Publications by authors named "Matthew T Roe"

449 Publications

Intensity of statin treatment after acute coronary syndrome, residual risk, and its modification by alirocumab: insights from the ODYSSEY OUTCOMES trial.

Eur J Prev Cardiol 2021 03 27;28(1):33-43. Epub 2020 Jul 27.

Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, FACT (French Alliance for Cardiovascular Trials), and INSERM, France.

Aims: Statins are pivotal to the secondary prevention of major adverse cardiovascular events, but some patients are statin-intolerant. We examined the effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab on the risk of major adverse cardiovascular events according to the intensity of background statin treatment.

Methods And Results: The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with acute coronary syndrome and dyslipidaemia despite intensive or maximum-tolerated statin treatment (including no statin if intolerance was documented). The primary outcome (major adverse cardiovascular events) comprised coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina. Median follow-up was 2.8 years. Baseline statin treatment was high-intensity (88.8%), low/moderate-intensity (8.7%) or none (2.4%). Median baseline low-density lipoprotein cholesterol was 86, 89 and 139 mg/dL (P < 0.001) in these statin treatment categories, respectively. Alirocumab produced similar relative reductions in low-density lipoprotein cholesterol from baseline across statin treatment subgroups, but the mean absolute reductions differed (52.9, 56.7 and 86.1 mg/dL, respectively; P < 0.001). With placebo, the incidence of major adverse cardiovascular events was highest in the no statin subgroup (10.8%, 10.7% and 26.0% respectively). Alirocumab reduced major adverse cardiovascular events in each statin subgroup (hazard ratio 0.88, 95% confidence interval (CI) 0.80-0.96; 0.68, 0.49-0.94; and 0.65, 0.44-0.97, respectively; Pinteraction = 0.14) with a gradient of absolute risk reduction: 1.25%, 95% CI 0.34-2.16; 3.16%, 0.38-5.94; 7.97%, 0.42-15.51; Pinteraction = 0.106).

Conclusions: PCSK9 inhibition with alirocumab reduces the relative risk of major adverse cardiovascular events after acute coronary syndrome irrespective of background statin treatment. However, patients on no statin are at high absolute risk for recurrent major adverse cardiovascular events; alirocumab substantially reduces that risk. PCSK9 inhibition may be an important therapeutic strategy for statin-intolerant patients with acute coronary syndrome.
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http://dx.doi.org/10.1177/2047487320941987DOI Listing
March 2021

Risk Factor Burden and Long-Term Prognosis of Patients With Premature Coronary Artery Disease.

J Am Heart Assoc 2020 12 8;9(24):e017712. Epub 2020 Dec 8.

Duke Clinical Research Institute Duke University School of Medicine Durham NC.

Background Coronary artery disease (CAD) is increasing among young adults. We aimed to describe the cardiovascular risk factors and long-term prognosis of premature CAD. Methods and Results Using the Duke Databank for Cardiovascular Disease, we evaluated 3655 patients admitted between 1995 and 2013 with a first diagnosis of obstructive CAD before the age of 50 years. Major adverse cardiovascular events (MACEs), defined as the composite of death, myocardial infarction, stroke, or revascularization, were ascertained for up to 10 years. Cox proportional hazard regression models were used to assess associations with the rate of first recurrent event, and negative binomial log-linear regression was used for rate of multiple event recurrences. Past or current smoking was the most frequent cardiovascular factor (60.8%), followed by hypertension (52.8%) and family history of CAD (39.8%). Within a 10-year follow-up, 52.9% of patients had at least 1 MACE, 18.6% had at least 2 recurrent MACEs, and 7.9% had at least 3 recurrent MACEs, with death occurring in 20.9% of patients. Across follow-up, 31.7% to 37.2% of patients continued smoking, 81.7% to 89.3% had low-density lipoprotein cholesterol levels beyond the goal of 70 mg/dL, and 16% had new-onset diabetes mellitus. Female sex, diabetes mellitus, chronic kidney disease, multivessel disease, and chronic inflammatory disease were factors associated with recurrent MACEs. Conclusions Premature CAD is an aggressive disease with frequent ischemic recurrences and premature death. Individuals with premature CAD have a high proportion of modifiable cardiovascular risk factors, but failure to control them is frequently observed.
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http://dx.doi.org/10.1161/JAHA.120.017712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955368PMC
December 2020

Long-Term Bleeding Risk Prediction with Dual Antiplatelet Therapy After Acute Coronary Syndromes Treated Without Revascularization.

