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Coronary Artery Disease: HELP
Articles by Marc S. Sabatine
Based on 25 articles published since 2010
(Why 25 articles?)
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Between 2010 and 2020, Marc S. Sabatine wrote the following 25 articles about Coronary Artery Disease.
 
+ Citations + Abstracts
1 Guideline 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2016

Levine, Glenn N / Bates, Eric R / Bittl, John A / Brindis, Ralph G / Fihn, Stephan D / Fleisher, Lee A / Granger, Christopher B / Lange, Richard A / Mack, Michael J / Mauri, Laura / Mehran, Roxana / Mukherjee, Debabrata / Newby, L Kristin / O'Gara, Patrick T / Sabatine, Marc S / Smith, Peter K / Smith, Sidney C / Halperin, Jonathan L / Levine, Glenn N / Al-Khatib, Sana M / Birtcher, Kim K / Bozkurt, Biykem / Brindis, Ralph G / Cigarroa, Joaquin E / Curtis, Lesley H / Fleisher, Lee A / Gentile, Federico / Gidding, Samuel / Hlatky, Mark A / Ikonomidis, John S / Joglar, José A / Pressler, Susan J / Wijeysundera, Duminda N. · ·J Thorac Cardiovasc Surg · Pubmed #27751237.

ABSTRACT: -- No abstract --

2 Guideline 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2016

Levine, Glenn N / Bates, Eric R / Bittl, John A / Brindis, Ralph G / Fihn, Stephan D / Fleisher, Lee A / Granger, Christopher B / Lange, Richard A / Mack, Michael J / Mauri, Laura / Mehran, Roxana / Mukherjee, Debabrata / Newby, L Kristin / O'Gara, Patrick T / Sabatine, Marc S / Smith, Peter K / Smith, Sidney C. · ·J Am Coll Cardiol · Pubmed #27036918.

ABSTRACT: -- No abstract --

3 Editorial Using Aptamer-Based Technology to Probe the Plasma Proteome for Cardiovascular Disease Prediction. 2016

Sabatine, Marc S. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts. ·JAMA · Pubmed #27327798.

ABSTRACT: -- No abstract --

4 Review 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. 2016

Levine, Glenn N / Bates, Eric R / Bittl, John A / Brindis, Ralph G / Fihn, Stephan D / Fleisher, Lee A / Granger, Christopher B / Lange, Richard A / Mack, Michael J / Mauri, Laura / Mehran, Roxana / Mukherjee, Debabrata / Newby, L Kristin / O'Gara, Patrick T / Sabatine, Marc S / Smith, Peter K / Smith, Sidney C. ·Focused Update writing group members are required to recuse themselves from voting on sections to which their specific relationships with industry may apply; see Appendix 1 for detailed information. ACC/AHA Task Force on Clinical Practice Guidelines Liaison. ACC/AHA Representative. Evidence Review Committee Chair. American Society of Anesthesiologists/Society of Cardiovascular Anesthesiologists Representative. American Association for Thoracic Surgery/Society of Thoracic Surgeons Representative. Society for Cardiovascular Angiography and Interventions Representative. ·Circulation · Pubmed #27026020.

ABSTRACT: -- No abstract --

5 Review Detection of high-risk atherosclerotic plaque: report of the NHLBI Working Group on current status and future directions. 2012

Fleg, Jerome L / Stone, Gregg W / Fayad, Zahi A / Granada, Juan F / Hatsukami, Thomas S / Kolodgie, Frank D / Ohayon, Jacques / Pettigrew, Roderic / Sabatine, Marc S / Tearney, Guillermo J / Waxman, Sergio / Domanski, Michael J / Srinivas, Pothur R / Narula, Jagat. ·Division of Cardiovascular Sciences, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892, USA. flegj@nhlbi.nih.gov ·JACC Cardiovasc Imaging · Pubmed #22974808.

ABSTRACT: The leading cause of major morbidity and mortality in most countries around the world is atherosclerotic cardiovascular disease, most commonly caused by thrombotic occlusion of a high-risk coronary plaque resulting in myocardial infarction or cardiac death, or embolization from a high-risk carotid plaque resulting in stroke. The lesions prone to result in such clinical events are termed vulnerable or high-risk plaques, and their identification may lead to the development of pharmacological and mechanical intervention strategies to prevent such events. Autopsy studies from patients dying of acute myocardial infarction or sudden death have shown that such events typically arise from specific types of atherosclerotic plaques, most commonly the thin-cap fibroatheroma. However, the search in human beings for vulnerable plaques before their becoming symptomatic has been elusive. Recently, the PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study demonstrated that coronary plaques that are likely to cause future cardiac events, regardless of angiographic severity, are characterized by large plaque burden and small lumen area and/or are thin-cap fibroatheromas verified by radiofrequency intravascular ultrasound imaging. This study opened the door to identifying additional invasive and noninvasive imaging modalities that may improve detection of high-risk atherosclerotic lesions and patients. Beyond classic risk factors, novel biomarkers and genetic profiling may identify those patients in whom noninvasive imaging for vulnerable plaque screening, followed by invasive imaging for risk confirmation is warranted, and in whom future pharmacological and/or device-based focal or regional therapies may be applied to improve long-term prognosis.

6 Clinical Trial Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab: An Analysis of FOURIER Trial Data. 2019

Qamar, Arman / Giugliano, Robert P / Keech, Anthony C / Kuder, Julia F / Murphy, Sabina A / Kurtz, Christopher E / Wasserman, Scott M / Sever, Peter S / Pedersen, Terje R / Sabatine, Marc S. ·Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia. · Amgen, Thousand Oaks, California. · National Heart and Lung Institute, Imperial College London, London, United Kingdom. · Oslo University Hospital, Ullevål and Medical Faculty, University of Oslo, Oslo, Norway. · Deputy Editor. ·JAMA Cardiol · Pubmed #30540337.

ABSTRACT: Importance: Little is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications. Objective: To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug evolocumab. Design, Setting, and Participants: We examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018. Main Outcomes and Measures: Interindividual variation in percent reduction in LDL-C with evolocumab. Results: There were 27 564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21 768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with evolocumab. During the first year, a total of 10 325 of 10902 patients in the evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10 669 of 10 902 (97.9%) had a reduction 30% or more, and 10 849 of 10 902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of ≥25%, 531 patients [4.9%]; decreases of ≥25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with evolocumab were 50% or greater in 9839 of 10 866 patients (90.5%) and 30% or greater in 10 846 of 10 866 patients (99.8%). Results were consistent across clinically relevant subgroups. Conclusions and Relevance: There appears to be a highly consistent robust reduction in LDL-C levels with evolocumab use. Trial Registration: ClinicalTrials.gov identifier: NCT01764633.

