Primecuts – This Week in the Journals

January 25, 2021

PrimeCuts 6 min read

By Neha Nagpal, MD

Peer Reviewed 

Introduction: 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.

Primecuts

Clinical Implications of Removing Race from Estimates of Kidney Function [1]

There has recently been a growing emphasis on our role as healthcare providers in managing health disparities and understanding how they are propagated throughout our healthcare decisions. One area that has received significant attention is that of the race-based GFR adjustment. This adjustment has not always been standard of practice; in fact, the original Cockroft and Gault GFR estimation took into account only age, sex, and body weight [2]. It wasn’t until over 20 years later that discussion around other predictors for a more accurate measurement were investigated [3]. In this cross-sectional study by Diao et al., they examined data from the National Health and Nutrition Examination Survey (NHANES) between 2001-2018, including 9,522 non-Hispanic black adults. They calculated an estimated GFR using the CKI-EPI equation both with and without the (self-reported) race coefficient [4]. After removing the race coefficient, they estimated a mean change in GFR of -14.1; median GFR decreased from 102.9 mL/min/1.73m2  to 88.1 mL/min/1.73m2. This translates to an increase of overall CKD prevalence among black adults from 14.9% to 18.4% and a change of CKD3b prevalence from 2.3% to 3.5%. Potential limitations of this study include the method of estimating GFR; this study examines the CKD-EPI equation, while many institutions utilize the MDRD equation. It is also not clear whether simply removing race from the equation alters any other aspects of the equation, making it less reliable; some approaches have been to remove race entirely, while others may simply categorize all patients as a white/other category. This increase in diagnosis of CKD could ultimately lead to increased medical therapy and referral to specialty services. As more data emerges about the numerous medications that may slow the progression to end-stage renal disease and even improve mortality, it is important to be more cognizant about how we can optimize the management of patients at risk. 

Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure [5]

In the past, studies focusing on agents to improve cardiac contractility in patients with heart failure with reduced ejection fraction (HFrEF) have actually demonstrated some adverse effects [6]. New agents that function as direct cardiac myosin activators have been of interest given their theoretical effect on coupling between actin and myosin. In this phase 3, randomized, placebo-controlled trial, the investigators assigned patients with symptomatic HFrEF with an EF of 35% or less to receive either omecamtiv mecarbil or placebo. Over half of the study population had NYHA Class II Heart Failure, while only 3% had Class IV. The primary outcome was a first-heart failure event or death from cardiovascular cause. They concluded that the intervention group had a significant, but modest, lowering of the incidence of the primary outcome, with an absolute difference of 2.1% (NNT of 47.6). The study team notes that their trial was initiated prior to the data regarding SLGT2 inhibitors [7] and ARNI medications being an accepted part of clinical management. For this reason, a very small percentage of patients in the trial were on these medications (about 20% on ARNI in both placebo and intervention groups and less than 3% on SLGT2 inhibitors in both arms). Overall, the data seem promising for an additional medication to improve outcomes in patients with HFrEF, but it is worth weighing these results in light of the study population having relatively less severe symptoms and not being maximized on current emerging standards of care.

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease [8]

We’ve been seeing the benefits of SLGT2 inhibitors touted in recent years, and it seems like a new potential indication for these medications emerges every few weeks. This study team investigated the use of sotagliflozin, which of note has both SLGT2 inhibitory properties working at the level of the kidney as well as SGLT1 inhibitory properties to inhibit glucose absorption at the level of the gastrointestinal tract. In this phase 3, randomized, double-blind, placebo-controlled trial they randomized an initial 10,500 patients to receive either sotagliflozin or placebo. The intended primary outcome was first major adverse cardiovascular event (MACE) and the first occurrence of death from a cardiovascular cause or hospitalization for heart failure. However, the trial was stopped early due to loss of funding and they changed the primary outcome to total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The inclusion criteria of prior studies with dapagligflozin [9] and canagliflozin [10] have included patients with pre-existing levels of albuminuria; this study examined patients with CKD regardless of the presence of albuminuria. Even with the study ending early, patients were treated with the intervention for an average of 14 months. They did find a lower rate of the primary composite outcome in the sotagliflozin vs placebo group with 5.6 vs 7.5 events per 100 patients. Though adverse event rates were similar between both groups, the sotagliflozin group had higher rates specifically of diarrhea, diabetic ketoacidosis, volume depletion, and genital mycotic infections. Overall, this study sheds light on the continued desire to prevent progression to the end-stage consequences of underlying diabetes. In this case, the question is whether there is any benefit in patients even before we start to see evidence of effect at the level of the kidney. It is certainly an important question, but this study does seem to lack the appropriate follow-up and trial length to draw these conclusions.

