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High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.
Omote, K, Yokota, I, Nagai, T, Sakuma, I, Nakagawa, Y, Kamiya, K, Iwata, H, Miyauchi, K, Ozaki, Y, Hibi, K, et al
Journal of atherosclerosis and thrombosis. 2022;(1):50-68
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AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) <120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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Dose-Dependent Inhibitory Effect of Rosuvastatin in Japanese Patients with Acute Myocardial Infarction on Serum Concentration of Matrix Metalloproteinases-INVITATION Trial.
Shirakawa, T, Fujisue, K, Nakamura, S, Yamamoto, N, Oshima, S, Matsumura, T, Tsunoda, R, Hirai, N, Koide, S, Tayama, S, et al
Journal of atherosclerosis and thrombosis. 2022;(2):229-241
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AIM: Matrix metalloproteinases (MMPs) play critical roles in acute myocardial infarction (AMI). This trial was conducted to determine the potential effects of higher-dose rosuvastatin on circulating MMP levels in patients with AMI. METHODS This was a multicenter, open-label, 1:1 randomized, parallel-group study. Patients with AMI were randomly assigned to the appropriate-dose group (10 mg rosuvastatin once daily) or the low-dose group (2.5 mg rosuvastatin once daily) within 24 hours after percutaneous coronary intervention. MMP-2 and MMP-9 levels were measured on day 1 and at week 4, 12, and 24 after enrollment. The primary endpoint was the change in MMP levels at 24 weeks after enrollment. The secondary endpoints were change in MMP levels at day 1 and weeks 4 and 12 after enrollment. RESULTS Between August 2017 and October 2018, 120 patients with AMI from 19 institutions were randomly assigned to either the appropriate-dose or the low-dose group. There were 109 patients who completed the 24-week follow-up. The primary endpoint for both MMP-2 and MMP-9 was not significantly different between the two groups. The change in the active/total ratio of MMP-9 at week 12 after baseline was significantly lower in the appropriate-dose group compared with the low-dose group (0.81 [-52.8-60.1]% vs. 70.1 [-14.5-214.2]%, P=0.004), while the changes in MMP-2 were not significantly different between the two groups during the study period. CONCLUSIONS This study could not demonstrate the superiority of appropriate-dose of rosuvastatin in inhibiting serum MMPs levels in patients with AMI.
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Differential Effects of DPP-4 Inhibitors, Anagliptin and Sitagliptin, on PCSK9 Levels in Patients with Type 2 Diabetes Mellitus who are Receiving Statin Therapy.
Furuhashi, M, Sakuma, I, Morimoto, T, Higashiura, Y, Sakai, A, Matsumoto, M, Sakuma, M, Shimabukuro, M, Nomiyama, T, Arasaki, O, et al
Journal of atherosclerosis and thrombosis. 2022;(1):24-37
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AIM: Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the low-density lipoprotein (LDL) receptor, leading to hypercholesterolemia and cardiovascular risk. Treatment with a statin leads to a compensatory increase in circulating PCSK9 level. Anagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to decrease LDL cholesterol (LDL-C) levels to a greater extent than that by sitagliptin, another DPP-4 inhibitor, in the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. We investigated PCSK9 concentration in type 2 diabetes mellitus (T2DM) and the impact of treatment with anagliptin or sitagliptin on PCSK9 level as a sub-analysis of the REASON trial. METHODS PCSK9 concentration was measured at baseline and after 52 weeks of treatment with anagliptin (n=122) or sitagliptin (n=128) in patients with T2DM who were receiving statin therapy. All of the included patients had been treated with a DPP-4 inhibitor prior to randomization. RESULTS Baseline PCSK9 level was positively, but not significantly, correlated with LDL-C and was independently associated with platelet count and level of triglycerides. Concomitant with reduction of LDL-C, but not hemoglobin A1c (HbA1c), by anagliptin, PCSK9 level was significantly increased by treatment with sitagliptin (218±98 vs. 242±115 ng/mL, P=0.01), but not anagliptin (233±97 vs. 250±106 ng/mL, P=0.07). CONCLUSIONS PCSK9 level is independently associated with platelet count and level of triglycerides, but not LDL-C, in patients with T2DM. Anagliptin reduces LDL-C level independent of HbA1c control in patients with T2DM who are on statin therapy possibly by suppressing excess statin-mediated PCSK9 induction and subsequent degradation of the LDL receptor.
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Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.
