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

BACKGROUND The 2018 U.S. cholesterol management guideline recommends additional lipid-lowering therapy with ezetimibe for secondary prevention in very high-risk patients with low-density lipoprotein cholesterol (LDL-C) $70 mg/dL despite maximally tolerated statin. OBJECTIVES The purpose of this study was to evaluate the relationship between baseline LDL-C above and below 70 mg/dL and the benefit of adding ezetimibe to statin in patients post-acute coronary syndrome (ACS). METHODS IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a double-blind, placebo-controlled, randomized trial of ezetimibe/simvastatin vs placebo/simvastatin in post-ACS patients followed for 6 years (median). A total of 17,999 patients were stratified by LDL-C at qualifying event into 3 groups (50-<70, 70-<100, and 100-125 mg/dL). The primary endpoint was a composite of cardiovascular death, major coronary events, or stroke. RESULTS Absolute differences in median LDL-C achieved at 4 months between treatment arms were similar (17-20 mg/dL). The effect of ezetimibe/simvastatin vs placebo/simvastatin on primary endpoint was consistent regardless of baseline LDL-C of 50-<70 mg/dL (HR: 0.92 [95% CI: 0.80-1.05]), 70-<100 mg/dL (HR: 0.93 [95% CI: 0.87-1.01]), or 100-125 mg/dL (HR: 0.94 [95% CI: 0.86-1.03]; P interaction = 0.95). Normalized relative risk reductions per 1-mmol/L difference in achieved LDL-C at 4 months between treatment arms were 21% in patients with baseline LDL-C of 50-<70 mg/dL, 16% in those with 70-<100 mg/dL, and 13% in those with 100-125 mg/dL (P interaction = 0.91). No significant treatment interactions by baseline LDL-C were present for safety endpoints. CONCLUSIONS Adding ezetimibe to statin consistently reduced the risk for cardiovascular events in post-ACS patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C <70 mg/dL. (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878) (C) 2021 by the American College of Cardiology Foundation.

Objectives: Subjects in a Phase 2b study of MK-7264, a P2X3 antagonist, were evaluated to characterize the baseline profile and potential cough triggers of patients with refractory chronic cough (1). Methods: In a double-blind, parallel group study (NCT02612610) conducted in the US and UK, subjects with refractory or unexplained chronic cough (duration ≥1 year) were randomized to placebo or MK-7264. Randomized subjects completed a medical history questionnaire at baseline in which they reported their frequency of triggers eliciting cough (i.e., ‘Always,’ ‘Most of the Time,’ ‘A Lot of the Time,’ ‘Some of the Time,’ ‘Little of the Time,’ or ‘Never’). Results: In the 253 subjects who were randomized, mean age was 60 years, 76% of subjects were female, mean BMI was 27.7 kg/m2, and median duration of cough was 11 years. Of 252 subjects who completed the questionnaire, items/triggers eliciting ‘Always’ to ‘A Lot of the Time’ responses included: ‘My cough is unpredictable’ (79%), ‘A tickle in my throat’ (73%), and ‘An irritation in my throat’ (73%), followed by external triggers of ‘Poor air quality’ (50%) and ‘A change in air temperature’ (43%). Only 4-5% of subjects reported ‘Never’ for throat tickle or irritation. Conclusions: Refractory chronic cough subjects in this trial were mostly female, on average middle/older age, and slightly overweight. Overall, cough triggers were characterized as unpredictable, although a high proportion of patients reported triggers consistent with a neuronal hypersensitivity. Reference: (1) Smith JA et al. American Thoracic Society 2017.

We read with interest the recent publication by MORICE et al. [1] “The effect of gefapixant, a P2X3 antagonist, on cough reflex sensitivity: a randomised placebo-controlled study” and the accompanying editorial by TURNER and BIRRING [2] “Chronic cough: ATP, afferent pathways and hypersensitivity”. The authors of both publications conclude the results are suggestive of two separate neuronal pathways mediating the cough reflex; however, there are significant issues with this interpretation of the data.

