Clinical Endpoint Committee Research Articles

Sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients stratified according to use of mineralocorticoid receptor antagonists: Insight from the PARADISE MI trial.

It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

Endpoint adjudication in cardiovascular clinical trials.

Endpoint adjudication (EA) is a common feature of contemporary randomized controlled trials (RCTs) in cardiovascular medicine. Endpoint adjudication refers to a process wherein a group of expert reviewers, known as the clinical endpoint committee (CEC), verify potential endpoints identified by site investigators. Events that are determined by the CEC to meet pre-specified trial definitions are then utilized for analysis. The rationale behind the use of EA is that it may lessen the potential misclassification of clinical events, thereby reducing statistical noise and bias. However, it has been questioned whether this is universally true, especially given that EA significantly increases the time, effort, and resources required to conduct a trial. Herein, we compare the summary estimates obtained using adjudicated vs. non-adjudicated site designated endpoints in major cardiovascular RCTs in which both were reported. Based on these data, we lay out a framework to determine which trials may warrant EA and where it may be redundant. The value of EA is likely greater when cardiovascular trials have nuanced primary endpoints, endpoint definitions that align poorly with practice, sub-optimal data completeness, greater operator variability, and lack of blinding. EA may not be needed if the primary endpoint is all-cause death or all-cause hospitalization. In contrast, EA is likely merited for more nuanced endpoints such as myocardial infarction, bleeding, worsening heart failure as an outpatient, unstable angina, or transient ischaemic attack. A risk-based approach to adjudication can potentially allow compromise between costs and accuracy. This would involve adjudication of a small proportion of events, with further adjudication done if inconsistencies are detected.

Design and Rationale of the Safe Surveillance of PCI Under Mechanical Circulatory Support With the Saranas Early Bird Bleed Monitoring System (SAFE-MCS) Study.

High-risk percutaneous coronary intervention (PCI) with mechanical circulatory support (MCS) has been associated with varying rates of bleeding due to variable bleeding definitions, incomplete data relative to site-specific bleeding, and inclusion of variable patient populations. SAFE-MCS (NCT05077657) is a multicenter, single-arm, open-label study designed to evaluate the safety of complex high-risk PCI using Impella and surveillance with the Saranas Early Bird Bleed Monitoring System (EBBMS). The study aims to enroll 184 evaluable subjects at up to 15 US centers. The primary clinical end point is the incidence of access-site related BARC type III or V bleeding. Secondary clinical end points include the incidence of each of the Saranas EBBMS level 1, 2, and 3 indicators and the incidence of all BARC type III or V bleeding. Enrollment is anticipated to complete in September 2023 with no longitudinal follow-up. SAFE-MCS is the first study to exclusively assess bleeding complications in patients undergoing PCI with Impella with independent adjudication via a clinical end point committee and will gather meaningful real-world data using contemporary practice.

Long-term Efficacy of Satralizumab in Adults with Aquaporin-4-IgG-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from SAkuraMoon (S5.001)

Long-term Efficacy of Satralizumab in Adults with Aquaporin-4-IgG-seropositive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD): Results from SAkuraMoon (S5.001)

Neuronal nets and logistic regression analysis provide improved prediction of infective endocarditis compared to the modified Duke Score: a post-hoc analysis of the prospective PRO-ENDOCARDITIS study

Abstract Introduction The modified Duke score is the currently recommended diagnostic algorithm in suspected infective endocarditis (IE). The categorization in major and minor criteria enables an easy clinical application, but may not optimally utilize individual patient's information. In contrast, detailed statistical evaluation of multiple characteristics using artificial intelligence and logistic regression report improved prediction of various cardiovascular diseases over conventional clinical strategies. We tested the hypothesis that neuronal nets and logistic regression analysis would provide improved prediction of IE as compared to the modified Duke score. Methods This post-hoc evaluation of the prospective observational PRO-ENDOCARDITIS study was conducted at the West German Heart and Vascular center between December 2017 and May 2019 and includes 261 patients. Duke criteria and clinical characteristics were prospectively collected. Transesophageal echocardiography (TEE) imaging was evaluated by a blinded cardiologist at a central core-lab. IE as primary endpoint was adjudicated by an independent clinical endpoint committee. The database was divided into a training (70%) and validation cohort (30%). We compared the value of the Duke score, neuronal nets and logistic regression analysis for prediction of the primary endpoint. Results The mean age was 60.1±16.1 years, 37.2% were female. In 47 cases, IE was present. The modified Duke score achieved an AUC of 0.863 in the training cohort and 0.913 within the validation cohort. The logistic regression and the neural net exceeded the predictive value in both cohorts (training cohort: 0.992 and 0.986; validation cohort: 0.964, 0.957; for logistic regression and neuronal nets, respectively, Figure 1). Without the use of TEE, the remaining Duke criteria only poorly predicted IE (training cohort: 0.771, 0.951 and 0.938; validation cohort: 0.835, 0.862 and 0.780, for the Duke score, logistic regression and neuronal nets, respectively). Discussion Logistic regression analysis and neuronal nets provide improved prediction of IE as compared to the clinically established modified Duke score. Further studies on larger databases are needed to confirm our results and provide algorithms for clinical routine. Funding Acknowledgement Type of funding sources: None.

