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1. Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes A Prespecified Secondary Analysis of a Randomized Clinical Trial

Author

Darren K. McGuire, John P.H. Wilding, Marc S. Sabatine, Avivit Cahn, Thomas A Zelniker, Hiddo J. Lambers Heerspink, Lawrence A. Leiter, KyungAh Im, Itamar Raz, Deepak L. Bhatt, Erica L. Goodrich, Stephen D. Wiviott, Jamie P. Dwyer, Anna Maria Langkilde, Ofri Mosenzon, Ingrid Gause-Nilsson, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Kidney Center (GKC)

Subjects
Male, medicine.medical_specialty, Urology, Renal function, Type 2 diabetes, 030204 cardiovascular system & hematology, Placebo, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Glucosides, medicine, Albuminuria, Humans, 030212 general & internal medicine, Dapagliflozin, Benzhydryl Compounds, Renal Insufficiency, Chronic, Sodium-Glucose Transporter 2 Inhibitors, Aged, Original Investigation, Heart Failure, Creatinine, business.industry, Middle Aged, medicine.disease, Treatment Outcome, chemistry, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Relative risk, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Kidney disease, Glomerular Filtration Rate
Abstract

ImportanceSodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.ObjectiveTo assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).Design, setting, and participantsThis secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (InterventionsDapagliflozin vs placebo.Main outcomes and measuresThe dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.ResultsAt baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.Conclusions and relevanceThe effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.Trial registrationClinicalTrials.gov Identifier: NCT01730534.

Published
2021

2. Causes and Risk Factors for Death in Diabetes

Author

Benjamin M. Scirica, Darren K. McGuire, Deepak L. Bhatt, Eugene Braunwald, KyungAh Im, Itamar Raz, Ilaria Cavallari, Ph. Gabriel Steg, Lawrence A. Leiter, and Ofri Mosenzon

Subjects
medicine.medical_specialty, business.industry, Diabetes mellitus, Internal medicine, medicine, MEDLINE, Cardiology and Cardiovascular Medicine, medicine.disease, Competing risks, business, TIMI
Published
2021

3. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials

Author

Anthony C Keech, Nicholas A Marston, Christopher P. Cannon, Eugene Braunwald, KyungAh Im, Marc S. Sabatine, Peter S. Sever, Baris Gencer, and Robert P. Giugliano

Subjects
Acute coronary syndrome, medicine.medical_specialty, Statin, medicine.drug_class, Myocardial Infarction, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ezetimibe, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Stroke, Aged, Randomized Controlled Trials as Topic, business.industry, Cholesterol, Anticholesteremic Agents, PCSK9, Cholesterol, LDL, General Medicine, medicine.disease, Treatment Outcome, chemistry, Cardiovascular Diseases, Relative risk, business, Risk Reduction Behavior, medicine.drug
Abstract

Summary Background The clinical benefit of LDL cholesterol lowering treatment in older patients remains debated. We aimed to summarise the evidence of LDL cholesterol lowering therapies in older patients. Methods In this systematic review and meta-analysis, we searched MEDLINE and Embase for articles published between March 1, 2015, and Aug 14, 2020, without any language restrictions. We included randomised controlled trials of cardiovascular outcomes of an LDL cholesterol-lowering drug recommended by the 2018 American College of Cardiology and American Heart Association guidelines, with a median follow-up of at least 2 years and data on older patients (aged ≥75 years). We excluded trials that exclusively enrolled participants with heart failure or on dialysis because guidelines do not recommend lipid-lowering therapy in such patients who do not have another indication. We extracted data for older patients using a standardised data form for aggregated study-level data. We meta-analysed the risk ratio (RR) for major vascular events (a composite of cardiovascular death, myocardial infarction or other acute coronary syndrome, stroke, or coronary revascularisation) per 1 mmol/L reduction in LDL cholesterol. Findings Data from six articles were included in the systematic review and meta-analysis, which included 24 trials from the Cholesterol Treatment Trialists' Collaboration meta-analysis plus five individual trials. Among 244 090 patients from 29 trials, 21 492 (8·8%) were aged at least 75 years, of whom 11 750 (54·7%) were from statin trials, 6209 (28·9%) from ezetimibe trials, and 3533 (16·4%) from PCSK9 inhibitor trials. Median follow-up ranged from 2·2 years to 6·0 years. LDL cholesterol lowering significantly reduced the risk of major vascular events (n=3519) in older patients by 26% per 1 mmol/L reduction in LDL cholesterol (RR 0·74 [95% CI 0·61–0·89]; p=0·0019), with no statistically significant difference with the risk reduction in patients younger than 75 years (0·85 [0·78–0·92]; pinteraction=0·37). Among older patients, RRs were not statistically different for statin (0·82 [0·73–0·91]) and non-statin treatment (0·67 [0·47–0·95]; pinteraction=0·64). The benefit of LDL cholesterol lowering in older patients was observed for each component of the composite, including cardiovascular death (0·85 [0·74–0·98]), myocardial infarction (0·80 [0·71–0·90]), stroke (0·73 [0·61–0·87]), and coronary revascularisation (0·80 [0·66–0·96]). Interpretation In patients aged 75 years and older, lipid lowering was as effective in reducing cardiovascular events as it was in patients younger than 75 years. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin treatment, in older patients. Funding None.

Published
2020

4. Cognition After Lowering LDL-Cholesterol With Evolocumab

Author

Brian R. Ott, Fourier Investigators, Marc S. Sabatine, KyungAh Im, Huei Wang, Jianping Guo, Baris Gencer, Anthony C Keech, Christopher E. Kurtz, Terje R. Pedersen, Robert P. Giugliano, François Mach, and Andrea Ruzza

Subjects
Adult, Male, medicine.medical_specialty, Statin, medicine.drug_class, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Placebo, 03 medical and health sciences, chemistry.chemical_compound, Cognition, 0302 clinical medicine, Double-Blind Method, Internal medicine, medicine, Humans, Cognitive Dysfunction, 030212 general & internal medicine, Effects of sleep deprivation on cognitive performance, Cognitive decline, Aged, Aged, 80 and over, business.industry, Cholesterol, Anticholesteremic Agents, PCSK9, Cholesterol, LDL, Middle Aged, Atherosclerosis, Evolocumab, chemistry, Cardiovascular Diseases, Drug Therapy, Combination, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business
Abstract

The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C 20 mg/dl.

Published
2020

5. Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography

Author

Marc S. Sabatine, Remo H.M. Furtado, Jianping Guo, L. Kristin Newby, KyungAh Im, Jose C. Nicolau, Jennifer A. White, and Robert P. Giugliano

Subjects
Male, medicine.medical_specialty, Acute coronary syndrome, 030204 cardiovascular system & hematology, Coronary Angiography, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, ST segment, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Non-ST Elevated Myocardial Infarction, Aged, Morphine, business.industry, Hazard ratio, Odds ratio, Middle Aged, Clopidogrel, medicine.disease, Analgesics, Opioid, Treatment Outcome, Concomitant, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Platelet Aggregation Inhibitors, medicine.drug
Abstract

Background Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial. Objectives This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls. Methods Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days. Results In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; pinteraction = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; pinteraction = 0.46). Conclusions When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome; NCT00089895 )

Published
2020

6. Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54

Author

KyungAh Im, P. Gabriel Steg, Remo H.M. Furtado, Eugene Braunwald, Róbert Gábor Kiss, Ramón Corbalán, Andrzej Budaj, Eva C. Jensen, Frederic Kontny, Robert F. Storey, Giulia Magnani, Maria Teresa B. Abola, Jindrich Spinar, Jose C. Nicolau, Per Johanson, Deepak L. Bhatt, Marc P. Bonaca, and Marc S. Sabatine

Subjects
Relative risk reduction, Ticagrelor, medicine.medical_specialty, Adenosine, Myocardial Infarction, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Secondary Prevention, Humans, Medicine, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Stroke, Aspirin, business.industry, Hazard ratio, medicine.disease, Treatment Outcome, Purinergic P2Y Receptor Antagonists, Cardiology, Drug Therapy, Combination, Cardiology and Cardiovascular Medicine, business, Platelet Aggregation Inhibitors, Mace, TIMI, medicine.drug
Abstract

Aims PEGASUS-TIMI 54 demonstrated that long-term dual antiplatelet therapy (DAPT) with aspirin and ticagrelor reduced the risk of major adverse cardiovascular events (MACE), with an acceptable increase in bleeding, in patients with prior myocardial infarction (MI). While much of the discussion around prolonged DAPT has been focused on stented patients, patients with prior MI without prior coronary stenting comprise a clinically important subgroup. Methods and results This was a pre-specified analysis from PEGASUS-TIMI 54, which randomized 21 162 patients with prior MI (1–3 years) and additional high-risk features to ticagrelor 60 mg, 90 mg, or placebo twice daily in addition to aspirin. A total of 4199 patients had no history of coronary stenting at baseline. The primary efficacy outcome (MACE) was the composite of cardiovascular death, MI, or stroke. Patients without history of coronary stenting had higher baseline risk of MACE [13.2% vs. 8.0%, adjusted hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.15–1.73, in the placebo arm]. The relative risk reduction in MACE with ticagrelor (pooled doses) was similar in patients without (HR 0.82, 95% CI 0.68–0.99) and with prior stenting (HR 0.85, 95% CI 0.75–0.96; P for interaction = 0.76). Conclusion Long-term ticagrelor reduces thrombotic events in patients with prior MI regardless of whether they had prior coronary stenting. These data highlight the benefits of DAPT in prevention of spontaneous atherothrombotic events and indicate that long-term ticagrelor may be considered in high-risk patients with prior MI even if they have not been treated with stenting. ClinicalTrials.gov Identifier NCT01225562.

Published
2019

7. Long-Term Ticagrelor in Patients With Prior Coronary Stenting in the PEGASUS-TIMI 54 Trial

Author

KyungAh Im, Robert F. Storey, Marc P. Bonaca, Christian W. Hamm, Andrzej Budaj, Brian A. Bergmark, Róbert Gábor Kiss, Per Johanson, Julia F Kuder, Frans Van de Werf, Jindřich Špinar, Deepak L. Bhatt, Giulia Magnani, Eugene Braunwald, Ton Oude Ophuis, Marc S. Sabatine, Gilles Montalescot, Yared Gurmu, P. Gabriel Steg, Harvard Medical School [Boston] (HMS), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Medical Center of Postgraduate Education [Warsaw] (MCPE), University of Sheffield [Sheffield], University Hospital of Parma [Parme, Italie], Canisius-Wilhelmina Hospital [Nijmegen, The Netherlands], Universität Giessen [Germany], St. Anne’s University Hospital [Brno], University Hospitals Leuven [Leuven], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AstraZeneca, and University of Colorado Anschutz [Aurora]

Subjects
Ticagrelor, Cardiac & Cardiovascular Systems, medicine.medical_treatment, Myocardial Infarction, Coronary Artery Disease, SECONDARY PREVENTION, 030204 cardiovascular system & hematology, antiplatelet therapy, PRIOR MYOCARDIAL-INFARCTION, 0302 clinical medicine, Clinical Studies, Secondary Prevention, Stent, Coronary Heart Disease, 030212 general & internal medicine, Stent thrombosis, Original Research, DUAL ANTIPLATELET THERAPY, Coronary stenting, Drug-Eluting Stents, PCI, 3. Good health, Stroke, Treatment Outcome, CLOPIDOGREL, Cardiology, Drug Therapy, Combination, Stents, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, TIMI, medicine.drug, Acute coronary syndrome, medicine.medical_specialty, Hemorrhage, P2Y12 inhibitor, acute coronary syndrome, 03 medical and health sciences, ATHEROTHROMBOTIC RISK STRATIFICATION, Percutaneous Coronary Intervention, INFLAMMATION, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Coronary stent, medicine, Diseases of the circulatory (Cardiovascular) system, Humans, In patient, cardiovascular diseases, P2Y(12) inhibitor, Pharmacology, Science & Technology, business.industry, RIVAROXABAN, Thrombosis, medicine.disease, equipment and supplies, ASPIRIN, ATHEROSCLEROSIS, RC666-701, Conventional PCI, Cardiovascular System & Cardiology, VORAPAXAR, business, Platelet Aggregation Inhibitors
Abstract

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long‐term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS‐TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug‐eluting stent and first‐ versus later‐generation drug‐eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelor pooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75–96) regardless of stent type (bare metal stent versus drug‐eluting stent: p interaction =0.767; first versus later generation: p interaction =0.940). The rate of any stent thrombosis was numerically lower with ticagrelor pooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50–1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90–3.68). Conclusions Long‐term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

Published
2021

8. A Targeted Proteomic Approach Identifies Novel Biomarkers of Arterial Thromboembolic Risk in ENGAGE AF-TIMI 48

Author

KyungAh Im, Howard Rutman, Elliott M. Antman, Christian T. Ruff, Minao Tang, Petr Jarolim, Robert P. Giugliano, David A. Morrow, David D. Berg, and Eugene Braunwald

Subjects
Oncology, Male, Proteomics, medicine.medical_specialty, Pyridines, MEDLINE, Hemorrhage, Risk Assessment, Article, Risk Factors, Internal medicine, Thromboembolism, Atrial Fibrillation, medicine, Humans, Randomized Controlled Trials as Topic, business.industry, Middle Aged, Thromboembolic risk, Thiazoles, Female, Cardiology and Cardiovascular Medicine, business, TIMI, Biomarkers, Factor Xa Inhibitors
Published
2021

9. Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction

Author

Eugene Braunwald, Brian A. Bergmark, Yared Gurmu, Estella Kanevsky, KyungAh Im, Avivit Cahn, Itamar Raz, Benjamin M. Scirica, Deepak L. Bhatt, Ph. Gabriel Steg, Darren K. McGuire, Investigators, and Ofri Mosenzon

Subjects
Male, Risk, medicine.medical_specialty, 030204 cardiovascular system & hematology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, Diabetes mellitus, Post-hoc analysis, medicine, Humans, Hypoglycemic Agents, 030212 general & internal medicine, Aged, Heart Failure, business.industry, Kidney dysfunction, Type 2 Diabetes Mellitus, Middle Aged, medicine.disease, Survival Analysis, Metformin, Treatment Outcome, Diabetes Mellitus, Type 2, Heart failure, Cardiology, Female, Kidney Diseases, Cardiology and Cardiovascular Medicine, business, Biomarkers, TIMI, Follow-Up Studies, medicine.drug
Abstract

Background: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved. Methods: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models. Results: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min −1 ·1.73 m −2 ). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76–1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59–0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease. Conclusions: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01107886.

Published
2019

10. Lorcaserin and Renal Outcomes in Obese and Overweight Patients in the CAMELLIA-TIMI 61 Trial

Author

KyungAh Im, Silvio E. Inzucchi, Arman Qamar, Milan Gupta, Marc S. Sabatine, Anthony C Keech, Sabina A. Murphy, Jamie P. Dwyer, Marc P. Bonaca, Benjamin M. Scirica, Investigators, Tushar Patel, Darren K. McGuire, Wenfeng Miao, Lawrence A. Leiter, Carlos Perdomo, Erin A. Bohula, Christian T. Ruff, Stephen D. Wiviott, and Steven R. Smith

Subjects
Male, medicine.medical_specialty, Time Factors, Diet, Reducing, Blood Pressure, Disease, 030204 cardiovascular system & hematology, Overweight, Kidney, Risk Assessment, Lorcaserin, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Risk Factors, Weight loss, Physiology (medical), Internal medicine, Appetite Depressants, Weight Loss, medicine, Humans, Obesity, 030212 general & internal medicine, Glycated Hemoglobin, Appetite Regulation, business.industry, Benzazepines, Middle Aged, medicine.disease, Treatment Outcome, medicine.anatomical_structure, Disease Progression, Albuminuria, Cardiology, Female, Kidney Diseases, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Risk Reduction Behavior, Biomarkers, Serotonin 5-HT2 Receptor Agonists, TIMI, Glomerular Filtration Rate, medicine.drug
Abstract

Background: Obesity is thought to increase renal hyperfiltration, thereby increasing albuminuria and the progression of renal disease. The effect of pharmacologically mediated weight loss on renal outcomes is not well-described. Lorcaserin, a selective serotonin 2C receptor agonist that promotes appetite suppression, led to sustained weight loss without any increased risk for major adverse cardiovascular (CV) events in the CAMELLIA-TIMI 61 trial (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients-Thrombolysis in Myocardial Infarction 61). Methods: CAMELLIA-TIMI 61 randomly assigned 12 000 overweight or obese patients with or at high risk for atherosclerotic CV disease to lorcaserin or placebo on a background of lifestyle modification. The primary renal outcome was a composite of new or worsening persistent micro- or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death. Results: At baseline, 23.8% of patients had an estimated glomerular filtration rate (eGFR) −1 ·1.73 m −2 and 19.0% had albuminuria (urinary albumin:creatinine ratio ≥30 mg/g). Lorcaserin reduced the risk of the primary renal composite outcome (4.2% per year versus 4.9% per year; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.79–0.96; P =0.0064). The benefit was consistent across subpopulations at increased baseline CV and renal risk. Lorcaserin improved both eGFR and urinary albumin:creatinune ratio within the first year after randomization. The effect of lorcaserin on weight, hemoglobin A1c, and systolic blood pressure was consistent regardless of baseline renal function. Likewise, there was no excess in cardiovascular events in patients assigned to lorcaserin in comparison with placebo, regardless of renal function. After adjustment for baseline characteristics, those with evidence of kidney disease were at increased risk of major CV events. Compared with patients with an eGFR ≥90 mL·min −1 ·1.73 m −2 , those with an eGFR 60-90 and those −1 ·1.73 m–2 had HRs of 1.25 (95% CI, 1.01, 1.56) and 1.51 (95% CI, 1.17, 1.95), respectively ( P for trend 0.0015). Likewise, compared with patients with no albuminuria (P for trend Conclusions: Renal dysfunction was associated with increased CV risk in overweight and obese patients. When added to diet and lifestyle, lorcaserin reduced the rate of new-onset or progressive renal impairment in comparison with placebo. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02019264.

