LDLc and residual risk reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with acute vs. chronic coronary syndrome not candidates for PCSK9 inhibitors treatment

LDLc and residual risk reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with acute vs. chronic coronary syndrome not candidates for PCSK9 inhibitors treatment | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article LDLc and residual risk reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with acute vs. chronic coronary syndrome not candidates for PCSK9 inhibitors treatment Alberto Cordero, David Escribano, M. Amparo Quintanilla, M. Dolores Masiá, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1491516/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Most patients with coronary heart disease (CHD) might be candidates for statin plus ezetimibe combination to achieve low-density lipoprotein cholesterol (LDLc) <55 mg/dl. Fixed-dose combinations increase adherence but there is less evidence on for rosuvastatin plus ezetimibe in patients with CHD. Methods: Retrospective analysis of patients with CHD that received fixed-dose combination with rosuvastatin-ezetimibe between January 2019 and March 2020 in a single center. Inclusion criteria were: patients initiating this treatment and LDLc 100 mg/dl without previous lipid-lowering treatments. Results: We included 208 patients, 55 (26.44%) acute coronary (ACS) patients. Most chronic coronary syndrome (CCS) patients (90.04%), but just 27.27% of the ACS patients, were on statins. Mean LDLc before treatment was 102.48 (29.78) mg/dl and it was higher in patients with ACS (p<0.001). Median time to second blood test was 203 days and mean on-treatment LDLc was 57.76 (20.23) mg/dl: ACS 53.45 (22.15) vs. CCS 59.65 (19.12) mg/dl (p=0.073). Mean LDLc reduction was 41.00% and it was higher in was higher in ACS patients (49.35% vs. 37.36%; p<0.003). LDLc <55 mg/dl was achieved in 65.31% ACS patients vs. 41.96% CCS patients (p=0.006). ACS patients had significant reductions in triglycerides/HDL ratio and C-reactive protein; all patients had reductions in cholesterol remnants and residual lipid risk. Reductions of C-reactive protein correlated to LDLc reductions. Conclusions: Fixed-dose combination with rosuvastatin-ezetimibe in patients with CHD, not candidates for PCSK9 inhibitors, is effective for LDLc reduction especially in patients with ACS, and improves residual lipid risk. Rosuvastatin Ezetimibe LDLc Acute coronary syndrome Chronic coronary syndrome Figures Figure 1 Figure 2 Introduction Low-density lipoprotein cholesterol (LDLc) control in patients with coronary heart disease (CHD) remains a clinical challenge 1 , 2 and most real-world registries have highlighted the poor treatment targets achievement and the underutilization of lipid-lowering therapies 3 – 6 . Fixed-dose drug combinations are widely used and have strong recommendations for the treatment of other relevant cardiovascular risk factors, such as hypertension or diabetes 7 . Nonetheless, lipid-lowering drug combinations and, especially, fixed-doses combinations are not commonly used for LDLc treatment 5 , 6 , 8 , 9 . According to current European Society of Cardiology and European Association of Atherosclerosis (ESC/EAS) guidelines statin plus ezetimibe combination has a recommendation class I, level of evidence B, for LDLc reduction 2 . Since current treatment target for patients with coronary heart disease (CHD) is LDLc < 55 mg/dl 1, 2 most patients might need lipid-lowering drugs combinations 10 and fixed-dose combinations are known to increase adherence and efficacy 11 . Current conditions for PCSK9 inhibitors treatment reimbursement patients with CHD in Spain 12 , as well as most other countries and recommendations 10 , are restricted to those with LDL > 100 mg/dl, under maximal dose tolerated of statins. Thereafter, patients with chronic coronary syndrome (CCS) and LDLc between 55 and 99 mg/dl or admitted for a first acute coronary syndrome (ACS) that are not taking statins, are not initially candidates to PCSK9 treatment. Rosuvastatin and ezetimibe are available as generic in Europe and fixed-dose combinations are being commercialized since 2018 and there is scarce evidence of their efficacy on real-world clinical practice apart from clinical trials 13 , 14 . The aim of our study was evaluating the efficacy of LDLc reduction and treatment target achievement in patients with CHD treated with a fixed-dose combination of rosuvastatin plus ezetimibe. Methods Study design This is an investigator-initiated retrospective analysis of patients with coronary heart disease that received fixed-dose combination with rosuvastatin-ezetimibe between March 2019 and June 2020. Patients were selected from the an out-patient specialized unit for patients discharged after an ACS or CCS 4 . Patients were classified in 2 groups according to the time when the treatment was initiated: at the time of hospital discharge after an ACS or in any of the follow-up visits in the outpatient clinics, who were categorized as CCS. A total of 212 patients were identified and 4 patients did not have a second blood test available; thereafter, 208 were included. We excluded patients that would be candidate for PCSK9 treatment. Current indications for treatment reimbursement in Spain are 3: patients with familial hypercholesterolemia without cardiovascular disease but LDLc > 100 mg/dl, patients with cardiovascular disease but LDLc > 100 mg/dl despite maximum tolerated lipid-lowering treatment and, statin intolerant patients with LDLc > 100 mg/dl 12 . Thereafter, the inclusion criteria for our study were: CCS and LDLc 100 mg/dl without previous lipid-lowering treatments. We collected the results of the last biochemical determination before initiating the fixed-dose combination as well as the first one being on-treatment. All venous blood samples were obtained after an overnight fasting into dipotassium ethylenediaminetetraacetic acid (dipotassium EDTA) test tubes for CBC test. The Sysmex-XE 2000i (Sysmex, Kobe, Japan) automatic blood cell analyzer were used for analyzes. Biochemical tests, total cholesterol, triglycerides, high density lipoprotein (HDLc), measurements were carried out via standard laboratory procedures with the Roche Cobas C501 (Germany) with spectrophotometric methods. LDLc was estimated by the Friedewald equation. Variables Lipid residual risk was assessed as follows: 1) the estimation of LDL particle size, by the triglycerides/HDLc ratio and values < 2 were assumed as low and dense LDL particles 2 , 15 ; 2) cholesterol remnants was estimated by the equation: total cholesterol minus LDLc minus HDLc and values ≥ 30 were considered high 16 ; 3) total cholesterol/HDLc and values > 3 were considered high 17 ; 4) the triglycerides-to-glucose index, obtained as the natural logarithm of (triglycerides*glucose/2) 18 . Non-HDL cholesterol, obtained was total cholesterol minus HDLc 2 . Cardiovascular risk factors, clinical characteristics and medical treatments were collected in all patients. Before-treatment and on-treatment LDLc were registered, as well as main biochemical determinations. According to their equivalencies, intensive statin treatment was considered atorvastatin 40–80 mg/day or rosuvastatin 20–40 mg/day 1, 2 .For the antecedent of previous coronary heart disease patients needed to have a clinical diagnosis of myocardial infarction, stable or unstable angina or angina-driven coronary revascularization. Glomerular filtration rate was estimated from serum creatinine values with the CKD-EPI Eq. 1 9 . Previous heart failure was codified if patients had at least one hospitalization with such main diagnosis at discharge-medical report as well as those with typical signs and symptoms of heart failure that had a compatible imagine diagnosis (X-ray or echocardiogram). The ethics committee of the hospital approved the study protocol and informed consent. Overall estimation of comorbidities was assessed by the Charlson index, adapted for patients with CHD 20 . Statistical analyses Quantitative variables with normal distribution are presented as mean (SD) and differences were assessed by ANOVA one-way test; in contrast, quantitative variables with non-normal distribution are presented as median and interquartile range (IQR) and differences were analyzed by Kruskal-Wallis test. Absolute and relative differences between biochemical determinations were calculated. Qualitative variables are presented as percentage and differences were assessed by Chi 2 and t-student test. We tested the possible presence of interactions between LDLc reduction and type of CHD but no significant results were observed. Correlation between continuous variables was assessed by linear regression. Statistical difference was accepted at p < 0.05. All analyses were performed using STATA 14.3 (StataCorp. 