Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Considerations in testing treatment effects on transient event driven health status changes measured by patient reported outcomes.

Many treatments and drugs are intended to reduce the occurrence of negative events of interest, control the severity of the events, accelerate recovery from the events, or a combination of these effects. While assessing the clinical effect is typically the primary objective of a trial, testing the treatment effect on the health status of patients based on patient reported outcome (PRO) can be a useful component in determining the value of a treatment. Analysis of PROs in this setting, however, face the following challenges: the PRO value immediately after the event occurrence is often not captured, and the effect of the event on health status measured by the PRO is transient as subjects recover over time. Therefore, traditional statistical methods used to assess treatment effects suffer from low power for PROs. In this manuscript, we apply a kernel smoothing technique to estimate before- and after-event PRO values. We also propose new test outcomes based on observed and estimated PRO values and evaluate tests that focus on the tail distributions. We demonstrate that the tail distribution tests using the new outcomes can achieve high power under certain conditions.

Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.

BACKGROUND: Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We conducted two extension studies to obtain longer-term data. METHODS: In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined. RESULTS: As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003). CONCLUSIONS: During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.).

Discrete choice experiment to estimate breast cancer patients' preferences and willingness to pay for prophylactic granulocyte colony-stimulating factors.

OBJECTIVES: Rising out-of-pocket costs for cancer patients have increased shared decision making. Clinical guidelines recommend prophylactic granulocyte colony-stimulating factor (G-CSF) for patients receiving chemotherapy with a 20% or greater risk of febrile neutropenia. A discrete choice experiment was conducted to explore breast cancer patients' preferences and willingness to pay (WTP) for prophylactic G-CSF to decrease the risk of chemotherapy-induced febrile neutropenia. METHODS: An online discrete choice experiment questionnaire survey of a national US convenience sample of self-reported breast cancer patients with prior chemotherapy treatment was conducted. Sixteen paired G-CSF treatment scenarios, each with four attributes (risk of disruption to chemotherapy schedule due to low white blood cell counts, risk of developing an infection requiring hospitalization, frequency of administration, and total out-of-pocket cost) were presented with a follow-up "no treatment" option. Participant preferences and WTP out of pocket were estimated by logistic regression. RESULTS: Participants (n = 296) preferred G-CSF regimens with lower out-of-pocket costs, lower risk of chemotherapy disruption, lower risk of infection, and greater convenience (one G-CSF injection per chemotherapy cycle). Participants' WTP was $1076 out of pocket per cycle to reduce the risk (high to low) of disrupting their chemotherapy schedule, $884 per cycle to reduce the risk (24% [high] to 7% [low]) of infection, and $851 per cycle to decrease the number of G-CSF injections (11 to 1) per cycle. CONCLUSIONS: Participants highly valued specific features of prophylactic G-CSF treatment including maintaining their chemotherapy schedule, lowering their risk of infection, and reducing the number of injections. Physicians should consider patient preferences to inform the best treatment choices for individual patients.

Incidence, treatment, and consequences of chemotherapy-induced febrile neutropenia in the inpatient and outpatient settings.

