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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.

Keywords: cholesterol, LDL; coronary artery disease; hydroxymethylglutaryl-CoA reductase inhibitors; long-term adverse effects; secondary prevention; stroke.

Figure 1.

Disposition of patients. The reasons for not meeting the eligibility criteria were not mutually exclusive. ACS indicates acute coronary syndrome; FAS, full analysis set; LDL-C, low-density lipoprotein cholesterol; and SAS, safety analysis set.

Figure 2.

Changes in lipid parameters and high-sensitivity C-reactive protein (hsCRP) levels over time. A through C, Changes over time in low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. D, Change in hsCRP from baseline to 6 months. Values at baseline and at 6 months were basically derived from central laboratory measurements. If a value from central laboratory measurement was not available or not calculable, a value obtained from the measurement at each institution was used instead. If any value other than those centrally measured was missing, that value was not imputed from other data but was handled as a missing value and excluded from analysis. Central laboratory measurements were available for LDL cholesterol in 11 813 patients at baseline and in 11 319 patients at 6 months, whereas those for total cholesterol, triglycerides, and HDL cholesterol were available in 12 026 patients at baseline and in 11 320 patients at 6 months. Central laboratory measurements for hsCRP were available in 12 026 patients at baseline and in 11 319 patients at 6 months. Values at 1, 2, and 3 years were derived from measurements at each institution. P values were for the main therapeutic effect and for the interaction effect between therapeutic effect and time.

Figure 3.

Kaplan-Meier curves for the primary end point and a secondary composite end point (primary end point plus coronary revascularization). The cumulative incidence was estimated by the Kaplan-Meier method. A and B, Kaplan-Meier curves for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization) and for a secondary composite end point (a composite of primary end point or coronary revascularization based on clinical indication), respectively. Coronary revascularization as a component of the secondary composite end point excluded target-lesion revascularization for lesions treated at the time of prior percutaneous coronary intervention. CI indicates confidence interval; and HR, hazard ratio.

Figure 4.

Subgroup analyses of the effects of high- vs low-dose pitavastatin for the primary end point and for a secondary composite end point (primary end point plus coronary revascularization) in the prespecified subgroups. A and B, Subgroup analysis for the primary end point and for a secondary composite end point, respectively. Numbers of patients with event were summarized per subgroup within each treatment. Hazard ratios (HRs) were calculated within each subgroup level for the treatment effect of pitavastatin 4 mg relative to pitavastatin 1 mg. The P value was derived from an interaction test between the subgroup factors and treatment effect of pitavastatin 4 mg relative to pitavastatin 1 mg. Horizontal bars indicate 95% confidence intervals (CIs). Coronary revascularization as a component of the secondary composite end point excluded target-lesion revascularization for lesions treated at the time of prior percutaneous coronary intervention. HDL indicates high-density lipoprotein; hsCRP, high sensitivity C-reactive protein; and LDL, low-density lipoprotein.