7 Clinical Trial AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). 2014

Desai, Nihar R / Giugliano, Robert P / Zhou, Jing / Kohli, Payal / Somaratne, Ransi / Hoffman, Elaine / Liu, Thomas / Scott, Robert / Wasserman, Scott M / Sabatine, Marc S. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Division of Cardiovascular Medicine, University of California at San Francisco, San Francisco, California. · Amgen, Inc., Thousand Oaks, California. · TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: msabatine@partners.org. ·J Am Coll Cardiol · Pubmed #24161333.

ABSTRACT: OBJECTIVES: This study sought to define the ability of AMG 145, a monoclonal antibody directed against proprotein convertase subtilisin kexin type 9 (PCSK9), to enable subjects at high risk for major adverse cardiovascular events to achieve National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) parameters for low-density lipoprotein cholesterol (LDL-C) and other lipid goals. BACKGROUND: Many patients at high risk for adverse cardiovascular events are unable to achieve the NCEP-ATP III LDL-C goal of <70 mg/dl, even with high-potency statin therapy. METHODS: In 282 subjects from the LAPLACE-TIMI 57 (LDL-C Assessment with PCSK9 monoclonaL Antibody Inhibition Combined With Statin thErapy-Thrombolysis In Myocardial Infarction 57) trial at high risk according to NCEP-ATP III criteria, we compared the proportion of subjects achieving the NCEP-ATP III recommended LDL-C goal of <70 mg/dl across treatment arms. Other outcomes included the triple goals of LDL-C <70 mg/dl, non-high-density lipoprotein cholesterol (HDL-C) <100 mg/dl, and apolipoprotein B (ApoB) <80 mg/dl. RESULTS: During the dosing interval, more than 90% of subjects in both of the top dose groups every 2 weeks and every 4 weeks attained this lipid target over the dosing interval, with similar success rates for the triple lipid goal. CONCLUSIONS: PCSK9 inhibition with AMG 145 enables high-risk patients to achieve established lipid goals. If this therapy demonstrates efficacy for reducing cardiovascular events with a favorable safety profile in ongoing phase 3 trials, we believe it will have major public health implications.

8 Article Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54. 2019

Dellborg, Mikael / Bonaca, Marc P / Storey, Robert F / Steg, P Gabriel / Im, Kyung A / Cohen, Marc / Bhatt, Deepak L / Oude Ophuis, Ton / Budaj, Andrezej / Hamm, Christian / Spinar, Jindrich / Kiss, Robert G / Lopez-Sendon, José / Kamensky, Gabriel / Van de Werf, Frans / Ardissino, Diego / Kontny, Frederic / Montalescot, Gilles / Johanson, Per / Bengtsson, Olof / Himmelmann, Anders / Braunwald, Eugene / Sabatine, Marc S. ·Department of Medicine, University of Gothenburg, Institute of Medicine, Sahlgrenska Academy, Sahlgrenska University Hospital/Östra, Diagnosvägen 11, Gothenburg, Sweden. · Harvard Medical School, TIMI Study Group, Boston, MA, USA. · University of Sheffield, Sheffield, UK. · University Paris Diderot, INSERM Unite 1148, Hôptial Bichat, Paris, France. · Newark Beth Israel Medical Center, Rutgers New Jersey Medical School, Newark, NJ, USA. · Canisius-Wilhelmina Hospital, Nijmegen, the Netherlands. · Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland. · Kerckhoff Heart Center, Bad Nauheim, University of Giessen, Giessen, Germany. · University Hospital, Jihlavska, Brno, Czech Republic. · Department of Cardiology, Military Hospital, Budapest, Hungary. · Cardiovascular Division, University Hospital La Paz, Madrid, Spain. · Department of Noninvasive Cardiovascular Diagnostics, Vth Internal Clinic, University Hospital Bratislava, Bratislava, Slovakia. · University of Leuven, Leuven, Belgium. · Division of Cardiology, Azienda Ospedaliero Universitaria di Parma, Parma, Italy. · Department of Cardiology, Stavanger University Hospital, Stavanger, Norway. · Drammen Heart Center, Drammen, Norway. · Sorbonne Université Paris 6, ACTION Study Group, INSERM-UMRS 1166, Institut de Cardiologie, Pitié-Salpêtrière Hospital (AP-HP), Paris, France. · AstraZeneca, Mölndal, Sweden. ·Eur Heart J Cardiovasc Pharmacother · Pubmed #31218354.

ABSTRACT: AIMS: In PEGASUS-TIMI 54, ticagrelor significantly reduced the risk of the composite of major adverse cardiovascular (CV) events by 15-16% in stable patients with a prior myocardial infarction (MI) 1-3 years earlier. We report the efficacy and safety in the subpopulation recommended for treatment in the European (EU) label, i.e. treatment with 60 mg b.i.d. initiated up to 2 years from the MI, or within 1 year after stopping previous adenosine diphosphate receptor inhibitor treatment. METHODS AND RESULTS: Of the 21 162 patients enrolled in PEGASUS-TIMI 54, 10 779 patients were included in the primary analysis for this study, randomized to ticagrelor 60 mg (n = 5388) or matching placebo (n = 5391). The cumulative proportions of patients with events at 36 months were calculated by the Kaplan-Meier (KM) method. The composite of CV death, MI, or stroke occurred less frequently in the ticagrelor group (7.9% KM rate vs. 9.6%), hazard ratio (HR) 0.80 [95% confidence interval (CI) 0.70-0.91; P = 0.001]. Ticagrelor also reduced the risk of all-cause mortality, HR 0.80 (0.67-0.96; P = 0.018). Thrombolysis in myocardial infarction major bleeding was more frequent in the ticagrelor group 2.5% vs. 1.1%; HR 2.36 (1.65-3.39; P < 0.001). The corresponding HR for fatal or intracranial bleeding was 1.17 (0.68-2.01; P = 0.58). CONCLUSION: In PEGASUS-TIMI 54, treatment with ticagrelor 60 mg as recommended in the EU label, was associated with a relative risk reduction of 20% in CV death, MI, or stroke. Thrombolysis in myocardial infarction major bleeding was increased, but fatal or intracranial bleeding was similar to placebo. There appears to be a favourable benefit-risk ratio for long-term ticagrelor 60 mg in this population. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT01225562.