2009. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). Results As shown in Table 1 , a quarter of the cohort corresponded to ACS patients. Median time since the onset of CHD in patients CCS was 48 months (interquartile range 36.0–60.0). No relevant differences in clinical characteristics were observed in ACS vs. CCS patients. All CCS patients but 3 (90.04%) were on statins before initiating fixed-dose statin plus ezetimibe; in contrast, roughly one quarter of the ACS patients were receiving any statin before admission. Mean LDLc before treatment was 102.48 (29.78) mg/dl and it was higher in patients with ACS (p < 0.001). Table 1 Clinical features of the cohort at baseline. Total ACS CCS p N 208 55 (26.44%) 153 (73.56%) Age 62.19 (12.64) 60.44 (12.50) 63.80 (12.62) 0.091 Women 21.84% 18.18% 23.18% 0.443 BMI 27.92 (3.57) 28.26 (4.08) 27.76 (27.00) 0.502 Hypertension 54.81% 45.45% 58.17% 0.104 Dyslipidemia 60.10% 52.73% 62.75% 0.193 Current smoker 32.85% 46.30% 28.10% 0.014 Diabetes 22.12% 21.82% 22.22% 0.512 Heart failure 3.37% 1.82% 3.92% 0.458 Previous stroke 6.73% 9.09% 5.88% 0.415 Atrial fibrillation 3.85% 3.64% 3.92% 0.925 Peripheral arterial disease 7.21% 1.01% 9.80% 0.016 COPD 5.29% 3.64% 5.88% 0.523 GFR < 60 ml/min/1.72m 2 80.16 (24.43) 86.26 (29.44) 77.92 (22.01) 0.030 GFR 4 18.36% 14.81% 19.61% 0.434 Previous statin 56.73% 27.27% 90.04% < 0.01 Previous ezetimibe 11.06% 12.73% 10.46% 0.645 Total cholesterol (mg/dl) 176.97 (37.30) 188.36 (48.98) 172.85 (31.24) 0.008 LDLc (mg/dl) 102.48 (29.79) 117.83 (38.19) 96.99 (24.00) < 0.01 HDLc (mg/dl) 47.80 (22.29) 45.73 (36.56) 48.55 (14.05) 0.423 triglycerides (mg/dl) 145.51 (88.92) 164.65 (127.59) 138.59 (69.16) 0.062 C-reactive protein 0.84 (2.00) 1.97 (3.04) 0.32 (0.90) < 0.001 AST (U/ml) 28.93 (26.85) 50.55 (41.02) 20.97 (11.80) < 0.001 ALT (U/ml) 28.70 (24.69) 40.49 (37.70) 24.00 (14.74) < 0.001 Creatinine (mg/dl) 1.03 (0.56) 0.95 (0.26) 1.07 (0.63) 0.127 GFR (ml/min/1.72m 2 ) 80.16 (24.43) 86.26 (29.44) 77.92 (22.01) 0.030 Fasting glucose (mg/dl) 114.0 (41.78) 119.04 (46.24) 112.17 (40.06) 0.230 Hemoglobin (g/dl) 14.55 (1.59) 14.52 (1.77) 14.57 (1.53) 0.795 ALT: Alanine transaminase; AST: Aspartate transaminase; COPD: chronic obstructive pulmonary disease; GFR: glomerular filtration rate; HDLc: high-density lipoprotein cholesterol; LDLc: low-density lipoprotein cholesterol; BMI: Body mass index. Median time to second blood test was 203 days (IQR 122–300); mean post-treatment LDLc was 57.76 (20.23) mg/dl and no difference (p = 0.073) was found in patients with ACS vs CCS: 53.45 (22.15) vs 59.65 (19.12) mg/dl. As shown in Table 2 , significant reductions in LDLc, total cholesterol and triglycerides were observed in all patients. Mean LDLc reduction was 41.0% and it was higher in was higher in ACS patients (49.35% vs. 37.36%; p < 0.003). No interaction was observed between LDLc reduction and the type of CHD (p = 0.842) and Fig. 1 shows that LDLc reductions were proportionated in ACS and CCS. LDLc < 55 mg/dl was achieved in 49.07% of the patients and more frequently in ACS patients: 65.31% vs. 41.96% (p = 0.006). According to lipid-residual risk, only ACS patients had significant decrease in the triglycerides-to-HDL ratio translated into significantly lower percentage of patients with such ratio > 2. Both group of patients experienced reduction in the cholesterol-to-HDL ratio, cholesterol remnants and glucose-triglycerides index. Table 2 Biochemical determinations before and during fixed-dose combination rosuvastatin plus ezetimibe in patients with acute coronary syndromes (ACS) or chronic coronary syndrome (CCS). ACS CCS Before On-treatment p Before On-treatment p Total cholesterol (mg/dl) 188.36 (48.98) 122.42 (30.21) < 0.001 172.85 (31.24) 131.38 (26.78) < 0.001 LDLc (mg/dl) 117.83 (38.19) 53.49 (22.15) < 0.001 96.99 (24.00) 59.65 (19.12) < 0.001 HDLc (mg/dl) 45.73 (36.56) 44.53 (9.16) 0.824 48.55 (14.04) 47.27 (10.45) 0.419 Triglycerides (mg/dl) 164.65 (127.59) 124.34 (84.82) 0.006 138.59 (69.16) 120.09 (64.74) 0.028 Non-HDL cholesterol (mg/ml) 142.64 (56.32) 78.20 (28.90) < 0.001 124.30 (30.74) 84.11 (25.33) < 0.001 Fasting glucose (mg/dl) 119.04 (46.24) 136.04 (59.32) < 0.451 112.17 (40.06) 111.13 (36.17) 0.829 C-reactive protein (mg/ml) 1.97 (3.04) 0.15 (0.37) < 0.001 0.26 (58) 0.25 (0.85) 0.927 AST (U/ml) 50.55 (41.02) 25.65 (20.00) < 0.001 20.97 (11.80) 23.19 (11.24) 0.142 ALT (U/ml) 40.49 (37.70) 34.19 (36.21) 0.422 24.00 (14.74) 25.32 (15.93) 0.530 Triglycerides/HDL (mg/ml) 4.35 (4.06) 2.94 (1.98) 0.030 3.19 (2.13) 2.86 (2.34) 0.234 Triglycerides/HDL (mg/ml) > 2 83.64% 69.39% 0.030 71.71% 69.39% 0.630 Cholesterol/HDL (mg/ml) 4.71 (1.64) 2.82 (0.74) < 0.001 3.78 (1.08) 2.89 (0.82) < 0.001 Cholesterol remnants (mg/ml) 29.28 (14.63) 24.39 (13.48) 0.044 28.09 (14.72) 24.19 (13.61) 0.029 Triglycerides/Glucose index 8.95 (0.68) 8.68 (0.63) 0.039 8.82 (0.578) 8.66 (0.57) 0.020 ALT: Alanine transaminase; AST: Aspartate transaminase; HDLc: high-density lipoprotein cholesterol; LDLc: low-density lipoprotein cholesterol. Interestingly, only ACS patients experienced significant reductions in C-reactive protein. As shown in Fig. 2, C-reactive protein reductions correlated to LDLc reductions (B = 0.21; p = 0.016) and no significant interaction with the type of CHD was observed (p = 0.189). ACS patients also had significant reductions in aspartate transaminase. No significant changes in aspartate transaminase were observed. Discussion This retrospective study of patients with chronic and acute coronary syndrome demonstrated the efficacy of the fixed-dose combination rosuvastatin plus ezetimibe in LDLc reduction and achievement of LDLc < 55 mg/dl, especially in patients with ACS. The effect of statin plus ezetimibe was also translated into lower percentage of small and dense LDL particles in ACS patients and lower atherogenic indexes and cholesterol remnants. Lipid-lowering therapies combination, especially in the setting of ACS, are highly encouraged in the 2019 ESC/EAS guidelines 2 and our results clearly support it. The fixed-dose combination statin plus ezetimibe might be an excellent treatment for CHD patients that are not, at least initially under current recommendations, candidates for PCSK9 and our results demonstrate the high percentage of patients that achieve LDLc < 55 m/dl, especially when initiated at the time of hospital discharge from an ACS. As clinical features and LDLc values are similar to previous reports 3 – 6 , 8 , 9 , 13 , 14 , 21 , 22 we believe that these results might be representative and applicable to daily clinical practice. Intensive LDLc reduction, particularly with lipid-lowering combination, has demonstrated to be the most in efficient therapy to reduce LDLc and cardiovascular events 1 , 2 , 10 . The 2019 ESC/EAS guidelines introduced to key issues for patients with CHD: 1) the treatment target of LDLc 50% reduction and; 2) the recommendation of intensive and fast LDLc reduction for patients discharged after an ACS. The pivotal study that demonstrated the efficacy of ezetimibe was precisely performed in the setting of ACS, the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) 23 trial, and provided the first evidence of the benefit of such on-treatment low LDLc levels. Subsequently, an analysis of the SWEDEHEART registry with > 40.000 patients verified the beneficial impact of the guidelines recommendations 21 . Mid-term adherence to high-intensity statins after an acute myocardial infarction is quite low 24 , 25 but rosuvastatin might the best tolerated high-intensity statin 2 , 10 . Moreover, the addition of ezetimibe increases the efficacy on LDLc reduction and might not increase side effects or withdrawals 23 . More interestingly, the combination of statin plus ezetimibe has demonstrated to be the most efficient strategy for plaque volume reduction, assessed by coronary intravascular ultrasound 26 . Our study demonstrates that ACS patients receiving the fixed-dose combination of rosuvastatin plus ezetimibe had higher LDLc reduction and two thirds