Comparison of Investigator-Reported vs Centrally Adjudicated Major Adverse Cardiac Events

In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, there was a significant reduction in the adjudicated primary outcome among patients with stable atherosclerotic vascular disease randomized to dual pathway inhibition (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily) vs aspirin monotherapy, but not with rivaroxaban 5 mg twice daily vs aspirin monotherapy. Whether the results are similar without adjudication is unknown. To examine the impact of dual pathway inhibition (with rivaroxaban plus aspirin) or rivaroxaban monotherapy compared with aspirin monotherapy on investigator-reported CV events and to understand the extent of concordance between investigator-reported and centrally adjudicated clinical events. This is a secondary analysis of the COMPASS trial, an international, double-blind, double-dummy, randomized clinical trial with a 3-by-2 partial factorial design that evaluated participants with stable atherosclerotic vascular disease receiving rivaroxaban plus aspirin, rivaroxaban monotherapy, or aspirin monotherapy. End points were collected by blinded site investigators and adjudicated by a blinded clinical end point committee. Data were analyzed from March 2013 through February 2017. Participants received dual inhibition pathway (2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily), rivaroxaban monotherapy (5 mg twice daily), or aspirin monotherapy (100 mg once daily). The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or myocardial infarction (MI). Adjudicated and investigator-reported end points were compared. A total of 27 395 patients (mean [SD] age, 68.2 [7.9] years; 78.0% men) were assessed, including 9152 patients randomized to dual pathway inhibition, 9117 patients randomized to rivaroxaban monotherapy, and 9126 patients randomized to aspirin monotherapy. Adjudication reduced the number of events by 10% to 15% for most end points. Among investigator-reported end points, dual pathway inhibition significantly reduced the rate of the primary efficacy outcome compared with aspirin alone (411 patients [4.5%] vs 542 patients [5.9%]; hazard ratio [HR], 0.75 [95% CI, 0.66-0.85]; P < .001), with similar reduction in adjudicated end points, (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76 [95% CI, 0.66-0.86]; P < .001). Likewise, effects on ischemic end points were highly concordant (κ statistic = 0.94 [95% CI, 0.93-0.95] for the primary composite end point). Unlike with adjudicated outcomes, there was a significant reduction in the primary end point with rivaroxaban monotherapy vs aspirin monotherapy using investigator-reported events (477 patients [5.2%] vs 542 patients [5.9%]; HR, 0.88 [95% CI, 0.78-0.99]; P = .04) compared with adjudicated events (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90 [95% CI, 0.79-1.03]; P = .12). This secondary analysis of the COMPASS trial found that whether assessed by blinded site investigators or adjudicators, dual pathway inhibition significantly reduced CV events among patients with stable atherosclerotic disease compared with aspirin plus placebo. These findings suggest that using investigator-reported events in blinded clinical trials may be a more efficient alternative to adjudication. ClinicalTrials.gov Identifier: NCT01776424.

Sacubitril/valsartan compared to ramipril in high risk post myocardial infarction patients stratified according use of mineralocorticoid receptor antagonists: insight from PARADISE MI trial

Abstract Background Mineralocorticoid receptor antagonists (MRAs) reduce the risk of cardiovascular death or heart failure admission in patients with myocardial infarction (MI) and left ventricular systolic dysfunction (LVSD) combined with either heart failure (HF) or diabetes. Whether use of MRA and initiation of sacubitril/valsartan are safe and whether MRAs modify the effect of sacubitril/valsartan initiation in high-risk MI patients is unknown. Purpose This analysis examined whether background treatment with a MRA modifies the treatment effect and safety of sacubitril/valsartan in patients with a MI and LVSD and/or pulmonary congestion. Methods In the PARADISE MI Trial (Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction) N=5661 patients were randomized to either sacubitril/valsartan (97/103 mg twice daily) or ramipril (5 mg twice daily) within 7 days of their MI. The primary outcome in this analysis was the composite of worsening HF (HF hospitalization or outpatient worsening) or cardiovascular death evaluated by the clinical endpoint committee (CEC-adjudicated) or the investigators. Safety was defined as symptomatic hypotension, hyperkalemia &amp;gt;5.5 mmol/L or permanent drug discontinuation. Results A total of 2338 patients (41%) were treated with an MRA and they were more often Caucasian (79% vs. 73%), had worse left ventricular ejection fraction (34±8 vs. 38±10%), a higher KILLIP Class (63% vs. 55% in class II or more) and a lower estimated Glomerular filtration rate (71 vs. 73 ml/min/1.73 m2), than patients not taking an MRA. Age (63 years), sex (24% females), and frequency of diabetes (42%) did not differ. The treatment effect of sacubitril/valsartan compared with ramipril was similar in patients taking or not taking an MRA: hazard ratio (MRA): (95% confidence interval [CI]): 0.96 (0.77, 1.19) versus (95% CI: 0.87 (0.71, 1.05), respectively, for the primary endpoint (p value for interaction = 0.51) (CEC adjudicated) (Figure 1); similar findings were observed if investigator reported endpoints were evaluated (P=0.61 for interaction). Safety of sacubitril/valsartan compared to ramipril initiation was not changed by +/−MRA use, but an increase in symptomatic hypotension was observed (HR(MRA): 1.37 and HR: 1.39, P&amp;lt;0.001) in both groups (P=0.968 for interaction), whereas an increased risk of hyperkalemia or permanent drug discontinuation was not observed in the sacubitril/valsartan group (P&amp;gt;0.05 for all comparisons). Conclusions As expected, patients taking MRAs had a higher risk. Use of a MRA did not modify the treatment effect and safety of initiation of sacubitril/valsartan compared to ramipril in the post MI setting in patients with LVSD and/or congestion. Our analyses support that sacubitril/valsartan and MRAs can be used simultaneously. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novartis sponsored Randomized clinical trial