Circ Cardiovasc Qual Outcomes 2020 09 31;13(9):e006582. Epub 2020 Aug 31.

Duke Clinical Research Institute, Durham, NC (G.M.G., M.L.N., R.A., E.M.O., M.T.R.).

Background: Longitudinal bleeding risk scores have been validated in patients treated with dual antiplatelet therapy (DAPT) following percutaneous coronary intervention. How these scores apply to the population of patients with acute coronary syndrome (ACS) treated without revascularization remains unknown. The objective was to evaluate and compare the performances of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) bleeding risk scores in the medically managed patients with ACS treated with DAPT.

Methods And Results: TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a double-blind, placebo-controlled randomized trial conducted from 2008 to 2012 over a median follow-up of 17.0 months in 966 sites (52 countries). High-risk patients with unstable angina or non-ST-segment-elevation myocardial infarction who did not undergo revascularization were randomized to prasugrel or clopidogrel. The PRECISE-DAPT, PARIS, and DAPT (bleeding component) risk scores were applied in the TRILOGY ACS population to evaluate their performance to predict adjudicated non-coronary artery bypass grafting-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe/life-threatening/moderate and TIMI (Thrombolysis in Myocardial Infarction) major/minor bleeding with time-dependent c-indices. Among the 9326 participants, median age was 66 years (interquartile range, 59-74 years), and 3650 were females (39.1%). A total of 158 (1.69%) GUSTO severe/life-threatening/moderate and 174 (1.87%) TIMI major/minor non-coronary artery bypass grafting bleeding events occurred. The c-indices (95% CI) of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) scores through 12 months were 0.716 (0.677-0.758), 0.693 (0.658-0.733), and 0.674 (0.637-0.713), respectively, for GUSTO bleeding and 0.624 (0.582-0.666), 0.612 (0.578-0.651), and 0.608 (0.571-0.649), respectively, for TIMI bleeding. There was no significant difference in the c-indices of each score based upon pairwise comparisons.

Conclusions: Among medically managed patients with ACS treated with DAPT, the performances of the PRECISE-DAPT, PARIS, and DAPT (bleeding component) scores were reasonable and similar to their performances in the derivation percutaneous coronary intervention populations. Bleeding risk scores may be used to predict longitudinal bleeding risk in patients with ACS treated with DAPT without revascularization and help support shared decision making. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00699998.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.006582DOI Listing
September 2020

Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

Am J Kidney Dis 2020 12 5;76(6):842-850. Epub 2020 Aug 5.

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.
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http://dx.doi.org/10.1053/j.ajkd.2020.05.026DOI Listing
December 2020

Leveraging electronic health record data for pragmatic randomized trials.

Authors:
Matthew T Roe

Clin Trials 2020 08 15;17(4):368-369. Epub 2020 Jul 15.

Duke Clinical Research Institute, Durham, NC, USA.

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http://dx.doi.org/10.1177/1740774520931036DOI Listing
August 2020

Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI.

J Am Coll Cardiol 2020 07;76(2):162-171

Duke Clinical Research Institute, Durham, North Carolina; Division of Cardiology, Duke University School of Medicine, Durham, North Carolina. Electronic address:

Background: The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.

Objectives: The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.

Methods: In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.

Results: Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).

Conclusions: Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.
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http://dx.doi.org/10.1016/j.jacc.2020.05.031DOI Listing
July 2020

Effect of intervention timing on one-year mortality in elderly non-ST-segment elevation myocardial infarction patients.

Coron Artery Dis 2021 Mar;32(2):138-144

Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University.

Background: The best timing for early invasive therapy in non-ST-segment elevation myocardial infarction (NSTEMI) patients remains controversial. We sought to determine the optimal timing of early catheterization in order to improve long-term outcomes in elderly (>65  years old) patients with NSTEMI.

Methods: Using data from the CRUSADE registry linked to Medicare claims, we evaluated the association of early catheterization within the first 24  h or earlier time cut-points of NSTEMI presentation with long-term mortality among older Medicare beneficiaries.

