Research Spotlight

Park, S.H., Mazumder, N.R., Mehrotra, S., Ho, B., Kaplan, B. and Ladner, D.P. (2021). “Artificial Intelligence-related Literature in Transplantation: A Practical Guide.” Transplantation 105(4): 704-708.

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Since John McCarthy introduced the term “artificial intelligence (AI)” in 1955,1 AI research has been growing. “AI” is an umbrella term that encompasses a vast degree of computer technologies (eg, expert systems, computer vision, robotics, and machine learning) (Figure 1A) as well as a concept of a machine-imitating human intelligence2,3 (Table 1). Modern AI is defined as a system’s ability to (1) perceive the current world, ie, data; (2) to cause and compare different approaches to achieve specific goals based on given data; (3) to tune their performance and apply to unseen data; and (4) to repeat the previous processes multiple times and update the previous learning.4 When reviewing results from AI models, it is therefore critical to understand whether they are appropriately developed and validated (Figure 1B). [No abstract; excerpt from article].

Packer, M. and McMurray, J.J.V. (2021). “Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction.” Eur J Heart Fail Mar 11. [Epub ahead of print].

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Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.

Packer, M., Anker, S.D., Butler, J., Filippatos, G., Ferreira, J.P., Pocock, S.J., Sattar, N., Brueckmann, M., Jamal, W., Cotton, D., Iwata, T. and Zannad, F. (2021). “Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.” J Am Coll Cardiol 77(11): 1381-1392.

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BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention. OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload. METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment. RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients. CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Packer, M. (2021). “What causes exertional dyspnoea in patients with atrial fibrillation? Implications for catheter ablation in patients with heart failure.” Eur J Heart Fail Mar 26. [Epub ahead of print].

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Patients with atrial fibrillation (AF) often complain of exertional dyspnoea, and many physicians believe that the atrial tachyarrhythmia is the cause of the impairment in functional capacity. The assumption of a causal relationship has led electrophysiologists to propose that suppression of AF (either pharmacologically or by catheter ablation) can improve exercise tolerance and yield important clinical benefits, both with respect to quality of life and major outcomes. [No abstract; excerpt from article].

