Prespecified Primary End Point Research Articles

Echocardiography-Guided Left Ventricular Lead Placement for Cardiac Resynchronization Therapy

Background— Cardiac resynchronization therapy improves mortality and morbidity in patients with heart failure (HF) with wide QRS complex and diminished left ventricular (LV) function, but response is variable. Methods and Results— The Speckle Tracking Assisted Resynchronization Therapy for Electrode Region (STARTER) was a prospective, double-blind, randomized controlled trial testing the hypothesis that an incremental benefit to cardiac resynchronization therapy would be gained by echo-guided (EG) transvenous LV lead placement versus a routine fluoroscopic approach. EG LV lead placement was attempted at the site of latest time to peak radial strain by speckle tracking echocardiography. The prespecified primary end point was first HF hospitalization or death. Of 187 New York Heart Association class II to IV patients with HF (62% ischemic; ejection fraction 26±6%; QRS 159±27 ms), 110 were randomized to EG and 77 to routine strategies. Primary events included 30 deaths and 37 HF hospitalizations over 1.8 years. Using intention-to-treat, patients randomized to an EG strategy had a significantly more favorable event-free survival (hazard ratio, 0.48; 95% confidence interval, 0.28–0.82; P =0.006). Exact or adjacent concordance of LV lead with latest site could be achieved in 85% of the EG group and occurred fortuitously in 66% of controls ( P =0.010) and was associated with an improvement in event-free survival (hazard ratio, 0.40; 95% confidence interval, 0.22–0.71; P =0.002). Conclusions— A strategy of EG LV lead placement for cardiac resynchronization therapy improved patient outcomes by reducing the combined risk of death or HF hospitalizations and has implications for delivery of cardiac resynchronization therapy. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00156390.

Reply to S. Buti and S. Culine

The comments Buti1 and Culine2 regarding our article3 about the role of cetuximab with or without paclitaxel in patients with advanced urothelial cancer. Their comments highlight some of the challenges in conducting clinical trials in this area. Buti proposes an additional analysis comparing the study's overall survival to the expected survival on the basis of the distribution of patient characteristics using the Bellmunt criteria published in 2010.4 Using these criteria, seven patients in the combination arm of our study had zero risk factors, 13 patients had one risk factor, seven patients had two risk factors, and one patient had three risk factors. The small size of these subsets precludes a meaningful statistical comparison of survival. We did report the progression-free and overall survival of patients who received chemotherapy for metastatic disease and those who had visceral metastases. However, because of the small sample size, we believe these results should be considered hypothesis generating only, and we discuss this limitation in our article.3 We agree with Culine that time from prior chemotherapy may be an important prognostic factor. We have contributed data from this study to a pooled analysis that recently demonstrated that a shorter time from prior chemotherapy is associated with worse response.5 This information may be used to design additional studies. KRAS mutation status was not known to be predictive of response to cetuximab in advanced colorectal cancer when this study began enrolling patients in 2006. However, we would not recommend testing for KRAS mutational status as an entry criteria for future studies of this combination on the basis of the low probability of finding a KRAS mutation in a patient with metastatic urothelial cancer. Juanpere et al6 found just one KRAS mutation among the 33 patients within the cohort of high-grade invasive bladder cancer. A higher but still low frequency of KRAS mutations were found in superficial tumor samples, which have a lower probability for metastasis. Other investigators have also found a low frequency of KRAS mutations in patients with urothelial carcinoma.7,8 This study was designed as a noncomparative phase II study; therefore, each arm was investigated separately. We hope to test this combination in a randomized comparative fashion using paclitaxel as a control arm. Vinflunine, although available in Europe, is not available in the United States and is not a practical comparator arm. Our study met its prespecified primary end point, which demonstrated that the combination of cetuximab and paclitaxel extended progression-free survival compared with historical controls, providing the rationale for future testing of this combination in a larger randomized trial.

Abstract 2095: A phase 2 study of Amuvatinib (MP-470), the first RAD51 inhibitor in combination with platinum-etoposide (PE) in refractory or relapsed small cell lung cancer (ESCAPE).