Neuronal nets and logistic regression analysis provide improved prediction of infective endocarditis compared to the modified Duke Score: a post-hoc analysis of the prospective PRO-ENDOCARDITIS study

Abstract Introduction The modified Duke score is the currently recommended diagnostic algorithm in suspected infective endocarditis (IE). The categorization in major and minor criteria enables an easy clinical application, but may not optimally utilize individual patient's information. In contrast, detailed statistical evaluation of multiple characteristics using artificial intelligence and logistic regression report improved prediction of various cardiovascular diseases over conventional clinical strategies. We tested the hypothesis that neuronal nets and logistic regression analysis would provide improved prediction of IE as compared to the modified Duke score. Methods This post-hoc evaluation of the prospective observational PRO-ENDOCARDITIS study was conducted at the West German Heart and Vascular center between December 2017 and May 2019 and includes 261 patients. Duke criteria and clinical characteristics were prospectively collected. Transesophageal echocardiography (TEE) imaging was evaluated by a blinded cardiologist at a central core-lab. IE as primary endpoint was adjudicated by an independent clinical endpoint committee. The database was divided into a training (70%) and validation cohort (30%). We compared the value of the Duke score, neuronal nets and logistic regression analysis for prediction of the primary endpoint. Results The mean age was 60.1±16.1 years, 37.2% were female. In 47 cases, IE was present. The modified Duke score achieved an AUC of 0.863 in the training cohort and 0.913 within the validation cohort. The logistic regression and the neural net exceeded the predictive value in both cohorts (training cohort: 0.992 and 0.986; validation cohort: 0.964, 0.957; for logistic regression and neuronal nets, respectively, Figure 1). Without the use of TEE, the remaining Duke criteria only poorly predicted IE (training cohort: 0.771, 0.951 and 0.938; validation cohort: 0.835, 0.862 and 0.780, for the Duke score, logistic regression and neuronal nets, respectively). Discussion Logistic regression analysis and neuronal nets provide improved prediction of IE as compared to the clinically established modified Duke score. Further studies on larger databases are needed to confirm our results and provide algorithms for clinical routine. Funding Acknowledgement Type of funding sources: None.

Long-term secondary prevention of cardiovascular disease with a Mediterranean diet and a low-fat diet (CORDIOPREV): a randomised controlled trial