9 Article Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: Analysis From FOURIER. 2018

Sabatine, Marc S / De Ferrari, Gaetano M / Giugliano, Robert P / Huber, Kurt / Lewis, Basil S / Ferreira, Jorge / Kuder, Julia F / Murphy, Sabina A / Wiviott, Stephen D / Kurtz, Christopher E / Honarpour, Narimon / Keech, Anthony C / Sever, Peter S / Pedersen, Terje R. ·TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.S.S., R.P.G., J.F.K., S.A.M., S.D.W.). · Department of Molecular Medicine, University of Pavia and Cardiac Intensive Care Unit and Laboratories for Experimental Cardiology, Istituto di Ricerca e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Italy (G.M.D.F.). · Third Department of Medicine, Cardiology, and Intensive Care Medicine and Sigmund Freud University, Medical School, Vienna, Austria (K.H.). · Lady Davis Carmel Medical Center, Haifa, Israel (B.S.L.). · Hospital de Santa Cruz, Lisbon, Portugal (J.F.). · Amgen, Thousand Oaks, CA (C.E.K., N.H.). · Sydney Medical School, National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia (A.C.K.). · International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, UK (P.S.S.). · Oslo University Hospital, Ulleval and Medical Faculty, University of Oslo, Norway (T.R.P.). ·Circulation · Pubmed #29626068.

ABSTRACT: BACKGROUND: The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab. METHODS: The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared. RESULTS: A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22-1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ≈1% in the low-risk groups (0.8%, 1.3%, and 1.2%). CONCLUSIONS: Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

10 Article Ticagrelor for Secondary Prevention of Atherothrombotic Events in Patients With Multivessel Coronary Disease. 2018

Bansilal, Sameer / Bonaca, Marc P / Cornel, Jan H / Storey, Robert F / Bhatt, Deepak L / Steg, Ph Gabriel / Im, Kyungah / Murphy, Sabina A / Angiolillo, Dominick J / Kiss, Robert G / Parkhomenko, Alexander N / Lopez-Sendon, Jose / Isaza, Daniel / Goudev, Assen / Kontny, Frederic / Held, Peter / Jensen, Eva C / Braunwald, Eugene / Sabatine, Marc S / Oude Ophuis, A J. ·Zena and Michael Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. · TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. · Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar and Dutch Network for Cardiovascular Research (WCN), the Netherlands. · Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom. · DHU (Département Hospitalo-Universitaire)-FIRE (Fibrosis, Inflammation, REmodelling), Hôpital Bichat, AP-HP (Assistance Publique-Hôpitaux de Paris), Université Paris-Diderot, Sorbonne-Paris Cité, and FACT (French Alliance for Cardiovascular clinical Trials), an F-CRIN network, INSERM U-1148, Paris, France; National Heart and Lung Institute, Institute of Cardiovascular Medicine and Science, Royal Brompton Hospital, Imperial College, London, United Kingdom. · Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida. · Department of Cardiology, Military Hospital, Budapest, Hungary. · Emergency Cardiology Department, Institute of Cardiology, Kiev, Ukraine. · Hospital Universitario La Paz, Madrid, Spain. · Fundacion Cardioinfantil, Instituto de Cardiología, Bogotá, Cundinamarca, Colombia. · Medical University Sofia, Queen Ioanna Hospital, Sofia, Bulgaria. · Department of Cardiology, Stavanger University Hospital, Stavanger, Norway; Drammen Heart Center, Drammen, Norway. · AstraZeneca Research and Development, Mölndal, Sweden. · TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: msabatine@partners.org. · Department of Cardiology, Noordwest Ziekenhuisgroep, Alkmaar and Dutch Network for Cardiovascular Research (WCN), the Netherlands; Department of Cardiology, CWZ Hospital, Nijmegen, the Netherland. ·J Am Coll Cardiol · Pubmed #29406853.

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 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).

11 Article Potent P2Y 2017

Lau, Emily S / Braunwald, Eugene / Murphy, Sabina A / Wiviott, Stephen D / Bonaca, Marc P / Husted, Steen / James, Stefan K / Wallentin, Lars / Clemmensen, Peter / Roe, Matthew T / Ohman, E Magnus / Harrington, Robert A / Mega, Jessica L / Bhatt, Deepak L / Sabatine, Marc S / O'Donoghue, Michelle L. ·Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. · Department of Cardiology, Århus University Hospital, Århus, Denmark. · Department of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden. · Department of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany; Department of Medicine, Nykoebing F Hospital, University of Southern Denmark, Odense, Denmark. · Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina. · Department of Medicine, Stanford University, Stanford, California. · Verily Life Sciences, Mountain View, California. · TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: modonoghue@partners.org. ·J Am Coll Cardiol · Pubmed #28335837.

ABSTRACT: BACKGROUND: Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain. OBJECTIVES: The study investigated the efficacy and safety of the potent P2Y METHODS: A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y RESULTS: Potent P2Y CONCLUSIONS: In randomized trials, the efficacy and safety of the potent P2Y

12 Article Consistent platelet inhibition with ticagrelor 60 mg twice-daily following myocardial infarction regardless of diabetes status. 2017

Thomas, Mark R / Angiolillo, Dominick J / Bonaca, Marc P / Ajjan, Ramzi A / Judge, Heather M / Rollini, Fabiana / Franchi, Francesco / Ahsan, Arif J / Bhatt, Deepak L / Kuder, Julia F / Steg, Philippe Gabriel / Cohen, Marc / Muthusamy, Rangasamy / Sabatine, Marc S / Storey, Robert F. ·Prof. Robert F. Storey, MD DM FESC, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK, E-mail: r.f.storey@sheffield.ac.uk. ·Thromb Haemost · Pubmed #28300867.

