High-dose statin therapy and the risk of haemorrhagic stroke in Asian patients with stable coronary artery disease: insights from the REAL-CAD study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Takahashi ◽  
K Tsuchida ◽  
Y Sato ◽  
S Iimuro ◽  
K Kario ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Dose Group ◽  
Low Dose ◽  
Japanese Patients ◽  
Haemorrhagic Stroke ◽  
High Dose ◽  
The Real ◽  
Artery Disease ◽  
Stable Cad ◽  
Bleeding Score

Abstract Background/Introduction The REAL-CAD study identified that aggressive lipid lowering with high-dose statin reduced cardiovascular events also in Japanese patients with coronary artery disease (CAD). However, data from the SPARCL trial found that the benefits of high-dose atorvastatin treatment were partially offset by an increase in haemorrhagic stroke (HS). Although meta-analysis showed statin does not increase HS in Western countries, the evidence about the relation between statin and HS in Asian countries is still conflicting. In addition, the CREDO-Kyoto score is one of the prediction scorings for bleeding after coronary revascularization and might be a useful tool for the prediction of HS in this cohort. Recognizing the risk of HS and predicting of HS in the Asian cohort is clinically important. Purpose This study examined the factors associated with HS using the REAL-CAD cohort. Furthermore, we evaluated the performance of the CREDO-Kyoto bleeding risk score to predict HS in this cohort. We also performed the corresponding analysis of ischaemic stroke for reference purposes. Methods We sub-analysed the REAL-CAD study, prospective, multicentre, randomized, open-label, blinded endpoint study, in which 13,054 Japanese patients with stable CAD were randomized to high-dose (4 mg/day) or low-dose (1 mg/day) pitavastatin. Associations for stroke were determined using competing risk models: the Fine and Gray subdistribution hazards model accounting for the competing risk of death in models of haemorrhagic and ischaemic stroke in REAL-CAD trial. Patients were categorized to low (score 0), moderate (score 1–2), and high (score>3) according to CREDO-Kyoto bleeding score for predicting of HS. Results The HS events in high-dose group tended to be higher than low-dose group (4mg vs. 1mg: 43 (0.7%) vs. 30 (0.5%)). The associated factors of HS on univariate analysis were non-prior myocardial (hazard ratio (HR): 0.62, 95% CI: 0.39–0.99) and non-prior cerebral (HR: 0.25, 95% CI: 0.09–0.70) infarction, atrial fibrillation (HR: 2.4, 95% CI: 1.2–4.7), prior HS (HR: 4.2, 95% CI: 1.5–11.8), anaemia (HR: 2.4, 95% CI: 1.4–4.1), and non-statins use before run-in period (HR: 0.52, 95% CI: 0.28–0.99). High-dose pitavastatin was not a correlate with HS. The multivariate analysis revealed anaemia might have a relation with HS (HR: 4.3, 95% CI: 0.90–20.6). The number of HS was the highest in the high CREDO-Kyoto bleeding score group (Figure 1, HR: 2.4, 95% CI: 1.3–4.6), whereas there was no significant difference in the number of HS between the moderate- and low-risk groups (HR: 1.4, 95% CI: 0.84–2.3). Conclusions High-dose pitavastatin was not associated with the incidence of HS in this large Japanese cohort with stable CAD. High CREDO-Kyoto bleeding score was associated with HS as compared with low or moderate scores, even each of the variables consisting of CREDO-Kyoto score was not associated with HS. Figure 1 Funding Acknowledgement Type of funding source: None

scholarly journals High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD)

Circulation ◽  
2018 ◽  
Vol 137 (19) ◽  
pp. 1997-2009 ◽  
Author(s):  
Isao Taguchi ◽  
Satoshi Iimuro ◽  
Hiroshi Iwata ◽  
Hiroaki Takashima ◽  
Mitsuru Abe ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Low Dose ◽  
Stable Coronary Artery Disease ◽  
Japanese Patients ◽  
High Dose ◽  
Artery Disease

scholarly journals Total Homocysteine Lowering Treatment Among Coronary Artery Disease Patients in the Era of Folic Acid Fortified Cereal Grain Flour

Circulation ◽  
2001 ◽  
Vol 103 (suppl_1) ◽  
pp. 1367-1367
Author(s):  
Andrew G Bostom ◽  
Gintaras Liaugaudas ◽  
Paul F Jacques ◽  
Irwin H Rosenberg ◽  
Jacob Selhub
Keyword(s):  
Coronary Artery Disease ◽  
Folic Acid ◽  
Coronary Artery ◽  
Geometric Mean ◽  
High Dose ◽  
Cereal Grain ◽  
Pre Treatment ◽  
Artery Disease ◽  
Stable Cad ◽  
B Vitamin