Mediterranean and low-fat diets are effective in the primary prevention of cardiovascular disease. We did a long-term randomised trial to compare the effects of these two diets in secondary prevention of cardiovascular disease. The CORDIOPREV study was a single-centre, randomised clinical trial done at the Reina Sofia University Hospital in Córdoba, Spain. Patients with established coronary heart disease (aged 20-75 years) were randomly assigned in a 1:1 ratio by the Andalusian School of Public Health to receive a Mediterranean diet or a low-fat diet intervention, with a follow-up of 7 years. Clinical investigators (physicians, investigators, and clinical endpoint committee members) were masked to treatment assignment; participants were not. A team of dietitians did the dietary interventions. The primary outcome (assessed by intention to treat) was a composite of major cardiovascular events, including myocardial infarction, revascularisation, ischaemic stroke, peripheral artery disease, and cardiovascular death. This study is registered with ClinicalTrials.gov, NCT00924937. From Oct 1, 2009, to Feb 28, 2012, a total of 1002 patients were enrolled, 500 (49·9%) in the low-fat diet group and 502 (50·1%) in the Mediterranean diet group. The mean age was 59·5 years (SD 8·7) and 827 (82·5%) of 1002 patients were men. The primary endpoint occurred in 198 participants: 87 in the Mediterranean diet group and 111 in the low-fat group (crude rate per 1000 person-years: 28·1 [95% CI 27·9-28·3] in the Mediterranean diet group vs 37·7 [37·5-37·9] in the low-fat group, log-rank p=0·039). Multivariable-adjusted hazard ratios (HRs) of the different models ranged from 0·719 (95% CI 0·541-0·957) to 0·753 (0·568-0·998) in favour of the Mediterranean diet. These effects were more evident in men, with primary endpoints occurring in 67 (16·2%) of 414 men in the Mediterranean diet group versus 94 (22·8%) of 413 men in the low-fat diet group (multiadjusted HR 0·669 [95% CI 0·489-0·915], log-rank p=0·013), than in 175 women for whom no difference was found between groups. In secondary prevention, the Mediterranean diet was superior to the low-fat diet in preventing major cardiovascular events. Our results are relevant to clinical practice, supporting the use of the Mediterranean diet in secondary prevention. Fundacion Patrimonio Comunal Olivarero; Fundacion Centro para la Excelencia en Investigacion sobre Aceite de Oliva y Salud; local, regional, and national Spanish Governments; European Union.

Discordant diagnostic criteria for pneumonia in COPD trials: a review.

Inhaled corticosteroids (ICS) have a class effect of increasing pneumonia risk in patients with COPD. However, pneumonia incidence varies widely across clinical trials of ICS use in COPD. This review clarifies methodological differences in defining and recording pneumonia events in these trials and discusses factors that could contribute to the varying pneumonia incidence. Literature searches and screening yielded 40 relevant references for inclusion. Methods used to capture pneumonia events in these studies included investigator-reported pneumonia adverse events, standardised list of signs or symptoms, radiographic confirmation of suspected cases and/or confirmation by an independent clinical end-point committee. In general, more stringent pneumonia diagnosis criteria led to lower reported pneumonia incidence rates. In addition, studies varied in design and population characteristics, including exacerbation history and lung function, factors that probably contribute to the varying pneumonia incidence. As such, cross-trial comparisons are problematic. A minimal set of standardised criteria for diagnosis and reporting of pneumonia should be used in COPD studies, as well as reporting of patients' pneumonia history at baseline, to allow comparison of pneumonia rates between trials. Currently, within-trial comparison of ICS-containing versus non-ICS-containing treatments is the appropriate method to assess the influence of ICS on pneumonia incidence.

Sex-specific differences in total ischemic time coincide with similar cardiovascular outcome in patients with acute coronary syndrome: a Swiss multicentre cohort study

Abstract Background Previous studies showed prolonged patient and system delay in female patients with acute coronary syndromes (ACS) which is thought to be a major driver of discrepancies in their cardiovascular (CV) outcomes. Indeed, timely management is particularly important in patients with ST-segment elevation myocardial infarction (STEMI), as increased total ischemic time augments infarct size and relates to poor CV survival. However, contemporary evidence on sex-specific differences in ACS management and discrepancies in outcomes is limited and controversial. Purpose We sought to systematically investigate whether a sex-gap in symptom-to-door (STD), door-to-balloon (DTB)/door-to-PCI (DTP) time exists in a prospective ACS cohort and if such differences translate into different rates of major adverse cardiovascular events (MACE) at one year. Methods From 2009 to 2019, 4'930 ACS patients with a main diagnosis of NSTEMI (43.3%), STEMI (53.3%) or unstable angina (3.4%) were enrolled in the multicentre, prospective SPUM-ACS study of which 4'671 completed follow-up at one year. STD, DTB and DTP time was analyzed. The primary endpoint, a composite measure of all-cause death, nonfatal myocardial infarction, nonfatal stroke and ischemia-driven revascularization, was adjudicated by an independent clinical endpoint committee. Kaplan-Meier and multivariate-adjusted Cox proportional hazard regression models were used for time-to-event analyses. Results A total of 1'019 (20.7%) women and 3'911 (79.3%) men with a main diagnosis of ACS were included in the study. At presentation, women were older (69.6±12.0 vs. 62.2±12.1 years, P&amp;lt;0.001), more likely to have impaired renal function (median, 81.2 vs. 89.2 ml/min/1.73m2, P&amp;lt;0.001) and a history of hypertension (63.9% vs. 54.3%, P&amp;lt;0.001). STD time was significantly higher in female STEMI (median, 3.2 vs. 2.5 hours, P&amp;lt;0.001) and NSTEMI patients (median, 7.0 vs. 5.0 hours, P=0.015). Importantly, DTB time did not differ between sexes in STEMI patients (1.0 vs. 1.0 hour, P=0.430). Similarly, DTP time of female NSTEMI patients was comparable to males (4.3 vs. 4.4 hours, P=0.855). In the entire cohort, female ACS patients did not show a higher occurrence of the primary endpoint at one year (crude HR 0.86, 95% CI 0.72–1.04; adjusted HR 0.83, 95% CI, 0.66–1.05). In a multivariate-adjusted subgroup analysis, neither female STEMI (adjusted HR 0.82, 95% CI 0.59–1.15) nor NSTEMI patients (adjusted HR 0.87, 95% CI 0.61–1.24) showed higher hazards for the primary endpoint compared to male patients. Conclusions Women with a main diagnosis of STEMI show considerably higher prehospital delay, thus prolonged total ischemic time which is mainly driven by increased STD time. Intriguingly, this does not translate into higher rates of MACE compared to men at one year. Women with ACS may particularly benefit from measures aimed at reducing prehospital delay, as this may further improve long-term prognosis after the acute event. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swiss National Science Foundation - SNFFoundation for Cardiovascular Research - Zurich Heart House