Results: Of 15  575 NSTEMI patients from 398 CRUSADE hospitals (2003-2006), 3880 (24.9%) received early (≤12  h) catheterization. Compared with those undergoing later catheterization, patients treated early were younger and had less comorbid illness. Relative to those treated later, patients receiving early catheterization had similar 1-year all-cause mortality (11.8% vs 11.9%, P  =  0.90). Using on- vs off-hour presentation as an instrumental variable, balancing potential measured and unmeasured confounders, early and later catheterization patients had nonsignificant differences in 1-year mortality (+5.6% [-11.5%, +22.7%]). Similar results were observed in clinically relevant subgroups, such as age (< or ≥75  years), gender, diabetes status, Global Registry of Acute Coronary Events score (< or ≥140), presence of heart failure, and sensitivity analyses of alternative definitions of early catheterization (≤6 and ≤24  h).

Conclusions: Among older NSTEMI patients, we found that <24  h or earlier (neither <6 nor 12  h) of catheterization timing were not significantly associated with differences in long-term mortality.
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http://dx.doi.org/10.1097/MCA.0000000000000916DOI Listing
March 2021

Comparative Efficacy and Safety of Oral P2Y Inhibitors in Acute Coronary Syndrome: Network Meta-Analysis of 52 816 Patients From 12 Randomized Trials.

Circulation 2020 Jul 29;142(2):150-160. Epub 2020 May 29.

Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University Hospital, Sweden (S.B., L.W., S.J.).

Background: New randomized, controlled trials have become available on oral P2Y inhibitors in acute coronary syndrome. We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor, and clopidogrel in acute coronary syndrome by a meta-analysis of randomized controlled trials.

Methods: We performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from 12 randomized controlled trials including a total of 52 816 patients with acute coronary syndrome.

Results: In comparison with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio [HR], 0.82 [95% CI, 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). In comparison with each other, there were no significant differences in mortality (HR prasugrel versus ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). In comparison with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel versus clopidogrel (28%-50% range of reduction). In comparison with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored.

Conclusions: Prasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison with clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42019155648.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489363PMC
July 2020

Elevated Uric Acid Prevalence and Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction: Insights from RELAX.

Am J Med 2020 12 13;133(12):e716-e721. Epub 2020 May 13.

Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, NC; Duke Clinical Research Institute, Durham, NC.

Purpose: We aimed to 1) describe characteristics of patients with heart failure with preserved ejection fraction (HFpEF) enrolled in RELAX stratified by normal or elevated baseline serum uric acid (sUA) level; 2) evaluate the association between sUA level and surrogate clinical measures; and 3) assess associations between changes in sUA level over time and changes in surrogate clinical measures.

Methods: We analyzed 212 patients with HFpEF and normal or elevated (>6 mg/dL) baseline sUA measurements from the RELAX trial. Variables examined included clinical characteristics, cardiopulmonary exercise testing, 6-minute walk testing, quality of life, echocardiography, and serum biomarker testing. Baseline characteristics between groups were compared and scatter plots with quadratic regression lines and linear regression modeling were used to assess the relationship between baseline sUA and clinical measures. Kaplan-Meier curves were used to describe composite death or cardiovascular/renal hospitalization.

Results: The prevalence of elevated baseline sUA was 68.9%. Patients with elevated sUA had more baseline comorbidities and poorer functional status on cardiopulmonary exercise testing than those without. After adjustment, significant associations between baseline sUA levels and cystatin C, N-terminal pro B-type natriuretic peptide, high-sensitivity troponin I, and high-sensitivity C-reactive protein were identified. Higher baseline sUA was also associated with worsening peak VO, 6-minute walk testing, and left ventricular mass. No significant association was found between baseline sUA levels and the composite of death or cardiovascular/renal hospitalization at 24 weeks.

Conclusion: sUA is an important marker of comorbidities and functional status in patients with HFpEF. Clinical trials of sUA-lowering therapies in patients with HFpEF are promising.
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http://dx.doi.org/10.1016/j.amjmed.2020.03.054DOI Listing
December 2020

Comparison of Characteristics and Outcomes of Patients With Heart Failure With Preserved Ejection Fraction With Versus Without Hyperuricemia or Gout.

Am J Cardiol 2020 07 22;127:64-72. Epub 2020 Apr 22.

Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina.

