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.

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.

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.

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.

Granulocyte-colony stimulating factor use and medical costs after initial adjuvant chemotherapy in older patients with early-stage breast cancer.

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) reduces the risk of severe neutropenia associated with chemotherapy, but its cost implications following chemotherapy are unknown. OBJECTIVE: Our objective was to examine associations between G-CSF use and medical costs after initial adjuvant chemotherapy in early-stage (stage I-III) breast cancer (ESBC). METHODS: Women diagnosed with ESBC from 1999 to 2005, who had an initial course of chemotherapy beginning within 180 days of diagnosis and including ≥1 highly myelosuppressive agent, were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Medicare claims were used to describe the initial chemotherapy regimen according to the classes of agents used: anthracycline ([A]: doxorubicin or epirubicin); cyclophosphamide (C); taxane ([T]: paclitaxel or docetaxel); and fluorouracil (F). Patients were classified into four study groups according to their G-CSF use: (i) primary prophylaxis, if the first G-CSF claim was within 5 days of the start of the first chemotherapy cycle; (ii) secondary prophylaxis, if the first claim was within 5 days of the start of the second or subsequent cycles; (iii) G-CSF treatment, if the first claim occurred outside of prophylactic use; and (iv) no G-CSF. Patients were described by age, race, year of diagnosis, stage, grade, estrogen (ER) and progesterone (PR) receptor status, National Cancer Institute (NCI) Co-morbidity Index, chemotherapy regimen and G-CSF use. Total direct medical costs ($US, year 2009 values) to Medicare were estimated from 4 weeks after the last chemotherapy administration up to 48 months. Medical costs included those for ESBC treatment and all other medical services received after chemotherapy. Least squares regression, using inverse probability weighting (IPW) to account for censoring within the cohort, was used to evaluate adjusted associations between G-CSF use and costs. RESULTS: A total of 7026 patients were identified, with an average age of 72 years, of which 63% had stage II disease, and 59% were ER and/or PR positive. Compared with no G-CSF, those receiving G-CSF primary prophylaxis were more likely to have stage III disease (30% vs. 16%; p < 0.0001), to be diagnosed in 2003-5 (87% vs. 26%; p < 0.0001), and to receive dose-dense AC-T (26% vs. 1%; p < 0.0001), while they were less likely to receive an F-based regimen (12% vs. 42%; p < 0.0001). Overall, the estimated average direct medical cost over 48 months after initial chemotherapy was $US 42,628. In multivariate analysis, stage II or III diagnosis (compared with stage I), NCI Co-morbidity Index score 1 or ≥2 (compared with 0), or FAC or standard AC-T (each compared with AC) were associated with significantly higher IPW 48-month costs. Adjusting for patient demographic and clinical factors, costs in the G-CSF primary prophylaxis group were not significantly different from those not receiving primary prophylaxis (the other three study groups combined). In an analysis that included four separate study groups, G-CSF treatment was associated with significantly greater costs (incremental cost = $US 2938; 95% CI 285, 5590) than no G-CSF. CONCLUSIONS: Direct medical costs after initial chemotherapy were not statistically different between those receiving G-CSF primary prophylaxis and those receiving no G-CSF, after adjusting for potential confounders.

Use of electronic medical records (EMR) for oncology outcomes research: assessing the comparability of EMR information to patient registry and health claims data.

UNLABELLED: Electronic medical records (EMRs) are used increasingly for research in clinical oncology, epidemiology, and comparative effectiveness research (CER). OBJECTIVE: To assess the utility of using EMR data in population-based cancer research by comparing a database of EMRs from community oncology clinics against Surveillance Epidemiology and End Results (SEER) cancer registry data and two claims databases (Medicare and commercial claims). STUDY DESIGN AND SETTING: DEMOGRAPHIC, CLINICAL, AND TREATMENT PATTERNS IN THE EMR, SEER, MEDICARE, AND COMMERCIAL CLAIMS DATA WERE COMPARED USING SIX TUMOR SITES: breast, lung/bronchus, head/neck, colorectal, prostate, and non-Hodgkin's lymphoma (NHL). We identified various challenges in data standardization and selection of appropriate statistical procedures. We describe the patient and clinic inclusion criteria, treatment definitions, and consideration of the administrative and clinical purposes of the EMR, registry, and claims data to address these challenges. RESULTS: Sex and 10-year age distributions of patient populations for each tumor site were generally similar across the data sets. We observed several differences in racial composition and treatment patterns, and modest differences in distribution of tumor site. CONCLUSION: Our experience with an oncology EMR database identified several factors that must be considered when using EMRs for research purposes or generalizing results to the US cancer population. These factors were related primarily to evaluation of treatment patterns, including evaluation of stage, geographic location, race, and specialization of the medical facilities. While many specialty EMRs may not provide the breadth of data on medical care, as found in comprehensive claims databases and EMR systems, they can provide detailed clinical data not found in claims that are extremely important in conducting epidemiologic and outcomes research.

Use of latent growth curve models for assessing the effects of darbepoetin alfa on hemoglobin and fatigue.

BACKGROUND: The relationship between darbepoetin alfa and fatigue in chemotherapy-induced anemia (CIA) patients is complex because of patients receiving transfusions and the mediating effect of hemoglobin. Latent growth models (LGMs) were used to examine simultaneously relationships among drug exposure, fatigue outcomes, covariates, and mediating factors. METHODS: Data from four CIA studies (AMG 20010145: small cell lung cancer, n=547; AMG 980297: lung cancer, n=288; AMG 20000161: lymphoproliferative malignancies, n=339; AMG 20030232: non-myeloid malignancies, n=320) were analyzed separately. Patients reported fatigue using the FACT-Fatigue. The effect of darbepoetin alfa on FACT-F changes mediated through hemoglobin changes was examined with LGMs controlling for transfusions, age, sex, baseline ECOG performance status, and health status (EQ-5D VAS). Model fit was assessed using multiple indices including the comparative fit index (CFI). RESULTS: Darbepoetin alfa increased hemoglobin levels which were associated with decreases in fatigue. Increases in hemoglobin were statistically significantly (p<0.05) related to decreases in fatigue in the studies (AMG 20030145: beta=0.28; AMG 980297: beta=0.46; AMG 20000161: beta=0.59; and AMG 20030232: beta=0.39). Darbepoetin alfa statistically significantly increased hemoglobin (AMG 20010145:beta=0.50, AMG 980297:beta=0.53, AMG 20000161:beta=0.47, and AMG 20030232:beta=0.30) while controlling for covariates. Model fit was acceptable (CFI> or =0.89) in all studies. CONCLUSIONS: Results indicate LGMs may be a valuable statistical method for modeling complex relationships among clinical and patient reported outcomes. A statistically significant effect of darbepoetin alfa on fatigue change through hemoglobin change occurred across four studies, after modeling the effects of transfusions, age, sex, EQ-5D VAS and ECOG.