High plasma levels of soluble LOX-1 portends poor survival in acute coronary syndromes beyond GRACE 2.0: a multicentre prospective cohort study

Abstract Background While inflammatory states and dyslipidemias confer a dismal prognosis following myocardial ischaemia, the role of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) which sits at the confluence of these conditions remains elusive. Given soluble LOX-1' (sLOX-1) pivotal role in inflammatory processes underlying atherosclerotic plaque progression, we sought to study its prognostic utility on the risk of adverse events in acute coronary syndromes (ACS). Purpose Hence, we aimed to investigate whether sLOX-1 is an independent predictor of all-cause death at one year beyond traditional and emerging risk factors for poor survival following ACS. Methods 2678 ACS patients were recruited in the prospective, multicentre SPUM-ACS trial, of which 2525 completed follow-up at one year. Major adverse cardiovascular events, including death from any cause, were adjudicated by an independent clinical endpoint committee. By employing high-sensitive enzyme-linked immunosorbent assay, sLOX-1 was assessed in the plasma at the time of presentation in ACS and age-matched chronic coronary syndrome (CCS) patients. Kaplan-Meier survival analysis and Cox proportional hazard regression models, adjusted for baseline variables and the GRACE 2.0 score, were used to study the predictive utility of sLOX-1. Results At the time of presentation, ACS patients, specifically those with ST-segment elevation ACS, had significantly elevated sLOX-1 levels as compared to patients with CCS (median, 35.40 vs. 2.00 pg/ml, P&amp;lt;0.0001). Patients in the upper sLOX-1 tertile were at heightened risk for both death from any cause (crude HR 1.785, 95% CI 1.083–2.941, P&amp;lt;0.05; adjusted HR 2.035, 95% CI 1.176–3.519, P&amp;lt;0.05) and CV death (crude HR 2.447, 95% CI 1.285–4.663, P&amp;lt;0.01; adjusted HR 2.383, 95% CI 1.206–4.710, P&amp;lt;0.05) compared to those in the first tertile. Importantly, sLOX-1 remained an independent predictor of all-cause death after adjustment for known risk factors of adverse outcome and the GRACE 2.0 score (adjusted + GRACE 2.0 HR 1.896, 95% CI 1.034–3.476, P&amp;lt;0.05). Conclusions Plasma sLOX-1 is elevated in ACS patients and predicts poor survival independent of both traditional and emerging risk factors and provides prognostic information beyond GRACE 2.0. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swiss National Science FoundationFoundation for Cardiovascular Research - Zurich Heart House

Comparative Reductions in Investigator-Reported and Adjudicated Ischemic Events in REDUCE-IT

BackgroundREDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized statin-treated patients with elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in adjudicated events, including the primary endpoint (cardiovascular [CV] death, myocardial infarction [MI], stroke, coronary revascularization, unstable angina requiring hospitalization) and key secondary endpoint (CV death, MI, stroke) with IPE. ObjectivesThe purpose of this study was to determine the effects of IPE on investigator-reported events. MethodsPotential endpoints were collected by blinded site investigators and subsequently adjudicated by a blinded Clinical Endpoint Committee (CEC) according to a prespecified charter. Investigator-reported events were compared with adjudicated events for concordance. ResultsThere was a high degree of concordance between investigator-reported and adjudicated endpoints. The simple Kappa statistic between CEC-adjudicated vs site-reported events for the primary endpoint was 0.89 and for the key secondary endpoint was 0.90. Based on investigator-reported events in 8,179 randomized patients, IPE significantly reduced the rate of the primary endpoint (19.1% vs 24.6%; HR: 0.74 [95% CI: 0.67-0.81]; P < 0.0001) and the key secondary endpoint (10.5% vs 13.6%; HR: 0.75 [95% CI: 0.66-0.85]; P < 0.0001). Among adjudicated events, IPE similarly reduced the rate of the primary and key secondary endpoints. ConclusionsIPE led to consistent, significant reductions in CV events, including MI and coronary revascularization, as determined by independent, blinded CEC adjudication as well as by blinded investigator-reported assessment. These results highlight the robust evidence for the substantial CV benefits of IPE seen in REDUCE-IT and further raise the question of whether adjudication of CV outcome trial endpoints is routinely required in blinded, placebo-controlled trials. (Evaluation of the Effect of AMR101 on Cardiovascular Health and Mortality in Hypertriglyceridemic Patients With Cardiovascular Disease or at High Risk for Cardiovascular Disease: REDUCE-IT [Reduction of Cardiovascular Events With EPA - Intervention Trial]; NCT01492361)