Minicuts

Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure [11]

The same study team that looked at sotagliflozin for patients with CKD also examined its use in patients hospitalized with decompensated heart failure in an effort to expand its use from stable cardiac patients to those who may be more unstable. This phase 3, randomized, double-blind, placebo-controlled trial included a total of 1,222 patients who received sotagliflozin vs placebo. The rate of death from cardiovascular causes and hospitalizations for heart failure was significantly lower in the sotagliflozin group (hazard ratio, 0.67; 95% confidence interval, 0.52 to 0.85). Almost half of the patients were safely dosed prior to discharge, the remainder shortly after, which may support more aggressive medication titration during hospitalization when patients are most actively engaged. 

Red Meat Intake and Risk of Coronary Heart Disease among US Men: Prospective Cohort Study [12]

In this prospective study, they examined data from the Health Professionals Follow-Up Study, which began in 1986. In this analysis, they demonstrate the benefit of a plant-based diet compared to both processed and unprocessed meat. Across the board, the foods that were most consistently associated with lower coronary heart disease included soy, legumes, nuts, and plant based protein.

Machine Learning-Based Prediction of Adverse Events Following an Acute Coronary Syndrome (PRAISE): A Modelling Study of Pooled Datasets [13]

Patients who undergo percutaneous interventions with stent placements are often on multiple antiplatelet agents for up to a year, if not longer. Numerous studies have attempted to risk stratify those patients who may be at the greatest risk of bleeding or complications, but generalizability of this data to large cohorts is lacking. In this study, the researchers used pooled data from over 20,000 individuals who underwent percutaneous interventions to develop a model for predicting 1 year risk of all-cause death, myocardial infarction, and major bleeding. They were able to classify patients as low vs. high risk for these outcomes using this precise, algorithm based approach to stratification. This could be beneficial in determining follow-up for patients and appropriate duration of medical therapy post-PCI.

Dr. Neha Nagpal is a 3rd year resident at NYU Langone Health

Peer Reviewed by Pamela Boodram, MD, associate editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

  1. Diao JA, Wu GJ, Taylor HA, et al. Clinical Implications of Removing Race From Estimates of Kidney Function. JAMA. 2021;325(2):184–186. doi:10.1001/jama.2020.22124  https://www.mdlinx.com/journal-summary/clinical-implications-of-removing-race-from-estimates-of-kidney-function/4QvvBRpiroXq4ghjRkJkfq
  2. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. doi: 10.1159/000180580. PMID: 1244564.
  3. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999 Mar 16;130(6):461-70. doi: 10.7326/0003-4819-130-6-199903160-00002. PMID: 10075613.
  4. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease: summary of recommendation statements. Kidney Int Suppl (2011). 2013;3(1):5-14. doi:10.1038/kisup.2012.77.
  5. Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105-116.  https://www.nejm.org/doi/full/10.1056/NEJMoa2025797
  1. Swedberg Karl. (2021) Stimulation of Contractility in Systolic Heart Failure. N Engl J Med 384:2, 178-179.
  1. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
  2. Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2030186 (2020)
  1. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-1446.
  1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
  1. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117-128. https://www.nejm.org/doi/full/10.1056/NEJMoa2030183
  1. Al-Shaar Laila, Satija Ambika, Wang Dong D, RimmEric B, Smith-Warner Stephanie A, Stampfer Meir Jet al. Red meat intake and risk of coronary heart disease among US men: prospective cohort studyBMJ 2020; 371 :m4141

13. D’Ascenzo F, De Filippo O, Gallone G, Mittone G, Deriu MA, Iannaccone M, Ariza-Solé A, Liebetrau C, Manzano-Fernández S, Quadri G, Kinnaird T, Campo G, Simao Henriques JP, Hughes JM, Dominguez-Rodriguez A, Aldinucci M, Morbiducci U, Patti G, Raposeiras-Roubin S, Abu-Assi E, De Ferrari GM; PRAISE study group. Machine learning-based prediction of adverse events following an acute coronary syndrome (PRAISE): a modelling study of pooled datasets. Lancet. 2021 Jan 16;397(10270):199-207. doi: 10.1016/S0140-6736(20)32519-8. PMID: 3  https://www.researchgate.net/profile/James_Hughes3/publication/348501148_Machine_learning-based_prediction_of_adverse_events_following_an_acute_coronary_syndrome_PRAISE_a_modelling_study_of_pooled_datasets/links/6002a81ba6fdccdcb858b6c2/Machine-learning-based-prediction-of-adverse-events-following-an-acute-coronary-syndrome-PRAISE-a-modelling-study-of-pooled-datasets.pdf