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Baseline low-density lipoprotein cholesterol predicts the benefit of adding ezetimibe on statin in statin-naïve acute coronary syndrome.
Im, J, Kawada-Watanabe, E, Yamaguchi, J, Arashi, H, Otsuki, H, Matsui, Y, Sekiguchi, H, Fujii, S, Mori, F, Ogawa, H, et al
Scientific reports. 2021;(1):7480
Abstract
We aimed to evaluate the effect of baseline low-density lipoprotein cholesterol (LDL-C) on the outcomes of patients with the acute coronary syndrome (ACS) receiving pitavastatin monotherapy or the combination of pitavastatin + ezetimibe. In the HIJ-PROPER study, 1734 ACS patients with dyslipidemia were randomly assigned to receive pitavastatin or pitavastatin + ezetimibe therapy. Statin-naïve participants (n = 1429) were divided into two groups based on the median LDL-C level (131 mg/dL) at enrollment. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. The median follow-up was 3.2 years. In the < 131 mg/dL group (n = 686), LDL-C changes were - 34.0% and - 49.8% in the pitavastatin monotherapy and pitavastatin + ezetimibe-treated groups (P < 0.0001), respectively; in the ≥ 131 mg/dL group (n = 743), LDL-C changes were - 42.9% and - 56.4% (P < 0.0001, respectively. Kaplan-Meier analyses revealed that the primary endpoint was not significantly different between the treatment groups for the < 131 mg/dL group, however, it was significantly lower in patients treated with pitavastatin + ezetimibe in the ≥ 131 mg/dL group (Hazard ratio = 0.72, 95% confidence interval = 0.56-0.91, P = 0.007, P value for interaction = 0.012). Statin-naïve ACS patients with baseline LDL-C < 131 mg/dL did not clinically benefit from pitavastatin + ezetimibe, while patients with baseline LDL-C ≥ 131 mg/dL treated with pitavastatin + ezetimibe showed better clinical results than those treated with pitavastatin monotherapy.Clinical Trial Registration: Original HIJ PROPER study; URL: http://www.umin.ac.jp/ctr . Unique Identifier; UMIN000002742, registered as an International Standard Randomized Controlled Trial.
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Effect of Ezetimibe + Pitavastatin on Cardiovascular Outcomes in Patients with ST-Segment Elevation Myocardial Infarction (from the HIJ-PROPER Study).
Otsuki, H, Arashi, H, Yamaguchi, J, Kawada-Watanabe, E, Ogawa, H, Hagiwara, N
The American journal of cardiology. 2020;:15-21
Abstract
Lipid-lowering therapy is necessary to reduce cardiovascular event rates in patients with ST-segment elevation myocardial infarction (STEMI). This study aimed to evaluate the effect of intensive lipid-lowering therapy, which comprised pitavastatin and ezetimibe, on patients with STEMI. We therefore undertook a post hoc subanalysis of the HIJ-PROPER study's data that examined the clinical outcomes of the patients with dyslipidemia and STEMI (n = 880) who received pitavastatin and ezetimibe therapy (intensive lipid-lowering therapy group) or pitavastatin monotherapy (standard lipid-lowering therapy group), and we evaluated their cardiovascular events. The primary end point was a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina, and ischemia-driven revascularization. During the median 3.4-year follow-up period, the cumulative rates of the primary end point were 31.9% and 39.7% in the intensive lipid-lowering therapy and standard lipid-lowering therapy groups, respectively (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62 to 0.97; p = 0.02). Compared with the standard lipid-lowering therapy group, the intensive lipid-lowering therapy group had significantly lower all-cause death (6.9% vs 3.2%; HR, 0.45; 95% CI, 0.23 to 1.84; p = 0.01) and nonfatal stroke (2.9% vs 1.6%; HR, 0.77; 95% CI, 0.62 to 0.97; p = 0.02) rates. Patients with pitavastatin and ezetimibe therapy, as compared with pitavastatin monotherapy, had a lower cardiovascular event in STEMI patients. In conclusion, adding ezetimibe to statin therapy may be beneficial for patients with dyslipidemia and STEMI.
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Intensified lipid lowering using ezetimibe after publication of the IMPROVE-IT trial: A contemporary analysis from the SPUM-ACS cohort.
