256 results on '"Terje R. Pedersen"'
Search Results
2. 2016 ESC/EAS GUIDELINES FOR THE MANAGEMENT OF DYSLIPIDAEMIAS
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Alberico L. Catapano, Ian Graham, Guy De Backer, Olov Wiklund, John M. Chapman, Heinz Drexel, Arno V. Hoes, Catriona S. Jennings, Ulf Landmesser, Terje R. Pedersen, Željko Reiner, Gabriele Riccardi, Marja-Riitta Taskinen, Lale Tokgozoglu, W. M. Monique Verschuren, Charalambos Vlachopoulos, David A. Wood, Jose Luis Zamorano, and Marie-Therese Cooney
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dyslipidaemias ,cholesterol ,triglycerides ,low-density lipoproteins ,high-density lipoproteins ,apolipoprotein b ,lipoprotein remnants ,total cardiovascular risk ,treatment ,lifestyle ,drugs ,adherence ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR)
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- 2017
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3. Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease
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Lars Wallentin, Claes Held, Paul W. Armstrong, Christopher P. Cannon, Richard Y. Davies, Christopher B. Granger, Emil Hagström, Robert A. Harrington, Judith S. Hochman, Wolfgang Koenig, Sue Krug‐Gourley, Emile R. Mohler, Agneta Siegbahn, Elizabeth Tarka, Philippe Gabriel Steg, Ralph A. H. Stewart, Robert Weiss, Ollie Östlund, Harvey D. White, Andrzej Budaj, Diego Ardissino, Alvaro Avezum, Philip E. Aylward, Alfonso Bryce, Hong Chen, Ming‐Fong Chen, Ramon Corbalan, Anthony J. Dalby, Nicolas Danchin, Robbert J. De Winter, Stefan Denchev, Rafael Diaz, Moses Elisaf, Marcus D. Flather, Assen R. Goudev, Liliana Grinfeld, Steen Husted, Hyo‐Soo Kim, Ales Linhart, Eva Lonn, José López‐Sendón, Athanasios J. Manolis, José C. Nicolau, Prem Pais, Alexander Parkhomenko, Terje R. Pedersen, Daniel Pella, Marco A. Ramos‐Corrales, Mikhail Ruda, Mátyás Sereg, Saulat Siddique, Peter Sinnaeve, Piyamitr Sritara, Henk P. Swart, Rody G. Sy, Tamio Teramoto, Hung‐Fat Tse, W. Douglas Weaver, Margus Viigimaa, Dragos Vinereanu, and Junren Zhu
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atherosclerosis ,coronary disease ,inflammation ,lipoprotein ,myocardial infarction ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundWe evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and ResultsPlasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. ConclusionsAlthough high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity. Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.
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- 2016
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4. Efficacy and Safety of Long-Term Evolocumab Use Among Asian Subjects ― A Subgroup Analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) Trial ―
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Chung-Wah Siu, Peter S. Sever, Robert P. Giugliano, John Amerena, Donghoon Choi, Armando Lira Pineda, Prakash Deedwania, Min-Ji Charng, Terje R. Pedersen, Anthony C Keech, Leslie Tay, Marc S. Sabatine, Vijay K. Chopra, Chen Lu, Kazuma Oyama, Atsushi Hirayama, Wan Azman Wan Ahmad, Sabina A. Murphy, and Minao Tang
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medicine.medical_specialty ,Statin ,medicine.drug_class ,Subgroup analysis ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Internal medicine ,Clinical endpoint ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Unstable angina ,business.industry ,PCSK9 ,PCSK9 Inhibitors ,Cholesterol, LDL ,General Medicine ,Atherosclerosis ,medicine.disease ,Evolocumab ,Treatment Outcome ,Heart Disease Risk Factors ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,business - Abstract
BACKGROUND There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 [IQR 78-104] mg/dL vs. 92 [80-109] mg/dL; P
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- 2021
5. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials
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Christina Reith, Colin Baigent, Lisa Blackwell, Jonathan Emberson, Enti Spata, Kelly Davies, Heather Halls, Lisa Holland, Kate Wilson, Jane Armitage, Charlie Harper, David Preiss, Alistair Roddick, Anthony Keech, John Simes, Rory Collins, Elizabeth Barnes, Jordan Fulcher, William G Herrington, Adrienne Kirby, Borislava Mihaylova, Rachel O'Connell, Pierre Amarenco, Philip Barter, D John Betteridge (deceased), Michael Blazing, Jackie Bosch, Louise Bowman, Eugene Braunwald, Christopher P Cannon, Michael Clearfield, Stuart Cobbe, Helen M Colhoun, Björn Dahlöf, Barry Davis, James de Lemos, John R Downs, Paul N Durrington, Bengt Fellström, Ian Ford, Maria Grazia Franzosi, John Fuller (deceased), Curt Furberg, Robert Glynn, David Gordon, Antonio Gotto Jr, Richard Grimm, Ajay Gupta, C Morton Hawkins, Graham A Hitman, Hallvard Holdaas (deceased), Alan Jardine, J Wouter Jukema, John JP Kastelein, Sharon Kean, John Kjekshus, Genell Knatterud (deceased), Robert H Knopp (deceased), Wolfgang Koenig, Michael Koren, Vera Krane, Martin Landray, John LaRosa, Roberto Latini, Eva Lonn, Donata Lucci, Jean MacFadyen, Peter Macfarlane, Stephen MacMahon, Aldo Maggioni, Roberto Marchioli, Ian Marschner, Lemuel Moyé, Sabina Murphy, Andrew Neil, Enrico B Nicolis, Chris Packard, Sarah Parish, Terje R Pedersen, Richard Peto, Marc Pfeffer, Neil Poulter, Sara Pressel, Jeffrey Probstfield, Mahboob Rahman, Paul M Ridker, Michele Robertson, Frank Sacks, Naveed Sattar, Roland Schmieder, Patrick W Serruys, Peter Sever, John Shaw (deceased), James Shepherd (deceased), Lara Simpson, Peter Sleight (deceased), Luigi Tavazzi, Gianni Tognoni, Andrew Tonkin, Stella Trompet, Christoph Wanner, Hans Wedel, Stephen Weis, K Michael Welch, Harvey White, John Wikstrand, Lars Wilhelmsen, Stephen Wiviott, Robin Young, Salim Yusuf, Faiez Zannad, Hiroyuki Arashi, Robert Byington, Robert Clarke, Marcus Flather, Uri Goldbourt, Shinya Goto, Jemma Hopewell, Kees Hovingh, Patricia Kearney, George Kitas, Connie Newman, Marc S Sabatine, Greg Schwartz, Liam Smeeth, Jonathan Tobert, John Varigos, Junichi Yamaguchi, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, ACS - Pulmonary hypertension & thrombosis, Experimental Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, and Collaboration, Cholesterol Treatment Trialists'
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Male ,Muscles ,Australia ,Humans ,Female ,General Medicine ,Myalgia ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Middle Aged ,Atherosclerosis ,Randomized Controlled Trials as Topic - Abstract
Background: Statin therapy is effective for the prevention of atherosclerotic cardiovascular disease and is widely prescribed, but there are persisting concerns that statin therapy might frequently cause muscle pain or weakness. We aimed to address these through an individual participant data meta-analysis of all recorded adverse muscle events in large, long-term, randomised, double-blind trials of statin therapy. Methods: Randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years, and involved a double-blind comparison of statin versus placebo or of a more intensive versus a less intensive statin regimen. We analysed individual participant data from 19 double-blind trials of statin versus placebo (n=123 940) and four double-blind trials of a more intensive versus a less intensive statin regimen (n=30 724). Standard inverse-variance-weighted meta-analyses of the effects on muscle outcomes were conducted according to a prespecified protocol. Findings: Among 19 placebo-controlled trials (mean age 63 years [SD 8], with 34 533 [27·9%] women, 59 610 [48·1%] participants with previous vascular disease, and 22 925 [18·5%] participants with diabetes), during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01–1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04–1·10), corresponding to an absolute excess rate of 11 (6–16) events per 1000 person-years, which indicates that only one in 15 ([1·07–1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin. After year 1, there was no significant excess in first reports of muscle pain or weakness (0·99; 0·96–1·02). For all years combined, more intensive statin regimens (ie, 40–80 mg atorvastatin or 20–40 mg rosuvastatin once per day) yielded a higher RR than less intensive or moderate-intensity regimens (1·08 [1·04–1·13] vs 1·03 [1·00–1·05]) compared with placebo, and a small excess was present (1·05 [0·99–1·12]) for more intensive regimens after year 1. There was no clear evidence that the RR differed for different statins, or in different clinical circumstances. Statin therapy yielded a small, clinically insignificant increase in median creatine kinase values of approximately 0·02 times the upper limit of normal. Interpretation: Statin therapy caused a small excess of mostly mild muscle pain. Most (>90%) of all reports of muscle symptoms by participants allocated statin therapy were not due to the statin. The small risks of muscle symptoms are much lower than the known cardiovascular benefits. There is a need to review the clinical management of muscle symptoms in patients taking a statin. Funding: British Heart Foundation, Medical Research Council, Australian National Health and Medical Research Council.
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- 2022
6. Sustained Improvement of Arterial Stiffness and Blood Pressure after Long-Term Rosuvastatin Treatment in Patients with Inflammatory Joint Diseases: Results from the RORA-AS Study.
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Eirik Ikdahl, Silvia Rollefstad, Jonny Hisdal, Inge C Olsen, Terje R Pedersen, Tore K Kvien, and Anne Grete Semb
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Medicine ,Science - Abstract
OBJECTIVE:Patients with inflammatory joint diseases (IJD) have a high prevalence of hypertension and increased arterial stiffness. The aim of the present study was to evaluate the effect of long-term rosuvastatin treatment on arterial stiffness, measured by augmentation index (AIx) and aortic pulse wave velocity (aPWV), and blood pressure (BP) in IJD patients with established atherosclerosis. METHODS:Eighty-nine statin naïve IJD patients with carotid atherosclerotic plaque(s) (rheumatoid arthritis n = 55, ankylosing spondylitis n = 23, psoriatic arthritis n = 11) received rosuvastatin for 18 months to achieve low-density lipoprotein cholesterol goal ≤1.8 mmol/L. Change in AIx (ΔAIx), aPWV (ΔaPWV), systolic BP (ΔsBP) and diastolic BP (ΔdBP) from baseline to study end was assessed by paired samples t-tests. Linear regression was applied to evaluate associations between cardiovascular disease (CVD) risk factors, rheumatic disease specific variables and medication, and ΔAIx, ΔaPWV, ΔsBP and ΔdBP. RESULTS:AIx, aPWV, sBP and dBP were significantly reduced from baseline to study end. The mean (95%CI) changes were: ΔAIx: -0.34 (-0.03, -0.65)% (p = 0.03), ΔaPWV: -1.69 (-0.21, -3.17) m/s2 (p = 0.03), ΔsBP: -5.27 (-1.61, -8.93) mmHg (p = 0.004) and ΔdBP -2.93 (-0.86, -5.00) mmHg (p = 0.01). In linear regression models, ∆aPWV was significantly correlated with ΔsBP and ΔdBP (for all: p
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- 2016
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7. The Effect of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism
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Christian T. Ruff, Anthony C Keech, Nicholas A Marston, Robert P. Giugliano, Giorgio E. M. Melloni, Marc S. Sabatine, Terje R. Pedersen, Yared Gurmu, Peter S. Sever, Baris Gencer, Marc P. Bonaca, Carolina Roselli, Patrick T. Ellinor, Michelle L. O'Donoghue, and Steven A. Lubitz
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medicine.medical_specialty ,numbers needed to treat ,venous thromboembolism ,030204 cardiovascular system & hematology ,THERAPY ,LDL ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,PCSK9 protein ,STATINS ,LIPOPROTEIN(A) ,cardiovascular diseases ,human ,ROSUVASTATIN ,METAANALYSIS ,030304 developmental biology ,Ldl cholesterol ,0303 health sciences ,Cholesterol ,business.industry ,PCSK9 ,Subtilisin ,cholesterol ,Proprotein convertase ,PREVENTION ,Evolocumab ,Endocrinology ,chemistry ,evolocumab ,ATHEROSCLEROSIS ,Kexin ,Cardiology and Cardiovascular Medicine ,business ,Venous thromboembolism - Abstract
Background: The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk. Methods: We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. Results: In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50–1.00; P =0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57–1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33–0.88]; P =0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53–0.90]; P =0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30–0.89]; P =0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk ( P interaction 0.087 for HR; P heterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction ( P interaction =0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative ( P interaction =0.04) and absolute VTE reduction ( P heterogeneity =0.009) in comparison with those without high genetic risk. Conclusions: PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.
