High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (P<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P=0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P=0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.

Taguchi I ，Iimuro S ，Iwata H ，Takashima H ，Abe M ，Amiya E ，Ogawa T ，Ozaki Y ，Sakuma I ，Nakagawa Y ，Hibi K ，Hiro T ，Fukumoto Y ，Hokimoto S ，Miyauchi K ，Yamazaki T ，Ito H ，Otsuji Y ，Kimura K ，Takahashi J ，Hirayama A ，Yokoi H ，Kitagawa K ，Urabe T ，Okada Y ，Terayama Y ，Toyoda K ，Nagao T ，Matsumoto M ，Ohashi Y ，Kaneko T ，Fujita R ，Ohtsu H ，Ogawa H ，Daida H ，Shimokawa H ，Saito Y ，Kimura T ，Inoue T ，Matsuzaki M ，Nagai R ... -  《-》

Low-density lipoprotein cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidaemia: the HIJ-PROPER study, a prospective, open-label, randomized trial.

To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L). The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91). Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed. UMIN000002742, registered as an International Standard Randomized Controlled Trial.

Hagiwara N ，Kawada-Watanabe E ，Koyanagi R ，Arashi H ，Yamaguchi J ，Nakao K ，Tobaru T ，Tanaka H ，Oka T ，Endoh Y ，Saito K ，Uchida T ，Matsui K ，Ogawa H ... -  《-》

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

Miyauchi K ，Kimura T ，Shimokawa H ，Daida H ，Iimuro S ，Iwata H ，Ozaki Y ，Sakuma I ，Nakagawa Y ，Hibi K ，Hiro T ，Fukumoto Y ，Hokimoto S ，Ohashi Y ，Ohtsu H ，Saito Y ，Matsuzaki M ，Nagai R ，REAL-CAD Trial Investigaters ... -  《-》

Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.

Vallejo-Vaz AJ ，Fayyad R ，Boekholdt SM ，Hovingh GK ，Kastelein JJ ，Melamed S ，Barter P ，Waters DD ，Ray KK ... -  《-》

Relation of renal function to mid-term prognosis of stable angina patients with high- or low-dose pitavastatin treatment: REAL-CAD substudy.

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. 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. 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). 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.

Abe M ，Ozaki Y ，Takahashi H ，Ishii M ，Masunaga N ，Ismail TF ，Iimuro S ，Fujita R ，Iwata H ，Sakuma I ，Nakagawa Y ，Hibi K ，Hiro T ，Fukumoto Y ，Hokimoto S ，Miyauchi K ，Ogawa H ，Daida H ，Shimokawa H ，Saito Y ，Matsuzaki M ，Akao M ，Kimura T ，Nagai R ... -  《-》