Note on simultaneous inferences about non-inferiority and superiority for a primary and a secondary endpoint

2011 ◽  
Vol 53 (6) ◽  
pp. 927-937 ◽  
Author(s):  
Olivier Guilbaud
Keyword(s):  
Secondary Endpoint ◽  
Simultaneous Inferences

REDUCE-IT: outcomes by baseline statin type

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Bhatt ◽  
M Miller ◽  
P.G Steg ◽  
E.A Brinton ◽  
T.A Jacobson ◽  
...  
Keyword(s):  
Statin Therapy ◽  
Risk Reduction ◽  
Coronary Revascularization ◽  
Secondary Endpoint ◽  
Nonfatal Stroke ◽  
Funding Source ◽  
Icosapent Ethyl ◽  
Prescription Form ◽  
One Year ◽  
The Impact

Abstract Background REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) randomized 8,179 statin-treated patients with elevated triglycerides and increased cardiovascular (CV) risk to either icosapent ethyl (IPE), a pure, stable prescription form of eicosapentaenoic acid, 4g/day or placebo. IPE significantly reduced time to first occurrence of the primary composite endpoint of major adverse CV events (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) (HR 0.75, CI 0.68–0.83) and key secondary endpoint events (composite of CV death, nonfatal MI, or nonfatal stroke) (HR 0.74, CI 0.65–0.83) versus placebo (all p<0.0001). A modest reduction in placebo-corrected LDL-C was observed (−6.6%; p<0.0001). The mechanisms for the CV benefit of icosapent ethyl are not fully understood. Purpose Explore the impact of statin type and lipophilic/lipophobic category on outcomes, and on LDL-C, to further consider the possible relevance of LDL-C pathways to the observed CV benefit of icosapent ethyl. Methods Primary and key secondary endpoint analyses and LDL-C changes from baseline were explored by individual statin type (atorvastatin, simvastatin, rosuvastatin, or pravastatin) at baseline, and then by categorizing these statins into lipophilic (i.e., hydrophobic: atorvastatin, simvastatin) and lipophobic (i.e., hydrophilic: rosuvastatin, pravastatin) statin groups; 96.1% of patients fell within these individual statin groups. Results CV outcomes were similar across statin types (interaction p=0.61) and lipophilic/lipophobic categories (interaction p=0.51) (Figure). Statin type and category had a similar lack of meaningful impact on the modest placebo-corrected median LDL-C changes from baseline to one year, which ranged from −5.8 to −8.4% (all p≤0.0003). Conclusion No meaningful treatment differences in the primary or key secondary endpoints across statin type or lipophilic/lipophobic category were observed. A similar lack of treatment difference was observed in LDL-C changes from baseline to one year. Therefore, the LDL-C changes and CV risk reduction in REDUCE-IT appear independent of the type of concomitant statin therapy. These data provide clinicians with additional insight regarding concomitant statin therapy considerations when prescribing icosapent ethyl and suggest there are important mechanisms of action for the substantial CV risk reduction observed with icosapent ethyl that are distinct from the LDL receptor pathway. Funding Acknowledgement Type of funding source: Other. Main funding source(s): The study was funded by Amarin Pharma, Inc.

P1-263: Secondary endpoint and responder analyses in a study of rosiglitazone XR in APOE4-stratified subjects with mild-to-moderate Alzheimer's disease

2009 ◽  
Vol 5 (4S_Part_8) ◽  
pp. P254-P254 ◽  
Author(s):  
Claire Alderton ◽  
Marina Zvartau-Hind ◽  
Sally Ritchie ◽  
Ann Saunders ◽  
Suzanne Craft ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Secondary Endpoint

Abstract 15091: Significant Reductions in Both Adjudicated and Investigator-Reported Ischemic Events in REDUCE-IT

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Deepak L Bhatt ◽  
Robert Giugliano ◽  
Philippe G Steg ◽  
Michael Miller ◽  
Eliot A Brinton ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Coronary Revascularization ◽  
Hazard Ratio ◽  
Secondary Endpoint ◽  
Icosapent Ethyl ◽  
Clinical Events ◽  
High Degree ◽  
Ischemic Events ◽  
Fatal Myocardial Infarction