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- 2020
8. Cognition After Lowering LDL-Cholesterol With Evolocumab
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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
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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.
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- 2020
9. Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score Results From the FOURIER Trial
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Marc S. Sabatine, Huei Wang, Terje R. Pedersen, Frederick K. Kamanu, Anthony C Keech, Yared Gurmu, Francesco Nordio, Nicholas A Marston, Steven A. Lubitz, Carolina Roselli, Christian T. Ruff, Robert P. Giugliano, Patrick T. Ellinor, Peter S. Sever, and Armando Lira Pineda
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Oncology ,medicine.medical_specialty ,Multifactorial Inheritance ,Disease ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Article ,03 medical and health sciences ,0302 clinical medicine ,cardiovascular disease ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,PCSK9 protein ,risk factors ,In patient ,genetics ,CORONARY-HEART-DISEASE ,human ,Genetic risk ,METAANALYSIS ,030304 developmental biology ,0303 health sciences ,business.industry ,PCSK9 ,Atherosclerotic disease ,Antibodies, Monoclonal ,Proprotein convertase ,Evolocumab ,evolocumab ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. Methods: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27–single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2–4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. Results: After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events ( P trend =0.005) and major coronary events ( P trend P =0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75–0.998], P =0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55–0.86], P =0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk ( P trend for HR=0.017, ARR P trend =0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. Conclusion: Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.
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- 2020
10. Corrigendum to '2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk' [Atherosclerosis 290 (2019) 140–205]
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Francois Mach, Colin Baigent, Alberico L. Catapano, Konstantinos C. Koskinas, Manuela Casula, Lina Badimon, M. John Chapman, Guy G. De Backer, Victoria Delgado, Brian A. Ference, Ian M. Graham, Alison Halliday, Ulf Landmesser, Borislava Mihaylova, Terje R. Pedersen, Gabriele Riccardi, Dimitrios J. Richter, Marc S. Sabatine, Marja-Riitta Taskinen, Lale Tokgozoglu, Olov Wiklund, Djamaleddine Nibouche, Parounak H. Zelveian, Peter Siostrzonek, Ruslan Najafov, Philippe van de Borne, Belma Pojskic, Arman Postadzhiyan, Lambros Kypris, Jindřich Špinar, Mogens Lytken Larsen, Hesham Salah Eldin, Margus Viigimaa, Timo E. Strandberg, Jean Ferrieres, Rusudan Agladze, Ulrich Laufs, Loukianos Rallidis, Laszlo Bajnok, Thorbjorn Gudjonsson, Vincent Maher, Yaakov Henkin, Michele Massimo Gulizia, Aisulu Mussagaliyeva, Gani Bajraktari, Alina Kerimkulova, Gustavs Latkovskis, Omar Hamoui, Rimvydas Slapikas, Laurent Visser, Philip Dingli, Victoria Ivanov, Aneta Boskovic, Mbarek Nazzi, Frank Visseren, Irena Mitevska, Kjetil Retterstol, Piotr Jankowski, Ricardo Fontes-Carvalho, Dan Gaita, Marat Ezhov, Marina Foscoli, Vojislav Giga, Daniel Pella, Zlatko Fras, Leopoldo Perez de Isla, Emil Hagstrom, Roger Lehmann, Leila Abid, Oner Ozdogan, Olena Mitchenko, Riyaz S. Patel, Stephan Windecker, Victor Aboyans, Jean-Philippe Collet, Veronica Dean, Donna Fitzsimons, Chris P. Gale, Diederick Grobbee, Sigrun Halvorsen, Gerhard Hindricks, Bernard Iung, Peter Juni, Hugo A. Katus, Christophe Leclercq, Maddalena Lettino, Basil S. Lewis, Bela Merkely, Christian Mueller, Steffen Petersen, Anna Sonia Petronio, Marco Roffi, Evgeny Shlyakhto, Iain A. Simpson, Miguel Sousa-Uva, and Rhian M. Touyz
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Cardiology and Cardiovascular Medicine - Published
- 2020
11. Erratum to '2019 ESC/EAS guidelines for the management of dyslipidemias: Lipid modification to reduce cardiovascular risk' [Atherosclerosis 290 (2019) 140–205]
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Francois Mach, Colin Baigent, Alberico L. Catapano, Konstantinos C. Koskinas, Manuela Casula, Lina Badimon, M. John Chapman, Guy G. De Backer, Victoria Delgado, Brian A. Ference, Ian M. Graham, Alison Halliday, Ulf Landmesser, Borislava Mihaylova, Terje R. Pedersen, Gabriele Riccardi, Dimitrios J. Richter, Marc S. Sabatine, Marja-Riitta Taskinen, Lale Tokgozoglu, Olov Wiklund, Djamaleddine Nibouche, Parounak H. Zelveian, Peter Siostrzonek, Ruslan Najafov, Philippe van de Borne, Belma Pojskic, Arman Postadzhiyan, Lambros Kypris, Jindřich Špinar, Mogens Lytken Larsen, Hesham Salah Eldin, Margus Viigimaa, Timo E. Strandberg, Jean Ferrieres, Rusudan Agladze, Ulrich Laufs, Loukianos Rallidis, Laszlo Bajnok, Thorbjorn Gudjonsson, Vincent Maher, Yaakov Henkin, Michele Massimo Gulizia, Aisulu Mussagaliyeva, Gani Bajraktari, Alina Kerimkulova, Gustavs Latkovskis, Omar Hamoui, Rimvydas Slapikas, Laurent Visser, Philip Dingli, Victoria Ivanov, Aneta Boskovic, Mbarek Nazzi, Frank Visseren, Irena Mitevska, Kjetil Retterstol, Piotr Jankowski, Ricardo Fontes-Carvalho, Dan Gaita, Marat Ezhov, Marina Foscoli, Vojislav Giga, Daniel Pella, Zlatko Fras, Leopoldo Perez de Isla, Emil Hagstrom, Roger Lehmann, Leila Abid, Oner Ozdogan, Olena Mitchenko, Riyaz S. Patel, Stephan Windecker, Victor Aboyans, Jean-Philippe Collet, Veronica Dean, Donna Fitzsimons, Chris P. Gale, Diederick Grobbee, Sigrun Halvorsen, Gerhard Hindricks, Bernard Iung, Peter Juni, Hugo A. Katus, Christophe Leclercq, Maddalena Lettino, Basil S. Lewis, Bela Merkely, Christian Mueller, Steffen Petersen, Anna Sonia Petronio, Marco Roffi, Evgeny Shlyakhto, Iain A. Simpson, Miguel Sousa-Uva, and Rhian M. Touyz
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03 medical and health sciences ,0302 clinical medicine ,business.industry ,Medicine ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Lipid modification ,Cardiology and Cardiovascular Medicine ,Bioinformatics ,business - Published
- 2020
12. Correction
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Prakash Deedwania, David M. Charytan, Scott M. Wasserman, Terje R. Pedersen, Robert Giugliano, Anders G. Olsson, J-G Park, Sabatine, Anthony Keech, Peter S. Sever, and Armando Lira Pineda
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Evolocumab ,medicine.medical_specialty ,business.industry ,Urology ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease ,Kidney disease - Published
- 2019
13. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials
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Terje R. Pedersen, Gregory G. Schwartz, Andrew Tonkin, Anastasia Lesogor, Helen M. Colhoun, Christiane Drechsler, Florian Kronenberg, Peter Willeit, John Simes, Paul M. Ridker, Sotirios Tsimikas, Anders G. Olsson, Samia Mora, Paul J. Nestel, and Christoph Wanner
- Subjects
Male ,medicine.medical_specialty ,Statin ,Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ,medicine.drug_class ,Hypercholesterolemia ,Population ,Cardiovascular Diseases/blood ,Lipoprotein(a)/blood ,Hypercholesterolemia/drug therapy ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Humans ,Medicine ,030212 general & internal medicine ,education ,Stroke ,Aged ,Randomized Controlled Trials as Topic ,Cholesterol, HDL/blood ,education.field_of_study ,biology ,business.industry ,Cholesterol ,Cholesterol, HDL ,Hazard ratio ,Cholesterol, LDL ,General Medicine ,Lipoprotein(a) ,Middle Aged ,medicine.disease ,Cholesterol, LDL/blood ,chemistry ,Cardiovascular Diseases ,Meta-analysis ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Biomarkers ,Biomarkers/blood ,Lipoprotein - Abstract
BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain.METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials.FUNDING: Novartis Pharma AG.
