HomeJournal of the American Heart AssociationAhead of PrintImpact of Ezetimibe on New‐Onset Diabetes: A Substudy of IMPROVE‐IT Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessLetterPDF/EPUBImpact of Ezetimibe on New‐Onset Diabetes: A Substudy of IMPROVE‐IT Nishant P. Shah, Darren K. McGuire, Christopher P. Cannon, Robert P. Giugliano, Yuliya Lokhnygina, Courtney B. Page, Andrew M. Tershakovec, Eugene Braunwald and Michael A. Blazing Nishant P. ShahNishant P. Shah *Correspondence to: Nishant P. Shah, MD, Duke Hospital North, 2301 Erwin Road, Suite 7400, Cubicle 13, Durham, NC 27710. Email: E-mail Address: [email protected] https://orcid.org/0000-0002-2666-7132 , Duke University School of Medicine, , Durham, , NC, , USA, , Duke Clinical Research Institute, , NC, , Durham, , USA, , Darren K. McGuireDarren K. McGuire https://orcid.org/0000-0002-6412-7989 , University of Texas Southwestern Medical Center, , Dallas, , TX, , USA, , Parkland Health and Hospital System, , Dallas, , TX, , USA, , Christopher P. CannonChristopher P. Cannon https://orcid.org/0000-0003-4596-2791 , TIMI Study Group, Brigham and Women's Hospital, , Boston, , MA, , USA, , Robert P. GiuglianoRobert P. Giugliano https://orcid.org/0000-0003-4110-7675 , TIMI Study Group, Brigham and Women's Hospital, , Boston, , MA, , USA, , Yuliya LokhnyginaYuliya Lokhnygina , Duke University School of Medicine, , Durham, , NC, , USA, , Duke Clinical Research Institute, , NC, , Durham, , USA, , Courtney B. PageCourtney B. Page https://orcid.org/0000-0001-7671-3355 , Duke Clinical Research Institute, , NC, , Durham, , USA, , Andrew M. TershakovecAndrew M. Tershakovec , Merck & Co., Inc., , Kenilworth, , NJ, , USA, , Eugene BraunwaldEugene Braunwald https://orcid.org/0000-0002-3472-626X , TIMI Study Group, Brigham and Women's Hospital, , Boston, , MA, , USA, and Michael A. BlazingMichael A. Blazing , Duke University School of Medicine, , Durham, , NC, , USA, , Duke Clinical Research Institute, , NC, , Durham, , USA, Originally published22 Jun 2023https://doi.org/10.1161/JAHA.122.029593Journal of the American Heart Association. 2023;0:e029593Statins have been associated with an increased risk for new‐onset diabetes (NOD).1 However, it is unclear if the addition of the nonstatin therapy ezetimibe to a statin would affect the incidence of NOD. We therefore evaluated the risk of NOD with ezetimibe added to simvastatin versus placebo added to simvastatin in IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).2These analyses were carried out in patients without diabetes at baseline (no prior diagnosis of diabetes, no antihyperglycemic medication, and no elevated blood glucose [≥126 mg/dL fasting or ≥200 nonfasting] at randomization). Because glycosylated hemoglobin was not measured systematically during the trial, NOD was defined for the primary analysis as either the initiation of an antihyperglycemic medication or 2 consecutive blood glucose measurements of ≥126 mg/dL and was analyzed as time‐to‐event outcome. Sensitivity analyses using other potential indicators to define NOD were also performed (Table). To account for interval censored data due to medications and blood glucose recorded only at the study visits, parametric Weibull regression univariable and multivariable models were used to determine predictors of NOD.Table 1. Sensitivity Analyses for the Development of New‐Onset Diabetes in IMPROVE‐ITDefinitionSimvastatinSimvastatin/ezetimibeHR (95% CI)P valuePrimary definition of new‐onset diabetes694/4740720/47601.03 (0.93–1.15)0.549Sensitivity analysesS1: Initiation of diabetic medication post randomization547/6084578/60421.06 (0.95–1.21)0.300S2: Two consecutive post. baseline glucose ≥126 mg/dL335/4650348/46751.03 (0.9–1.22)0.655S3: Diabetes‐related AE or SAE defined from clinical review of Medical Dictionary for Regulatory Activities codes501/6141510/61131.03 (0.91–1.17)0.692S4: Diabetes‐related AE/SAE or diabetic medication post randomization671/6084690/60421.02 (0.93–1.13)0.718S5: Diabetes‐related AE/SAE or diabetic medication post randomization or 2 consecutive postbaseline fasting glucose ≥126 mg/dL786/4746804/47631.03 (0.93–1.16)0.530Sensitivity analyses with respective hazard ratios (HRs), 95% CIs, and P values for the simvastatin vs simvastatin/ezetimibe arms of IMPROVE‐IT. AE indicates adverse event; IMPROVE‐IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial; and SAE, serious adverse event.Baseline characteristics included age, sex, self‐identified race, current smoking, hypertension, waist circumference, metabolic syndrome, body mass index, systolic and diastolic blood pressure, total cholesterol, low‐ and high‐density lipoprotein cholesterol, triglycerides, glucose at randomization, use of prior statin, beta blocker, and angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker. Metabolic syndrome at randomization was defined as ≥3 of the criteria defined by the American Heart Association.3 Reported P values are 2‐sided, with <0.05 considered statistically significant. Analyses were completed using SAS version 9.4.The data that support the findings of this study are available from the corresponding author upon reasonable request. Institutional review board approval or informed consent was not needed because this was a prespecified analysis of a clinical trial already conducted and published.Patients were evaluated at 30 days after randomization and then every 4 months, with a minimum 2.5‐year and median 6‐year follow‐up. Of the 18 144 patients enrolled in IMPROVE‐IT, 8644 were excluded due to a history of diabetes (N=5284), or missing data (N=3360), leaving 9500 patients for the study population. After randomization, 1414 patients (14.9%) met criteria for NOD for an annualized incidence of approximately 2.7% per year. For those who developed NOD there were no differences in baseline characteristics between those who received simvastatin/ezetimibe (n=720) and those who received simvastatin/placebo (n=694). Compared with patients who did not develop NOD (n=8086), those with NOD were more likely at baseline to have a higher body mass index (hazard ratio [HR], 1.27 [95% CI, 1.20–1.35]), higher systolic blood pressure (HR, 1.07 [95% CI, 1.00–1.14]), higher triglycerides (HR, 1.33 [95% CI, 1.17–1.53]), and ≥3 components of the metabolic syndrome (HR, 1.36 [95% CI, 1.17–1.61]). There were no major differences in baseline medical therapies