Gencer, B, Carballo, D, Nanchen, D, Koskinas, KC, Klingenberg, R, Räber, L, Auer, R, Carballo, S, Heg, D, Windecker, S, et al
International journal of cardiology. 2020;:8-13
Abstract
BACKGROUND The relevance of the IMPROVE-IT trial on real-life practice has not been explored in patients with ACS. METHODS A prospective Swiss cohort of 6266 patients hospitalized for ACS between 2009 and 2017 with a one-year follow-up. The primary endpoints were the ezetimibe use overall or in combination with high-intensity statin at discharge and at one year after ACS. Secondary endpoint was LDL-C target achievement at one year in a subsample of 2984 patients. Relative Ratios (RR) were used to assess changes in primary endpoints before and after the publication of IMPROVE-IT, adjusting for age, sex, diabetes, prior myocardial infarction, LDL-C and attendance to cardiac rehabilitation. RESULTS The period following the publication of the IMPROVE-IT trial was associated with a steady increase in the use of ezetimibe at discharge (from 1.8% to 3.8%, P < 0.001, adjusted RR 2.85, 95% CI 1.90-4.25) and at one year (from 5.0% to 13.8%, P < 0.001, adjusted RR 3.00, 95% CI 2.40-3.75). The combination of high-intensity statin and ezetimibe rose from 0.9% to 2.1% at discharge (P < 0.001, adjusted RR 3.35, 95% CI 1.90-5.89) and from 2.1% to 7.8% at one year (P < 0.001, adjusted RR 3.98, 95% CI 2.90-5.47). The period following the publication of the IMPROVE-IT trial was associated with an improvement of LDL-C target <1.8 mmol/L (adjusted RR 1.37, 95% CI 1.12-1.68). CONCLUSIONS After the publication of the IMPROVE-IT trial, the use of ezetimibe was increased by three-fold in a large contemporary cohort of ACS patients, concomitant with an improved LDL-C target achievement.
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Getting to an ImprOved Understanding of Low-Density Lipoprotein-Cholesterol and Dyslipidemia Management (GOULD): Methods and baseline data of a registry of high cardiovascular risk patients in the United States.
Cannon, CP, de Lemos, JA, Rosenson, RS, Ballantyne, CM, Liu, Y, Yazdi, D, Elliott-Davey, M, Mues, KE, Bhatt, DL, Kosiborod, MN, et al
American heart journal. 2020;:70-77
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Abstract
BACKGROUND Guidelines for managing patients with atherosclerotic cardiovascular disease (ASCVD) recommend statin therapy initially. Target levels/goals for low-density lipoprotein-cholesterol (LDL-C) were initially included, subsequently de-emphasized in 2013, and then re-introduced as thresholds, leading to confusion in clinical practice. We designed a multicenter, observational registry of patients with ASCVD, to describe and track LDL-C treatment patterns in the United States over time. METHODS Patients with ASCVD receiving any pharmacologic lipid-lowering therapy were eligible for enrollment in one of three cohorts: 1) currently receiving a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), or not receiving PCSK9i with 2) LDL-C 70-99 mg/dL, or 3) LDL-C ≥100 mg/dL. Patients undergo a 1-year retrospective chart review, followed by chart reviews and phone interviews every 6 months for 2 years. RESULTS A total of 5006 patients were enrolled at 119 centers. Mean age was 68 years, 40% of patients were female, 86% were white, 80% had coronary artery disease, and 33% had type 2 diabetes mellitus. Among those not on a PCSK9i, high-intensity statins and ezetimibe were utilized in only 44% and 9%, respectively. Among women vs men, only 36.6% vs 48.2% received high-intensity statins (P < .001). Among patients on a PCSK9i, only one-third were receiving a statin, suggesting statin intolerance is a driver of PCSK9i use at present. CONCLUSION Our data on current practice in the US continue to illustrate that high-intensity statins and ezetimibe are underutilized in at-risk patients outside of clinical trials, particularly women. This study will track temporal changes in treatment patterns and identify opportunities for improvement in lipid management in patients with ASCVD.
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A Comparison of Two LDL Cholesterol Targets after Ischemic Stroke.