ABSTRACT: Diabetes increases cardiovascular risk and reduces pharmacodynamic response to some oral antiplatelet drugs. This study aimed to determine whether ticagrelor 60 mg twice daily (bid) provided potent and consistent platelet inhibition in patients with vs without diabetes in the PEGASUS-TIMI 54 platelet function substudy. Out of 180 patients studied, 58 patients were randomised to and had received at least four weeks of ticagrelor 60 mg bid, with 20 (34 %) having diabetes, 58 patients received ticagrelor 90 mg bid, with 12 (21 %) having diabetes, and 64 patients received placebo, with 18 (28 %) having diabetes. Blood was sampled pre- and 2 hours post-maintenance dose. In patients treated with ticagrelor 60 mg bid, on-treatment platelet reactivity to ADP, as determined by light transmission aggregometry (LTA), VerifyNow and VASP, was similar in patients with vs without diabetes (LTA post-dose, ADP 20 µM: 29 ± 14 vs 34 ± 10 %, respectively; p = 0.19). A consistent inhibitory effect of ticagrelor 60 mg bid was observed pre- and post-dose regardless of diabetes status, even in insulin-treated patients. Patients with diabetes did not have an increased incidence of high platelet reactivity in either ticagrelor group. Platelet reactivity was similar in patients with diabetes treated with ticagrelor 60 mg vs 90 mg bid. Pharmacokinetics of ticagrelor were not affected by diabetes status. In conclusion, ticagrelor 60 mg bid is equally effective at reducing platelet reactivity in patients with and without diabetes, yielding a consistently high level of platelet inhibition regardless of diabetes status.

13 Article Prevention of Stroke with Ticagrelor in Patients with Prior Myocardial Infarction: Insights 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). 2016

Bonaca, Marc P / Goto, Shinya / Bhatt, Deepak L / Steg, P Gabriel / Storey, Robert F / Cohen, Marc / Goodrich, Erica / Mauri, Laura / Ophuis, Ton Oude / Ruda, Mikhail / Špinar, Jindřich / Seung, Ki-Bae / Hu, Dayi / Dalby, Anthony J / Jensen, Eva / Held, Peter / Morrow, David A / Braunwald, Eugene / Sabatine, Marc S. ·From TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (M.P.B., D.L.B., E.G., D.A.M., E.B., M.S.) · Tokai University School of Medicine · Institute of Medical Science, Isehara, Japan (S.G.) · FACT, DHU-FIRE INSERM Unité 1148, Assistance Publique-Hôpitaux de Paris and Université Paris Diderot, Paris, France, and NHLI Imperial College, Royal Brompton Hospital, London, UK (P.G.S.) · University of Sheffield, United Kingdom (R.F.S.) · Division of Cardiology, Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School, Newark (M.C.) · Brigham and Women's Hospital and Harvard Clinical Research Institute, Harvard Medical School, Boston, MA (L.M.) · CWZ Hospital, Nijmegen, The Netherlands (T.O.O.) · Cardiology Research and Production complex MH RF, Moscow, Russia (M.R.) · Internal Cardiology Department, University Hospital and Medical faculty, Brno, Czech Republic (J.S.) · Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea (K.-B.S.) · Heart Institute, Intervention Center, People Hospital of Peking University, China (D.H.) · Life Fourways Hospital, Randburg, South Africa (A.J.D.) · and AstraZeneca, Mölndal, Sweden (E.J., P.H.). ·Circulation · Pubmed #27576775.

ABSTRACT: BACKGROUND: In the PEGASUS-TIMI 54 trial (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), ticagrelor reduced the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior myocardial infarction, resulting in the approval of ticagrelor 60 mg twice daily for long-term secondary prevention. We investigated the incidence of stroke, outcomes after stroke, and the efficacy of ticagrelor focusing on the approved 60 mg twice daily dose for reducing stroke in this population. METHODS: Patients were followed for a median of 33 months. Stroke events were adjudicated by a central committee. Data from similar trials were combined using meta-analysis. RESULTS: Of 14 112 patients randomly assigned to placebo or ticagrelor 60 mg, 213 experienced a stroke; 85% of these strokes were ischemic. A total of 18% of strokes were fatal and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke (hazard ratio, 0.75; 95% confidence interval, 0.57-0.98; P=0.034), driven by a reduction in ischemic stroke (hazard ratio, 0.76; 95% confidence interval, 0.56-1.02). Hemorrhagic stroke occurred in 9 patients on placebo and 8 patients on ticagrelor. A meta-analysis across 4 placebo-controlled trials of more intensive antiplatelet therapy in 44 816 patients with coronary disease confirmed a marked reduction in ischemic stroke (hazard ratio, 0.66; 95% confidence interval, 0.54-0.81; P=0.0001). CONCLUSIONS: High-risk patients with prior myocardial infarction are at risk for stroke, approximately one-third of which are fatal or lead to moderate-to-severe disability. The addition of ticagrelor 60 mg twice daily significantly reduced this risk without an excess of hemorrhagic stroke but with more major bleeding. In high-risk patients with coronary disease, more intensive antiplatelet therapy should be considered not only to reduce the risk of coronary events, but also of stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01225562.

14 Article Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice. 2016

Sabatine, Marc S / Underberg, James A / Koren, Michael / Baum, Seth J. ·a Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine , Brigham and Women's Hospital. · b Department of Medicine , Harvard Medical School , Boston , MA. · c NYU Medical School, NYU Center for CVD Prevention , Bellevue Hospital Lipid Clinic , New York , NY. · d Jacksonville Center for Clinical Research. · e Academy of Physicians in Clinical Research , Jacksonville , FL. · f MB Clinical Research. · g American Society for Preventive Cardiology. · h The FH Foundation. ·Postgrad Med · Pubmed #27422124.

ABSTRACT: Elevation of low-density lipoprotein cholesterol (LDL-C) is an important cause of atherosclerotic cardiovascular disease (ASCVD). Over the years, clinical outcome studies with LDL-C lowering agents have revealed that reducing LCL-C levels is effective in reducing rates of major ASCVD events. Although secondary factors play a role in clinical expression, severe lipid disorders often have a strong genetic component. Genetic revelations have provided novel targets for improving LDL-C management in high-risk individuals. Most recently, researchers have explored how the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) alters LDL metabolism and lowers LDL-C levels to achieve lipid goals and potentially reduce ASCVD risk in patients with severe lipid disorders, including familial hypercholesterolemia (FH). This CMHC Spotlight article summarizes the clinical evidence demonstrating the safety, tolerability, and efficacy of PCSK9 inhibitors in lowering LDL-C levels. Reductions in LDL-C levels by PCSK9 inhibitors alone in patients who are statin intolerant or combined with maximally tolerated statins in patients with severe lipid disorders demonstrate the potential for reduced morbidity and mortality associated with ASCVD.