Accuracy of Cardiovascular Trial Outcome Ascertainment and Treatment Effect Estimates from Routine Health Data: A Systematic Review and Meta-Analysis.

Registry-based randomized controlled trials allow for outcome ascertainment using routine health data (RHD). While this method provides a potential solution to the rising cost and complexity of clinical trials, comparative analyses of outcome ascertainment by clinical end point committee (CEC) adjudication compared with RHD sources are sparse. Among cardiovascular trials, we set out to systematically compare the incidence of cardiovascular events and estimated randomized treatment effects ascertained from RHD versus traditional clinical evaluation and adjudication. We searched MEDLINE (1976 to August 2020) for studies where outcome ascertainment was performed by both RHD and CEC adjudication to compare the incidence of cardiovascular events and treatment effects. We derived ratios of hazard ratios to compare treatment effects from RHD and CEC adjudication. We pooled ratios of hazard ratios using an inverse variance random-effects meta-analysis. Nine studies (1988-2020; 32 156 patients) involving 10 randomized control trials compared outcome ascertainment with RHD and CEC in patients with or at risk of cardiovascular disease. There was a high degree of agreement and interrater reliability between CEC and RHD outcome determination for all-cause mortality (agreement percentage: 98.4%-100% and κ: 0.95-1.0) and cardiovascular mortality (agreement percentage: 97.8%-99.9% and κ: 0.66-0.99). For myocardial infarction, the κ values ranged from 0.67-0.98, and for stroke the values ranged from 0.52-0.89. In contrast, the κ value for peripheral artery disease was low (κ: 0.27). There was little difference in the randomized treatment effect derived from CEC and RHD ascertainment of events based on the ratios of hazard ratio, with pooled ratios of hazard ratios ranging from 0.93 (95% CI, 0.63-1.39) for cardiovascular mortality to 1.27 (95% CI, 0.67-2.41) for stroke. Clinical outcome ascertainment using retrospectively acquired RHD displayed high levels of agreement with CEC adjudication for identifying all-cause mortality and cardiovascular outcomes. Importantly, cardiovascular treatment effects in randomized control trials determined from RHD and CEC resulted in similar point estimates. Overall, our review supports the use of RHD as a potential alternative source for clinical outcome ascertainment in cardiovascular trials. Validation studies with prospectively planned linkage are warranted.

Evaluation of the Gore TAG thoracic branch endoprosthesis in the treatment of proximal descending thoracic aortic aneurysms

BackgroundThoracic endovascular aortic repair has radically transformed the treatment of descending thoracic aortic aneurysms. However, when aneurysms involve the aortic arch in the region of the left subclavian artery, branch vessel preservation must be considered. Branched aortic endografts have provided a new option to maintain branch patency. MethodsSix investigative sites enrolled 31 patients in a nonrandomized, prospective investigational device exemption feasibility trial of a single branched aortic endograft for the management of aneurysms that include the distal aortic arch. The Gore TAG thoracic branch endoprosthesis (W. L. Gore & Associates, Inc, Flagstaff, Ariz), an investigational device, allows for graft placement proximal to the left subclavian artery and incorporates a single side branch for left subclavian perfusion. ResultsAll 31 patients (100%) had undergone successful implantation of the investigational device in landing zone 2. Men slightly outnumbered women (51.6%). Their average age was 74.1 ± 10.4 years. The aneurysm morphology was fusiform in 12 and saccular in 19 patients, with a mean maximum aortic diameter of 54.8 ± 10.9 mm. The mean follow-up period for the cohort was 25.2 ± 11.1 months. We have reported the patient outcomes at 1 month and 1 year. At 1 month, the side branch patency was 100% and the freedom from core laboratory-reported device-related endoleak (types I and III) was 96.7%, without 30-day death or permanent paraplegia. One patient experienced a procedure-related stroke. Through 1 year, five patients had died; none of the deaths were related to the device or procedure (clinical endpoint committee adjudicated). One thoracic reintervention was required. No conversions were required, and no aneurysm growth (core laboratory) was reported. One case of the loss of side branch patency was diagnosed in the left subclavian artery in an asymptomatic individual from computed tomography at 6 months, with no reported subsequent adverse events due to loss of patency. Endoleaks were reported by the core laboratory in five patients at 12 months (two, type II; and three, indeterminate). ConclusionsThe present investigational device exemption feasibility study has reported the preliminary results of the use of a single side branch endograft to treat patients with proximal descending thoracic aortic aneurysms.