achieved the treatment target of LDLc < 55 mg/dl. The higher LDLc reductions observed in ACS patients might be explained by the higher rate of patients not receiving statins. Adding ezetimibe is more effective than increasing the dose of statins 2 and our results provide reliable evidence related to the fixed-dose combination rosuvastatin plus ezetimibe in real-world setting. In fact, mean LDLc values in our cohort were much lower than baseline LDLc levels in the GRAVITY (GRAVITY: Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY) 13 trial, a fase IIIb trial designed to assess the effect of rosuvastatin plus ezetimibe on LDLc and several biomarkers. Fixed-dose combinations are widely used for the treatment of diabetes o hypertension 7 but, in contrast, are rarely used for the treatment of LDLc. Fixed-dose combinations are known to increase adherence 10 , 11 and for the case of lipid-lowering drugs this might be closely related to LDLc reductions and treatment target achievement. Relative LDLc reduction with any lipid-lowering therapy is not attenuated in patients starting with lower baseline LDLc levels 27 , 28 and, thereafter, intensive LDLc-lowering therapies should be applied in all high or very high cardiovascular risk patients. Moreover, rosuvastatin and ezetimibe are already available as generic and, therefore, are much more affordable for patients and systems of care 29 . Our results clearly remark the short-term efficacy of the fixed-dose combination rosuvastatin plus ezetimibe on LDLc reduction with as well as the excellent tolerability. Beyond the efficacy of LDLc reduction, results also demonstrate the effect of the fixed-dose combination rosuvastatin plus ezetimibe on LDL particle characteristics and C-reactive protein in ACS patients. Both statins and ezetimibe reduce in LDLc but our results also suggest significant effects on LDL particles. Small and dense LDL particles are the leading effectors of atherosclerosis 30 . LDL particles size and functional characterization is expensive and takes time, but its estimation by the triglycerides-to-HDL ratio has demonstrated a fair correlation and, also, has a good predictive capacity 15 . Similarly, reductions in total cholesterol-to-HDL ratio and the triglyceride-glucose index were observed in ACS and CCS reflecting qualitative improvements in lipid profile and insulin resistance, beyond LDLc reductions. Non-HDL cholesterol was proposed as the most reliable lipid parameter for cardiovascular risk estimation in the 2021 guidelines on Prevention of the European Society of Cardiology 31 . Similarly, cholesterol remnants have been identified as on the most powerful predictors of cardiovascular events in high-risk patients 16 . Thereafter, we believe that our results suppor tthe beneficial effect of intensive lipid-lowering strategies beyond LDLc reduction levels. Similarly, ACS patients had higher baseline C-reactive protein and just after 3 months values decreased to a comparable range of CCS patients. A subanalysis of the PROVE IT–TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22) trial demonstrated that C-reactive protein decreased in all ACS patients but reductions were higher in patients that received a high-intensity statin, atorvastatin, compared to those receiving pravastatin, a classified as intermediate intensity statin 32 . These results were also observed in the above-mentioned GRAVITY 13 trial. C-reactive protein reduction is not a recommended treatment goal although it is a positive finding since lower on-treatment levels are associated to lower mortality rates 32 . Our study has some limitations that should be addressed. Firstly, as all observational studies there are some inherent limitations such as the lack of randomization and unmeasured variables than could induce confusion. Second, this is not a randomized trial comparing 2 alternative treatment. Third, there are other fixed-dose combinations, such as atorvastatin plus ezetimibe, that were not analyzed. Fourth, treatment adherence to lipid-lowering drugs was self-reported by the patients and we cannot assure that all patients used them correctly. Finally, we only assessed short-term efficacy on LDLc reduction and outcomes although this could be performed prospectively. As LDLc reductions and clinical features and were similar to previous reports 3 – 6 , 8 , 9 , 13 , 14 , 21 , 22 we believe that our results might be representative of daily clinical practice. Conclusions The fixed-dose combination with rosuvastatin-ezetimibe in patients with CHD, not candidates for PCSK9 inhibitors, reduced LDLc by 41%. Reduction was higher in ACS patients because most of them were naïve on lipid-lowering therapies. LDLc reductions correlated to reductions in C-reactive protein levels. Fixed-dose combination of rosuvastatin plus ezetimibe was associated, also, to improvements LDL particles, cholesterol remnants and surrogate markers of lipid residual risk. Declarations Funding This study received the support of the National Network for Biomedical Cardiovascular Research of Cardiovascular Disease (CIBERCV, Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares). Conflict of interest Alberto Cordero reports a) honoraria for lectures from AstraZeneca, AMGEN, Bristol-Myers Squibb, Ferrer, Boehringer Ingelheim, MSD, Daichy Sankio and Novartis; b) consulting fees from AstraZeneca, Ferrer and AMGEN. Dr. Vicente Bertomeu-González reports a) honoraria for lectures from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Pfizer-BMS, LivaNova, Ferrer, Cardiome, MSD; b) consulting fees none; c) research grants from Medtronic Iberica. 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Efficacy of high-dose atorvastatin or rosuvastatin loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials with GRADE qualification of available evidence. European Journal of Clinical Pharmacology 2022; 78: 111–126. DOI: 10.1007/s00228-021-03196-9 . Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387–2397. DOI: 10.1056/NEJMoa1410489 . Colantonio LD, Huang L, Monda KL, et al. Adherence to High-Intensity Statins Following a Myocardial Infarction Hospitalization Among Medicare BeneficiariesHigh-Intensity Statin Use After Myocardial InfarctionHigh-Intensity Statin Use After Myocardial Infarction. JAMA Cardiology 2017; 2: 890–895. DOI: 10.1001/jamacardio.2017.0911 . Guedeney P, Claessen BE, Baber U, et al. Temporal Trends in Statin Prescriptions and Residual Cholesterol Risk in Patients With Stable Coronary Artery Disease Undergoing Percutaneous Coronary Intervention. The American Journal of Cardiology 2019; 123: 1788–1795. DOI: https://doi.org/10.1016/j.amjcard.2019.03.005 . Catapano AL, Farnier M, Foody JM, et al. Combination therapy in dyslipidemia: where are we now? Atherosclerosis 2014; 237: 319–335. DOI: 10.1016/j.atherosclerosis.2014.09.026 . Marcusa DP, Giugliano RP, Park J-G, et al. Association of Baseline Low-Density Lipoprotein Cholesterol and Percentage Low-Density Lipoprotein Cholesterol Reduction With Statins, Ezetimibe, and PCSK9 Inhibition. JAMA Cardiology 2021; 6: 582–586. DOI: 10.1001/jamacardio.2020.6184 . The Lancet Diabetes & Endocrinology 2020; 8: 36–49. DOI: 10.1016/S2213-8587(19)30388-2. Salami JA, Warraich H, Valero-Elizondo J, et al. National Trends in Statin Use and Expenditures in the US Adult Population From 2002 to 2013: Insights From the Medical Expenditure Panel Survey. JAMA Cardiology 2017; 2: 56–65. DOI: 10.1001/jamacardio.2016.4700 . Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38: 2459–2472. DOI: 10.1093/eurheartj/ehx144 . Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: Developed by the Task Force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies With the special contribution of the European Association of Preventive Cardiology (EAPC). European Heart Journal 2021; 42: 3227–3337. DOI: 10.1093/eurheartj/ehab484 . Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005; 352: 20–28. 2005/01/07. DOI: 10.1056/NEJMoa042378. Additional Declarations No competing interests reported. Supplementary Files Centralillustration.