Research Spotlight

DeSa, T. and Gong, T. (2021). “SGLT2 inhibitors: a new pillar of the heart failure regimen.” Rev Cardiovasc Med 22(4): 1253-1269.

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Initially intended as an adjunct treatment for type 2 diabetes mellitus (T2DM), SGLT2-inhibitors (SGLT2i) have transformed into an unexpected pillar of the heart failure (HF) regimen. The past several years have witnessed a meteoric rise of this drug class, starting with the serendipitous results of trials assessing the safety of the glucose-lowering therapy in a broad range of cardiovascular patients and culminating with the demonstration of a reduction in hospitalizations for heart failure and cardiovascular mortality in dedicated heart failure populations. The heart failure benefits of SGLT2i are independent of a patient’s glycemic status, but the salient mechanisms of cardioprotection remain a subject of robust debate and ongoing research. Cardiologists as well as physicians of other disciplines should become familiar with the main indications, benefits, and clinical consideration of implementation. In this review, we will discuss the advance of SGLT2i in heart failure, ranging from the results of large randomized clinical trials to potential mechanisms of action

Delimpasi, S., Mateos, M.V., Auner, H.W., Gavriatopoulou, M., Dimopoulos, M.A., Quach, H., Pylypenko, H., Hájek, R., Leleu, X., Dolai, T.K., Sinha, D.K., Venner, C.P., Benjamin, R., Garg, M.K., Doronin, V., Levy, Y., Moreau, P., Chai, Y., Arazy, M., Shah, J., Shacham, S., Kauffman, M.G., Richardson, P.G. and Grosicki, S. (2021). “Efficacy and tolerability of once-weekly selinexor, bortezomib, and dexamethasone in comparison with standard twice-weekly bortezomib and dexamethasone in previously treated multiple myeloma with renal impairment: Subgroup analysis from the BOSTON study.” Am J Hematol Dec 9. [Epub ahead of print].

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Patients with hematological malignancies, particularly multiple myeloma (MM), typically have a high prevalence of renal impairment (RI). When combined with the nephrotoxic risk of anticancer drugs, especially with an older patient population like that frequently observed in MM, optimizing treatment regimens that are both safe and efficacious is difficult.1 Taken together, there is a need to identify effective therapeutic options that can be used in patients with RI and do not pose or induce additional renal toxicity in patients with MM.[No abstract; excerpt from article].

Davis, J., Israni, R., Betts, K.A., Mu, F., Cook, E.E., Anzalone, D., Szerlip, H., Yin, L., Uwaifo, G.I. and Wu, E.Q. (2021). “Real-World Management of Hyperkalemia in the Emergency Department: An Electronic Medical Record Analysis.” Adv Ther Dec 27. [Epub ahead of print].

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INTRODUCTION: Hyperkalemia is often managed in the emergency department (ED) and it is important to understand how ED management and post-discharge outcomes vary by hyperkalemia severity. This study was conducted to characterize ED management and post-discharge outcomes across hyperkalemia severities. METHODS: Adults with an ED visit with hyperkalemia (at least one serum potassium lab measure above 5.0 mEq/L) were selected from US electronic medical record data (2012-2018). Patient characteristics, potassium levels, treatments, and monitoring prior to and during the ED visit were compared by hyperkalemia severity (mild [> 5.0-5.5 mEq/L], moderate [> 5.5-6.0], severe [> 6.0]) using unadjusted analyses. Death, immediate inpatient admission, 30-day hyperkalemia recurrence, and 30-day inpatient admission were also assessed by severity. RESULTS: Of 6222 patients included, 4432 (71.2%) had mild hyperkalemia, 1085 (17.4%) had moderate, and 705 (11.3%) had severe hyperkalemia. Chronic kidney disease (39.9-50.1%) and heart failure (21.6-24.3%) were common. In the ED, electrocardiograms (mild, 56.5%; moderate, 69.6%; severe, 81.0%) and patients with at least two potassium laboratory values increased with severity (15.0%; 40.4%; 75.5%). Among patients with at least two potassium laboratory values, over half of patients (60.4%) had potassium levels ≤ 5.0 mEq/L prior to discharge. Use of potassium-binding treatments (sodium polystyrene sulfonate: mild = 4.1%; moderate = 17.1%; severe = 27.4%), temporizing agents (5.6%; 15.5%; 31.6%), or dialysis (0.4%; 0.8%; 3.0%) increased with severity; treatment at discharge was not common. Death (1.1%; 3.7%; 10.6%), immediate admission to inpatient care (5.8%; 8.7%; 12.7%), 30-day hyperkalemia recurrence (2.9%; 19.0%; 32.5%), 30-day inpatient admission with hyperkalemia (6.5%; 7.9%; 9.3%) also increased with severity. CONCLUSION: Patients with moderate and severe hyperkalemia experienced elevated risk of hyperkalemia recurrence and hyperkalemia-related inpatient readmission following discharge from the ED from a descriptive analysis. Future research to assess strategies to reduce hyperkalemia recurrence and inpatient admission in this patient population would be beneficial.