Introduction: REDUCE-IT was an event-driven trial that randomized 8,179 statin-treated patients with controlled LDL-C and moderately elevated triglycerides to icosapent ethyl (IPE) 4g daily or placebo, with a median of 4.9 years of follow-up. There was a significant reduction in the prespecified adjudicated rates of the primary endpoint (cardiovascular [CV] death, non-fatal myocardial infarction [MI], non-fatal stroke, coronary revascularization, and unstable angina requiring hospitalization) and of the key secondary endpoint (CV death, MI, stroke), as well as in all the primary endpoint components. We sought to determine the effect of IPE on investigator-reported events. Methods: The Clinical Endpoint Committee (CEC) blindly adjudicated investigator-reported events according to a prespecified charter. Medical records and reports were also reviewed to assess for clinical events not reported by investigators. An endpoint management team compiled and electronically provided event packets to the CEC via an adjudication database. The CEC Chair provided final adjudication if the two primary adjudicators could not reach consensus. Results: IPE significantly reduced the rate of the primary endpoint (hazard ratio 0.74, p=0.0000000002) and the key secondary endpoint (hazard ratio 0.75, p=0.000007) as reported by the site investigators, with consistent benefits in each component of the primary endpoint (Table). There was a high degree of concordance between investigator-reported and adjudicated endpoints. Conclusions: Icosapent ethyl significantly reduced multiple types of ischemic events, both by independent, blinded adjudication as well as by investigator-reported assessment. These results underscore the robustness of the benefits of icosapent ethyl seen in REDUCE-IT.

P5639Risk stratification for mortality using electrocardiographic markers based on 24-hour holter recordings: the JANIES-SHD study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Kinoshita ◽  
K Hashimoto ◽  
K Yoshioka ◽  
Y Miwa ◽  
K Yodogawa ◽  
...  
Keyword(s):  
Heart Disease ◽  
Risk Stratification ◽  
Primary Endpoint ◽  
Left Ventricular ◽  
Hazard Ratio ◽  
Secondary Endpoint ◽  
Cardiac Mortality ◽  
Holter Ecg ◽  
All Cause Mortality ◽  
Holter Recordings

Abstract Background Recent guidelines have stated that reduced left ventricular ejection fraction (LVEF) is the gold standard marker for identifying patients at risk for cardiac mortality. Although reduced LVEF identifies patients at an increased risk of cardiac arrest, sudden cardiac deaths (SCDs) occur considerably more often in patients with relatively preserved LVEF. Current guidelines on SCD risk stratification do not adequately cover this general population pool. Several noninvasive electrocardiographic (ECG) risk stratifiers that reflect depolarization abnormality, repolarization abnormality, and autonomic imbalance have been evaluated so far. With current therapeutic advances using new medicines or devices, an LVEF is often preserved in patients with structural heart disease (SHD). However, the usefulness of noninvasive ECG markers for risk stratification in such a patient population has not yet been elucidated. Purpose This study aimed to assess clinical indices and ECG markers based on 24-hour Holter ECG recordings for predicting cardiac mortality in patients with SHD who have left ventricular dysfunction (LVD) but relatively preserved LVEF. Methods In total, 1,829 patients were enrolled into the Japanese Multicenter Observational Prospective Study (JANIES study). In this study, we analyzed data of 719 patients (569 men, age 64±13 years) with SHD including mainly ischemic heart disease (65.8%). As ECG markers based on 24-hour Holter recordings, nonsustained ventricular tachycardia (NSVT), ventricular late potentials, and heart rate turbulence (HRT) were assessed. The primary endpoint was all-cause mortality, and the secondary endpoint was fatal arrhythmic events. Results During a mean follow-up of 21±11 months, all-cause mortality was eventually observed in 39 patients (5.4%). Among those patients, 32 patients (82%) suffered from cardiac causes such as heart failure and arrhythmia. Multivariate Cox regression analysis showed that after adjustment for age and LVEF, documented NSVT (hazard ratio=2.82, 95% confidence interval [CI]: 1.38–5.76, P=0.005) and abnormal HRT (hazard ratio=2.31, 95% CI: 1.15–4.65, P=0.02) were significantly associated with the primary endpoint. These two ECG markers also had significant predictive values with the secondary endpoint. The combined assessment documented NSVT and abnormal HRT improved predictive accuracy. Conclusion This study demonstrated that combined assessment of documented NSVT and abnormal HRT based on 24-hour Holter ECG recordings are recommended for predicting future serious events in SHD patients who have relatively preserved LVEF. Acknowledgement/Funding Grants-in-Aid (21590909, 24591074, and 15K09103 to T.I.) for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technol

Prognostic value of left ventricular remodelling index in idiopathic dilated cardiomyopathy