15 Article Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel. Insights from the ELEVATE-TIMI 56 Trial. 2016

Carreras, Edward T / Hochholzer, Willibald / Frelinger, Andrew L / Nordio, Francesco / O'Donoghue, Michelle L / Wiviott, Stephen D / Angiolillo, Dominick J / Michelson, Alan D / Sabatine, Marc S / Mega, Jessica L. ·Edward T. Carreras, MD, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA, Tel.: +1 617 732 5500, E-mail: ecarreras@partners.org. · Marc S. Sabatine, MD, MPH, Brigham & Women's Hospital, 75 Francis Street, Boston, MA 02115, USA, E-mail: msabatine@partners.org. ·Thromb Haemost · Pubmed #27009617.

ABSTRACT: Both diabetes mellitus (DM) and carriage of the CYP2C19*2 allele are associated with a reduced response to clopidogrel. The relative contributions of these factors and whether higher clopidogrel doses can overcome both factors remain unknown. The objective of this study was to test the ability of clopidogrel doses up to 300 mg daily to decrease platelet reactivity in patients with DM and/or CYP2C19*2. ELEVATE-TIMI 56 randomised 333 patients with coronary artery disease to different maintenance doses of clopidogrel in four treatment periods, each lasting approximately 14 days. On-treatment platelet reactivity was compared between patients stratified by DM, CYP2C19*2 status and clopidogrel dose. Both DM and CYP2C19*2 were independently associated with elevated on-treatment platelet reactivity with clopidogrel 75 mg daily (p<0.0001 for each). With 75 mg, mean on-treatment PRU was progressively higher (p trend <0.001) when evaluating patients: with neither DM nor CYP2C19*2 (150.7; 95 % CI 140.5-162.6), with only DM (187.2; 95 % CI, 171.3-206.9), with only CYP2C19*2 (227.9; 95 % CI, 205.1-250.8), and with both DM and CYP2C19*2 (239.9; 95 % CI, 209.7-270.1). Notably, with 75 mg, patients with only CYP2C19*2 had higher on-treatment platelet reactivity than those with only DM (p=0.0068). To achieve on-treatment platelet reactivity similar to that seen with clopidogrel 75 mg in patients with neither DM nor CYP2C19*2, the following doses were required: 150 mg with only DM, 225 mg with only CYP2C19*2, and 300 mg with both DM and CYP2C19*2. Patients with both DM and CYP2C19*2 required a four-fold increase in clopidogrel maintenance dose as compared to patients without these factors to achieve a similar antiplatelet response.

16 Article Platelet Inhibition With Ticagrelor 60 mg Versus 90 mg Twice Daily in the PEGASUS-TIMI 54 Trial. 2016

Storey, Robert F / Angiolillo, Dominick J / Bonaca, Marc P / Thomas, Mark R / Judge, Heather M / Rollini, Fabiana / Franchi, Francesco / Ahsan, Arif J / Bhatt, Deepak L / Kuder, Julia F / Steg, Philippe Gabriel / Cohen, Marc / Muthusamy, Rangasamy / Braunwald, Eugene / Sabatine, Marc S. ·Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom. Electronic address: r.f.storey@sheffield.ac.uk. · Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, Florida. · Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. · Cardiovascular Research Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom. · Trent Cardiac Centre, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom. · INSERM-Unité 1148, Assistance Publique-Hôpitaux de Paris, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, and Université Paris-Diderot, Sorbonne-Paris Cité, Paris, France. · Newark Beth Israel Medical Center, Rutgers-New Jersey Medical School, Newark, New Jersey. · Department of Cardiology, Rotherham NHS Foundation Trust, Rotherham, United Kingdom. ·J Am Coll Cardiol · Pubmed #26965534.

ABSTRACT: BACKGROUND: 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 studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. OBJECTIVES: In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. METHODS: A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units [PRU]), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. RESULTS: Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. CONCLUSIONS: Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.

17 Article Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54. 2016

Bonaca, Marc P / Bhatt, Deepak L / Steg, P Gabriel / Storey, Robert F / Cohen, Marc / Im, Kyungah / Oude Ophuis, Ton / Budaj, Andrej / Goto, Shinya / López-Sendón, José / Diaz, Rafael / Dalby, Anthony / Van de Werf, Frans / Ardissino, Diego / Montalescot, Gilles / Aylward, Philip / Magnani, Giulia / Jensen, Eva C / Held, Peter / Braunwald, Eugene / Sabatine, Marc S. ·TIMI Study Group, Brigham and Women's Hospital, Heart & Vascular Center, 75 Francis Street, Boston, MA 02115, USA mbonaca@partners.org. · TIMI Study Group, Brigham and Women's Hospital, Heart & Vascular Center, 75 Francis Street, Boston, MA 02115, USA. · Département de Cardiologie, Hôpital Bichat, Assistance Publique, Paris, France. · University of Sheffield, Sheffield, UK. · Cardiovascular Division, Newark Beth Israel Medical Center, Mount Sinai School of Medicine, New York, USA. · CWZ Hospital, Nijmegen, The Netherlands. · Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland. · Tokai University School of Medicine, Institute of Medical Science, Tokyo, Japan. · Hospital Universitario La Paz, Instituto de Investigación La PAZ, Madrid, Spain. · ECLA (Estudios Clínicos Latino América), Rosario, Argentina. · Milpark Hospital, Johannesburg, South Africa. · Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. · Cardiovascular Division, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. · Institut de Cardiologie, Pitié-Salpêtrière Hospital, 47 boul de l'Hôpital, Paris, France. · Division of Medicine, Cardiac & Critical Care Services, Flinders Medical Centre, Adelaide, South Australia, Australia. · AstraZenecaAZ R&D, Molndal, Sweden. ·Eur Heart J · Pubmed #26491109.

ABSTRACT: AIMS: Ticagrelor reduced major adverse cardiovascular event (MACE) by 15-16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. METHODS AND RESULTS: Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: ≤30, >30-360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [≤30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12-1.93, P = 0.0051; 30 days-1 year, HRadj 1.28, 95% CI 0.98-1.67, P = 0.073] compared with those who stopped >1 year prior (P-trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61-0.87), 0.86 (0.71-1.04), and 1.01 (0.80-1.27), respectively, by category (P-trend for interaction < 0.001). The benefit in those ≤30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs. ≥2 years, HR 0.71, 95% CI 0.50-1.00). CONCLUSION: The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov NCT01225562.