Published
2019

11. Prevalence and Outcomes of Polyvascular (Coronary, Peripheral, or Cerebrovascular) Disease in Patients With Diabetes Mellitus (From the SAVOR-TIMI 53 Trial)

Author

Marc P. Bonaca, KyungAh Im, Ph. Gabriel Steg, Ofri Mosenzon, Deepak L. Bhatt, Benjamin M. Scirica, Eugene Braunwald, Itamar Raz, Boaz Hirshberg, and Jorge Antonio Gutierrez

Subjects
Male, medicine.medical_specialty, Adamantane, Coronary Disease, Disease, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, Risk Factors, law, Internal medicine, Diabetes mellitus, Prevalence, medicine, Clinical endpoint, Humans, 030212 general & internal medicine, Myocardial infarction, Aged, Peripheral Vascular Diseases, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Hazard ratio, Type 2 Diabetes Mellitus, Dipeptides, Middle Aged, medicine.disease, Cerebrovascular Disorders, Treatment Outcome, Diabetes Mellitus, Type 2, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, TIMI
Abstract

We sought to assess the prevalence of polyvascular disease in patients with type 2 diabetes mellitus (T2DM) and its impact on ischemic events. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53, a large contemporary, randomized trial, evaluated the effect of saxagliptin versus placebo in 16,492 patients with T2DM and a history of or at risk for cardiovascular (CV) events. Polyvascular disease was defined as a history of clinical events involving 2 or more vascular beds (coronary, peripheral, or cerebrovascular system) at the time of randomization. The primary composite endpoint of CV death, myocardial infarction, or ischemic stroke was compared according to the number of diseased arterial beds. At the time of randomization, 3,667 (22.2%) patients had risk factors for CV events; 11,423 (69.3%) had established 1 arterial bed disease; 1,298 (7.9%) had 2 bed disease; and 104 (0.6%) had 3 bed disease. Compared with diabetic patients with no established atherosclerosis, the adjusted hazard ratio for the composite primary end point in 1, 2, or 3 diseased beds was 1.95, 3.54, and 4.64, respectively (trend p < 0.0001). The adjusted risk for overall mortality increased in a similar stepwise fashion from 1.47 to 2.33 to 3.12, respectively (trend p = 0.0001) with each additional diseased arterial territory. In conclusion, in patients with confirmed atherosclerosis enrolled in SAVOR-TIMI 53, 11% had polyvascular disease; and compared with diabetic patients with single bed disease, the risk of ischemic events and overall mortality was substantially higher in patients with T2DM and polyvascular disease.

Published
2019

12. Sex, Permanent Drug Discontinuation, and Study Retention in Clinical Trials: Insights From the TIMI trials

Author

Elliott M. Antman, Marc S. Sabatine, Michelle L. O'Donoghue, Erin A. Bohula, David A. Morrow, Marc P. Bonaca, KyungAh Im, Benjamin M. Scirica, Stephen D. Wiviott, Deepak L. Bhatt, Eugene Braunwald, Emily S. Lau, Jianping Guo, C. Michael Gibson, Robert P. Giugliano, and Christopher P. Cannon

Subjects
Male, medicine.medical_specialty, Study drug, Drug discontinuation, business.industry, Middle Aged, Clinical trial, Sex Factors, Drug Therapy, Physiology (medical), Internal medicine, Early Termination of Clinical Trials, medicine, Humans, Female, Cardiology and Cardiovascular Medicine, business, TIMI, Aged
Abstract

Background: Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug or withdraw consent once enrolled in a clinical trial is unknown. Methods: Eleven phase 3/4 TIMI (Thrombolysis in Myocardial Infarction) trials were included (135 879 men and 51 812 women [28%]). The association between sex and premature study drug discontinuation and withdrawal of consent were examined by multivariable logistic regression after adjusting for potential confounders in each individual trial and combining the individual point estimates in random effects models. Results: After adjusting for baseline differences, women had 22% higher odds of premature drug discontinuation (adjusted odds ratio [OR adj ], 1.22 [95% CI, 1.16–1.28]; P adj , 1.20 [95% CI, 1.13–1.27]) and active therapy arms (OR adj , 1.23 [95% CI, 1.17–1.30)]; there was some evidence for regional heterogeneity ( P interaction P =0.60). Women were also more likely to withdraw consent compared with men (OR adj , 1.26 [95% CI, 1.17–1.36]; P Conclusions: Women were more likely than men to prematurely discontinue study drug and withdraw consent across cardiovascular outcome trials. Premature study drug discontinuation was not explained by baseline differences by sex or a higher proportion of adverse events. Future trials should better capture reasons for drug discontinuation and withdrawal of consent to understand barriers to continued study drug use and clinical trial participation, particularly among women.

Published
2021

13. Predictors, Type, and Impact of Bleeding on the Net Clinical Benefit of Long‐Term Ticagrelor in Stable Patients With Prior Myocardial Infarction

Author

Gabriel Kamensky, Alexander Parkhomenko, Marc S. Sabatine, Ton Oude Ophius, Andrzej Budaj, Eugene Braunwald, Deepak L. Bhatt, Jose Lopez-Sendon, Per Johanson, Diego Ardissino, Marc P. Bonaca, P. Gabriel Steg, Marc Cohen, KyungAh Im, Giulia Magnani, Dominick J. Angiolillo, Assen Goudev, and Robert F. Storey

Subjects
medicine.medical_specialty, Ticagrelor, Hemorrhage, Coronary Artery Disease, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, benefit‐risk ratio, Coronary Heart Disease, Humans, Diseases of the circulatory (Cardiovascular) system, In patient, 030212 general & internal medicine, Myocardial infarction, Survival rate, Original Research, Aspirin, business.industry, Incidence (epidemiology), Follow up studies, Thrombosis, medicine.disease, bleeding, myocardial infarction, RC666-701, Cardiology, long‐term ticagrelor, Platelet aggregation inhibitor, Cardiology and Cardiovascular Medicine, business, Acute Coronary Syndromes, medicine.drug
Abstract

Background Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. Methods and Results PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin—Thrombolysis in Myocardial Infarction 54) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long‐term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3‐fold higher rates of bleeding with ticagrelor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; P =0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65–0.96; P interaction = 0.03). Conclusions In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor. Registration URL https://www.clinicaltrials.gov/ . Unique identifier: NCT01225562.

Published
2021

14. Abstract 13787: Efficacy of Lowering Low-density Lipoprotein Cholesterol in Elderly Subjects: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Author

KyungAh Im, Marc S. Sabatine, Robert P. Giugliano, Anthony C Keech, Nicholas A Marston, Baris Gencer, and Peter S. Sever

Subjects
medicine.medical_specialty, business.industry, PCSK9, Low density lipoprotein cholesterol, law.invention, Clinical trial, Randomized controlled trial, law, Physiology (medical), Internal medicine, Meta-analysis, Medicine, In patient, Cardiology and Cardiovascular Medicine, business
Abstract

Introduction: The clinical benefit from LDL-C lowering therapy in the elderly remains debated. Aim: To synthesize the efficacy of lowering LDL-C in patients aged ≥75 years in the light of most recently published data. Methods: Medline database was searched for the most recent evidence (2015-2020). The key inclusion criterion was a randomized controlled cardiovascular outcome trial testing an LDL-C lowering therapy with data available in patients aged ≥75 years at randomization. For efficacy, we meta-analyzed the risk ratio (RR) of major vascular events (a composite of cardiovascular (CV) death, myocardial infarction, stroke or coronary revascularization) per 1-mmol/L reduction in LDL-C. Results: Among 244,090 patients from 29 trials, 21,492 (8.8%) were elderly; 11,750 from statin trials, 6209 from ezetimibe trials, and 3533 from PCSK9 inhibitor trials. Median follow-up ranged from 2.2-6.0 years. LDL-C lowering therapy significantly reduced major vascular events (n=3519) in the elderly by 26% per 1-mmol/L LDL-C reduction (RR 0.74 [0.61-0.89], P=0.002), which was at least as good as the magnitude of effect seen in the non-elderly patients (RR 0.85 [0.78-0.92]; P interaction =0.24). Amongst the elderly, the RR was similar for statin (0.81 [0.70-0.94]) and non-statin therapy (0.67 [0.47-0.95]; P interaction =0.60). The benefit of LDL-C lowering in the elderly was observed for each component of the composite, including CV death (RR 0.85 [0.73-0.996], P=0.045), myocardial infraction (RR 0.80 [0.70-0.92], P=0.001), stroke (RR 0.71 [0.58-0.87], P=0.001) and coronary revascularization (RR 0.78 [0.63-0.96], P=0.017). Conclusion: In patients 75 years and older, lipid-lowering therapy is as effective in reducing CV events as it is in younger adults. These results should strengthen guideline recommendations for the use of lipid-lowering therapies, including non-statin therapy, in the elderly.

Published
2020

15. Abstract 16139: A Targeted Proteomic Approach to Identify Circulating Biomarkers of Heart Failure Risk in Patients With Type 2 Diabetes Mellitus in DECLARE-TIMI 58

Author

Darren K. McGuire, Itamar Raz, Marc S. Sabatine, Deepak L. Bhatt, John P.H. Wilding, Frederick K. Kamanu, David D. Berg, Ofri Mosenzon, Diego Ardissino, Petr Jarolim, Jose Lopez-Sendon, David A. Morrow, KyungAh Im, Lawrence A. Leiter, Ingrid Gause-Nilsson, Yong Huo, Stephen D. Wiviott, and Avivit Cahn

Subjects
medicine.medical_specialty, business.industry, Type 2 Diabetes Mellitus, medicine.disease, Circulating biomarkers, Physiology (medical), Internal medicine, Heart failure, medicine, Cardiology, In patient, Cardiology and Cardiovascular Medicine, business, TIMI
Abstract

Background: Patients (pts) with type 2 diabetes mellitus (T2DM) are at increased risk of heart failure (HF); however, the underlying mechanisms by which T2DM contributes to HF are incompletely understood. Hypothesis: We aimed to identify biological pathways associated with risk of hospitalization for HF (HHF) in a well-characterized cohort with T2DM followed for a median of 4.2 yrs. Methods: DECLARE-TIMI 58 was a randomized trial of dapagliflozin in pts with T2DM. We performed a nested case-control study of 184 candidate biomarkers (Olink CV II and CV III) in pts hospitalized for HF (n=432) and controls matched on age, sex, prior HF, prior CV disease, and f/u time (n=432). We evaluated associations between baseline biomarkers and HHF using logistic regression with a stringent threshold for significance (Bonferroni). Biomarkers were ranked according to Wald χ 2 values. ORs for the top 10 biomarkers were further adjusted for the components of the TIMI Risk Score for HF in Diabetes (AF, UACR, eGFR, CAD). ORs are per 1-SD. Results: 45 biomarkers were significantly associated with HHF. The 10 strongest associations were seen with N-terminal pro-B type natriuretic peptide (NT-proBNP), B type natriuretic peptide (BNP), spondin-1 (SPON1), insulin-like growth factor-binding protein 7 (IGFBP7), interleukin-6 (IL-6), fibroblast growth factor-23 (FGF-23), transferrin receptor protein 1 (TR), metalloproteinase inhibitor 4 (TIMP4), matrix metalloproteinase-2 (MMP-2), C-X-C motif chemokine 16 (CXCL16) ( Fig ). All 10 biomarkers were significantly associated with HHF both in pts with and without a history of HF. These proteins represent pathobiological axes implicated in hemodynamic stress, inflammation, myocardial hypertrophy, and cellular senescence, among others. Conclusions: A targeted proteomic approach identified established (NT-proBNP, BNP), investigational (IGFBP7, FGF-23, IL-6, TR, TIMP4, MMP-2, CXCL16), and novel (SPON1) biomarkers of HHF in pts with T2DM.

Published
2020

16. Modes and timing of death in 66 252 patients with non-ST-segment elevation acute coronary syndromes enrolled in 14 TIMI trials

Author

KyungAh Im, Elliott M. Antman, Michelle L. O'Donoghue, L. Kristin Newby, Eugene Braunwald, Amir Kashani, Deepak L. Bhatt, C. Michael Gibson, Marc S. Sabatine, Robert P. Giugliano, David A. Morrow, Stephen D. Wiviott, David D. Berg, Jianping Guo, Christopher P. Cannon, and Jessica L. Mega

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Myocardial Infarction, 030204 cardiovascular system & hematology, Sudden death, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Clinical Research, Interquartile range, Internal medicine, Epidemiology, medicine, Humans, ST segment, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Aged, business.industry, Thrombolysis, Middle Aged, medicine.disease, Death, Sudden, Cardiac, Editorial, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, TIMI, Cohort study
Abstract

Aims Although presenting features and early sequelae of non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are well described, less is known about longer-term risks and modes of death. The purpose of this study was to characterize modes of death following NSTE-ACS in clinical trial populations. Methods and results We evaluated 66 252 patients with NSTE-ACS enrolled in 14 Thrombolysis in Myocardial Infarction (TIMI) trials, examining baseline characteristics and modes and timing of death. Of the 66 252 patients followed for a median of 372 (interquartile range 218-521) days, 3147 (4.8%) died by the time of last follow-up. Of the 2606 patients (82.8%) with known modes of death, 75.1% were related to a cardiovascular (CV) event, 3.0% were related to a bleeding event (including intracranial haemorrhage), and 21.8% were related to a non-CV/non-bleeding event. The most common modes of CV death were sudden death (SD) and recurrent myocardial infarction (MI) (36.4% and 23.4%, respectively, of CV deaths). The proportion of CV deaths related to recurrent MI was higher in the first 30 days than it was after 30 days following NSTE-ACS (30.6% vs. 18.7%), whereas the proportion of SD was lower in the first 30 days than after 30 days (21.6% vs. 46.2%). Conclusion Sudden death represents the largest proportion of CV deaths after 30 days among patients enrolled in CV clinical trials with NSTE-ACS. Further investigations aimed at defining the epidemiology of SD and developing specific therapies and management approaches to reduce SD following NSTE-ACS may be critical to reducing late mortality.

Published
2018

17. LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial

Author

Terje R. Pedersen, Marc S. Sabatine, Ioanna Gouni-Berthold, Beat Knusel, Robert P. Giugliano, Anthony C Keech, Huei Wang, Peter S. Sever, KyungAh Im, Michelle L. O'Donoghue, Amgen Inc, and Univ of Sydney (original funder Amgen Inc)

Subjects
Male, 2019-20 coronavirus outbreak, medicine.medical_specialty, Cardiac & Cardiovascular Systems, STATIN THERAPY, Epidemiology, 030204 cardiovascular system & hematology, Age and sex, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Patient age, Internal medicine, gender, LDL-cholesterol, Medicine, Humans, In patient, 030212 general & internal medicine, Angina, Unstable, Adverse effect, Aged, Ldl cholesterol, Science & Technology, business.industry, Anticholesteremic Agents, Antibodies, Monoclonal, Cholesterol, LDL, cardiovascular outcomes, Evolocumab, Treatment Outcome, evolocumab, age, Child, Preschool, Cardiovascular System & Cardiology, LDL Cholesterol Lipoproteins, Female, Proprotein Convertase 9, PRIMARY PREVENTION, Cardiology and Cardiovascular Medicine, business, Life Sciences & Biomedicine
Abstract

Aims Some trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor. Methods and results FOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan–Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72–0.96, Q2 0.88, 0.76–1.01, Q3 0.82, 0.71–0.95, Q4 0.86, 0.74–1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61–0.89), Q2 0.83 (0.69–1.00), Q3 0.78 (0.65–0.94), Q4 0.82 (0.69–0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan–Meier at 3 years 12.5 vs. 15.3%, respectively, P Conclusions The efficacy and safety of evolocumab are similar throughout a broad range of ages and in both men and women.