Amarenco, P, Kim, JS, Labreuche, J, Charles, H, Abtan, J, Béjot, Y, Cabrejo, L, Cha, JK, Ducrocq, G, Giroud, M, et al
The New England journal of medicine. 2020;(1):9
Abstract
BACKGROUND The use of intensive lipid-lowering therapy by means of statin medications is recommended after transient ischemic attack (TIA) and ischemic stroke of atherosclerotic origin. The target level for low-density lipoprotein (LDL) cholesterol to reduce cardiovascular events after stroke has not been well studied. METHODS In this parallel-group trial conducted in France and South Korea, we randomly assigned patients with ischemic stroke in the previous 3 months or a TIA within the previous 15 days to a target LDL cholesterol level of less than 70 mg per deciliter (1.8 mmol per liter) (lower-target group) or to a target range of 90 mg to 110 mg per deciliter (2.3 to 2.8 mmol per liter) (higher-target group). All the patients had evidence of cerebrovascular or coronary-artery atherosclerosis and received a statin, ezetimibe, or both. The composite primary end point of major cardiovascular events included ischemic stroke, myocardial infarction, new symptoms leading to urgent coronary or carotid revascularization, or death from cardiovascular causes. RESULTS A total of 2860 patients were enrolled and followed for a median of 3.5 years; 1430 were assigned to each LDL cholesterol target group. The mean LDL cholesterol level at baseline was 135 mg per deciliter (3.5 mmol per liter), and the mean achieved LDL cholesterol level was 65 mg per deciliter (1.7 mmol per liter) in the lower-target group and 96 mg per deciliter (2.5 mmol per liter) in the higher-target group. The trial was stopped for administrative reasons after 277 of an anticipated 385 end-point events had occurred. The composite primary end point occurred in 121 patients (8.5%) in the lower-target group and in 156 (10.9%) in the higher-target group (adjusted hazard ratio, 0.78; 95% confidence interval, 0.61 to 0.98; P = 0.04). The incidence of intracranial hemorrhage and newly diagnosed diabetes did not differ significantly between the two groups. CONCLUSIONS After an ischemic stroke or TIA with evidence of atherosclerosis, patients who had a target LDL cholesterol level of less than 70 mg per deciliter had a lower risk of subsequent cardiovascular events than those who had a target range of 90 mg to 110 mg per deciliter. (Funded by the French Ministry of Health and others; Treat Stroke to Target ClinicalTrials.gov number, NCT01252875.).
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Usefulness of Ezetimibe Versus Evolocumab as Add-On Therapy for Secondary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus.
Arbel, R, Hammerman, A, Azuri, J
The American journal of cardiology. 2019;(8):1273-1276
Abstract
Evolocumab and ezetimibe, were both proven to significantly reduce the incidence of major adverse cardiovascular events (MACE), in type 2 diabetes patients with atherosclerotic cardiovascular disease and low-density lipoprotein (LDL) cholesterol >70 mg/dl despite statin therapy. Providing evolocumab for all such patients may be a significant burden on healthcare systems. Therefore, we analyzed the treatment cost of ezetimibe versus evolocumab to prevent 1 MACE. We extracted the number needed to treat (NNT) with evolocumab or with ezetimibe for avoiding MACE from the published FOURIER and IMPROVE-IT trials respectively. Drug costs were based on 2018 US prices. Sensitivity and scenario analyses were performed to overcome variances in terms of population risk, efficacy of therapies, and costs. In FOURIER, the 1-year NNT for avoiding MACE with evolocumab was 104 (95% confidence intervals [CI] 66 to 235). In IMPROVE-IT, the 1-year NNT with ezetimibe was 124 (95% CI 73 to 288). The annual cost of evolocumab and ezetimibe is $6,540 and $88, respectively. Therefore, the cost to prevent 1 MACE in the FOURIER and IMPROVE-IT trials would have been $678,981 (95% CI $429,810 to $1,537,910,149) and $10,870 (95% CI $6,384 to $25,322), respectively. Ezetimibe was consistently a cost-saving strategy compared with evolocumab, in all analyses performed, except for the case where evolocumab price is significantly reduced and the branded ezetimibe is used. In conclusion, treatment with ezetimibe seems to be a major cost-saving strategy for preventing MACE in this patient population.
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Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): A Randomized, Controlled Trial.