18 Article Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial. 2016

Magnani, Giulia / Storey, Robert F / Steg, Gabriel / Bhatt, Deepak L / Cohen, Marc / Kuder, Julia / Im, Kyungah / Aylward, Philip / Ardissino, Diego / Isaza, Daniel / Parkhomenko, Alexander / Goudev, Assen R / Dellborg, Mikael / Kontny, Frederic / Corbalan, Ramon / Medina, Felix / Jensen, Eva C / Held, Peter / Braunwald, Eugene / Sabatine, Marc S / Bonaca, Marc P. ·TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, USA. · Department of Cardiovascular Science, University of Sheffield, Sheffield, UK. · Cardiology Department, DHU-FIRE, Hôpital Bichat, Paris, France Université Paris-Diderot, Paris, France INSERM U1148, Paris, France. · Cardiovascular Division, Department of Medicine, Rutgers-New Jersey Medical School, New York, USA. · Division of Medicine, Cardiac & Critical Care Services, Flinders University and Medical Centre, Adelaide, Australia. · Cardiovascular Division, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. · Fundacion CardioInfantil, Bogota, Colombia. · Ukranian Strazhesko Institute of Cardiology, Kiev, Ukraine. · Department of Cardiology, Queen Giovanna University Hospital, Sofia, Bulgaria. · Department of Molecular and Clinical Medicine/Cardiology, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. · Department of Cardiology, Stavanger University Hospital, Stavanger, Norway. · Cardiovascular Division, Pontificia Universidad Católica de Chile, Santiago, Chile. · Hospital Nacional Cayetano Heredia, San Martin de Porres, Lima, Peru. · AstraZenecaAZ R&D, Molndal, Sweden. · TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA, USA mbonaca@partners.org. ·Eur Heart J · Pubmed #26443023.

ABSTRACT: AIMS: We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior myocardial infarction (MI). METHODS AND RESULTS: Patients with a history of MI 1-3 years prior from PEGASUS-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with <60 mL/min/1.73 m(2) pre-specified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events, MACE) and the primary safety endpoint of TIMI major bleeding. Of 20 898 patients, those with eGFR <60 (N = 4849, 23.2%) had a greater risk of MACE at 3 years relative to those without, which remained significant after multivariable adjustment (hazard ratio, HRadj 1.54, 95% confidence interval, CI 1.27-1.85, P < 0.001). The relative risk reduction in MACE with ticagrelor was similar in those with eGFR <60 (ticagrelor pooled vs. placebo: HR 0.81; 95% CI 0.68-0.96) vs. ≥60 (HR 0.88; 95% CI 0.77-1.00, Pinteraction = 0.44). However, due to the greater absolute risk in the former group, the absolute risk reduction with ticagrelor was higher: 2.7 vs. 0.63%. Bleeding tended to occur more frequently in patients with renal dysfunction. The absolute increase in TIMI major bleeding with ticagrelor was similar in those with and without eGFR <60 (1.19 vs. 1.43%), whereas the excess of minor bleeding tended to be more pronounced (1.93 vs. 0.69%). CONCLUSION: In patients with a history of MI, patients with renal dysfunction are at increased risk of MACE and consequently experience a particularly robust absolute risk reduction with long-term treatment with ticagrelor.

19 Article Variability of individual platelet reactivity over time in patients treated with clopidogrel: insights from the ELEVATE-TIMI 56 trial. 2014

Hochholzer, Willibald / Ruff, Christian T / Mesa, Robert A / Mattimore, John F / Cyr, John F / Lei, Lanyu / Frelinger, Andrew L / Michelson, Alan D / Berg, David D / Angiolillo, Dominick J / O'Donoghue, Michelle L / Sabatine, Marc S / Mega, Jessica L. ·Universitaets Herzzentrum Freiburg, Klinik für Kardiologie und Angiologie II, Bad Krozingen, Germany. · TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Harvard Clinical Research Institute, Boston, Massachusetts. · Center for Platelet Research Studies, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. · University of Florida College of Medicine-Jacksonville, Jacksonville, Florida. · TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: jmega@partners.org. ·J Am Coll Cardiol · Pubmed #25060370.

ABSTRACT: BACKGROUND: The degree of antiplatelet response to clopidogrel has been associated with clinical outcomes. Studies have investigated whether adjustment of antiplatelet therapies based on a single platelet function test is beneficial. OBJECTIVES: The aim of the study was to test the stability of platelet reactivity measurements over time among patients treated with standard and double doses of clopidogrel. METHODS: The ELEVATE-TIMI 56 (Escalating Clopidogrel by Involving a Genetic Strategy-Thrombolysis In Myocardial Infarction 56) investigators genotyped 333 patients with coronary artery disease and randomized them to various clopidogrel regimens. Patients with at least 2 platelet function results on the same maintenance dose of clopidogrel (75 mg or 150 mg) were analyzed. Platelet aggregation was measured using P2Y12 reaction units (PRU). RESULTS: In total, the mean platelet reactivity and the total number of nonresponders (PRU ≥230) with clopidogrel did not change between 2 periods for the 75-mg (22.4% vs. 21.9%; p = 0.86) and 150-mg doses of clopidogrel (11.5% vs. 11.5%; p = 1.00). In contrast, when evaluating each patient individually, 15.7% of patients taking clopidogrel 75 mg and 11.4% of patients taking 150 mg had a change in their responder status when tested at 2 different time points (p < 0.001). Despite being treated with the same dose of clopidogrel, >40% of patients had a change in PRU >40 on serial sampling, which approximates the average PRU difference caused by increasing the clopidogrel dose from 75 mg to 150 mg. CONCLUSIONS: Measurements of platelet reactivity vary over time in a significant proportion of patients. Thus, treatment adjustment according to platelet function testing at a single time point might not be sufficient for guiding antiplatelet therapy in clinical or research settings. (Escalating Clopidogrel by Involving a Genetic Strategy-Thrombolysis In Myocardial Infarction 56 [ELEVATE-TIMI 56]; NCT01235351).

20 Article Fibroblast growth factor-23, cardiovascular prognosis, and benefit of angiotensin-converting enzyme inhibition in stable ischemic heart disease. 2014

Udell, Jacob A / Morrow, David A / Jarolim, Petr / Sloan, Sarah / Hoffman, Elaine B / O'Donnell, Thomas F / Vora, Amit N / Omland, Torbjørn / Solomon, Scott D / Pfeffer, Marc A / Braunwald, Eugene / Sabatine, Marc S. ·Women's College Research Institute and Division of Cardiology, Department of Medicine, Women's College Hospital, University of Toronto, Toronto, Ontario, Canada. · TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Duke Clinical Research Institute, Durham, North Carolina. · Department of Cardiology, Division of Medicine, Akershus University Hospital, and Center for Heart Failure Research and KG Jebsen Cardiac Research Centre, University of Oslo, Oslo, Norway. · Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: msabatine@partners.org. ·J Am Coll Cardiol · Pubmed #24727254.