Abstract Background: Amuvatinib is an oral multi-targeted TKI of c-Kit and PDGFRα and modulates DNA repair by down regulation of Rad51. Rad51 is a key protein in the homologous recombination repair pathway for DNA double strand breaks which can mediate resistance to DNA-damaging agents. Amuvatinib has demonstrated synergistic activity preclinically with DNA damaging chemotherapy agents including etoposide and doxorubicin. Amuvatinib in combination with DNA damaging agents resulted in clinical responses in SCLC patients, induced Rad51 suppression, and increased DNA damage (53BP1 foci) in skin punch biopsies. These results provided the justification for a Phase 2, OL study of amuvatinib in combination with platinum and etoposide (PE) chemotherapy in SCLC patients who have not responded to or relapsed after standard treatment (ESCAPE; TrEatment of Small Cell lung cancer with Amuvatinib in combination with Platinum Etoposide). Methods: Patients ≥ 18 years, ECOG PS 0-2, with confirmed SCLC who met one of the following major eligibility criteria were enrolled based on prior PE response: 1) disease progression during PE, 2) relapse ≤ 90 days, 3) SD as best response after at least 2 cycles. Patients who received second-line therapy were eligible if they met any one of these 3 conditions and all other study eligibility criteria. An optimal Simon 2-stage design was employed (α=10%, β=10%, p0=10%, p1=25%). In Stage 1, 21 patients were to be enrolled and ≥ 3 confirmed responses (CR or PR) were required in order to proceed to Stage 2, where an additional 29 patients were to be enrolled. Amuvatinib was administered PO 300 mg TID. Results: Twenty-three patients, median age of 62 years (range, 44-80); 11 M/12 F; ECOG PS 0 (n=3), 1 (n=12), 2 (n=6), were enrolled in Stage 1 and received a median of two 21-day cycles (range, 1-10). At study entry, 9 (39%), 11 (48%), and 3 (13%) patients presented with disease progression, relapse ≤ 90 days, and SD after at least 2 cycles of PE, respectively. Per PI's assessment, 4 PRs and 7 SDs were observed as best response. Per RECIST 1.1, 2 PRs and 3 SDs were confirmed by follow-up scan ≥ 4 weeks apart for an overall clinical benefit rate (CBR) of 5/23 (22%). No CRs were observed. Grade 3/4 suspected amuvatinib related AEs were neutropenia, thrombocytopenia, atrial fibrillation, diarrhea, esophagitis, and hypercalcemia (1 patient each; 4%); hypokalemia and leukopenia, (2 patients each; 9%). By IHC, baseline expression of RAD51, ERCC1, Chk2, ATM, cKit, and RB will be evaluated and correlated with response. Conclusions: Amuvatinib demonstrated an overall CBR of 22% in refractory SCLC. While clinical activity was observed, the response rate in Stage 1 did not meet pre-specified study primary endpoint. The safety profile of amuvatinib is consistent with previous published reports of manageable toxicity with non-overlapping toxicities with PE chemotherapy. Citation Format: Lauren Byers, Leora Horn, Jitendra Gandhi, Goetz Kloecker, Taofeek K. Owonikoko, Saiama Waqar, Maciej J. Krzakowski, Gavin Choy, Nancy Cecchettini, Pietro Taverna, Amarpal Sahai, Mojtaba Noursalehi, Mohammad Azab, D. Ross Camidge. A phase 2 study of Amuvatinib (MP-470), the first RAD51 inhibitor in combination with platinum-etoposide (PE) in refractory or relapsed small cell lung cancer (ESCAPE). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2095. doi:10.1158/1538-7445.AM2013-2095

Decitabine: A Review of its Use in Older Patients with Acute Myeloid Leukaemia

Decitabine (Dacogen(®)) is a deoxynucleoside analogue of cytidine that selectively inhibits DNA methyltransferases. Decitabine administered at a dose of 20 mg/m(2) by a 1-h intravenous infusion for 5 consecutive days of a 4-week cycle has been approved by the European Medicines Agency (EMA) for use in adult patients aged ≥65 years with de novo or secondary acute myeloid leukaemia (AML) who are not candidates for standard induction therapy. Decitabine, compared with treatment choice (cytarabine or supportive care), did not result in a statistically significant improvement in median overall survival (OS) in older patients with AML at the pre-specified primary endpoint of a pivotal phase III trial. However, the improvement in OS was considered by the EMA to be clinically meaningful. After a further year of follow-up, an analysis of the mature survival data demonstrated a statistical significance in median OS in favour of decitabine over treatment choice. Complete remission (CR) rates in the phase III trial were significantly improved with decitabine versus treatment choice. The overall safety profile of decitabine in older patients with AML was generally similar to that of cytarabine, with pyrexia, thrombocytopenia and anaemia being the most commonly reported adverse events. In conclusion, low-dose decitabine may be considered as an effective and generally well tolerated alternative treatment to cytarabine or supportive care in older patients with AML who are not candidates for standard induction therapy.