- Published
- 2018
14. LDL-cholesterol lowering and clinical outcomes in hypercholesterolemic subjects with and without a familial hypercholesterolemia phenotype: Analysis from the secondary prevention 4S trial
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Raul D. Santos, Terje R. Pedersen, Alberico L. Catapano, Gerald F. Watts, Evan A. Stein, Brian A. Ference, Antonio J. Vallejo-Vaz, Kausik K. Ray, Chris J. Packard, John J.P. Kastelein, Vascular Medicine, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
0301 basic medicine ,Relative risk reduction ,medicine.medical_specialty ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Cardiovascular disease prevention ,Placebo ,Coronary artery disease ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Secondary Prevention ,medicine ,Humans ,Family history ,1102 Cardiorespiratory Medicine and Haematology ,business.industry ,Absolute risk reduction ,Statins ,1103 Clinical Sciences ,Cholesterol, LDL ,medicine.disease ,Phenotype ,Cholesterol ,030104 developmental biology ,Cardiovascular System & Hematology ,Simvastatin ,LDL cholesterol ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
BACKGROUND AND AIMS: Trial evidence for the benefits of cholesterol-lowering is limited for familial hypercholesterolemia (FH) patients, since they have not been the focus of large outcome trials. We assess statin use in coronary artery disease (CAD) subjects with low-density lipoprotein cholesterol (LDL-C) ≥4.9 mmol/L with or without an FH phenotype. METHODS: The 4S trial randomized hypercholesterolemic CAD patients to simvastatin or placebo. We first stratified participants into baseline LDL-C
- Published
- 2021
15. Association of APOE genotype and lipid lowering with cognitive function in a randomized placebo‐controlled trial of Evolocumab
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Terje R. Pedersen, Christopher Kurtz, Laura E. Korthauer, Peter S. Sever, Anthony C Keech, Marc S. Sabatine, Jianping Guo, Brian R. Ott, Christian T. Ruff, Robert P. Giugliano, and François Mach
- Subjects
Apolipoprotein E ,medicine.medical_specialty ,Epidemiology ,business.industry ,Health Policy ,Placebo-controlled study ,Cognition ,Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Evolocumab ,Developmental Neuroscience ,Internal medicine ,Genotype ,Medicine ,Neurology (clinical) ,Lipid lowering ,Geriatrics and Gerontology ,business ,Association (psychology) - Published
- 2020
16. Abstract 16688: Effects of Evolocumab in Patients With Prior Percutaneous Coronary Intervention: An Analysis From the Fourier Trial
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Huei Wang, Terje R. Pedersen, Kazuma Oyama, Remo H.M. Furtado, Antonio Fagundes, Anthony C Keech, Brian A. Bergmark, Marc S. Sabatine, Sabina A. Murphy, Julia F Kuder, Minao Tang, Thomas A Zelniker, Robert P. Giugliano, and Andrew Hammer
- Subjects
medicine.medical_specialty ,education.field_of_study ,Atherosclerotic cardiovascular disease ,business.industry ,medicine.medical_treatment ,PCSK9 ,Population ,Percutaneous coronary intervention ,Evolocumab ,Physiology (medical) ,Internal medicine ,Conventional PCI ,medicine ,Cardiology ,In patient ,Cardiology and Cardiovascular Medicine ,education ,business - Abstract
Introduction: Among patients with atherosclerotic cardiovascular disease (ASCVD), those with history of PCI represent an important population for potential high risk for cardiovascular (CV) events. We examined the clinical efficacy of the PCSK9 inibitor evolocumab in patients with prior PCI. Methods: FOURIER randomized 27,564 patients with ASCVD on statin therapy to evolocumab or placebo with a median follow-up of 2.2 yrs. The primary end point (PEP) was the composite of CV death, MI, stroke, unstable angina, or coronary revascularization; major coronary events were the composite of coronary death, MI, or coronary revascularization. The risk of events in patients with and without a history of PCI were compared in the placebo arm. The clinical benefit of evolocumab vs. placebo was compared using a Cox proportional hazards model. Results: 17,073 (62%) patients had prior PCI at baseline. Among patients in the placebo arm, those with prior PCI (N=8563) had a 1.6x higher rate of the PEP (16.8 vs 10.7%; adjusted HR 1.61; 95% CI 1.42-1.84 P Conclusions: In a contemporary cohort with ASCVD on statin therapy, patients with prior PCI were at heightened risk for coronary events. Evolocumab was highly effective in this group, reducing major coronary events by 18% with a NNT at 3 years of only 36.
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- 2020
17. Abstract 13200: Relationship Between Baseline Low-Density Lipoprotein Cholesterol and Percent Low-Density Lipoprotein Cholesterol Reduction With Evolocumab in the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) Trial
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Andrew Hamer, Robert P. Giugliano, Dan P Marcusa, Marc S. Sabatine, Anthony C Keech, Peter S. Sever, Jeong-Gun Park, Terje R. Pedersen, and Huei Wang
- Subjects
medicine.medical_specialty ,business.industry ,High intensity ,PCSK9 ,Low density lipoprotein cholesterol ,Evolocumab ,Physiology (medical) ,Internal medicine ,Cardiology ,medicine ,lipids (amino acids, peptides, and proteins) ,In patient ,Cardiology and Cardiovascular Medicine ,business ,Cardiovascular outcomes - Abstract
Introduction: The FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab robustly reduced LDL-C amongst patients on moderate or high intensity statins. We investigated whether the magnitude of the percentage LDL-C reduction is consistent across baseline LDL-C levels. Methods: FOURIER enrolled 27,564 patients with ASCVD and an LDL-C ≥70 mg/dl or a non-HDL-C ≥100 mg/dl on optimized statin therapy at the time of enrollment. The % LDL-C reduction from baseline to 12 wks was examined in patients on study drug through 12 wks (N=25,847) using a quadratic regression model including terms for treatment (evolocumab vs. placebo), baseline LDL-C and [LDL-C] 2 , and interaction terms. Stratified analyses were done for patients on high vs. moderate intensity statin. Results: Overall, compared with placebo, evolocumab reduced LDL-C by 61% (95% CI 61-62%). Patients with lower baseline LDL-C had significantly greater % LDL-C reductions (Figure top; P Conclusions: The magnitude of % LDL-C reduction with evolocumab is greater in patients with lower baseline LDL-C levels. These data are encouraging for the use of PCSK9 inhibition even for patients at the lower end of LDL-C.
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- 2020
18. Abstract 14770: Reduction With Evolocumab in Complex Coronary Disease Requiring Revascularization: Insights From the FOURIER Trial
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Huei Wang, Andrew Hamer, Marc S. Sabatine, Antonio Fagundes, Remo H.M. Furtado, Terje R. Pedersen, Anthony C Keech, Brian A. Bergmark, Sabina A. Murphy, Minao Tang, Thomas A Zelniker, Kazuma Oyama, Julia F Kuder, and Robert P. Giugliano
- Subjects
medicine.medical_specialty ,business.industry ,PCSK9 ,medicine.medical_treatment ,Coronary disease ,medicine.disease ,Revascularization ,Coronary revascularization ,Coronary artery disease ,Evolocumab ,Physiology (medical) ,Internal medicine ,Cardiology ,medicine ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,PCSK9 Inhibitors ,business ,Reduction (orthopedic surgery) - Abstract
Introduction: Although PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall, their ability to specifically reduce the risk of complex coronary atherosclerosis requiring revascularization has not been explored. Methods: FOURIER was a randomized trial of the PCSK9 inhibitor evolocumab vs. placebo in 27,564 patients with ASCVD on statin therapy (median achieved LDL-C 32 mg/dL vs. 89 mg/dL) followed for a median of 2.2 years. The study database was blindly reviewed to assess characteristics of coronary revascularization procedures. Complex revascularization was the composite of complex PCI (per GLOBAL LEADERS criteria, at least one of: multivessel PCI, 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI with 2 or more stents, or total stent length >60 mm) or CABG. PCI complications included no-reflow, side branch loss, thrombus formation, major dissection, or perforation. The effects of evolocumab on types of revascularization and PCI complications were evaluated using Cox proportional hazards models. Results: 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22% (HR 0.78; 95%CI 0.70-0.88; P Conclusions: Adding evolocumab to statin therapy reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. Together with prior coronary imaging findings, these data suggest very aggressive LDL-C lowering to
- Published
- 2020
19. An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial
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Basil S. Lewis, Michelle L. O'Donoghue, Kurt Huber, Julia F Kuder, Ioanna Gouni-Berthold, Zbigniew Gaciong, Robert P. Giugliano, Brian A. Bergmark, François Mach, J. Wouter Jukema, S. Lale Tokgozoglu, Terje R. Pedersen, Richard Ceska, Marc S. Sabatine, Marat V. Ezhov, Henrik Jensen, Sabina A. Murphy, and Francois Schiele
- Subjects
medicine.medical_specialty ,business.industry ,Proportional hazards model ,Hazard ratio ,030204 cardiovascular system & hematology ,medicine.disease ,Placebo ,law.invention ,03 medical and health sciences ,Evolocumab ,0302 clinical medicine ,Randomized controlled trial ,Aortic valve replacement ,Interquartile range ,law ,Internal medicine ,Aortic valve stenosis ,medicine ,Cardiology ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business - Abstract
Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P =.002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P =.001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P =.14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.
- Published
- 2020
20. 2019 ESC/EAS Guidelines for themanagement of dyslipidaemias: lipid modification to reduce cardiovascular risk
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Borislava Mihaylova, Colin Baigent, Terje R. Pedersen, Victoria Delgado, Manuela Casula, François Mach, Ulf Landmesser, M. John Chapman, Alberico L. Catapano, Ian Graham, Marc S. Sabatine, Lina Badimon, Dimitrios J. Richter, Konstantinos С. Koskinas, Lale Tokgozoglu, Marja-Riitta Taskinen, Brian А. Ference, Olov Wiklund, Gabriele Riccardi, Guy De Backer, and Alison Halliday
- Subjects
high-density lipoproteins ,medicine.medical_specialty ,treatment (drugs) ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,lipoprotein(a) ,Internal medicine ,total cardiovascular risk ,medicine ,low-density lipoproteins ,Diseases of the circulatory (Cardiovascular) system ,030212 general & internal medicine ,guidelines ,triglycerides ,biology ,treatment ,Task force ,business.industry ,lipoprotein remnants ,dyslipidaemias ,cholesterol ,Lipoprotein(a) ,RC666-701 ,(lifestyle) ,European atherosclerosis society ,biology.protein ,Cardiology ,apolipoprotein b ,Cardiology and Cardiovascular Medicine ,business - Abstract
The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS)
- Published
- 2020
21. Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis
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Narimon Honarpour, Marc S. Sabatine, Anthony C Keech, Terje R. Pedersen, Sabina A. Murphy, Scott M. Wasserman, Jeffrey L. Saver, Peter S. Sever, Armando Lira Pineda, Robert P. Giugliano, Huei Wang, and Erin A. Bohula
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Male ,Statin ,medicine.drug_class ,Hypercholesterolemia ,Myocardial Infarction ,Pharmacology ,Antibodies, Monoclonal, Humanized ,chemistry.chemical_compound ,Peripheral Arterial Disease ,Double-Blind Method ,Risk Factors ,medicine ,Humans ,Aged ,Proportional Hazards Models ,Advanced and Specialized Nursing ,Cholesterol ,business.industry ,PCSK9 ,Anticholesteremic Agents ,Subtilisin ,Cholesterol, LDL ,Middle Aged ,Proprotein convertase ,Atherosclerosis ,Stroke ,Evolocumab ,chemistry ,Kexin ,Female ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
Background and Purpose— The PCSK9 (proprotein convertase subtilisin-kexin type 9) monoclonal antibody evolocumab lowered LDL (low-density lipoprotein) cholesterol by 59% to 0.8 (0.5–1.2) mmol/L and significantly reduced major vascular events in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk). Herein, we report the results of a prespecified analysis of cerebrovascular events in the overall trial population and in patients stratified by prior stroke. Methods— FOURIER was a randomized, double-blind trial comparing evolocumab versus placebo in patients with established atherosclerosis, additional risk factors, and LDL cholesterol levels ≥1.8 (or non-HDL [high-density lipoprotein] ≥2.6 mmol/L) on statin therapy. The median follow-up was 2.2 years. We analyzed the efficacy of evolocumab to reduce overall stroke and stroke subtypes, as well as the primary cardiovascular composite end point by subgroups according to a history of stroke. Results— Among the 27 564 patients, 469 (1.7%) experienced a total of 503 strokes of which 421 (84%) were ischemic. Prior ischemic stroke, diabetes mellitus, elevated CRP (C-reactive protein), history of heart failure, older age, nonwhite race, peripheral arterial disease, and renal insufficiency were independent predictors of stroke. Evolocumab significantly reduced all stroke (1.5% versus 1.9%; hazard ratio, 0.79 [95% CI, 0.66–0.95]; P =0.01) and ischemic stroke (1.2% versus 1.6%; hazard ratio, 0.75 [95% CI, 0.62–0.92]; P =0.005), with no difference in hemorrhagic stroke (0.21% versus 0.18%; hazard ratio, 1.16 [95% CI, 0.68–1.98]; P =0.59). These findings were consistent across subgroups, including among the 5337 patients (19%) with prior ischemic stroke in whom the hazard ratios (95% CIs) were 0.85 (0.72–1.00) for the cardiovascular composite, 0.90 (0.68–1.19) for all stroke, and 0.92 (0.68–1.25) for ischemic stroke ( P interactions, 0.91, 0.22, and 0.09, respectively, compared with patients without a prior ischemic stroke). Conclusions— Inhibition of PCSK9 with evolocumab added to statin in patients with established atherosclerosis reduced ischemic stroke and cardiovascular events in the total population and in key subgroups, including those with prior ischemic stroke. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01764633.
