, 94.3% for two doses and previous infection, 92.5% for three doses and no previous infection, and 100% for three doses and previous infection.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
How does protection against COVID-19 differ among patients with natural immunity, vaccine immunity, and hybrid immunity, and how quickly does that protection wane?
Bottom line
Both natural immunity and hybrid immunity provide protection against subsequent COVID-19 infection that is on par with that of boosted patients. Patients who have recovered from COVID-19 should still get the vaccine. Unfortunately, immunity wanes over time for all groups.
Reference
Goldberg Y, Mandel M, Bar-on YM, et al. Protection and waning of natural and hybrid immunity to SARS-CoV-2. N Engl J Med. 2022;386(23):2201-2212.
Study design: Cohort (retrospective)
Funding source: Government
Setting: Population-based
Synopsis
This study from the Israeli Ministry of Health used national data on infections during the Delta wave of COVID-19 (August and September 2021) to compare four different kinds of immunity: (1) vaccination with two or three doses of the Pfizer/BioNTech vaccine, (2) recovery from COVID-19 infection, (3) recovery from COVID-19 followed by a single vaccine dose, and (4) a single vaccine dose followed by recovery from COVID-19. The primary outcome was the number of cases per 100,000 person-days of follow-up based on a Poisson regression model that adjusted for age, sex, and religious group (general Jewish, ultraorthodox Jewish, or Arab). Unvaccinated persons who had recovered from COVID-19 had good protection from subsequent infection, and it was actually better than that of those who had two vaccine doses at each time point (recall that unboosted individuals did not have much protection from infection with the Delta variant). There was only limited follow-up for those with a single booster, but their protection was good out to two months. Those with hybrid immunity had impressive protection out to eight months, without much difference depending on whether infection or vaccine came first. For example, at four to six months following infection or vaccine, the hybrid immunity and natural immunity groups had only 10 infections per 100,000 person-days compared with the two-dose vaccine group, which had 70 infections. The authors did not have much information on severe infections, and we do not know about the protection afforded by infection with the Omicron variant.
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Clinical question
Should primary care clinicians recommend low-dose aspirin for the primary prevention of cardiovascular disease in adults 60 years or older?
Bottom line
In this updated review, the USPSTF recommends against initiating low-dose aspirin use (81 mg daily) for the primary prevention of CVD in adults 60 years or older (D recommendation). The Task Force recommends shared decision-making regarding the initiation of low-dose aspirin for the primary prevention of CVD in adults 40 to 59 years of age with a 10% or greater risk of CVD and without an increased risk of bleeding (C recommendation). Risk factors for bleeding include older age, history of peptic ulcer disease, alcoholism, liver disease, long-term nonsteroidal anti-inflammatory drug or steroid use, and anticoagulant therapy.
Reference
US Preventive Services Task Force, Davidson KW, Barry MJ, et al. Aspirin use to prevent cardiovascular disease. US Preventive Services Task Force recommendation statement. JAMA. 2022;327(16):1577-1584.
Study design: Practice guideline
Funding source: Government
Setting: Population-based
Synopsis
The U.S. Preventive Services Task Force (USPSTF) found adequate evidence that low-dose aspirin used for the primary prevention cardiovascular disease (CVD) reduces the risk of major cardiovascular events. There is no high-quality evidence, however, that low-dose aspirin reduces the risk of cardiovascular mortality or all-cause mortality. Similarly, evidence remains uncertain of a benefit for reducing the risk of colorectal cancer. Potential harms include a significant risk of major bleeding events, with increasing risk proportional to increasing age. New recommendations (which replace the 2016 guidelines) include considering aspirin for high-risk individuals at 40 years of age instead of 50 years of age, and no longer recommending aspirin for primary prevention in adults 60 years or older. For those patients already taking aspirin or choosing to start taking aspirin, the Task Force recommends stopping aspirin at approximately age 75 years of age. The American Heart Association recommends shared decision-making regarding the use of aspirin for the primary prevention of CVD in high-risk adults 40 to 70 years of age who do not have an increased risk of bleeding.
David C. Slawson, MD
Professor and Chair of Family Medicine Atrium Health
Charlotte, NC
Clinical question
How should patients with type 2 diabetes be treated?
Bottom line
These NICE treatment guidelines continue the move toward modifying cardiovascular risk over glycemic control when making treatment decisions for type 2 diabetes. Although metformin treatment is still the cornerstone, these updated guidelines make way for routine treatment with SGLT2 inhibitors. For patients with chronic heart failure, patients at high risk of or with established atherosclerotic cardiovascular disease, or patients with chronic kidney disease, consider adding an SGLT2 inhibitor. The guidance makes no specific recommendation for an HbA1c treatment goal, other than to suggest switching or adding treatments if an "individually agreed threshold" is not met. A useful decision tree is available here.
Overuse alert: This POEM aligns with the following Choosing Wisely Canada recommendations:
The Canadian Geriatrics Society’s recommendation: Avoid using medications known to cause hypoglycemia to achieve hemoglobin A1c < 7.5% in many adults 65 years and older; moderate control is generally better.
The Canadian Society of Endocrinology and Metabolism’s recommendation: Don’t recommend routine or multiple daily self-glucose monitoring in adults with stable type 2 diabetes on agents that do not cause hypoglycemia.
Reference
Moran GM, Bakhai C, Song SH, Agwu JC, Guideline Committee. Type 2 diabetes: summary of updated NICE guidance. BMJ. 2022;377:o775.
Study design: Practice guideline
Funding source: Government
Setting: Various (guideline)
Synopsis
These National Institute of Health and Care Excellence (NICE) guidelines are based on a review of the best evidence on the treatment of type 2 diabetes along with explicit consideration of cost effectiveness. The complete guideline can be found here. These guidelines continue to evolve our thinking away from glycemic control treatment goals and toward goals that consider cardiovascular risk and kidney function. Metformin should be the first medicine used in patients with type 2 diabetes; the modified-release version (Glumetza) should be considered for patients with continued gastrointestinal symptoms. Assess kidney function via albumin to creatinine ratio and cardiovascular disease status and risk via the QRISK2 calculator. As in previous guidelines, chronic kidney disease should be treated, and a sodium glucose co-transporter 2 (SGLT2) inhibitor should be considered. Patients with chronic heart failure (strong recommendation) or established cardiovascular disease (weak recommendation) should be treated with an SGLT2 inhibitor, as well. The guidelines hint that empagliflozin (Jardiance), canagliflozin (Invokana), or dapagliflozin (Farxiga, Forxiga), which have stronger evidence of cardiovascular disease protection, should be used. The guidance does not specify a specific level of glycemic control as a goal.
Allen F. Shaughnessy, PharmD, MMedEd
Professor of Family Medicine
Tufts University
Boston, MA
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.