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

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.

REDUCE-IT: accumulation of data across prespecified interim analyses to final results

Abstract Background REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), an event-driven trial, randomized 8,179 statin-treated patients with elevated triglycerides (TGs) and increased cardiovascular (CV) risk to icosapent ethyl (IPE); pure, stable prescription eicosapentaenoic acid, 4g/day or placebo. 1,612 primary endpoint events (CV death, nonfatal myocardial infarction [MI], nonfatal stroke, coronary revascularization, or hospitalization for unstable angina) projected 90% power to detect 15% relative risk reduction (5% 2-sided alpha). The key secondary composite endpoint was CV death, nonfatal MI, or nonfatal stroke. An independent data and safety monitoring committee (DMC) performed prespecified interim analyses (IAs) at ∼60% (IA1 31 May 2016 data cutoff; 2.9 y median primary endpoint follow-up) and ∼80% (IA2 01 May 2017; 3.7 y) of events; final analysis included 1,606 events (06 Sep 2018; 4.9 y median study follow-up). Purpose Explore REDUCE-IT efficacy and safety across prespecified IAs for insight into progression of robustness and consistency of conclusions. Methods The interim statistical analysis plan guided study continuation decisions by a prespecified decision-making process, including assessment of safety, treatment arm performance, primary composite endpoint formal analyses, and informal robustness analyses, with no futility or efficacy stopping requirements. Prior to DMC IA study continuation decisions, the need for a mature dataset to support the robustness of final efficacy and safety findings was discussed. Sponsor, Steering Committee, and Clinical Endpoint Committee were blinded throughout. Results Primary and key secondary endpoints achieved statistical significance at IA1 and IA2 that persisted at final analyses (p-value below final adjusted 2-sided alpha of 0.0437); hazard ratios also remained consistent and similar robustness was observed across individual endpoint components; clarity of findings across endpoints and subgroups improved with more events. Stopping for overwhelming efficacy was discussed at each IA; prior to IA study continuation recommendations, the DMC considered historical examples of failed CV outcome studies for TG-lowering and mixed omega-3 therapies, reflected on the potential for overestimating final demonstrated benefit using incomplete data, and weighed societal impacts of fuller datasets relative to patient therapy access. Conclusions Consistent, potent efficacy emerged early and persisted across the two prespecified interim and final analyses. The mature dataset demonstrated highly statistically significant reductions in the primary (25%; p=0.00000001) and key secondary (26%; p=0.0000006) endpoints and allowed robust analyses to support overall efficacy and safety conclusions. Allowing the REDUCE-IT dataset to fully mature provided clinicians with robust, consistent, and reliable data upon which to base clinical decisions for IPE in CV risk reduction. Funding Acknowledgement Type of funding source: Other. Main funding source(s): The study was funded by Amarin Pharma, Inc.

Adjudication Of Cause-specific Endpoints In Heart Failure Trials

Introduction Clinical endpoints are standard outcomes measures used to prove treatment effect in clinical trials. Differences in endpoint definitions and ascertainment of cause-specific clinical events influence the validity of heart failure (HF) trials. Cause-specific clinical events have become preferred endpoints because they separate signals of efficacy from noise (non-related events). Clinical endpoints could be ascertained through case report forms (CRFs) by investigators or through a central adjudication method by a Clinical Endpoint Committee (CEC). Investigator reporting is more efficient and inexpensive but is affected by inaccuracy, geographic variability, and complexity of endpoint definitions. CEC adjudication is a standardized, blind and independent ascertainment process but may be limited by high costs. Aims To analyze cause-specific endpoints, and the need for CEC adjudication in HF trials, comparing HF with reduced versus preserved ejection fraction (EF). Methods We analyzed 10 HF with reduced EF (HFrEF) trials and five HF with preserved EF (HFpEF) trials. For each trial we described and compared the prevalence of all-cause and cause-specific mortality. Results A comparison between all-cause mortality and cardiovascular mortality in 9 selected HFrEF and HFpEF clinical trials is presented in Figure 1. The relative proportion of CV death was significantly lower in HFpEF compared with HFrEF trials. Additionally, in HFrEF, the relative proportion of CV death was significantly lower in recent trials compared with early trials. CV specific endpoints were the primary cause of death in HF trials. Conclusions There are more CV deaths in HFrEF trials, although it is the primary mode of death in both populations. CEC adjudication may be more beneficial in HFpEF vs. HFrEF trials, and in recent HFrEF trials due to the increase in non-CV events which may attenuate the treatment effect.

Adjudication of cardiovascular events in patients with chronic obstructive pulmonary disease: SUMMIT trial.