Abe, M, Ozaki, Y, Takahashi, H, Ishii, M, Masunaga, N, Ismail, TF, Iimuro, S, Fujita, R, Iwata, H, Sakuma, I, et al
American heart journal. 2021;:89-100
Abstract
BACKGROUND It has not yet been established whether higher-dose statins have beneficial effects on cardiovascular events in patients with stable coronary artery disease (CAD) and renal dysfunction. METHODS The REAL-CAD study is a prospective, multicenter, open-label trial. As a substudy, we categorized patients by an estimated glomerular filtration rate (eGFR) as follows: eGFR ≥60 (n = 7,768); eGFR ≥45 and <60 (n = 3,176); and eGFR <45 mL/Min/1.73 m2 (n = 1,164), who were randomized to pitavastatin 4mg or 1mg therapy. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina, and was assessed by the log-rank test and Cox proportional hazards model. RESULTS The baseline characteristics and medications were largely well-balanced between two groups. The magnitude of low-density lipoprotein cholesterol (LDL-C) reduction at 6 months in high- and low-dose pitavastatin groups was comparable among all eGFR categories. During a median follow-up of 3.9 years, high- compared with low-dose pitavastatin significantly reduced cardiovascular events in patients with eGFR ≥60 (hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58-0.91; P = .006), and reduced but not significant for patients with eGFR ≥45 and <60 (HR 0.85; 95% CI, 0.63-1.14; P = .27) or eGFR <45 mL/Min/1.73 m2 (HR 0.90; 95% CI 0.62-1.33; P = .61). An interaction test of treatment by eGFR category was not significant (P value for interaction = .30). CONCLUSION Higher-dose pitavastatin therapy reduced LDL levels and cardiovascular events in stable CAD patients irrespective of eGFR level, although the effect on events appeared to be numerically lower in patients with lower eGFR.
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Reported muscle symptoms during statin treatment amongst Italian dyslipidaemic patients in the real-life setting: the PROSISA Study.
Casula, M, Gazzotti, M, Bonaiti, F, OImastroni, E, Arca, M, Averna, M, Zambon, A, Catapano, AL, ,
Journal of internal medicine. 2021;(1):116-128
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AIM: Statin-associated muscle symptoms (SAMS) are a major determinant of poor treatment adherence and/or discontinuation, but a definitive diagnosis of SAMS is challenging. The PROSISA study was an observational retrospective study aimed to assess the prevalence of reported SAMS in a cohort of dyslipidaemic patients. METHODS Demographic/anamnestic data, biochemical values and occurrence of SAMS were collected by 23 Italian Lipid Clinics. Adjusted logistic regression was performed to estimate odds ratio (OR) and 95% confidence intervals for association between probability of reporting SAMS and several factors. RESULTS Analyses were carried out on 16 717 statin-treated patients (mean ± SD, age 60.5 ± 12.0 years; 52.1% men). During statin therapy, 9.6% (N = 1599) of patients reported SAMS. Women and physically active subjects were more likely to report SAMS (OR 1.23 [1.10-1.37] and OR 1.35 [1.14-1.60], respectively), whist age ≥ 65 (OR 0.79 [0.70-0.89]), presence of type 2 diabetes mellitus (OR 0.62 [0.51-0.74]), use of concomitant nonstatin lipid-lowering drugs (OR 0.87 [0.76-0.99]), use of high-intensity statins (OR 0.79 [0.69-0.90]) and use of potential interacting drugs (OR 0.63 [0.48-0.84]) were associated with lower probability of reporting SAMS. Amongst patients reporting SAMS, 82.2% underwent dechallenge (treatment interruption) and/or rechallenge (change or restart of statin therapy), with reappearance of muscular symptoms in 38.4% (3.01% of the whole cohort). CONCLUSIONS The reported prevalence of SAMS was 9.6% of the whole PROSISA cohort, but only a third of patients still reported SAMS after dechallenge/rechallenge. These results emphasize the need for a better management of SAMS to implement a more accurate diagnosis and treatment re-evaluation.
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Effect of statins on post-contrast acute kidney injury: a multicenter retrospective observational study.
Lin, M, Xu, T, Zhang, W, Li, D, Li, Y, Hong, X, Luan, Y, Zhang, W, Wang, M
Lipids in health and disease. 2021;(1):63
Abstract
BACKGROUND Post-contrast acute kidney injury (PC-AKI) is a severe complication of coronary angiography (CAG) and percutaneous coronary intervention (PCI). Currently, the effect of statins on PC-AKI and its mechanism remains unclear. METHODS This multicenter retrospective observational study included 4386 patients who underwent CAG or PCI from December 2006 to December 2019 in Sir Run Run Shaw Hospital and its medical consortium hospitals. Serum creatinine pre- or post-procedure within 72 h after PCI was recorded. Multivariate logical regression was used to explore whether preoperative use of statins was protective from PC-AKI. The path analysis model was then utilized to look for the mediation factors of statins. RESULTS Four thousand three hundred eighty-six patients were enrolled totally. The median age of the study population was 68 years old, 17.9% with PC-AKI, and 83.3% on preoperative statins therapy. The incidence of PC-AKI was significantly lower in group of patients on statins therapy. Multivariate regression indicated that preoperative statins therapy was significantly associated with lower percentage of elevated creatinine (β: -0.118, P < 0.001) and less PC-AKI (OR: 0.575, P < 0.001). In the preoperative statins therapy group, no statistically significant difference was detected between the atorvastatin and rosuvastatin groups (OR: 1.052, P = 0.558). Pathway model analysis indicated a direct protective effect of preoperative statins therapy on PC-AKI (P < 0.001), but not through its lipid-lowering effect (P = 0.277) nor anti-inflammatory effect (P = 0.596). Furthermore, it was found that "low-density lipoprotein cholesterol (LDL-C)→C-reactive protein (CRP)" mediated the relationship between preoperative statins therapy and PC-AKI (P = 0.007). However, this only explained less than 1% of the preoperative protective effects of statins on PC-AKI. CONCLUSION Preoperative statins therapy is an independent protective factor of PC-AKI, regardless of its type. This protective effect is not achieved by lipid-lowering effect or anti-inflammatory effect. These findings underscore the potential use of statins in preventing PC-AKI among those at risk.