O’Toole, R.V., Joshi, M., Carlini, A.R., Murray, C.K., Allen, L.E., Huang, Y., Scharfstein, D.O., O’Hara, N.N., Gary, J.L., Bosse, M.J., Castillo, R.C., Bishop, J.A., Weaver, M.J., Firoozabadi, R., Hsu, J.R., Karunakar, M.A., Seymour, R.B., Sims, S.H., Churchill, C., Brennan, M.L., Gonzales, G., Reilly, R.M., Zura, R.D., Howes, C.R., Mir, H.R., Wagstrom, E.A., Westberg, J., Gaski, G.E., Kempton, L.B., Natoli, R.M., Sorkin, A.T., Virkus, W.W., Hill, L.C., Hymes, R.A., Holzman, M., Malekzadeh, A.S., Schulman, J.E., Ramsey, L., Cuff, J.A.N., Haaser, S., Osgood, G.M., Shafiq, B., Laljani, V., Lee, O.C., Krause, P.C., Rowe, C.J., Hilliard, C.L., Morandi, M.M., Mullins, A., Achor, T.S., Choo, A.M., Munz, J.W., Boutte, S.J., Vallier, H.A., Breslin, M.A., Frisch, H.M., Kaufman, A.M., Large, T.M., LeCroy, C.M., Riggsbee, C., Smith, C.S., Crickard, C.V., Phieffer, L.S., Sheridan, E., Jones, C.B., Sietsema, D.L., Reid, J.S., Ringenbach, K., Hayda, R., Evans, A.R., Crisco, M.J., Rivera, J.C., Osborn, P.M., Kimmel, J., Stawicki, S.P., Nwachuku, C.O., Wojda, T.R., Rehman, S., Donnelly, J.M., Caroom, C., Jenkins, M.D., Boulton, C.L., Costales, T.G., LeBrun, C.T., Manson, T.T., Mascarenhas, D.C., Nascone, J.W., Pollak, A.N., Sciadini, M.F., Slobogean, G.P., Berger, P.Z., Connelly, D.W., Degani, Y., Howe, A.L., Marinos, D.P., Montalvo, R.N., Reahl, G.B., Schoonover, C.D., Schroder, L.K., Vang, S., Bergin, P.F., Graves, M.L., Russell, G.V., Spitler, C.A., Hydrick, J.M., Teague, D., Ertl, W., Hickerson, L.E., Moloney, G.B., Weinlein, J.C., Zelle, B.A., Agarwal, A., Karia, R.A., Sathy, A.K., Au, B., Maroto, M., Sanders, D., Higgins, T.F., Haller, J.M., Rothberg, D.L., Weiss, D.B., Yarboro, S.R., McVey, E.D., Lester-Ballard, V., Goodspeed, D., Lang, G.J., Whiting, P.S., Siy, A.B., Obremskey, W.T., Jahangir, A.A., Attum, B., Burgos, E.J., Molina, C.S., Rodriguez-Buitrago, A., Gajari, V., Trochez, K.M., Halvorson, J.J., Miller, A.N., Goodman, J.B., Holden, M.B., McAndrew, C.M., Gardner, M.J., Ricci, W.M., Spraggs-Hughes, A., Collins, S.C., Taylor, T.J. and Zadnik, M. (2021). “Effect of Intrawound Vancomycin Powder in Operatively Treated High-risk Tibia Fractures: A Randomized Clinical Trial.” JAMA Surg Mar 24;e207259. [Epub ahead of print]. e207259.

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IMPORTANCE: Despite the widespread use of systemic antibiotics to prevent infections in surgically treated patients with fracture, high rates of surgical site infection persist. OBJECTIVE: To examine the effect of intrawound vancomycin powder in reducing deep surgical site infections. DESIGN, SETTING, AND PARTICIPANTS: This open-label randomized clinical trial enrolled adult patients with an operatively treated tibial plateau or pilon fracture who met the criteria for a high risk of infection from January 1, 2015, through June 30, 2017, with 12 months of follow-up (final follow-up assessments completed in April 2018) at 36 US trauma centers. INTERVENTIONS: A standard infection prevention protocol with (n = 481) or without (n = 499) 1000 mg of intrawound vancomycin powder. MAIN OUTCOMES AND MEASURES: The primary outcome was a deep surgical site infection within 182 days of definitive fracture fixation. A post hoc comparison assessed the treatment effect on gram-positive and gram-negative-only infections. Other secondary outcomes included superficial surgical site infection, nonunion, and wound dehiscence. RESULTS: The analysis included 980 patients (mean [SD] age, 45.7 [13.7] years; 617 [63.0%] male) with 91% of the expected person-time of follow-up for the primary outcome. Within 182 days, deep surgical site infection was observed in 29 of 481 patients in the treatment group and 46 of 499 patients in the control group. The time-to-event estimated probability of deep infection by 182 days was 6.4% in the treatment group and 9.8% in the control group (risk difference, -3.4%; 95% CI, -6.9% to 0.1%; P = .06). A post hoc analysis of the effect of treatment on gram-positive (risk difference, -3.7%; 95% CI, -6.7% to -0.8%; P = .02) and gram-negative-only (risk difference, 0.3%; 95% CI, -1.6% to 2.1%; P = .78) infections found that the effect of vancomycin powder was a result of its reduction in gram-positive infections. CONCLUSIONS AND RELEVANCE: Among patients with operatively treated tibial articular fractures at a high risk of infection, intrawound vancomycin powder at the time of definitive fracture fixation reduced the risk of a gram-positive deep surgical site infection, consistent with the activity of vancomycin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02227446.