Published
2019

18. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study

Author

Michael R McClung, Michelle L O'Donoghue, Socrates E Papapoulos, Henry Bone, Bente Langdahl, Kenneth G Saag, Ian R Reid, Douglas P Kiel, Ilaria Cavallari, Marc P Bonaca, Stephen D Wiviott, Tobias de Villiers, Xu Ling, Kurt Lippuner, Toshitaka Nakamura, Jean-Yves Reginster, Jose Adolfo Rodriguez-Portales, Christian Roux, José Zanchetta, Cristiano A F Zerbini, Jeong-Gun Park, KyungAh Im, Abby Cange, Laura T Grip, Norman Heyden, Carolyn DaSilva, Dosinda Cohn, Rachid Massaad, Boyd B Scott, Nadia Verbruggen, Deborah Gurner, Deborah L Miller, Micki L Blair, Adam B Polis, S Aubrey Stoch, Arthur Santora, Antonio Lombardi, Albert T Leung, Keith D Kaufman, Marc S Sabatine, Carlos Alfredo Mautalén, Zulema Man, Jose Ruben Zanchetta, Clelia Haydee Magaril, Philip Sambrook, Piet Geusens, Stefan Goemaere, Ben Hur Albergaria, Cristiano Augusto de Freitas Zerbini, Marise Lazaretti Castro, Luiz Henrique Gregorio, Rumen Stoilov, Anna-Maria I Borissova, Kiril Hristov Hristozov, Nataliya L Temelkova, Ivona Kirilova Daskalova, Stefka Ivanova Kuzmanova, Daniela Yaneva-Bichovska, Anastas Zgurov Batalov, Pablo Riedemann, José Adolfo Rodriguez Portales, Hai Tang, hanmin Zhu, Zhenlin Zhang, Aijun Chao, Yali Hu, Zhiming Liu, Juming Lu, Mingcai Qiu, Xin Gao, Shaofen Zhang, Ling Xu, Weibo Xia, Eryuan Liao, Wenying Yang, Wen Wu, Kerong Dai, Renming Hu, Juan Jose Jaller, Francisco Cabal, José Fernando Molina, Carlos A Cure Cure, Hernan Yupanqui-Lozno, Philippe Chalem, John Londono, Mauricio Abello, Edgardo D Tobias, William Otero, Tatjana Nikolic, Blazenka Miskic, Jan Stepan, Vaclav Vyskocil, Libor Novosad, Jan Slesinger, Pavel Novosad, Erika Vlckova, Ladislav Bortlik, Eva Dokoupilova, Tomas Hala, Jens-Erik Beck Jensen, Kim Torsten Brixen, Bente Lomholt Langdahl, Peter Schwarz, Peter Claes Eskildsen, Pia Agnete Eiken, Anne Pernille Hermann, Jeppe Gram, Maiken Brix Schou, Peter Alexandersen, Bettina Nedergaard, Dolores Magdalena Mejía, Lourdes Estrella De Henriquez, Norka Páez, Casimiro Velazco, Ivo Valter, Kadri-Liina Vahula, Ingrid Kull, Katre Maasalu, Roland Chapurlat, Patrice Fardellone, Claude Laurent Benhamou, Georges Weryha, Volkmar Herkt, Rene Martz, Ruth Nischik, Wolfgang Spieler, Christel Contzen, Dieter Felsenberg, Isolde Frieling, Eike Frahm, Henry Briones, Boris Sandoval, Patricia Barrios, Abraham García, Carlos Avendaño, Magdalena González, Jeremías Guerra, Maria Tuna, Olga Marina Díaz, Eduardo Samayoa, Edgar López, José Raúl Barrera, Mainor Palencia, Mayra Cifuentes, Georgina Alvarado, Miriam López, Nilmo Chavez, Franklin Haase, Ruddy Rivera, Claudio González, Kathryn Tan, Ping Chung Leung, Sheshadri Mandalam, Shailesh Umakant Pitale, Ganapathi Bantwal, Ariachery Chinamma Ammini, Shehla Sajid Akhta Shaikh, Prasanna Kumar Kanakatte Mylariah, Mala Dharmalingam, Satinath Mukhopadhyay, Arpit Jain, Parminder Singh, Naresh Shetty, Srikanta Shamanna Sathyanarayana, Nalini Shah, Manoj Dharam Chadha, Rajendra Bhandankar, Kumaravel Velayutham, Sudha Marwah, Mathew John, Rakesh Kumar Sahay, Silvano Adami, Ranuccio Nuti, Gerolamo Bianchi, Maria Luisa Brandi, Salvatore Minisola, Carmelo Erio Fiore, Alessandro Rubinacci, Hisayuki Miyajima, Hiroo Yamane, Yuji Nakatani, Sumiaki Okamoto, Koji Kuroda, Motoaki Fujimori, Akira Itabashi, Kuniaki Katayama, Satoru Nakajo, Yoshiaki Somekawa, Yoshimitsu Ohsawa, Wataru Tajima, Katsunori Mizuno, Shigeru Mori, Takato Kanabuchi, Hiroyuki Hashizume, Nobuyuki Oka, Kazutoshi Hamada, Motoi Yamaguchi, Fumiki Hirahara, Masaaki Atobe, Yoshiharu Ohtake, Shuichi Ichikawa, Tomoyuki Onishi, Kou Matsumoto, Tetsuro Nakamura, Eishi Shirasawa, Ko Katayama, Mitsugu Takahashi, Tadanori Oguma, Hideo Matsui, Yoshiharu Katoh, Keiichi Shigenobu, Tsutomu Onishi, Masato Shibukawa, Satoshi Ikeda, Kazuhiro Osaka, Ryosuke Kanda, Yoshito Inobe, Masaharu Shigenobu, Morimasa Hasegawa, Tetsuo Yamaji, Yu Miyazaki, Takayasu Ito, Eisuke Nakamura, Shinji Nagai, Sung-Kil Lim, Yoon-Sok Chung, Chan-Soo Shin, Yong-Ki Min, Ghi Su Kim, Hyun Koo Yoon, Moo-Il Kang, Kyu-Hyun Yang, Hyoung Moo Park, In Joo Kim, Dong Jin Chung, Ho Yeon Chung, Sandra Jaundzeikare, Dace Andersone, Agita Medne, Yasser Yaghi, Vidmantas Alekna, Vytautas Kasiulevicius, Irina Purtokaite - Labutiniene, Aurelija Krasauskiene, Jurate Varanaviciene, Vida Basijokiene, Agne Abraitiene, Lina Radzeviciene, Jesus Walliser, Pedro Alberto García Hernández, Maria Frida Araujo, Hilario Ernesto Avila Armengol, Pilar De la Peña, Juan Tamayo, Beatriz Zazueta, Fidencio Cons, Nigel Leslie Gilchrist, Ian Reginald Reid, Robert Leikis, Peter Jones, Joe Gragrath Pradeep Singh, Johan Inge Halse, Unni Syversen, Hans Olav Høivik, Erik Snorre Øfjord, Hans Christian Gulseth, Sigbjørn Elle, Paal Dag Norheim, Armando A. Calvo Quiroz, Pastor A. Cesar Augusto, Manuel Gustavo León Portocarrero, Luis Fernando Vidal Neira, Jose Chavez, Boris Garro Barrera, Rita Kuroiwa Sampei, Bellatín V. Luis Fernando, Rogger Oquelis Cabredo, Sonia Castillo, Agustin Miguel G Morales, Perry Pua Tan, Liberato Antonio C Leagogo, Edward HM Wang, Julie T Li-Yu, Andrzej Z Sawicki, Barbara Stasiuk, Grzegorz Kania, Roman Lorenc, Anna Sidorowicz-Bialynicka, Leszek Szczepanski, Edward Franek, Rafal Filip, Jan Sekula, Tomasz Blicharski, Piotr Leszczynski, Ewa Sewerynek, Tomasz Miazgowski, Andrzej Milewicz, Magda Dabrowska, Jerzy Romaszko, Wojciech Pluskiewicz, Lukasz Wojnowski, Catalin Codreanu, Horatiu Bolosiu, Ruxandra Ionescu, Ioana Zosin, Liviu Macovei, Mihai Bojinca, Florin Radulescu, Simona Pop, Adrian Sarbu, Lidia I Benevolenskaya, Evgeny L Nasonov, Lyudmila Ya Rozhinskaya, Raphael G Oganov, Svetlana S Rodionova, Eugeny Vladimirovich Shlyakhto, Vasiliy Trofimov, Eugeny G Zotkin, Irina E Zazerskaya, Elena N Grineva, Olga Ershova, Olga Lesnyak, Olga D Ostroumova, Svetlana B Malichenko, Eduard G Pikhlak, Valery G Pilyaev, Tatiana Raskina, Elena V Zonova, Valery S Shirinsky, Aleksandar N Dimic, Goran Cobeljic, Svetlana Vujovic, Graham Charlston Ellis, Stanley Lipschitz, Tobias Johannes De Villiers, Albert Jan De Weerd, Tasneem Vally, Yvonne Trinder, Jacobus Ludewikus Coetsee, Charles Pierre Davis, Savithree Nayiager, Frans Stephanus Hough, Louis F Oelofse, Eugene van der Walt, Johannes Jurgens Lombaard, Suzanne Blignaut, Uttam Govind, Leon Frederik Fouche, Dawid Stephanus Kruger, Johannes Paul Dalmeyer, Mada M Ferreira, Alejandro Escudero-Contreras, Manuel Muñoz Torres, Federico Hawkins Carranza, Jose Luis Perez Castrillon, Juan Antonio García Meijide, Esteban Jodar Gimeno, Santiago Palacios Gil-Antuñana, Luis de Teresa Parreno, Emilio Martín Mola, Carmen Alvarez Sanchez, Keh-Sung Tsai, Shih-Te Tu, Jung-Fu Chen, Oscar Kuang-Sheng Lee, Wen-Wei Hsu, Natalia Viktorivna Grygorieva, Vladyslav Volodymyrovych Povoroznyuk, Mykola Oleksiiovych Korzh, Oleksandr Levgeniiovych Loskutov, Andriy Borysovych Chukov, Rex Sarmiento, Hawys Thomas, Hugh Donnachie, Irina Pavel-Knox, Hilary Shaw, Hana Hassanin, Essam Eldin Ahmed Abdulhakim, Naren Savani, Gloria A Bachmann, Elizabeth Barrett-Connor, Neil C Binkley, Henry G Bone, Donald M Brandon, Darin David Checketts, Neil J Fraser, Nelson B Watts, Steven A Geller, Joseph S Gimbel, Maria White Greenwald, Peter A Holt, Cyrus Conrad Johnston, Chien Fang, David J Klashman, E. Michael Lewiecki, Mitchell B Lowenstein, Michael Roy McClung, Susan M Nattrass, Alberto Odio, Julie Levengood, Josefina Romaguera, Mohamed Bassam Sebai, Brian Snyder, Mark Eliot Kutner, Dan Streja, Elliott P Schwartz, and Mark G Christiansen

Subjects
cathepsin-k inhibitor, Endocrinology, Diabetes and Metabolism, Osteoporosis, Placebo-controlled study, law.invention, Fractures, Bone, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Randomized controlled trial, Bone Density, law, Outpatient clinic, 030212 general & internal medicine, Osteoporosis, Postmenopausal, Aged, 80 and over, density, Hip fracture, Bone Density Conservation Agents, odanacatib, postmenopausal osteoporosis, LOFT, extension study, Treatment Outcome, medicine.anatomical_structure, Spinal Fractures, Female, women, strength, Odanacatib, medicine.medical_specialty, 030209 endocrinology & metabolism, Placebo, 03 medical and health sciences, Double-Blind Method, Internal medicine, Internal Medicine, medicine, Humans, bone mass, fracture, mortality, denosumab, turnover, therapy, Aged, Femoral neck, Hip Fractures, business.industry, Biphenyl Compounds, medicine.disease, chemistry, business, Osteoporotic Fractures
Abstract

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

Published
2019

19. 192Effect of dapagliflozin on cardiovascular outcomes in patients with type 2 diabetes according to baseline renal function and albuminuria status: Insights from DECLARE-TIMI 58

Author

Thomas A Zelniker, Marc S. Sabatine, AM Langkilde, Darren K. McGuire, Deepak L. Bhatt, John P.H. Wilding, Jamie P. Dwyer, H J L Heerspink, Stephen D. Wiviott, L A Leiter, KyungAh Im, Ofri Mosenzon, Ingrid Gause-Nilsson, Avivit Cahn, and Itamar Raz

Subjects
Creatinine, medicine.medical_specialty, Surrogate endpoint, business.industry, Renal function, Type 2 diabetes, medicine.disease, chemistry.chemical_compound, chemistry, Internal medicine, Diabetes mellitus, medicine, Albuminuria, Dapagliflozin, medicine.symptom, Cardiology and Cardiovascular Medicine, business, TIMI
Abstract

Background Renal dysfunction including both reduced estimated glomerular filtration rate (eGFR) and the presence of albuminuria have each been shown to predict cardiovascular (CV) outcomes. Sodium glucose co-transporter 2 inhibitors (SGLT2i), which promote glucose excretion in the kidneys, reduce CV events and hospitalizations for heart failure (HHF) in patients with type 2 diabetes mellitus (T2DM). Purpose To analyze the CV efficacy of dapagliflozin according to baseline renal function and albuminuria status in DECLARE-TIMI 58. Methods The DECLARE-TIMI 58 trial compared dapagliflozin vs. placebo in 17,160 patients with T2DM and a creatinine clearance >60 ml/min/1.73m2 at enrollment. The dual primary endpoints were CV death/HHF and MACE (MI, stroke, CV death). We categorized patients according baseline eGFR [ Results In total, 5198 (30.3%) patients had albuminuria (UACR 30–300: n=4029; UACR >300: n=1169) and 1265 (7.4%) had an eGFR 0.29), though numerically greatest (42%) in patients with reduced eGFR and albuminuria. However, the absolute risk difference increased substantially in patients with greater kidney damage (absolute risk difference of CV death/HHF: −0.5%, −1.0%, and −8.3%, respectively; P-INT for ARD 0.002; Figure). See figure for MACE and component outcomes. Conclusions Patients with baseline renal disease had higher rates of adverse CV outcomes. Dapagliflozin reduced events with generally consistent relative risk, but reduced the absolute risk of CVD/HHF by the greatest amount in patients with kidney disease evidenced by both reduced eGFR and albuminuria. Acknowledgement/Funding AstraZeneca, Deutsche Forschungsgemeinschaft (ZE 1109/1-1)

Published
2019

20. Impact of Antithrombotic Regimen on Mortality, Ischemic, and Bleeding Outcomes after Transcatheter Aortic Valve Replacement

Author

Pinak B. Shah, Ryan A. Watson, Anubodh S. Varshney, Robert P. Giugliano, Jeffrey E. Rossi, Andrew Noll, and KyungAh Im

Subjects
medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Valve replacement, Internal medicine, Antithrombotic, medicine, 030212 general & internal medicine, Myocardial infarction, Antithrombosis, Stroke, Original Research, business.industry, Aortic stenosis, Mortality rate, Anticoagulant, Hazard ratio, Transcatheter aortic valve replacement, medicine.disease, Regimen, Cardiology, Cardiology and Cardiovascular Medicine, business
Abstract

Introduction Optimal antithrombotic therapy after transcatheter aortic valve replacement (TAVR) remains unclear. We evaluated the association between antithrombotic regimens and outcomes in TAVR patients. Methods We retrospectively analyzed consecutive patients who underwent TAVR at a single academic center from April 2009 to March 2014. Antithrombotic regimens were classified as single or dual antiplatelet therapy (AP), single antiplatelet plus anticoagulant (SAC), or triple therapy (TT). The primary endpoint was a composite of death, myocardial infarction (MI), stroke, and major bleeding. Adjusted hazard ratios (HRs) were obtained with best subset variable selection methods using bootstrap resampling. Results Of 246 patients who underwent TAVR, 241 were eligible for analysis with 133, 88, and 20 patients in the AP, SAC, and TT groups, respectively. During a median 2.1-year follow-up, 53.5% had at least one endpoint—the most common was death (68%), followed by major bleeding (23%), stroke (6%), and MI (3%). At 2 years, the composite outcome occurred in 70% of TT, 42% of SAC, and 31% of AP patients. Compared to AP, adjusted HRs for the composite outcome were 2.88 [95% Confidence intervals (CI) (1.61–5.16); p = 0.0004] and 1.66 (95% CI [1.13-2.42]; p = 0.009) in the TT and SAC groups, respectively. Mortality rates at 2 years were 61% in the TT, 32% in the SAC, and 26% in the AP groups (p = 0.005). Conclusions The risk of the composite outcome of death, MI, stroke, or major bleeding at 2-year follow-up was significantly higher in TAVR patients treated with TT or SAC versus AP, even after multivariate adjustment.

Published
2018

21. Hypoglycaemia manifestations and recurrent events: Lessons from the SAVOR-TIMI 53 outcome study

Author

Ilan Yanuv, Estella Kanevsky, Christina Stahre, Boaz Hirshberg, KyungAh Im, Gil Leibowitz, Aliza Rozenberg, Avivit Cahn, Itamar Raz, Deepak L. Bhatt, Ofri Mosenzon, and Nayyar Iqbal

Subjects
Male, medicine.medical_specialty, Activities of daily living, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adamantane, 030209 endocrinology & metabolism, Type 2 diabetes, 030204 cardiovascular system & hematology, Saxagliptin, Hypoglycemia, Placebo, Severity of Illness Index, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Recurrence, Internal medicine, Activities of Daily Living, Severity of illness, Internal Medicine, medicine, Humans, Precision Medicine, Meals, Aged, Randomized Controlled Trials as Topic, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Insulin, Dipeptides, Middle Aged, medicine.disease, Combined Modality Therapy, Diabetes Mellitus, Type 2, chemistry, Patient Compliance, Female, Self Report, business, TIMI
Abstract

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose3.0 mmol/l (54 mg/dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event.