- Published
- 2020
22. Lipid-lowering therapy and low-density lipoprotein cholesterol goal achievement in patients with acute coronary syndromes: The ACS patient pathway project
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Gabriel Steg, J. Wouter Jukema, Pepe Zamorano, Francois Schiele, Ulrich Laufs, François Mach, Ulf Landmesser, Terje R. Pedersen, Alberico L. Catapano, Angela Pirillo, Azfar Zaman, Michel Farnier, Marco Tubaro, and Luis Masana
- Subjects
Male ,Acute coronary syndrome ,medicine.medical_specialty ,Low density lipoprotein cholesterol ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Guidelines ,Patient pathway ,Lipid-lowering therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Goal achievement ,Humans ,In patient ,Low-density lipoprotein cholesterol ,030212 general & internal medicine ,Aged ,medicine.diagnostic_test ,business.industry ,Anticholesteremic Agents ,Statins ,Disease Management ,General Medicine ,Cholesterol, LDL ,Lipid-lowering therapies ,medicine.disease ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,Lipid profile ,business ,Goals - Abstract
Background and aims: Post-acute coronary syndrome (ACS) patients are at very high risk for recurrent events and mortality, despite the availability of effective pharmacological approaches. Aim of this survey was to evaluate the compliance to ESC/EAS guidelines during the management of ACS patients and the effectiveness of secondary prevention in seven European countries.Methods: By means of an online questionnaire, data on 2775 ACS patients (either acute case or follow-up patients) were collected, including data on lipid profile, medications, follow-up visit planning, screening for familial hypercholesterolemia.Results: Lipid profiles were obtained for 91% of ACS patients in the acute phase, mostly within the first day of hospitalization (73%). During hospitalization, 93% of the patients received a lipid-lowering treatment; at discharge, only 66% of the patients received a high intensity statin therapy. At the first follow-up, most of the patients (77.6%) had LDL-C 70 mg/dL; among them, 41% had no change in their lipid-lowering therapies. Similar data were obtained during the second follow-up visit. The analysis of a subgroup of patients with at least 2 follow-up visits and known LDL-C levels showed that the percentage of patients at goal increased from 9% to 32%, and patients with LDL-C
- Published
- 2020
23. LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial
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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
24. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk
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François Mach, Colin Baigent, Alberico L. Catapano, Konstantinos C. Koskinas, Manuela Casula, Lina Badimon, M. John Chapman, Guy G. De Backer, Victoria Delgado, Brian A. Ference, Ian M. Graham, Alison Halliday, Ulf Landmesser, Borislava Mihaylova, Terje R. Pedersen, Gabriele Riccardi, Dimitrios J. Richter, Marc S. Sabatine, Marja-Riitta Taskinen, Lale Tokgozoglu, Olov Wiklund, Stephan Windecker, Victor Aboyans, Jean-Philippe Collet, Veronica Dean, Donna Fitzsimons, Chris P. Gale, Diederick Grobbee, Sigrun Halvorsen, Gerhard Hindricks, Bernard Iung, Peter Jüni, Hugo A. Katus, Christophe Leclercq, Maddalena Lettino, Basil S. Lewis, Bela Merkely, Christian Mueller, Steffen Petersen, Anna Sonia Petronio, Marco Roffi, Evgeny Shlyakhto, Iain A. Simpson, Miguel Sousa-Uva, Rhian M. Touyz, Djamaleddine Nibouche, Parounak H. Zelveian, Peter Siostrzonek, Ruslan Najafov, Philippe van de Borne, Belma Pojskic, Arman Postadzhiyan, Lambros Kypris, Jindřich Špinar, Mogens Lytken Larsen, Hesham Salah Eldin, Margus Viigimaa, Timo E. Strandberg, Jean Ferrières, Rusudan Agladze, Ulrich Laufs, Loukianos Rallidis, László Bajnok, Thorbjörn Gudjónsson, Vincent Maher, Yaakov Henkin, Michele Massimo Gulizia, Aisulu Mussagaliyeva, Gani Bajraktari, Alina Kerimkulova, Gustavs Latkovskis, Omar Hamoui, Rimvydas Slapikas, Laurent Visser, Philip Dingli, Victoria Ivanov, Aneta Boskovic, Mbarek Nazzi, Frank Visseren, Irena Mitevska, Kjetil Retterstøl, Piotr Jankowski, Ricardo Fontes-Carvalho, Dan Gaita, Marat Ezhov, Marina Foscoli, Vojislav Giga, Daniel Pella, Zlatko Fras, Leopoldo Perez de Isla, Emil Hagström, Roger Lehmann, Leila Abid, Oner Ozdogan, Olena Mitchenko, Riyaz S. Patel, HUS Heart and Lung Center, Clinicum, CAMM - Research Program for Clinical and Molecular Metabolism, Research Programs Unit, and University of Helsinki
- Subjects
Male ,CHRONIC KIDNEY-DISEASE ,Very low-density lipoprotein ,Apolipoprotein B ,Lipoprotein remnants ,030204 cardiovascular system & hematology ,INTIMA-MEDIA THICKNESS ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,030212 general & internal medicine ,High-density lipoproteins ,HIGH-DOSE ATORVASTATIN ,Hypolipidemic Agents ,ALL-CAUSE MORTALITY ,biology ,Treatment (drugs) ,Lipoprotein(a) ,Middle Aged ,Lipids ,C-REACTIVE PROTEIN ,3. Good health ,Treatment (adherence) ,Treatment Outcome ,Cholesterol ,DENSITY-LIPOPROTEIN CHOLESTEROL ,Cardiovascular Diseases ,Drug Therapy, Combination ,Female ,Low-density lipoproteins ,Cardiology and Cardiovascular Medicine ,Familial hypercholesterolaemia ,Adult ,medicine.medical_specialty ,Consensus ,Very low-density lipoproteins ,TYPE-2 DIABETES-MELLITUS ,Guidelines ,Total cardiovascular risk ,Risk Assessment ,STATIN-TREATED PATIENTS ,Treatment (lifestyle) ,03 medical and health sciences ,Internal medicine ,Journal Article ,medicine ,Humans ,CORONARY-HEART-DISEASE ,HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA ,Dyslipidaemias ,Triglycerides ,Aged ,Dyslipidemias ,business.industry ,C-reactive protein ,Type 2 Diabetes Mellitus ,Endocrinology ,chemistry ,Intima-media thickness ,3121 General medicine, internal medicine and other clinical medicine ,biology.protein ,Lipid modification ,business ,Risk Reduction Behavior ,Biomarkers - Abstract
Correction: Volume: 292 Pages: 160-162 DOI: 10.1016/j.atherosclerosis.2019.11.020 Published: JAN 2020
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- 2019
25. Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation
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Unnur Thorsteinsdottir, Sridharan Rajamani, Páll Melsted, Erna V. Ivarsdottir, Jonas B. Nielsen, Jon Thor Sverrisson, David O Arnar, Maja-Lisa Løchen, Cristen J. Willer, Atli S Valgardsson, Oddgeir L. Holmen, Terje R. Pedersen, Daniel F. Gudbjartsson, Vinicius Tragante, Olafur B. Davidsson, Gardar Sveinbjornsson, Hilma Holm, Gisli H. Halldorsson, Ingileif Jonsdottir, Patrick Sulem, Marc S. Sabatine, Bjarni Torfason, Anna Helgadottir, Stefan Jonsson, Bjarni V. Halldorsson, Dan M. Roden, Solveig Gretarsdottir, Kristian Hveem, Gudmundur L. Norddahl, Ragnar P. Kristjansson, Folkert W. Asselbergs, Rosa B. Thorolfsdottir, Kari Stefansson, Gudmar Thorleifsson, and Dawood Darbar
- Subjects
0301 basic medicine ,Medicine (miscellaneous) ,Genome-wide association study ,030204 cardiovascular system & hematology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Journal Article ,Missense mutation ,splice ,Gene ,lcsh:QH301-705.5 ,Sequence (medicine) ,Genetic association ,Genetics ,VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801 ,Atrial fibrillation ,medicine.disease ,Exon skipping ,3. Good health ,030104 developmental biology ,lcsh:Biology (General) ,VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801 ,General Agricultural and Biological Sciences - Abstract
Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in RPL3L, the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in RPL3L results in exon skipping. We also observe an association with a missense variant in MYZAP (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
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- 2018
26. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial
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Gaetano M. De Ferrari, Basil S. Lewis, Prakash Deedwania, Stephen D. Wiviott, Lawrence A. Leiter, Terje R. Pedersen, Julia F Kuder, Narimon Honarpour, Robert P. Giugliano, Anthony C Keech, Sabina A. Murphy, Peter S. Sever, Armando Lira Pineda, Yehuda Handelsman, Ioanna Gouni-Berthold, Marc S. Sabatine, National Institute for Health Research, and Amgen Inc
- Subjects
medicine.medical_specialty ,Diabetes risk ,business.industry ,Endocrinology, Diabetes and Metabolism ,PCSK9 ,030209 endocrinology & metabolism ,030204 cardiovascular system & hematology ,Placebo ,medicine.disease ,03 medical and health sciences ,Evolocumab ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Physical therapy ,Clinical endpoint ,Myocardial infarction ,Prediabetes ,business - Abstract
Summary Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduced LDL cholesterol and cardiovascular events in the FOURIER trial. In this prespecified analysis of FOURIER, we investigated the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes. Methods FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) versus placebo in 27 564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years. In this prespecified analysis, we investigated the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA 1c of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. We also assessed the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline. HbA 1c was measured at baseline then every 24 weeks and FPG was measured at baseline, week 12, week 24, and every 24 weeks thereafter, and potential cases of new-onset diabetes were adjudicated centrally. In a post-hoc analysis, we also investigated the effects on glycaemia and diabetes risk in patients with prediabetes (HbA 1c 5·7–6·4% [39–46 mmol/mol] or FPG 5·6–6·9 mmol/L) at baseline. FOURIER is registered with ClinicalTrials.gov, number NCT01764633. Findings At study baseline, 11 031 patients (40%) had diabetes and 16 533 (60%) did not have diabetes (of whom 10 344 had prediabetes and 6189 had normoglycaemia). Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0·83 (95% CI 0·75–0·93; p=0·0008) for patients with diabetes and 0·87 (0·79–0·96; p=0·0052) for patients without diabetes (p interaction =0·60). For the key secondary endpoint, the HRs were 0·82 (0·72–0·93; p=0·0021) for those with diabetes and 0·78 (0·69–0·89; p=0·0002) for those without diabetes (p interaction =0·65). Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1·05, 0·94–1·17), including in those with prediabetes (HR 1·00, 0·89–1·13). Levels of HbA 1c and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes, or normoglycaemia. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78·5% (4327 of 5513 patients) in the evolocumab group and 78·3% (4307 of 5502 patients) in the placebo group; among patients without diabetes at baseline, the proportions with adverse events were 76·8% (6337 of 8256 patients) in the evolocumab group and 76·8% (6337 of 8254 patients) in the placebo group. Interpretation PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes. Funding Amgen.