Hyperuricemia and gout are common in patients with heart failure (HF) and are associated with poor outcomes. Data describing hyperuricemia and gout in patients with HF with preserved ejection fraction (HFpEF) are limited. We used data from the Duke University Health System to describe characteristics of patients with HFpEF and hyperuricemia (serum uric acid >6 mg/dl) or gout (gout diagnosis or gout medication within the previous year) and to explore associations with 5-year outcomes (death and hospitalization). We identified 7,004 patients in the Duke University Health System with a known diagnosis of HFpEF who underwent transthoracic echocardiography between January 1, 2005 and December 31, 2017. A total of 1,136 (16.2%) patients with HFpEF also had hyperuricemia or gout. Patients with HFpEF and hyperuricemia or gout had a greater co-morbidity burden, more echocardiographic findings of cardiac remodeling, and higher unadjusted rates of all-cause death, all-cause hospitalization, and HF hospitalization compared with those with HFpEF without hyperuricemia or gout. After multivariable adjustment, patients with HFpEF and hyperuricemia or gout had a significantly higher rates of first all-cause hospitalization (adjusted hazard ratio 1.10 [95% confidence interval 1.02 to 1.19]; p = 0.020) and recurrent all-cause hospitalization (associated rate ratio 1.13 [95% confidence interval 1.01 to 1.25]; p = 0.026). After adjustment, no significant differences in death or HF hospitalization were observed. In conclusion, patients with HFpEF and hyperuricemia or gout were found to have a higher burden of co-morbidities and a higher rate of all-cause hospitalization, even after multivariable adjustment, compared to patients with HFpEF without hyperuricemia or gout.
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http://dx.doi.org/10.1016/j.amjcard.2020.04.026DOI Listing
July 2020

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial.

J Am Coll Cardiol 2020 05;75(18):2297-2308

Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Université de Paris, French Alliance for Cardiovascular Trials, Institut National de la Santé et de la Recherche Médicale U1148, Paris, France; National Heart and Lung Institute, Imperial College, Royal Brompton Hospital, London, United Kingdom. Electronic address: https://twitter.com/gabrielsteg.

Background: Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.

Objectives: This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.

Methods: A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.

Results: Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.

Conclusions: In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).
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http://dx.doi.org/10.1016/j.jacc.2020.03.029DOI Listing
May 2020

Targeting Vascular Calcification in Chronic Kidney Disease.

JACC Basic Transl Sci 2020 Apr 27;5(4):398-412. Epub 2020 Apr 27.

Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina.

Cardiovascular (CV) disease remains an important cause of morbidity and mortality for patients with chronic kidney disease (CKD). Although clustering of traditional risk factors with CKD is well recognized, kidney-specific mechanisms are believed to drive the disproportionate burden of CV disease. One perturbation that is frequently observed at high rates in patients with CKD is vascular calcification, which may be a central mediator for an array of CV sequelae. This review summarizes the pathophysiological bases of intimal and medial vascular calcification in CKD, current strategies for diagnosis and management, and posits vascular calcification as a risk marker and therapeutic target.
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http://dx.doi.org/10.1016/j.jacbts.2020.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188874PMC
April 2020

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements.

Sci Rep 2020 04 10;10(1):6169. Epub 2020 Apr 10.

National University of Singapore, Singapore, Singapore.

Changes in platelet physiology are associated with simultaneous changes in microRNA concentrations, suggesting a role for microRNA in platelet regulation. Here we investigated potential associations between microRNA and platelet reactivity (PR), a marker of platelet function, in two cohorts following a non-ST elevation acute coronary syndrome (NSTE-ACS) event. First, non-targeted microRNA concentrations and PR were compared in a case (N = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: -0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with PR in the TRILOGY-ACS and independent Singapore post-ACS cohorts, suggesting the measurement of circulating microRNA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.
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http://dx.doi.org/10.1038/s41598-020-63263-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148370PMC
April 2020

Peripheral Artery Disease and Venous Thromboembolic Events After Acute Coronary Syndrome: Role of Lipoprotein(a) and Modification by Alirocumab: Prespecified Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial.

Circulation 2020 May 29;141(20):1608-1617. Epub 2020 Mar 29.

Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA (D.L.B.).

Background: Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C.

Methods: This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-C) for cholesterol content in lipoprotein(a).

Results: At baseline, median lipoprotein(a) and LDL-C were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (=0.0021), and tended to associate with baseline quartile of LDL-C (=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (=0.06), but not LDL-C (=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; =0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; =0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (=0.03), but not LDL-C (=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-C, was associated with the risk of VTE and the composite of VTE and PAD events.

Conclusions: In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242174PMC
May 2020

Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial.

JAMA Cardiol 2020 05;5(5):598-607

Duke Clinical Research Institute, Durham, North Carolina.

