Primecuts – This Week in the Journals

September 9, 2020


By Zach Reilly, 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.

Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis [1]

The use of steroids in critically ill patients with severe infection has been a topic of debate, particularly in COVID-19 due to the dearth of data looking at clinical outcomes for these patients. The authors of this paper organized a meta-analysis of 1703 patients in seven clinical trials to assess the use of corticosteroids in patients with severe COVID-19 infection. The primary outcome was 28-day mortality.

The results showed 222 deaths among 678 patients randomized to corticosteroids and 425 deaths among 1025 patients randomized to usual care, with a summary OR of 0.66 (95% CI, 0.53-0.82; P < 0.001). These findings correlate with a number needed to treat of 11.5 patients.  The decrease in mortality was statistically significant for patients with and without mechanical ventilation, men and women, patients with symptoms at least 7 days prior to randomization, and those younger and older than 60 years. The difference in mortality was not statistically significant for patients receiving vasoactive agents at the time of randomization and those with symptoms less than 7 days prior to randomization.

One limitation of the study is potential selection and publication bias. Additionally, follow-up was censored when participants were discharged from the hospital, so long term data is limited. Definitions of serious adverse events were not consistent across the trials, so analysis of adverse events was unable to be completed. Concerns of generalizability come from the trials only recruiting adults and that they were mostly conducted in high-income settings. Lastly, the RECOVERY trial contributed to the majority (57%) of the data in the primary meta-analysis. This could mean that results of this meta-analysis are overly influenced by and reflective of the findings of the RECOVERY trial. Despite this, analysis found little inconsistency between the effects of corticosteroids on 28-day mortality estimated by the different trials. Despite these limitations, this is the first meta-analysis of corticosteroid use in severe COVID-19, making it the strongest evidence we currently have to guide practice and should influence the care provided for these patients. 

Coronary Angiography After Cardiac Arrest Without ST Segment Elevation: One-Year Outcomes of the COACT Randomized Clinical Trial [2]

The Coronary Angiography After Cardiac Arrest (COACT) trial analyzed survival after cardiac arrest without evidence of STEMI in patients who were randomized to either immediate coronary angiography or coronary angiography delayed until after neurologic recovery.

No significant difference was found in the trial’s primary endpoint, which was survival at 90 days. Data showed 176 of 273 patients (64.5%) surviving in the immediate coronary angiography group compared with 178 of 265 patients (67.2%) in the delayed group (OR, 0.89; 0.62-1.27; P = 0.51). There was also no difference in mortality between 90 days and 1 year (HR was 0.85 (95% CI, 0.26-2.87). Mortality between 90 days and 1 year was found to be 2.2%.

Limitations of the study include the authors’ inability to fully blind treatment teams and the exclusion of patients with shock, severe renal dysfunction, or persistent ST-segment elevation. The authors also note that the COACT trial was powered for the primary outcome of 90-day mortality and not the secondary analysis. This trial provides further evidence that immediate angiography after cardiac arrest without STEMI does not provide mortality benefit and that the majority of death occurs early rather than later after arrest.

Early Rhythm-Control Therapy in Patients with Atrial Fibrillation [3]

This article published results from The Early Treatment of Atrial Fibrillation for Stroke Prevention Trial (EAST-AFNET 4). The trial goals were to explore early rhythm control with either antiarrhythmic drugs or atrial fibrillation ablation against usual guidelines-based management.

The trial enrolled 2789 adults with early atrial fibrillation, defined as atrial fibrillation diagnosed less than 12 months before enrollment, who were older than 75 with a history of TIA or stroke or with risk factors that placed them at a high risk of stroke. All patient received treatment for cardiovascular conditions, anticoagulation, and rate control. Early rhythm control group received antiarrhythmic drugs or atrial fibrillation ablation. Patients who were randomly assigned to usual care were initially treated with rate-control therapy without rhythm-control therapy.