OBJECTIVE: To examine the incidence, treatment, and consequences of febrile neutropenia across inpatient and outpatient care settings. METHODS: Data were obtained from Humedica's National Electronic Health Record-Derived Longitudinal Patient-Level Database (2007-2010). The study population included adult patients who received myelosuppressive chemotherapy for a solid tumor or non-Hodgkin's lymphoma. For each patient, each chemotherapy regimen course and each cycle within each regimen course was characterized. Febrile neutropenia episodes were identified on a cycle-specific basis based on any of the following: (1) absolute neutrophil count <1.0 × 10(9)/L and evidence of infection or fever; (2) inpatient diagnosis of neutropenia, fever, or infection; (3) outpatient diagnosis of neutropenia and non-prophylactic antimicrobial use; or (4) mention of febrile neutropenia in physician notes. Febrile neutropenia episodes were categorized as inpatient or outpatient based on the initial setting of care (i.e. acute-care inpatient facility vs. ambulatory care facility). Febrile neutropenia consequences included hospital length of stay and mortality (inpatient cases only), as well as number of febrile neutropenia-related outpatient encounters. RESULTS: Among the 2131 patients in this study, 401 experienced a total of 458 febrile neutropenia episodes. Risk of febrile neutropenia during the chemotherapy regimen course was 16.8% (95% CI: 15.3, 18.4). In cycle 1 alone, risk of febrile neutropenia was 8.1% (7.1, 9.3). Most febrile neutropenia episodes (83.2%) were initially treated in the inpatient setting; the hospital mortality rate was 8.1% (5.8, 11.1), and mean hospital length of stay was 8.4 days (7.7, 9.1). Among febrile neutropenia episodes initially treated in the outpatient setting (16.8%), the mean number of outpatient management encounters was 2.6 (2.1, 3.1), most of which were in the physician's office (69.2%) or emergency department (26.9%). CONCLUSIONS: Febrile neutropenia remains a common occurrence among patients receiving myelosuppressive chemotherapy and typically results in extended hospitalization and, for many patients, death. A minority of patients are, however, treated exclusively on an outpatient basis.

Risk and consequences of chemotherapy-induced neutropenic complications in patients receiving daily filgrastim: the importance of duration of prophylaxis.

BACKGROUND: To examine duration of daily filgrastim prophylaxis, and risk and consequences of chemotherapy-induced neutropenic complications (CINC) requiring inpatient care. METHODS: Using a retrospective cohort design and US healthcare claims data (2001-2010), we identified all cancer patients who initiated ≥1 course of myelosuppressive chemotherapy and received daily filgrastim prophylactically in ≥1 cycle. Cycles with daily filgrastim prophylaxis were pooled for analyses. CINC was identified based on hospital admissions with a diagnosis of neutropenia, fever, or infection; consequences were characterized in terms of hospital mortality, hospital length of stay (LOS), and CINC-related healthcare expenditures. RESULTS: Risk of CINC requiring inpatient care-adjusted for patient characteristics-was 2.4 (95% CI: 1.6-3.4) and 1.9 (1.3-2.8) times higher with 1-3 (N = 8371) and 4-6 (N = 3691) days of filgrastim prophylaxis, respectively, versus ≥7 days (N = 2226). Among subjects who developed CINC, consequences with 1-3 and 4-6 (vs. ≥7) days of filgrastim prophylaxis were: mortality (8.4% [n/N = 10/119] and 4.0% [3/75] vs. 0% [0/34]); LOS (means: 7.4 [N = 243] and 7.1 [N = 99] vs. 6.5 [N = 40]); and expenditures (means: $18,912 [N = 225] and $14,907 [N = 94] vs. $13,165 [N = 39]). CONCLUSIONS: In this retrospective evaluation, shorter courses of daily filgrastim prophylaxis were found to be associated with an increased risk of CINC as well as poorer outcomes among those developing this condition. Because of the limitations inherent in healthcare claims databases specifically and retrospective evaluations generally, additional research addressing these limitations is needed to confirm the findings of this study.

Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial.

IMPORTANCE: In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. OBJECTIVE: To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. DESIGN, SETTING, AND PATIENTS: Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. INTERVENTIONS: Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. MAIN OUTCOMES AND MEASURES: Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. RESULTS: Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). CONCLUSIONS AND RELEVANCE: In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01763866.

Hemoglobin decline in cancer patients receiving chemotherapy without an erythropoiesis-stimulating agent.