Importance: Determining the right dosage of aspirin for the secondary prevention treatment of atherosclerotic cardiovascular disease (ASCVD) remains an unanswered and critical question.

Objective: To report the rationale and design for a randomized clinical trial to determine the optimal dosage of aspirin to be used for secondary prevention of ASCVD, using an innovative research method.

Design, Setting, And Participants: This pragmatic, open-label, patient-centered, randomized clinical trial is being conducted in 15 000 patients within the National Patient-Centered Clinical Research Network (PCORnet), a distributed research network of partners including clinical research networks, health plan research networks, and patient-powered research networks across the United States. Patients with established ASCVD treated in routine clinical practice within the network are eligible. Patient recruitment began in April 2016. Enrollment was completed in June 2019. Final follow-up is expected to be completed by June 2020.

Interventions: Participants are randomized on a web platform in a 1:1 fashion to either 81 mg or 325 mg of aspirin daily.

Main Outcomes And Measures: The primary efficacy end point is the composite of all-cause mortality, hospitalization for nonfatal myocardial infarction, or hospitalization for a nonfatal stroke. The primary safety end point is hospitalization for major bleeding associated with a blood-product transfusion. End points are captured through regular queries of the health systems' common data model within the structure of PCORnet's distributed data environment.

Conclusions And Relevance: As a pragmatic study and the first interventional trial conducted within the PCORnet electronic data infrastructure, this trial is testing several unique and innovative operational approaches that have the potential to disrupt and transform the conduct of future patient-centered randomized clinical trials by evaluating treatments integrated in clinical practice while at the same time determining the optimal dosage of aspirin for secondary prevention of ASCVD.

Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.
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http://dx.doi.org/10.1001/jamacardio.2020.0116DOI Listing
May 2020

Meta-Analysis of Intraocular Bleeding With Dual Antiplatelet Therapy Using P2Y12 Inhibitors Prasugrel or Ticagrelor.

Am J Cardiol 2020 04 29;125(8):1280-1283. Epub 2020 Jan 29.

University of Adelaide and Royal Adelaide Hospital, Adelaide, South Australia. Electronic address:

Intraocular bleeding is a devastating clinical event due to its potentially blinding nature. It is not known if determine if dual antiplatelet therapy using aspirin and potent P2Y12 inhibitors increases this risk. We searched MEDLINE and ClinicalTrials.gov for randomized controlled trials that were phase III, randomly assigned patients to dual antiplatelet therapy with either aspirin and a potent P2Y12 inhibitor or aspirin and clopidogrel, had follow-up of 6 months, and at least 200 patients. Corresponding authors were contacted for intraocular bleeding data. Inverse-variance, weighted, fixed-effects meta-analysis was undertaken, with random-effects meta-analysis performed as a sensitivity analysis. Four trials enrolling 42,850 patients were included. The median follow-up ranged from 12 to 14 months. There was overall low risk of bias. Pooled analysis demonstrated no statistically significant increase in the risk of intraocular bleeding with dual antiplatelet therapy using potent P2Y12 inhibitors compared with clopidogrel (risk ratio 0.89, 95% confidence interval 0.58 to 1.36). There was no significant heterogeneity observed across trials (I statistic 0%, p = 0.98). The use of random-effects meta-analysis did not change the effect estimate or confidence intervals, and the results appeared similar when stratified by potent P2Y12 inhibitor (p = 0.97). In conclusion, this collaborative meta-analysis of dual antiplatelet trials does not suggest that the risk of intraocular bleeding is increased with the use of potent P2Y12 inhibitors compared with clopidogrel. Our results suggest that these potent P2Y12 inhibitors may continue to be used cautiously where indicated as part of dual antiplatelet therapy, even in those at high risk of spontaneous intraocular bleeding.
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http://dx.doi.org/10.1016/j.amjcard.2020.01.012DOI Listing
April 2020

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Circulation 2020 03 29;141(10):843-862. Epub 2020 Jan 29.

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.).

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.041022DOI Listing
March 2020

Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome.

J Am Coll Cardiol 2020 01;75(2):133-144

Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado.

Background: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).

Objectives: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).

Methods: One to 12 months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12 months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.

Results: Baseline lipoprotein(a) levels (median: 21.2 mg/dl; interquartile range [IQR]: 6.7 to 59.6 mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0 mg/dl (IQR: 0 to 13.5 mg/dl), corrected LDL-C by 51.1 mg/dl (IQR: 33.7 to 67.2 mg/dl), and reduced the risk of MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95% CI: 0.990 to 0.999; p = 0.0081).