Efficacy and Safety of Canagliflozin Treatment in Older Subjects With Type 2 Diabetes Mellitus: A Randomized Trial

Introduction: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). Our randomized, double-blind, placebo-controlled, phase 3 study (www.clinicaltrials.gov: NCT01106651) evaluated the efficacy and safety of canagliflozin therapy in older subjects (aged 55–80 years) with T2DM inadequately controlled on their current regimen of blood glucose–lowering agents (any approved oral or injectable treatment). Methods: Subjects (N = 716) aged 55 to 80 years (mean, 63.6 years) with glycated hemoglobin (HbA1c) levels ≥ 7.0% to ≤ 10.0% were randomized. Seven hundred fourteen received canagliflozin 100 mg or 300 mg or placebo (1:1:1) daily. The prespecified primary endpoint was change from baseline in HbA1c level at week 26. Prespecified secondary endpoints included proportion of subjects achieving HbA1c levels < 7.0%, change from baseline in fasting plasma glucose (FPG) level and systolic blood pressure (BP), and percent change from baseline in body weight, triglyceride levels, and high-density lipoprotein cholesterol (HDL-C) level. Adverse events (AEs) were reported throughout the study. Results: At week 26, treatment with canagliflozin 100 mg and 300 mg significantly reduced HbA1c levels compared with placebo (−0.60%, corresp0.73%, corresp0.03%, respectively; P < 0.001); more subjects achieved HbA1c levels < 7.0%) with both canagliflozin doses compared with placebo (P < 0.001). Both canagliflozin doses significantly reduced body weight, FPG level, and systolic BP, and increased HDL-C level compared with placebo (P < 0.001); low-density lipoprotein cholesterol level was increased with both canagliflozin doses compared with placebo. The overall AE incidence was slightly higher with canagliflozin 300 mg than with canagliflozin 100 mg or placebo (78.0%), 72.2%), 73.4%o, respectively). Serious AE and AE-related discontinuation rates were low across groups. Both canagliflozin doses were associated with higher rates than placebo of genital mycotic infections, urinary tract infections, and osmotic diuresis–related AEs (ie, pollakiuria, polyuria). Documented hypoglycemia rates were modestly higher with both canagliflozin doses compared with placebo. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in older subjects with T2DM who were on background therapy with a variety of blood glucose–lowering agents.

Phytosterol capsules and serum cholesterol in hypercholesterolemia: A randomized controlled trial

ObjectivePhytosterols are recommended in combination with diet therapy to reduce elevated LDL-cholesterol level. Meta-analyses indicate a 10% reduction in LDL-cholesterol from intake of approximately 2 g phytosterols/d incorporated into fat-based foods. However, the cholesterol lowering effect from capsules containing phytosterols is less documented. The pre-specified primary endpoint of the present study was to investigate the effect of capsules with phytosterols on circulating LDL-cholesterol in patients with mild to moderate hypercholesterolemia. MethodsIn a double-blinded, randomized, placebo-controlled crossover study, 41 men and women were randomized into two four-weeks intervention periods with softgel capsules containing either phytosterols (2.0 g/d) or sunflower oil. There was a three-weeks washout period between the intervention periods. ResultsNo significant difference in total- or LDL-cholesterol between the phytosterol and the placebo period were observed after four weeks intervention (0.0 mmol/L (95%CI: −0.3 to 0.2), P = 0.74 and −0.1 mmol/L (95%CI: −0.3 to 0.1), P = 0.32, respectively). ConclusionDaily intake of capsules containing 2 g phytosterols did not reduce total- or LDL-cholesterol significantly in a highly relevant target group for the use of phytosterol products. The present results may emphasize the importance of choosing a suitable dosage-delivery system in order to achieve optimal cholesterol lowering effect.The study was registered at www.clinicaltrials.gov, IDno:NCT00485095.

Levels of Cholesterol in Small LDL Particles Predict Atherosclerosis Progression and Incident CHD in the HDL-Atherosclerosis Treatment Study (HATS)

ObjectiveTest whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses.MethodsGradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments.ResultsThe change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2–24.6 nm) and LDL-IVa (23.3–24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values.ConclusionsPlasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol.Trial RegistrationClinicalTrials.gov NCT00000553

Optimal Timing of Coronary Invasive Strategy in Non–ST-Segment Elevation Acute Coronary Syndromes