Kawashima, H., Serruys, P.W., Hara, H., Ono, M., Gao, C., Wang, R., Garg, S., Sharif, F., de Winter, R.J., Mack, M.J., Holmes, D.R., Morice, M.C., Kappetein, A.P., Thuijs, D., Milojevic, M., Noack, T., Mohr, F.W., Davierwala, P.M. and Onuma, Y. (2021). “10-Year All-Cause Mortality Following Percutaneous or Surgical Revascularization in Patients With Heavy Calcification.” JACC Cardiovasc Interv Dec 20;S1936-8798(21)01965-8. [Epub ahead of print].

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OBJECTIVES: The aim of this study was to assess 10-year all-cause mortality in patients with heavily calcified lesions (HCLs) undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). BACKGROUND: Limited data are available on very long term outcomes in patients with HCLs according to the mode of revascularization. METHODS: This substudy of the SYNTAXES (Synergy Between PCI With Taxus and Cardiac Surgery Extended Survival) study assessed 10-year all-cause mortality according to the presence of HCLs within lesions with >50% diameter stenosis and identified during the calculation of the anatomical SYNTAX (Synergy Between PCI With Taxus and Cardiac Surgery) score among 1,800 patients with the 3-vessel disease and/or left main disease randomized to PCI or CABG in the SYNTAX trial. Patients with HCLs were further stratified according to disease type (3-vessel disease or left main disease) and assigned treatment (PCI or CABG). RESULTS: The 532 patients with ≥1 HCL had a higher crude mortality rate at 10 years than those without (36.4% vs 22.3%; hazard ratio [HR]: 1.79; 95% confidence interval [CI]: 1.49-2.16; P < 0.001). After adjustment, an HCL remained an independent predictor of 10-year mortality (HR: 1.36; 95% CI: 1.09-1.69; P = 0.006). There was a significant interaction in mortality between treatment effect (PCI and CABG) and the presence or absence of HCLs (P(interaction) = 0.005). In patients without HCLs, mortality was significantly higher after PCI than after CABG (26.0% vs 18.8%; HR: 1.44; 95% CI: 0.97-1.41; P = 0.003), whereas in those with HCLs, there was no significant difference (34.0% vs 39.0%; HR: 0.85; 95% CI: 0.64-1.13; P = 0.264). CONCLUSIONS: At 10 years, the presence of an HCL was an independent predictor of mortality, with a similar prognosis following PCI or CABG. Whether HCLs require special consideration when deciding the mode of revascularization beyond their current contribution to the anatomical SYNTAX score deserves further evaluation. (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES], NCT03417050; SYNTAX Study: TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX], NCT00114972).

Lindman, B.R., Sukul, D., Dweck, M.R., Madhavan, M.V., Arsenault, B.J., Coylewright, M., Merryman, W.D., Newby, D.E., Lewis, J., Harrell, F.E., Jr., Mack, M.J., Leon, M.B., Otto, C.M. and Pibarot, P. (2021). “Evaluating Medical Therapy for Calcific Aortic Stenosis: JACC State-of-the-Art Review.” J Am Coll Cardiol 78(23): 2354-2376.

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Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.