Conclusions: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).
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http://dx.doi.org/10.1016/j.jacc.2019.10.057DOI Listing
January 2020

Continued investigator engagement: Reasons principal investigators conduct multiple FDA-regulated drug trials.

Contemp Clin Trials Commun 2020 Mar 23;17:100502. Epub 2019 Nov 23.

Clinical Trials Transformation Initiative, Durham, NC, USA.

Background/aims: Numerous reasons have been identified for why U.S.-based principal investigators choose to not continue participating in FDA-regulated trials. However, unexplored are reasons why a substantial number of principal investigators, facing the same challenges, remain engaged in clinical research. This study aimed to both describe barriers and identify factors that contribute to active investigators' success in conducting multiple FDA-regulated trials.

Methods: We conducted qualitative in-depth interviews (IDIs) with "active" multi-trial investigators. Interviews focused on investigators' experiences with FDA-regulated drug trials, challenges faced, and factors contributing to success. Investigators also reflected on previously identified barriers and shared advice for new investigators. Narratives were analyzed using applied thematic analysis.

Results: We interviewed 23 experienced investigators, representing a variety of backgrounds. Most reported that demonstrated ability to conduct a trial led to being approached again by sponsors. Investigators cited infrastructure, staff support, advance planning, and personal qualities as key factors in successfully conducting multiple trials. Nearly all cited difficulties related to trial finances. Three-quarters pointed to challenges with patient recruitment; others described challenges related to data and safety reporting and to the time that trial implementation takes away from other activities. Aspiring investigators were advised to engage in research-specific training and seek out mentorship opportunities.

Conclusion: Investigators in our sample faced many of the same challenges identified in previous research, yet they had evolved strategies to overcome them. The amount and type of support to which investigators have access may represent a crucial difference between "active" investigators and principal investigators who leave FDA-regulated trials.
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http://dx.doi.org/10.1016/j.conctc.2019.100502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926102PMC
March 2020

Antithrombotic Therapy for Atrial Fibrillation with Stable Coronary Disease.

N Engl J Med 2019 12;381(25):2479-2480

Duke Clinical Research Institute, Durham, NC

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http://dx.doi.org/10.1056/NEJMc1914049DOI Listing
December 2019

Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis.

Eur Heart J 2020 06;41(24):2248-2258

Hopital Bichat, Universiteé de Paris, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Assistance Publique-Hopitaux de Paris, Paris, France.

Aims: Lowering low-density lipoprotein cholesterol (LDL-C) reduces cardiovascular risk irrespective of age, but the evidence is less strong for older patients.

Methods And Results: This prespecified analysis from ODYSSEY OUTCOMES compared the effect of alirocumab vs. placebo in 18 924 patients with recent acute coronary syndrome (ACS) according to age. We examined the effect of assigned treatment on occurrence of the primary study outcome, a composite of coronary heart disease death, myocardial infarction, ischaemic stroke, or unstable angina requiring hospitalization [major adverse cardiovascular event (MACE)] and all-cause death. Relative risk reductions were consistent for patients ≥65 vs. <65 years for MACE [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.68-0.91 vs. 0.89, 0.80-1.00; Pinteraction = 0.19] and all-cause death [HR 0.77, 0.62-0.95 vs. 0.94, 0.77-1.15; Pinteraction = 0.46], and consistent for MACE when dichotomizing at age 75 years (HR 0.85, 0.64-1.13 in ≥75 vs. 0.85, 0.78-0.93 in <75, Pinteraction = 0.19). When considering age as a continuous variable in regression models, advancing age increased risk of MACE, as well as the absolute reduction in MACE with alirocumab, with numbers-needed-to-treat for MACE at 3 years of 43 (25-186) at age 45 years, 26 (15-97) at age 75 years, and 12 (6-81) for those at age 85 years. Although adverse events were more frequent in older patients, there were no differences between alirocumab and placebo.

Conclusion: In patients with recent ACS, alirocumab improves outcomes irrespective of age. Increasing absolute benefit but not harm with advancing age suggests that LDL-C lowering is an important preventive intervention for older patients after ACS.
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http://dx.doi.org/10.1093/eurheartj/ehz809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308542PMC
June 2020

Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials.