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- 2017
27. A Missense Variant in PLEC Increases Risk of Atrial Fibrillation
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Anna Helgadottir, Hilma Holm, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Audur Magnusdottir, Sridharan Rajamani, Dawood Darbar, Stefania Benonisdottir, Marc S. Sabatine, Solveig Gretarsdottir, Terje R. Pedersen, Dan M. Roden, Ingileif Jonsdottir, Patrick Sulem, Rosa B. Thorolfsdottir, Kari Stefansson, David O. Arnar, Gardar Sveinbjornsson, and Olafur B. Davidsson
- Subjects
Risk ,Sarcomeres ,0301 basic medicine ,Myosin Light Chains ,Population ,Mutation, Missense ,Genome-wide association study ,Electrocardiography ,03 medical and health sciences ,Atrial Fibrillation ,Humans ,Medicine ,Missense mutation ,education ,Gene ,Genetic association ,Genetics ,education.field_of_study ,business.industry ,Atrial fibrillation ,Odds ratio ,medicine.disease ,030104 developmental biology ,Genomic Structural Variation ,Plectin ,MYH6 ,Cardiology and Cardiovascular Medicine ,business ,Genome-Wide Association Study - Abstract
Background Genome-wide association studies (GWAS) have yielded variants at >30 loci that associate with atrial fibrillation (AF), including rare coding mutations in the sarcomere genes MYH6 and MYL4. Objectives The aim of this study was to search for novel AF associations and in doing so gain insights into the mechanisms whereby variants affect AF risk, using electrocardiogram (ECG) measurements. Methods The authors performed a GWAS of 14,255 AF cases and 374,939 controls, using whole-genome sequence data from the Icelandic population, and tested novel signals in 2,002 non-Icelandic cases and 12,324 controls. They then tested the AF variants for effect on cardiac electrical function by using measurements in 289,297 ECGs from 62,974 individuals. Results The authors discovered 2 novel AF variants, the intergenic variant rs72700114, between the genes LINC01142 and METTL11B (risk allele frequency = 8.1%; odds ratio [OR]: 1.26; p = 3.1 × 10−18), and the missense variant p.Gly4098Ser in PLEC (frequency = 1.2%; OR: 1.55; p = 8.0 × 10−10), encoding plectin, a cytoskeletal cross-linking protein that contributes to integrity of cardiac tissue. The authors also confirmed 29 reported variants. p.Gly4098Ser in PLEC significantly affects various ECG measurements in the absence of AF. Other AF variants have diverse effects on the conduction system, ranging from none to extensive. Conclusions The discovery of a missense variant in PLEC affecting AF combined with recent discoveries of variants in the sarcomere genes MYH6 and MYL4 points to an important role of myocardial structure in the pathogenesis of the disease. The diverse associations between AF variants and ECG measurements suggest fundamentally different categories of mechanisms contributing to the development of AF.
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- 2017
28. Atherothrombotic Risk Stratification and Ezetimibe for Secondary Prevention
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Yale B. Mitchel, Jennifer A. White, Robert P. Giugliano, Ping He, Eugene Braunwald, Jeong-Gun Park, Michael A. Blazing, Sabina A. Murphy, David A. Morrow, Terje R. Pedersen, Adrian J B Brady, Christopher P. Cannon, Y. Antero Kesäniemi, and Erin A. Bohula
- Subjects
medicine.medical_specialty ,Acute coronary syndrome ,Framingham Risk Score ,business.industry ,030204 cardiovascular system & hematology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Ezetimibe ,Simvastatin ,Internal medicine ,medicine ,Physical therapy ,Cardiology ,030212 general & internal medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,Prospective cohort study ,Risk assessment ,business ,TIMI ,medicine.drug - Abstract
Background Ezetimibe improves cardiovascular (CV) outcomes in patients stabilized after acute coronary syndrome (ACS) when added to statin therapy. After ACS, patients vary considerably in their risk for recurrent CV events. Objectives This study tested the hypothesis that atherothrombotic risk stratification may be useful to identify post-ACS patients who have the greatest potential for benefit from the addition of ezetimibe to statin therapy. Methods The TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention (TRS 2°P) is a simple 9-point risk stratification tool, previously developed in a large population with atherothrombosis to predict CV death, myocardial infarction (MI), and ischemic stroke (CV death/MI/ischemic cerebrovascular accident [iCVA]). The current study applied this tool prospectively to 17,717 post-ACS patients randomized either to ezetimibe and simvastatin or to placebo and simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Treatment efficacy was assessed by baseline risk for CV death/MI/iCVA, the IMPROVE-IT composite endpoints (CE), and individual component endpoints at 7 years. Results All 9 clinical variables in the TRS 2°P were independent risk indicators for CV death/MI/iCVA (p Conclusions Atherothrombotic risk stratification using the TRS 2°P identifies high-risk patients who derive greatest benefit from the addition of ezetimibe to statin therapy for secondary prevention after ACS. (Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT]; NCT00202878)
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- 2017
29. Relation of Lipid-Lowering Therapy to Need for Aortic Valve Replacement in Patients With Asymptomatic Mild to Moderate Aortic Stenosis
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Simon Ray, Terje R. Pedersen, Kurt Boman, Kristian Wachtell, Y. Antero Kesäniemi, Casper N. Bang, Anders M. Greve, and Kenneth Egstrup
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Aortic valve ,Male ,medicine.medical_specialty ,Simvastatin ,Time Factors ,030204 cardiovascular system & hematology ,Asymptomatic ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Pharmacotherapy ,Aortic valve replacement ,Double-Blind Method ,Internal medicine ,Severity of illness ,medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Prospective cohort study ,Aged ,Dyslipidemias ,Aged, 80 and over ,Heart Valve Prosthesis Implantation ,business.industry ,Anticholesteremic Agents ,Aortic Valve Stenosis ,Middle Aged ,medicine.disease ,Ezetimibe ,Echocardiography, Doppler ,Lipoproteins, LDL ,Stenosis ,medicine.anatomical_structure ,Treatment Outcome ,Aortic Valve ,Asymptomatic Diseases ,cardiovascular system ,Cardiology ,Disease Progression ,lipids (amino acids, peptides, and proteins) ,Drug Therapy, Combination ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers ,Lipoprotein ,Follow-Up Studies - Abstract
In this study, we aimed to determine if pretreatment low-density lipoprotein (LDL) levels and aortic stenosis (AS) severity alter the efficacy of lipid-lowering therapy on reducing aortic valve replacement (AVR). We used 1,687 patients with asymptomatic mild-to-moderate AS, who were randomly assigned (1:1) to 40/10 mg simvastatin/ezetimibe combination versus. placebo in the simvastatin and ezetimibe in aortic stenosis (SEAS) trial. Pretreatment LDL levels (>4 mmol/L) and peak aortic jet velocity (3 m/s) were used to partition study participants into 4 groups, which were followed for a primary endpoint of AVR. Cox regression with tests for interaction was used to study the effect of randomized treatment in each subgroup. During a median follow-up of 4.3 years (IQR 4.2 to 4.7 years; total 7,396 patient-years of follow-up), 478 (28%) patients underwent AVR and 146 (9%) died. A significant risk dependency was detected between simvastatin/ezetimibe combination, LDL levels and mild versus moderate AS on rates of AVR (p = 0.01 for interaction). In stratified analyses, randomized treatment, therefore, reduced the rate of AVR in patients with LDL levels >4 mmol and mild AS at baseline (HR 0.4; 95% CI: 0.2 to 0.9). There was no detectable effect of randomized treatment on the need for AVR in the 3 other participants subgroups. We conclude, that in a secondary analysis from a prospective randomized clinical trial, treatment with simvastatin/ezetimibe combination reduced the need for AVR in a subset of patients with mild AS and high pretreatment LDL levels (Unique identifier on clinicaltrials.gov: NCT00092677).