ABSTRACT: OBJECTIVES: This study sought to test 2 hypotheses: 1) fibroblast growth factor (FGF)-23 identifies patients with stable ischemic heart disease (SIHD) at high risk of cardiovascular events independent of clinical factors, renal function, and established cardiovascular biomarkers; and 2) FGF-23 identifies patients who derive greater clinical benefit from angiotensin-converting enzyme inhibitor therapy. BACKGROUND: FGF-23 is an endocrine regulator of mineral metabolism and markedly elevated levels are associated with cardiovascular events in patients with chronic kidney disease. Data in patients with SIHD are more sparse. METHODS: FGF-23 levels were measured in 3,627 patients with SIHD randomly assigned to trandolapril or placebo within the PEACE (Prevention of Events With Angiotensin-Converting Enzyme) trial and followed up for a median of 5.1 years. RESULTS: After adjustment for clinical risk predictors, left ventricular ejection fraction, markers of renal function, and established cardiovascular biomarkers, FGF-23 concentration was independently associated with an increased risk of cardiovascular death or heart failure among patients allocated to placebo (quartile 4 hazard ratio: 1.73; 95% confidence interval, 1.09 to 2.74; p = 0.02) and significantly improved metrics of discrimination. Furthermore, among patients in the top quartile of FGF-23 levels, trandolapril significantly reduced cardiovascular death or incident heart failure (hazard ratio: 0.45; 95% confidence interval: 0.28 to 0.72), whereas there was no clinical benefit in the remaining patients (hazard ratio: 1.07; 95% confidence interval: 0.75 to 1.52; p interaction = 0.0039). This interaction was independent of and additive to stratification based on renal function. CONCLUSIONS: Elevated levels of FGF-23 are associated with cardiovascular death and incident heart failure in patients with SIHD and identify patients who derive significant clinical benefit from angiotensin-converting enzyme inhibitor therapy regardless of renal function. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]: NCT00000558).

21 Article Lipoprotein(a) for risk assessment in patients with established coronary artery disease. 2014

O'Donoghue, Michelle L / Morrow, David A / Tsimikas, Sotirios / Sloan, Sarah / Ren, Angela F / Hoffman, Elaine B / Desai, Nihar R / Solomon, Scott D / Domanski, Michael / Arai, Kiyohito / Chiuve, Stephanie E / Cannon, Christopher P / Sacks, Frank M / Sabatine, Marc S. ·TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: modonoghue@partners.org. · TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. · Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California. · Section of Cardiovascular Medicine, Department of Medicine, Yale School of Medicine; Center for Outcomes Research and Evaluation, Yale-New Haven Health System, New Haven, Connecticut. · Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. · Mount Sinai School of Medicine, Cardiovascular Division, New York, New York. · Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California; Division of Cardiology, Tokyo Women's Medical University, Tokyo, Japan. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. · Channing Laboratory and Cardiology Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. ·J Am Coll Cardiol · Pubmed #24161323.

ABSTRACT: OBJECTIVES: The purpose of this study was to assess the prognostic utility of lipoprotein(a) [Lp(a)] in individuals with coronary artery disease (CAD). BACKGROUND: Data regarding an association between Lp(a) and cardiovascular (CV) risk in secondary prevention populations are sparse. METHODS: Plasma Lp(a) was measured in 6,708 subjects with CAD from 3 studies; data were then combined with 8 previously published studies for a total of 18,978 subjects. RESULTS: Across the 3 studies, increasing levels of Lp(a) were not associated with the risk of CV events when modeled as a continuous variable (odds ratio [OR]: 1.03 per log-transformed SD, 95% confidence interval [CI]: 0.96 to 1.11) or by quintile (Q5:Q1 OR: 1.05, 95% CI: 0.83 to 1.34). When data were combined with previously published studies of Lp(a) in secondary prevention, subjects with Lp(a) levels in the highest quantile were at increased risk of CV events (OR: 1.40, 95% CI: 1.15 to 1.71), but with significant between-study heterogeneity (p = 0.001). When stratified on the basis of low-density lipoprotein (LDL) cholesterol, the association between Lp(a) and CV events was significant in studies in which average LDL cholesterol was ≥130 mg/dl (OR: 1.46, 95% CI: 1.23 to 1.73, p < 0.001), whereas this relationship did not achieve statistical significance for studies with an average LDL cholesterol <130 mg/dl (OR: 1.20, 95% CI: 0.90 to 1.60, p = 0.21). CONCLUSIONS: Lp(a) is significantly associated with the risk of CV events in patients with established CAD; however, there exists marked heterogeneity across trials. In particular, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear.

22 Article Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. 2013

Omland, Torbjørn / Pfeffer, Marc A / Solomon, Scott D / de Lemos, James A / Røsjø, Helge / Šaltytė Benth, Jūratė / Maggioni, Aldo / Domanski, Michael J / Rouleau, Jean L / Sabatine, Marc S / Braunwald, Eugene / Anonymous2880750. ·Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway. torbjorn.omland@medisin.uio.no ·J Am Coll Cardiol · Pubmed #23414791.

ABSTRACT: OBJECTIVES: The aims of this study were to assess the prognostic value of cardiac troponin I levels, measured with a new high-sensitivity assay, in low-risk patients with stable coronary artery disease (CAD) and to contrast its determinants and prognostic merit with that of high-sensitivity cardiac troponin T (hs-TnT). BACKGROUND: New, highly sensitive cardiac troponin assays permit evaluation of the association between troponin levels and outcomes in patients with stable CAD. METHODS: High-sensitivity cardiac troponin I (hs-TnI) levels at baseline were assessed in 3,623 patients with stable CAD and preserved systolic function enrolled in the PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy) trial. RESULTS: In total, 98.5% of patients had hs-TnI concentrations higher than the detection level (1.2 pg/ml). hs-TnI correlated moderately with hs-TnT (r = 0.44) and N-terminal pro-B-type natriuretic peptide (r = 0.39) but only weakly with age (r = 0.17) and estimated glomerular filtration rate (r = -0.11). During a median follow-up period of 5.2 years, 203 patients died of cardiovascular causes or were hospitalized for heart failure, and 209 patients had nonfatal myocardial infarctions. In analyses adjusting for conventional risk markers, N-terminal pro-B-type natriuretic peptide, and hs-TnT, hs-TnI levels in the fourth compared with the 3 lower quartiles were associated with the incidence of cardiovascular death or heart failure (hazard ratio: 1.84; 95% confidence interval: 1.30 to 2.61; p < 0.001). [corrected]. There was a [corrected] weaker association with nonfatal myocardial infarction (hazard ratio: 1.37; 95% confidence interval: 0.98 to 1.92; p = 0.066). [corrected]. In the same models, hs-TnT concentrations were associated with the incidence of cardiovascular death or heart failure but not of myocardial infarction. CONCLUSIONS: In patients with stable CAD, hs-TnI concentrations are associated with cardiovascular risk independently of conventional risk markers and hs-TnT. (Prevention of Events With Angiotensin-Converting Enzyme Inhibitor Therapy [PEACE]; NCT00000558).