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Effect of the Million Hearts Cardiovascular Disease Risk Reduction Model on Initiating and Intensifying Medications: A Prespecified Secondary Analysis of a Randomized Clinical Trial.
Peterson, GG, Pu, J, Magid, DJ, Barterian, L, Kranker, K, Barna, M, Conwell, L, Rose, A, Blue, L, Markovitz, A, et al
JAMA cardiology. 2021;(9):1050-1059
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IMPORTANCE The Million Hearts Cardiovascular Disease (CVD) Risk Reduction Model pays provider organizations for measuring and reducing Medicare patients' cardiovascular risk. OBJECTIVE To assess whether the model increases the initiation or intensification of antihypertensive medications or statins among patients with blood pressure or low-density lipoprotein (LDL) cholesterol levels above guideline thresholds for treatment intensification. DESIGN, SETTING, AND PARTICIPANTS This prespecified secondary analysis of a cluster-randomized, pragmatic trial included primary care and cardiology practices, health care centers, and hospital-based outpatient departments across the US. Participants included Medicare patients who were enrolled into the model in 2017 by participating organizations and who were at high risk and at medium risk of a myocardial infarction or stroke in 10 years. Patient outcomes were analyzed for 1 year postenrollment (through December 2018) using an intent-to-treat design. Analysis began November 2019. INTERVENTIONS US Centers for Medicare & Medicaid Services paid organizations for risk stratifying Medicare patients and reducing CVD risk among high-risk patients through discussing risk scores, developing individualized risk reduction plans, and following up with patients twice yearly. MAIN OUTCOMES AND MEASURES Initiating or intensifying statin or antihypertensive therapy within 1 year of enrollment, measured in Medicare Part D claims, and LDL cholesterol and systolic blood pressure levels approximately 1 year after enrollment, measured in usual care and reported to Centers for Medicare & Medicaid Services via a data registry (data complete for 51% of high-risk enrollees). The study's primary outcome (incidence of first-time myocardial infarction and stroke) is not reported because the trial is ongoing. RESULTS A total of 330 primary care and cardiology practices, health care centers, and hospital-based outpatient departments and 125 436 Medicare patients were included in this analysis. High-risk patients in the intervention group had a mean (SD) age of 74 (4.1), 15 213 (63%) were male, 21 657 (90%) were receiving antihypertensive medication at baseline, and 16 558 (69%) were receiving statins. Almost all (21 791 [91%]) high-risk intervention group patients had above-threshold systolic blood pressure level (>130 mm Hg), LDL cholesterol level (>70 mg/dL), or both. Patients in the intervention group with these risk factors were more likely than control patients (8127 [37.3%] vs 4753 [32.4%]; adjusted difference in percentage points, 4.8; 95% CI, 2.9-6.7; P < .001) to initiate or intensify statins or antihypertensive medication. Centers for Medicare & Medicaid Services did not pay for CVD risk reduction for medium-risk enrollees, but initiation or intensification rates for these enrollees were also higher in the intervention vs control groups (12 668 [27.9%] vs 7544 [24.8%]; adjusted difference in percentage points, 3.1; 95% CI, 1.9-4.3; P < .001). Among high-risk enrollees with clinical data approximately 1 year after enrollment, LDL cholesterol level was slightly lower in the intervention vs control groups (mean [SD], 89 [31.8] vs 91 [32.1] mg/dL; adjusted difference in percentage points, -1.8; 95% CI, -2.9 to -0.6; P = .002), as was systolic blood pressure (mean [SD], 133 [15.7] vs 135 [16.4] mm Hg; adjusted difference in percentage points, -1.7; 95% CI, -2.8 to -0.6; P = .003). CONCLUSIONS AND RELEVANCE In this study, a pay-for-performance model led to modest increases in the use of CVD medications in a range of organizations, despite high medication use at baseline.