The first primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with heart failure or acute coronary syndrome. These outcomes occurred less often in patients assigned to early rhythm control than in patients assigned to usual care (hazard ratio 0.79; 96% confidence interval [CI], 0.66 to 0.94; P=0.005). The second primary outcome was the number of nights spent in the hospital per year.  There was no significant difference in the mean number of nights spent in the hospital between the groups (early rhythm control, 5.8±21.9 days per year; usual care, 5.1±15.5 days per year; P=0.23). The early rhythm-control group had more adverse events related to rhythm-control therapy, but the incidence of the overall safety outcome events was similar in the two groups. The most common adverse effect of antiarrhythmic drug therapy was bradycardia (1% of patients) and of ablation was major bleeding (0.4% of patients).

The authors note generalizability limitations based on the study selecting only patients with early atrial fibrillation and that the study likely excluded the most symptomatic patients. This trial differed from other rate vs. rhythm control trials in that it included ablation as part of rhythm control therapy, which may have contributed to the difference between the groups. This study provides useful information on potential benefits of ensuring patients receive early rhythm control in new atrial fibrillation.

SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials [4]

Previous publications have shown that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the risk of cardiovascular death or hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF). Authors of this article used data published from Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF) and The Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) trials to estimate the effect of SGLT2 inhibition on heart failure events and renal outcomes in patients with HFrEF and in some subgroups detailed below.

Study subgroups analyzed were type 2 diabetes, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) class II or III–IV, race, region, age younger or older than 65 years, history of hospitalization for heart failure, eGFR lower or higher than 60 mL/min, and body-mass index (BMI). The primary endpoint of the meta-analysis was time to all-cause death. Secondary endpoints were time to cardiovascular death, first hospitalization for heart failure or cardiovascular death, first hospitalization for heart failure, recurrent hospitalizations for heart failure or cardiovascular death, and a renal composite of 50% or greater sustained decline in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), or renal death.

Of 8474 patients in the trials, SLGT2 inhibitors resulted in a 13% reduction in all-cause death (pooled HR 0.87, 95% CI 0.77–0.98; p=0.018) resulting in a NNT of 60 and ARR of 0.016. Findings also showed a 14% reduction in cardiovascular death (0.86, 95% CI 0.76–0.98; p=0.027) corresponding to a NNT of 69.7 and ARR of 0.014. SGLT2 inhibition led to a 26% reduction in the combined risk of cardiovascular death or first hospitalization for heart failure (NNT 19.5; ARR 0.051), a 25% decrease in the composite of recurrent hospitalizations for heart failure or cardiovascular death (NNT 11.8; ARR 0.084), and a 31% reduction in the risk of first hospitalization for heart failure (NNT 23; ARR 0.043). Lastly, the risk of a composite renal endpoint was significantly reduced (0.62, 95% CI= 0.43–0.90; p=0.013; NNT 163; ARR 0.006).

The authors discussed several limitations: lack of access to the individual patient data from DAPA-HF, no correction for multiplicity of subgroup testing, and that statistical heterogeneity cannot be assessed on only two studies. The publication otherwise produces important evidence for the use of SGLT2 inhibitors to improve cardiac and renal outcomes in patients with HFrEF, suggesting their use in all HFrEF patients whether the patients have diabetes or not.

Minicuts

 Weight loss in Underserved Patients—A Cluster-Randomized Trial [5]

The trial was designed to assess the primary outcome of percent change in baseline body weight in 24 months after the incorporation of an intensive lifestyle-based intervention in primary care clinics in low income populations. Patients in the intervention group lost significantly more weight (−4.99% change in body weight; 95% CI, −6.02 to −3.96) than patients in the usual-care group (−0.48%; 95% CI, −1.57 to 0.61; P<0.001). These findings show that lifestyle-based interventions in primary care clinics might be an effective means of addressing obesity in low income settings.

Total Body Irradiation and Risk of Breast Cancer After Blood or Marrow Transplantation: A Blood or Marrow Transplantation Survivor Study Report [6]

Analyzing data from a retrospective cohort study of 1,464 patients, this article shows that exposure to total body irration (TBI) was associated with an increased risk of subsequent breast cancer among allogeneic BMT survivors (HR 3.7 [95% CI, 1.2 to 11.8]; P = 0.03) and autologous BMT survivors (HR 2.6 [95% CI, 1.0 to 6.8]; P = 0.048). The association between TBI and subsequent breast cancer should be considered when assessing breast cancer screening timing and intervals.

