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Circulating Mature PCSK9 Level Predicts Diminished Response to Statin Therapy.
Kuyama, N, Kataoka, Y, Takegami, M, Nishimura, K, Harada-Shiba, M, Hori, M, Ogura, M, Otsuka, F, Asaumi, Y, Noguchi, T, et al
Journal of the American Heart Association. 2021;(11):e019525
Abstract
Background Statin-mediated efficacy of lowering low-density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine-protease associated with LDL metabolism, which circulates as mature and furin-cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin-naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10-ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01-1.24 [P=0.03]), whereas furin-cleaved level was not (per 10-ng/mL increase: OR, 1.37; 95% CI, 0.73-2.58 [P=0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.
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Patient characteristics, treatment patterns, and adherence to lipid-lowering therapies following an acute coronary syndrome.
Bruckert, E, Desamericq, G, Khachatryan, A, Ngo, P, Gusto, G, Sorio-Vilela, F
Reviews in cardiovascular medicine. 2020;(4):643-650
Abstract
Despite dyslipidaemia management guidelines, many patients do not reach low-density lipoprotein cholesterol targets due to insufficiently intensive regimens or lack of adherence to their medication. This was a retrospective cohort study on the Pharmacoepidemiologic General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Patients included were ≥ 18 years old who suffered an ACS between 2013 and 2016, and treated with lipid-lowering therapy (LLT) at hospital discharge or within 92 days. Patients were followed up to 12 months' post index ACS, a new cardiovascular event, loss to follow-up or death. Treatment intensity (high, moderate and low intensity statins ± ezetimibe) and adherence (proportion of days covered > 80%) are described. A total of 2,695 patients were included; mean age [SD] was 63.1 [12.8] years, and 77% were men. High, moderate and low intensity statins were started in 56% (1,520), 36% (971), and 3% (86) of patients, respectively. A further 2% (46) were on statin/ezetimibe combination, 2% (42) on other LLT and 1% (30) on ezetimibe alone. At follow-up, around 70% of patients were adherent to LLT, with those on moderate intensity treatments showing better adherence (76%) than those on low (63%) or high (67%) intensity treatments. Despite guideline recommendations, many patients following an ACS are not treated with high intensity statins, and adherence remains far from optimal. Effort should be made to increase the proportion of patients treated with high intensity statins following an ACS and to further improve treatment adherence.
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Arterial stiffness improvement after adding on PCSK9 inhibitors or ezetimibe to high-intensity statins in patients with familial hypercholesterolemia: A Two-Lipid Center Real-World Experience.
Mandraffino, G, Scicali, R, Rodríguez-Carrio, J, Savarino, F, Mamone, F, Scuruchi, M, Cinquegrani, M, Imbalzano, E, Di Pino, A, Piro, S, et al
Journal of clinical lipidology. 2020;(2):231-240
Abstract
BACKGROUND Familial hypercholesterolemia (FH) is characterized by increased cardiovascular risk; despite-high intensity statins, only few patients with FH achieve the recommended low-density lipoprotein cholesterol (LDL-C) targets. OBJECTIVE We aimed to evaluate the effectiveness of six-month add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) or ezetimibe on lipid profile and pulse wave velocity (PWV) in patients with FH. METHODS In this observational study, we evaluated 98 genetically confirmed patients with FH with an LDL-C off-target despite high-intensity statins with or without ezetimibe; of these, 53 patients (statin plus ezetimibe) added PCSK9-i (PCSK9-i group) and 45 (statin only) added ezetimibe (EZE group) per applicable guidelines and reimbursement rules. All patients obtained biochemical analysis and PWV evaluation at baseline and after six months of optimized treatment. RESULTS After 6 months of add-on therapy, most patients achieving LDL-C targets were in the PCSK9-i group (77.3% PCSK9-i group vs 37.8% EZE group, P < .001). The PCSK9-i group achieved both a greater LDL-C and PWV reduction than the EZE group [-51% vs -22.8%, P < .001 and -15% vs -8.5%, P < .01, respectively]. In a linear regression analysis, we showed a coefficient (r) of 0.334 for the relationship between ΔPWV and ΔLDL (P < .05); moreover, in an exploratory analysis, the relationship appeared to be stronger in patients with FH without cardiovascular events (r = 0.422, P < .01). CONCLUSIONS Lipid and PWV profiles in patients with FH significantly improved after addition of PCSK9-i or ezetimibe to high-intensity statin therapy; moreover, ΔPWV was associated with ΔLDL. Our results are consistent with a beneficial role of these novel therapies in FH subjects.
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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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An innovative lipid-lowering approach to enhance attainment of low-density lipoprotein cholesterol goals.