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Does Lowering Low-Density Lipoprotein Cholesterol With Statin Restore Low Risk in Middle-Aged Adults? Analysis of the Observational MESA Study.
Liu, K, Wilkins, JT, Colangelo, LA, Lloyd-Jones, DM
Journal of the American Heart Association. 2021;(11):e019695
Abstract
Background It is unclear if statin therapy in midlife can restore low cardiovascular risk in hypercholesterolemic individuals. Methods and Results At baseline, we grouped 5687 MESA (Multi-Ethnic Study of Atherosclerosis) participants aged ≥50 years without clinical cardiovascular disease (CVD) by Adult Treatment Panel III statin treatment recommendation and statin treatment status. We used Cox regression to compare the risks for coronary heart disease and CVD between the untreated group with low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (reference) and other groups, adjusting for CVD risk factors. We also grouped participants by LDL-C level (< or ≥100 mg/dL), coronary artery calcium score (0 or >0 Agatston units), and statin status (untreated or treated) with the untreated LDL-C <100 mg/dL and coronary artery calcium=0 Agatston units as the reference. There were 567 coronary heart disease and 848 CVD events over 15 years of follow-up. The hazard ratios (HRs) for coronary heart disease and CVD in the group with statin-treated LDL-C <100 mg/dL were 1.16 (95% CI, 0.85-1.58) and 1.02 (95% CI, 0.78-1.32), respectively. However, participants with coronary artery calcium >0 Agatston units, treated to LDL-C <100 mg/dL had HRs of 2.6 (95% CI, 1.7-4.2) for coronary heart disease and 1.8 (95% CI, 1.2-2.6) for CVD. Conclusions Individuals treated with statins to LDL-C <100 mg/dL had similar levels of risk for atherosclerotic CVD as individuals with untreated LDL-C <100 mg/dL. However, individuals with coronary artery calcium >0 Agatston units have substantially higher risks despite lipid-lowering therapy, suggesting that statin treatment in midlife may not restore a low-risk state in primary prevention patients with established coronary atherosclerosis.
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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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Antihypertensives and Statin Therapy for Primary Stroke Prevention: A Secondary Analysis of the HOPE-3 Trial.
Bosch, J, Lonn, EM, Dagenais, GR, Gao, P, Lopez-Jaramillo, P, Zhu, J, Pais, P, Avezum, A, Sliwa, K, Chazova, IE, et al
Stroke. 2021;(8):2494-2501
Abstract
BACKGROUND AND PURPOSE The HOPE-3 trial (Heart Outcomes Prevention Evaluation–3) found that antihypertensive therapy combined with a statin reduced first stroke among people at intermediate cardiovascular risk. We report secondary analyses of stroke outcomes by stroke subtype, predictors, treatment effects in key subgroups. METHODS Using a 2-by-2 factorial design, 12 705 participants from 21 countries with vascular risk factors but without overt cardiovascular disease were randomized to candesartan 16 mg plus hydrochlorothiazide 12.5 mg daily or placebo and to rosuvastatin 10 mg daily or placebo. The effect of the interventions on stroke subtypes was assessed. RESULTS Participants were 66 years old and 46% were women. Baseline blood pressure (138/82 mm Hg) was reduced by 6.0/3.0 mm Hg and LDL-C (low-density lipoprotein cholesterol; 3.3 mmol/L) was reduced by 0.90 mmol/L on active treatment. During 5.6 years of follow-up, 169 strokes occurred (117 ischemic, 29 hemorrhagic, 23 undetermined). Blood pressure lowering did not significantly reduce stroke (hazard ratio [HR], 0.80 [95% CI, 0.59–1.08]), ischemic stroke (HR, 0.80 [95% CI, 0.55–1.15]), hemorrhagic stroke (HR, 0.71 [95% CI, 0.34–1.48]), or strokes of undetermined origin (HR, 0.92 [95% CI, 0.41–2.08]). Rosuvastatin significantly reduced strokes (HR, 0.70 [95% CI, 0.52–0.95]), with reductions mainly in ischemic stroke (HR, 0.53 [95% CI, 0.37–0.78]) but did not significantly affect hemorrhagic (HR, 1.22 [95% CI, 0.59–2.54]) or strokes of undetermined origin (HR, 1.29 [95% CI, 0.57–2.95]). The combination of both interventions compared with double placebo substantially and significantly reduced strokes (HR, 0.56 [95% CI, 0.36–0.87]) and ischemic strokes (HR, 0.41 [95% CI, 0.23–0.72]). CONCLUSIONS Among people at intermediate cardiovascular risk but without overt cardiovascular disease, rosuvastatin 10 mg daily significantly reduced first stroke. Blood pressure lowering combined with rosuvastatin reduced ischemic stroke by 59%. Both therapies are safe and generally well tolerated. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT00468923.