- Published
- 2019
30. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk Insights From the FOURIER Trial
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Henrik Jensen, Kyung Ah Im, Anthony C Keech, Kurt Huber, Erik S.G. Stroes, S. Lale Tokgozoglu, François Mach, Ioanna Gouni-Berthold, Terje R. Pedersen, J. Wouter Jukema, Robert P. Giugliano, Marat V. Ezhov, Michelle L. O'Donoghue, Richard Ceska, Marc S. Sabatine, Estella Kanevsky, Peter S. Sever, Armando Lira Pineda, Sergio Fazio, Scott M. Wasserman, and Amgen Inc
- Subjects
medicine.medical_specialty ,Cardiac & Cardiovascular Systems ,MONOCLONAL-ANTIBODY ,medicine.drug_class ,PCSK9 inhibitor ,030204 cardiovascular system & hematology ,Monoclonal antibody ,THERAPY ,DISEASE ,1117 Public Health and Health Services ,03 medical and health sciences ,DOUBLE-BLIND ,0302 clinical medicine ,lipoprotein(a) ,Physiology (medical) ,Internal medicine ,medicine ,stable atherosclerosis ,030212 general & internal medicine ,Stroke ,1102 Cardiorespiratory Medicine and Haematology ,Science & Technology ,biology ,business.industry ,PCSK9 ,Subtilisin ,1103 Clinical Sciences ,clinical trial ,Lipoprotein(a) ,Proprotein convertase ,medicine.disease ,TARGETING APOLIPOPROTEIN(A) ,Endocrinology ,Peripheral Vascular Disease ,Cardiovascular System & Hematology ,biology.protein ,Cardiovascular System & Cardiology ,Kexin ,HEART ,REDUCES LIPOPROTEIN(A) ,atherosclerosis ,Cardiology and Cardiovascular Medicine ,business ,Life Sciences & Biomedicine ,STROKE ,Lipoprotein - Abstract
Background: Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. Methods: Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. Results: The median (interquartile range) baseline Lp(a) concentration was 37 (13–165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01–1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%–46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r =0.37; 95% CI, 0.36–0.39; P median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80–1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. Conclusions: Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
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- 2019
31. Efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial
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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)
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- 2019
32. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: A prespecified analysis from the FOURIER Trial
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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
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- 2019
33. Interindividual Variation in Low-Density Lipoprotein Cholesterol Level Reduction With Evolocumab: An Analysis of FOURIER Trial Data
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Terje R. Pedersen, Arman Qamar, Scott M. Wasserman, Christopher E. Kurtz, Sabina A. Murphy, Marc S. Sabatine, Anthony C Keech, Julia F Kuder, Peter S. Sever, and Robert P. Giugliano
- Subjects
medicine.medical_specialty ,education.field_of_study ,business.industry ,PCSK9 ,Brief Report ,Population ,030204 cardiovascular system & hematology ,Placebo ,Gastroenterology ,law.invention ,03 medical and health sciences ,Regimen ,Evolocumab ,0302 clinical medicine ,Randomized controlled trial ,Interquartile range ,law ,Internal medicine ,Cohort ,Medicine ,030212 general & internal medicine ,Cardiology and Cardiovascular Medicine ,business ,education - 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
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- 2018
34. Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy
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Peter S. Sever, Narimon Honarpour, André Scheen, Armando Lira Pineda, Terje R. Pedersen, Marc S. Sabatine, Prakash Deedwania, Robert P. Giugliano, Sabina A. Murphy, Anthony C Keech, and J. Badariene
- Subjects
Male ,medicine.medical_specialty ,Statin ,medicine.drug_class ,Myocardial Infarction ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Myocardial Revascularization ,medicine ,Clinical endpoint ,Humans ,Angina, Unstable ,030212 general & internal medicine ,Myocardial infarction ,National Cholesterol Education Program ,Aged ,Original Investigation ,Metabolic Syndrome ,Unstable angina ,business.industry ,PCSK9 ,PCSK9 Inhibitors ,Cholesterol, LDL ,Middle Aged ,Atherosclerosis ,medicine.disease ,Hospitalization ,Stroke ,Evolocumab ,Cardiovascular Diseases ,Drug Therapy, Combination ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business - Abstract
IMPORTANCE: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. OBJECTIVE: To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS: The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS: Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES: The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P
- Published
- 2021
35. Assessing Optimal Blood Pressure in Patients With Asymptomatic Aortic Valve Stenosis
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Terje R. Pedersen, Ahmad Sajadieh, Anders M. Greve, Y. Antero Kesäniemi, Christoph A. Nienaber, Ronnie Willenheimer, Muhammad Sabbah, Kurt Boman, Olav W. Nielsen, Kristian Wachtell, and Michael H. Olsen
- Subjects
Simvastatin ,medicine.medical_specialty ,hypertension ,Blood Pressure ,aortic valve stenosis ,030204 cardiovascular system & hematology ,Asymptomatic ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Ezetimibe ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,In patient ,030212 general & internal medicine ,Aged ,business.industry ,Anticholesteremic Agents ,blood pressure ,Aortic Valve Stenosis ,Middle Aged ,medicine.disease ,mortality ,Surgery ,Stenosis ,Blood pressure ,Aortic valve stenosis ,Hypertension ,Cardiology ,prognosis ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,aortic valve stenosis blood pressure hypertension mortality prognosis echocardiographic-assessment cardiovascular events hypertension guidelines management outcomes disease trial Cardiovascular System & Cardiology ,Follow-Up Studies ,medicine.drug - Abstract
Background: Evidence for treating hypertension in patients with asymptomatic aortic valve stenosis is scarce. We used data from the SEAS trial (Simvastatin Ezetimibe in Aortic Stenosis) to assess what blood pressure (BP) would be optimal. Methods: A total of 1767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease were analyzed. Outcomes were all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. BP was analyzed in Cox models as the cumulative average of serially measured BP and a time-varying covariate. Results: The incidence of all-cause mortality was highest for average follow-up systolic BP ≥160 mm Hg (4.3 per 100 person-years; 95% confidence interval [CI], 3.1–6.0) and lowest for average systolic BP of 120 to 139 mm Hg (2.0 per 100 person-years; 95% CI, 1.6–2.6). In multivariable analysis, all-cause mortality was associated with average systolic BP P =0.033) and BP of 120 to 129 mm Hg (HR, 1.6; P =0.039). Conclusions: Optimal BP seems to be systolic BP of 130 to 139 mm Hg and diastolic BP of 70 to 90 mm Hg in these patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease or diabetes mellitus. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00092677.
- Published
- 2016
36. Efficacy of Evolocumab on Cardiovascular Outcomes in Patients With Recent Myocardial Infarction
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Narimon Honarpour, Jorge Ferreira, Basil S. Lewis, Anthony C Keech, Terje R. Pedersen, Sabina A. Murphy, Marc S. Sabatine, Christopher E. Kurtz, François Mach, Baris Gencer, Gaetano M. De Ferrari, Huei Wang, Robert P. Giugliano, Kurt Huber, and Peter S. Sever
- Subjects
Male ,medicine.medical_specialty ,Statin ,medicine.drug_class ,Myocardial Infarction ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Ezetimibe ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,030212 general & internal medicine ,Myocardial infarction ,Stroke ,Hypolipidemic Agents ,business.industry ,Unstable angina ,PCSK9 ,Cholesterol, HDL ,Middle Aged ,medicine.disease ,Evolocumab ,Treatment Outcome ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Drug Therapy, Combination ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business ,medicine.drug - Abstract
The 2018 American Heart Association/American College of Cardiology Multisociety Guideline on the Management of Blood Cholesterol identified patients with recent (past 12 months) myocardial infarction (MI) as very high risk, in whom a PCSK9 inhibitor is reasonable to add to maximally tolerated statin combined with ezetimibe if their low-density lipoprotein cholesterol level is 70 mg/dL or greater or non-high-density lipoprotein cholesterol level is 100 mg/dL or greater.To examine the clinical efficacy of evolocumab in patients with recent MI.This was a prespecified secondary analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, in which 27 564 patients with atherosclerotic cardiovascular disease treated with a statin were randomized to evolocumab vs placebo. Patients with prior MI with a known date (n = 22 320) were stratified as having a recent MI (within 12 months of randomization) or a remote MI (more than 12 months prior to randomization). Per protocol, patients with MI within 4 weeks prior to randomization were excluded from the FOURIER trial. Data were collected from February 2013 to November 2016, and data were analyzed from May 2019 to February 2020.The primary composite end point was cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary composite end point was cardiovascular death, MI, or stroke.Of 22 320 included patients, 17 516 (78.5%) were male, and the mean (SD) age was 62.2 (9.0) years. Compared with 16 609 patients with a remote MI, 5711 patients with a recent MI were younger and more likely to be treated with high-intensity statin (77.3% [4415] vs 69.3% [11 506]). In the placebo arm, the 3-year Kaplan-Meier rate for the primary end point was 17.2% in patients with recent MI compared with 14.4% in those with remote MI (adjusted HR, 1.45; 95% CI, 1.29-1.64; P .001). Similarly, the 3-year Kaplan-Meier rates for the key secondary end point was also higher in those with recent MI (10.9% vs 9.5%; adjusted HR, 1.45; 95% CI, 1.24-1.69; P .001). In patients with a recent MI, evolocumab reduced the risk of the primary and key secondary end points by 19% (hazard ratio [HR], 0.81; 95% CI, 0.70-0.93) and 25% (HR, 0.75; 95% CI, 0.62-0.91), respectively. In patients with a remote MI, evolocumab reduced the risk of the primary and key secondary end points by 8% (HR, 0.92; 95% CI, 0.84-1.01; P for interaction = .13) and 15% (HR, 0.85; 95% CI, 0.76-0.96; P for interaction = .24), respectively. Given the higher event rates in patients with a recent MI, the absolute risk reductions over 3 years with evolocumab were 3.7% in those with recent MI vs 1.1% in those with remote MI for the primary end point and 3.2% vs 1.3%, respectively, for the key secondary end point.Patients with a recent MI were at higher risk of cardiovascular events and tended to experience greater absolute risk reductions with evolocumab than those with remote MIs. These findings support the concept in US and European guidelines to aggressively lower low-density lipoprotein cholesterol levels in very high-risk patients, such as those with a recent MI.ClinicalTrials.gov Identifier: NCT01764633.
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- 2020
37. Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction
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David A. Morrow, Sabina A. Murphy, Terje R. Pedersen, Anthony C Keech, Gaetano M. De Ferrari, Danielle M Forni, Marc S. Sabatine, Robert P. Giugliano, Kurt Huber, Narimon Honarpour, Julia F Kuder, Basil S. Lewis, Peter S. Sever, Stephen D. Wiviott, and Christopher E. Kurtz
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Myocardial Infarction ,030204 cardiovascular system & hematology ,Coronary Angiography ,Antibodies, Monoclonal, Humanized ,Placebo ,Severity of Illness Index ,Sudden death ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,Risk Factors ,law ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Myocardial infarction ,Aged ,Original Investigation ,Aged, 80 and over ,biology ,business.industry ,Anticholesteremic Agents ,PCSK9 ,PCSK9 Inhibitors ,Thrombolysis ,Middle Aged ,medicine.disease ,Troponin ,Evolocumab ,Treatment Outcome ,Cardiology ,biology.protein ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
IMPORTANCE: The PCSK9 inhibitor evolocumab reduced major vascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, yet the types and sizes of myocardial outcomes in FOURIER have not been previously explored. OBJECTIVE: To assess the types and sizes of myocardial infarction (MI) and the effect of evolocumab on MI by subtype. DESIGN, SETTING, AND PARTICIPANTS: A prespecified analysis of a multicenter double-blind randomized clinical trial. Patients were randomized to evolocumab or placebo and followed up for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Clinical end points were evaluated by the Thrombolysis in Myocardial Infarction clinical events committee. Rates presented are 3-year Kaplan-Meier estimates. Data were collected from 2013 to 2016 and analyzed from June 2017 to December 2019. MAIN OUTCOMES AND MEASURES: Myocardial infarction was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass, ST-segment elevation myocardial infarction [STEMI] vs non–STEMI) and by MI size (determined by peak troponin level). RESULTS: A total of 27 564 patients were randomized, with a mean (SD) age of 62.5 (9.0) years, and 20 795 (75%) were male. Of these, 1107 patients experienced a total of 1288 MIs. Most MIs (68%) were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention–related (type 4). Sudden death (type 3) and coronary artery bypass grafting–related (type 5) accounted for a total of 21 MIs (