P86 Background: The prevalence of both deficient plasma folate status, and elevated total (t) plasma levels of the putatively atherothrombotic amino acid homocysteine (Hcy), have been dramatically reduced since the recent advent of fortification of all enriched cereal grain flour products with physiological amounts (i.e., 140 μg/ 100 g flour) of folic acid. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid based B-vitamin supplementation among stable coronary artery disease (CAD) patients. Methods and Results: Using a 2x2 factorial design, we randomly assigned 131 stable CAD patients (mean age 60.1 years; 29.8 % women) to folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d [ FA group] or FA placebo [PL] , ± B6 [ B6 group] 50 mg/d or B6 placebo[PL], for 12 weeks of treatment. All pre-treatment and final on-treatment analyte values were based on the average of two blood collections performed within 1-week. Geometric mean pre-treatment, on-treatment, and pre-treatment minus on-treatment change in (Δ) tHcy levels (μmol/L), were- FA, B6 (n=31): 8.7 (pre-), 7.4 (on-), Δ= -1.3; B6, PL (n=32): 8.7 (pre-), 9.1 (on-), Δ= + 0.4; FA, PL (n=34): 9.0 (pre-), 8.0 (on-), Δ= - 1.0; PL, PL (n=34): 8.4 (pre-), 8.5 (on-), Δ= + 0.1. ANCOVA adjusted for baseline tHcy levels revealed that the very modest (i.e., ∼ 1.0 μmol/L) reductions in fasting values afforded by the FA containing treatments were statistically significant (p <0.05). Conclusions: In the era of cereal grain flour products fortified with physiological amounts of folic acid, stable CAD patients supplemented with high dose, folic acid containing B-vitamin regimens experience only very modest reductions in their mean plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.

scholarly journals The Role of Direct Oral Anticoagulants in Patients With Coronary Artery Disease

2018 ◽  
Vol 24 (2) ◽  
pp. 103-112 ◽  
Author(s):  
Ricky D. Turgeon ◽  
Margaret L. Ackman ◽  
Hazal E. Babadagli ◽  
Jade E. Basaraba ◽  
June W. Chen ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Triple Therapy ◽  
Antiplatelet Therapy ◽  
Low Dose ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Artery Disease ◽  
Stable Cad

Despite contemporary management, patients with coronary artery disease (CAD) remain at high risk for thrombotic events. Several randomized controlled trials have evaluated the use of direct oral anticoagulants (DOACs) in patients with CAD, including in the setting of acute coronary syndrome (ACS) and stable CAD, and in patients with concomitant atrial fibrillation. Trials of apixaban and dabigatran in patients with ACS demonstrate no benefit with an increased risk of bleeding. Conversely, rivaroxaban at a reduced dose of 2.5 mg twice daily reduced thrombotic events and all-cause mortality when added to dual antiplatelet therapy in patients with ACS. Similarly, the addition of low-dose rivaroxaban to acetylsalicylic acid reduced the risk of thrombotic events in patients with stable CAD. However, the addition of a DOAC to antiplatelet therapy increased the risk of major bleeding. In patients with atrial fibrillation undergoing percutaneous coronary intervention, dual-pathway or low-dose triple therapy regimens including dabigatran or rivaroxaban reduced bleeding risk compared to traditional warfarin-based triple therapy, although it remains unclear whether these regimens preserve antithrombotic efficacy. DOAC–based antithrombotic regimens prove useful in patients with CAD in various settings; however, careful selection of patients and regimens per trial protocols are critical to achieving net benefit.

P5320Reduction in high-sensitivity C-reactive protein by pitavastatin was associated with improved outcomes in Japanese patients with stable coronary artery disease: results from REAL-CAD study

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Iwata ◽  
S Iimuro ◽  
A Inoue ◽  
K Miyauchi ◽  
I Taguchi ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Cardiovascular Events ◽  
Stable Coronary Artery Disease ◽  
High Sensitivity ◽  
Japanese Patients ◽  
The Real ◽  
Reactive Protein ◽  
Hs Crp ◽  
Artery Disease ◽  
Stable Cad