The optimal timing of coronary intervention in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) is a matter of debate. Conflicting results among published studies partly relate to different risk profiles of the studied populations. To do the most comprehensive meta-analysis of current evidence on early versus delayed invasive treatment in NSTE-ACS. MEDLINE, PubMed Central, and Google Scholar databases; conference proceedings; ClinicalTrials.gov registry; and Current Controlled Trials registry through May 2012. Available randomized, controlled trials (RCTs) and observational studies comparing early versus delayed intervention in the NSTE-ACS population. Data were extracted for populations, interventions, outcomes, and risk of bias. All-cause mortality was the prespecified primary end point. The longest follow-up available in each study was chosen. The odds ratio with 95% CI was the effect measure. Seven RCTs (5370 patients) and 4 observational studies (77 499 patients) were included. Early intervention was less than 20 hours after hospitalization or randomization for RCTs and 24 hours or less for observational studies. Meta-analysis of the RCTs was inconclusive for a survival benefit associated with the early invasive strategy (odds ratio, 0.83 [95% CI, 0.64 to 1.09]; P = 0.180); a similar result emerged from the observational studies. With early versus late intervention, the odds ratios in the RCTs were 1.15 (CI, 0.65 to 2.01; P = 0.63) and 0.76 (CI, 0.56 to 1.04; P = 0.090) for myocardial infarction and major bleeding during follow-up, respectively. Current evidence from RCTs is limited by the small overall sample size, low numbers of events in some trials, and heterogeneity in the timing of intervention and in patient risk profiles. At present, there is insufficient evidence either in favor of or against an early invasive approach in the NSTE-ACS population. A more definitive RCT is warranted to guide clinical practice.

A Blood-Based Gene Expression Test for Obstructive Coronary Artery Disease Tested in Symptomatic Nondiabetic Patients Referred for Myocardial Perfusion Imaging The COMPASS Study

BACKGROUND- Obstructive coronary artery disease diagnosis in symptomatic patients often involves noninvasive testing before invasive coronary angiography. A blood-based gene expression score (GES) was previously validated in nondiabetic patients referred for invasive coronary angiography but not in symptomatic patients referred for myocardial perfusion imaging (MPI). METHODS AND RESULTS- This prospective, multicenter study obtained peripheral blood samples for GES before MPI in 537 consecutive patients. Patients with abnormal MPI usually underwent invasive coronary angiography; all others had research coronary computed tomographic angiography, with core laboratories defining coronary anatomy. A total of 431 patients completed GES, coronary imaging (invasive coronary angiography or computed tomographic angiography), and MPI. Mean age was 56±10 years (48% women). The prespecified primary end point was GES receiver-operating characteristics analysis to discriminate ≥50% stenosis (15% prevalence by core laboratory analysis). Area under the receiver-operating characteristics curve for GES was 0.79 (95% confidence interval, 0.73-0.84; P<0.001), with sensitivity, specificity, and negative predictive value of 89%, 52%, and 96%, respectively, at a prespecified threshold of ≤15 with 46% of patients below this score. The GES outperformed clinical factors by receiver-operating characteristics and reclassification analysis and showed significant correlation with maximum percent stenosis. Six-month follow-up on 97% of patients showed that 27 of 28 patients with adverse cardiovascular events or revascularization had GES >15. Site and core-laboratory MPI had areas under the curve of 0.59 and 0.63, respectively, significantly less than GES. CONCLUSIONS- GES has high sensitivity and negative predictive value for obstructive coronary artery disease. In this population clinically referred for MPI, the GES outperformed clinical factors and MPI. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01117506.

Linking clinic and home: a randomized, controlled clinical effectiveness trial of real-time, wireless blood pressure monitoring for older patients with kidney disease and hypertension.

Older adults with chronic kidney disease have a high rate of uncontrolled hypertension. Home monitoring of blood pressure (BP) is an integral part of management, but requires that patients bring records to clinic visits. Telemonitoring interventions, however, have not targeted older, less technologically-skilled populations. Veterans with stage 3 or greater chronic kidney disease and uncontrolled hypertension were randomized to a novel telemonitoring device pairing a Bluetooth-enabled BP cuff with an Internet-enabled hub, which wirelessly transmitted readings (n=28), or usual care (n=15). Home recordings were reviewed weekly and telemonitoring participants were contacted if BP was above goal. The prespecified primary endpoints were improved data exchange and device acceptability. Secondary endpoint was BP change. Forty-three participants (average age 68 years, 75% white) completed the 6-month study. Average start-of-study BP was 147/78 mmHg. Those in the intervention arm had a median of 29 (IQR 22, 53) transmitted BP readings per month, with 78% continuing to use the device regularly, whereas only 20% of those in the usual care group brought readings to in-person visits. The median number of telephone contacts triggered by the wireless monitoring was 2 (IQR 1, 4) per patient. Both groups had a significant improvement in systolic BP (P<0.05, for both changes); systolic BP fell a median of 13 mmHg in monitored participants compared with 8.5 mmHg in usual care participants (P for comparison 0.31). This low-cost wireless monitoring strategy led to greater sharing of data between patients and clinic and produced a trend toward improvements in BP control over usual care at 6 months.