- Published
- 2020
38. PERFORMANCE OF A NOVEL GENETIC RISK SCORE TO IDENTIFY RISK OF VENOUS THROMBOEMBOLISM IN PATIENTS WITH CARDIOMETABOLIC DISEASE
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Patrick T. Ellinor, Carolina Roselli, Christina Ji-Young Lee, Robert F. Storey, Ilaria Cavallari, Frederick K. Kamanu, Terje R. Pedersen, Giorgio E. M. Melloni, Marc Cohen, Eugene Braunwald, Christian T. Ruff, Ofri Mosenzon, Marc P. Bonaca, Deepak L. Bhatt, Robert P. Giugliano, Marc S. Sabatine, Benjamin M. Scirica, Steven A. Lubitz, Yared Gurmu, Anthony C Keech, Itamar Raz, Philippe Gabriel Steg, and Nicholas A Marston
- Subjects
medicine.medical_specialty ,business.industry ,equipment and supplies ,Cardiometabolic disease ,surgical procedures, operative ,Internal medicine ,medicine ,Genetic predisposition ,In patient ,cardiovascular diseases ,Genetic risk ,Cardiology and Cardiovascular Medicine ,business ,Venous thromboembolism ,TIMI - Abstract
Venous thromboembolism (VTE) is the third leading cause of CV mortality and has an established genetic predisposition. We tested the performance of a 10-SNP genetic risk score (GRS) for its ability to predict VTE in 3 TIMI trials. We included patients from the FOURIER, PEGASUS-TIMI 54, and SAVOR
- Published
- 2020
39. Cognitive Function in a Randomized Trial of Evolocumab
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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
40. 5002Benefit of LDL-C lowering with evolocumab on cardiovascular outcomes by age & sex: an analysis of the FOURIER trial
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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
41. Comparison of Low-Density Lipoprotein Cholesterol Assessment by Martin/Hopkins Estimation, Friedewald Estimation, and Preparative Ultracentrifugation: Insights From the FOURIER Trial
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Jose Lopez-Miranda, Richard Ceska, Terje R. Pedersen, Sabina A. Murphy, Borislav Georgiev, Robert P. Giugliano, Peter S. Sever, Anthony C Keech, Matti J. Tikkanen, Marc S. Sabatine, Seth S. Martin, Alberto J. Lorenzatti, Scott M. Wasserman, Evan A. Stein, Amgen Inc, and National Institute for Health Research
- Subjects
Male ,Cardiac & Cardiovascular Systems ,Cholesterol, VLDL ,Statistics as Topic ,030204 cardiovascular system & hematology ,LDL-CHOLESTEROL ,law.invention ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,Interquartile range ,law ,EQUATION ,Medicine ,030212 general & internal medicine ,Randomized Controlled Trials as Topic ,Brief Report ,Anticholesteremic Agents ,Antibodies, Monoclonal ,Middle Aged ,3. Good health ,lipids (amino acids, peptides, and proteins) ,Female ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,medicine.medical_specialty ,Urology ,Low density lipoprotein cholesterol ,Hyperlipidemias ,Placebo ,Preparative ultracentrifugation ,Antibodies, Monoclonal, Humanized ,Risk Assessment ,03 medical and health sciences ,MANAGEMENT ,Humans ,Triglycerides ,Aged ,Science & Technology ,business.industry ,Cholesterol ,PCSK9 ,Cholesterol, HDL ,ADULTS ,Cholesterol, LDL ,Atherosclerosis ,Evolocumab ,chemistry ,Cardiovascular System & Cardiology ,UPDATE ,business ,Ultracentrifugation - Abstract
Importance: Recent studies have shown that Friedewald underestimates low-density lipoprotein cholesterol (LDL-C) at lower levels, which could result in undertreatment of high-risk patients. A novel method (Martin/Hopkins) using a patient-specific conversion factor provides more accurate LDL-C levels. However, this method has not been tested in proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor-treated patients. Objective: To investigate accuracy of 2 different methods for estimating LDL-C levels (Martin/Hopkins and Friedewald) compared with gold standard preparative ultracentrifugation (PUC) in patients with low LDL-C levels in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk (FOURIER) trial. Design, Setting, and Participants: The FOURIER trial was a randomized clinical trial of evolocumab vs placebo added to statin therapy in 27 564 patients with stable atherosclerotic cardiovascular disease. The patients' LDL-C levels were assessed at baseline, 4 weeks, 12 weeks, 24 weeks, and every 24 weeks thereafter, and measured directly by PUC when the level was less than 40 mg/dL per the Friedewald method (calculated as non-HDL-C level - triglycerides/5). In the Martin/Hopkins method, patient-specific ratios of triglycerides to very low-density lipoprotein cholesterol (VLDL-C) ratios were determined and used to estimate VLDL-C, which was subtracted from the non-HDL-C level to obtain the LDL-C level. Main Outcomes and Measures: Low-density lipoprotein cholesterol calculated by the Friedewald and Martin/Hopkins methods, with PUC as the reference method. Results: For this analysis, the mean (SD) age was 62.7 (9.0) years; 2885 of the 12 742 patients were women (22.6%). A total of 56 624 observations from 12 742 patients had Friedewald, Martin/Hopkins, and PUC LDL-C measurements. The median difference from PUC LDL-C levels for Martin/Hopkins LDL-C levels was -2 mg/dL (interquartile range [IQR], -4 to 1 mg/dL) and for Friedewald LDL-C levels was -4 mg/dL (IQR, -8 to -1 mg/dL; P
- Published
- 2018
42. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial
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John J.P. Kastelein, Terje R. Pedersen, Dariush Mozaffarian, Wolfgang Koenig, Darren K. McGuire, Kausik K. Ray, Stephen J. Nicholls, Paul M. Ridker, Torbjörn Lundström, Björn W. Karlson, Michael H. Davidson, A. Michael Lincoff, Philip J. Barter, Steven E. Nissen, Kathy Wolski, Christie M. Ballantyne, Dianna Bash, ACS - Atherosclerosis & ischemic syndromes, Vascular Medicine, and ACS - Pulmonary hypertension & thrombosis
- Subjects
Cardiac & Cardiovascular Systems ,DYSLIPIDEMIA ,Carboxylic Acids ,030204 cardiovascular system & hematology ,Global Health ,NON-HDL CHOLESTEROL ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,Clinical endpoint ,030212 general & internal medicine ,Myocardial infarction ,Omega-3 carboxylic acids ,Stroke ,Randomized Controlled Trials as Topic ,POLYUNSATURATED FATTY-ACIDS ,Hypertriglyceridemia ,omega-3 fatty acids ,Incidence ,General Medicine ,Cardiovascular Diseases ,CORONARY-ARTERY-DISEASE ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,cardiovascular risk ,medicine.medical_specialty ,Statin ,CARDIOVASCULAR RISK REDUCTION ,medicine.drug_class ,Trial Designs ,HEART-DISEASE ,1102 Cardiovascular Medicine And Haematology ,EVENTS ,03 medical and health sciences ,Internal medicine ,Fatty Acids, Omega-3 ,medicine ,Humans ,METAANALYSIS ,Triglycerides ,INTERVENTION TRIAL ,clinical trials ,Science & Technology ,Unstable angina ,Cholesterol ,business.industry ,Cholesterol, HDL ,medicine.disease ,chemistry ,Cardiovascular System & Hematology ,Cardiovascular System & Cardiology ,LDL CHOLESTEROL ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business - Abstract
It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to 4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.
- Published
- 2018
43. Coding variants in
- Author
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Rosa B, Thorolfsdottir, Gardar, Sveinbjornsson, Patrick, Sulem, Jonas B, Nielsen, Stefan, Jonsson, Gisli H, Halldorsson, Pall, Melsted, Erna V, Ivarsdottir, Olafur B, Davidsson, Ragnar P, Kristjansson, Gudmar, Thorleifsson, Anna, Helgadottir, Solveig, Gretarsdottir, Gudmundur, Norddahl, Sridharan, Rajamani, Bjarni, Torfason, Atli S, Valgardsson, Jon T, Sverrisson, Vinicius, Tragante, Oddgeir L, Holmen, Folkert W, Asselbergs, Dan M, Roden, Dawood, Darbar, Terje R, Pedersen, Marc S, Sabatine, Cristen J, Willer, Maja-Lisa, Løchen, Bjarni V, Halldorsson, Ingileif, Jonsdottir, Kristian, Hveem, David O, Arnar, Unnur, Thorsteinsdottir, Daniel F, Gudbjartsson, Hilma, Holm, and Kari, Stefansson
- Abstract
Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in
- Published
- 2018
44. Inflammatory and Cholesterol Risk in the FOURIER Trial
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Terje R. Pedersen, Peter S. Sever, Armando Lira Pineda, Anthony C Keech, Robert P. Giugliano, Lawrence A. Leiter, Subodh Verma, Erin A. Bohula, Huei Wang, Jeong-Gun Park, Narimon Honarpour, Sabina A. Murphy, and Marc S. Sabatine
- Subjects
Male ,Time Factors ,Anti-Inflammatory Agents ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Interquartile range ,Risk Factors ,030212 general & internal medicine ,Aged, 80 and over ,education.field_of_study ,biology ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Absolute risk reduction ,Antibodies, Monoclonal ,Middle Aged ,C-Reactive Protein ,Treatment Outcome ,Cardiovascular Diseases ,Cardiology ,Female ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Population ,Antibodies, Monoclonal, Humanized ,Risk Assessment ,03 medical and health sciences ,Double-Blind Method ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,cardiovascular diseases ,education ,Aged ,Dyslipidemias ,Inflammation ,Unstable angina ,business.industry ,PCSK9 ,C-reactive protein ,Cholesterol, LDL ,medicine.disease ,Evolocumab ,Relative risk ,biology.protein ,business ,Biomarkers - Abstract
Background: In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. It is not known whether the efficacy of evolocumab is modified by baseline inflammatory risk. We explored the efficacy of evolocumab stratified by baseline high-sensitivity C-reactive protein (hsCRP). We also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL-C concentrations. Methods: Patients (n=27 564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). The effects of evolocumab on the primary end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization, and the key secondary end point of cardiovascular death, myocardial infarction, or stroke were compared across strata of baseline hsCRP (3 mg/dL). Outcomes were also assessed across values for baseline hsCRP and 1-month LDL-C in the entire trial population. Multivariable models adjusted for variables associated with hsCRP and 1-month LDL-C were evaluated. Results: A total of 7981 (29%) patients had a baseline hsCRP3 mg/L. Median (interquartile range) baseline hsCRP was 1.8 (0.9–3.6) mg/L and levels were not altered by evolocumab (change at 48 weeks of –0.2 mg/dL [–1.0 to 0.4] in both treatment arms). In the placebo arm, patients in higher baseline hsCRP categories experienced significantly higher 3-year Kaplan-Meier rates of the primary and key secondary end points: 12.0%, 13.7%, and 18.1% for the primary end point ( P trend P trend 3 mg/dL, respectively. The relative risk reductions for the primary end point and key secondary end point with evolocumab were consistent across hsCRP strata ( P -interactions>0.15 for both). In contrast, the absolute risk reductions with evolocumab tended to be greater in patients with higher hsCRP: 1.6%, 1.8%, and 2.6% and 0.8%, 2.0%, and 3.0%, respectively, for the primary and key secondary end points across hsCRP strata. In adjusted analyses of the association between LDL-C and hsCRP levels and cardiovascular risk, both LDL-C and hsCRP were independently associated with the primary outcome ( P Conclusions: LDL-C reduction with evolocumab reduces cardiovascular events across hsCRP strata with greater absolute risk reductions in patients with higher-baseline hsCRP. Event rates were lowest in patients with the lowest hsCRP and LDL-C. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
- Published
- 2018
45. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease: An Analysis from FOURIER
- Author
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Basil S. Lewis, Gaetano M. De Ferrari, Kurt Huber, Terje R. Pedersen, Robert P. Giugliano, Anthony C Keech, Peter S. Sever, Narimon Honarpour, Jorge Ferreira, Stephen D. Wiviott, Christopher E. Kurtz, Julia F Kuder, Sabina A. Murphy, Marc S. Sabatine, and Amgen Inc
- Subjects
Male ,PCSK9 protein, human ,Time Factors ,Cardiac & Cardiovascular Systems ,Cost effectiveness ,PROGRESSION ,Coronary Artery Disease ,SECONDARY PREVENTION ,030204 cardiovascular system & hematology ,Severity of Illness Index ,THERAPY ,COST-EFFECTIVENESS ,PCSK9 ,Coronary artery disease ,0302 clinical medicine ,Recurrence ,Risk Factors ,Cause of Death ,030212 general & internal medicine ,Myocardial infarction ,Aged, 80 and over ,RISK ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Middle Aged ,Hospitalization ,Clinical trial ,Treatment Outcome ,myocardial infarction ,1117 Public Health And Health Services ,Disease Progression ,Cardiology ,Female ,TRIAL ,Proprotein Convertase 9 ,INFARCTION ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,Ticagrelor ,medicine.drug ,Adult ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Antibodies, Monoclonal, Humanized ,Risk Assessment ,1102 Cardiovascular Medicine And Haematology ,LDL ,EVENTS ,03 medical and health sciences ,Double-Blind Method ,Physiology (medical) ,Internal medicine ,cholesterol, LDL ,medicine ,Humans ,PCSK9 protein ,TICAGRELOR ,human ,LDL-C ,Aged ,Science & Technology ,business.industry ,cholesterol ,1103 Clinical Sciences ,Proprotein convertase ,medicine.disease ,Evolocumab ,Peripheral Vascular Disease ,Cardiovascular System & Hematology ,Cardiovascular System & Cardiology ,clinical trial [publication type] ,ATHEROSCLEROTIC CARDIOVASCULAR-DISEASE ,business ,Biomarkers - 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 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.
