By Jonathan Galati, MD
Peer Reviewed
With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.
Compression Therapy to Prevent Recurrent Cellulitis of the Leg [1] (https://www.nejm.org/doi/10.1056/NEJMoa1917197)
Lower extremity cellulitis is a common and costly (total cost for cellulitis discharges was USD 3.74 billion in 2013) [2,3] cause of hospital admission. It carries significant morbidity [4] and has a high rate of recurrence [5]. It is well established that chronic leg edema is a significant risk factor for lower extremity cellulitis and recurrent cellulitis [4]. While compression therapy is often recommended to prevent recurrent cellulitis in patients with chronic leg edema, there is limited data to support this.
The aim of this single-center, randomized, controlled, nonblinded trial was to determine if compression therapy could prevent recurrent cellulitis in patients with chronic leg edema. The trial enrolled 84 patients with a history of 2 or more episodes of cellulitis in the same leg 2 years prior to the start of the trial, and edema lasting longer than 3 months in one or both legs. The patients were randomized in a 1:1 ratio into a cellulitis education group (control), and education plus compression therapy group. Participants in the compression group underwent therapist-applied compression bandaging prior to garment fitting, and were provided compression garments. They were instructed to wear their compression garments daily. The primary outcome was recurrence of cellulitis. The trial was intended to last 3 years; however, it was stopped after 2 years for efficacy. The interim analysis revealed that the compression group experienced significantly fewer episodes of recurrent cellulitis compared to the control group (hazard ratio 0.23; 95% CI, 0.09 to 0.059; P = 0002 | post hoc analysis of relative risk 0.37; 95% CI, 0.16 to 0.84; P = 0.02).
Compression therapy’s ability to reduce recurrent cellulitis in patients with lower extremity edema is an affordable and safe method that could greatly benefit patients while reducing the burden cellulitis places on healthcare costs. While this trial has some limitations – had a small sample size, took place at a single center, was nonblinded and involved lymphedema physiotherapists, its findings should not be discounted. Larger trials that better reflect real world outpatient practices where patients do not necessarily have access to lymphedema specialists should be pursued to confirm that these findings are generalizable.
Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC) [6] (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30539-0/fulltext)
Gallstone pancreatitis is a condition with significant morbidity and mortality. While urgent ERCP is recommended in patients with gallstone pancreatitis complicated by cholangitis (Reminder: Charcot’s Cholangitis Triad | jaundice, fever and right upper quadrant pain), it is unclear whether patients with gallstone pancreatitis without cholangitis would also benefit from urgent ERCP [7]. In this multicenter, randomized, controlled trial, Schepers et al sought to determine if urgent ERCP with sphincterotomy was superior to conversative medical management in the treatment of patients with severe acute gallstone pancreatitis without cholangitis.
This trial recruited 232 patients with severe gallstone pancreatitis (defined as an APACHE-II score of 8 or more, Imrie score of 3 or more or C-reactive protein greater than 150 mg/L within 24 hours of admission, and evidence of gallstones or dilated common bile duct on imaging or an ALT concentration twice the upper limit of normal) and randomly assigned them to urgent ERCP with biliary sphincterotomy (performed within 24 hours of hospitalization and within 72 hours after symptom onset) or conservative management. The primary endpoint was a composite of mortality and major complications within 6 months of randomization. At the conclusion of the study, the researchers found no difference in occurrence of the primary endpoint between the urgent ERCP group (38%) and conservative management group (44%) (risk ratio 0.87, 95% CI 0.64 to 1.18; P = 0.37). These findings persisted even when analyzing individual components of the primary endpoint. There was also no difference in adverse events reported.
Despite being beneficial in patients with gallstone pancreatitis with cholangitis, given this study’s findings, urgent ERCP with sphincterotomy may not be the best first line treatment for severe gallstone pancreatitis without cholangitis. The data suggest conservative management should be tried first with ERCP reserved for patients who develop cholangitis or have persistent cholestasis. It is important to keep in mind that the APACHE-II and Imrie scores used in this study are moderately accurate at predicting the severity of pancreatitis [8], thus patients with less severe gallstone pancreatitis may have been included in this study. It would have benefited the study to have BUN and creatinine cut-offs as part of its inclusion criteria since both have been shown to be markedly elevated in cases of severe pancreatitis [8,9,10].
Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis [11] (https://gut.bmj.com/content/69/8/1441)
Irritable bowel syndrome (IBS) is a complex disease that is difficult to manage [12]. It is debilitating, greatly impairing quality of life [13]. While the American College of Gastroenterology’s IBS guidelines recommend using psychological interventions (provider-directed cognitive behavioral therapy (CBT), relaxation therapy, hypnotherapy, and multicomponent psychological therapy) [14] to treat IBS symptoms, it is unclear which interventions are truly efficacious.
To elucidate this, Black et al performed a systemic review and network meta-analysis (standard meta-analysis can only compare two interventions whereas a network meta-analysis allows for the comparison of multiple interventions by combining direct and indirect evidence) [15] of randomized controlled trials that investigated the efficacy of psychological therapies in patients with IBS. To be included in the analyses, trials had to compare psychological therapies against each other or a control group, have a duration of therapy of four weeks or greater, and collected data regarding IBS symptom resolution or improvement. In total, 41 trials met inclusion criteria, contributing 4072 participants. The primary outcome was efficacy of psychological therapies versus each other and control interventions on IBS symptoms. Initially, their analysis showed that contingency management, group CBT and CBT via telephone were the most efficacious psychological therapies when compared to the control interventions; however, this was based on a few small trials skewing the data. Once the researchers accounted for number of trials and patients recruited, they found that self-administered or minimal contact CBT was most efficacious followed by face-to-face CBT and gut-direct hypnotherapy when compared to control interventions. None of the psychological therapies were significantly more efficacious than the other psychological therapies.
This study had several limitations. Systemic reviews and meta-analyses often use a funnel plot to assess for bias. In an ideal study, the funnel plot will appear symmetrical due to sampling variation [16]. Asymmetrical funnel plots indicate the presence of bias. Most often, this takes the form of publication bias where studies with positive findings are more likely to get published than studies with negative findings [16]. After pooling the data, the researchers for this study found funnel plot asymmetry indicating that there was bias. Despite having a seemingly adequate number of trials and participants included in the meta-analysis, the effective sample size for each psychological intervention was relatively small given the number of psychological interventions studied (20 total). Thus, while an interesting and important study for IBS management, further randomized controlled trials investigating the effect of psychological therapies on IBS symptoms are needed to accurately determine which therapies are most efficacious.
Effect of Probiotic Use on Antibiotic Administration Among Care Home Residents [17] (https://jamanetwork.com/journals/jama/article-abstract/2767862)
In the last 20 years, the global human probiotics market has burgeoned, worth approximately USD 42.55 billion in 2017. Probiotics are often touted for their health benefits, especially in the setting of preventing antibiotic-associated diarrhea [18]. Few studies have examined if taking probiotics can prevent infections or reduce antibiotic use.
In this multicenter, randomized, controlled, double blinded study, the authors were interested in investigating if daily probiotic use in care home residents (residential, nursing, or dual registered homes), a population prone to infection and antibiotic administration, reduced antibiotic administration over the course of a year. They recruited 310 care home residents 65 years or older who were not immunocompromised (ongoing immune-suppressants; long-term, high-dose, oral, intramuscular, or intravenous steroids) or already taking probiotics and randomized them into two groups: a daily probiotic (combination of Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12) group and daily placebo group. A total of 195 care home residents completed the study. The probiotic group had a mean of 12.9 cumulative systemic antibiotic administration days while the placebo group had a mean of 12.0 (absolute difference, 0.9 days, 95% CI, –3.25 to 5.05; adjusted incidence rate ratio, 1.13 95% CI, 0.79 to 1.63; P = 0.50).
