From the Desk of the Editor-in-Chief
A review of recent papers of immediate clinical significance, harvested from major international journals
(1).SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes. A clinical practice guideline. https://www.bmj.com/content/bmj/373/bmj.n1091.full.pdf
Clinical question
What are the benefits and harms of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists when added to usual care (lifestyle interventions and/or other diabetes drugs) in adults with type 2 diabetes at different risk for cardiovascular and kidney outcomes?
Current practice
Clinical decisions about treatment of type 2 diabetes have been led by glycaemic control for decades. SGLT-2 inhibitors and GLP-1 receptor agonists are traditionally used in people with elevated glucose level after metformin treatment. This has changed through trials demonstrating atherosclerotic cardiovascular disease (CVD) and chronic kidney disease (CKD) benefits independent of medications’ glucose-lowering potential.
Recommendations
The guideline panel issued risk-stratified recommendations concerning the use of SGLT-2 inhibitors or GLP-1 receptor agonists in adults with type 2 diabetes:
(a)Three or fewer cardiovascular risk factors without established CVD or CKD: Weak recommendation against starting SGLT-2 inhibitors or GLP-1 receptor agonists.
(b)More than three cardiovascular risk factors without established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and weak against starting GLP-1 receptor agonists.
(c)Established CVD or CKD: Weak recommendation for starting SGLT-2 inhibitors and GLP-1 receptor agonists.
(d)Established CVD and CKD: Strong recommendation for starting SGLT-2 inhibitors and weak recommendation for starting GLP-1 receptor agonists.
(e)For those committed to further reducing their risk for CVD and CKD outcomes: Weak recommendation for starting SGLT-2 inhibitors rather than GLP-1receptor agonists
(2).Treatment timing and the effects of rhythm control strategy in patients with atrial fibrillation: nationwide cohort study, https://www.bmj.com/content/373/bmj.n991
Objective
To investigate whether the results of a rhythm control strategy differ according to the duration between diagnosis of atrial fibrillation and treatment initiation.
Design
Longitudinal observational cohort study.
Setting
Population based cohort from the Korean National Health Insurance Service database.
Participants
22635 adults with atrial fibrillation and cardiovascular conditions, newly treated with rhythm control (antiarrhythmic drugs or ablation) or rate control strategies between 28 July 2011 and 31 December 2015.
Main outcome measure
A composite outcome of death from cardiovascular causes, ischemic stroke, admission to hospital for heart failure, or acute myocardial infarction.
Results
Twelve thousand and two hundred (53.9%) were male, the median age was 70, and the median follow-up duration was two years. Among patients with early treatment for atrial fibrillation (initiated within one year since diagnosis), compared with rate control, rhythm control was associated with a lower risk of the primary composite outcome.
No difference in the risk of the primary composite outcome was found between rhythm and rate control in patients with late treatment for atrial fibrillation (initiated after one year since diagnosis).
No significant differences in safety outcomes were found between the rhythm and rate control strategies across different treatment timings.
Earlier initiation of treatment was linearly associated with more favorable cardiovascular outcomes for rhythm control compared with rate control.
Conclusions
Early initiation of rhythm control treatment was associated with a lower risk of adverse cardiovascular outcomes than rate control treatment in patients with recently diagnosed atrial fibrillation.
This association was not found in patients who had had atrial fibrillation for more than one year.
(3).Closed incision negative pressure wound therapy versus standard dressings in obese women undergoing caesarean section: multicentre parallel group randomised controlled trial.https://www.bmj.com/content/373/bmj.n893
Objective
To determine the effectiveness of closed incision negative pressure wound therapy (NPWT) compared with standard dressings in preventing surgical site infection (SSI) in obese women undergoing caesarean section.
Design
Multicenter, pragmatic, randomized, controlled, parallel group, superiority trial.
Setting
Four Australian tertiary hospitals between October 2015 and November 2019.
Participants
Eligible women had a pre-pregnancy body mass index of 30 or greater and gave birth by elective or semi-urgent caesarean section.