Ouchi, Y, Sasaki, J, Arai, H, Yokote, K, Harada, K, Katayama, Y, Urabe, T, Uchida, Y, Hayashi, M, Yokota, N, et al
Circulation. 2019;(12):992-1003
Abstract
BACKGROUND Evidence regarding the primary prevention of coronary artery disease events by low-density lipoprotein cholesterol (LDL-C) lowering therapy in older individuals, aged ≥75 years, is insufficient. This trial tested whether LDL-C-lowering therapy with ezetimibe is useful for the primary prevention of cardiovascular events in older patients. METHODS This multicenter, prospective, randomized, open-label, blinded end-point evaluation conducted at 363 medical institutions in Japan examined the preventive efficacy of ezetimibe for patients aged ≥75 years, with elevated LDL-C without history of coronary artery disease. Patients, who all received dietary counseling, were randomly assigned (1:1) to receive ezetimibe (10 mg once daily) versus usual care with randomization stratified by site, age, sex, and baseline LDL-C. The primary outcome was a composite of sudden cardiac death, myocardial infarction, coronary revascularization, or stroke. RESULTS Overall, 3796 patients were enrolled between May 2009 and December 2014, and 1898 each were randomly assigned to ezetimibe versus control. Median follow-up was 4.1 years. After exclusion of 182 ezetimibe patients and 203 control patients because of lack of appropriate informed consent and other protocol violations, 1716 (90.4%) and 1695 (89.3%) patients were included in the primary analysis, respectively. Ezetimibe reduced the incidence of the primary outcome (hazard ratio [HR], 0.66; 95% CI, 0.50-0.86; P=0.002). Regarding the secondary outcomes, the incidences of composite cardiac events (HR, 0.60; 95% CI, 0.37-0.98; P=0.039) and coronary revascularization (HR, 0.38; 95% CI, 0.18-0.79; P=0.007) were lower in the ezetimibe group than in the control group; however, there was no difference in the incidence of stroke, all-cause mortality, or adverse events between trial groups. CONCLUSIONS LDL-C-lowering therapy with ezetimibe prevented cardiovascular events, suggesting the importance of LDL-C lowering for primary prevention in individuals aged ≥75 years with elevated LDL-C. Given the open-label nature of the trial, its premature termination and issues with follow-up, the magnitude of benefit observed should be interpreted with caution. Clinical Registration: URL: https://www.umin.ac.jp. Unique identifier: UMIN000001988.
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Impact of statin-ezetimibe combination on coronary atheroma plaque in patients with and without chronic kidney disease - Sub-analysis of PRECISE-IVUS trial.
Fujisue, K, Nagamatsu, S, Shimomura, H, Yamashita, T, Nakao, K, Nakamura, S, Ishihara, M, Matsui, K, Yamamoto, N, Koide, S, et al
International journal of cardiology. 2018;:23-26
Abstract
BACKGROUND Chronic kidney disease (CKD) deteriorates the prognosis of patients undergoing percutaneous coronary intervention (PCI). Because coronary artery disease (CAD) is the major cause of death in CKD patients, cardiovascular risk reduction has been clinically important in CKD. We hypothesized intensive lipid-lowering with statin/ezetimibe attenuated coronary atherosclerotic development even in patients with CKD. METHODS In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound (IVUS)-guided PCI were randomly assigned to receive atorvastatin/ezetimibe combination or atorvastatin alone (the dosage of atorvastatin was up-titrated to achieve the level of low-density lipoprotein cholesterol < 70 mg/dL). Serial volumetric IVUS findings obtained at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients were compared stratified by the presence or absence of CKD. RESULTS CKD was observed in 52 patients (26%) among 202 enrolled patients. Compared with the non-CKD group, the CKD group was significantly older (71.5 ± 8.6 years vs. 64.4 ± 9.6 years, P < 0.001) with similar prevalence of comorbid coronary risk factors and lipid profiles. Similar to the non-CKD group (-1.4 [-2.8 to -0.1]% vs. -0.2 [-1.7 to 1.0]%, P = 0.002), the atorvastatin/ezetimibe combination significantly reduced ∆PAV compared with atorvastatin alone even in the CKD group (-2.6 [-5.6 to -0.4]% vs. -0.9 [-2.4 to 0.2]%, P = 0.04). CONCLUSIONS As with non-CKD, intensive lipid-lowering therapy with atorvastatin/ezetimibe demonstrated stronger coronary plaque regression effect even in patients with CKD compared with atorvastatin monotherapy. TRIAL REGISTRATION NCT01043380 (ClinicalTrials.gov).