CTST-21: A Phase 2, Randomized, Double-Blind, Multi-Center Study Comparing 15G Cross-Linked Polyelectrolyte (CLP) versus Placebo in Heart Failure Patients with Chronic Kidney Disease

The goal of this double-blind, randomized, placebo-controlled trial was to evaluate the effects of a cross-linked polyelectrolyte (CLP) on serum potassium and measures of congestion in patients with heart failure (HF) and chronic kidney disease (CKD). The pre-specified primary endpoint was change in serum K+ over time, with an associated goal of facilitating the initiation of aldosterone blockers in patients at risk for hyperkalemia. Since CLP also removes fluid through the GI tract, we also hypothesized that this intervention would ameliorate congestion as assessed by serial weights and its associated symptoms, as assessed by NYHA class, quality of life (assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), and 6 minute walk test (6MWT) after 8 weeks of CLP treatment.

Phase II open-label study of sunitinib in patients with advanced breast cancer

This multicenter, open-label phase II study was conducted to evaluate sunitinib monotherapy in patients with either metastatic or locoregionally recurrent advanced breast cancer. Patients received sunitinib 37.5 mg on a continuous daily dosing schedule. The primary endpoint was objective response rate (ORR); the predefined target ORR was 25 %. All 83 patients enrolled into the study received study treatment. The majority of patients (90 %) had metastatic disease; 92 % had received prior systemic therapies, and 60 % had received two or more regimens for early and/or advanced disease. The ORR was 8 % (95 % exact CI, 4-17), comprising seven partial responses. In patients with superficial lesions (defined as cutaneous or palpable chest wall lesions), the ORR was 20 % (three of 15 evaluable patients), which was higher than that in patients with non-superficial disease (9 %; six of 64 patients). Median progression-free survival in the overall population was 3.6 months (95 % CI, 2.4-3.9); median overall survival was 15.6 months (95 % CI, 14.0-22.7). No new or unexpected safety findings were reported. The most commonly reported adverse events (AEs) were fatigue (60 %), diarrhea (54 %), and nausea (49 %). The most commonly reported grade 3/4 AEs were fatigue (17 %), neutropenia (16 %), and thrombocytopenia (11 %). Four patients (5 %) had a dose reduction due to an AE, and 39 patients (47 %) had temporary discontinuations of therapy due to AEs. Two on-study deaths were reported, one due to a pulmonary embolism (considered related to treatment) and one attributed to dyspnea and a myocardial infarction (considered unrelated to treatment). Patient-reported outcomes suggested that sunitinib treatment did not have a negative impact overall on patients' functional domains or the majority of symptom scales. The trial did not meet its prespecified primary endpoint, and in view of the negative results obtained in several other trials, sunitinib will not be developed further for this indication.

Detecting Obstructive Coronary Disease With CT Angiography and Noninvasive Fractional Flow Reserve

