Research Spotlight

Baylor Health Sciences Library brings to you each month the latest published research from the Baylor Scott & White community. Each newly published article features the researcher, the abstract, and link to the full text. For information on including your own research, please contact John Fullinwider, john.fullinwider@baylorhealth.edu. 214-828-8989.


Posted September 15th 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.

Michael J. Mack M.D.

Michael J. Mack M.D.

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].

Full text of this article.

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).


Posted September 15th 2019

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.

Moshe Y. Levy M.D.

Moshe Y. Levy M.D.

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.

Full text of this article.

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.).


Posted September 15th 2019

Why Are Physicians So Confused about Acute Heart Failure?

Milton Packer M.D.E

Milton Packer M.D.

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

Full text of this article.

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.)


Posted September 15th 2019

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.

Milton Packer M.D.

Milton Packer M.D.

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].

Full text of this article.

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.).


Posted September 15th 2019

Transcatheter Aortic-Valve Replacement in Low-Risk Patients. Reply.

Michael J. Mack M.D.

Michael J. Mack M.D.

Mack, M. J. and M. B. Leon (2019). “Transcatheter Aortic-Valve Replacement in Low-Risk Patients. Reply.” New England Journal of Medicine 381(7): 684-685.

Full text of this article.

Kaul’s major concern is that there were fewer primary end-point events in the Placement of Aortic Transcatheter Valves (PARTNER) 3 trial than in earlier trials. He states that the inclusion of rehospitalization in the composite primary end point led it to become the main driver for the superiority of TAVR and also introduced a bias against surgery owing to the number of concomitant procedures performed in the surgical group. In PARTNER 3, the primary end point was specifically chosen to account for the lower event rate expected in low-risk patients and was powered on the basis of anticipated event rates from previous PARTNER trials. The sample size assumed a composite end-point event rate of 16.6% in the surgery group and 14.6% in the TAVR group. In fact, the primary event rates were 15.1% and 8.5%, respectively, and all components of the composite end point directionally favored TAVR. Rehospitalization was included because we believe it is a meaningful adverse outcome in low-risk patients, and it has been used as the sole primary end point in other recent trials. The higher rate of concomitant procedures in surgery (26.4% vs. 7.9%), mentioned both by Kaul and by Perella and Anwar, is a reflection of real-world surgical practice. The heart team at each site concluded before randomization that either approach, surgery or TAVR, would yield the best possible outcome. Since those patients who had a concomitant procedure did not have a higher rate of primary end-point events, there was no bias against surgery. Data available at the 10-year follow-up should give further insight into the risks and benefits of each approach, especially among patients who underwent concomitant coronary revascularization. Baldetti et al. noted a higher incidence of new-onset LBBB among patients who underwent TAVR, which suggests the possibility of the unfavorable prognostic effect of mechanical dyssynchrony. We agree and have recently published an analysis of patients in the earlier, higher-risk trials that shows worse left ventricular systolic function and more adverse clinical outcomes in patients with new LBBB. Precisely for these reasons, all patients will be followed with clinical, echocardiographic, and electrocardiographic assessment annually for 10 years. Finally, Savas et al. express concern that the higher rate of mild paravalvular leak with TAVR may lead to increased late mortality, citing data from a PARTNER trial involving high-risk patients. Although we share their concern, subsequent analyses of intermediate-risk patients have not shown an increase in mortality with mild paravalvular regurgitation.4 Nonetheless, all patients will be carefully followed for 10 years to address this concern. (Authors’ response to several commentaries on their previously published studies: Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med 2019;380:1695-1705 and Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med 2016;374:1609-1620.)