2020 ◽  
Author(s):  
Yuanwei Xu ◽  
Jiayi Lin ◽  
Yaodan Liang ◽  
Ke Wan ◽  
Weihao Li ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Dilated Cardiomyopathy ◽  
Primary Endpoint ◽  
Prognostic Value ◽  
Extracellular Volume ◽  
Left Ventricular ◽  
Secondary Endpoint ◽  
Idiopathic Dilated Cardiomyopathy ◽  
All Cause Mortality ◽  
Secondary Endpoints

Abstract Aims To evaluate the prognostic value of left ventricular (LV) remodelling index (RI) in idiopathic dilated cardiomyopathy (DCM) patients. Methods and results We prospectively enrolled 412 idiopathic DCM patients and 130 age- and sex-matched healthy volunteers who underwent cardiovascular magnetic resonance imaging between September 2013 and March 2018. RI was defined as the cubic root of the LV end-diastolic volume divided by the mean LV wall thickness on basal short-axis slice. The primary endpoint included all-cause mortality and heart transplantation. The secondary endpoint included the primary endpoint and heart failure (HF) readmission. During the median follow-up of 28.1 months (interquartile range: 19.3–43.0 months), 62 (15.0%) and 143 (34.7%) patients reached the primary and secondary endpoints, respectively. Stepwise multivariate Cox regression showed that RI [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.11–1.30, P < 0.001], late gadolinium enhancement (LGE) presence and log (N-terminal pro-B-type natriuretic peptide) were independent predictors of the primary endpoint, while RI (HR 1.15, 95% CI 1.08–1.23, P < 0.001) and extracellular volume were independent predictors of the secondary endpoint. The addition of RI to LV ejection fraction (EF) and LGE presence showed significantly improved global χ2 for predicting primary and secondary endpoints (both P < 0.001). Furthermore, RI derived from echocardiography also showed independent prognostic value for primary and secondary endpoints with clinical risk factors. Conclusions RI is an independent predictor of all-cause mortality, heart transplantation, and HF readmission in DCM patients and provides incremental prognostic value to LVEF and LGE presence.

scholarly journals P6419Machine learning in critical care: the role of diabetes and age in acute coronary syndromes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Cenko ◽  
M Van Der Schaar ◽  
J Yoon ◽  
Z Vasiljevic ◽  
S Kedev ◽  
...  
Keyword(s):  
Medical Treatment ◽  
Primary Endpoint ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Secondary Endpoint ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Patients With Diabetes ◽  
The Impact

Abstract Background Patients with diabetes and non-ST elevation acute coronary syndrome (NSTE-ACS) have an increased risk of mortality and adverse outcomes following percutaneous coronary intervention (PCI). Purpose We aimed to investigate the impact of early, within 24 hours PCI compared with only routine medical treatment on clinical outcomes in a large international cohort of patients with NSTE-ACS and diabetes. Methods We identified 1,250 patients with diabetes and NSTE-ACS from a registry-based population between October 2010 and April 2016. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was the composite outcome of 30-day all-cause mortality and left ventricular dysfunction (ejection fraction <40%). We undertook analyses to explore the heterogeneity of treatment effects using meta-classification (MC) algorithms followed by propensity score matching and inverse-probability-of-treatment weighting (IPTW) from a landmark of 24 hours from hospitalization. Results Of 1,250 NSTE-ACS first-day survivors with diabetes (median age 67 years; 59%, men), 470 (37.6%) received early PCI and 780 routine medical treatment. The overall 30-day all-cause mortality rates were higher in the routine medical treatment than the early PCI group (6.3% vs. 2.5%). The prediction results of the MC algorithms accounted for only one interaction term that was statistically significant: age ≥65 years. After propensity-matched analysis as well as IPTW, early PCI was associated with reduced 30-day all-cause mortality in the older age (OR: 0.35; 95% CI: 0.14 to 0.92 and 0.43; 95% CI: 0.21 to 0.86, respectively), whereas younger age had no association with the primary endpoint. Similar results were also obtained for the secondary endpoint. Conclusions Among patients with diabetes hospitalized for NSTE-ACS, an early, within 24 hours, PCI strategy is associated with reduced odds of 30-day mortality only for patients aged 65 years or over. MC algorithms provide accurate identification of treatment effect modifiers.

scholarly journals CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933

2015 ◽  
Vol 126 (2) ◽  
pp. 327-336 ◽  
Author(s):  
Chip Caine ◽  
Snehal Deshmukh ◽  
Vinai Gondi ◽  
Minesh Mehta ◽  
Wolfgang Tomé ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Secondary Endpoint ◽  
Memory Tests
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