Intervention
Two thousand and thirty five consenting women were randomized before the caesarean procedure to closed incision NPWT (n = 1017) or standard dressing (n = 1018). Allocation was concealed until skin closure.
Main outcome measures
The primary outcome was cumulative incidence of SSI. Secondary outcomes included depth of SSI (superficial, deep, or organ/body space), rates of wound complications (dehiscence, hematoma, seroma, bleeding, bruising), length of stay in hospital, and rates of dressing related adverse events. Women and clinicians were not masked, but the outcome assessors and statistician were blinded to treatment allocation. The pre-specified primary intention to treat analysis was based on a conservative assumption of no SSI for a minority of women (n = 28) with missing outcome data. Post hoc sensitivity analyses included best case analysis and complete case analysis.
Results
In the primary intention to treat analysis, SSI occurred in 75 (7.4%) women treated with closed incision NPWT and in 99 (9.7%) women with a standard dressing (risk ratio 0.76, 95% confidence interval 0.57 to 1.01; P = 0.06). Post hoc sensitivity analyses to explore the effect of missing data found the same direction of effect (closed incision NPWT reducing SSI), with statistical significance. Blistering occurred in 40/996 (4.0%) women who received closed incision NPWT and in 23/983 (2.3%) who received the standard dressing (risk ratio 1.72, 1.04 to 2.85; P = 0.03).
Conclusion
Prophylactic closed incision NPWT for obese women after caesarean section resulted in a 24% reduction in the risk of SSI (3% reduction in absolute risk) compared with standard dressings. This difference was close to statistical significance, but it likely underestimates the effectiveness of closed incision NPWT in this population.
The results of the conservative primary analysis, multivariable adjusted model, and post hoc sensitivity analysis need to be considered alongside the growing body of evidence of the benefit of closed incision NPWT and given the number of obese women undergoing caesarean section globally.
The decision to use closed incision NPWT must also be weighed against the increases in skin blistering and economic considerations and should be based on shared decision making with patients.
(4).Risk of colorectal cancer in first degree relatives of patients with colorectal polyps: nationwide case-control study in Sweden. https://doi.org/10.1136/bmj.n877
Objective
To assess the risk of colorectal cancer (CRC) in first degree relatives (parents and full siblings) of patients with precursor lesions (polyps) for CRC.
Design
Case-control study. Setting Linkage to the multi-generation register and gastrointestinal ESPRESSO (Epidemiology Strengthened by histoPathology Reports in Sweden) histopathology cohort in Sweden.
Participants
Sixty eight thousand and sixty patients with CRC and 333,753 matched controls.
Main outcome measures
Multivariable adjusted odds ratios of CRC according to the number of first-degree relatives with a colorectal polyp and the histology of polyps and age at diagnosis in first degree relatives. Subgroup analysis was also performed according to age at CRC diagnosis and evaluated the joint association of family history of colorectal polyps and family history of CRC.
Results
After adjusting for family history of CRC and other covariates, having a first degree relative with a colorectal polyp (8.4% (5742/68 060) in cases and 5.7% (18 860/333 753) in controls) was associated with a higher risk of CRC (odds ratio 1.40, 95% confidence interval 1.35 to 1.45).
The odds ratios ranged from 1.23 for those with hyperplastic polyps to 1.44 for those with tubulovillous adenomas.
To better put this risk in perspective, the age specific absolute risk of colon and rectal cancers was estimated according to family history of polyps based on the 2018 national CRC incidence in Sweden. For example, the absolute risk of colon cancer in individuals aged 60-64 years with and without a family history of colorectal polyp was, respectively, 94.3 and 67.9 per 100 000 for men and 89.1 and 64.1 per 100 000 for women. The association between family history of polyps and CRC risk was strengthened by the increasing number of first-degree relatives with polyps (≥2 first degree relatives: 1.70, 1.52 to 1.90, P < 0.001 for trend) and decreasing age at polyp diagnosis (<50 years: 1.77, 1.57 to 1.99, P < 0.001 for trend). A particularly strong association was found for early onset CRC diagnosed before age 50 years (≥2 first degree relatives: 3.34, 2.05 to 5.43, P = 0.002 for heterogeneity by age of CRC diagnosis). In the joint analysis, the odds ratio of CRC for individuals with two or more first degree relatives with polyps but no CRC was 1.79 (1.52 to 2.10), with one first degree relative with CRC but no polyps was 1.70 (1.65 to 1.76), and with two or more first degree relatives with both polyps and CRC was 5.00 (3.77 to 6.63) (P < 0.001 for interaction).