Published
2017

22. Effect of Saxagliptin on Renal Outcomes in the SAVOR-TIMI 53 Trial

Author

Gil Leibowitz, Eugene Braunwald, Benjamin M. Scirica, KyungAh Im, Deepak L. Bhatt, Christina Stahre, Boaz Hirshberg, Itamar Raz, Ofri Mosenzon, Cheryl Wei, Ilan Yanuv, Avivit Cahn, Kausik K. Ray, Aliza Rozenberg, and Nayyar Iqbal

Subjects
CHRONIC KIDNEY-DISEASE, Blood Glucose, Male, Endocrinology, Diabetes and Metabolism, Adamantane, Type 2 diabetes, 030204 cardiovascular system & hematology, Saxagliptin, chemistry.chemical_compound, 0302 clinical medicine, Diabetic Nephropathies, Body surface area, POST-HOC ANALYSIS, CARDIOVASCULAR RISK, PROTEINURIA, 11 Medical And Health Sciences, Dipeptides, Middle Aged, Creatinine, Female, medicine.symptom, Life Sciences & Biomedicine, TIMI, Glomerular Filtration Rate, medicine.medical_specialty, NEPHROPATHY, INHIBITION, Urology, Renal function, 030209 endocrinology & metabolism, Endocrinology & Metabolism, 03 medical and health sciences, Double-Blind Method, Internal medicine, Internal Medicine, medicine, Albuminuria, Humans, INDUCED DIABETIC-RATS, Serum Albumin, Aged, Advanced and Specialized Nursing, Dipeptidyl-Peptidase IV Inhibitors, Science & Technology, business.industry, MICROALBUMINURIA, medicine.disease, REDUCTION, Endocrinology, Diabetes Mellitus, Type 2, chemistry, Microalbuminuria, business
Abstract

OBJECTIVEDipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy.RESEARCH DESIGN AND METHODSWe studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial.RESULTSAt baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] 300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was −19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m2 (BSA), −105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and −245.2 mg/g (P = 0.086) for eGFR 6.0 mg/dL, were similar as well.CONCLUSIONSTreatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control.

Published
2016

23. Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials

Author

KyungAh Im, Brian A. Ference, Michael G. Silverman, Michelle L. O'Donoghue, Stephen D. Wiviott, Marc S. Sabatine, Robert P. Giugliano, and Nicholas A Marston

Subjects
Risk, medicine.medical_specialty, 030204 cardiovascular system & hematology, Fatty acids.omega 3, Niacin, Article, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Physiology (medical), Internal medicine, Fatty Acids, Omega-3, Medicine, Humans, Meta-regression, 030212 general & internal medicine, Triglycerides, Randomized Controlled Trials as Topic, Triglyceride, business.industry, Cholesterol, LDL, chemistry, Cardiovascular Diseases, Lipid lowering, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business
Abstract

Background: Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. Methods: We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. Results: A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non–high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non–high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76–0.82; P P P =0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76–0.83; P P =0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91–0.95]; P Conclusions: In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.

Published
2019

24. Outcomes of Women Compared With Men After Non-ST-Segment Elevation Acute Coronary Syndromes

Author

C. Michael Gibson, Stephen D. Wiviott, Christopher P. Cannon, Amy Sarma, Robert P. Giugliano, L. Kristin Newby, KyungAh Im, Jianping Guo, Elliott M. Antman, Marc S. Sabatine, Michelle L. O'Donoghue, Eugene Braunwald, and David A. Morrow

Subjects
Male, medicine.medical_specialty, 030204 cardiovascular system & hematology, Lower risk, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Myocardial infarction, Acute Coronary Syndrome, Stroke, Randomized Controlled Trials as Topic, Sex Characteristics, Proportional hazards model, business.industry, Hazard ratio, Absolute risk reduction, medicine.disease, Clinical Trials, Phase III as Topic, Female, Cardiology and Cardiovascular Medicine, business, Mace, TIMI
Abstract

It remains disputed whether women are at excess risk of adverse outcomes versus men after non-ST-segment elevation acute coronary syndromes (NSTEACS) or whether differences are explained by discordant risk factors.A sex-specific analysis of cardiovascular outcomes after NSTEACS across trials conducted by the Thrombolysis In Myocardial Infarction (TIMI) Study Group was performed to determine the impact of sex on cardiovascular outcomes in this dataset.Ten TIMI trials were identified that enrolled2,500 patients with NSTEACS within 30 days of hospitalization. Cox proportional hazards models were used to examine the association of sex with major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, or stroke) after adjusting for relevant risk factors in individual trials; point estimates were then combined by using random effects models. Individual components of the composite outcome and all-cause mortality were also analyzed.Among 68,730 patients with NSTEACS, 19,827 (29%) were women. Women were older and more frequently had hypertension, diabetes, prior heart failure, and renal impairment than men. Before considering relevant confounders, women were at similar risk of MACE compared with men (hazard ratio [HR]: 1.04; 95% confidence interval [CI]: 0.99 to 1.09; p = 0.16) but at higher risk of all-cause death (HR: 1.12; 95% CI: 1.01 to 1.24; p = 0.03). After adjustment for baseline differences, risks of MACE (HR: 0.93; 95% CI: 0.88 to 0.98; p 0.01) and all-cause death (HR: 0.84; 95% CI: 0.78 to 0.90; p 0.0001) were lower among women compared with men.After accounting for cardiovascular risk factors, women enrolled in clinical trials were at lower risk of MACE than men after NSTEACS. Women, however, remain undertreated with many evidence-based therapies.

Published
2019

25. Efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial

Author

Anders G. Olsson, Marc S. Sabatine, David M. Charytan, KyungAh Im, Robert P. Giugliano, Prakash Deedwania, Peter S. Sever, Jeong-Gun Park, Armando Lira Pineda, Terje R. Pedersen, Scott M. Wasserman, Anthony C Keech, and Investigators

Subjects
Male, Cardiac & Cardiovascular Systems, PROGRESSION, 030204 cardiovascular system & hematology, FOURIER Steering Committee and Investigators, PCSK9, 0302 clinical medicine, cardiovascular disease, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, Aged, 80 and over, Kidney, OUTCOMES, Anticholesteremic Agents, PCSK9 Inhibitors, Middle Aged, Treatment Outcome, medicine.anatomical_structure, Cardiovascular Diseases, Female, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, REDUCING LIPIDS, medicine.drug, Adult, cardiovascular risk, medicine.medical_specialty, EZETIMIBE, Urology, Antibodies, Monoclonal, Humanized, Placebo, 1117 Public Health and Health Services, lipids, 03 medical and health sciences, Double-Blind Method, Ezetimibe, medicine, Humans, Renal Insufficiency, Chronic, CARDIOVASCULAR EVENTS, Aged, Science & Technology, urogenital system, business.industry, Cholesterol, LDL, medicine.disease, SIMVASTATIN, Evolocumab, LOWERING LDL CHOLESTEROL, Cardiovascular System & Hematology, Simvastatin, Cardiovascular System & Cardiology, atherosclerosis, business, chronic kidney disease, Follow-Up Studies, Kidney disease
Abstract

Background Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited. Objectives The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function. Methods The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non–high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate. Results There were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with ≥stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage ≥3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); pint = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (pint = 0.75)—preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were −2.5% (95% CI: -4.7% to -0.4%) for stage ≥3 CKD compared with −1.7% (95% CI: -2.8% to 0.5%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage. Conclusions LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633)

Published
2019

26. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: A prespecified analysis from the FOURIER Trial

Author

Anthony C Keech, Zbigniew Gaciong, KyungAh Im, Terje R. Pedersen, Peter S. Sever, Derek L. Connolly, J. Wouter Jukema, Robert P. Giugliano, Christopher E. Kurtz, Richard Ceska, Narimon Honarpour, Kalman Toth, Marc S. Sabatine, Sabina A. Murphy, Marat V. Ezhov, Stephen D. Wiviott, Matti J. Tikkanen, and Amgen Inc

Subjects
Male, Cardiac & Cardiovascular Systems, STATIN THERAPY, Myocardial Infarction, 030204 cardiovascular system & hematology, ATORVASTATIN, Rate ratio, law.invention, 0302 clinical medicine, Randomized controlled trial, law, Clinical endpoint, PARTICIPANTS, 030212 general & internal medicine, Myocardial infarction, Stroke, Original Investigation, Anticholesteremic Agents, CHOLESTEROL, PCSK9 Inhibitors, Middle Aged, Treatment Outcome, Cardiovascular Diseases, Cardiology, Female, Cardiology and Cardiovascular Medicine, Life Sciences & Biomedicine, medicine.medical_specialty, Injections, Subcutaneous, Antibodies, Monoclonal, Humanized, Drug Administration Schedule, 03 medical and health sciences, Percutaneous Coronary Intervention, Double-Blind Method, Internal medicine, medicine, Humans, Angina, Unstable, METAANALYSIS, Science & Technology, Unstable angina, business.industry, PCSK9, ACUTE CORONARY SYNDROMES, medicine.disease, EFFICACY, SIMVASTATIN, Evolocumab, REDUCTION, MYOCARDIAL-INFARCTION, Cardiovascular System & Cardiology, business, Follow-Up Studies
Abstract

Importance: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events. Objective: To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists. Design, Setting, and Participants: Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019. Main Outcomes and Measures: The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms. Results: The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P

Published
2019

27. Reduction in Subtypes and Sizes of Myocardial Infarction With Ticagrelor in PEGASUS–TIMI 54

Author

Stephen D. Wiviott, Julia F Kuder, Eva C. Jensen, Andrzej Budaj, Giulia Magnani, Alexander Parkhomenko, Eugene Braunwald, Robert F. Storey, Marc S. Sabatine, Jose Lopez-Sendon, Marc P. Bonaca, Per Johanson, Assen Goudev, Frans Van de Werf, Jose C. Nicolau, KyungAh Im, Marc Cohen, Deepak L. Bhatt, P. Gabriel Steg, Ramón Corbalán, Christian W. Hamm, Mikael Dellborg, David A. Morrow, and Rafael Diaz

Subjects
medicine.medical_specialty, biology, business.industry, Hazard ratio, 030204 cardiovascular system & hematology, medicine.disease, Sudden death, Troponin, Confidence interval, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Cardiology, medicine, biology.protein, 030212 general & internal medicine, Myocardial infarction, Cardiology and Cardiovascular Medicine, business, Ticagrelor, Stroke, TIMI, medicine.drug
Abstract

Background Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance. Methods and Results MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow‐up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention–related (Type 4a) and coronary artery bypass graft–related (Type 5) each accounted for P =0.0055). The benefit was consistent among the subtypes, including a 31% reduction in MIs with a peak troponin ≥100× upper limit of normal (hazard ratio 0.69, 95% confidence interval 0.53–0.92, P =0.0096) and a 40% reduction in ST‐segment elevation MI (hazard ratio 0.60, 95% confidence interval 0.46–0.78, P =0.0002). Conclusions In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high biomarker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST‐segment elevation MI. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.

Published
2018

28. Reduction in Ischemic Events With Ticagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS–TIMI 54

Author

Ph. Gabriel Steg, Marc P. Bonaca, Eugene Braunwald, Deepak L. Bhatt, Sabina A. Murphy, Marc S. Sabatine, Dominick J. Angiolillo, Marc Cohen, Sameer Bansilal, Robert F. Storey, KyungAh Im, and Peter Held

Subjects
Male, Ticagrelor, medicine.medical_specialty, Acute coronary syndrome, Adenosine, Myocardial Infarction, Coronary Disease, Hemorrhage, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Diabetes mellitus, Internal medicine, Diabetes Mellitus, Secondary Prevention, medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Stroke, Aged, Secondary prevention, Dose-Response Relationship, Drug, business.industry, Middle Aged, medicine.disease, Purinergic P2Y Receptor Antagonists, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Mace, TIMI, medicine.drug
Abstract

Patients with diabetes appear to be at elevated risk of atherothrombotic events.The purpose of this study was to determine the effect of antiplatelet therapy with ticagrelor on recurrent ischemic events in patients with diabetes and prior myocardial infarction (MI).We examined the subgroups of patients with diabetes (n = 6,806) and without diabetes (n = 14,355) from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54), in which 21,162 patients with a history of MI 1 to 3 years prior and with additional risk factors were randomized to ticagrelor (90 or 60 mg twice daily) or placebo. Patients were followed for a median of 33 months. The primary efficacy endpoint was major adverse cardiovascular events (MACE) (cardiovascular death, MI, stroke) and the primary safety endpoint was TIMI (Thrombolysis In Myocardial Infarction) major bleeding.The relative risk reduction in MACE with ticagrelor was consistent for the pooled doses versus placebo in patients with diabetes (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.72 to 0.99; p = 0.035) and without diabetes (HR: 0.84; 95% CI: 0.74 to 0.96; p = 0.013; p interaction = 0.99). As patients with diabetes were at higher risk of MACE, the absolute risk reduction tended to be greater in patients with versus without diabetes (1.5% vs. 1.1%, with corresponding 3-year number needed to treat of 67 vs. 91). In patients with diabetes requiring pharmacological therapy (n = 5,960), the absolute risk reduction was 1.9% with a 3-year number needed to treat of 53. Additionally, in patients with diabetes, ticagrelor reduced cardiovascular death by 22% and coronary heart disease death by 34%. Similar to patients without diabetes, there was increased TIMI major bleeding in patients with diabetes (HR: 2.56; 95% CI: 1.52 to 4.33; p = 0.0004).In patients with diabetes with prior MI, adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events, including cardiovascular and coronary heart disease death. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).

Published
2016

29. Predisposing Factors for Any and Major Hypoglycemia With Saxagliptin Versus Placebo and Overall: Analysis From the SAVOR-TIMI 53 Trial

Author

Eugene Braunwald, Christina Stahre, Boaz Hirshberg, Benjamin M. Scirica, Gil Leibowitz, Mikaela Sjöstrand, Estella Kanevsky, KyungAh Im, Itamar Raz, Ilan Yanuv, Deepak L. Bhatt, Avivit Cahn, Nayyar Iqbal, Aliza Rozenberg, and Ofri Mosenzon

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Adamantane, 030209 endocrinology & metabolism, Type 2 diabetes, Saxagliptin, Hypoglycemia, Placebo, Body Mass Index, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, Glyburide, Internal Medicine, medicine, Humans, Hypoglycemic Agents, Insulin, Renal Insufficiency, 030212 general & internal medicine, education, Aged, Proportional Hazards Models, Glycated Hemoglobin, Advanced and Specialized Nursing, education.field_of_study, business.industry, Insulin, Short-Acting, Hazard ratio, nutritional and metabolic diseases, Dipeptides, Middle Aged, medicine.disease, Surgery, Sulfonylurea Compounds, Diabetes Mellitus, Type 2, chemistry, Multivariate Analysis, Female, Microalbuminuria, business, Follow-Up Studies
Abstract

OBJECTIVE To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study. RESEARCH DESIGN AND METHODS Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement RESULTS At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia. CONCLUSIONS The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy.