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1491516","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":97010526,"identity":"35606f73-4ada-4147-b608-97c14833677f","order_by":0,"name":"Alberto Cordero","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYLACHiBmbwASH4CYjZ1YLTwHGBgbZ4C0MJOipRnEYCCkhb/98LEPbyruyfGw9z5/bPNrmzwfMwPjh485uLVInElLnjnnTLExD89xw+bcvtuGbcwMzJIzt+Gx5gaPMTNvW0Lifok0xubcntuMQC1szLx4tMiDtfxLSOwBabHsuW1PUIsBWEsDVAvDj9uJBLUYAv3COOdYAtAvxxhn9jbcTm5jZmzG6xe544cPM7ypSQCGWBvDhx9/btvOb28++OEjPu+jAMY2MNlArHoQ+EOK4lEwCkbBKBgpAAAeAEvKIqSOHQAAAABJRU5ErkJggg==","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Cordero","suffix":""},{"id":97010531,"identity":"6bb5b379-a2dc-4c64-a7d1-029976e6a4b0","order_by":1,"name":"David Escribano","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Escribano","suffix":""},{"id":97010533,"identity":"76b2c909-139a-4b89-aef4-b76811859052","order_by":2,"name":"M. Amparo Quintanilla","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"M.","middleName":"Amparo","lastName":"Quintanilla","suffix":""},{"id":97010538,"identity":"edc491e5-794b-454f-aa9d-8b48c78f8e3b","order_by":3,"name":"M. Dolores Masiá","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"M.","middleName":"Dolores","lastName":"Masiá","suffix":""},{"id":97010542,"identity":"f5c9d728-fb70-4392-b5fd-577c2d4da4c7","order_by":4,"name":"Marta Monteagudo","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Monteagudo","suffix":""},{"id":97010547,"identity":"8f886cfb-2f87-4962-803b-1cc34049bdae","order_by":5,"name":"Jose Moreno-Arribas","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jose","middleName":"","lastName":"Moreno-Arribas","suffix":""},{"id":97010552,"identity":"097a8bd4-cf5e-4c74-96c6-b090511f8179","order_by":6,"name":"Jose M Lopez-Ayala","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jose","middleName":"M","lastName":"Lopez-Ayala","suffix":""},{"id":97010554,"identity":"a80d53dc-bcd5-4066-9f94-25baf6587087","order_by":7,"name":"Pilar Zuazola","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pilar","middleName":"","lastName":"Zuazola","suffix":""},{"id":97010556,"identity":"8d74c20c-1fac-43e3-a734-16895e0a0e6a","order_by":8,"name":"Vicente Bertomeu-Gonzalez","email":"","orcid":"","institution":"Hospital Universitario de San Juan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vicente","middleName":"","lastName":"Bertomeu-Gonzalez","suffix":""}],"badges":[],"createdAt":"2022-03-26 08:14:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1491516/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1491516/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":20243510,"identity":"5a1db12f-8c1a-4b8f-ac18-317c0ca1d793","added_by":"auto","created_at":"2022-04-12 13:51:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":667567,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between baseline and on-treatment low-density lipoprotein cholesterol (LDLc) in patients with acute coronary syndrome (ACS) and chronic coronary syndrome (CCS).\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1491516/v1/91d9cde3d8e201ad92fe160f.jpg"},{"id":20243509,"identity":"8fecd204-1111-4adf-b854-724f26a06ff2","added_by":"auto","created_at":"2022-04-12 13:51:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":527018,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between low-density lipoprotein cholesterol (LDLc) reductions and C-reactive protein reductions.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1491516/v1/095441557cb31bf89359cad8.jpg"},{"id":20243644,"identity":"2cf4e1bb-9a8b-4868-9d41-bc0a97721209","added_by":"auto","created_at":"2022-04-12 13:56:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":443643,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1491516/v1/b14b3ee8-99f9-4e9b-845b-79d68dfb0f18.pdf"},{"id":20243511,"identity":"483d949a-0aaf-40b3-964b-12cca2e50b9c","added_by":"auto","created_at":"2022-04-12 13:51:02","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":378386,"visible":true,"origin":"","legend":"","description":"","filename":"Centralillustration.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1491516/v1/f1c7eec3d32390b88c5338c5.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"LDLc and residual risk reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with acute vs. chronic coronary syndrome not candidates for PCSK9 inhibitors treatment","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLow-density lipoprotein cholesterol (LDLc) control in patients with coronary heart disease (CHD) remains a clinical challenge\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and most real-world registries have highlighted the poor treatment targets achievement and the underutilization of lipid-lowering therapies\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Fixed-dose drug combinations are widely used and have strong recommendations for the treatment of other relevant cardiovascular risk factors, such as hypertension or diabetes\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Nonetheless, lipid-lowering drug combinations and, especially, fixed-doses combinations are not commonly used for LDLc treatment\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. According to current European Society of Cardiology and European Association of Atherosclerosis (ESC/EAS) guidelines statin plus ezetimibe combination has a recommendation class I, level of evidence B, for LDLc reduction\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Since current treatment target for patients with coronary heart disease (CHD) is LDLc\u0026thinsp;\u0026lt;\u0026thinsp;55 mg/dl\u003csup\u003e1, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e most patients might need lipid-lowering drugs combinations\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e and fixed-dose combinations are known to increase adherence and efficacy\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Current conditions for PCSK9 inhibitors treatment reimbursement patients with CHD in Spain\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, as well as most other countries and recommendations\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, are restricted to those with LDL\u0026thinsp;\u0026gt;\u0026thinsp;100 mg/dl, under maximal dose tolerated of statins. Thereafter, patients with chronic coronary syndrome (CCS) and LDLc between 55 and 99 mg/dl or admitted for a first acute coronary syndrome (ACS) that are not taking statins, are not initially candidates to PCSK9 treatment.\u003c/p\u003e \u003cp\u003eRosuvastatin and ezetimibe are available as generic in Europe and fixed-dose combinations are being commercialized since 2018 and there is scarce evidence of their efficacy on real-world clinical practice apart from clinical trials\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. The aim of our study was evaluating the efficacy of LDLc reduction and treatment target achievement in patients with CHD treated with a fixed-dose combination of rosuvastatin plus ezetimibe.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis is an investigator-initiated retrospective analysis of patients with coronary heart disease that received fixed-dose combination with rosuvastatin-ezetimibe between March 2019 and June 2020. Patients were selected from the an out-patient specialized unit for patients discharged after an ACS or CCS\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Patients were classified in 2 groups according to the time when the treatment was initiated: at the time of hospital discharge after an ACS or in any of the follow-up visits in the outpatient clinics, who were categorized as CCS. A total of 212 patients were identified and 4 patients did not have a second blood test available; thereafter, 208 were included.\u003c/p\u003e \u003cp\u003eWe excluded patients that would be candidate for PCSK9 treatment. Current indications for treatment reimbursement in Spain are 3: patients with familial hypercholesterolemia without cardiovascular disease but LDLc\u0026thinsp;\u0026gt;\u0026thinsp;100 mg/dl, patients with cardiovascular disease but LDLc\u0026thinsp;\u0026gt;\u0026thinsp;100 mg/dl despite maximum tolerated lipid-lowering treatment and, statin intolerant patients with LDLc\u0026thinsp;\u0026gt;\u0026thinsp;100 mg/dl\u003csup\u003e12\u003c/sup\u003e. Thereafter, the inclusion criteria for our study were: CCS and LDLc\u0026thinsp;\u0026lt;\u0026thinsp;100 mg/dl despite statin treatment or ACS\u0026thinsp;\u0026gt;\u0026thinsp;100 mg/dl without previous lipid-lowering treatments.