- Published
- 2018
46. Lipoprotein(A) Predicts Cardiovascular Events In Statin Outcome Trials: Pooled Analysis Of Seven Randomised Controlled Trials
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Terje R. Pedersen, Christoph Wanner, Peter Willeit, Florian Kronenberg, Sotirios Tsimikas, Christiane Drechsler, Paul M. Ridker, Anders G. Olsson, John Simes, Gregory G. Schwartz, Andrew Tonkin, Paul J. Nestel, Helen M. Colhoun, Samia Mora, and A. Lesogor
- Subjects
medicine.medical_specialty ,Statin ,Pooled analysis ,biology ,business.industry ,medicine.drug_class ,Internal medicine ,biology.protein ,Medicine ,Lipoprotein(a) ,Cardiology and Cardiovascular Medicine ,business ,Outcome (game theory) - Published
- 2019
47. Mutations in RPL3L and MYZAP increase risk of atrial fibrillation
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Gudmundur L. Norddahl, Ragnar P. Kristjansson, Marc S. Sabatine, G Sveinbjörnsson, Sridharan Rajamani, Folkert W. Asselbergs, Anna Helgadottir, Ingileif Jonsdottir, Rosa B. Thorolfsdottir, Bjarni V. Halldorsson, Kari Stefansson, Erna V. Ivarsdottir, Atli S Valgardsson, Páll Melsted, David O. Arnar, Terje R. Pedersen, Olafur B. Davidsson, Maja-Lisa Løchen, Tragante, Solveig Gretarsdottir, Bjarni Torfason, Dawood Darbar, G. Thorleifsson, Unnur Thorsteinsdottir, Dan M. Roden, Hilma Holm, Gisli H. Halldorsson, Stefan Jonsson, Jon Thor Sverrisson, Patrick Sulem, and Daniel F. Gudbjartsson
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Genetics ,0303 health sciences ,Mutation ,Atrial fibrillation ,030204 cardiovascular system & hematology ,Ribosomal RNA ,Biology ,medicine.disease_cause ,medicine.disease ,Exon skipping ,Right ventricular cardiomyopathy ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Ribosomal protein ,medicine ,Missense mutation ,splice ,030304 developmental biology - Abstract
We performed a meta-analysis of genome-wide association studies on atrial fibrillation (AF) among 14,710 cases and 373,897 controls from Iceland and 14,792 cases and 393,863 controls from the UK Biobank, focusing on low frequency coding and splice mutations, with follow-up in samples from Norway and the US. We observed associations with two missense (OR=1.19 for both) and one splice-donor mutation (OR=1.52) in RPL3L, encoding a ribosomal protein primarily expressed in skeletal muscle and heart. Analysis of 167 RNA samples from the right atrium revealed that the splice donor mutation in RPL3L results in exon skipping. AF is the first disease associated with RPL3L and RPL3L is the first ribosomal gene implicated in AF. This finding is consistent with tissue specialization of ribosomal function. We also found an association with a missense variant in MYZAP (OR=1.37), encoding a component of the intercalated discs of cardiomyocytes, the organelle harbouring most of the mutated proteins involved in arrhythmogenic right ventricular cardiomyopathy. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
- Published
- 2017
48. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 inhibition in subjects with elevated risk)
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Patrice Nault, Ransi Somaratne, Marc P. Bonaca, Estella Kanevsky, Lale Tokgozoglu, Robert P. Giugliano, Terje R. Pedersen, Peter S. Sever, Armando Lira Pineda, Marc S. Sabatine, J. Wouter Jukema, Anthony C Keech, Julia F Kuder, Sabina A. Murphy, Basil S. Lewis, Amgen Inc, and Kardiyoloji
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PCSK9 protein, human ,medicine.medical_specialty ,Arterial disease ,Disease ,030204 cardiovascular system & hematology ,1102 Cardiovascular Medicine And Haematology ,LDL ,03 medical and health sciences ,0302 clinical medicine ,peripheral arterial disease ,Physiology (medical) ,Internal medicine ,amputation ,cholesterol, LDL ,medicine ,PCSK9 protein ,In patient ,human ,030212 general & internal medicine ,business.industry ,PCSK9 ,cholesterol ,1103 Clinical Sciences ,intermittent claudication ,Proprotein convertase ,Intermittent claudication ,Surgery ,Evolocumab ,evolocumab ,1117 Public Health And Health Services ,Cardiovascular System & Hematology ,Cardiovascular System & Cardiology ,Cardiology ,Kexin ,medicine.symptom ,atherosclerosis ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. Methods: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of Results: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66–0.94; P =0.0098) and without PAD (HR 0.86; 95% CI, 0.80–0.93; P =0.0003; P interaction =0.40). For the key secondary end point, the HRs were 0.73 (0.59–0.91; P =0.0040) for those with PAD and 0.81 (0.73–0.90; P P interaction =0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38–0.88; P =0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events ( P =0.026 for the beta coefficient) that extended down to Conclusions: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
- Published
- 2017
49. Dynamic path analysis - a useful tool to investigate mediation processes in clinical survival trials
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Terje R. Pedersen, Ørnulf Borgan, Odd O. Aalen, Susanne Strohmaier, Rune Hoff, and Kjetil Røysland
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FOS: Computer and information sciences ,Statistics and Probability ,Research design ,Clinical Trials as Topic ,Mediation (statistics) ,Time Factors ,Epidemiology ,Computer science ,Proportional hazards model ,Directed acyclic graph ,Survival Analysis ,Methodology (stat.ME) ,Treatment Outcome ,Research Design ,Data Interpretation, Statistical ,Covariate ,Econometrics ,Humans ,Hazard model ,Computer Simulation ,Path analysis (statistics) ,Statistics - Methodology ,Survival analysis ,Proportional Hazards Models - Abstract
When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention-to-treat principle. Thereby a lot of potentially useful information is lost, as collection of time-to-event data often goes hand in hand with collection of information on biomarkers and other internal time-dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis, a model for mediation analysis in the presence of a time-to-event outcome and time-dependent covariates to investigate direct and indirect effects in a study of different lipid lowering treatments in patients with previous myocardial infarctions. Further, we address the question whether survival in itself may produce associations between the treatment and the mediator in dynamic path analysis and give an argument that, due to linearity of the assumed additive hazard model, this is not the case. We further elaborate on our view that, when studying mediation, we are actually dealing with underlying processes rather than single variables measured only once during the study period. This becomes apparent in results from various models applied to the study of lipid lowering treatments as well as our additionally conducted simulation study, where we clearly observe, that discarding information on repeated measurements can lead to potentially erroneous conclusions.
- Published
- 2015
50. Rosuvastatin-Induced Carotid Plaque Regression in Patients With Inflammatory Joint Diseases: The Rosuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and Other Inflammatory Joint Diseases Study
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Terje R. Pedersen, K.T. Smerud, Eirik Ikdahl, T.K. Kvien, Hilde Berner Hammer, Anne Grete Semb, Ingar Holme, George D. Kitas, Jonny Hisdal, Inge C. Olsen, and Silvia Rollefstad
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medicine.medical_specialty ,education.field_of_study ,Cholesterol ,business.industry ,Immunology ,Population ,Arthritis ,medicine.disease ,Gastroenterology ,Surgery ,chemistry.chemical_compound ,Rosuvastatin Calcium ,Psoriatic arthritis ,Rheumatology ,chemistry ,Interquartile range ,Internal medicine ,Rheumatoid arthritis ,medicine ,Immunology and Allergy ,lipids (amino acids, peptides, and proteins) ,Rosuvastatin ,education ,business ,medicine.drug - Abstract
Objective Patients with rheumatoid arthritis (RA) and carotid artery plaques have an increased risk of acute coronary syndromes. Statin treatment with the goal of achieving a low-density lipoprotein (LDL) cholesterol level of ≤1.8 mmoles/liter (≤70 mg/dl) is recommended for individuals in the general population who have carotid plaques. The aim of the ROsuvastatin in Rheumatoid Arthritis, Ankylosing Spondylitis and other inflammatory joint diseases (RORA-AS) study was to evaluate the effect of 18 months of intensive lipid-lowering treatment with rosuvastatin with regard to change in carotid plaque height. Methods Eighty-six patients (60.5% of whom were female) with carotid plaques and inflammatory joint disease (55 with RA, 21 with AS, and 10 with psoriatic arthritis) were treated with rosuvastatin to obtain the LDL cholesterol goal. Carotid plaque height was evaluated by B-mode ultrasonography. Results The mean ± SD age of the patients was 60.8 ± 8.5 years, and the median compliance with rosuvastatin treatment was 97.9% (interquartile range [IQR] 96.0–99.4). At baseline, the median number and height of the carotid plaques were 1.0 (range 1–8) and 1.80 mm (IQR 1.60–2.10), respectively. The mean ± SD change in carotid plaque height after 18 months of treatment with rosuvastatin was −0.19 ± 0.35 mm (P < 0.0001). The mean ± SD baseline LDL cholesterol level was 4.0 ± 0.9 mmoles/liter (154.7 ± 34.8 mg/dl), and the mean reduction in the LDL cholesterol level was −2.3 mmoles/liter (95% confidence interval [95% CI] −2.48, −2.15) (−88.9 mg/dl [95% CI −95.9, −83.1]). The mean ± SD LDL cholesterol level during the 18 months of rosuvastatin treatment was 1.7 ± 0.4 mmoles/liter (area under the curve). After adjustment for age/sex/blood pressure, no linear relationship between a reduction in carotid plaque height and the level of LDL cholesterol exposure during the study period was observed. Attainment of the LDL cholesterol goal of ≤1.8 mmoles/liter (≤70 mg/dl) or the amount of change in the LDL cholesterol level during the study period did not influence the degree of carotid plaque height reduction. Conclusion Intensive lipid-lowering treatment with rosuvastatin induced atherosclerotic regression and reduced the LDL cholesterol level significantly in patients with inflammatory joint disease.
- Published
- 2015
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