Published
2016

30. Reduction in Total Cardiovascular Events With Ezetimibe/Simvastatin Post-Acute Coronary Syndrome

Author

Daniel Isaza, Craig J. Reist, KyungAh Im, Jennifer A. White, Andrew M. Tershakovec, Robert P. Giugliano, Eugene Braunwald, Michael A. Blazing, Christopher P. Cannon, Mikael Dellborg, Erin A. Bohula, Sabina A. Murphy, Uma Kher, Yuliya Lokhnygina, and Jose Lopez-Sendon

Subjects
medicine.medical_specialty, Acute coronary syndrome, business.industry, Unstable angina, 030204 cardiovascular system & hematology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Ezetimibe, Simvastatin, Internal medicine, Cardiology, Clinical endpoint, Medicine, Ezetimibe/simvastatin, 030212 general & internal medicine, Myocardial infarction, business, Cardiology and Cardiovascular Medicine, Stroke, medicine.drug
Abstract

Background Intensive low-density lipoprotein cholesterol therapy with ezetimibe/simvastatin in IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial) significantly reduced the first primary endpoint (PEP) in patients post-acute coronary syndrome (ACS) compared to placebo/simvastatin. Objectives This analysis tested the hypothesis that total events, including those beyond the first event, would also be reduced with ezetimibe/simvastatin therapy. Methods All PEP events (cardiovascular [CV] death, myocardial infarction [MI], stroke, unstable angina [UA] leading to hospitalization, coronary revascularization ≥30 days post-randomization) during a median 6-year follow-up were analyzed in patients randomized to receive ezetimibe/simvastatin or placebo/simvastatin in IMPROVE-IT. Negative binomial regression was used for the primary analysis. Results Among 18,144 patients, there were 9,545 total PEP events (56% were first events and 44% subsequent events). Total PEP events were significantly reduced by 9% with ezetimibe/simvastatin vs placebo/simvastatin (incidence-rate ratio [RR]: 0.91; 95% confidence interval [CI]: 0.85 to 0.97; p = 0.007), as were the 3 pre-specified secondary composite endpoints and the exploratory composite endpoint of CV death, MI, or stroke (RR: 0.88; 95% CI: 0.81 to 0.96; p = 0.002). The reduction in total events was driven by decreases in total nonfatal MI (RR: 0.87; 95% CI: 0.79 to 0.96; p = 0.004) and total NF stroke (RR: 0.77; 95% CI: 0.65 to 0.93; p = 0.005). Conclusions Lipid-lowering therapy with ezetimibe plus simvastatin improved clinical outcomes. Reductions in total PEP events, driven by reductions in MI and stroke, more than doubled the number of events prevented compared with examining only the first event. These data support continuation of intensive combination lipid-lowering therapy after an initial CV event. (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878 )

Published
2016
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31. Frequency of cancer events with saxagliptin in the SAVOR-TIMI 53 trial

Author

Benjamin M. Scirica, Ofri Mosenzon, Joost B. L. Hoekstra, L A Leiter, Boaz Hirshberg, Itamar Raz, Avivit Cahn, Hwee Teoh, Deepak L. Bhatt, KyungAh Im, Michael Alvarsson, C. A. M. Stahre, Amsterdam Cardiovascular Sciences, Amsterdam Gastroenterology Endocrinology Metabolism, and General Internal Medicine

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adamantane, 030209 endocrinology & metabolism, Saxagliptin, Kidney, Placebo, law.invention, Cohort Studies, 03 medical and health sciences, chemistry.chemical_compound, Sex Factors, 0302 clinical medicine, Endocrinology, Double-Blind Method, Randomized controlled trial, Risk Factors, law, Neoplasms, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Humans, Diabetic Nephropathies, 030212 general & internal medicine, Mortality, Adverse effect, Aged, Dyslipidemias, Dipeptidyl-Peptidase IV Inhibitors, Dose-Response Relationship, Drug, business.industry, Mortality rate, Smoking, Cancer, Dipeptides, Middle Aged, medicine.disease, Diabetes Mellitus, Type 2, chemistry, Female, business, TIMI, Follow-Up Studies, Glomerular Filtration Rate
Abstract

The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial randomized trial of 16,492 patients (placebo, n = 8212; saxagliptin, n = 8280) treated and followed for a median of 2.1 years afforded an opportunity to explore whether there was any association with cancer reported as a serious adverse event. At least one cancer event was reported by 688 patients (4.1%): 362 (4.3%) and 326 (3.8%) in the placebo and saxagliptin arms, respectively (p = 0.13). There were 59 (0.6%) deaths adjudicated as malignancy deaths with placebo and 53 (0.6%) with saxagliptin. Stratification by gender, age, race and ethnicity, diabetes duration, baseline glycated haemoglobin and pharmacotherapy did not show any clinically meaningful differences between the two study arms. The overall number of cancer events and malignancy-associated mortality rates were generally balanced between the placebo and saxagliptin groups, suggesting a null relationship with saxagliptin use over the median follow-up of 2.1 years. Multivariable modelling showed that male gender, dyslipidaemia and current smoking were independent predictors of cancer. These randomized data with adequate numbers of cancer cases are reassuring but limited, by the short follow-up in a trial not designed to test this hypothesis.

Published
2015

32. SEX AND PERMANENT DRUG DISCONTINUATION IN CLINICAL TRIALS: INSIGHTS FROM THE TIMI TRIALS

Author

KyungAh Im, Elliott M. Antman, C. Michael Gibson, Eugene Braunwald, Benjamin M. Scirica, Emily S. Lau, Marc S. Sabatine, Michelle L. O'Donoghue, Erin A. Bohula, Jianping Guo, Deepak L. Bhatt, Robert P. Giugliano, Christopher P. Cannon, and David A. Morrow

Subjects
Clinical trial, medicine.medical_specialty, Study drug, business.industry, Drug discontinuation, Internal medicine, Medicine, Cardiology and Cardiovascular Medicine, business, TIMI, Odds
Abstract

Women are underrepresented across cardiovascular clinical trials. Whether women are more likely than men to prematurely discontinue study drug is unknown. Eleven phase 3 TIMI trials were included [135,879 men and 51,812 women (28%)]. The association between sex and odds of premature study drug

Published
2020

33. Cognitive Function in a Randomized Trial of Evolocumab

Author

Jingjing Schneider, Anthony C Keech, Kenton Zavitz, Narimon Honarpour, Jennifer G. Robinson, KyungAh Im, Brian R. Ott, Christopher E. Kurtz, Wang H, Scott M. Wasserman, Marc S. Sabatine, Robert P. Giugliano, François Mach, Terje R. Pedersen, Estella Kanevsky, Peter S. Sever, and Investigators Ebbinghaus

Subjects
Evolocumab, medicine.medical_specialty, Physical medicine and rehabilitation, Randomized controlled trial, law, business.industry, medicine, Cognition, business, law.invention
Published
2018

34. Cardiovascular Safety of Lorcaserin in Overweight or Obese Patients

Author

Erin A, Bohula, Stephen D, Wiviott, Darren K, McGuire, Silvio E, Inzucchi, Julia, Kuder, KyungAh, Im, Christina L, Fanola, Arman, Qamar, Conville, Brown, Andrzej, Budaj, Armando, Garcia-Castillo, Milan, Gupta, Lawrence A, Leiter, Neil J, Weissman, Harvey D, White, Tushar, Patel, Bruce, Francis, Wenfeng, Miao, Carlos, Perdomo, Shobha, Dhadda, Marc P, Bonaca, Christian T, Ruff, Anthony C, Keech, Steven R, Smith, Marc S, Sabatine, Benjamin M, Scirica, and C, Ince

Subjects
Male, medicine.medical_specialty, Hypertension, Pulmonary, Aortic Valve Insufficiency, 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Overweight, Placebo, Lorcaserin, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, Weight loss, law, Risk Factors, Internal medicine, Weight Loss, medicine, Humans, Myocardial infarction, Obesity, Stroke, Aged, Unstable angina, business.industry, General Medicine, Benzazepines, Middle Aged, medicine.disease, Hypoglycemia, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Female, Anti-Obesity Agents, medicine.symptom, business, medicine.drug, Follow-Up Studies
Abstract

Lorcaserin, a selective serotonin 2C receptor agonist that modulates appetite, has proven efficacy for weight management in overweight or obese patients. The cardiovascular safety and efficacy of lorcaserin are undefined.We randomly assigned 12,000 overweight or obese patients with atherosclerotic cardiovascular disease or multiple cardiovascular risk factors to receive either lorcaserin (10 mg twice daily) or placebo. The primary safety outcome of major cardiovascular events (a composite of cardiovascular death, myocardial infarction, or stroke) was assessed at an interim analysis to exclude a noninferiority boundary of 1.4. If noninferiority was met, the primary cardiovascular efficacy outcome (a composite of major cardiovascular events, heart failure, hospitalization for unstable angina, or coronary revascularization [extended major cardiovascular events]) was assessed for superiority at the end of the trial.At 1 year, weight loss of at least 5% had occurred in 1986 of 5135 patients (38.7%) in the lorcaserin group and in 883 of 5083 (17.4%) in the placebo group (odds ratio, 3.01; 95% confidence interval [CI], 2.74 to 3.30; P0.001). Patients in the lorcaserin group had slightly better values with respect to cardiac risk factors (including blood pressure, heart rate, glycemic control, and lipids) than those in the placebo group. During a median follow-up of 3.3 years, the rate of the primary safety outcome was 2.0% per year in the lorcaserin group and 2.1% per year in the placebo group (hazard ratio, 0.99; 95% CI, 0.85 to 1.14; P0.001 for noninferiority); the rate of extended major cardiovascular events was 4.1% per year and 4.2% per year, respectively (hazard ratio, 0.97; 95% CI, 0.87 to 1.07; P=0.55). Adverse events of special interest were uncommon, and the rates were generally similar in the two groups, except for a higher number of patients with serious hypoglycemia in the lorcaserin group (13 vs. 4, P=0.04).In a high-risk population of overweight or obese patients, lorcaserin facilitated sustained weight loss without a higher rate of major cardiovascular events than that with placebo. (Funded by Eisai; CAMELLIA-TIMI 61 ClinicalTrials.gov number, NCT02019264 .).

Published
2018

35. 5002Benefit of LDL-C lowering with evolocumab on cardiovascular outcomes by age & sex: an analysis of the FOURIER trial

Author

Michelle L. O'Donoghue, Anthony C Keech, Marc S. Sabatine, Ioanna Gouni-Berthold, KyungAh Im, Peter S. Sever, Scott M. Wasserman, Robert P. Giugliano, Terje R. Pedersen, and Fourier Trial

Subjects
medicine.medical_specialty, Evolocumab, business.industry, Internal medicine, Cardiology, medicine, Cardiology and Cardiovascular Medicine, business, Cardiovascular outcomes
Published
2018

36. Association of Fibroblast Growth Factor 23 With Recurrent Cardiovascular Events in Patients After an Acute Coronary Syndrome: A Secondary Analysis of a Randomized Clinical Trial

Author

Michelle L. O'Donoghue, Andrzej Budaj, Jacob A. Udell, Eugene Braunwald, David A. Morrow, Marc S. Sabatine, Brian A. Bergmark, Christian W. Hamm, Petr Jarolim, KyungAh Im, Dylan L. Steen, Jianping Guo, Julia F Kuder, and Christopher P. Cannon

Subjects
0301 basic medicine, Male, Acute coronary syndrome, medicine.medical_specialty, Phospholipase A2 Inhibitors, Myocardial Infarction, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Recurrence, Darapladib, Internal medicine, Oximes, Clinical endpoint, Medicine, Humans, Myocardial infarction, Risk factor, Acute Coronary Syndrome, Aged, Original Investigation, Heart Failure, biology, business.industry, C-reactive protein, Hazard ratio, Middle Aged, medicine.disease, Fibroblast Growth Factors, Hospitalization, Stroke, Survival Rate, Fibroblast Growth Factor-23, 030104 developmental biology, Benzaldehydes, biology.protein, Female, Cardiology and Cardiovascular Medicine, business, Biomarkers
Abstract

IMPORTANCE: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers. OBJECTIVE: To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS). DESIGN, SETTING, AND PARTICIPANTS: C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A(2) inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017. EXPOSURE: The FGF-23 concentration at baseline. MAIN OUTCOMES AND MEASURES: The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure. RESULTS: In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high-sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P

Published
2018

37. Impact of Diabetes Mellitus on Hospitalization for Heart Failure, Cardiovascular Events, and Death

Author

Peter W.F. Wilson, Kim A. Eagle, Shinya Goto, Sidney C. Smith, E. Magnus Ohman, KyungAh Im, Julia F Kuder, Deepak L. Bhatt, Matthew A. Cavender, and Ph. Gabriel Steg

Subjects
Male, medicine.medical_specialty, Internationality, Time Factors, Health Status, Cohort Studies, Coronary artery disease, Physiology (medical), Internal medicine, Diabetes mellitus, Diabetes Mellitus, medicine, Humans, In patient, Prospective Studies, Registries, Myocardial infarction, Mortality, Aged, Heart Failure, business.industry, Hazard ratio, Nonfatal stroke, Thrombosis, Middle Aged, Atherosclerosis, medicine.disease, Hospitalization, Treatment Outcome, Heart failure, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Cardiovascular outcomes, Follow-Up Studies
Abstract

Background— Despite the known association of diabetes mellitus with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes mellitus. We sought to describe cardiovascular outcomes at 4 years and to identify predictors of these events in patients with diabetes mellitus. Methods and Results— The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes mellitus were determined with the corrected group prognosis method. Of the 45 227 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19 699) had diabetes mellitus at baseline. The overall risk and hazard ratio (HR) of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were greater in patients with diabetes compared with patients without diabetes (16.5% versus 13.1%; adjusted HR, 1.27; 95% confidence interval [CI] 1.19–1.35). There was also an increase in both cardiovascular death (8.9% versus 6.0%; adjusted HR, 1.38; 95% CI, 1.26–1.52) and overall death (14.3% versus 9.9%; adjusted HR, 1.40; 95% CI, 1.30–1.51). Diabetes mellitus was associated with a 33% greater risk of hospitalization for heart failure (9.4% versus 5.9%; adjusted odds ratio, 1.33; 95% CI, 1.18–1.50). In patients with diabetes mellitus, heart failure at baseline was independently associated with cardiovascular death (adjusted HR, 2.45; 95% CI, 2.17–2.77; P P Conclusions— Diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure. Patients with both diabetes mellitus and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.

Published
2015

38. Impact of treatment with saxagliptin on glycaemic stability and β-cell function in the SAVOR-TIMI 53 study

Author

Itamar Raz, Gil Leibowitz, Benjamin M. Scirica, Cheryl Wei, W. H.-H. Sheu, Eugene Braunwald, J. L. Sendon, Avivit Cahn, Deepak L. Bhatt, Ofri Mosenzon, Boaz Hirshberg, György Jermendy, and KyungAh Im

Subjects
Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adamantane, Type 2 diabetes, Dipeptidyl peptidase-4 inhibitor, Pharmacology, Saxagliptin, Placebo, Gastroenterology, chemistry.chemical_compound, Endocrinology, Double-Blind Method, Insulin-Secreting Cells, Internal medicine, Diabetes mellitus, Internal Medicine, Humans, Hypoglycemic Agents, Insulin, Medicine, Prospective Studies, Aged, Glycated Hemoglobin, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Hazard ratio, Dipeptides, Fasting, Middle Aged, medicine.disease, Diabetes Mellitus, Type 2, chemistry, Female, business, TIMI, medicine.drug
Abstract

Aims To study the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on glycaemic stability and β-cell function in the SAVOR-TIMI 53 trial. Methods We randomized 16 492 patients with type 2 diabetes (T2D) to saxagliptin or placebo, added to current antidiabetic medications, and followed them for a median of 2.1 years. Glycaemic instability was defined by: (i) a glycated haemoglobin (HbA1c) increase of ≥0.5% post-randomization; (ii) the initiation of new antidiabetic medications for ≥3 months; or (iii) an increase in dose of oral antidiabetic medication or ≥25% increase in insulin dose for ≥3 months. β-cell function was assessed according to fasting homeostatic model 2 assessment of β-cell function (HOMA-2β) values at baseline and at year 2 in patients not treated with insulin. Results Compared with placebo, participants treated with saxagliptin had a reduction in the development of glycaemic instability (hazard ratio 0.71; 95% confidence interval 0.68–0.74; p

Published
2015

39. Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Moderate or Severe Renal Impairment: Observations From the SAVOR-TIMI 53 Trial

Author

Ramón Corbalán, Robert Frederich, Eugene Braunwald, Matthew A. Cavender, Amarachi A. Umez-Eronini, Itamar Raz, Lawrence A. Leiter, Investigators, Jacob A. Udell, Ph. Gabriel Steg, Boaz Hirshberg, Ping He, Deepak L. Bhatt, Jose C. Nicolau, Darren K. McGuire, KyungAh Im, Benjamin M. Scirica, Jaime A. Davidson, and Ofri Mosenzon

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Population, Myocardial Infarction, Renal function, Adamantane, Type 2 diabetes, Saxagliptin, Severity of Illness Index, chemistry.chemical_compound, Internal medicine, Internal Medicine, Humans, Medicine, Diabetic Nephropathies, Renal Insufficiency, Myocardial infarction, education, Aged, Heart Failure, Advanced and Specialized Nursing, education.field_of_study, business.industry, Incidence, Hazard ratio, Dipeptides, Middle Aged, medicine.disease, Surgery, Hospitalization, Stroke, Treatment Outcome, Diabetes Mellitus, Type 2, chemistry, Cardiovascular Diseases, Heart failure, Albuminuria, Cardiology, Female, medicine.symptom, business
Abstract

OBJECTIVE The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function. RESEARCH DESIGN AND METHODS Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m2; n = 13,916), moderate renal impairment (eGFR 30–50 mL/min/1.73 m2; n = 2,240), or severe renal impairment (eGFR RESULTS After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95–2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28–6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m2 (HR 1.23 [95% CI 0.99–1.55]), eGFR 30–50 mL/min/1.73 m2 (HR 1.46 [95% CI 1.07–2.00]), and in patients with eGFR CONCLUSIONS Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function.