\u003c/p\u003e \u003cp\u003eWe collected the results of the last biochemical determination before initiating the fixed-dose combination as well as the first one being on-treatment. All venous blood samples were obtained after an overnight fasting into dipotassium ethylenediaminetetraacetic acid (dipotassium EDTA) test tubes for CBC test. The Sysmex-XE 2000i (Sysmex, Kobe, Japan) automatic blood cell analyzer were used for analyzes. Biochemical tests, total cholesterol, triglycerides, high density lipoprotein (HDLc), measurements were carried out via standard laboratory procedures with the Roche Cobas C501 (Germany) with spectrophotometric methods. LDLc was estimated by the Friedewald equation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eVariables\u003c/h2\u003e \u003cp\u003eLipid residual risk was assessed as follows: 1) the estimation of LDL particle size, by the triglycerides/HDLc ratio and values\u0026thinsp;\u0026lt;\u0026thinsp;2 were assumed as low and dense LDL particles\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e; 2) cholesterol remnants was estimated by the equation: total cholesterol minus LDLc minus HDLc and values\u0026thinsp;\u0026ge;\u0026thinsp;30 were considered high\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e; 3) total cholesterol/HDLc and values\u0026thinsp;\u0026gt;\u0026thinsp;3 were considered high\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e; 4) the triglycerides-to-glucose index, obtained as the natural logarithm of (triglycerides*glucose/2)\u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eNon-HDL cholesterol, obtained was total cholesterol minus HDLc\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Cardiovascular risk factors, clinical characteristics and medical treatments were collected in all patients. Before-treatment and on-treatment LDLc were registered, as well as main biochemical determinations. According to their equivalencies, intensive statin treatment was considered atorvastatin 40\u0026ndash;80 mg/day or rosuvastatin 20\u0026ndash;40 mg/day\u003csup\u003e1, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.For the antecedent of previous coronary heart disease patients needed to have a clinical diagnosis of myocardial infarction, stable or unstable angina or angina-driven coronary revascularization. Glomerular filtration rate was estimated from serum creatinine values with the CKD-EPI Eq.\u0026nbsp;1\u003csup\u003e9\u003c/sup\u003e. Previous heart failure was codified if patients had at least one hospitalization with such main diagnosis at discharge-medical report as well as those with typical signs and symptoms of heart failure that had a compatible imagine diagnosis (X-ray or echocardiogram). The ethics committee of the hospital approved the study protocol and informed consent. Overall estimation of comorbidities was assessed by the Charlson index, adapted for patients with CHD\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eQuantitative variables with normal distribution are presented as mean (SD) and differences were assessed by ANOVA one-way test; in contrast, quantitative variables with non-normal distribution are presented as median and interquartile range (IQR) and differences were analyzed by Kruskal-Wallis test. Absolute and relative differences between biochemical determinations were calculated. Qualitative variables are presented as percentage and differences were assessed by Chi\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and t-student test. We tested the possible presence of interactions between LDLc reduction and type of CHD but no significant results were observed. Correlation between continuous variables was assessed by linear regression. Statistical difference was accepted at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. All analyses were performed using STATA 14.3 (StataCorp. 2009. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAs shown in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, a quarter of the cohort corresponded to ACS patients. Median time since the onset of CHD in patients CCS was 48 months (interquartile range 36.0\u0026ndash;60.0). No relevant differences in clinical characteristics were observed in ACS vs. CCS patients. All CCS patients but 3 (90.04%) were on statins before initiating fixed-dose statin plus ezetimibe; in contrast, roughly one quarter of the ACS patients were receiving any statin before admission. Mean LDLc before treatment was 102.48 (29.78) mg/dl and it was higher in patients with ACS (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of the cohort at baseline.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eACS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCCS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55 (26.44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e153 (73.56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.19 (12.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60.44 (12.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63.80 (12.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWomen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.84%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18.18%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.18%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.443\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.92 (3.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28.26 (4.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27.76 (27.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.502\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e54.81%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45.45%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e58.17%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.104\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyslipidemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.73%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62.75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurrent smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.85%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46.30%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28.10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22.12%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21.82%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e22.22%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.512\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.37%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.82%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.92%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.458\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious stroke\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.73%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.09%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.88%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.415\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fibrillation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.85%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.64%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.92%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.925\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeripheral arterial disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.21%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.01%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.80%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.016\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCOPD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.29%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.64%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.88%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.523\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.72m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.16 (24.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86.26 (29.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77.92 (22.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR\u0026thinsp;\u0026lt;\u0026thinsp;60 ml/min/1.72m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.10%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.55%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.67%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.714\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.08 (2.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.91 (1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.14 (2.