Abstract Background The effect of statins on lowering high sensitivity C-reactive protein (hs-CRP) as well as low density lipoprotein cholesterol (LDL-C) has been associated with reduced risk for cardiovascular events in patients with elevated hs-CRP. However, it remains unclear whether this statin effect applies to low-risk patients with stable coronary artery disease (CAD). In this pre-specified sub-study within the REAL-CAD trial, we explored the association between achieved LDL-C/hs-CRP levels and cardiovascular events in Japanese patients with stable CAD who were treated with pitavastatin 1 mg or 4 mg/day. Methods The REAL-CAD trial randomly allocated 13,054 patients with stable CAD to pitavastatin 1 mg or 4 mg/day. LDL-C and hs-CRP were measured at baseline and at 6 months after randomization. We excluded those patients without 6-month data and those with endpoint events before 6 months (N=1915). The primary endpoint of the study was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. Outcomes were assessed by landmark analysis beyond 6 months among 4 groups that were configured based on LDL-C (median) and hs-CRP (median) targets: achieving neither target, achieving LDL-C target only, achieving hs-CRP target only, and achieving both targets. Data were adjusted for baseline characteristics including age, gender, diabetes and baseline values of LDL-C and hs-CRP. Results Median LDL-C and hs-CRP levels were 88 mg/dL and 0.52 mg/L at baseline and 80 mg/dL and 0.48 mg/L after 6 months, respectively. There was no correlation between the change in LDL-C and hs-CRP levels from baseline to 6 months (correlation coefficient: 0.009, P=0.331). Of the 11,677 patients included in the study, 25.1% (N=2799) achieved both LDL-C and hs-CRP targets, 25.3% (N=2282) met neither target, 24.8% (N=2765) met only the hs-CRP target, and 24.7% (N=2753) met only the LDL-C target. Risk of primary endpoint occurrence was significantly lower in those achieving either or both targets than in those meeting neither target (Figure A). In the subgroup analysis stratified by the randomized dose of pitavastatin, the risk for the primary endpoint was significantly lower in patients achieving both targets in both the 1mg and 4 mg arms, and in patients achieving only hs-CRP target in the 1 mg arm (Figure B, C). Figure 1 Conclusions In this subanalysis of the REAL-CAD trial, the hs-CRP lowering effect of pitavastatin was independent from LDL-C lowering. Lower achieved hs-CRP was associated with lower risk for cardiovascular events in Japanese patients with stable CAD. Acknowledgement/Funding Public Health Research Foundation, The company manufacturing the study drug (Kowa Pharmaceutical Co Ltd) was one of the entities providing financial s

Impact of chronic kidney disease on mid-term prognosis of stable angina patients with high-dose or low-dose pitavastatin treatment: REAL-CAD sub-study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Abe ◽  
Y Ozaki ◽  
H Takahashi ◽  
M Akao ◽  
T Kimura ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Cardiovascular Events ◽  
Low Dose ◽  
Coronary Revascularization ◽  
Composite Endpoint ◽  
Japanese Patients ◽  
Cardiovascular Death ◽  
High Dose ◽  
Artery Disease ◽  
Emergency Hospitalization

Abstract Background We previously demonstrated that high-dose (4 mg/day) compared with low-dose (1 mg/day) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease in the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study. However, little is known about whether the advantage of high-dose statins over low-dose statins is consistent among non-, mild, and moderate to severe chronic kidney disease (CKD) patients. Purpose The aim of this study was to clarify the effect of high-dose statins on cardiovascular events in Japanese patients with or without CKD. Methods The REAL-CAD study is a prospective, multicenter, randomized, open-label, blinded endpoint, physician-initiated superiority trial. In this sub-analysis of REAL-CAD study, patients were categorized into three groups according to estimated glomerular filtration rate (eGFR). Patients on hemodialysis were excluded in this study. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (MI), non-fatal ischemic stroke, or unstable angina requiring emergency hospitalization. A secondary composite endpoint was defined as a composite of the primary endpoint event or clinically-indicated coronary revascularization excluding target-lesion revascularization. Results The total population of the REAL-CAD study was 12,413 patients. After exclusion of patients lacking eGFR data, the numbers of patients categorized into non-CKD (eGFR ≥60 mL/min/1.73m2), mild CKD (eGFR; 45–60), and moderate to severe CKD (eGFR &lt;45) were 7,778 (64%), 3,176 (26%), and 1,164 (10%), respectively. The median follow-up period was 3.9 years. The baseline characteristics and medications were well balanced between the two groups in each CKD group. While high-dose compared to low-dose pitavastatin significantly reduced the primary endpoint in non-CKD patients, the effect was not observed in mild CKD and moderate to severe CKD patients (Figure 1). High-dose compared with low-dose pitavastatin did not significantly reduce the secondary composite endpoint in both mild and moderate to severe CKD patients as well. High-dose pitavastatin significantly reduced the risks of MI and any coronary revascularization in non-CKD patients, however, the effects were diminished in mild CKD and moderate to severe CKD patients. There was no significant difference between high-dose and low-dose pitavastatin treatment in the risk of all-cause death, cardiovascular death, ischemic stroke, or unstable angina requiring emergency hospitalization in patients with or without CKD. Conclusion Although high-dose pitavastatin therapy significantly reduced cardiovascular events in non-CKD patients with stable angina compared to low-dose pitavastatin, such beneficial effects had diminished in Japanese patients with mild or moderate to severe CKD patients. Figure 1. Kaplan-Meier Curves for Endpoints Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Clinical Research of Lifestyle-Related Disease of the Public Health Research Foundation

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