Am Heart J 2019 12 12;218:110-122. Epub 2019 Sep 12.

Duke University School of Medicine, Durham, NC.

Background: Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes.

Methods: We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection.

Results: Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest.

Conclusions: Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.
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http://dx.doi.org/10.1016/j.ahj.2019.09.002DOI Listing
December 2019

Alirocumab Reduces Total Hospitalizations and Increases Days Alive and Out of Hospital in the ODYSSEY OUTCOMES Trial.

Circ Cardiovasc Qual Outcomes 2019 11 11;12(11):e005858. Epub 2019 Nov 11.

Division of Cardiology, University of Colorado School of Medicine, Aurora, CO (G.G.S.).

Background: In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab was compared with placebo, added to high-intensity or maximum tolerated statin treatment after acute coronary syndrome in 18 924 patients. Alirocumab reduced first occurrence of the primary composite end point-coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or hospitalization for unstable angina-as well as total nonfatal cardiovascular events and all-cause deaths. The present analysis determined whether alirocumab reduced total (first and subsequent) hospitalizations and death and increased days alive and out of hospital (DAOH) and percent DAOH in ODYSSEY OUTCOMES.

Methods And Results: In prespecified analyses, hazard functions for total hospitalizations and death were jointly estimated by a semiparametric model, while in post hoc analyses, DAOH and percent DAOH were compared between treatment groups with Poisson regression and one-inflated beta regression, respectively. With 16 629 total hospitalizations and 726 deaths, 331 fewer hospitalizations, and 58 fewer deaths were observed with alirocumab compared with placebo, translating to 15.6 total hospitalizations or deaths avoided with alirocumab per 1000 patient-years of assigned treatment. Alirocumab reduced total hospitalizations (hazard ratio, 0.96 [95% CI, 0.92-1.00]; =0.04) and increased DAOH relative to placebo (rate ratio, 1.003 [95% CI, 1.000-1.007]; =0.05), primarily through a reduction in days dead (rate ratio, 0.847 [95% CI, 0.728-0.986]; =0.03). Patients randomized to alirocumab were also more likely to survive to the end of the study without hospitalization (odds ratio, 1.06 [95% CI, 1.00-1.13]; =0.03).

Conclusions: Alirocumab reduced total hospitalizations with corresponding small increases in DAOH and percent DAOH. These outcomes provide alternative patient-centered metrics to capture the totality of alirocumab clinical efficacy after acute coronary syndrome.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01663402.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.119.005858DOI Listing
November 2019

Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES.

Circulation 2019 12 11;140(25):2054-2062. Epub 2019 Nov 11.

Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Université de Paris, FACT (French Alliance for Cardiovascular Trials), INSERM U1148, Paris (P.G.S.).

Background: Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C <15 mg/dL. This prespecified analysis was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. We hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and of history of cerebrovascular disease.

Methods: Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed.

Results: Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72 [95% CI, 0.57-0.91]) and ischemic stroke (HR, 0.73 [95% CI, 0.57-0.93]) without increasing hemorrhagic stroke (HR, 0.83 [95% CI, 0.42-1.65]). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of <80, 80 to 100, and >100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity (=0.31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease (=0.37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group.

Conclusions: In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919220PMC
December 2019

Improving and sustaining the site investigator community: Recommendations from the Clinical Trials Transformation Initiative.

Contemp Clin Trials Commun 2019 Dec 17;16:100462. Epub 2019 Oct 17.

Duke Clinical Research Institute, 2400 Pratt St, Durham, NC, 27705, USA.

The Clinical Trials Transformation Initiative (CTTI) Strengthening the Investigator Community Project was prompted by the need to understand the reasons for high rates of turnover among investigators who lead US Food and Administration-regulated clinical trials at research sites. Because investigator knowledge and experience directly affect the quality and ultimate success of clinical trials, investigator turnover has important implications for the research enterprise, as well as the patients and other stakeholders who depend on the outcomes of clinical research. The CTTI project team used findings from both quantitative and qualitative research activities, as well as input from an expert meeting with multiple stakeholders, to delineate key concerns faced by investigators and recommend practical, action-based solutions. The recommendations focus on strengthening four key categories of site-based research activity: developing site-based research infrastructure and staff, optimizing trial execution and conduct, improving site budget development and contract negotiations, and discovering opportunities for conducting additional trials.
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http://dx.doi.org/10.1016/j.conctc.2019.100462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831713PMC
December 2019

Addressing the Conundrum of Bleeding and Cancer Detection With Antithrombotic Therapies for Chronic Atherosclerotic Cardiovascular Disease.