PHYSICIANS COMMONLY ENCOUNTER PATIENTS REPORTing chest discomfort. In these cases, the physician needs to determine whether the patient has obstructive coronary artery disease (CAD), and if so, whether the patient is at increased risk of future cardiovascular events. The ultimate goal of this evaluation is to direct optimal medical therapy and potentially lead to ischemiadriven coronary revascularization. The fractional flow reserve (FFR) performed during invasive coronary angiography has been shown to provide lesion-specific data on ischemia, which, when used to direct revascularization, leads to improved clinical outcomes. Fractional flow reserve is the ratio of the mean coronary artery pressure distal to an obstructive coronary lesion relative to the mean aortic pressure during maximal coronary blood flow and represents a physiologic measure of coronary stenosis. Current guidelines recommend that this evaluation should be differential based on patient pretest risk assessment. Lowrisk patients should receive only expectant management, intermediate-risk patients should be referred for noninvasive testing, and high-risk patients should undergo invasive cardiac catheterization. To date, noninvasive tests have performed this evaluation by taking either an anatomic approach such as computed tomographic (CT) angiography to identify obstructive CAD or a functional approach to determine ischemia by perfusion or wall motion function via a variety of stress and imaging modes. Therefore, technologies that provide both a highly sensitive anatomic evaluation for obstructive disease and a highly specific physiologic evaluation for ischemia represent the “holy grail” for noninvasive imaging for CAD. It is with this background that Min et al report the findings of the DeFACTO study in this issue of JAMA evaluating CT angiography with a novel noninvasive FFR computed from CT (FFRCT) compared with the reference standard of invasive FFR determined by conventional coronary angiography. The investigators performed a multicenter (17 centers in 5 countries) diagnostic performance study involving 288 stable patients with known or suspected CAD, of whom 252 patients had evaluable images that were compared with invasive FFR. The study’s prespecified aim was to determine if FFRCT plus CT could improve the per-patient diagnostic accuracy such that the lower boundary of the 95% confidence interval exceeded 70%. The investigators went to great lengths to ensure blinding, such as using core laboratories for CT angiography evaluation, FFRCT evaluation, and invasive coronary angiography as well as an integration core laboratory that helped register the images and identify locations for FFRCT vs reference FFR analysis. The investigators report that 137 patients (54.4%) had an abnormal FFR based on invasive angiography. In the perpatient analysis, FFRCT had an accuracy of 73% (95% CI, 67%-78%) arising from a sensitivity of 90% (95% CI, 84%95%) and specificity of 54% (95% CI, 46%-83%). However, this level of diagnostic accuracy did not meet the prespecified primary end point because the lower bound of the 95% CI for accuracy was 67%. For lesions of 50% or greater, CT angiography had an accuracy of 64% (95% CI, 58%70%) with a sensitivity of 84% (95% CI, 77%-90%) and a specificity of 42% (95% CI, 34%-51%). The investigators rightly conclude that FFRCT plus CT was associated with improved diagnostic accuracy and discrimination compared with CT angiography alone. This well-conducted multicenter study provides important data about the performance both of FFRCT plus CT and CT angiography. Additionally, beyond the sheer novelty of the FFRCT technology, the investigators raise the bar by comparing this diagnostic technology with a reference standard of both invasive angiography and invasive FFR. This change in reference standard may in part explain some of the accuracy findings. So how should these findings be considered with regard to current clinical evaluation for chest pain?

1571P - Prevention of Delayed Nausea (DN): A Pooled Analysis of 562 Women Receiving Highly Emetogenic Chemotherapy (HEC) in Prospective Clinical Trials of Palonosetron (PALO)

ABSTRACT Purpose Chemotherapy-induced nausea occurs more frequently than vomiting, and women are particularly prone to experience DN instead of delayed vomiting. We conducted a pooled analysis to evaluate the efficacy of three regimens for preventing DN: 1-day regimen (n = 241): Palo plus dexamethasone 8 mg IV (Day 1); 3-day regimen (n = 209): Palo plus dexamethasone 8 mg (Day 1) and dexamethasone 8 mg PO (Days 2 and 3); triple regimen (n = 112): Palo plus dexamethasone 12 mg and aprepitant (Day 1) and dexamethasone 8 mg PO plus aprepitant (Days 2 and 3). Methods The analysis was based upon outcomes in 562 chemo-naive women (mean age 52.7 years; PS ECOG 0: 93%; metastatic disease: 11%) with solid tumors (90% breast cancer) enrolled in two Phase III and two Phase II trials of HEC (AC-based: 91%; cisplatin: 9%). The pre-specified primary end point was the proportion of patients with no nausea during the delayed period (Days 2-5) after the first cycle of chemotherapy. The two primary comparisons were 3-day regimen vs. 1-day regimen, and triple regimen vs. 3-day regimen. Penalized multivariable logistic regressions were also performed adopting the Firth's correction in order to adjust estimates for potential over-fitting, skewed data and multi-collinearity. Results were reported as adjusted odds ratios (OR) with two-sided probability values. Results The 3-day to 1-day regimen comparison was not statistically significant (DN, 46.4% vs. 44.4%, two-sided Fisher's exact test, P = 0.777). The triple regimen to 3-day regimen comparison was significant (DN, 58.9% vs. 46.4%; P Conclusions This analysis suggests that Palo plus 1-day or 3-day dexamethasone have similar effects on DN. The addition of aprepitant to 3-day regimen improves the prevention of DN in women receiving HEC. Complete results accounting for risk factors (age and alcohol consumption) will also be presented. Disclosure All authors have declared no conflicts of interest.