Buonvino, C, Chopard, R, Guillon, B, Puymirat, E, Farnier, M, Ferrières, J, Krempf, M, Bruckert, E, Meneveau, N, Schiele, F
European heart journal. Acute cardiovascular care. 2020;(8):879-887
Abstract
AIMS: To improve attainment of LDL-cholesterol (LDL-c) targets, an expert group proposed an algorithm for lipid-lowering therapy during hospitalization for acute coronary syndrome and during follow-up. We aimed to assess adherence to this algorithm, and evaluate its impact on LDL-c levels and on attainment of therapeutic LDL-c targets in a population of post-acute coronary syndrome patients. METHODS AND RESULTS Prospective, observational study including patients admitted for acute coronary syndrome between February 2017 and September 2018. Patients admitted without statins or ezetimibe were considered 'naïve'. Baseline LDL-c was admission LDL-c in naïve patients, and for those taking lipid-lowering therapy at admission, baseline LDL-c was back-calculated. In line with the most recent guidelines, the target was a >50% reduction in naïve LDL-c and <55 mg/dL. In total, 270 patients were analysed, mean age 67 ± 12 years, 78% men, 26% diabetic. At admission, 175 (65%) were naïve, 95 (35%) had previous lipid-lowering therapy, of which 13 (5%) statin+ezetimibe. Average LDL-c at admission was 120 ± 47 mg/dL (136 ± 44 mg/dL in naïve, 91 ± 39 mg/dL in pretreated patients). Discharge prescription was in compliance with the algorithm in 204 (76%) patients. Average LDL-c at two months was 57 ± 28 mg/dL; it was <55 mg/dL in 135 (50%), and 178 (66%) achieved a >50% reduction. Overall, 125/270 (46%) achieved the LDL-c goal. The reduction in LDL-c observed at two months persisted at five months. CONCLUSION Prescription of high-intensity statins, associated with ezetimibe where applicable, achieves LDL-c levels <55 mg/dL in 50% of patients at two months, and attains therapeutic goals defined by the European Society of Cardiology in 46% of cases.
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Management of High and Very High-Risk Subjects with Familial Hypercholesterolemia: Results from an Observational Study in Bulgaria.
Petrov, IS, Postadzhiyan, AS, Tokmakova, MP, Kitova, LG, Tsonev, SN, Addison, J, Petkova, RT, Lachev, VI
Folia medica. 2018;(3):389-396
Abstract
BACKGROUND Familial hypercholesterolaemia (FH) is a genetic disorder causing accelerated atherosclerosis and premature cardiovascular disease (CVD). This retrospective observational study examined the clinical characteristics and management of FH subjects in Bulgaria over a 12-month period. MATERIALS AND METHODS Twelve cardiology sites participated in this study from May 2015 to May 2016. Eligible subjects had at least two routine low-density lipo-protein cholesterol (LDL C) measurements and a prescription for lipid-lowering therapy (LLT) at the start of the observation period. Mean values for gender, age and cardiovascular (CV) event history at baseline and LDL-C over time were estimated. RESULTS Of the 220 eligible subjects, 196 fulfilled the criteria for FH diagnosis: 27 definite, 94 probable and 75 possible. Mean age at enrolment was 54.4 years and 64.1% of subjects were male. Mean CV risk classification at baseline was 26.8% high-risk (HR) and 73.2% very high-risk (VHR). Mean LDL-C was 5.6 mmol/L at enrolment and 4.1 mmol/L at last observation visit (12 months). The ESC/EAS Guideline LDL-C targets (applicable at the time of the study) were achieved by 14.5% of HR and 5.0% of VHR subjects. Most subjects (n=219) received statins. One subject was statin intolerant (ezetimibe therapy). Intensive statin treatment (atorvastatin 40-80 mg/daily and rosuvastatin 20-40 mg/daily) was used in 38.6% of individuals during the observation period and 10% of subjects received combination therapy (statin plus ezetimibe or other LLT). CONCLUSIONS Most subjects with FH do not reach the ESC/EAS defined LDL-C targets. Early identification and physician education may improve FH management.
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Eligibility for PCSK9 Inhibitors According to American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines After Acute Coronary Syndromes.
Gencer, B, Koskinas, KC, Räber, L, Karagiannis, A, Nanchen, D, Auer, R, Carballo, D, Carballo, S, Klingenberg, R, Heg, D, et al
Journal of the American Heart Association. 2017;(11)
Abstract
BACKGROUND The American College of Cardiology (ACC) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) have recently published recommendations for the use of proprotein convertase subtilisin/kexin-9 (PCSK9) inhibitors in situations of very high risk. We aim to assess in the real world the suitability of PCSK9 inhibitors for acute coronary syndromes. METHODS AND RESULTS We analyzed a prospective Swiss cohort of 2023 patients hospitalized for acute coronary syndromes between 2009 and 2014 with available data for low-density lipoprotein cholesterol and lipid-lowering therapy at 1 year. Clinical familial hypercholesterolemia was defined using the Dutch Lipid Clinic Network algorithm as unlikely, possible, probable, or definite. We simulated a fixed relative reduction of 24% in low-density lipoprotein cholesterol levels at 1 year in all patients not treated with ezetimibe, irrespective of the low-density lipoprotein cholesterol levels and statin regimen. At 1 year, 94.3% of patients were treated with statin, 5.8% with ezetimibe, and 35.8% of patients had on-target low-density lipoprotein cholesterol levels (<1.8 mmol/L); 25.6% met criteria for possible or probable/definite familial hypercholesterolemia. After a simulation of the lipid-lowering effect of ezetimibe, the proportion of patients who would be eligible for PCSK9 inhibitors at 1 year was 13.4% using American College of Cardiology criteria and 2.7% using European Society of Cardiology/European Atherosclerosis Society criteria. Patients with possible or probable/definite familial hypercholesterolemia were more eligible for PCSK9 inhibitors compared with their non-familial hypercholesterolemia counterparts: 27.6% versus 8.8% according to American College of Cardiology criteria and 6.6% versus 1.8% according to European Society of Cardiology/European Atherosclerosis Society criteria (P<0.001). CONCLUSIONS Recommendations made by the American College of Cardiology guidelines would lead to 5-fold higher eligibility rates for PCSK9 inhibitors compared to the European Society of Cardiology/European Atherosclerosis Society consensus statement in acute coronary syndrome patients.