Given the results of this trial, it does not appear that daily probiotic use reduces antibiotic administration in care home residents. That being said, the authors looked at a specific probiotic that contained Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp lactis BB-12. It is possible that a different combination of bacteria may yield different results in this patient population. Additionally, while the study said the probiotic group and control group had similar baseline characteristics, they did not include data pertaining to chronic health conditions that may make participants more prone to infection. It would have been interesting to see subgroup analyses for patients with conditions that place them at higher risk for infection and thus antibiotic use.
Minicuts
Impact of rheumatoid arthritis on major cardiovascular events in patients with and without coronary artery disease [19] (https://ard.bmj.com/content/79/9/1182)
Patients with rheumatoid arthritis (RA) are known to have an increased risk of cardiovascular disease [20]. In this retrospective study, the researchers sought to determine if they could risk stratify patients with RA based on the presence or absence of coronary artery disease (CAD). They found that regardless of the presence or absence of CAD, RA was significantly associated with an increased 10-year risk of MI, major adverse cardiovascular events (MACE) defined as MI, ischemic stroke, or cardiac death, and all-cause mortality. Patients with RA and CAD were at highest risk followed by patients with CAD without RA and finally patients with RA without CAD. Given these findings, physicians should risk stratify their patients with RA for MI and MACE based on the presence or absence of CAD. Further studies should look into screening and measures to prevent cardiovascular events in patients with RA and CAD.
Effect of Continuous Glucose Monitoring on Hypoglycemia in Older Adults With Type 1 Diabetes [21] (https://jamanetwork.com/journals/jama/article-abstract/2767159)
Older patients with type 1 diabetes are at higher risk of hypoglycemia. This randomized control trial sought to evaluate if continuous glucose monitoring (CGM) as opposed to standard glucose monitoring reduced the percentage of time per day patients were hypoglycemic (glucose less than 70 mg/dL). They found that patients in the CGM group spent significantly less time hypoglycemic (2.7%, 39 minutes per day) than the patients in the standard glucose monitoring group (4.9%, 70 minutes per day) (adjusted treatment difference, -1.9%, -27 minutes per day; 95% CI, -2.8% to -1.1%; P < 0.001). While significantly different, it is unclear if this finding is clinically significant since the difference between the groups was quite small. Further research in this field is needed to understand the clinical ramifications, if there are any, of these findings.
Subcutaneous or Transvenous Defibrillator Therapy [22] (https://www.nejm.org/doi/full/10.1056/NEJMoa1915932)
Transvenous defibrillators (ICD), while effective at preventing sudden cardiac death, can cause serious complications [23]. To implant a transvenous ICD, their electrodes must be introduced into a large vein and navigated to the heart where they are implanted. The newer subcutaneous ICDs neither require venous access nor implant their electrodes into the heart. Rather, their electrodes are embedded under the skin near the heart, allowing them to deliver effective shocks but unable to perform pacing. This randomized controlled trial sought to determine if subcutaneous ICDs were noninferior to transvenous ICDs in patient who required a defibrillator (class I or IIa indication) but not bradycardia or biventricular pacing. A total of 849 patients were recruited and randomly assigned to the subcutaneous or transvenous ICD groups. The primary outcome was a composite of device-related complications and inappropriate shocks. They found that the primary outcome occurred in 15.1% of the patients in the subcutaneous ICD group and 15.7% of the patients in the transvenous ICD group (hazard ratio, 0.99; 95% CI, 0.71 to 1.39; P = 0.01 for noninferiority). Thus, the authors concluded that subcutaneous ICDs are noninferior to the transvenous ICDs with respect to device-related complications or inappropriate shocks delivered to patients. In patients requiring an ICD without a need for pacing, subcutaneous ICDs are effective and, at this point in time, comparable to transvenous ICDs. As subcutaneous ICDs become more common, it is likely that their complication rate will improve as physicians become more experienced at implanting them necessitating further trials to reevaluate their complication rate.
Dr. Jonathan Galati is a first-year resident in internal medicine at NYU Langone Health
Peer reviewed by Daniel Sartori, MD, assistant professor, NYU Grossman School of Medicine
Image courtesy of Wikimedia Commons
References
[1] Webb E, Neeman T, Bowden FJ, et al. Compression Therapy to Prevent Recurrent Cellulitis of the Leg. NEJM. 2020;383(7): 630-639.