or low‐density lipoprotein cholesterol between any of the groups. Compared with the placebo/simvastatin arm, there was no difference in risk of NOD with the addition of ezetimibe to simvastatin (HR, 1.03 [95% CI, 0.93–1.15]). This relationship remained qualitatively consistent across sensitivity analyses using various NOD definitions including the following: initiation of a diabetes medication (HR, 1.06 [95% CI, 0.95–1.21]), 2 glucose measurements ≥126 mg/dL (HR, 1.03 [95% CI, 0.90–1.22]), diabetes‐related adverse event (HR, 1.03 [95% CI, 0.91–1.17]), diabetes‐related adverse event or initiation of diabetes medication (HR, 1.02 [95% CI, 0.93–1.13]), and diabetes‐related adverse event or initiation of diabetes medication or 2 glucose readings ≥126 mg/dL (HR, 1.01 [95% CI, 0.93–1.16]); Table). The addition of ezetimibe did not affect risk of NOD in either statin‐naïve (not on previous statin before trial qualifying event) or statin‐experienced (on previous statin before trial qualifying event) patients (HR, 1.01 [95% CI, 0.89–1.15] versus HR, 1.08 [95% CI, 0.87–1.36], respectively; Pinteraction = 0.50). Furthermore, in an additional sensitivity analysis to assess the risk of NOD based on presence of metabolic syndrome at baseline, the addition of ezetimibe did not affect risk in those with metabolic syndrome or in those without metabolic syndrome (HR, 1.06 [95% CI, 0.94–1.21] versus HR, 0.98 [95% CI, 0.81–1.18], respectively, Pinteraction = 0.46).In this analysis of patients enrolled in IMPROVE‐IT, we found no increase in the risk of NOD with addition of ezetimibe to statin therapy. Our data are consistent and supported by the findings from a recent trial that found a lower risk of NOD with lower dose rosuvastatin and ezetimibe versus higher dose rosuvastatin.4 Similar lack of NOD has been seen with PCSK9 inhibitors.5 Limitations of the present study include not having glycosylated hemoglobin measurements or glucose tolerance tests and use of only simvastatin as the background statin therapy. However, sensitivity analyses were performed for validation, and the results are further strengthened by being obtained in the context of a large randomized clinical trial with 6 years follow‐up. Therefore, given outcomes from IMPROVE‐IT, and absence of any signal that ezetimibe increases risk of NOD, our results support the use and safety of this medication as an adjunct to statins for further low‐density lipoprotein cholesterol lowering, which, combined with recent trials and the PCSK9 inhibitor data, could be important for national guidelines.Sources of FundingThis study was funded by Merck and Co. The sponsor had no role in the development of the analytic plan, data analysis, or data interpretation. No additional external sources of funding was obtained.DisclosuresN.P.S. reports the following research grants: Amgen, Janssen, National Institutes of Health; consultant/advisor: Esperion, Amgen, Norvartis. D.K.M.: honoraria for trial leadership from Boehringer Ingelheim, Sanofi, Merck & Co, Pfizer, AstraZeneca, Novo Nordisk, Esperion, Lilly USA, Lexicon, CSL Behring, and honoraria for consultancy from Lilly USA, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Sanofi, CSL Behring, Bayer, Altimmune, Intercept, and GSK. C.P.C. reports research grants from Amgen, Better Therapeutics, Boehringer‐Ingelheim (BI), Bristol‐Myers Squibb (BMS), Daiichi Sankyo, Merck, Novo Nordisk, Pfizer; consulting fees from Aegerion/Amryt, Alnylam, Amarin, Amgen, Applied Therapeutics, Ascendia, BI, BMS, Eli Lilly, Janssen, Lexicon, Merck, Pfizer, Rhoshan, Sanofi; serves on data and safety monitoring board for Applied Therapeutics and NovoNordisk. R.P.G. reports research grants: Amgen, Anthos Therapeutics: Ionis; consulting fees: Amarin, Amgen, Artivion, Bayer, Boston Scientific, Daiichi Sankyo, Gilead, Inari, Inventiva, Labcorp, Medpace, Paratek, Pfizer, PhaseBio Pharmaceuticals, St. Lukes Hospital System, Samsung, Sanofi Aventis. Y.L.: institutional grant to DCRI from Merck during the conduct of the study and institutional grants to DCRI from Amylin Pharmaceuticals Inc (a wholly owned subsidiary of AstraZeneca). A.M.T. is employed by Merck. E.B.: research support: AstraZeneca, Daiichi Sankyo, Merck, and Novartis; consultancies with Amgen, Cardurion, MyoKardia, Novo Nordisk, and Verve. The remaining authors have no disclosures to report.Footnotes*Correspondence to: Nishant P. Shah, MD, Duke Hospital North, 2301 Erwin Road, Suite 7400, Cubicle 13, Durham, NC 27710. Email: nishant.[email protected]eduThis article was sent to Mahasin S. Mujahid, PhD, MS, FAHA, Associate Editor, for review by expert referees, editorial decision, and final disposition.For Disclosures and Sources of Funding, see page 2.References1 Preiss D. Risk of incident diabetes with intensive‐dose compared with moderate‐dose statin therapy. JAMA. 2011; 305:2556–2564. doi: 10.1001/jama.2011.860CrossrefMedlineGoogle Scholar2 Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015; 372:2387–2397. doi: 10.1056/NEJMoa1410489CrossrefMedlineGoogle Scholar3 Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, Gordon DJ, Krauss RM, Savage PJ, Smith SC, et al. Diagnosis and management of the metabolic syndrome. Circulation. 2005; 112:2735–2752. doi: 10.1161/CIRCULATIONAHA.105.169404LinkGoogle Scholar4 Kim BK, Hong SJ, Lee YJ, Hong SJ, Yun KH, Hong BK, Heo JH, Rha SW, Cho YH, Lee SJ, et al. Long‐term efficacy and safety of moderate‐intensity statin with ezetimibe combination therapy versus high‐intensity statin monotherapy in patients with atherosclerotic cardiovascular disease (RACING): a randomised, open‐label, non‐inferiority trial. Lancet. 2022; 400:380–390. doi: 10.1016/S0140-6736(22)00916-3CrossrefMedlineGoogle Scholar5 Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, Murphy SA, Kuder JF, Gouni‐Berthold I, Lewis BS, et al. 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. Lancet Diabetes Endocrinol. 2017; 5:941–950. doi: 10.1016/S2213-8587(17)30313-3CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails Article InformationMetrics Copyright © 2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley BlackwellThis is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.https://doi.org/10.1161/JAHA.122.029593PMID: 37345760 Originally publishedJune 22, 2023 KeywordsdiabetespreventionlipidsLDL‐CezetimibePDF download SubjectsCardiovascular DiseaseLipids and Cholesterol