BACKGROUND An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. OBJECTIVES The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). METHODS Within IMPROVE-IT, 17,708 patients post-acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took $1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. RESULTS In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). CONCLUSIONS Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (C) 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

We thank J.A. Smith and co-workers for their interest in our paper [1]. Perhaps an even more ancient truth, that of William of Occam [2], should be applied to this discussion. The human cough reflex has separate, distinct pathways http://bit.ly/2PZgybq

Low-density lipoprotein cholesterol (LDL-C) has been identified as a causative factor for atherosclerosis and related coronary heart disease, and as the main target for cholesterol- and lipid-lowering therapy. Statin drugs inhibit cholesterol synthesis in the liver and are typically the first line of therapy to lower elevated levels of LDL-C. On the other hand, a different drug, Ezetimibe, inhibits the absorption of cholesterol by the small intestine and provides a different mechanism of action. Many clinical trials have been carried out on safety and efficacy evaluation of cholesterol lowering drugs. To synthesize the results from different clinical trials, we examine treatment level (aggregate) network meta-data from 29 double-blind, randomized, active, or placebo-controlled statins +/$-$ Ezetimibe clinical trials on adult treatment-naïve patients with primary hypercholesterolemia. In this article, we propose a new approach to carry out Bayesian inference for arm-based network meta-regression. Specifically, we develop a new strategy of grouping the variances of random effects, in which we first formulate possible sets of the groups of the treatments based on their clinical mechanisms of action and then use Bayesian model comparison criteria to select the best set of groups. The proposed approach is especially useful when some treatment arms are involved in only a single trial. In addition, a Markov chain Monte Carlo sampling algorithm is developed to carry out the posterior computations. In particular, the correlation matrix is generated from its full conditional distribution via partial correlations. The proposed methodology is further applied to analyze the network meta-data from 29 trials with 11 treatment arms.

Purpose: Quantitative benefit-risk (B-R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the average patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real-world data to further personalize the treatment profiles. Methods: Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models. Trial hazard ratios, relative to placebo, were applied to baseline risk estimates to compute expected attributable risks, summed to derive a per-patient net clinical benefit (NCB). High risk subgroups were defined a priori, and Gaussian mixture models (GMM) were fit to characterize the NCB distribution and identify subgroups with similar NCBs. Results: NCB was consistently positive for all subgroups, likely due to the outcome correlation, and would remain positive with a 12-fold increase in bleeding risk. GMMs identified three distinct NCB subgroups. Compared with the middle/lower NCB subgroups, those with a higher NCB tended to be older, female, and have higher CV disease burden. Conclusions: Personalized B-R assessments are feasible and clinically valuable and can be used to better predict who would benefit most from therapy.

We evaluated the effect of gefapixant on cough reflex sensitivity to evoked tussive challenge. In this phase 2, double-blind, two-period study, patients with chronic cough (CC) and healthy volunteers (HV) were randomised to single-dose gefapixant 100 mg or placebo in a crossover fashion. Sequential inhalational challenges with ATP, citric acid, capsaicin and distilled water were performed 1, 3 and 5 h after dosing. Mean concentrations evoking >= 2 coughs (C2) and >= 5 coughs (C5) post dose versus baseline were co-primary endpoints. Objective cough frequency (coughs.h(-1)) over 24 h and a cough severity visual analogue scale (VAS) were assessed in CC patients. Adverse events were monitored. 24 CC patients and 12 HV were randomised (mean age 61 and 38 years, respectively). The cough challenge threshold increased for ATP by 4.7-fold (C2, p <= 0.001) and 3.7-fold (C5, p= 0.007) for gefapixant versus placebo in CC patients; in HV, C2 and C5 increased 2.4-fold (C2, p= 0.113; C5, p= 0.003). The distilled water C2 and C5 thresholds increased significantly (p<0.001) by a factor of 1.4 and 1.3, respectively, in CC patients. Gefapixant had no effect on capsaicin or citric acid challenge. Median cough frequency was reduced by 42% and the least squares mean cough severity VAS was 18.0 mm lower for gefapixant versus placebo in CC patients. Dysgeusia was the most frequent adverse event (75% of HV and 67% of CC patients). ATP-evoked cough was significantly inhibited by gefapixant 100 mg, demonstrating peripheral target engagement. Cough count and severity were reduced in CC patients. Distilled water may also evoke cough through a purinergic pathway.