Published
2014

40. Heart Failure, Saxagliptin, and Diabetes Mellitus: Observations from the SAVOR-TIMI 53 Randomized Trial

Author

Petr Jarolim, Benjamin M. Scirica, Jaime A. Davidson, Jacob A. Udell, Eugene Braunwald, Basil S. Lewis, Matthew A. Cavender, Ph. Gabriel Steg, Darren K. McGuire, KyungAh Im, Robert Frederich, Itamar Raz, Pia S. Pollack, Amarachi A. Umez-Eronini, Deepak L. Bhatt, Ofri Mosenzon, David A. Morrow, and Boaz Hirshberg

Subjects
Male, medicine.medical_specialty, Adamantane, Saxagliptin, Risk Assessment, chemistry.chemical_compound, Troponin T, Physiology (medical), Internal medicine, Diabetes mellitus, Natriuretic Peptide, Brain, medicine, Humans, Myocardial infarction, Aged, Heart Failure, Dipeptidyl-Peptidase IV Inhibitors, business.industry, Hazard ratio, Type 2 Diabetes Mellitus, Dipeptides, Middle Aged, medicine.disease, Peptide Fragments, Confidence interval, Hospitalization, C-Reactive Protein, Endocrinology, Diabetes Mellitus, Type 2, chemistry, Heart failure, Multivariate Analysis, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, TIMI, Follow-Up Studies
Abstract

Background— Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point. Methods and Results— A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07–1.51; P =0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15–1.88; P =0.002), with no significant difference thereafter (time-varying interaction, P =0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin ( P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups. Conclusions— In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01107886.

Published
2014

41. Cognitive Function in a Randomized Trial of Evolocumab

Author

Robert P, Giugliano, François, Mach, Kenton, Zavitz, Christopher, Kurtz, Kyungah, Im, Estella, Kanevsky, Jingjing, Schneider, Huei, Wang, Anthony, Keech, Terje R, Pedersen, Marc S, Sabatine, Peter S, Sever, Jennifer G, Robinson, Narimon, Honarpour, Scott M, Wasserman, Brian R, Ott, L, Hardee, Calabrò, Paolo, Gragnano, Felice, and Pirro, Matteo

Subjects
Oncology, Male, Self-Assessment, RATIONALE, 030204 cardiovascular system & hematology, Spatial memory, DISEASE, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Cognition, Randomized controlled trial, DESIGN, law, Monoclonal, Clinical endpoint, Medicine, 030212 general & internal medicine, Prospective Studies, Episodic memory, Humanized, RISK, Aged, 80 and over, biology, Cambridge Neuropsychological Test Automated Battery, Anticholesteremic Agents, PCSK9 Inhibitors, Antibodies, Monoclonal, General Medicine, 11 Medical And Health Sciences, Middle Aged, Cholesterol, SPATIAL WORKING-MEMORY, SAFETY, Drug Therapy, Combination, Female, Antibody, Proprotein Convertase 9, Life Sciences & Biomedicine, REDUCING LIPIDS, Human, Adult, medicine.medical_specialty, Hypercholesterolemia, MEDLINE, Antibodies, Monoclonal, Humanized, Antibodies, LDL, 03 medical and health sciences, Medicine, General & Internal, Double-Blind Method, Memory, Internal medicine, General & Internal Medicine, EBBINGHAUS Investigators, Humans, CARDIOVASCULAR EVENTS, METAANALYSIS, Aged, Ldl cholesterol, Psychological Tests, Science & Technology, Working memory, business.industry, PCSK9, Cholesterol, LDL, EFFICACY, Atherosclerosis, Evolocumab, chemistry, biology.protein, Physical therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business
Abstract

Background Findings from clinical trials of proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors have led to concern that these drugs or the low levels of low-density lipoprotein (LDL) cholesterol that result from their use are associated with cognitive deficits. Methods In a subgroup of patients from a randomized, placebo-controlled trial of evolocumab added to statin therapy, we prospectively assessed cognitive function using the Cambridge Neuropsychological Test Automated Battery. The primary end point was the score on the spatial working memory strategy index of executive function (scores range from 4 to 28, with lower scores indicating a more efficient use of strategy and planning). Secondary end points were the scores for working memory (scores range from 0 to 279, with lower scores indicating fewer errors), episodic memory (scores range from 0 to 70, with lower scores indicating fewer errors), and psychomotor speed (scores range from 100 to 5100 msec, with faster times representing better performance). Assessments of cognitive function were performed at baseline, week 24, yearly, and at the end of the trial. The primary analysis was a noninferiority comparison of the mean change from baseline in the score on the spatial working memory strategy index of executive function between the patients who received evolocumab and those who received placebo; the noninferiority margin was set at 20% of the standard deviation of the score in the placebo group. Results A total of 1204 patients were followed for a median of 19 months; the mean (±SD) change from baseline over time in the raw score for the spatial working memory strategy index of executive function (primary end point) was −0.21±2.62 in the evolocumab group and −0.29±2.81 in the placebo group (P

Published
2017

42. Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease

Author

Marc P. Bonaca, Eva C. Jensen, Frederic Kontny, Deepak L. Bhatt, Robert F. Storey, Daniel Isaza, Alexander Parkhomenko, Assen Goudev, Sameer Bansilal, KyungAh Im, Sabina A. Murphy, Dominick J. Angiolillo, Róbert Gábor Kiss, Jose Lopez-Sendon, Ph. Gabriel Steg, Eugene Braunwald, A.J. Oude Ophuis, Marc S. Sabatine, Jan H. Cornel, and Peter Held

Subjects
Male, medicine.medical_specialty, Ticagrelor, Myocardial Infarction, Coronary Artery Disease, 030204 cardiovascular system & hematology, Drug Administration Schedule, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Secondary Prevention, Humans, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Stroke, Aged, Aspirin, business.industry, Vascular disease, Hazard ratio, Thrombosis, Middle Aged, medicine.disease, cardiovascular system, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Intracranial Hemorrhages, TIMI, Mace, Platelet Aggregation Inhibitors, medicine.drug
Abstract

Background Patients with prior myocardial infarction (MI) and multivessel coronary disease (MVD) are at high risk for recurrent coronary events. Objectives The authors investigated the efficacy and safety of ticagrelor versus placebo in patients with MVD in the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial. Methods Patients with a history of MI 1 to 3 years before inclusion in the PEGASUS-TIMI 54 trial were stratified in a pre-specified analysis based on the presence of MVD. The effect of ticagrelor (60 mg and 90 mg) on the composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events [MACE]), as well as the composite of coronary death, MI, or stent thrombosis (coronary events), and on TIMI major bleeding, intracranial hemorrhage (ICH), and fatal bleeding were evaluated over a median of 33 months. Results A total of 12,558 patients (59.4%) had MVD. In the placebo arm, compared with patients without MVD, those with MVD were at higher risk for MACE (9.37% vs. 8.57%, adjusted hazard ratio [HR adj ]: 1.24; p = 0.026) and for coronary events (7.67% vs. 5.34%, HR adj : 1.49; p = 0.0005). In patients with MVD, ticagrelor reduced the risk of MACE (7.94% vs. 9.37%, HR: 0.82; p = 0.004) and coronary events (6.02% vs. 7.67%, HR: 0.76; p Conclusions Patients with prior MI and MVD are at increased risk of MACE and coronary events, and experience substantial relative and absolute risk reductions in both outcomes with long-term ticagrelor treatment relative to those without MVD. Ticagrelor increases the risk of TIMI major bleeding, but not ICH or fatal bleeding. For patients with prior MI and MVD, ticagrelor is an effective option for long-term antiplatelet therapy. (Prevention of Cardiovascular Events [e.g., Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)

Published
2017

43. Efficacy and Safety of Ticagrelor Over Time in Patients With Prior MI in PEGASUS-TIMI 54

Author

Marc P. Bonaca, Mikhail Rudah, P. Gabriel Steg, Assen Goudev, Robert F. Storey, Sabina A. Murphy, KyungAh Im, Giulia Magnani, Pierre Theroux, Deepak L. Bhatt, Eva C. Jensen, Eugene Braunwald, Gabriel Kamensky, Daniel Isaza, Per Johanson, Marc Cohen, Alexander Parkhomenko, Marc S. Sabatine, Gilles Montalescot, and Ton Oude Ophuis

Subjects
Male, medicine.medical_specialty, Ticagrelor, Adenosine, Time Factors, Population, Myocardial Infarction, 030204 cardiovascular system & hematology, Placebo, Global Health, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Internal medicine, Cause of Death, medicine, Humans, Thrombolytic Therapy, 030212 general & internal medicine, Myocardial infarction, education, Stroke, Aged, Aspirin, education.field_of_study, Dose-Response Relationship, Drug, business.industry, Hazard ratio, Middle Aged, medicine.disease, Survival Rate, Treatment Outcome, Cardiology, Purinergic P2Y Receptor Antagonists, Female, Cardiology and Cardiovascular Medicine, business, TIMI, medicine.drug, Follow-Up Studies
Abstract

Background Ticagrelor reduces ischemic risk in patients with prior myocardial infarction (MI). It remains unclear whether ischemic risk and the benefits of prolonged P2Y12 inhibition in this population remain consistent over time. Objectives The study sought to investigate the pattern of ischemic risk over time and whether the efficacy and safety of ticagrelor were similar early and late after randomization. Methods The PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction) 54 trial randomized patients with prior MI (median 1.7 years prior) to ticagrelor 90 mg, ticagrelor 60 mg, or placebo on a background of aspirin. The rates of cardiovascular (CV) death, MI, and stroke as well as TIMI major bleeding were analyzed at yearly landmarks (years 1, 2, and 3). Results A total of 21,162 patients were randomized and followed for 33 months (median), with 28% of patients ≥5 years from MI at trial conclusion. The risk of CV death, MI, or stroke in the placebo arm remained roughly constant over the trial at an ∼3% annualized rate. The benefit of ticagrelor 60 mg was consistent at each subsequent landmark (year 1 hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.67 to 0.99; year 2 HR: 0.90; 95% CI: 0.74 to 1.11; and year 3 HR: 0.79; 95% CI: 0.62 to 1.00). TIMI major bleeding was increased with ticagrelor 60 mg at each landmark, but with the greatest hazard in the first year (year 1 HR: 3.22; year 2 HR: 2.07; year 3 HR: 1.65). Conclusions Patients with a history of MI remain at persistent high risk for CVD, MI, and stroke as late as 5 years after MI. The efficacy of low-dose ticagrelor is consistent over time with a trend toward less excess bleeding. (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562)

Published
2017

44. Predictors of Nonuse of a High‐Potency Statin After an Acute Coronary Syndrome: Insights From the Stabilization of Plaques Using Darapladib‐Thrombolysis in Myocardial Infarction 52 (SOLID‐TIMI 52) Trial

Author

Erica L. Goodrich, Eugene Braunwald, Anthony J. Dalby, KyungAh Im, Dylan L. Steen, Michelle L. O'Donoghue, Mary Ann Lukas, Shruti Daga, Jing Zhou, Alon Eisen, Jindrich Spinar, and Christopher P. Cannon

Subjects
Male, Simvastatin, medicine.medical_treatment, Myocardial Infarction, 030204 cardiovascular system & hematology, 0302 clinical medicine, Risk Factors, Cardiovascular Disease, Oximes, Atorvastatin, Odds Ratio, Secondary Prevention, Coronary Heart Disease, Renal Insufficiency, 030212 general & internal medicine, Myocardial infarction, Practice Patterns, Physicians', Rosuvastatin Calcium, Randomized Controlled Trials as Topic, Original Research, Lipids and Cholesterol, Age Factors, Thrombolysis, Middle Aged, Benzaldehydes, Cardiology, lipids (amino acids, peptides, and proteins), Female, Cardiology and Cardiovascular Medicine, guideline, TIMI, medicine.medical_specialty, Acute coronary syndrome, Statin, Phospholipase A2 Inhibitors, medicine.drug_class, acute coronary syndrome, 03 medical and health sciences, Sex Factors, Darapladib, Internal medicine, medicine, Humans, Potency, cardiovascular diseases, Angina, Unstable, Aged, Heart Failure, business.industry, nutritional and metabolic diseases, Guideline, medicine.disease, Logistic Models, statin therapy, Physical therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Acute Coronary Syndromes
Abstract

Background High‐potency statins reduce cardiovascular events after acute coronary syndromes but remain underused in clinical practice. We examined predictors of nonuse of high‐potency statins after acute coronary syndromes. Methods and Results The Stabilization of pLaques usIng Darapladib‐Thrombolysis in Myocardial Infarction (SOLID‐TIMI 52) trial enrolled patients after an acute coronary syndrome in 36 countries between 2009 and 2011. Statin use was strongly encouraged throughout the trial, and statin potency was at the discretion of the treating physician. A high‐potency statin was defined as ≥40 mg atorvastatin, ≥20 mg rosuvastatin, or 80 mg simvastatin daily. Predictors of nonuse of high‐potency statins were examined using logistic regression. Of the patients included (n=12 446), 11 850 (95.2%) were treated with a statin at baseline after acute coronary syndrome (median 14 days), but only 5212 (41.9%) were on a high‐potency statin. Selected patient factors associated with nonuse of high‐potency statins included age ≥75 years (odds ratio 1.39, 95% CI 1.24–1.56), female sex (odds ratio 1.11, 95% CI 1.02–1.22), renal dysfunction (odds ratio 1.17, 95% CI 1.03–1.32), and heart failure during hospital admission (odds ratio 1.43, 95% CI 1.27–1.62). At 3 months after baseline, only 49% of patients had low‐density lipoprotein cholesterol CI 1.11–1.19). Conclusion Despite the widespread use of statins after acute coronary syndromes, most patients are not treated with high‐potency statins early and late after the event, including patients at the highest risk of recurrent cardiovascular events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01000727.

Published
2017

45. Lipoprotein(a), PCSK9 Inhibition and cardiovascular risk: Insights from the Fourier trial

Author

Michelle L. O'Donoghue, Marc Sabatine, KyungAh Im, Anthony C Keech, Ransi Somaratne, T. Pederson, Robert P. Giugliano, Estella Kanevsky, Peter S. Sever, and A.Lira Pineda

Subjects
medicine.medical_specialty, biology, business.industry, PCSK9, Lipoprotein(a), 030204 cardiovascular system & hematology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Fourier transform, Endocrinology, Internal medicine, symbols, biology.protein, Medicine, 030212 general & internal medicine, Cardiology and Cardiovascular Medicine, business
Published
2018

46. PERSISTENCE OF VALVULOPATHY IN THE CAMELLIA-TIMI 61 TRIAL OF LORCASERIN IN OBESE OR OVERWEIGHT PATIENTS AT INCREASED CARDIOVASCULAR RISK

Author

Benjamin M. Scirica, Darren McGuire, Tushar Patel, Stephen D. Wiviott, Anthony Keech, Neil Weissman, Arman Qamar, KyungAh Im, Silvio Inzucchi, Marc S. Sabatine, Steven Smith, Wenfeng Miao, Christina L. Fanola, Carlos Perdomo, Julia F Kuder, and Erin A. Bohula

Subjects
Agonist, medicine.medical_specialty, medicine.drug_class, business.industry, Serotonin 2C Receptor, Overweight, Lorcaserin, Persistence (computer science), Increased risk, Weight loss, Internal medicine, medicine, Cardiology, medicine.symptom, Cardiology and Cardiovascular Medicine, business, TIMI, medicine.drug
Abstract

Lorcaserin, a serotonin 2C receptor agonist, recently demonstrated sustained weight loss without an increased risk of cardiovascular (CV) events or valvulopathy in obese or overweight pts at high CV risk. Here we evaluate the persistence of valvulopathy measures. The CAMELLIA-TIMI 61 trial