HomeCirculationVol. 148, No. 11Why Novel Therapies in Preventive Cardiology May Face a Marathon, Not a Sprint No AccessArticle CommentaryRequest AccessFull TextAboutView Full TextView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessArticle CommentaryRequest AccessFull TextWhy Novel Therapies in Preventive Cardiology May Face a Marathon, Not a Sprint Joanna S. Cavalier, Nishant P. Shah and Michael A. Blazing Joanna S. CavalierJoanna S. Cavalier Correspondence to: Joanna S. Cavalier, MD, Department of Medicine, Duke University School of Medicine, Durham, NC 27710. Email E-mail Address: [email protected] https://orcid.org/0000-0001-5061-6426 Department of Medicine (J.S.C., N.P.S., M.A.B.), Duke University School of Medicine, Durham, NC. , Nishant P. ShahNishant P. Shah https://orcid.org/0000-0002-2666-7132 Department of Medicine (J.S.C., N.P.S., M.A.B.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute (N.P.S., M.A.B.), Duke University School of Medicine, Durham, NC. and Michael A. BlazingMichael A. Blazing Department of Medicine (J.S.C., N.P.S., M.A.B.), Duke University School of Medicine, Durham, NC. Duke Clinical Research Institute (N.P.S., M.A.B.), Duke University School of Medicine, Durham, NC. Originally published11 Sep 2023https://doi.org/10.1161/CIRCULATIONAHA.122.063099Circulation. 2023;148:859–861FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 861.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Joanna S. Cavalier, MD, Department of Medicine, Duke University School of Medicine, Durham, NC 27710. Email joanna.cavalier@duke.eduREFERENCES1. Merrill J. Novartis sees reimbursement advantage for PCSK9 launch.Citeline. PharmaIntelligence. 2019. Accessed July 20, 2023. https://pharmaintelligence.informa.com/resources/product-content/novartis-sees-reimbursement-advantage-for-pcsk9-launch.Google Scholar2. Fang H, Frean M, Sylwestrzak G, Ukert B. Trends in disenrollment and reenrollment within US commercial health insurance plans, 2006-2018.JAMA Netw Open. 2022; 5:e220320. doi: 10.1001/jamanetworkopen.2022.0320CrossrefMedlineGoogle Scholar3. Chiou TT, Tomasi K, Taub PR, Wilkinson MJ. Inclisiran creates unique opportunities and challenges for patient access to therapy: early experience in a United States lipid clinic.J Clin Lipidol. 2023; 17:73–77. doi: 10.1016/j.jacl.2022.10.009CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetails September 12, 2023Vol 148, Issue 11 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.063099PMID: 37695831 Originally publishedSeptember 11, 2023 Keywordsdelivery of health caredrug costshyperlipidemiahypertensionMedicarePDF download Advertisement SubjectsCardiovascular DiseaseCost-EffectivenessEthics and PolicySecondary Prevention

Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content.To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins.This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment.ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG.The primary study outcome was incident myocardial infarction (MI).Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk.In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

The stroma of mature brown fat has been shown to contain cells which can proliferate and accumulate fat in monolayer cultures, and which have inherent characteristics distinct from those of white fat precursor cells. The purpose of the present investigation was to characterize by electron microscopic analysis these brown fat cells and their subsequent development when they were grown in vitro. By comparison with the existing ultrastructural data on brown fat in situ, it could thus be determined whether or not the precursor cells have the capacity to differentiate in culture. The stromal-vascular fraction isolated from the brown fat of weaned rats was identified as containing adipocyte stem cells, preadipocytes, endothelial cells and a few mature adipocytes. During the first week in culture (i.e., growth phase to confluence), when multilocular fat accumulation occurred, the mitochondria of the preadipocytes developed cristae and matrix granules, as they do in differentiating brown fat in situ. Such granules have been shown to be a sign of intense inner membrane synthetic activity. After confluence, the mitochondria regressed in internal structure and became morphologically more similar to white fat mitochondria. It was concluded that mature brown fat contains precursor cells which can differentiate in vitro. However, this differentiation was incomplete, and the necessity of specific factors for a full mitochondrial development in brown fat is discussed.

Importance Studies have demonstrated an association between single measures of high-sensitivity troponin (hsTn) and future cardiovascular events in patients with chronic coronary syndromes. However, limited data exist regarding the association between changes in serial values of hsTn and subsequent cardiovascular events in this patient population. Objective To evaluate the association between changes in high-sensitivity troponin T (hsTnT) and subsequent cardiovascular events in patients stabilized after acute coronary syndrome (ACS). Design, Setting, and Participants This is a secondary analysis from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), a randomized clinical trial of ezetimibe vs placebo on a background of simvastatin in 18 144 patients hospitalized for an ACS across 1147 sites in 39 countries. The current biomarker substudy includes the 6035 participants consenting to the biomarker substudy with available hsTnT at months 1 and 4. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed from February 28, 2021, through August 14, 2022. Main Outcomes and Measures The outcomes of interest were cardiovascular death, myocardial infarction (MI), stroke, or hospitalization for heart failure (HHF). Associations of absolute and relative changes in hsTnT between month 1 and month 4 as a function of the starting month 1 hsTnT and the composite outcome were examined using landmark analyses. Results Of 6035 patients in this analysis (median [IQR] age, 64 [57-71]), 1486 (24.6%) were female; 361 (6.0%) were Asian; 121 were (2.0%) Black; 252 (4.2%) were Spanish descent; 4959 were (82.2%) White; and 342 (5.7%) reported another race (consolidated owing to small numbers), declined to respond, or were not asked to report race owing to regulatory prohibitions. Most patients (4114 [68.2%]) had stable hsTnT values (change <3 ng/L), with 1158 (19.2%) and 763 (12.6%) having changes of 3 to less than 7 ng/L and 7 ng/L or more, respectively. After adjustment for clinical risk factors and stratification by the starting month 1 hsTnT level, an absolute increase in hsTnT of 7 ng/L or more was associated with a more than 3-fold greater risk of the composite outcome (adjusted hazard ratio [aHR], 3.33; 95% CI, 1.99-5.57; P < .001), whereas decreases of 7 ng/L or more were associated with similar to lower risk (aHR, 0.51; 95% CI, 0.26-1.03; P = .06) compared with stable values. There was a stepwise association moving from larger absolute decreases (aHR, 0.51; 95% CI, 0.26-1.03) to larger absolute increases (aHR, 3.33; 95% CI, 1.99-5.57) in hsTnT with future risk of the composite outcome (P trend <.001). A similar association was observed when analyzed on the basis of relative percent and continuous change. Conclusions and Relevance Among stable patients post-ACS, changes in hsTnT were associated with a gradient of risk of subsequent cardiovascular events across the range of starting hsTnT values. Serial assessment of hsTnT may refine risk stratification with the potential to guide therapy decisions in this patient population. Trial Registration ClinicalTrials.gov Identifier: NCT00202878.