Conclusions:
After adjusting for family history of CRC, the siblings and children of patients with colorectal polyps are still at higher risk of CRC, particularly early onset CRC. Early screening for CRC might be considered for first degree relatives of patients with polyps.
(5).Why is dying not seen as a diagnosis?https://www.bmj.com/content/373/bmj.n920
Audrey Chia explains why seeing dying as a diagnosis is important for patients at the end of life:
“My mother had developed rheumatoid arthritis in her twenties.
She reached her seventies and when she could no longer walk or feed herself, she chose to be cared for at a nursing home.
She later had cancer and a minor stroke but was generally in good spirits.
One Sunday, she refused her favorite spicy noodles. She commented that everything tasted worse than before.
The following week, she refused another favorite, braised pork with vegetables.
She was not eating much. She could not swallow. She felt nausea, as if something were pressing against her throat. She calmly told me she was going to die soon.
Tests and investigations
I took her to see a doctor. Her eyes no longer sparkled, she looked tired, thin, and fragile. The doctors were deeply concerned and admitted her for observation. We discussed the possible causes and the battery of tests began. The medical team diligently went about their investigations but it troubled me that there seemed to be little thought or questioning about whether the tests were reasonable with her condition.
The tests and treatments all caused her pain. My mother was so thin that every attempt to draw blood or to insert a drip caused even more pain. The process of giving the tests seemed automatic. There seemed to be little consideration of alternative means of obtaining the information needed. I kept wondering, could there have been less invasive or painful ways to help my mother?
Time to go home
After two months there was still no diagnosis and my mother’s condition had not improved, even after multiple efforts by the medical team. With my sister and a close friend, I made the decision to cease my mother’s treatment. My mother had entrusted me to make her decisions for her.
The drips, blood tests, scans, and attempts at ’scopes were stopped and it was time to go home. Her medical team found this decision hard to accept. They pressed me to persuade her to allow just one more test. I told them my mother had suffered enough and needed to rest. She received palliative care and died peacefully a week later.
Accepting death
During my mother’s care I had a good rapport with her doctors. They kept me informed through everything. But the only times we had discussed death and dying were before her surgeries. Perhaps, in our minds, dying was something that would occur quite suddenly during an intervention. We had not imagined it could instead happen gradually, over several months. Why did we not see that my mother was right? Her symptoms were consistent with the signs of dying.
Perhaps we were unwilling to accept death because there was no diagnosis. As we had to learn, “dying” is a diagnosis, too.
What you need to know?
Recognizing when a patient is dying and having open conversations will help patients and their families better prepare and feel involved.
Understanding a patient’s values, goals, and preferences will help ensure that care is appropriate and in line with their wishes.
Ensure patients and their families are involved in decision making around what tests should be conducted.
(6).New dimensions for hospital services and early detection of disease: A Review from the Lancet Commission into liver disease in the UK. https://doi.org/10.1016/S0140-6736(20)32396-5
This review, in addressing the unacceptably high mortality of patients with liver disease admitted to acute hospitals, reinforces the need for integrated clinical services.
The masterplan described is based on regional, geographically sited liver centers, each linked to four to six surrounding district general hospitals—a pattern of care similar to that successfully introduced for stroke services.
The plan includes the establishment of a lead and deputy lead clinician in each acute hospital, preferably a hepatologist or gastroenterologist with a special interest in liver disease, who will have prime responsibility for organizing the care of admitted patients with liver disease on a 24/7 basis.
Essential for the plan is greater access to intensive care units and high-dependency units, in line with the reconfiguration of emergency care due to the COVID-19 pandemic.