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The nonalcoholic fatty liver disease (NAFLD) fibrosis score, cardiovascular risk stratification and a strategy for secondary prevention with ezetimibe.
Simon, TG, Corey, KE, Cannon, CP, Blazing, M, Park, JG, O'Donoghue, ML, Chung, RT, Giugliano, RP
International journal of cardiology. 2018;:245-252
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OBJECTIVE The nonalcoholic fatty liver disease fibrosis score (NFS) is comprised of unique metabolic risk indicators that may accurately predict residual cardiovascular (CV) risk in patients with established coronary disease and metabolic dysfunction. METHODS We applied the NFS prospectively to 14,819 post-ACS patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), in the IMPROVE-IT trial, using validated NFS cutoffs. The primary endpoint included CV death, myocardial infarction, unstable angina, revascularization or stroke. Outcomes were compared between NFS categories and treatment arms using frequency of events, KM rates and adjusted Cox proportional hazard models. The ability of the NFS to predict recurrent CV events was independently validated in 5395 placebo-treated patients enrolled in the SOLID-TIMI 52 trial. RESULTS Among 14,819 patients enrolled in IMPROVE-IT, 14.2% (N = 2106) were high-risk (NFS > 0.67). The high-risk group had a 30% increased risk of recurrent major CV events, compared to the low-risk NFS group (HR 1.30 [1.19-1.43]; p < 0.001). Among high-risk patients, ezetimibe/simvastatin conferred a 3.7% absolute reduction in risk of recurrent CV events, compared to placebo/simvastatin (HR 0.85 [0.74-0.98]), translating to a number-needed-to-treat of 27. Similar benefit was not found in the low-risk group (HR ezetimibe/simvastatin vs. placebo/simvastatin, 1.01 [0.91-1.12]; p-interaction = 0.053). The relationship between NFS category and recurrent CV events was independently validated in patients enrolled in SOLID-TIMI 52 (HR for NFS > 0.67 vs. NFS < -1.455 = 1.55 [1.32-1.81]; p < 0.001). CONCLUSION Stratification of cardiovascular risk by NFS identifies an independent population of patients who are at highest risk of recurrent events, and most likely to benefit from dual lipid-lowering therapy. Clinical trials.gov: NCT00202878.
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Predictive Value of Baseline High-Sensitivity C-Reactive Protein Level and Renal Function for Patients With Acute Coronary Syndrome Undergoing Aggressive Lipid-Lowering Therapy: A Subanalysis of HIJ-PROPER.
Kawada-Watanabe, E, Yamaguchi, J, Kanbayashi, K, Sekiguchi, H, Arashi, H, Ogawa, H, Hagiwara, N
The American journal of cardiology. 2018;(11):1817-1823
Abstract
The systematic inflammatory response might confound renal impairment, and both have been reported to affect clinical outcomes after acute coronary syndrome. We examined the impacts of the high-sensitivity C-reactive protein (hsCRP) level and estimated glomerular filtration rate level on the prognosis for acute coronary syndrome patients who underwent aggressive lipid-lowering therapy in contemporary practice. This was a subanalysis of the HIJ-PROPER study, and 1,734 patients were enrolled. Patients were divided into 4 groups using an hsCRP value of 10mg/L and an estimated glomerular filtration rate value of 60 ml/min/1.73 m2 as the cut-off points. Groups were defined as follows: group A, low hsCRP and normal or mild renal impairment; group B, low hsCRP and renal impairment; group C, high hsCRP and normal or mild renal impairment; and group D, high hsCRP and renal impairment. The primary end point was defined as the composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina or coronary revascularizations. The median follow-up period was 3.9years, and the follow-up rate was 99%. Compared with group A, the 2 higher hsCRP groups (groups C and D) showed a significantly higher incidence of primary end points (hazard ratio 1.36, 95% confidence interval 1.12 to 1.65, p = 0.002; and hazard ratio 1.40, 95% CI 1.10 to 1.80, p = 0.008). Such a difference was not found compared with group B. In conclusion, patients with higher hsCRP levels had worse prognoses regardless of renal impairment and aggressive lipid-lowering therapy.