[2] Levell NJ, Wingfield CG, Garioch JJ. Severe lower limb cellulitis is best diagnosed by dermatologists and managed with shared care between primary and secondary care. Br J Dermatol. 2011;164(6):1326-8.
[3] Peterson RA, Polgreen LA, Cavanaugh JE, Polgreen PM. Increasing Incidence, Cost and Seasonality in Patients Hospitalized for Cellulitis. Open Forum Infect Dis. 2017;4(1):1-4.
[4] Cox NH, Colver GB, Paterson WD. Management and morbidity of cellulitis of the leg. JRSM. 1998;91(12):633-637.
[5] Cox, NH. Oedema as a risk factor for multiple episodes of cellulitis/erysipelas of the lower leg: a series with community follow-up. Br J Dermatol. 2006;155(5):947-50.
[6] Schepers NJ, Hallensleben NDL, Besselink MG, et al. Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomised controlled trial. Lancet. 2020;396(10245):167-176.
[7] Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013;108(9):1400-16.
[8] Mounzer R, Langmead CJ, Wu BU, et al. Comparison of existing clinical scoring systems to predict persistent organ failure in patients with acute pancreatitis. Gastroenterology 2012; 142(7): 1476–82.
[9] Wu BU, Bakker OJ, Papachristou GI, et al. Blood urea nitrogen in the early assessment of acute pancreatitis: an international validation study. Arch Intern Med. 2011;171(7):669-76.
[10] Muddana V, Whitcomb DC, Khalid A, et al. Elevated serum creatinine as a marker of pancreatic necrosis in acute pancreatitis. Am J Gastroenterol. 2009;104(1):164-70.
[11] Black CJ, Thakur ER, Houghton LA, et al. Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis. Gut. 2020;69(8):1441-1451.
[12] Rouse B, Chaimani A, Li T. Network Meta-Analysis: An Introduction for Clinicians. Intern Emerg Med. 2016;12(1):103-111.
[13] Holtmann GJ, Ford AC, Talley NJ. Pathophysiology of irritable bowel syndrome. Lancet Gastroenterol Hepatol. 2016;1(2);133-146.
[14] Pace F, Molteni P, Bollani S, et al. Inflammatory bowel disease versus irritable bowel syndrome: a hospital-based, case-control study of disease impact on quality of life. Scand J Gastroenterol. 2003;38(10):1031-8.
[15] Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1-18.
[16] Sterne JC, Sutton AJ, Ioannidis JPA, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.
[17] Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systemic review and meta-analysis. JAMA. 2012; 307(18):1959-69.
[18] Blaabjerg S, Artzi DM, Aabenhus R. Probiotics for the Prevention of Antibiotic-Associated Diarrhea in Outpatients-A Systematic Review and Meta-Analysis. Antibiotics (Basel). 2017;6(4):21
[19] Løgstrup BB, Olesen KKW, Masic D, et al. Impact of rheumatoid arthritis on major cardiovascular events in patients with and without coronary artery disease. Ann Rheum Dis. 2020.
[20] Nurmohamed MT, Heslinga M, Kitas GD. Cardiovascular comorbidity in rheumatic diseases. Nat Rev Rheumatol. 2015;11(12):693–704.
[21] Pratlet RE, Kanapka LG, Rickels MR, et al. Effect of Continuous Glucose Monitoring on Hypoglycemia in Older Adults With Type 1 Diabetes: A Randomized Control Trial. JAMA. 2020;323(23):2397-2406.
[22] Knops RE, Nordkamp LRA, Delnoy PPHM, et al. Subcutaneous or Transvenous Defibrillator Therapy. NEJM. 2020;363(6):526-536.
[23] Kirkfeldt RE, Johansen JB, Nohr EA, Jørgensen OD, Nielsen JC. Complications after cardiac implantable electronic device implantations: an analysis of a complete, nationwide cohort in Denmark. Eur Heart J. 2014;35(18):1186-94