Research Spotlight

Mack, M. J. (2019). “RESPONSE: Adapting to Change in a Time of Uncertainty.” J Am Coll Cardiol 74(6): 816-817.

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Historically, the specialty of thoracic surgery has always been, as Han states, one of “paradigm shifts” or, as euphemistically referred to within the specialty, “staying one operation ahead of extinction.” To wit, the specialty began as one to treat tuberculosis until the introduction of sulfa drugs greatly diminished the role of surgery for that disease. The specialty then evolved to the management of rheumatic heart disease for which surgery was a mainstay of treatment until penicillin dramatically reduced the incidence of the disease in developed countries. Next, the central role of surgical coronary revascularization in the treatment of coronary artery disease was significantly modulated by the introduction of percutaneous coronary intervention. Furthermore, many other procedures began as thoracic and cardiac surgical procedures, including bronchoscopy, esophagoscopy, permanent pacemaker, defibrillator implantation, and insertion of intra-aortic balloon pumps, only to have those procedures move to other specialties as the devices become smaller and more easily implanted without general anesthesia. Despite the evolution in the core treatments delivered by our specialty in different eras, we have not become extinct, nor has the specialty diminished; rather, it has survived and thrived . . . As I reflect on the types of operations I was performing when I finished training in 1982, they bear little resemblance to the procedures being performed today. However, that offers little solace to the trainee whose sands are now shifting beneath her/his feet. As the Greek philosopher Heraclitus stated, “the only constant is change.” You cannot worry too much that you chose the wrong career path or succumb to the fear that you will be left behind. Rather, embrace what you love to do and be cognizant of the changes in the ecosystem in which you work. Learn to lead change, embrace that which is currently good, have the vision to determine what needs to change, and have the wisdom to know the difference. To paraphrase Charles Darwin, it’s not the strongest of a species that survives, or the most intelligent, but the one most responsive to change. (Excerpts from text, p. 816-817.)

Thuijs, D., A. P. Kappetein, P. W. Serruys, F. W. Mohr, M. C. Morice, M. J. Mack, D. R. Holmes, Jr., N. Curzen, P. Davierwala, T. Noack, M. Milojevic, K. D. Dawkins, B. R. da Costa, P. Juni and S. J. Head (2019). “Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.” Lancet Aug 30. [Epub ahead of print].

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BACKGROUND: The Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease, and reported results up to 5 years. We now report 10-year all-cause death results. METHODS: The SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries. Patients with de-novo three-vessel and left main coronary artery disease were randomly assigned (1:1) to the PCI group or CABG group. Patients with a history of PCI or CABG, acute myocardial infarction, or an indication for concomitant cardiac surgery were excluded. The primary endpoint of the SYNTAXES study was 10-year all-cause death, which was assessed according to the intention-to-treat principle. Prespecified subgroup analyses were performed according to the presence or absence of left main coronary artery disease and diabetes, and according to coronary complexity defined by core laboratory SYNTAX score tertiles. This study is registered with ClinicalTrials.gov, NCT03417050. FINDINGS: From March, 2005, to April, 2007, 1800 patients were randomly assigned to the PCI (n=903) or CABG (n=897) group. Vital status information at 10 years was complete for 841 (93%) patients in the PCI group and 848 (95%) patients in the CABG group. At 10 years, 244 (27%) patients had died after PCI and 211 (24%) after CABG (hazard ratio 1.17 [95% CI 0.97-1.41], p=0.092). Among patients with three-vessel disease, 151 (28%) of 546 had died after PCI versus 113 (21%) of 549 after CABG (hazard ratio 1.41 [95% CI 1.10-1.80]), and among patients with left main coronary artery disease, 93 (26%) of 357 had died after PCI versus 98 (28%) of 348 after CABG (0.90 [0.68-1.20], pinteraction=0.019). There was no treatment-by-subgroup interaction with diabetes (pinteraction=0.66) and no linear trend across SYNTAX score tertiles (ptrend=0.30). INTERPRETATION: At 10 years, no significant difference existed in all-cause death between PCI using first-generation paclitaxel-eluting stents and CABG. However, CABG provided a significant survival benefit in patients with three-vessel disease, but not in patients with left main coronary artery disease. FUNDING: German Foundation of Heart Research (SYNTAXES study, 5-10-year follow-up) and Boston Scientific Corporation (SYNTAX study, 0-5-year follow-up).