PURPOSE: The aim of this study was to examine the rate and timing of hemoglobin decline from <10 g/dL to <9 g/dL in cancer patients receiving chemotherapy. METHODS: Pooled data from the placebo arms of six randomized, controlled trials (RCTs) of darbepoetin alfa and data from an aggregated US community oncology clinic electronic medical records (EMR) database were analyzed. Patients had baseline hemoglobin ≥10 g/dL (RCTs) or baseline hemoglobin between ≥10 g/dL and <11 g/dL (EMR episodes) that declined to <10 g/dL at least once during the study period. The proportion of patients/episodes with hemoglobin decline to <9 g/dL by 3, 6, and 9 weeks without erythropoiesis-stimulating agents was estimated from data in each of the data sources, as was the rate of transfusions in the RCTs. RESULTS: Data from 411 patients receiving placebo in the RCTs and 10,523 patients (10,942 episodes) in the EMR database were analyzed. Forty percent and 35 % of RCT patients and EMR episodes, respectively, had a hemoglobin decline from <10 g/dL to <9 g/dL at week 3, 54 % and 43 % at week 6, and 58 % and 46 % at week 9. Of patients in the RCTs, 43 % required an RBC transfusion. CONCLUSIONS: Hemoglobin can rapidly decline in cancer patients receiving chemotherapy with hemoglobin levels around 10 g/dL, particularly in patients ≥65 years of age. The rapid rate of hemoglobin decline in these patients should be considered for optimal anemia management.

Technical evaluation of methods for identifying chemotherapy-induced febrile neutropenia in healthcare claims databases.

BACKGROUND: Healthcare claims databases have been used in several studies to characterize the risk and burden of chemotherapy-induced febrile neutropenia (FN) and effectiveness of colony-stimulating factors against FN. The accuracy of methods previously used to identify FN in such databases has not been formally evaluated. METHODS: Data comprised linked electronic medical records from Geisinger Health System and healthcare claims data from Geisinger Health Plan. Subjects were classified into subgroups based on whether or not they were hospitalized for FN per the presumptive "gold standard" (ANC <1.0×10(9)/L, and body temperature ≥38.3°C or receipt of antibiotics) and claims-based definition (diagnosis codes for neutropenia, fever, and/or infection). Accuracy was evaluated principally based on positive predictive value (PPV) and sensitivity. RESULTS: Among 357 study subjects, 82 (23%) met the gold standard for hospitalized FN. For the claims-based definition including diagnosis codes for neutropenia plus fever in any position (n=28), PPV was 100% and sensitivity was 34% (95% CI: 24-45). For the definition including neutropenia in the primary position (n=54), PPV was 87% (78-95) and sensitivity was 57% (46-68). For the definition including neutropenia in any position (n=71), PPV was 77% (68-87) and sensitivity was 67% (56-77). CONCLUSIONS: Patients hospitalized for chemotherapy-induced FN can be identified in healthcare claims databases--with an acceptable level of mis-classification--using diagnosis codes for neutropenia, or neutropenia plus fever.

Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF.

A central factor in the pathogenesis of heart failure (HF) with reduced ejection fraction is the initial decrease in systolic function. Prior attempts at increasing cardiac contractility with oral drugs have uniformly resulted in signals of increased mortality at pharmacologically effective doses. Omecamtiv mecarbil is a novel, selective cardiac myosin activator that has been shown to improve cardiac function and to decrease ventricular volumes, heart rate, and N-terminal pro-B-type natriuretic peptide in patients with chronic HF. The GALACTIC-HF (Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure) trial tests the hypotheses that omecamtiv mecarbil can safely improve symptoms, prevent clinical HF events, and delay CV death in patients with chronic HF. The GALACTIC-HF trial is an international, multicenter, randomized, double-blind, placebo-controlled, event-driven cardiovascular outcomes trial. More than 8,000 patients with chronic symptomatic (New York Heart Association functional class II to IV) HF, left ventricular ejection fraction ≤35%, elevated natriuretic peptides, and either current hospitalization for HF or history of hospitalization or emergency department visit for HF within a year of screening will be randomized to either oral placebo or omecamtiv mecarbil employing a pharmacokinetic-guided dose titration strategy using doses of 25, 37.5, or 50 mg twice daily. The primary efficacy outcome is the time to cardiovascular death or first HF event. The study has 90% power to assess a final hazard ratio of approximately 0.80 in cardiovascular death, the first secondary outcome. The GALACTIC-HF trial is the first trial examining whether selectively increasing cardiac contractility in patients with HF with reduced ejection fraction will result in improved clinical outcomes. (Registrational Study With Omecamtiv Mecarbil/AMG 423 to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction: GALACTIC-HF baseline characteristics and comparison with contemporary clinical trials.