Introduction: Ezetimibe (EZE) added to statin further reduces LDL-C and CV events. Prior studies demonstrated large inter-individual variability in LDL-C reduction with statins. Whether similar variability exists with EZE has not been reported in a large study. Methods: We assessed the placebo (PBO)-adjusted LDL-C reduction from randomization to 4 months in IMPROVE-IT, a double-blind RCT of EZE vs placebo (PBO) added to simvastatin (SIMVA) post-ACS. Inter-individual variation in % LDL-C reduction was calculated via rank-ordered subtraction of PBO/SIMVA from EZE/SIMVA. Patients not on study drug or with missing LDL-C values at either timepoint were excluded. Using the overall distribution of PBO-adjusted LDL-C reductions with EZE, we modelled the % of patients anticipated to achieve guideline-recommended LDL-C targets at 4 months with the addition of EZE across a range of baseline LDL-C values. Results: In 14,970 pts, the median baseline LDL-C in both groups was 80 mg/dL (IQR 65-96). The median change from baseline at 4 months was -37% (IQR -20% to -51%) in the EZE/SIMVA arm and -14% (IQR +7% to -31%) with PBO/SIMVA ( Panel A ). The PBO-adjusted median change in LDL-C at 4 months with EZE/SIM was -23% with low variability (IQR -19 to -27%; Panel A) . Based on this distribution, modelling predicts that fewer than half of patients would achieve the U.S. and European targets of <70 and <55 mg/dL when the baseline LDL-C is >91 mg/dL and >72 mg/dL, respectively, with the addition of EZE to statin therapy ( Panel B ). Conclusions: Addition of EZE to statin therapy results in a consistent median 23% reduction in LDL-C, with 75% of patients achieving at least a 19% reduction. The distribution of LDL-C reduction can be used to estimate how likely a patient will be to achieve guideline LDL-C targets with the addition of EZE to statin therapy.

The infection caused by severe acute respiratory syndrome coronavirus-2, or COVID-19, can result in myocardial injury, heart failure, and arrhythmias. In addition to the viral infection itself, investigational therapies for the infection can interact with the cardiovascular system. As cardiologists and cardiovascular service lines will be heavily involved in the care of patients with COVID-19, our division organized an approach to manage these complications, attempting to balance resource utilization and risk to personnel with optimal cardiovascular care. The model presented can provide a framework for other institutions to organize their own approaches and can be adapted to local constraints, resource availability, and emerging knowledge.