Chari, A., D. T. Vogl, M. Gavriatopoulou, A. K. Nooka, A. J. Yee, C. A. Huff, P. Moreau, D. Dingli, C. Cole, S. Lonial, M. Dimopoulos, A. K. Stewart, J. Richter, R. Vij, S. Tuchman, M. S. Raab, K. C. Weisel, M. Delforge, R. F. Cornell, D. Kaminetzky, J. E. Hoffman, L. J. Costa, T. L. Parker, M. Levy . . . and S. Jagannath (2019). “Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.” New England Journal of Medicine 381(8): 727-738.

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BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor kappaB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

Packer, M. (2019). “Why Are Physicians So Confused about Acute Heart Failure?” New England Journal of Medicine 381(8): 776-777.

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For most of the past 3000 years, physicians believed that all patients with heart failure had acute heart failure. Heart failure was viewed as an episodic disorder — that is, patients were considered to have heart failure when they presented with fluid retention, and they no longer had heart failure after diuresis. The chronicity of heart failure was recognized only when invasive and noninvasive measurements showed severe ongoing structural and functional abnormalities between episodes. To develop approaches to preventing hospitalizations and minimizing the functional and prognostic consequences of heart failure, clinical investigators needed to focus on the underlying disease process. Extensive research beginning in the 1980s established that combination therapy with neurohormonal antagonists reverses ventricular remodeling, improves functional capacity, and reduces the risk of disease progression and death. However, use of these drugs in primary care has been distinctly suboptimal, possibly because physicians have been inclined to discount the importance of intensive treatment for a disease whose progression is typically clinically silent. Instead, practitioners have focused on the treatment of worsening episodes that require hospitalization . . . However, most patients who are hospitalized with worsening heart failure do not have a new, acute disorder. Instead, they present with decompensation of chronic underlying ventricular dysfunction as a consequence of gradual but progressive increases in cardiac filling pressures in the preceding weeks. Sometimes the deterioration is triggered by cardiac arrhythmia or pulmonary infection, but typically the deterioration is not sudden or immediately life-threatening. Are these episodes of worsening heart failure a medical emergency akin to acute pulmonary edema decades ago? Most patients recover within a few days after intensification of medical therapy. However, these events are often accompanied by the early release of troponin, indicating a small degree of myocardial injury that is possibly related to acute ventricular distention. Could emergency interventions to reduce volume overload salvage a few cardiomyocytes, which might (in turn) have benefits for long-term prognosis? We know that each hospitalization accelerates the rate of progression of heart failure. So, is decompensated heart failure similar to an acute coronary syndrome, for which it is critical to perform an emergency intervention to minimize irreversible cardiac injury? The hypothesis that exceptionally early short-term therapy during a hospitalization for heart failure might yield long-term benefits was supported by the findings of the Relaxin in Acute Heart Failure (RELAX-AHF) trial. In that trial, a 48-hour infusion of the vasodilator serelaxin decreased the release of troponin and resulted in a remarkable 37% lower risk of death during the subsequent 6 months than placebo. However, because the benefit with respect to mortality was based on a sparse number of deaths, it was greeted with great skepticism. Outsized mortality benefits that have been observed in underpowered phase 2 trials in patients with heart failure often have not been subsequently confirmed in definitive phase 3 trials . . . Hospitalization for worsening symptoms is an important event in chronic heart failure; it identifies patients with particularly rapid advancement of the underlying disorder. However, decompensation is not an acute illness or an indicator of subclinical myocardial injury that requires emergency intervention with a novel treatment; the acute elevation of troponin level may subside, but the troponin level remains elevated after hospital discharge. Although it is important to achieve clinical stabilization, it is more critical to ensure that patients are treated vigorously between hospitalizations to decrease the risk of readmission and death. A focus on intensive outpatient care (rather than an obsession with inpatient therapy) is needed to reduce the burden of heart failure. (Excerpts from text, p. 776-777; no abstract available.)

Solomon, S. D., J. J. V. McMurray, I. S. Anand, J. Ge, C. S. P. Lam, A. P. Maggioni, F. Martinez, M. Packer . . . and M. P. Lefkowitz (2019). “Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.” New England Journal of Medicine. Sep 1. [Epub ahead of print].

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BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).