Higher-Dose Pitavastatin Superior in Treating Japanese Patients With Stable Coronary Artery Disease: Presented at AHA

By Walter Alexander

ANAHEIM, California -- November 14, 2017 -- High-dose (4 mg/day) pitavastatin reduced cardiovascular events significantly in Japanese patients with stable coronary-artery disease (CAD) compared with low-dose (1 mg/day) pitavastatin, according to results of the open-label REAL-CAD (Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease) trial, presented at the 2017 Annual Scientific Sessions of the American Heart Association (AHA).

Cardiovascular event rates are lower in Asian patients than in Western patients, explained study co-author Hiroaki Shimokawa, MD, Public Health Research Foundation, Kowa Pharmaceutical Co. Ltd, Tokyo, Japan, speaking here at a press conference on November 12. The clinical relevance of benefits demonstrated for high-intensity statins in Western patients may not persist for the Asian patient at lower risk of an event, he added.

Findings from the REAL-CAD study support administration of higher doses of statins in this population, regardless of baseline low-density lipoprotein cholesterol (LDL-C) levels.

The REAL-CAD investigators enrolled 13,054 stable patients with CAD from 733 Japanese institutions, and randomised them on a 1:1 basis, after a pitavastatin 1-mg/day, 1-month run-in to pitavastatin 1 mg/day or 4mg/day, and followed them for 36 to 60 months. All subjects (mean age, 68 years; 83% male) had LDL-C <120 mg/dL on 1 mg/day pitavastatin. Dr. Shimokawa pointed out that the pitavastatin 1-mg and 4-mg doses are equivalent to atorvastatin 5-mg and 20-mg doses, respectively.

At follow-up, LDL-C reductions were significantly greater in the pitavastatin 4-mg/day group (P < .001), as were reductions in triglycerides (P < .001) and high-sensitivity C reactive protein (hs-CRP) (P < .001). High-density lipoprotein cholesterol (HDL-C) increased significantly in the pitavastatin 4-mg/day group (P < .001).

After 5 years, the primary endpoint of combined cardiovascular death, myocardial infarction, ischaemic stroke or unstable angina was reduced in the 4-mg group (4.3%) compared with the 1-mg group (5.4%, hazard ratio [HR] 0.81 [95% confidence interval {CI}, 0.69 to 0.95]; P = .01). The number needed to treat was 63.

The secondary endpoint, adding need for coronary revascularisation to the primary endpoint, was also reduced in the 4-mg group at 7.9% as compared with 9.7% in the 1-mg group (hazard ratio [HR] 0.83 [95% CI, 0.73 to 0.93]; P = .002). The number needed to treat was 41. The pattern persisted across numerous subgroups.

Among safety outcomes, muscle complaints were higher in the pitavastatin 4-mg group at 1.9% versus 0.7% in the 1-mg group (P < .001). There was no difference in rates of rhabdomyolysis or any other adverse event.

“This trial should give comfort that this strategy is safe, well tolerated and beneficial,” noted AHA discussant Karol E. Watson, MD, PhD, UCLA Program in Preventive Cardiology, Los Angeles, California. She also noted that further benefits and tolerance with greater LDL-C reductions remain unknown in this population.

Dr. Shimokawa suggested that, while ACC/AHA guidelines recommend a “fire and forget” strategy of high-intensity statin therapy (atorvastatin 40/80 mg, rosuvastatin 20/40 mg or simvastatin 80 mg) for lipid lowering in patients with established CAD, European Society of Cardiology guidelines recommend a “treat to target” strategy of 70 mg/dL or lower. He pointed out that high-intensity statins are not widely used in daily practice, especially in Asia. Furthermore, the doses cited in the ACC/AHA guidelines are not approved in Japan.

In Japanese patients, however, significant dose-related reductions in LDL-C levels have been shown at 33.6% for pitavastatin 1 mg and 41.8% and 47.0% for pitavastatin 2 mg and 4 mg, respectively (Saito Y, et al. Arzneimittelforschung. 2002;52: 251-5).

[Presentation title: Does High-Intensity Pitavastatin Therapy Further Improve Clinical Outcomes? The REAL-CAD Study in 13,054 Patients With Stable Coronary Artery Disease.]

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