Therapies Offered at Residential Addiction Treatment Programs in the United States [7]

Researchers in this study surveyed 613 residential addiction treatment programs to assess the availability of opioid agonist therapy (OAT) availability at each site. They found that 29% of facilities offered OAT, an additional 31% offered OAT only for short-term detoxification, 39% did not offer OAT or had unclear availability, and 21% actively discouraged callers from using OAT. These findings highlight a critical deficit in the availability of an effective, evidence-based treatment for opioid use disorder at residential treatment programs in the United States.

Effects of first-line antiretroviral therapy on the CD4/CD8 ratio and CD8 cell counts in CoRIS: a prospective multicentre cohort study [8]

It has been previously established that a low CD4/CD8 ratio during antiretroviral therapy (ART) identifies people with increased risk of mortality. This study provides data showing that integrase strand transfer inhibitor (INSTI) based antiretroviral therapy had a greater CD4/CD8 gain than protease inhibitor-based or non-nucleoside reverse transcriptase inhibitor (NNRTI) based ART. This evidence posits the use of INSTI as first line ART.

Dr. Zach Reilly is a 2nd Year Resident at NYU Langone Health

Peer reviewed by Neil Shapiro, MD, Editor-in-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

[1] The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. Published online September 02, 2020. doi:10.1001/jama.2020.17023. https://jamanetwork.com/journals/jama/fullarticle/2770279.

[2] Lemkes JS, Janssens GN, van der Hoeven NW, et al. Coronary Angiography After Cardiac Arrest Without ST Segment Elevation: One-Year Outcomes of the COACT Randomized Clinical Trial. JAMA Cardiol. Published online September 02, 2020. doi:10.1001/jamacardio.2020.3670. https://jamanetwork.com/journals/jamacardiology/fullarticle/2769883.

[3] Kirchhof, Paulus, et al. “Early Rhythm-Control Therapy in Patients with Atrial Fibrillation.” New England Journal of Medicine, 2020, doi:10.1056/nejmoa2019422. https://www.nejm.org/doi/full/10.1056/NEJMoa2019422.

[4] Zannad, Faiez, et al. “SGLT2 Inhibitors in Patients with Heart Failure with Reduced Ejection Fraction: a Meta-Analysis of the EMPEROR-Reduced and DAPA-HF Trials.” The Lancet, 2020, doi:10.1016/s0140-6736(20)31824-9. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31824-9/fulltext#seccestitle10.

[5] Katzmarzyk, Peter T., et al. “Weight Loss in Underserved Patients — A Cluster-Randomized Trial.” New England Journal of Medicine, vol. 383, no. 10, 2020, pp. 909–918., doi:10.1056/nejmoa2007448. https://www.nejm.org/doi/full/10.1056/NEJMoa2007448#article_citing_articles.

[6] Mcdonald, Andrew M., et al. “Total Body Irradiation and Risk of Breast Cancer After Blood or Marrow Transplantation: A Blood or Marrow Transplantation Survivor Study Report.” Journal of Clinical Oncology, vol. 38, no. 25, 2020, pp. 2872–2882., doi:10.1200/jco.20.00231. https://ascopubs.org/doi/full/10.1200/JCO.20.00231.

[7] Beetham T, Saloner B, Gaye M, Wakeman SE, Frank RG, Barnett ML. Therapies Offered at Residential Addiction Treatment Programs in the United States. JAMA. 2020;324(8):804–806. doi:10.1001/jama.2020.8969. https://jamanetwork.com/journals/jama/fullarticle/2769709.

[8] Serrano-Villar, Sergio, et al. “Effects of First-Line Antiretroviral Therapy on the CD4/CD8 Ratio and CD8 Cell Counts in CoRIS: a Prospective Multicentre Cohort Study.” The Lancet HIV, vol. 7, no. 8, 2020, doi:10.1016/s2352-3018(20)30202-2. https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(20)30202-2/fulltext#articleInformation

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