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.522\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharlson index\u0026thinsp;\u0026gt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.36%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.81%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.61%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.434\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious statin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56.73%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27.27%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e90.04%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious ezetimibe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.06%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.73%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.46%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.645\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e176.97 (37.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e188.36 (48.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e172.85 (31.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDLc (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e102.48 (29.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e117.83 (38.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e96.99 (24.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDLc (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47.80 (22.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e45.73 (36.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48.55 (14.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003etriglycerides (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e145.51 (88.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e164.65 (127.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e138.59 (69.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.84 (2.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.97 (3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.32 (0.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.93 (26.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50.55 (41.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.97 (11.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28.70 (24.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.49 (37.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24.00 (14.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCreatinine (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.03 (0.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.95 (0.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.07 (0.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGFR (ml/min/1.72m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80.16 (24.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86.26 (29.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77.92 (22.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting glucose (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114.0 (41.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e119.04 (46.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e112.17 (40.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.230\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.55 (1.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14.52 (1.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.57 (1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.795\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eALT: Alanine transaminase; AST: Aspartate transaminase; COPD: chronic obstructive pulmonary disease; GFR: glomerular filtration rate; HDLc: high-density lipoprotein cholesterol; LDLc: low-density lipoprotein cholesterol; BMI: Body mass index.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMedian time to second blood test was 203 days (IQR 122\u0026ndash;300); mean post-treatment LDLc was 57.76 (20.23) mg/dl and no difference (p\u0026thinsp;=\u0026thinsp;0.073) was found in patients with ACS vs CCS: 53.45 (22.15) vs 59.65 (19.12) mg/dl. As shown in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, significant reductions in LDLc, total cholesterol and triglycerides were observed in all patients. Mean LDLc reduction was 41.0% and it was higher in was higher in ACS patients (49.35% vs. 37.36%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.003). No interaction was observed between LDLc reduction and the type of CHD (p\u0026thinsp;=\u0026thinsp;0.842) and Fig.\u0026nbsp;1 shows that LDLc reductions were proportionated in ACS and CCS. LDLc\u0026thinsp;\u0026lt;\u0026thinsp;55 mg/dl was achieved in 49.07% of the patients and more frequently in ACS patients: 65.31% vs. 41.96% (p\u0026thinsp;=\u0026thinsp;0.006). According to lipid-residual risk, only ACS patients had significant decrease in the triglycerides-to-HDL ratio translated into significantly lower percentage of patients with such ratio\u0026thinsp;\u0026gt;\u0026thinsp;2. Both group of patients experienced reduction in the cholesterol-to-HDL ratio, cholesterol remnants and glucose-triglycerides index.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBiochemical determinations before and during fixed-dose combination rosuvastatin plus ezetimibe in patients with acute coronary syndromes (ACS) or chronic coronary syndrome (CCS).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eACS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eCCS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eBefore\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eOn-treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eBefore\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eOn-treatment\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal cholesterol (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e188.36 (48.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e122.42 (30.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e172.85 (31.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e131.38 (26.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLDLc (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117.83 (38.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.49 (22.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96.99 (24.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e59.65 (19.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHDLc (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.73 (36.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44.53 (9.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e48.55 (14.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47.27 (10.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e164.65 (127.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124.34 (84.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e138.59 (69.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e120.09 (64.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-HDL cholesterol (mg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e142.64 (56.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78.20 (28.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e124.30 (30.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e84.11 (25.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting glucose (mg/dl)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119.04 (46.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e136.04 (59.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.451\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e112.17 (40.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e111.13 (36.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.829\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein (mg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.97 (3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.15 (0.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.26 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.25 (0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.927\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAST (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.55 (41.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.65 (20.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20.97 (11.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23.19 (11.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.142\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (U/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.49 (37.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.19 (36.