Research Spotlight

Martin, M., A. Chan, L. Dirix, J. O’Shaughnessy, R. Hegg, A. Manikhas, M. Shtivelband, P. Krivorotko, N. Batista Lopez, M. Campone, M. Ruiz Borrego, Q. J. Khan, J. T. Beck, M. Ramos Vazquez, P. Urban, S. Goteti, E. Di Tomaso, C. Massacesi and S. Delaloge (2016). “A randomized adaptive phase ii/iii study of buparlisib, a pan-class i pi3k inhibitor, combined with paclitaxel for the treatment of her2- advanced breast cancer (belle-4).” Ann Oncol: 2016 Nov [Epub ahead of print].

Full text of this article.

BACKGROUND: Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. PATIENTS AND METHODS: BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after >/=125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. RESULTS: As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 vs 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 vs 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (>/=40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. CONCLUSIONS: Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Brindis, R. G. and G. J. Dehmer (2016). “The volume-outcome relationship revisited: Does it matter for high-risk pci?” JACC Cardiovasc Interv 9(20): 2094-2096.

Full text of this article.

The National Cardiovascular Data Registry (NCDR) CathPCI registry collects clinical data from >90% of all PCIs performed in the United States. Excluding patients with ST-segment elevation myocardial infarctions, aggregate data from 2015 show an in-hospital mortality rate of 0.89%, while elective PCI mortality is 0.65% 5 and 6. The small number of deaths for a given operator, coupled with estimates of the case volume for operators in the United States (mean 59 cases annually, with 61% of operators performing <40 cases annually in 2008), results in a very wide confidence interval around the point estimate of PCI mortality for an operator (7). In addition, the interplay between facility and individual operator volumes, the operator’s lifetime experience, and the operator’s performance of non-PCI procedures (structural and peripheral arterial interventions) confound the assessment of a relationship between operator PCI case volume and outcomes (3). On the basis of these considerations, there are 2 possible approaches for a continuing examination of the relationship between operator volume and outcomes. One approach would require the collection of operator mortality data over many years to obtain a sample size that would allow meaningful differentiation among operators. For an individual operator, this would likely include mostly low-complexity, low-risk cases mixed with a few high-complexity, high-risk cases. Given the low and decreasing case volume for U.S. operators, the time required to obtain an adequate number of cases is impractical. The alternative approach is to focus on high-complexity, high-risk cases, for which the number of cases needed to discriminate among operators should be lower and obtainable. This latter approach was examined by Xu et al. (8) in a report in this issue of JACC: Cardiovascular Interventions.

Nickenig, G., C. Hammerstingl, R. Schueler, Y. Topilsky, P. A. Grayburn, A. Vahanian, D. Messika-Zeitoun, M. Urena Alcazar, S. Baldus, R. Volker, M. Huntgeburth, O. Alfieri, A. Latib, G. La Canna, E. Agricola, A. Colombo, K. H. Kuck, F. Kreidel, C. Frerker, F. C. Tanner, O. Ben-Yehuda and F. Maisano (2016). “Transcatheter mitral annuloplasty in chronic functional mitral regurgitation: 6-month results with the cardioband percutaneous mitral repair system.” JACC Cardiovasc Interv 9(19): 2039-2047.

Full text of this article.

OBJECTIVES: This study sought to show safety and efficacy of the Cardioband system during 6 months after treatment. BACKGROUND: Current surgical and medical treatment options for functional mitral regurgitation (FMR) are limited. The Cardioband system (Valtech Cardio, OrYehuda, Israel) is a novel transvenous, transseptal direct annuloplasty device. METHODS: Thirty-one patients (71.8 +/- 6.9 years of age; 83.9% male; EuroSCORE II: 8.6 +/- 5.9) with moderate to severe FMR, symptomatic heart failure, and depressed left ventricular function (left ventricular ejection fraction 34 +/- 11%) were prospectively enrolled. RESULTS: Procedural success rate, defined as delivery of the entire device, was 100%. There were no periprocedural deaths (0%), and mortality rate at 1 month or prior to hospital discharge and at 7 months was 5% and 9.7% respectively. Cinching of the implanted Cardioband reduced the annular septolateral dimension by >30% from 3.7 +/- 0.5 cm at baseline to 2.5 +/- 0.4 cm after 1 month and to 2.4 +/- 0.4 cm after 6 months, respectively (p < 0.001). Percentage of patients with FMR >/=3 was reduced from 77.4% to 10.7% 1 month after the procedure (p < 0.001) and 13.6% (p < 0.001) at 7 months. Percentage of patients with New York Heart Association functional class III/IV decreased from 95.5% to 18.2% after 7 months (p < 0.001); exercise capacity as assessed by 6-min walking test increased from 250 +/- 107 m to 332 +/- 118 m (p < 0.001) and quality of life (Minnesota Living With Heart Failure Questionnaire) was also significantly improved (p < 0.001). CONCLUSIONS: In this feasibility trial in symptomatic patients with FMR, transcatheter mitral annuloplasty with the Cardioband was effective in reducing MR and was associated with improvement in heart failure symptoms and demonstrated a favorable safety profile.