23 Article Impact of smoking on antiplatelet effect of clopidogrel and prasugrel after loading dose and on maintenance therapy. 2011

Hochholzer, Willibald / Trenk, Dietmar / Mega, Jessica L / Morath, Tanja / Stratz, Christian / Valina, Christian M / O'Donoghue, Michelle L / Bernlochner, Isabell / Contant, Charles F / Guo, Jianping / Sabatine, Marc S / Schömig, Albert / Neumann, Franz-Josef / Kastrati, Adnan / Wiviott, Stephen D / Sibbing, Dirk. ·TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. whochholzer@partners.org ·Am Heart J · Pubmed #21884870.

ABSTRACT: BACKGROUND: Pharmacodynamic studies reported an amplified on-clopidogrel platelet inhibition in smokers potentially caused by an increased metabolic drug activation via induction of cytochrome P450 1A2. The aims of this analysis were to evaluate the impact of smoking on the antiplatelet effect of clopidogrel and prasugrel and to test the potential interaction of smoking with the treatment effect of these drugs. METHODS: A variety of platelet function results was analyzed from 2 large cohorts of patients undergoing coronary intervention after loading with clopidogrel 600 mg (n = 2,533 and n = 1,996), a cohort of patients undergoing dose adaptation from 75 to 150 mg according to response to clopidogrel (n = 117) and a crossover trial comparing clopidogrel 150 mg with prasugrel 10 mg (n = 87). Linear regression analyses were used to test the impact of smoking on platelet function and to identify independent predictors of on-treatment platelet reactivity. The potential interaction of smoking with the clinical effect of clopidogrel versus prasugrel was analyzed in the TRITON-TIMI 38 cohort (n = 13,608). RESULTS: No significant association of smoking with platelet reactivity on clopidogrel was seen in unadjusted and adjusted analyses. The variables most consistently associated with on-clopidogrel platelet function were age, sex, diabetes, and body mass index. There was no significant interaction of smoking status at presentation with the clinical efficacy of prasugrel versus clopidogrel (P for interaction = .39). CONCLUSIONS: Smoking does not impact on platelet reactivity in patients after loading or on different maintenance doses of clopidogrel. The clinical treatment effect of clopidogrel versus prasugrel is not affected by smoking status at presentation.

24 Article Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study. 2011

Turer, Aslan T / Addo, Tayo A / Martin, Justin L / Sabatine, Marc S / Lewis, Gregory D / Gerszten, Robert E / Keeley, Ellen C / Cigarroa, Joaquin E / Lange, Richard A / Hillis, L David / de Lemos, James A. ·Department of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas 75230-9047, USA. aslan.turer@utsouthwestern.edu ·J Am Coll Cardiol · Pubmed #21658559.

ABSTRACT: OBJECTIVES: The purpose of this study was to assess whether: 1) very small increases in troponin T, measured by a new highly sensitive cardiac troponin T (hs-cTnT), may reflect ischemia without necrosis; and 2) serial changes can discriminate ischemia from other causes of cardiac troponin T (cTnT) release. BACKGROUND: A new hs-cTnT assay offers greater sensitivity than current assays. METHODS: Nineteen patients referred for diagnostic catheterization underwent cannulation of the coronary sinus (CS). Serial CS and peripheral plasma samples were obtained at multiple time points during and after incremental rapid atrial pacing. cTnT was quantified using both a standard and a pre-commercial highly sensitive assay. Ischemia was determined by the presence of significant coronary artery disease (CAD) and myocardial lactate release with pacing. RESULTS: cTnT concentrations in CS blood increased from a median of 6.8 pg/ml prior to pacing to 15.6 pg/ml 60 min after termination of rapid atrial pacing (p < 0.0001), changes that were mirrored at 180 min in peripheral blood (5.1 to 11.8 pg/ml, p < 0.0001). Although peripheral cTnT concentrations tended to be higher at 180 min following pacing for patients with CAD and lactate elution (n = 7) when compared with those without either marker (n = 5) (25.0 pg/ml vs. 10.2 pg/ml, p = 0.10), relative (1.7-fold vs. 5.2-fold) and absolute (6.8 pg/ml vs. 8.8 pg/ml, p = 0.50) changes were not different between groups. CONCLUSIONS: Brief periods of ischemia, without frank infarction, cause low-level cTnT release, and small increases are common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive CAD. Additional research is needed before hs-cTnT assays are widely adopted in the management of subjects with chest pain syndromes.

25 Minor Current Smoking Is Associated With Lower Concentrations of High-Sensitivity Cardiac Troponin T in Patients With Stable Coronary Artery Disease: The PEACE Trial. 2019

Skranes, Julia B / Claggett, Brian L / Myhre, Peder L / Lyngbakken, Magnus N / Solomon, Scott D / Sabatine, Marc S / Pfeffer, Marc A / Omland, Torbjørn. ·Department of Cardiology, Akershus University Hospital, Lørenskog, Norway (J.B.S., P.L.M., M.N.L., T.O.). · Center for Heart Failure Research, Institute of Clinical Medicine, University of Oslo, Norway (J.B.S., P.L.M., M.N.L., T.O.). · Division of Cardiovascular Medicine (B.L.C., S.D.S., M.A.P.), Brigham and Women's Hospital, and Harvard Medical School, Boston, MA. · The Thrombolysis in Myocardial Infarction (TIMI) Study Group, Division of Cardiovascular Medicine (M.S.S.), Brigham and Women's Hospital, and Harvard Medical School, Boston, MA. ·Circulation · Pubmed #31815543.

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