Sugammadex is not associated with QT/QTc prolongation: methodology aspects of an intravenous moxifloxacin-controlled thorough QT study

Sugammadex is a novel γ-cyclodextrin and the first selective relaxant binding agent to be developed for the reversal of rocuronium and vecuroniuminduced neuromuscular blockade. According to International Conference on Harmonization (ICH) E14, a thorough QT/QTc study is required for most new compounds to assess the potential to cause QT prolongation, because a delay in cardiac repolarization may create an electrophysiological environment that favors the development of cardiac arrhythmias, most notably Torsade de Pointes. Therefore a thorough QTc study was conducted to evaluate the effect of sugammadex on the individually corrected QTc interval (QTcI). Following two baseline electrocardiogram (ECG) days (Day -2 and Day -1), in this randomized, double-blind, cross-over study, healthy volunteers received a sequence of four treatments comprising single intravenous doses of placebo, moxifloxacin 400 mg (positive control, open label), sugammadex 4 mg/kg and sugammadex 32 mg/kg. ECGs were recorded in triplicate at 12 time points up to ~ 24 h after study drug administration, and the QT intervals were evaluated manually under blinded conditions. The pre-specified primary endpoint was the largest time-matched mean QTcI difference compared with placebo across all time points. A total of 62 subjects received treatment, of which 58 completed the study. After intravenous moxifloxacin, QTcI prolongations compared with placebo exceeded the ICH E14 safety margin of 10 msec and the one-sided 95% lower confidence limit exceeded 5 msec, confirming assay sensitivity. For both sugammadex doses, the one-sided 95% upper confidence limits for the largest time-matched mean QTcI differences compared with placebo were ≤ 5.3 msec at each timepoint and thus considerably below the 10 msec safety margin. Unexpectedly, the two full-day baseline ECGs indicated systematically prolonged QTc values when comparing the first baseline with the second baseline day, reaching a maximum mean difference of 3.8 msec. Single therapeutic (4 mg/kg) and supra-therapeutic (32 mg/kg) intravenous doses of sugammadex are not associated with clinically important QTc prolongation.

Assessment of Myocardial Scarring Improves Risk Stratification in Patients Evaluated for Cardiac Defibrillator Implantation

We tested whether an assessment of myocardial scarring by cardiac magnetic resonance imaging (MRI) would improve risk stratification in patients evaluated for implantable cardioverter-defibrillator (ICD) implantation. Current sudden cardiac death risk stratification emphasizes left ventricular ejection fraction (LVEF); however, most patients suffering sudden cardiac death have a preserved LVEF, and many with poor LVEF do not benefit from ICD prophylaxis. One hundred thirty-seven patients undergoing evaluation for possible ICD placement were prospectively enrolled and underwent cardiac MRI assessment of LVEF and scar. The pre-specified primary endpoint was death or appropriate ICD discharge for sustained ventricular tachyarrhythmia. During a median follow-up of 24 months the primary endpoint occurred in 39 patients. Whereas the rate of adverse events steadily increased with decreasing LVEF, a sharp step-up was observed for scar size >5% of left ventricular mass (hazard ratio [HR]: 5.2; 95% confidence interval [CI]: 2.0 to 13.3). On multivariable Cox proportional hazards analysis, including LVEF and electrophysiological-study results, scar size (as a continuous variable or dichotomized at 5%) was an independent predictor of adverse outcome. Among patients with LVEF >30%, those with significant scarring (>5%) had higher risk than those with minimal or no (≤5%) scarring (HR: 6.3; 95% CI: 1.4 to 28.0). Those with LVEF >30% and significant scarring had risk similar to patients with LVEF ≤30% (p = 0.56). Among patients with LVEF ≤30%, those with significant scarring again had higher risk than those with minimal or no scarring (HR: 3.9; 95% CI: 1.2 to 13.1). Those with LVEF ≤30% and minimal scarring had risk similar to patients with LVEF >30% (p = 0.71). Myocardial scarring detected by cardiac MRI is an independent predictor of adverse outcome in patients being considered for ICD placement. In patients with LVEF >30%, significant scarring (>5% LV) identifies a high-risk cohort similar in risk to those with LVEF ≤30%. Conversely, in patients with LVEF ≤30%, minimal or no scarring identifies a low-risk cohort similar to those with LVEF >30%.

Response to Letter Regarding Article, “Percutaneous Femoral Arteriovenous Shunt Creation for Advanced Chronic Obstructive Pulmonary Disease: A Single-Center Safety and Efficacy Study”

We have read with great interest the letter to the editor by Faul et al regarding our recently published manuscript. First, Faul et al indicate that our study demonstrated an improvement in functional class. Although it is true that, as we reported, the New York Heart Association functional class improved at follow-up, this was not the primary end point and is the variable subject to significant observer bias, not to mention placebo effect (neither investigators nor patients were blinded to the treatment). More important, the prespecified primary end point, an objective assessment of functional capacity (6-Minute Walking Distance [6MWD]), did not demonstrate any improvements nor were there any favorable changes in several parameters assessing the patients' dyspnea and quality of life (St George Respiratory Questionnaire, Modified Medical Research Council Dyspnea Scale, Borg Scale, and Bode Index).1 Second, Faul et al indicate that it would be premature to conclude that the creation of an arteriovenous fistula does not improve walking distance and that the absence of a decline in walking distance may be considered a success. It is important to state, once again, that the …

A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y 12 Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention

We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention. In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure. In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

Palonosetron (PALO) plus 1-day versus 3-day dexamethasone (DEX) with or without aprepitant against delayed nausea (DN): Pooled analysis for 554 women receiving highly emetogenic chemotherapy (HEC).