AIMS: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is being tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial. Here we describe the baseline characteristics of participants in GALACTIC-HF and how these compare with other contemporary trials. METHODS AND RESULTS: Adults with established HFrEF, New York Heart Association (NYHA) functional class ≥II, ejection fraction ≤35%, elevated natriuretic peptides and either current hospitalization for heart failure or history of hospitalization/emergency department visit for heart failure within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic-guided dosing: 25, 37.5, or 50 mg bid). A total of 8256 patients [male (79%), non-white (22%), mean age 65 years] were enrolled with a mean ejection fraction 27%, ischaemic aetiology in 54%, NYHA class II 53% and III/IV 47%, and median N-terminal pro-B-type natriuretic peptide 1971 pg/mL. Heart failure therapies at baseline were among the most effectively employed in contemporary heart failure trials. GALACTIC-HF randomized patients representative of recent heart failure registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure <100 mmHg (n = 1127), estimated glomerular filtration rate <30 mL/min/1.73 m2 (n = 528), and treated with sacubitril/valsartan at baseline (n = 1594). CONCLUSIONS: GALACTIC-HF enrolled a well-treated, high-risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation.

Comparison of LDL-C Reduction Using Different Evolocumab Doses and Intervals: Biological Insights and Treatment Implications.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduces low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular events. OBJECTIVES: To compare LDL-C reduction using evolocumab 140 mg once every 2 weeks (Q2W) or 420 mg monthly (QM) versus lower doses (70 mg Q2W or 280 mg QM) or placebo. METHODS: Patients received evolocumab 70 or 140 mg Q2W, 280 or 420 mg QM, or placebo Q2W or QM in two 12-week phase 2 studies: one with and one without statins. Changes from baseline in LDL-C were compared across Q2W doses and across QM doses. RESULTS: The analysis included 741 patients. Mean (95% confidence interval [CI]) reduction in LDL-C across Q2W visits through week 12 was 63.0% (60.3% to 65.7%) for evolocumab 140 mg Q2W, compared to 41.3% (38.6% to 44.0%) for 70 mg Q2W and 1.9% (4.6% reduction to 0.8% increase) for placebo Q2W (each P < .001 vs 140 mg Q2W), and 62.7% (60.1% to 65.3%) for 420 mg QM, compared to 55.5% (52.9% to 58.0%) for 280 mg QM and 2.5% (5.1% reduction to 0.1% increase) for placebo QM (each P < .001 vs 420 mg QM). Similar results were observed at the mean of weeks 10 and 12. In a subgroup (n = 151) with weekly assessments from weeks 8 to 12, mean (95% CI) peak effect on LDL-C reduction was 72.8% (67.7% to 77.9%) for 140 mg Q2W and 69.0% (63.6% to 74.3%) for 420 mg QM. Trough effect at week 12 underestimated LDL-C reduction. Median peak-trough variability was 20.5%, 21.1%, 31.9%, and 35.1% for evolocumab 140 mg Q2W, 420 mg QM, 70 mg Q2W, and 280 mg QM, respectively. CONCLUSION: Evolocumab 140 mg Q2W and 420 mg QM yielded similar LDL-C reduction. These doses sustained maximal LDL-C reduction, resulting in greater stability in LDL-C reduction over the dosing interval compared to lower doses. These results support evolocumab doses of either 140 mg Q2W or 420 mg QM.

Evolocumab lowers LDL-C safely and effectively when self-administered in the at-home setting.