BACKGROUND: Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. OBJECTIVE: To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. METHODS: This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. RESULTS: Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29-0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P<.01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: -5.0 and -12.0, -2.0 and -5.4, and -1.5 and -12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: -5.0 and -19.9 and -2.0 and -7.3) in second-line studies. CONCLUSION: Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements. (C) 2019 Published by Elsevier Inc. on behalf of National Lipid Association.

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.

Background Polyvascular disease and type 2 diabetes are each associated with increased cardiovascular risk, but whether these risks are additive is unknown. In this exploratory analysis of a randomised trial, we explored the long-term cardiovascular risk associated with polyvascular disease, type 2 diabetes, and their combination in patients with acute coronary syndrome, and assessed the effect of ezetimibe given on top of statin therapy in patients with these concomitant conditions. Methods IMPROVE-IT was a multicentre, double-blind, randomised, placebo-controlled trial assessing the effect of ezetimibe added to statin therapy after acute coronary syndrome. Recruitment was from Oct 26, 2005, to July 8, 2010, and the trial was done at 1158 sites in 39 countries. 18 144 patients aged 50 years and older who had been stabilised after an acute coronary syndrome were randomly assigned to 40 mg per day simvastatin plus either 10 mg per day ezetimibe or matched placebo, for a median duration of 6 years. In this post-hoc exploratory analysis, we assessed the prespecified endpoints of the trial, including the primary composite endpoint (cardiovascular death, a major coronary event [non-fatal myocardial infarction, documented unstable angina requiring hospital admission, or coronary revascularisation occurring at least 30 days after randomisation], or stroke [ischaemic or haemorrhagic]) by concomitant polyvascular disease at baseline (peripheral artery disease or previous stroke or transient ischaemic attack) and stratified by concomitant type 2 diabetes. Efficacy analyses were done according to intention to treat and event rates. IMPROVE-IT is registered with ClinicalTrials.gov, number NCT00202878. Findings 1005 patients (6%) had peripheral artery disease and 1071 (6%) had stroke or transient ischaemic attack at baseline. Of these, 388 (39%) and 409 (38%) also had concomitant type 2 diabetes, respectively. At 7 years, patients with either polyvascular disease or type 2 diabetes had similar rates of the primary endpoint (39.8% and 39.9%, respectively), which were higher than patients without polyvascular disease or diabetes (29.6%). Polyvascular disease with concomitant type 2 diabetes was associated with further heightened risk (60.0% 7-year Kaplan-Meier rate, adjusted hazard ratio versus those with polyvascular disease 1.60, 95% CI 1.38-1.85; p<0.0001). Ezetimibe reduced cardiovascular risk consistently across groups with greater numerical absolute risk reductions in the highest-risk subgroups. Interpretation In patients with coronary artery disease, concomitant polyvascular disease or type 2 diabetes are associated with increased long-term cardiovascular risk. The combination of polyvascular disease and diabetes is additive, resulting in very high risk. The benefit of ezetimibe is consistent in patients with and without polyvascular disease and type 2 diabetes; however, by nature of their higher risk patients with one, or especially both, of these diseases might derive the greatest absolute benefits. Copyright (c) 2018 Elsevier Ltd. All rights reserved.