This Review strongly recommends full implementation of alcohol care teams in hospitals and improved working links with acute medical services.
We also endorse recommendations from pediatric liver services to improve overall survival figures by diagnosing biliary atresia earlier based on stool color charts and better caring for patients with impaired cognitive ability and developmental mental health problems.
Pilot studies of earlier diagnosis have shown encouraging progress, with 5–6% of previously undiagnosed cases of severe fibrosis or cirrhosis identified through use of a portable FibroScan in primary care.
Similar approaches to the detection of early asymptomatic disease are described in accounts from the devolved nations, and the potential of digital technology in improving the value of clinical consultation and screening programmes in primary care is highlighted.
The striking contribution of comorbidities, particularly obesity and diabetes (with excess alcohol consumption known to be a major factor in obesity), to mortality in COVID-19 reinforces the need for fiscal and other long delayed regulatory measures to reduce the prevalence of obesity.
These measures include the food sugar levy and the introduction of the minimum unit price policy to reduce alcohol consumption. Improving public health, this review emphasizes, will not only mitigate the severity of further waves of COVID-19, but is crucial to reducing the unacceptable burden from liver disease in the UK.
(7).Role of coronary artery calcium score in the primary prevention of cardiovascular disease. https://doi.org/10.1136/bmj.n776
First developed in 1990, the Agatston coronary artery calcium (CAC) score is an international guideline-endorsed decision aid for further risk assessment and personalized management in the primary prevention of atherosclerotic cardiovascular disease.
This review discusses key international studies that have informed this 30-year journey, from an initial coronary plaque screening paradigm to its current role informing personalized shared decision making.
Special attention is paid to the prognostic value of a CAC score of zero (the so called “power of zero”), which, in a context of low estimated risk thresholds for the consideration of preventive therapy with statins in current guidelines, may be used to de-risk individuals and thereby inform the safe delay or avoidance of certain preventive therapies.
We also evaluate current recommendations for CAC scoring in clinical practice guidelines around the world, and past and prevailing barriers for its use in routine patient care.
Finally, we discuss emerging approaches in this field, with a focus on the potential role of CAC informing not only the personalized allocation of statins and aspirin in the general population, but also of other risk-reduction therapies in special populations, such as individuals with diabetes and people with severe hypercholesterolemia.
(8).The COVID-19 infodemic. https://www.nejm.org/doi/full/10.1056/NEJMp2103798
Throughout the world, including the United States, medical professionals and patients are facing both a pandemic and an infodemic — the first caused by SARS-CoV-2 and the second by misinformation and disinformation.
Millions of people have been exposed to deceptive material alleging that SARS-CoV-2 is a hoax or that experts are exaggerating its severity and the extent of its spread, that masks are ineffective or increase infection risk, or that COVID-19 vaccines cause the disease, alter the recipient’s DNA, or include tracking devices. Believing such claims is associated with a lower likelihood of engaging in preventive behavior and a lower willingness to be vaccinated.
We believe the intertwining spreads of the virus and of misinformation and disinformation require an approach to counteracting deceptions and misconceptions that parallels epidemiologic models by focusing on three elements: real-time surveillance, accurate diagnosis, and rapid response.
Since lies tend to spread faster than accurate information does and an overwhelming amount of misinformation and disinformation circulates on social media, companies such as Facebook could provide researchers with access to aggregated and de-identified data on the spread of misinformation, as scholars have requested. Lack of access to such data is the equivalent of a near-complete blackout of epidemiologic data from disease epicenters.
Likelihood of acceptance of disinformation and misinformation varies. Our model will be more effective for people intrigued by misinformation but not yet under its thrall than for committed acolytes sequestered in echo chambers.
But the model’s strength, like that of epidemiology, is in recognizing that effective prevention and response requires mutually reinforcing interventions at all levels of society, including enhancing social-media algorithmic transparency, bolstering community-level norms, and establishing incentives for healthier media diets.
(9).Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma. https://www.nejm.org/doi/full/10.1056/NEJMoa2034975
Background
Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell–derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment.