Evolocumab has been shown to consistently reduce low-density lipoprotein cholesterol (LDL-C) across populations. The phase 3 studies included administration in the home-use and in-clinic settings but did not specifically evaluate the feasibility of home-use administration. Two clinical studies enrolled patients with hypercholesterolemia or mixed dyslipidemia on statin therapy and with/without ezetimibe received evolocumab in the home-use setting. Patients were randomized to self-administer evolocumab using one of two injection devices biweekly over 6 weeks (autoinjector or prefilled syringe; n = 149; ClinicalTrials.gov, NCT01849497) or monthly over 12 weeks (autoinjector or automated minidoser; n = 164; NCT01879319). The first self-administration occurred in the in-clinic setting, and two more were performed in the at-home setting. Patients were successful in self-administering evolocumab in the home-use setting in approximately 95 % of attempts and experienced LDL-C reductions from baseline to week 6 or the mean of weeks 10 and 12 of approximately 65 %. Rates of successful self-administration and LDL-C reduction were similar across dosing schedules and study devices. Adverse events were similar between randomized groups and generally mild in severity. In two clinical studies, therefore, patients were able to successfully self-administer evolocumab in both the in-clinic and at-home settings regardless of which dosing schedule or device they used.

Assessing patients' risk of febrile neutropenia: is there a correlation between physician-assessed risk and model-predicted risk?

This study evaluated the correlation between the risk of febrile neutropenia (FN) estimated by physicians and the risk of severe neutropenia or FN predicted by a validated multivariate model in patients with nonmyeloid malignancies receiving chemotherapy. Before patient enrollment, physician and site characteristics were recorded, and physicians self-reported the FN risk at which they would typically consider granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (FN risk intervention threshold). For each patient, physicians electronically recorded their estimated FN risk, orders for G-CSF primary prophylaxis (yes/no), and patient characteristics for model predictions. Correlations between physician-assessed FN risk and model-predicted risk (primary endpoints) and between physician-assessed FN risk and G-CSF orders were calculated. Overall, 124 community-based oncologists registered; 944 patients initiating chemotherapy with intermediate FN risk enrolled. Median physician-assessed FN risk over all chemotherapy cycles was 20.0%, and median model-predicted risk was 17.9%; the correlation was 0.249 (95% CI, 0.179-0.316). The correlation between physician-assessed FN risk and subsequent orders for G-CSF primary prophylaxis (n = 634) was 0.313 (95% CI, 0.135-0.472). Among patients with a physician-assessed FN risk ≥ 20%, 14% did not receive G-CSF orders. G-CSF was not ordered for 16% of patients at or above their physician's self-reported FN risk intervention threshold (median, 20.0%) and was ordered for 21% below the threshold. Physician-assessed FN risk and model-predicted risk correlated weakly; however, there was moderate correlation between physician-assessed FN risk and orders for G-CSF primary prophylaxis. Further research and education on FN risk factors and appropriate G-CSF use are needed.

Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy.

Low-density lipoprotein cholesterol (LDL-C) levels are significantly associated with atherosclerotic cardiovascular disease (ASCVD) risk, and studies using interventions that lower LDL-C levels have been shown to reduce the risk of ASCVD events and mortality. Statin treatment is the current first-line therapy for lowering LDL-C and reducing ASCVD risk. However, many patients are still unable to reach recommended LDL-C goals on maximally tolerated statin therapy. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. The aim of this phase 3 study is to evaluate the efficacy of 12 weeks of subcutaneous evolocumab (vs placebo) administered every 2 weeks or every month in combination with a statin in patients with hypercholesterolemia and mixed dyslipidemia. This study will also provide comparative efficacy, safety, and tolerability data between evolocumab and ezetimibe when added to background atorvastatin therapy.

A retrospective study of the clinical and economic burden during hospitalizations among cancer patients with febrile neutropenia.

