High-intensity statin therapy reduces CV events in Japanese CAD patients

REAL-CAD - Does High-Intensity Pitavastatin Therapy Further Improve Clinical Outcomes? The REAL-CAD Study in 13,054 Patients with Stable Coronary Artery Disease

Presented at AHA 2017 Scientific Sessions in Anaheim, CA, USA by Hiroaki Shimokawa (Tohoku University, Sendai, Japan)

News - Nov. 15, 2017

Background

Multiple studies have shown that higher vs. lower dose statins is better, with regard to reducing CV events. Guidelines for lipid-lowering therapy in patients with established CVD therefore recommend high-intensity statin therapy (ACC/AHA) or an LCL-c target level of 70 mg/dL or lower (ESC).

High-intensity statin therapy is, however, not widely used in Asia, and most of the high-intensity statins are not approved in Japan. Moreover, there is no clear evidence of the efficacy in the Asian population. The incidence of CV events is lower in Asia and therefore the documented benefits of high-intensity statin therapy might not be relevant in this patient population. Although pitavastatin lowered LDL-c levels in a dose-dependent manner in Japanese individuals (a lowering of 47% with 4 mg pitavastatin) and studies reported a reduction of plaque volume and carotid intima-media thickness (IMT) with high-dose statin, no mortality benefits have been demonstrated in the Asian population.

Therefore the Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) trial was designed. It was a prospective, multi-center, randomized, open-label, blinded endpoint, physician-initiated trial to determine whether high-dose (4 mg, 6528 patients) as compared with low-dose (1 mg, 6528 patients) pitavastatin therapy within the approved dose range could reduce CV events in Japanese patients with stable CAD. The primary endpoint consisted of a composite of CV death, non-fatal MI, non-fatal ischemic stroke, or unstable angina requiring emergency hospitalization.

Main results

Significantly lower levels of LDL-c, TG, hsCRP and higher HDL-c were observed after a median follow-up of 3.9 years with high-dose statin compared to low-dose (P<0.001).
HR for the primary endpoint was 0.81 (95%CI: 0.69-0.95, P=0.01) with 4.3% patients with events for high-dose pitavastatin and 5.4% for low-dose pitavastatin.
HR for the secondary endpoint (primary endpoint plus coronary revascularization) was 0.83 (95%CI: 0.73-0.93, P=0.02) with 7.9% patients with events for high-dose pitavastatin and 9.7% for low-dose pitavastatin.
Other secondary endpoints that showed a significant reduction with high-dose statin were: death from any cause, MI, coronary revascularization (all and non-TLR).
Pitavastatin treatment was very safe. Only more muscle-complaints were observed in the high-dose statin group compared with the low-dose (121% [0.7%] vs. 45% [1.9%], P=0.01)

Conclusion

High-dose pitavastatin therapy significantly reduced CV events and overall mortality in Japanese patients with stable CAD compared with low-dose pitavastatin therapy. This study supports that administration of higher doses of statins, within the range of local approval, is the preferred statin therapy in Japanese patients with established CAD, regardless of their baseline LDL-C levels.

*Discussion*

Discussant Karol Watson (UCLA, Los Angeles, CA, US) stated that this trial has provided information on the treatment of Asian CAD patients with high-dose statin. She expressed her surprise that also a mortality benefit was seen. All patients first received 1 mg daily, and after randomization LDL-c further reduced in those assigned to 4 mg. Importantly, treatment was very well treated.

She did raise the following points that are still unknown. Would outcomes have been improved with greater LDL-c reduction? She pointed out that the dose of 4 mg pitavastatin that was used in this study is considered a moderate-intensity statin therapy that results on average in a lowering of ~30% to <50%. It would be interesting to examine the effect of high-intensity statin therapy (> 50% LDL-c reduction) as recommended by the 2013 AHA-ACC cholesterol guidelines. However, would high intensity statin therapy be well tolerated in an Asian population? Concerns have been raised that Asians might tolerate high-intensity statins less well. In addition, Prof. Watson wondered whether these data translate to other statins, and what happened to the participants lost to follow-up?

Overall, this trial has demonstrated that high-dose statin strategy in Asian patients is safe, well tolerated and beneficial.

Disclosures

- Our reporting is based on the information provided at the AHA 2017 congress -