Published
2019

47. Ezetimibe added to statin therapy after acute coronary syndromes

Author

Cannon, Christopher P., Blazing, Michael A., Giugliano, Robert P., Mccagg, Amy, White, Jennifer A., Theroux, Pierre, Darius, Harald, Lewis, Basil S., Ophuis, Ton Oude, Jukema, J. Wouter, De Ferrari, Gaetano M., Ruzyllo, Witold, De Lucca, Paul, Kyungah, Im, Bohula, Erin A., Reist, Craig, Wiviott, Stephen D., Tershakovec, Andrew M., Musliner, Thomas A., Braunwald, Eugene, Califf, Musliner T, Robert M., Tershakovec, A, Gurfinkel, E, Aylward, P, Tonkin, A, Maurer, G, Van de Werf, F, Nicolau, Jc, Theroux, P, Genest, J, Armstrong, P, Corbalan, R, Isaza, D, Spinar, J, Grande, P, Voitk, J, Kesaniemi, A, Bassand, Jp, Farnier, M, Darius, H, Keltai, M, Mathur, A, Mittal, S, Reddy, K, Lewis, B, De Ferrari GM, Ophuis, To, Jukema, J, White, H, Pedersen, T, Britto, F, Ruzyllo, W, Carrageta, M, Duris, T, Dalby, A, Seung, Kb, Lopez-Sendon, J, Dellborg, M, Mach, F, Guneri, S, Parkhomenko, A, Brady, A, Cannon, C, Blazing, M, Ballantyne, C, de Lemos, J, Kleiman, N, Mcguire, Dk, Centeno, E, Casalins, M, Cartasegna, L, Beltrano, Mc, Guerrero, R, Fanuele, M, Berra, F, Egido, J, Colombo, H, Dellatorre, M, Terns, P, Blumberg, E, Reges, P, Azize, G, Ramos, H, Fernandez, R, Carlessi, C, Milesi, R, Schmuck, R, Duronto, E, Procopio, G, Carlevaro, O, Maffeo, H, Beloscar, J, Viso, M, Hominal, M, Castoldi, M, Bluguermann, J, Mauro, D, Macin, S, Cocco, N, Ruiz, N, Ricart, J, Lozada, A, Nani, S, Turri, D, Fernandez, H, Caruso, O, Zarandon, R, Bono, J, Arias, V, Allall, O, Marino, J, Cusimano, S, Schygiel, P, Buzetti, C, Penaloza, N, Berli, M, Worthley, S, Roach, A, Chew, D, Wright, T, Leitch, J, Hicks, E, Rankin, J, Venn-Edmonds, C, Lehman, R, Morrison, H, Shaw, J, Mak, V, Hii, C, Smith, K, Cross, D, Lilwall, L, Nelson, G, Loxton, A, Horowitz, J, Rose, J, Steinwender, C, Leisch, F, Kammler, J, Brussee, H, Zweiker, R, Niederl, E, Weihs, W, Giorgio, G, Lang, I, Drexel, H, Zanolin, D, Hoppe, U, Atzenhofer-Baumgartner, K, Pichler, M, Hainzer, D, Eber, B, Pichler, F, Foeger, B, Wechselberger, T, Mayr, H, Hofer, J, Stockenhuber, F, Warlits, B, Huber, K, Egger, F, Weidinger, F, Ziegler, B, Jirak, P, Metzler, B, Pachinger, O, Wanitschek, M, Auer, J, Grabscheit, G, Podczeck-Schweighofer, A, Priesnitz, T, Frank, H, El Allaf, D, Marechal, P, Roosen, J, Joly, E, Lefebvre, P, Arend, C, Sinnaeve, P, De Velder, L, Hellemans, S, Vanhauwaert, B, Van Dorpe, A, Heyse, A, Vantomme, C, Striekwold, H, Van Den Broeck, D, Lancellotti, P, Schoors, D, Lemoine, I, Taeymans, Y, De Wolf, L, Brike, C, Vercauteren, S, Tahon, S, Vervoort, G, Mestdagh, I, Pirenne, B, Cardinal, F, Lips, S, Dujardin, K, Debrouwer, K, Dhooghe, G, Holvoet, G, van de Borne, P, Renard, M, De Clippel, M, Lesseliers, H, Van Miert, N, Saraiva, J, Vicente, C, Rossi, P, Dos Santos LB, Duda, N, Tognon, Ap, Serrano, C, Gomes, Fl, Manenti, Er, Silveira, Ds, Maia, L, Mouco, Om, Paiva, M, Antonangelo, A, de Souza, J, Lino, Ea, Leães, P, Blacher, Mg, Kormann, A, Ultramari, Ft, Dutra, O, Mendelski, Am, Morgado, S, Ardito, W, Greque, G, Ardito, Rv, Pimentel Filho, P, Zucchetti, C, Alves, A, Seabra, Am, Mattos, M, Miranda, Lf, Silva, D, Uehara, Rm, Marin Neto, J, Schmidt, A, Braga, J, Rodrigues, A, Abrantes, J, Pinheiro, L, Bodanese, L, Magedanz, Éh, Piegas, L, Dos Santos ES, Wainstein, M, Ribeiro, J, Stein, R, Marino, R, Machado, Vm, Moraes Junior, J, Guimarães, S, da Costa FA, Ferraz, Rf, Albuquerque, D, Rocha, Rm, de Carvalho Moreira, R, Dohmann, H, Costantini, C, Tarastchuk, Jc, Coelho, O, Cirillo, W, Sousa, A, Almeira, As, Stefanini, E, Silva, F, Teixeira, M, da Cunha, C, Précoma, D, Facchi, Tl, Rupka, D, Thiessen, S, Warnica, J, Smith, B, Della Siega, A, Klinke, P, Nelson, S, Dion, D, Gilbert, N, Hui, W, Kvill, L, Sussex, B, Luther, A, Dupuis, R, Ouimet, F, Pandey, A, Clarus, S, Senaratne, M, Ferdinandis, H, Mukherjee, A, Bozek, B, Vizel, S, Markov, G, Zimmermann, R, Stephens, W, Tremblay, B, Wong, G, Uchida, N, Brossoit, R, Peck, C, Van Kieu, C, Forgione, M, Bata, I, Cossett, J, Kostuk, W, Arnold, M, Bone, C, Grondin, F, Bilodeau, N, Gosselin, G, David, M, Giannoccaro, J, Beresford, P, Polasek, P, Roberts, P, Doucet, M, Beaudry, M, Cheung, S, Cleveland, T, Bhargava, R, Mccallum, A, Ma, P, Morrissette, J, Cleveland, D, Chadwyn, D, Nigro, F, Weeks, A, Cryderman, C, Leader, R, Houde, G, Rousseau, S, Pearce, M, Radyk, M, Lonn, E, Magi, A, Lefkowitz, C, Sandrin, F, Coffin, N, Lubelsky, B, Coldwell, J, Habot, J, Mcpherson, C, De Larochelliere, R, Roy, M, Haichin, R, Barber, C, Bhesania, T, Kitagawa, H, To, T, Donnelly, B, Tymchak, W, Harris, L, Kouz, S, Huynh, T, St Jacques, B, Lamy, A, Rizzo, A, Stein, J, Childs, C, Wong, B, Poirier, R, Gupta, M, Dela Cruz, C, Constance, C, Gauthier, M, Ervin, F, Ouellette, M, Kokis, A, Lemay, C, Kwok, K, Leung, C, Lee, D, Nesmith, J, Renton, J, Syan, G, Turek, M, Hogan, D, Griffin, P, Lipson, A, Winestock, J, Abramson, B, Fogel, A, Gagne, C, Bergeron, J, Clarke, A, Slipp, S, Darcel, I, Carling-Chambers, L, Kannampuzha, P, Pallie, S, Krekorian, S, Vertes, G, Roth, S, Lai, K, Heath, J, Perez, L, Arriagada, G, Castro, P, Villa, F, Rodríguez, M, Ramos, G, Baraona, F, Núñez, A, García, M, Jofre, C, Silva, P, Lamich, R, Yovaniniz, P, Escobar, E, Dussaubat, A, Segura, E, Ramirez, M, Lapostol, C, Palma, A, Encina, L, Zapata, M, Baeza, N, Varela, P, Pérez, L, Jaramillo, C, Ruiz, S, Sanchez, G, Perdomo, I, Manzur, F, Cohen, Le, Velasquez, J, Arana, C, Alvarez, Y, Triana, M, Balaguera, J, de Salazar, D, Rendon, N, Botero, R, Ruiz, A, Saaibi, J, Medina, J, Jaramillo, M, Calderón, Mj, Delgado, J, Bohorquez, R, Medina, Mf, Herrera, M, Rosales, D, Mendoza, F, Martinez, S, Ternera, A, Castro, R, Baiz, A, Martinez, M, Orozco, A, Suarez, M, Fonseca, Y, Beltran, R, Cepeda, M, Jaramillo, N, Valenzuela, C, Gutierrez, M, Sanchez, A, Vitovec, J, Hlinomaz, O, Poloczek, M, Mayer, O, Veselka, J, Vejvoda, J, Soucek, M, Spac, J, Novobilsky, K, Srp, V, Francek, L, Branny, M, Sknouril, L, Motovska, Z, Rohac, F, Stankova, A, Fiala, T, Holub, M, Zeman, K, Pohludkova, L, Pospisilova, E, Tuma, P, Cihalik, C, Oral, I, Podpera, I, Stepanovova, R, Uricar, M, Solar, M, Pelouch, R, Porzer, M, Grussmannova, K, Stipal, R, Reichert, P, Hradec, J, Kral, J, Sejkova, B, Janek, B, Pitha, J, Linhart, A, Polacek, P, Koeber, L, Clemmensen, P, Hebin, Ch, Schmidt, E, Pedersen, Ms, Roseva-Nielsen, N, Kristensen, K, Bang-Hansen, T, Jensen, J, Laage-Petersen, J, Nielsen, H, Stokholm, E, Thayssen, P, Cappelen, H, Jensen, T, Winther-Friis, B, Klausen, I, Hedegaard, B, May, O, Andersen, M, Bottzauw, J, Lush, A, Markenvard, J, Vestager, Km, Bronnum-Schou, J, Hempel, H, Petersen, J, Nielsen, Aj, Thomsen, K, Nielsen, T, Nygaard, A, Sykulski, R, Jensen, Bs, Ralfkiaer, N, Gottschalck, H, Rasmussen, S, Pedersen, Lr, Dodt, K, Skovsbøl, M, Andersen, O, Tuxen, C, Meier, Aw, Kristensen, T, Rasmussen, O, Lopez, J, Salazar, D, Sanchez, L, Rosero, F, Penaherrera, E, Duarte, Yc, Marmol, R, Andrade, G, Guzman, E, Morillo, A, Aug, L, Loogna, I, Laanmets, P, Mustonen, J, Mäntylä, P, Kesäniemi, A, Ukkola, O, Kervinen, H, Juhela, S, Juvonen, J, Toppinen, A, Jarvenpaa, J, Syvanne, M, Svahn, T, Voutilainen, S, Huotari, A, Nikkila, M, Raiskinmäki, S, Kotila, M, Rajala, A, Laukkanen, J, Hiltunen, P, Melin, J, Nyman, K, Luukkonen, J, Kosonen, P, Huttunen, M, Seppänen, V, Airaksinen, J, Juonala, M, Lehto, S, Savolainen, K, Halkosaari, M, Sia, J, Palomaki, A, Luoma, J, Utriainen, S, Valpas, S, Tiensuu, T, Lilleberg, J, Kainulainen, R, Schiele, F, Bassand, J, Meneveau, N, Galinier, M, Jean, M, Martelet, M, Mouallem, J, Elbaz, M, Puel, J, Carrié, D, Coisne, D, Varroud-Vial, N, Jaboureck, O, Dujardin, J, Leroy, F, Mansourati, J, Funck, F, Jourdain, P, Guillard, N, Coviaux, F, Gay, A, Dourmap-Collas, C, Froger-Bompas, C, Paillard, F, Tricot, O, Maquin-Mavier, I, Dubois-Rande, Jl, Pongas, D, Paris, Ap, Delahaye, F, Ovize, M, Benyahya, L, Bonnet, J, Belle, L, Mangin, L, Lafitte, B, Zemour, G, Doux, N, Agraou, B, El Mansour, N, Traisnel, G, El Jarroudi, M, Ohlmann, P, Diadema, B, Escande, M, Legros, G, Demarcq, Jm, Haftel, Y, Alsagheer, S, Dambrine, P, Cottin, Y, Ghostine, S, Caussin, C, Gacem, A, Bouvier, Jm, Poulard, J, Davy, J, Furber, A, Prunier, F, Muenzel, T, Genth-Zotz, S, Appel, K, Kretzschmar, D, Ferrari, M, Terres, W, Uher, T, Schulze, H, Ochs, H, Morbach, S, Duengen, H, Gross, M, Oezcelik, C, Tahirovic, E, Heuer, H, Laschewski, B, Kadel, C, Rahn, G, Steiner, S, Kreuzer, J, Tsoy, I, Zeiher, A, Muegge, A, Hanefeld, C, Boehm, S, Boudriot, E, Hodenberg, E, Lippe, B, Hausdorf, C, Sydow, K, Baldus, S, Schlesner, C, Tiroch, K, Haltern, G, Guelker, H, Wilhelm, J, Dietz, S, Ebelt, H, Buerke, M, Rupprecht, H, Rittgen, J, Schaeufele, T, Meinhardt, G, Schieber, M, Honold, M, Sieprath, S, Nienaber, C, Hacker, J, Butter, C, Lapp, H, Hirn, S, Pauschinger, M, Zahn, R, Scheffler, U, Schaefer, A, Schieffer, B, Tebbe, U, Kriete, M, Mudra, H, Raeder, T, Braun, P, Zeymer, U, Kouraki, K, Reppel, M, Schunkert, H, Weil, J, Olbrich, H, Schwaiger, P, Mueller, O, Blessing, E, Buss, I, Bohlscheid, V, Kaddatz, J, Skowasch, D, Nickenig, G, Twelker, K, Osterhues, H, Varghese, T, Burghard, S, Kaeaeb, S, Klauss, V, Sohn, Hy, Hauptmann, K, 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E., Cullen, T., Eisenberg, S., Chronos, N., Allen, R.P., Erickson, B., Mahon, K., Kirby, A., Siegel, C., Stroud, L., Johnson, J., Panchal, V., Pearson, A., Abell, T., De Gregorio, M., Boomer, L., Vahdat, O., VanNatta, B., Long, P., Chalavarya, G., Skatrud, L., Carey, C., Wright, W., Mechem, C., Matthews, B., Adams, A., Vora, K., Wead, J., Koren, M., Gregory, D., El Khadra, M., Peacock, G., Kieval, J., Barron, M., Lewis, D., Grice, R., Bobek, M., Moore, C., Nygaard, T., Fischell, T., Salman, W., Schneider, C., Muhlestein, B., Peeler, D., Chang, D., Todd, A., Chilakamarri, V., Hanley, P., Gelormini, J., Iacona, M.A., Effron, B., Mazzurco, S., Mazzella, M., Wyman, P., Orchard, R., Battin, D., Rezkalla, S., Bishop, C., Sharp, S., Gredler, F., Knap, P., Fadel, M., Saucedo, J., Keng, A., Imburgia, M., Blank, E., Effat, M., Khoury, S., Mardis, R., Baldari, D., Tafuri, L., Mascolo, R., Taylor, D., Mandviwala, M., Khan, W., Mumford, T., Mayer, N., Mitchell, B., Oliver, T., Lombardi, W., Zimmerman, T., Rohrbeck, S., Cooke, L., Craig, M., Mego, D., Griffin, B., Perez, J., LeClerc, K., Addington, J., Aboufakher, R., Ahmed, A., Westecott, B., Steel, K., Hawkins, K., Shah, A., Ward, U., McGreevy, M., Goldberg, R., Prashad, R., McDonough, C., Silver, K., Josephson, R., Witsaman, S., Labib, S., Woodhead, G., Schrank, J., Bell, K., Chandna, H., Holly, D., Bethea, C., Fife, B., Gruberg, L., Singer, A., Ramgadoo, M., Lalonde, T., Morin, R., French, W., Barillas, O., Gradner, G., Kahn, Z., Gress, J., Rocco, D., Thew, S., Stifter, W., Fisher, M., McNamara, J., Kupfer, J., Agocha, A., Cush, S., Jones, S., Whitaker, T., Stover, T., Kumkumian, G., Kent, K., Greenberg, A., Pandey, P., Pytlewski, G., Matsumura, M., Kai, W., Sameshima, S., Thomas, J., MacNicholas, D., Pillai, K., Jones, D., Navas, J.P., Laskoe, B., Patel, P., Fini, G., Minor, S., Shipwash, T., Cabrera-Santamaria, A., Rivera, E., Mincher, L., Jafar, M., Yen, M., Finkle, C., Rahimtoola, A., Severson, L., Labroo, A., Jinich, D., Tam, K., Vogel, C., Aggarwal, R., Zakhary, B., Curtis, S., Lyster, M., Humphrey, K., Lavine, P., Fujise, K., Birnbaum, Y., Allen, J., Kesselbrenner, M., Michel, K., Staniloae, C., Liu, M., Sonel, A., Macioce-Caffas, A., Amidon, T., Leggett, J., Yedinak, S., Gudmundsson, G., Sabharwal, J., Dagefoerde, N., Wu, W., Meyerrose, G., Roongsritong, C., Jenkins, L., Lieberman, S., Sokol, S., Gutierrez, C., Nelson, C., Barrett, J., Hotchkiss, D., Farley, A., Atassi, K., Christy, L., Baig, M., Di Fazio, J., Meengs, M., Thomas, K., Surmitis, J., DeVault, S., Farhat, N., Hulyalkar, A., Riddell, L., Rivera, W., Sheynberg, B., Kobayashi, J., Katsaropoulos, J., Jan, M., Krucoff, M., Paterno, C., Chandrasekaran, S., Curry, R., Cassavar, D., Wheeler, M., McGarvey, J., Schwarz, L., Miller, E., Andrea, B., Carswell, B.S., Lurie, M., Patti, J., Bowden, W., Vasiliauskas, T., Latham, R., Schwartz, B., Bradford, L., Mattleman, S., Wertheimer, J., Goulden, D., Khan, M., Hawkins, B., Ostfeld, R., Mueller, H., Ash, Y., Wilson, V., Bayer, M., Marshall, J., Dobies, D., Dawson, G., Osman, A., Saba, F., Costello, T., Fuentes, F., Underwood, C., Vijay, N., Washam, M., Dietz, W., Glasgow, B., Mukherjee, S., Hinchion, N., Speirs, S., Thornley, A., Lee, K., Movahed, M., Strootman, D., Chernick, R., Parrott, C., Flock, C., Marques, V., Syzmanski, E., Rama, P., Domingo, D., Wu, L., Bauer, B., Dionisopoulos, P., Aggarwal, A., Holcomb, R., Foster, R., Hancock, T., Hargrove, J., Fletcher, A., Stine, R., Bullivant, M., Adams, K., Lohman, J., Klepper, V., Kabour, A., Neidhardt, J., Phillips, W., Tardiff, S., Aji, J., Corut, S., Foster, G., Firek, C., St Goar, F., Sumner, R., Davis, T., Schneider, R., Schneider, W., Villa, A., Desai, V., Chhabra, A., Banks, K., Herzog, W., Burley, T., Quyyumi, A., Smiley, W., Manocha, P., Fishbein, G., Weller, C., Coffman, A., Kim, C., Kedia, A., Firth, B., Rizvi, M., Dahiya, R., Foster, B., Balcells, E., Metzger, D.C., Lester, J., Bissett, J., Fahdi, I., Sides, E.A., Azrin, M., Martin, C., Quick, A., Conaway, D., Garg, M., Schallert, G., Lancaster, L., Mckissick, S., Atieh, M., Garbarino, J., Eisenberg, D., Uusinarkaus, K., Wirtemburg, P., Ellis, J., Cristaldi, J., Berglund, R., Negus, B., Pappas, J., Rocha, R., Nguyen, T., Stone, J., Janosik, D., Labovitz, A., Elmore, N., Dave, R., Loffredo, K., Gabriel, G., Snyder, C., Ahmed, O., Stone, H., Kelley, M., Diffenback, M., Friedman, B., Zirkle, J., Severa, L., Sample, S., Dignen, K., Raisinghani, A., Ben-Yehuda, O., Ghannadian, B., Moscoso, R., Mankowski, J., Boliek, W., Rukavina, M., Davis, W., Ledbetter, S., Handel, F., Mastouri, R., Mahenthiran, J., Foltz, J., Malhotra, V., Jonas, J., Berk, M., Singh, V., Nelson, M., Elsner, G., Gall, J., Kondo, N., Frank, S., Chandraratna, P., Ranasinghe, S., Ebrahimi, R., Treadwell, M., Walters, B., Hughes, L., Kramer, J., Kumar, K., Mente, T., Lachterman, B., Schifferdecker, B., Munshi, K., Sease, D., Waldo, D., Chandler, G., Manns, D., Nahhas, A., Kamalesh, M., Williams, V., Reich, D., Desalca, M., Sharma, S., Liston, M., Gupta, K., Costa, M., Altschuller, A., Lemmertz, K., Shanes, J., Hansen, C., Therrien, M., Mendelson, R., Ramnarine, R., Myers, G., Donovan, C., Klein, M., Fine, D., Owens, S., Murray, C., Ketroser, R., Heifetz, S., Darnell, Z., Touchon, R., Taghizadeh, B., Bohle, D., Norwood, D., Forrest, T., Jackson, S., Shumate, K., Bayles, A., Masroor, M., North, W.K., Fishberg, R., Merveil-Ceneus, B., Butcher, R., Menapace, F., Kilbride, S., Ramabadran, R.S., Loukinen, K., Khalil, J., Ramabadran, R., Walsh, S., Gill, S., Cyncar, R., McLachlan, J., Surakanti, V., Rusterholtz, L., Shoukfeh, F., Stephenson, L., Tsang, M., Nolan, V., Gilchrist, I., Jefferson, D., Feldman, T., Reyes, L., Santos, R., Little, W., Wesley, D., Gharib, W., Mendell, A., Esham, G., Kakavas, P., Whitcomb, C., Book, K., Bazzi, A., Alvarez, J., Cohen, Y., Ayres, T., Rhule, V., Labib, A., Schuler, P., Zughaib, M., Telck, K., Bikkina, M., Turnbull, K., Sharma, T., Orosz, S., Shah, R., Petrino, M., Hughes, M., Hershey, J., Hudock, D., Hui, P., Von Bakonyi, A., Arnold, A., Kappel, D., Pennock, G., Cloud, B., Tucker, K., Harp, L., Hoover, C., Eisenhauer, M., Roth, J., Young, C., Thai, H., Escalante, A., Bautista, J., Gazmuri, R., Nyland, J., Cubeddu, L., DeFranco, A., Dias, D., Fielding, M., Reeves, R., Hermany, P., Meissner-Dengler, S., Evans, M., Flores, E., Tannenbaum, A., McGarr, K., Moran, J., Stout, E., Allred, S., Henderson, D., Crandall, L., Strote, J., Voyles, W., Robeson, D., Bedoya, R., Omar, B., Pettyjohn, F., Revere, C., Coy, K., Margolis, J., Sotolongo, C., Scheffel, M., Munir, A., Shirwany, A., Douglas, L., Girala, R., Humphreys, R., Agarwal, J., Bankowski, D., Watson, R., Bishop, B., Klementowicz, P., Blais, D., Cohen, B., Lobur, E., Dimenna, J., Dempsey, K., Izzo, M., Bondi, L., Carell, E., Eaton, C., Saltiel, F., Grewal, G., Connolly, T., Little, T., Wiegman, P., Gips, S., Held, J., Paraschos, A., Quesada, R., Goudreau, E., Sears, M., Istfan, P., Holt, S., McClung, J., Nguyen, N., Quintana, O., Gottlieb, D., Knutson, T., Barringhaus, K., Lester, F., Sullivan, P., Rodriguez-Ospina, L., Cannon, Cp, Blazing, Ma, Giugliano, Rp, Mccagg, A, White, Ja, Theroux, P, Darius, H, Lewis, B, Ophuis, To, Jukema, Jw, De Ferrari, Gm, Ruzyllo, W, De Lucca, P, Im, K, Bohula, Ea, Reist, C, Wiviott, Sd, Tershakovec, Am, Musliner, Ta, Braunwald, E, Califf, Rm, for the IMPROVE-IT, Investigator, Cianflone, D, Cardiovascular Division (SZG), Brigham and Women's Hospital [Boston], College of Information Science and Engineering, Ritsumeikan University, Montreal Heart Institute (MONTREAL HEART INSTITUTE), Laboratoire des Micro-algues toxiques, Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD)-Institut de Recherche pour le Développement (IRD), Interuniversity Cardiology Institute Netherlands, Institute of Cardiology (WARSAW - Cardiology), Institute of Cardiology, Merck Sharp & Dohme Corp., Merck & Co. Inc, DIPARTIMENTO DI MEDICINA SPECIALISTICA, DIAGNOSTICA E SPERIMENTALE, Facolta' di MEDICINA e CHIRURGIA, AREA MIN. 06 - Scienze mediche, Cannon, C.P., Blazing, M.A., Giugliano, R.P., Mccagg, A., White, J.A., Lewis, B.S., Jukema, J.W., De Lucca, P., Im, K., Bohula, E.A., Reist, C., Wiviott, S.D., Tershakovec, A.M., Musliner, T.A., Braunwald, E., Califf, R.M., for the IMPROVE-IT Investigators [.., C. Rapezzi, ], Other departments, Cannon, Christopher P, Blazing, Michael A., Giugliano, Robert P., Mccagg, Amy, White, Jennifer A., Theroux, Pierre, Darius, Harald, Lewis, Basil S., Ophuis, Ton Oude, Jukema, J. Wouter, De Ferrari, Gaetano M., Ruzyllo, Witold, De Lucca, Paul, Kyungah, Im, Bohula, Erin A., Reist, Craig, Wiviott, Stephen D., Tershakovec, Andrew M., Musliner, Thomas A., Braunwald, Eugene, and Califf, Robert M.