OBJECTIVE: The objective of this study was to provide up-to-date estimates of the clinical and economic burden that occurs during inpatient treatment of cancer patients with febrile neutropenia (FN). METHODS: A retrospective cohort study was conducted using 2007-2010 hospital discharge data from the Premier database. The study population included adult patients with discharge diagnoses of neutropenia (ICD-9 code 288.0x) with fever or infection and receipt of intravenous antibiotics and female breast cancer, lung cancer, colorectal cancer, ovarian cancer, non-Hodgkin lymphoma (NHL), or Hodgkin lymphoma. Primary study outcomes were inpatient mortality, hospital length of stay (LOS), and total hospitalization cost for each patient's first FN-related hospitalization. Logistic regressions (for mortality) and multivariate linear regressions (for LOS and cost) were conducted to assess the effect of comorbidities and infection types on study outcomes, adjusting for other patient and hospital characteristics. RESULTS: Among 16,273 cancer patients hospitalized with FN, the inpatient case fatality rate was 10.6%, mean LOS was 8.6 days, and mean total hospitalization cost was $18,880. Lung cancer patients had the highest inpatient case fatality rate (15.7%), and NHL patients had the longest LOS (10.1 days) and the highest cost ($24,218). Multivariate analyses showed that most comorbidities were associated with a greater risk of mortality, longer LOS, and higher cost. Septicemia/bacteremia and pneumonia were associated with a greater risk of mortality, and most types of infection were associated with a longer LOS and higher cost. LIMITATIONS: The total burden of FN may be under-estimated in this study because outpatient treatment and any patient deaths or costs that occurred outside of Premier hospitals could not be captured. CONCLUSIONS: FN-related hospitalizations among cancer patients are costly and accompanied by considerable mortality risk. Substantial differences in the clinical and economic burden of FN exist depending on cancer types, comorbidities, and infection types.

Staff time and motion assessment for administration of erythropoiesis-stimulating agents: a two-phase pilot study in clinical oncology practices.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are used for the management of anaemia in patients with non-myeloid malignancies where anaemia is due to the effect of concomitant myelosuppressive chemotherapy. Assessing the impact of different ESA dosing regimens on office staff time and projected labour costs is an important component of understanding the potential for optimization of oncology practice efficiencies. OBJECTIVES: A two-phase study was conducted to evaluate staff time and labour costs directly associated with ESA administration in real-world oncology practice settings among cancer patients undergoing chemotherapy. The objective of Phase 1 was to determine the mean staff time required for the process of ESA administration in patients with anaemia due to concomitantly administered chemotherapy. The objective of Phase 2 was to quantify and compare the mean staff time and mean labour costs of ESA administered once weekly (qw) with ESA once every 3 weeks (q3w) over an entire course of chemotherapy. METHODS: Phase 1 was a prospective, cross-sectional time and motion study conducted in six private oncology practices in the US based on nine steps associated with ESA administration. Using findings from Phase 1, Phase 2 was conducted as a retrospective chart review to collect data on the number and types of visits in two private oncology practices for patients receiving a complete course of myelosuppressive chemotherapy. RESULTS: In Phase 1, the mean total time that clinic staff spent on ESA administration was 23.2 min for patient visits that included chemotherapy administration (n(chemo) = 37) and 21.5 min when only ESA was administered (n(ESAonly) = 36). In Phase 2, the mean duration of treatment was significantly longer for q3w than qw (53.84 days for qw vs. 113.38 for q3w, p < 0.0001); thus, analyses were adjusted using analysis of covariance (ANCOVA) for episode duration for between-group comparisons. Following adjustment by ANCOVA, qw darbepoetin alfa (DA) patients (n(qw) = 83) required more staff time for ESA + chemotherapy visits and ESA-only visits than q3w patients (n(q3w) = 118) over a course of chemotherapy. Overall, mean total staff time expended per chemotherapy course was greater for patients receiving qw versus q3w DA. Weekly DA dosing was associated with greater projected mean labour costs ($US38.16 vs. $US31.20 [average for 2007-2010]). CONCLUSIONS: The results from this real-world study demonstrate that oncology practices can attain staff time and labour costs savings through the use of q3w ESA. The degree of savings depends on the individual oncology practice's staffing model and ESA administration processes, including those that allow for optimized synchronization of patient visits for ESA and chemotherapy administration. These findings indicate that additional research using standard ESA administration protocols for longer periods of time with a larger number of oncology practices and patients should be conducted to confirm these findings.