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.422\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24.00 (14.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.32 (15.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.530\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides/HDL (mg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.35 (4.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.94 (1.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.19 (2.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.86 (2.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.234\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides/HDL (mg/ml)\u0026thinsp;\u0026gt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83.64%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69.39%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71.71%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e69.39%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCholesterol/HDL (mg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.71 (1.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.82 (0.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.78 (1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.89 (0.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCholesterol remnants (mg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.28 (14.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.39 (13.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.09 (14.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e24.19 (13.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTriglycerides/Glucose index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.95 (0.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.68 (0.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.039\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.82 (0.578)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.66 (0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.020\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eALT: Alanine transaminase; AST: Aspartate transaminase; HDLc: high-density lipoprotein cholesterol; LDLc: low-density lipoprotein cholesterol.\u003c/em\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eInterestingly, only ACS patients experienced significant reductions in C-reactive protein. As shown in Fig.\u0026nbsp;2, C-reactive protein reductions correlated to LDLc reductions (B\u0026thinsp;=\u0026thinsp;0.21; p\u0026thinsp;=\u0026thinsp;0.016) and no significant interaction with the type of CHD was observed (p\u0026thinsp;=\u0026thinsp;0.189). ACS patients also had significant reductions in aspartate transaminase. No significant changes in aspartate transaminase were observed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis retrospective study of patients with chronic and acute coronary syndrome demonstrated the efficacy of the fixed-dose combination rosuvastatin plus ezetimibe in LDLc reduction and achievement of LDLc\u0026thinsp;\u0026lt;\u0026thinsp;55 mg/dl, especially in patients with ACS. The effect of statin plus ezetimibe was also translated into lower percentage of small and dense LDL particles in ACS patients and lower atherogenic indexes and cholesterol remnants. Lipid-lowering therapies combination, especially in the setting of ACS, are highly encouraged in the 2019 ESC/EAS guidelines\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and our results clearly support it. The fixed-dose combination statin plus ezetimibe might be an excellent treatment for CHD patients that are not, at least initially under current recommendations, candidates for PCSK9 and our results demonstrate the high percentage of patients that achieve LDLc\u0026thinsp;\u0026lt;\u0026thinsp;55 m/dl, especially when initiated at the time of hospital discharge from an ACS. As clinical features and LDLc values are similar to previous reports\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e we believe that these results might be representative and applicable to daily clinical practice.\u003c/p\u003e \u003cp\u003eIntensive LDLc reduction, particularly with lipid-lowering combination, has demonstrated to be the most in efficient therapy to reduce LDLc and cardiovascular events\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The 2019 ESC/EAS guidelines introduced to key issues for patients with CHD: 1) the treatment target of LDLc\u0026thinsp;\u0026lt;\u0026thinsp;55 mg/dl or \u0026gt;\u0026thinsp;50% reduction and; 2) the recommendation of intensive and fast LDLc reduction for patients discharged after an ACS. The pivotal study that demonstrated the efficacy of ezetimibe was precisely performed in the setting of ACS, the IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e trial, and provided the first evidence of the benefit of such on-treatment low LDLc levels. Subsequently, an analysis of the SWEDEHEART registry with \u0026gt;\u0026thinsp;40.000 patients verified the beneficial impact of the guidelines recommendations\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Mid-term adherence to high-intensity statins after an acute myocardial infarction is quite low\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e but rosuvastatin might the best tolerated high-intensity statin\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Moreover, the addition of ezetimibe increases the efficacy on LDLc reduction and might not increase side effects or withdrawals\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. More interestingly, the combination of statin plus ezetimibe has demonstrated to be the most efficient strategy for plaque volume reduction, assessed by coronary intravascular ultrasound\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Our study demonstrates that ACS patients receiving the fixed-dose combination of rosuvastatin plus ezetimibe had higher LDLc reduction and two thirds achieved the treatment target of LDLc\u0026thinsp;\u0026lt;\u0026thinsp;55 mg/dl.\u003c/p\u003e \u003cp\u003eThe higher LDLc reductions observed in ACS patients might be explained by the higher rate of patients not receiving statins. Adding ezetimibe is more effective than increasing the dose of statins\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e and our results provide reliable evidence related to the fixed-dose combination rosuvastatin plus ezetimibe in real-world setting. In fact, mean LDLc values in our cohort were much lower than baseline LDLc levels in the GRAVITY (GRAVITY: Gauging the lipid effects of RosuvAstatin plus ezetimibe Versus sImvastatin plus ezetimibe TherapY)\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e trial, a fase IIIb trial designed to assess the effect of rosuvastatin plus ezetimibe on LDLc and several biomarkers.\u003c/p\u003e \u003cp\u003eFixed-dose combinations are widely used for the treatment of diabetes o hypertension\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e but, in contrast, are rarely used for the treatment of LDLc. Fixed-dose combinations are known to increase adherence\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e and for the case of lipid-lowering drugs this might be closely related to LDLc reductions and treatment target achievement. Relative LDLc reduction with any lipid-lowering therapy is not attenuated in patients starting with lower baseline LDLc levels\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e and, thereafter, intensive LDLc-lowering therapies should be applied in all high or very high cardiovascular risk patients. Moreover, rosuvastatin and ezetimibe are already available as generic and, therefore, are much more affordable for patients and systems of care\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Our results clearly remark the short-term efficacy of the fixed-dose combination rosuvastatin plus ezetimibe on LDLc reduction with as well as the excellent tolerability.