Background:Adjudicated cause-specific mortality has been used in major trials of chronic obstructive pulmonary disease. However, there is less experience with adjudicated major adverse cardiovascular events as a key efficacy outcome in chronic obstructive pulmonary disease trials. The Study to Understand Mortality and Morbidity in chronic obstructive pulmonary disease trial required a Clinical Endpoint Committee to adjudicate the outcomes of modified major adverse cardiovascular events and cause-specific mortality.Methods and results:A six-member Clinical Endpoint Committee reviewed adverse event and serious adverse event reports included in a list of 204 Medical Dictionary for Regulatory Activities terms. Adverse events were triaged by one Clinical Endpoint Committee member, and then reviewed by three reviewers (round 1). If these three disagreed on the adjudication, the event was discussed by the full committee to reach a consensus (round 2). Among 16,485 participants, 48,105 adverse events were reported, among which 3314 were reviewed by the Clinical Endpoint Committee. After triage, 1827 were adjudicated in round 1; 338 required committee consensus in round 2, yielding 450 myocardial infarctions, strokes, unstable anginas or transient ischaemic attacks. Only 20/1627 (1%) non-serious adverse events were adjudicated as cardiovascular events. Only 45/204 Medical Dictionary for Regulatory Activities terms reviewed yielded cardiovascular events. A total of 430 deaths were adjudicated in round 1 and 631 in round 2, yielding 459 cardiovascular deaths. Adjudication of chest pain and sudden death often required additional information from site investigators. Site assessment of cardiovascular death was moderately specific (501/602 = 83%) but not sensitive (256/459 = 56%).Conclusion:A Clinical Endpoint Committee is useful for adjudication of major adverse cardiovascular events in chronic obstructive pulmonary disease trials but requires considerable resources and effort by investigators. This process can be streamlined by reviewing only serious adverse events and filtering by selected Medical Dictionary for Regulatory Activities terms.

The impact of glutamate infusion on postoperative NT-proBNP in patients undergoing coronary artery bypass surgery: a randomized study

BackgroundGlutamate, a key intermediate in myocardial metabolism, may enhance myocardial recovery after ischemia and possibly reduce the incidence and severity of postoperative heart failure in coronary artery bypass surgery (CABG). N-terminal pro-B-type natriuretic peptide (NT-proBNP) can be used to assess postoperative heart failure (PHF) after CABG. Our hypothesis was that glutamate enhances myocardial recovery in post-ischemic heart failure and, therefore, will be accompanied by a mitigated postoperative increase of NT-proBNP.MethodsSubstudy of the GLUTAmate for Metabolic Intervention in Coronary Surgery (GLUTAMICS) trial (ClinicalTrials.gov Identifier: NCT00489827) a prospective triple-center double-blind randomized clinical trial on 399 patients undergoing CABG with or without concomitant procedure for acute coronary syndrome at three Swedish Cardiac Surgery centres (Linköping, Örebro, and Karlskrona) from May 30, 2007 to November 12, 2009. Patients were randomly assigned to intravenous infusion of 0.125 M l-glutamic acid or saline (1.65 mL/kg of body weight per hour) intraoperatively and postoperatively. Plasma NT-proBNP was measured preoperatively, the first (POD1) and third postoperative morning (POD3). A Clinical Endpoints Committee, blinded to both intervention and NT-proBNP used prespecified criteria to diagnose PHF. The primary endpoints were the absolute levels of postoperative NT-proBNP and the difference between preoperative and postoperative levels of NT-proBNP.ResultsOverall no significant difference was detected in postoperative NT-proBNP levels between groups. However, in high-risk patients (upper quartile of EuroSCORE II ≥ 4.15; glutamate group n = 56; control group n = 45) glutamate was associated with significantly lower postoperative increase of NT-proBNP (POD3-Pre: 3900 [2995–6260] vs. 6745 [3455–12,687] ng•L−1, p = 0.012) and lower NT-proBNP POD3 (POD3: 4845 [3426–7423] vs. 8430 [5370–14,100] ng•L−1, p = 0.001). After adjusting for significant differences in preoperative demographics, NT-proBNP POD3 in the glutamate group was 0.62 times of that in the control group (p = 0.002). Patients in the glutamate group also had shorter ICU stay (21 [19–26] vs. 25 [22–46] h, p = 0.025) and less signs of myocardial injury (Troponin T POD3 (300 [170–500] vs. 560 [210–910] ng•L−1, p = 0.025).ConclusionsPost hoc analysis of postoperative NT-proBNP suggests that intravenous infusion of glutamate may prevent or mitigate myocardial dysfunction in high-risk patients undergoing CABG. Further studies are necessary to confirm these findings.Trial registration Swedish Medical Products Agency 151:2003/70403 (prospectively registered with amendment about this substudy filed March 17, 2007). ClinicalTrials.gov Identifier: NCT00489827 (retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT00489827?term=glutamics&draw=1&rank=1