Background: Although cholesterol-lowering medications can reduce the risk of recurrent cardiovascular events, premature discontinuation limits effectiveness. Discontinuation rates have not been systematically reported for lipid-lowering trials. Methods and Results: We evaluated medication discontinuation in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which evaluated placebo+simvastatin versus ezetimibe+simvastatin in patients hospitalized with the acute coronary syndrome and followed longitudinally postdischarge. Reasons for discontinuation were evaluated from randomization through study end (median 71.9 [interquartile range 51.8–85.8] months). Kaplan-Meier (KM) discontinuation rates were evaluated at 30 days, 1 year, and through year 7, and compared by treatment arm and region, with Cox proportional hazards modeling used to evaluate predictors of discontinuation. Overall, 46.7% of subjects discontinued study medication (KM rate by study end 50.9% [95% CI, 50.1%–51.7%]). The risk of discontinuation was highest early in the trial but decreased with increasing time, with a terminal KM rate per 100 person-years of 8.4 (8.2–8.6) from years 1 to 7. Discontinuation was higher in the placebo+simvastatin versus ezetimibe+simvastatin arm (KM rate 52.0% versus 49.8%, P =0.049) and was highest in the United States (7-year KM rate 57.4%). In multivariable modeling, smoking, prior revascularization, hypertension, unstable angina, female sex, nonwhite race, and US location were associated with higher discontinuation rates. Conclusions: Although discontinuation was highest early and stabilized to 8% per year, because of prolonged follow-up, most discontinuation occurred after year 1. Adding ezetimibe to statin therapy did not increase discontinuation risk. Geographic differences and patient-level factors should be considered in trial design and analysis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Importance:Limited evidence is available regarding the benefit and hazard of higher-intensity treatment to lower lipid levels among patients 75 years or older. As a result, guideline recommendations differ for this age group compared with younger patients.Objective:To determine the effect on outcomes and risks of combination ezetimibe and simvastatin compared with simvastatin monotherapy to lower lipid levels among patients 75 years or older with stabilized acute coronary syndrome (ACS).Design, Setting, Participants:In this prespecified secondary analysis of the global, multicenter, prospective clinical randomized Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), outcomes and risks were compared by age among patients 50 years or older after a hospitalization for ACS. Data were collected from October 26, 2005, through July 8, 2010, with the database locked October 21, 2014. Data were analyzed May 29, 2015, through March 13, 2018, using Kaplan-Meier curves and Cox proportional hazards models.Interventions:Double-blind randomized assignment to combined simvastatin and ezetimibe or simvastatin and placebo with follow-up for a median of 6 years (interquartile range, 4.3-7.1 years).Main Outcomes and Measures:The primary composite end point consisted of death due to cardiovascular disease, myocardial infarction (MI), stroke, unstable angina requiring hospitalization, and coronary revascularization after 30 days. Individual adverse ischemic and safety end points and lipid variables were also analyzed.Results:Of 18 144 patients enrolled (13 728 men [75.7%]; mean [SD] age, 64.1 [9.8] years), 5173 (28.5%) were 65 to 74 years old, and 2798 (15.4%) were 75 years or older at randomization. Treatment with simvastatin-ezetimibe resulted in lower rates of the primary end point than simvastatin-placebo, including 0.9% for patients younger than 65 years (HR, 0.97; 95% CI, 0.90-1.05) and 0.8% for patients 65 to 74 years of age (hazard ratio [HR], 0.96; 95% CI, 0.87-1.06), with the greatest absolute risk reduction of 8.7% for patients 75 years or older (HR, 0.80; 95% CI, 0.70-0.90) (P = .02 for interaction). The rate of adverse events did not increase with simvastatin-ezetimibe vs simvastatin-placebo among younger or older patients.Conclusions and Relevance:In IMPROVE-IT, patients hospitalized for ACS derived benefit from higher-intensity therapy to lower lipid levels with simvastatin-ezetimibe compared with simvastatin monotherapy, with the greatest absolute risk reduction among patients 75 years or older. Addition of ezetimibe to simvastatin was not associated with any significant increase in safety issues among older patients. These results may have implications for guideline recommendations regarding lowering of lipid levels in the elderly.Trial Registration:ClinicalTrials.gov identifier: NCT00202878.

We consider estimating the effect that discontinuing a beneficial treatment will have on the distribution of a time to event clinical outcome, and in particular assessing whether there is a period of time over which the beneficial effect may continue after discontinuation. There are two major challenges. The first is to make a distinction between mandatory discontinuation, where by necessity treatment has to be terminated and optional discontinuation which is decided by the preference of the patient or physician. The innovation in this article is to cast the intervention in the form of a dynamic regime "terminate treatment optionally at time v unless a mandatory treatment-terminating event occurs prior to v" and consider estimating the distribution of time to event as a function of treatment regime v. The second challenge arises from biases associated with the nonrandom assignment of treatment regimes, because, naturally, optional treatment discontinuation is left to the patient and physician, and so time to discontinuation may depend on the patient's disease status. To address this issue, we develop dynamic-regime Marginal Structural Models and use inverse probability of treatment weighting to estimate the impact of time to treatment discontinuation on a time to event outcome, compared to the effect of not discontinuing treatment. We illustrate our methods using the IMPROVE-IT data on cardiovascular disease.

While the risk of sudden cardiac death (SCD) among acute coronary syndrome (ACS) patients with reduced left ventricular function is substantial, little is known about the long-term incidence and sentinel events (SEs) preceding SCD among stable ACS patients. We studied 18,144 clinically stable (key