Methods
We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire, Asthma Quality of Life Questionnaire and Asthma Symptom Diary.
Results
Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P < 0.001). In patients with a blood eosinophil count of less than 300 cells per microliter, the annualized rate was 1.02 (95% CI, 0.84 to 1.23) with tezepelumab and 1.73 (95% CI, 1.46 to 2.05) with placebo (rate ratio, 0.59; 95% CI, 0.46 to 0.75; P < 0.001). At week 52, improvements were greater with tezepelumab than with placebo with respect to the prebronchodilator FEV1 (0.23 vs. 0.09 liters; difference, 0.13 liters; 95% CI, 0.08 to 0.18; P < 0.001) and scores on the ACQ-6 (−1.55 vs. −1.22; difference, −0.33; 95% CI, −0.46 to −0.20; P < 0.001), AQLQ (1.49 vs. 1.15; difference, 0.34; 95% CI, 0.20 to 0.47; P<0.001), and ASD (−0.71 vs. −0.59; difference, −0.12; 95% CI, −0.19 to −0.04; P = 0.002). The frequencies and types of adverse events did not differ meaningfully between the two groups.
Conclusions
Patients with severe, uncontrolled asthma who received tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life than those who received placebo
(10).Clinical Guidelines,27 April 2021, Appropriate Use of High-Flow Nasal Oxygen in Hospitalized Patients for Initial or Postextubation Management of Acute Respiratory Failure: A Clinical Guideline from the American College of Physicians, https://doi.org/10.7326/M20-7533
Background
The American College of Physicians (ACP) developed this guideline to provide clinical recommendations on the appropriate use of high-flow nasal oxygen (HFNO) in hospitalized patients for initial or post-extubation management of acute respiratory failure. It is based on the best available evidence on the benefits and harms of HFNO, taken in the context of costs and patient values and preferences.
Methods
The ACP Clinical Guidelines Committee based these recommendations on a systematic review on the efficacy and safety of HFNO. The patient-centered health outcomes evaluated included all-cause mortality, hospital length of stay, 30-day hospital readmissions, hospital-acquired pneumonia, days of intubation or reintubation, intensive care unit (ICU) admission and ICU transfers, patient comfort, dyspnea, delirium, barotrauma, compromised nutrition, gastric dysfunction, functional independence at discharge, discharge disposition, and skin breakdown. This guideline was developed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method.
Target audience and patient population
The target audience is all clinicians, and the target patient population is adult patients with acute respiratory failure treated in a hospital setting (including emergency departments, hospital wards, intermediate or step-down units, and ICUs).
Recommendations
(a) ACP suggests that clinicians use high-flow nasal oxygen rather than noninvasive ventilation in hospitalized adults for the management of acute hypoxemic respiratory failure (conditional recommendation; low-certainty evidence).
(b) ACP suggests that clinicians use high-flow nasal oxygen rather than conventional oxygen therapy for hospitalized adults with pos-textubation acute hypoxemic respiratory failure (conditional recommendation; low-certainty evidence).
High-flow nasal oxygen (HFNO) therapy is a relatively new type of noninvasive respiratory support that has been gaining widespread use in hospitalized patients in recent years. It involves the delivery of warm and humidified oxygen via a small nasal cannula at a flow higher than the patient’s inspiratory flow (up to 60 L/min). The purported benefits of HFNO versus conventional oxygen therapy (COT) (low-flow systems [nasal cannulae or masks] and high-flow systems [masks]) and noninvasive ventilation (NIV) (continuous or bilevel positive airway pressure ventilation) include improved patient comfort and physiologic advantages, such as improved oxygenation and ventilation, better pulmonary compliance, reduced anatomical dead space, modest positive end-expiratory pressure, more efficient respiratory effort, reduced work of breathing, and secretion clearance . High-flow nasal oxygen can be used as respiratory support in critically ill patients for several indications, including initial or post-extubation management of respiratory failure. However, the effect of HFNO on clinical outcomes is not well established, and few clinical guidelines exist to provide clinicians with evidence-based recommendations on its appropriate use.