\u003c/p\u003e \u003cp\u003eBeyond the efficacy of LDLc reduction, results also demonstrate the effect of the fixed-dose combination rosuvastatin plus ezetimibe on LDL particle characteristics and C-reactive protein in ACS patients. Both statins and ezetimibe reduce in LDLc but our results also suggest significant effects on LDL particles. Small and dense LDL particles are the leading effectors of atherosclerosis\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. LDL particles size and functional characterization is expensive and takes time, but its estimation by the triglycerides-to-HDL ratio has demonstrated a fair correlation and, also, has a good predictive capacity\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Similarly, reductions in total cholesterol-to-HDL ratio and the triglyceride-glucose index were observed in ACS and CCS reflecting qualitative improvements in lipid profile and insulin resistance, beyond LDLc reductions. Non-HDL cholesterol was proposed as the most reliable lipid parameter for cardiovascular risk estimation in the 2021 guidelines on Prevention of the European Society of Cardiology\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Similarly, cholesterol remnants have been identified as on the most powerful predictors of cardiovascular events in high-risk patients\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Thereafter, we believe that our results suppor tthe beneficial effect of intensive lipid-lowering strategies beyond LDLc reduction levels. Similarly, ACS patients had higher baseline C-reactive protein and just after 3 months values decreased to a comparable range of CCS patients. A subanalysis of the PROVE IT\u0026ndash;TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy\u0026ndash;Thrombolysis in Myocardial Infarction 22) trial demonstrated that C-reactive protein decreased in all ACS patients but reductions were higher in patients that received a high-intensity statin, atorvastatin, compared to those receiving pravastatin, a classified as intermediate intensity statin\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. These results were also observed in the above-mentioned GRAVITY \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e trial. C-reactive protein reduction is not a recommended treatment goal although it is a positive finding since lower on-treatment levels are associated to lower mortality rates\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study has some limitations that should be addressed. Firstly, as all observational studies there are some inherent limitations such as the lack of randomization and unmeasured variables than could induce confusion. Second, this is not a randomized trial comparing 2 alternative treatment. Third, there are other fixed-dose combinations, such as atorvastatin plus ezetimibe, that were not analyzed. Fourth, treatment adherence to lipid-lowering drugs was self-reported by the patients and we cannot assure that all patients used them correctly. Finally, we only assessed short-term efficacy on LDLc reduction and outcomes although this could be performed prospectively. As LDLc reductions and clinical features and were similar to previous reports\u003csup\u003e\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e we believe that our results might be representative of daily clinical practice.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe fixed-dose combination with rosuvastatin-ezetimibe in patients with CHD, not candidates for PCSK9 inhibitors, reduced LDLc by 41%. Reduction was higher in ACS patients because most of them were na\u0026iuml;ve on lipid-lowering therapies. LDLc reductions correlated to reductions in C-reactive protein levels. Fixed-dose combination of rosuvastatin plus ezetimibe was associated, also, to improvements LDL particles, cholesterol remnants and surrogate markers of lipid residual risk.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received the support of the National Network for Biomedical Cardiovascular Research of Cardiovascular Disease (CIBERCV, Centro de Investigaci\u0026oacute;n Biom\u0026eacute;dica en Red de Enfermedades Cardiovasculares). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlberto Cordero reports a) honoraria for lectures from AstraZeneca, AMGEN, Bristol-Myers Squibb, Ferrer, Boehringer Ingelheim, MSD, Daichy Sankio and Novartis; b) consulting fees from AstraZeneca, Ferrer and AMGEN.\u003c/p\u003e\n\u003cp\u003eDr. Vicente Bertomeu-Gonz\u0026aacute;lez reports a) honoraria for lectures from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Pfizer-BMS, LivaNova, Ferrer, Cardiome, MSD; b) consulting fees none; c) research grants from Medtronic Iberica.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material (data transparency)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDatabase will provided under request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions of each authors\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAC, DE, JM and VB collected data, MDM, MM, JLA and MAQ included patients. PZ coordinated the registry. All authors reviewed the manuscript\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval (include appropriate approvals or waivers)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe registry of ACS patients has been approved by ethics committee of the institution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate (include appropriate statements)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAs retrospective study, patients consent was not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication (include appropriate statements)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe registry of ACS patients has been approved by ethics committee of the institution.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGrundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e/ABC/ACPM/ADA/AGS/APhA/ASPC/\u003c/span\u003e\u003c/span\u003eNLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 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DOI: 10.1056/NEJMoa042378.\u003c/div\u003e\n\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Rosuvastatin, Ezetimibe, LDLc, Acute coronary syndrome, Chronic coronary syndrome","lastPublishedDoi":"10.21203/rs.3.rs-1491516/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1491516/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Most patients with coronary heart disease (CHD) might be candidates for statin plus ezetimibe combination to achieve low-density lipoprotein cholesterol (LDLc) \u0026lt;55 mg/dl. Fixed-dose combinations increase adherence but there is less evidence on for rosuvastatin plus ezetimibe in patients with CHD. \u003c/p\u003e\u003cp\u003eMethods: Retrospective analysis of patients with CHD that received fixed-dose combination with rosuvastatin-ezetimibe between January 2019 and March 2020 in a single center. Inclusion criteria were: patients initiating this treatment and LDLc \u0026lt;100 mg/dl despite statin treatment or \u0026gt;100 mg/dl without previous lipid-lowering treatments. \u003c/p\u003e\u003cp\u003eResults: We included 208 patients, 55 (26.44%) acute coronary (ACS) patients. Most chronic coronary syndrome (CCS) patients (90.04%), but just 27.27% of the ACS patients, were on statins. Mean LDLc before treatment was 102.48 (29.78) mg/dl and it was higher in patients with ACS (p\u0026lt;0.001). Median time to second blood test was 203 days and mean on-treatment LDLc was 57.76 (20.23) mg/dl: ACS 53.45 (22.15) vs. CCS 59.65 (19.12) mg/dl (p=0.073). Mean LDLc reduction was 41.00% and it was higher in was higher in ACS patients (49.35% vs. 37.36%; p\u0026lt;0.003). LDLc \u0026lt;55 mg/dl was achieved in 65.31% ACS patients vs. 41.96% CCS patients (p=0.006). ACS patients had significant reductions in triglycerides/HDL ratio and C-reactive protein; all patients had reductions in cholesterol remnants and residual lipid risk. Reductions of C-reactive protein correlated to LDLc reductions. \u003c/p\u003e\u003cp\u003eConclusions: Fixed-dose combination with rosuvastatin-ezetimibe in patients with CHD, not candidates for PCSK9 inhibitors, is effective for LDLc reduction especially in patients with ACS, and improves residual lipid risk.\u003c/p\u003e","manuscriptTitle":"LDLc and residual risk reduction with fixed-dose combination rosuvastatin-ezetimibe in patients with acute vs. chronic coronary syndrome not candidates for PCSK9 inhibitors treatment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-04-12 13:51:00","doi":"10.21203/rs.3.rs-1491516/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41cada68-4b5d-4bd9-9661-9d26919017dc","owner":[],"postedDate":"April 12th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-04-12T13:56:02+00:00","versionOfRecord":[],"versionCreatedAt":"2022-04-12 13:51:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1491516","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1491516","identity":"rs-1491516","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}