Subjects
Male, Simvastatin, acute coronary syndrome, aged, anticholesteremic agents, azetidines, cardiovascular diseases, cholesterol, ldl, double-blind method, drug therapy, combination, ezetimibe, female, humans, hydroxymethylglutaryl-coa reductase inhibitors, kaplan-meier estimate, male, middle aged, simvastatin, triglycerides, medicine (all, [SDV]Life Sciences [q-bio], Kaplan-Meier Estimate, 030204 cardiovascular system & hematology, Bococizumab, Triglyceride, chemistry.chemical_compound, 0302 clinical medicine, Azetidine, Cardiovascular Disease, Anticholesteremic Agent, Acute Coronary Syndrome, Aged, Anticholesteremic Agents, Azetidines, Cardiovascular Diseases, Cholesterol, LDL, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Middle Aged, Triglycerides, 030212 general & internal medicine, Medicine (all), Research Support, Non-U.S. Gov't, Hazard ratio, General Medicine, Acute Coronary Syndrome, Aged, Anticholesteremic Agents, Azetidines, Cardiovascular Diseases, Ezetimibe, Female, Humans, Male, Middle Aged, 3. Good health, Multicenter Study, Editorial, Cholesterol, Randomized Controlled Trial, Combination, Ezetimibe, lipids (amino acids, peptides, and proteins), Human, medicine.drug, medicine.medical_specialty, Acute Coronary Syndroms, Urology, Acute Coronary Syndrome/drug therapy, Anticholesteremic Agents/adverse effects, Anticholesteremic Agents/therapeutic use, Azetidines/adverse effects, Azetidines/therapeutic use, Cardiovascular Diseases/epidemiology, Cardiovascular Diseases/mortality, Cardiovascular Diseases/prevention & control, Cholesterol, LDL/blood, Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use, Simvastatin/therapeutic use, Triglycerides/blood, NO, LDL, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Drug Therapy, Internal medicine, Journal Article, medicine, Comparative Study, Alirocumab, business.industry, PCSK9, ta3121, Lomitapide, DOENÇAS CARDIOVASCULARES, Endocrinology, chemistry, Statin Therapy, Hydroxymethylglutaryl-CoA Reductase Inhibitor, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (PCONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

Published
2015

48. Prognostic Implications of Biomarker Assessments in Patients With Type 2 Diabetes at High Cardiovascular Risk: A Secondary Analysis of a Randomized Clinical Trial

Author

Benjamin M. Scirica, Ofri Mosenzon, Ph. Gabriel Steg, Itamar Raz, David A. Morrow, KyungAh Im, Jacob A. Udell, Boaz Hirshberg, Pia S. Pollack, Deepak L. Bhatt, Petr Jarolim, Matthew A. Cavender, and Eugene Braunwald

Subjects
medicine.medical_specialty, Troponin T, business.industry, Hazard ratio, Type 2 diabetes, 030204 cardiovascular system & hematology, medicine.disease, law.invention, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Interquartile range, Internal medicine, Cardiology, Medicine, Biomarker (medicine), 030212 general & internal medicine, Myocardial infarction, Cardiology and Cardiovascular Medicine, business
Abstract

Cardiac biomarkers provide insights into pathophysiologic processes and offer an attractive strategy for the assessment of cardiovascular risk.To assess the incremental prognostic value of biomarkers that reflect different pathophysiologic processes in patients with type 2 diabetes.The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 is a randomized, double-blind, placebo-controlled clinical trial that evaluated the safety of saxagliptin vs placebo in 16 492 outpatients with type 2 diabetes with overt cardiovascular disease (CVD) or multiple risk factors. In this secondary analysis, widely used biomarkers were evaluated to ascertain whether they would provide incremental prognostic value in the risk stratification. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years). The study was performed from May 10, 2010, to June 15, 2013.Randomization to saxagliptin vs placebo in addition to standard care.Concentrations of high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein were analyzed continuously and by established cut points. Cardiovascular death, myocardial infarction, ischemic stroke, and hospitalization for heart failure (HF) were adjudicated by a blinded events committee.Of the 16 492 patients, 5455 (33.1%) were female and 11 037 (66.9%) were male. Mean (SD) age was 65.0 (8.5) years (range, 39-99 years). Baseline biomarkers were measured in 12 310 patients. Elevated levels of each biomarker were associated significantly with increased risk for all cardiovascular end points. When added to clinical variables, biomarkers significantly improved the discrimination and appropriate reclassification of risk. Elevated high-sensitivity troponin T was associated with an increased risk of cardiovascular death (adjusted hazard ratio [AHR], 3.07; 95% CI, 2.35-4.02; P .001), myocardial infarction (AHR, 2.13; 95% CI, 1.69-2.67; P .001), and hospitalization for HF (AHR, 3.85; 95% CI, 2.82-5.27; P .001). Elevated N-terminal pro-B-type natriuretic peptide was also associated with an increased risk of cardiovascular death (AHR, 3.09; 95% CI, 2.46-3.89; P .001), myocardial infarction (AHR, 1.95; 95% CI, 1.51-2.53; P .001), and hospitalization for HF (AHR, 3.92; 95% CI, 3.11-4.92; P .001). Elevated high-sensitivity C-reactive protein was more weakly associated with an increased risk of cardiovascular death (AHR, 1.49; 95% CI, 1.22-1.82; P .001) and hospitalization for HF (AHR, 1.47; 95% CI, 1.20-1.81; P .001). Consistent results were seen in patients with or without established CVD.A substantial proportion of patients with stable type 2 diabetes with established CVD or multiple clinical risk factors have evidence of ongoing myocardial injury, hemodynamic stress, or systemic inflammation. Biomarker risk stratification thus challenges the traditional differentiation between primary and secondary prevention based simply on clinical history. Strategies to improve risk stratification in patients with type 2 diabetes, with or without CVD, should consider incorporation of biomarker data into standard risk algorithms.clinicaltrials.gov Identifier: NCT01107886.

Published
2016

49. Serum potassium levels, cardiac arrhythmias, and mortality following non-ST-elevation myocardial infarction or unstable angina: insights from MERLIN-TIMI 36

Author

Benjamin M. Scirica, Sara Tannenbaum, David A. Morrow, Jianping Guo, Ana Viana-Tejedor, KyungAh Im, and Ravi B. Patel

Subjects
Male, Acute coronary syndrome, medicine.medical_specialty, Potassium, chemistry.chemical_element, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, Ventricular tachycardia, Article, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Ranolazine, Internal medicine, medicine, Humans, cardiovascular diseases, 030212 general & internal medicine, Myocardial infarction, Angina, Unstable, Non-ST Elevated Myocardial Infarction, Aged, medicine.diagnostic_test, Unstable angina, business.industry, Arrhythmias, Cardiac, Cardiovascular Agents, General Medicine, Middle Aged, medicine.disease, chemistry, Cardiovascular agent, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, TIMI
Abstract

In acute coronary syndrome (ACS), potassium levels3.5 mEq/L are associated with ventricular arrhythmias. Current guidelines therefore recommend a potassium target4.0 mEq/L in ACS. Our study evaluated the association between potassium levels, cardiac arrhythmias, and cardiovascular death in patients with non-ST-segment elevation myocardial infarction or unstable angina.Potassium levels were measured in 6515 patients prior to randomization to receive either ranolazine or a placebo in the MERLIN-TIMI 36 trial. A seven-day continuous electrocardiographic assessment was obtained to determine the incidence of non-sustained ventricular tachycardia (NSVT) and ventricular pauses. The association between potassium levels and cardiovascular death was evaluated using a Cox proportional hazards regression model with multivariable adjustment.NSVT lasting for at least eight consecutive beats occurred more frequently at potassium levels3.5 mEq/L than at potassium levels ⩾5 mEq/L (10.1 vs. 4.5%, p=0.03 for trend), whereas the inverse pattern was observed for ventricular pauses3 s, which occurred more frequently at potassium levels ⩾5 mEq/L than at potassium levels3.5 mEq/L (5.9 vs. 2.0%, p=0.03 for trend). There was a U-shaped relationship between the potassium level at admission and both early and late risk of cardiovascular death. Compared with patients with potassium levels of 3.5 to4 mEq/L, a potassium level3.5 mEq/L was associated with an increased risk of cardiovascular death at day 14 (2.4 vs. 0.8%, HRThe lowest risk of cardiovascular death was observed in patients with admission potassium levels between 3.5 and 4.5 mEq/L. Both lower and higher levels of potassium were associated with tachyarrhythmias and bradyarrhythmias, suggesting a potential mechanistic explanation for the increased risk of cardiovascular death at the extremes of potassium homeostasis.

Published
2016

50. TCT-78 Efficacy of Long-Term Ticagrelor in Stented Patients in PEGASUS-TIMI 54

Author

Philippe Gabriel Steg, KyungAh Im, Eugene Braunwald, Jindrich Spinar, Sameer Bansilal, Peter Held, Deepak L. Bhatt, Eva C. Jensen, Robert F. Storey, Róbert Gábor Kiss, Rafael Diaz, Andrej Budaj, Christian W. Hamm, Gilles Montalescot, Frans Van de Werf, Giulia Magnani, Marc P. Bonaca, Michael Ruda, Marc S. Sabatine, and T. Oude Ophuis

Subjects
medicine.medical_specialty, Randomization, business.industry, medicine.medical_treatment, Stent, 030204 cardiovascular system & hematology, equipment and supplies, medicine.disease, 3. Good health, 03 medical and health sciences, surgical procedures, operative, 0302 clinical medicine, Internal medicine, Conventional PCI, medicine, Cardiology, In patient, cardiovascular diseases, 030212 general & internal medicine, business, Cardiology and Cardiovascular Medicine, Stroke, Ticagrelor, TIMI, medicine.drug
Abstract

Ticagrelor in patients with prior MI reduced the incidence of CV death, MI, or stroke by 15-16% in PEGASUS-TIMI 54. We investigated the efficacy of ticagrelor in patients based on the presence and type of stent. Details of each patient's most recent PCI were collected at randomization. Stent

Published
2015
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