Circulation May 8, 2018 Issue

Dr Joseph Hill: My name is Joe Hill. I'm the Editor-in-Chief of Circulation and I'm very pleased today to be here today with Professor Daida from Juntendo University in Tokyo, Japan, as well as one of our associate editors, Professor Shinya Goto from Tokai University in Kanagawa, Japan. Dr. Daida is one of the senior authors on a very exciting clinical trial that we're publishing in Circulation. The first and largest trial comparing high-dose versus low-dose statins in Asia. Dr. Daida, would you please tell us more about the study?

Dr Hiroyuki Daida: Yes. Thank you. The trial, called REAL-CAD, is a randomized trial. We compare high-dose statins with low-dose statins in Japanese patients with stable coronary artery disease. The number of the patients is 13,000. It's the largest trial ever comparing high-dose and low-dose statins. We found that with that reduction of the primary end point, which is a composite end point, including cardiovascular death, non-fatal MI, non-fatal stroke, and unstable angina requiring hospitalization.

That is very exciting result because it is the largest trial ever and also the very first trial in Asia.

Professor Shinya Goto: Congratulations, Professor Daida, for that great achievement, in the REAL-CAD trial. Could you explain a little bit about the background and that the dose of statins in Japan is generally low, and what was the reason why we kept using low-dose statins, and is care to try change the standard of care in Japan and also East Asia? Could you give a comment on those two topics?

Dr Hiroyuki Daida: Our trial is quite similar to that of PNP trial of comparing Western extensive statin treatment and the Asia statin treatment. However, that extensive statin treatment, intensive statin treatment, is not popular in Asia, so we did that maximum clinical dose of statin, we use this dose in Japan. It is the maximum dose of statin approved in Japan.

Dr Joseph Hill: So as I understand it, the rationale was the thinking that Asians, East Asians, are unable to tolerate high-dose statin therapy. In this case you used pitavastatin. And, in fact, what you found was there were no increase in serious adversive events in high dose patients. And, just like Caucasians, they derived considerable benefit at multiple points in atherosclerotic cardiovascular disease metrics.

Dr Hiroyuki Daida: Actually, they didn't experience a really high-dose of statin in Japan so government approval is up to 4 mg of pitavastatin, a dose of that about 20.

Dr Joseph Hill: So, this is not what we would call high-intensity statin therapy but nonetheless, there was a dramatic benefit including an all-cause mortality, irrespective of the starting LDL level at the beginning of the trial?

Dr Hiroyuki Daida: That is right. We found that the effect is similar that the patient, the LDL is greater than 95 or less than 95. So, the effect is independent of the basal based on LDL level.

Professor Shinya Goto: The one thing, very exciting just like Joe mentioned, all cause of mortality, especially known cardiovascular caused mortality reduced with the use of high-intensive care of the statin. If any kind of speculation, what is the cause, reduce the inflammation or maybe reduce cancer, something like that. They have any kind of advance to an analysis?

Dr Hiroyuki Daida: We didn't have further analysis but we are not so keen to emphasis the total mortality because maybe that is a chance of the effect but this is the largest trial, so the result is really exciting in this kind of aspect.

Dr Joseph Hill: So, I would reiterate Shinya's congratulations. This is a monumental piece of work. The largest clinical trial comparing high dose versus low dose statin. The largest ever. The first in Asia. You found a benefit that makes total sense across what we know from other trials and this will change practice. Your work, I believe, will change the way patients with atherosclerotic cardiovascular disease is handled in Japan.

Dr Hiroyuki Daida: Yes, actually the current guideline in Japan for the secondary condition. The condition is LDL less than 100 and for the really high-risk secondary condition listed seventh. We didn't recommend high-dose statin initially, so, this trial result is kind of like this, changing.

Dr Joseph Hill: I can't resist asking, what comes next? What's your next project?

Dr Hiroyuki Daida: Maybe we need to have a further reduction of LDL. We have another drug, other potent drug recently. We need to investigate all of the new drug such as PCSK9 inhibitor in secondary prevention.

Professor Shinya Goto: That's wonderful. Do you have any time to extend observation of the trial? I think the trial is relatively still superior as compared to the global long-standing trial. Really, that's fine, that effect of statin on the cholesterol and even it's different from Japan and other regions of the world. There ought to be intriguing thing, I would like to know, what are you waiting to extend that observation now?

Dr Hiroyuki Daida: Fortunately, we do not intend to extend the follow-up. The whole thing is about four years but we do not plan to extend. We will further analyze the data for some group and our kind of CRP and effect of the baseline.

Dr Joseph Hill: Lots of secondary analysis underway, undoubtedly. Let me thank both of you for being here, Professor Daida and Professor Goto, I congratulate you again. It's not often that you make a practice-changing intervention in modern-day medicine. I salute you and we are honored and thrilled to publish your outstanding work in Circulation. Thank you both.

Dr Hiroyuki Daida: Thank you very much.

Professor Shinya Goto: Thank you very much.