Circulation 2019 10 28;140(18):1460-1462. Epub 2019 Oct 28.

Division of Medical Oncology, Department of Medicine (J.S.), Duke University Medical Center, Durham, NC.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042875DOI Listing
October 2019

Technology-Enabled Clinical Trials: Transforming Medical Evidence Generation.

Circulation 2019 10 21;140(17):1426-1436. Epub 2019 Oct 21.

Duke Clinical Research Institute, Durham, NC (G.M.-G., M.T.R., B.P.-L., E.D.P.).

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040798DOI Listing
October 2019

Revisiting the Role of Aspirin for the Primary Prevention of Cardiovascular Disease.

Circulation 2019 09 23;140(13):1115-1124. Epub 2019 Sep 23.

Duke Clinical Research Institute, Durham, NC (G.M.G., M.T.R., A.F.H., W.S.J.).

Aspirin is the cornerstone of the antithrombotic management of patients with established atherosclerotic cardiovascular disease, but major guidelines provide conflicting recommendations for its use in primary prevention. Findings from recent randomized trials totaling >47 000 patients called into question the net clinical benefits of aspirin in primary prevention for 3 key populations: patients with diabetes mellitus, community-dwelling elderly individuals, and patients without diabetes mellitus who are at intermediate risk for atherosclerotic events. In the context of increasing emphasis on the use of other treatments for primary prevention in patients with moderate-high future risk of developing atherosclerotic cardiovascular disease, the efficacy and safety of aspirin for primary prevention has become uncertain. Key unresolved questions regarding the role of aspirin in primary prevention include the optimal drug formulation, dosing schedule, weight-based dose selection, and interplay between sex and treatment response. In the current era, most patients without established atherosclerotic cardiovascular disease should not be prescribed aspirin. Rather, aggressive management of comorbidities tailored to the expected cardiovascular risk needs to be emphasized. In this context, informed shared decision making between clinicians and patients regarding the use of aspirin for primary prevention of cardiovascular events is a suitable and laudable approach. In this article, we revisit the role of aspirin for the primary prevention of cardiovascular diseases by critically reviewing the key scientific literature, highlight key areas of uncertainties for future research, and propose a decisional framework for clinicians to support prescription of aspirin in primary prevention.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.040205DOI Listing
September 2019

Associations of osteopontin and NT-proBNP with circulating miRNA levels in acute coronary syndrome.

Physiol Genomics 2019 10 18;51(10):506-515. Epub 2019 Sep 18.

Duke Molecular Physiology Institute, Durham, North Carolina.

The genomic regulatory networks underlying the pathogenesis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) are incompletely understood. As intermediate traits, protein biomarkers report on underlying disease severity and prognosis in NSTE-ACS. We hypothesized that integration of dense microRNA (miRNA) profiling with biomarker measurements would highlight potential regulatory pathways that underlie the relationships between prognostic biomarkers, miRNAs, and cardiovascular phenotypes. We performed miRNA sequencing using whole blood from 186 patients from the TRILOGY-ACS trial. Seven circulating prognostic biomarkers were measured: NH-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein, osteopontin (OPN), myeloperoxidase, growth differentiation factor 15, monocyte chemoattractant protein, and neopterin. We tested miRNAs for association with each biomarker with generalized linear models and controlled the false discovery rate at 0.05. Ten miRNAs, including known cardiac-related miRNAs 25-3p and 423-3p, were associated with NT-proBNP levels (min. = 7.5 × 10) and 48 miRNAs, including cardiac-related miRNAs 378a-3p, 20b-5p and 320a, -b, and -d, were associated with OPN levels (min. = 1.6 × 10). NT-proBNP and OPN were also associated with time to cardiovascular death, myocardial infarction (MI), or stroke in the sample. By integrating large-scale miRNA profiling with circulating biomarkers as intermediate traits, we identified associations of known cardiac-related and novel miRNAs with two prognostic biomarkers and identified potential genomic networks regulating these biomarkers. These results, highlighting plausible biological pathways connecting miRNAs with biomarkers and outcomes, may inform future studies seeking to delineate genomic pathways underlying NSTE-ACS outcomes.
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http://dx.doi.org/10.1152/physiolgenomics.00033.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054637PMC
October 2019