The natural history of patients hospitalized for acute coronary syndrome (ACS) with pre-existing versus (vs) de novo heart failure (HF) has not been previously reported over an extended duration of follow-up. The IMPROVE-IT trial enrolled 18,144 patients hospitalized for ACS and randomized them to combination simvastatin (40 mg)/ezetimibe (10 mg) vs simvastatin (40 mg). Subjects were divided into 3 groups: pre-existing HF (i.e., defined by past medical history), de novo HF (i.e., defined by Killip class II or greater during index admission), and no HF. The final analytical cohort included 14,792 patients (82%) with HF status recorded at baseline. In total, 790 patients (5.3%) reported a pre-existing diagnosis of HF and 1374 patients (9.3%) experienced de novo HF. Patients with pre-existing or de novo HF were older, more likely to be woman, and had a greater prevalence of atrial fibrillation and diabetes mellitus. The incidences of death/HF-hospitalizations at 5 years were 32%/20% for pre-existing HF, 18%/7% for de novo HF, and 8%/3% for no HF. After adjusting for potential confounders, a history of pre-existing or de novo HF was independently associated with increased risk of death (pre-existing HF: hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.68 to 2.22, p < 0.001; de novo HF: HR 1.51, 95% CI 1.33 to 1.72, p < 0.001) and hospitalizations for HF (pre-existing HF: HR 2.96, 95% CI 2.36 to 3.71, p < 0.001; de novo HF: HR 1.88, 95% CI 1.49 to 2.38, p < 0.001). There was no interaction among baseline HF status (i.e., pre-existing or de novo), lipid lowering therapy (i.e., simvastatin/ezetimibe vs simvastatin alone), and clinical outcomes. In conclusion, patients hospitalized for ACS with pre-existing or de novo HF were older and had a greater burden of medical co-morbidities. In conclusion, HF was independently associated with increased risk of long-term morbidity and mortality with the pre-existing HF cohort demonstrating the highest overall risk.

Objectives: We evaluated demographic and baseline characteristics associated with efficacy response with MK-7264, a P2X3 antagonist, in refractory chronic cough patients. Methods: Patients with chronic cough (duration of ≥1 year) refractory to treatment enrolled in a double-blind, parallel group study (NCT02612610) conducted in the US and UK and were randomized to placebo or MK-7264 (7.5 mg BID, 20 mg BID, or 50 mg BID). Awake Cough Frequency (ACF; coughs/hr) after 12 weeks was the primary endpoint; treatment effect was evaluated using a mixed model repeated measures analysis of log-transformed change from baseline adjusting for log-transformed baseline cough count, duration of cough, country, age, sex, visit, and treatment-by-visit interaction. Results: 253 patients (mean age 60 years; 76% female) were randomized. Adjusted to placebo, ACF was significantly reduced by MK-7264 50 mg (p=0.0027) (1); we observed a statistically significant country effect with a larger reduction in ACF in the US vs. the UK. Demographic and baseline cough characteristics between the two countries were comparable. Conclusions: This analysis suggests consistent treatment effect with MK-7264 across a range of factors (e.g. baseline cough count, duration of cough, age, sex, visit, and treatment-by-visit interaction), though some difference in response by region was observed. Further assessment across a broader range of subjects and regions would be informative. Reference: (1) Smith JA et al. American Thoracic Society 2017.

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.

Introduction: Elevated remnant-lipoprotein cholesterol (RLP-C, cholesterol mass in VLDL and IDL) increases cardiovascular disease (CVD) risk, particularly for patients with residual risk on lipid-lowering therapy (LLT). RLP-C assessment methods are not standardized and include measurement by immunoseparation (IM) and vertical auto profile ultracentrifugation (VAP [IDL+VLDL3]) or calculation (total cholesterol – HDL-C – LDL-C). This study assessed the effects of Eze, Eze + statins and statin monotherapy on RLP-C measured by these 3 methods in 1st line (statin naive/wash-out) and 2nd line (ongoing statin/uptitration) studies. Methods: RLP-C change and percent change from baseline were evaluated using pooled data from randomized 1st line (Eze vs placebo, Eze+statinsξ vs statinsξ) and 2nd line (Eze+statin‖ vs double statin¶ dose) studies. RLP-C was measured by all 3 methods for 1st line studies; VAP and calculated methods for 2nd line studies. Relationships between baseline covariates (lipids, hsCRP, age, gen...