Bakris, G. L., J. M. Burkart, E. D. Weinhandl, P. A. McCullough and M. A. Kraus (2016). “Intensive hemodialysis, blood pressure, and antihypertensive medication use.” Am J Kidney Dis 68(5s1): S15-s23.

Full text of this article.

Hypertension is a cardinal feature of end-stage renal disease (ESRD). Hypertensive nephropathy is the primary cause of ESRD for nearly 30% of patients, and the prevalence of hypertension is >85% in new patients with ESRD. In contemporary hemodialysis (HD) patients, mean predialysis systolic blood pressure (SBP) is nearly 150mmHg, and about 70%, 50%, and 40% use beta-blockers, calcium channel blockers, and renin-angiotensin system inhibitors, respectively. Predialysis SBP generally exhibits a U-shaped association with mortality risk. Interdialytic ambulatory SBP is more strongly associated with risk. Hypertension is multifactorial; key causes include persistent hypervolemia and elevated peripheral resistance. With 3 HD sessions per week, blood pressure (BP) climbs during the interdialytic interval, in step with interdialytic weight gain, particularly among elderly patients and those with higher dry weight. Elevated peripheral resistance can be attributed to inappropriate activation of the sympathetic nervous system due to higher plasma norepinephrine concentrations. Multiple randomized clinical trials show that intensive HD reduces BP and the need for oral medications indicated for hypertension. In the first 2 months of the Frequent Hemodialysis Network trial, the short daily schedule reduced predialysis SBP by 7.7mmHg, whereas the nocturnal schedule reduced predialysis SBP by 7.3mmHg, both relative to 3 sessions per week. Improvements were sustained after 12 months. Both schedules reduced antihypertensive medication use relative to 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, the mean number of prescribed antihypertensive agents decreased from 1.7 to 1.0 in 1 year, whereas the percentage of patients not prescribed antihypertensive agents increased from 21% to 47%. Nocturnal HD appears to markedly reduce total peripheral resistance and plasma norepinephrine and restore endothelium-dependent vasodilation. In conclusion, intensive HD reduces BP and the need for antihypertensive medications.

Copland, M., P. Komenda, E. D. Weinhandl, P. A. McCullough and J. A. Morfin (2016). “Intensive hemodialysis, mineral and bone disorder, and phosphate binder use.” Am J Kidney Dis 68(5s1): S24-s32.

Full text of this article.

Mineral and bone disorder is a common complication of end-stage renal disease. Notably, hyperphosphatemia likely promotes calcification of the myocardium, valves, and arteries. Hyperphosphatemia is associated with higher risk for cardiovascular mortality and morbidity along a gradient beginning at 5.0mg/dL. Among contemporary hemodialysis (HD) patients, mean serum phosphorus level is 5.2mg/dL, although 25% of patients have serum phosphorus levels of 5.5 to 6.9mg/dL; and 13%, >7.0mg/dL. Treatment of hyperphosphatemia is burdensome. Dialysis patients consume a mean of 19 pills per day, half of which are phosphate binders. Medicare Part D expenditures on binders for dialysis patients approached $700 million in 2013. Phosphorus removal with thrice-weekly HD (4 hours per session) is approximately 3,000mg/wk. However, clearance is unlikely to counterbalance dietary intake, which varies around a mean of 7,000mg/wk. Dietary restriction and phosphate binders are important interventions, but each has limitations. Dietary control is complicated by limited access to healthy food choices and unclear labeling. Meanwhile, adherence to phosphate binders is poor, especially in younger patients and those with high pill burden. Multiple randomized clinical trials show that intensive HD reduces serum phosphorus levels. In the Frequent Hemodialysis Network (FHN) trial, short daily and nocturnal schedules reduced serum phosphorus levels by 0.6 and 1.6mg/dL, respectively, relative to 3 sessions per week. A similar effect of nocturnal HD was observed in an earlier trial. In the daily arm of the FHN trial, intensive HD significantly lowered estimated phosphate binder dose per day, whereas in the nocturnal arm, intensive HD led to binder discontinuation in 75% of patients. However, intensive HD appears to have no meaningful effects on serum calcium and parathyroid hormone concentrations. In conclusion, intensive HD, especially nocturnal HD, lowers serum phosphorus levels and decreases the need for phosphate binders.