9133 Background: Nausea is more difficult to control than vomiting, because the incidence of the symptom continues to rise over the days after chemotherapy. This post-hoc analysis addressed two questions: 1) Does PALO plus single-dose DEX result in suboptimal control of DN when compared to the same regimen with additional DEX doses? 2) Is the combination of PALO, DEX, and aprepitant a more effective coverage against DN? Methods: The analysis was based upon outcomes in chemo-naïve women (median age =52) with solid tumors (89% breast) enrolled in two Phase III and two Phase II trials of HEC (AC combination or cisplatin). Patients received the following regimens: 1) PALO 0.25 mg plus DEX 8 mg IV on day 1 of chemotherapy (1-day regimen, n=243); 2) the same regimen on the day 1 followed by DEX 8 mg orally on days 2 and 3 (3-day regimen, n=207); or PALO plus DEX plus aprepitant 125 mg on day 1 followed by aprepitant 80 mg on days 2 and 3 (triple regimen, n=104). The pre-specified primary endpoint was the proportion of patients with no DN (days 2-5 after the first cycle of chemotherapy). The two primary comparisons were 1-day vs. 3-day regimen, and triple vs. 3-day regimen, with statistical significance set to the 0.025 level. Results: The 1-day to 3-day regimen comparison was not statistically significant (44% vs. 47.8%; risk difference (RD) = -3.8%, 95% CI (-5.4 to 12.9%), P=0.421 (two-sided chi-square test). The triple to 3-day regimen comparison was also not significant (57.7% vs. 47.8%), RD= +9.9%, 95% CI (-1.9 to 21.3%), P=0.101. More patients receiving triple regimen experienced no acute-onset nausea compared with those administered only DEX (97.1% vs. 51.2%, P&lt;0.0001). Conclusions: This analysis provides evidence that PALO plus 1-day or 3-day DEX yield similar prevention of DN. The addition of aprepitant does not improve the control of DN. Complete results utilizing a multivariable model accounting for risk factors and trial heterogeneity will also be presented.

Phase II trial of BNC105P as second-line chemotherapy for advanced malignant pleural mesothelioma (MPM): Australasian Lung Cancer Trials Group and NHMRC Clinical Trials Centre Collaboration.

7079^ Background: BNC105P is a tubulin polymerization inhibitor that acts as a Vascular Disrupting Agent (VDA), has direct cytotoxic effects, and had preclinical and phase I activity in MPM. This aim of this study was to determine activity and safety of BNC105P as second-line therapy after pemetrexed and a platin in MPM. Methods: Eligible patients had progressive MPM, prior pemetrexed and platinum, measurable disease by modified RECIST, ECOG 0-1, and adequate organ and cardiovascular function. Important exclusions included recent thromboembolic, cardiovascular or cerebrovascular disease, or therapeutic anticoagulation. Pts received BNC105P (16 mg/m2 IV) Day 1 + 8 q21d until progression or toxicity. The primary endpoint was centrally reviewed objective tumour response rate (RR); the Simon 2-stage design assumed a RR of interest of 20% and a RR of no interest of 5%, with α = β = 0.05. Continuation past first stage accrual required &gt;1 objective response in 24 patients. Results: 30 subjects were accrued over 10 months (90% male; median age 65 (range 41-83); 77% ECOG PS 1; histology epithelioid (67%), biphasic (10%), sarcomatoid (7%), other/unspecified (17%)). All pts received at least one dose of study drug; pts received a median of 2 cycles and median dose intensity was 100%. No significant haematologic, biochemical, peripheral neurotoxic or cardiac adverse events (AEs) including hypertension were observed. Grade 3 or 4 AEs occurred in 10 pts (33%). There were 2 deaths on study: 1 due to stroke, the other due to pneumonia and respiratory failure. We observed 1 partial response (3%) and 13 pts with SD as their best response (43%). Median progression free survival was 1.5 mo (95% CI 1.4-2.4); median overall survival was 8.7 mo (95% CI 3.8-NR). Lung function and QOL data was collected. Biomarker analyses correlating to pharmacological changes induced by BNC105P are ongoing and will be presented. Conclusions: BNC105P was safe and tolerable but its single agent response rate failed to meet the pre-specified primary endpoint of interest.