Trends in neutropenia-related inpatient events.

PURPOSE: Neutropenic complications (NCs) after myelosuppressive chemotherapy are associated with significant morbidity and mortality. We described NC rates by using US hospital discharge data. MATERIALS AND METHODS: This cross-sectional analysis used data from the US National Inpatient Sample database. Hospital discharges with cancer diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code) from 1989 to 2007 were analyzed for the ICD-9-CM neutropenia code. NC rates per 10,000 discharges were calculated for all adult discharges without radiation therapy (study population, all cancers); lung cancer, breast cancer, and non-Hodgkin's lymphoma (NHL); and all three combined. The use of growth factors and myelosuppressive chemotherapy from 1994 to 2008 was estimated by using the IMS Health Drug Distribution Database. RESULTS: Estimated lung cancer and breast cancer discharges remained relatively steady, whereas NHL discharges increased. NC rates for each study cancer increased two-fold until the late 1990s before stabilizing and/or declining. The average hospital stay for all three cancers decreased from 10.4 days to 7.1 days. The mortality rates for NCs for the three cancers combined decreased at a fairly constant rate from 10% in 1989 to 5.4% in 2007. Estimated discharges for NCs from 1989 to 2007 ranged from 111,000 to 169,000 for the study population, from 57,000 to 103,000 for all cancers, and from 21,000 to 40,000 for the three study cancers. The use of growth factors and myelosuppressive chemotherapy increased from 1994 to 2008. CONCLUSION: Whereas the number of hospitalizations with cancer diagnoses has remained steady since 1989, hospitalizations for NCs increased approximately two-fold from 1989 to 1997 and then stabilized.

Transfusion risk in cancer patients with chemotherapy-induced anemia when initiating darbepoetin alfa therapy at a baseline hemoglobin level of <9 g/dL versus 9 to <10 g/dL versus ≥ 10 g/dL: an exploratory analysis of a phase 3 trial.

Darbepoetin alfa (DA) is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anemia (CIA). Safety concerns have prompted changes to the ESA-product information, which now recommends initiating ESAs at hemoglobin (Hb) levels < 10 g/dL (US) or ≤ 10 g/dL (EU). The present exploratory analysis of a DA trial examined how baseline-Hb levels at ESA initiation affect transfusion rates, Hb response, and safety outcomes in CIA patients. Data were retrospectively analyzed from a phase 3 trial of CIA patients randomised to 500 mcg DA every 3 weeks (Q3 W) or to 2.25 mcg/kg DA weekly (QW) for 15 weeks. In the current analysis, data were reanalyzed by baseline-Hb categories of <9 g/dL (n = 126), 9 to <10 g/dL (n = 225), and ≥ 10 g/dL (n = 354). The Q3 W and QW groups were combined. Transfusion rates were highest in the <9 g/dL baseline-Hb group in all time periods examined. The Kaplan-Meier percentage (95% CI) of patients achieving Hb ≥ 10 g/dL was 68% (59, 78) and 88% (82, 92) in the <9 g/dL and 9 to <10 g/dL baseline-Hb groups, respectively. With lower baseline-Hb, incidence of a ≥ 1 g/dL-Hb rise in 14 days progressively decreased. Incidence of venous thromboembolic events was similar in all baseline-Hb groups and similar between patients with or without a ≥ 1 g/dL-Hb rise in 14 days. Overall, transfusion risk increased and Hb response decreased at lower baseline-Hb levels in this exploratory analysis. When following ESA-product information to initiate ESAs at Hb ≤ 10 g/dL, the greatest benefit may be achieved when initiating close to 10 g/dL. Prospective studies are needed to further examine this hypothesis.