Objective The nonalcoholic fatty liver disease fibrosis score (NFS) is comprised of unique metabolic risk indicators that may accurately predict residual cardiovascular (CV) risk in patients with established coronary disease and metabolic dysfunction. Methods We applied the NFS prospectively to 14,819 post-ACS patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), in the IMPROVE-IT trial, using validated NFS cutoffs. The primary endpoint included CV death, myocardial infarction, unstable angina, revascularization or stroke. Outcomes were compared between NFS categories and treatment arms using frequency of events, KM rates and adjusted Cox proportional hazard models. The ability of the NFS to predict recurrent CV events was independently validated in 5395 placebo-treated patients enrolled in the SOLID-TIMI 52 trial. Results Among 14,819 patients enrolled in IMPROVE-IT, 14.2% (N = 2106) were high-risk (NFS > 0.67). The high-risk group had a 30% increased risk of recurrent major CV events, compared to the low-risk NFS group (HR 1.30 [1.19–1.43]; p < 0.001). Among high-risk patients, ezetimibe/simvastatin conferred a 3.7% absolute reduction in risk of recurrent CV events, compared to placebo/simvastatin (HR 0.85 [0.74–0.98]), translating to a number-needed-to-treat of 27. Similar benefit was not found in the low-risk group (HR ezetimibe/simvastatin vs. placebo/simvastatin, 1.01 [0.91–1.12]; p-interaction = 0.053). The relationship between NFS category and recurrent CV events was independently validated in patients enrolled in SOLID-TIMI 52 (HR for NFS > 0.67 vs. NFS < −1.455 = 1.55 [1.32–1.81]; p < 0.001). Conclusion Stratification of cardiovascular risk by NFS identifies an independent population of patients who are at highest risk of recurrent events, and most likely to benefit from dual lipid-lowering therapy.Clinical trials.gov: NCT00202878.

Background: Patients who experience an acute coronary syndrome are at heightened risk of recurrent ischemic events, including stroke. Ezetimibe improved cardiovascular outcomes when added to statin therapy in patients stabilized after acute coronary syndrome. We investigated the efficacy of the addition of ezetimibe to simvastatin for the prevention of stroke and other adverse cardiovascular events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), with a focus on patients with a stroke before randomization. Methods: Patients who experienced acute coronary syndrome were randomized to a placebo/simvastatin or ezetimibe/simvastatin regimen and followed for a median of 6 years. Treatment efficacy was assessed for the entire population and by subgroups for the first and total (first and subsequent) events for the end points of stroke of any etiology, stroke subtypes, and the primary trial end point at 7 years. Results: Of 18 144 patients, 641 (3.5%) experienced at least 1 stroke; most were ischemic (527, 82%). Independent predictors of stroke included prior stroke, older age, atrial fibrillation, congestive heart failure, diabetes mellitus, myocardial infarction, and renal dysfunction. There was a nonsignificant reduction in the first event of stroke of any etiology (4.2% versus 4.8%; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.73–1.00; P =0.052) with ezetimibe/simvastatin versus placebo/simvastatin, driven by a significant 21% reduction in ischemic stroke (3.4% versus 4.1%; HR, 0.79; 95% CI, 0.67–0.94; P =0.008) and a nonsignificant increase in hemorrhagic stroke (0.8% versus 0.6%; HR, 1.38; 95% CI, 0.93–2.04; P =0.11). Evaluating total events, including the first and all recurrent strokes, ezetimibe/simvastatin reduced stroke of any etiology (HR, 0.83; 95% CI, 0.70–0.98; P =0.029) and ischemic stroke (HR, 0.76; 95% CI, 0.63–0.91; P =0.003). Patients who had experienced a stroke prior to randomization were at a higher risk of recurrence and demonstrated an absolute risk reduction of 8.6% for stroke of any etiology (10.2% versus 18.8%; number needed to treat=12; HR, 0.60; 95% CI, 0.38–0.95; P =0.030) and 7.6% for ischemic stroke (8.7% versus 16.3%; number needed to treat=13; HR, 0.52; 95% CI, 0.31–0.86; P =0.011) with ezetimibe added to simvastatin therapy. Conclusions: The addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00202878.

IMPORTANCE In the Improved Reduction of Outcomes: Vytorin Efficacy International Trial, intensive low-density lipoprotein cholesterol (LDL-C)-reducing therapy with ezetimibe/simvastatin compared with simvastatin alone was associated with a significant reduction in cardiovascular events in 18 144 patients after acute coronary syndrome. The safety of very low LDL-C levels over the long-term is unknown.OBJECTIVE To assess the safety and clinical efficacy of achieving a very low (< 30mg/dL) level of LDL-C at 1 month using data from the Improved Reduction of Outcomes: Vytorin Efficacy International Trial.DESIGN, SETTING, AND PARTICIPANTS This prespecified analysis compared outcomes in patients stratified by achieved LDL-C level at 1 month in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial and adjusted for baseline characteristics during 6 years' median follow-up. Patients were enrolled from October 26, 2005, to July 8, 2010, and the data analysis was conducted from December 2014 to February 2017.MAIN OUTCOMES AND MEASURES Safety end points included adverse events leading to drug discontinuation; adverse muscle, hepatobiliary, and neurocognitive events; and hemorrhagic stroke, heart failure, cancer, and noncardiovascular death. Efficacy events were as specified in the overall trial.RESULTS Among the 15 281 patients included in the study, 11 645 (76.2%) were men and the median age was 63 years (interquartile range, 56.6-70.7 years). In these patients without an event in the first month, the achieved LDL-C values at 1 month were less than 30mg/dL, 30 to 49mg/dL, 50 to 69mg/dL, and 70mg/dL or greater in 6.4%, 31%, 36%, and 26% of patients, respectively. Patients with LDL-C values less than 30mg/dL (median, 25mg/dL; interquartile range, 21-27mg/dL) at 1 month were more likely randomized to ezetimibe/simvastatin (85%), had lower baseline LDL-C values, and were more likely older, male, nonwhite, diabetic, overweight, statin naive, and presenting with a firstmyocardial infarction. After multivariate adjustment, there was no significant association between the achieved LDL-C level and any of the 9 prespecified safety events. The adjusted risk of the primary efficacy composite of cardiovascular death, major coronary events, or stroke was significantly lower in patients achieving an LDL-C level less than 30mg/dL at 1 month (adjusted hazard ratio, 0.79; 95% CI, 0.69-0.91; P =.001) compared with 70mg/dL or greater.CONCLUSIONS AND RELEVANCE Patients achieving an LDL-C level less than 30mg/dL at 1 month had a similar safety profile (and numerically the lowest rate of cardiovascular events) over a 6-year period compared with patients achieving higher LDL-C concentrations. These data provide reassurance regarding the longer-term safety and efficacy of the continuation of intensive lipid-lowering therapy in very higher-risk patients resulting in very low LDL-C levels.

BackgroundUnderstanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (ACS). Methods and ResultsIMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized ACS. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/non‐ST‐segment elevation myocardial infarction (UA/NSTEMI) and ST‐segment elevation myocardial infarction (STEMI), in those <65 and ≥65 years old, and males and females, over 7 years of follow‐up. Of 18 131 patients, the presenting event was STEMI for 5190 (29%) and UA/NSTEMI for 12 941 (71%); 10 173 (56%) patients were <65 years old and 7971 (44%) were ≥65 years old at presentation. UA/NSTEMI patients were older than STEMI patients, with more cardiovascular and noncardiovascular risk factors. In STEMI patients, the cumulative incidence of cardiovascular death was higher for ∼4 years following the index event, after which noncardiovascular death predominated. In UA/NSTEMI patients, the cumulative incidence of cardiovascular death remained higher than noncardiovascular death over the full follow‐up period. Patients ≥65 years old and <65 years old had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow‐up. Female patients had a higher incidence of cardiovascular death than noncardiovascular death for ∼6 years following the index event; male patients had a higher incidence of cardiovascular death than noncardiovascular death over the entirety of follow‐up. ConclusionsAmong post‐ACS patients enrolled in a long‐term clinical trial, the relative incidence of cardiovascular and noncardiovascular death differed based on type of ACS presentation and sex, but not age. These findings further delineate long‐term prognosis after ACS and should inform the design of future cardiovascular outcomes trials.

Background: Acute myocardial infarction complicated by systolic dysfunction and/or signs and symptoms of heart failure (HF) is associated with worse outcomes. However, the natural history of patien...

Introduction: Stable patients (pts) with previous acute coronary syndrome (ACS) vary significantly in their risk of recurrent cardiovascular (CV) events. We evaluated the prognostic implications of...

Background— Ezetimibe, when added to simvastatin therapy, reduces cardiovascular events after recent acute coronary syndrome. However, the impact of ezetimibe on cardiovascular-related hospitalizations and associated costs is unknown. Methods and Results— We used patient-level data from the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) to examine the impact of simvastatin–ezetimibe versus simvastatin–placebo on cardiovascular-related hospitalizations and related costs (excluding drug costs) over 7 years follow-up. Medicare Severity–Diagnosis Related Groups were assigned to all cardiovascular hospitalizations. Hospital costs were estimated using Medicare reimbursement rates for 2013. Associated physician costs were estimated as a percentage of hospital costs. The impact of treatment assignment on hospitalization rates and costs was estimated using Poisson and linear regression, respectively. There was a significantly lower cardiovascular hospitalization rate with ezetimibe compared with placebo (risk ratio, 0.95; 95% confidence interval, 0.90–0.99; P=0.031), mainly attributable to fewer hospitalizations for percutaneous coronary intervention, angina, and stroke. Consequently, cardiovascular-related hospitalization costs over 7 years were $453 per patient lower with ezetimibe (95% confidence interval, −$38 to −$869; P=0.030). Although all prespecified subgroups had lower cost with ezetimibe therapy, patients with diabetes mellitus, patients aged ≥75 years, and patients at higher predicted risk for recurrent ischemic events had even greater cost offsets. Conclusions— Addition of ezetimibe to statin therapy in patients with a recent acute coronary syndrome leads to reductions in cardiovascular-related hospitalizations and associated costs, with the greatest cost offsets in high-risk patients. These cost reductions may completely offset the cost of the drug once ezetimibe becomes generic, and may lead to cost savings from the perspective of the healthcare system, if treatment with ezetimibe is targeted to high-risk patients. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00202878