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Hirotoshi Watanabe, MD
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Dr. Hirotoshi Watanabe is a member of the Department of Cardiology, Kyoto University Hospital in Kyoto, Japan. He is the lead author on a paper, published in the June 25th issue of JAMA, entitled "Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial."

The study demonstrated that 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. Angioplasty.Org’s partner site, TCROSS NEWS, recently interviewed Dr. Watanabe, a principal author of the present study, regarding the background and important findings of the study.

    Hirotoshi Watanabe, MD
Hirotoshi Watanabe, MD

Q: The present study excluded patients who had already received drug-eluting stents other than CoCr-EES. What were the reasons for this exclusion?
Dr. Watanabe: This study was originally designed as the result of the STOPDAPT study which demonstrated non-significant difference between 3 months of DAPT and 12 months of DAPT. STOPDAPT-2 was designed to consider further reduction of the DAPT duration using the current standard DES. Since CoCr-EES was used in the original STOPDAPT trial, which had followed the RESET study (comparing the first-generation SES and CoCr-EES), we selected the current standard DES (CoCr-EES) for the present study.

However, unlike in STOPDAPT, we did not exclude patients who already had non-CoCr-EESs from previous PCIs, in order to include high risk patients in a series of consecutive cases.

Q: The patients in the present study received clopidogrel, but not aspirin as the single antiplatelet agent. Why was this the case and how does that reflect current clinical practice?
Dr. Watanabe: We originally planned to demonstrate the safety and efficacy of 3 months of DAPT in a randomized clinical trial, since the original STOPDAPT used historical control. However, since we already knew the safety and efficacy of 3 months of DAPT from STOPDAPT, we decided to further shorten the DAPT duration to one month in STOPDAPT-2.

Aspirin was not recommended as the single antiplatelet agent beyond 1-month DAPT since many Japanese investigators had concerns about increase of thrombosis at the beginning of the study planning, 2014. To avoid delaying the patient recruitment, we set the use of clopidogrel as the single antiplatelet agent in the 1-month DAPT group. Prasugrel is another alternative drug, but it is not reimbursed as a single antiplatelet therapy in current Japanese medical practice. As the result, beyond 1-year after index PCI, 1-month DAPT group will receive clopidogrel monotherapy and 12-month DAPT group will receive aspirin monotherapy. Therefore, we can compare the clopidogrel monotherapy and aspirin monotherapy for the patients after discontinuing DAPT by watching enrolled patients for long term. This is not a strict randomized control study comparing clopidogrel monotherapy versus aspirin monotherapy for patients discontinuing DAPT. However, we at least can see the direction of appropriate single therapy for the patients after DAPT.

As we all know, aspirin is a cost-effective drug. However, we also know the negative aspect of aspirin, such as gastrointestinal bleeding related to ulcer. We believe that clopidogrel is an agent which inhibits ischemic event without increasing bleeding risk.

Q: The present study included more than 3,000 patients from 90 Japanese centers. What was the biggest difficulty in implementing this kind of large-scale study in Japan and how did you overcome it?
Dr. Watanabe: Investigators from all over the country contributed to the study and various patients were included in the present study. I would like to show my sincerity to all investigators participated in the study. I also thank the secretariat of the study who managed the centers and execution of research. Additionally, thank you for people in CRC who made a great effort to enter mass data to complete the study.

Due to the complexity of the study protocol, we first visited some centers to explain the details. Indeed, we received many questions when the study protocol was submitted to an ethical committee in each hospital. Dr. Takenori Domei, an investigator from Kokura Memorial Hospital, entered the largest sample. He shared tips to accelerate patient enrollment and a technique to advance clinical study.

Q: Clopidogrel was prescribed in 62% of the patients in first 30 days, whereas the remaining patients (38%) received prasugrel. Was there a difference in the study outcome?
Dr. Watanabe: The protocol accepted use of a P2Y12 inhibitor in the first month, but indeed there was no significant difference in primary outcome in 60 days. One-year primary outcome was also equivalent between clopidogrel and prasugrel, as well as between one month of DAPT and 12 months of DAPT.

Q: As compared to 12 months of DAPT, 1 month of DAPT demonstrated significantly lower primary outcome (2.36% vs 3.70%: p=0.04). Did you expect this result?
Dr. Watanabe: The present study initially formed a hypothesis that 1 month of DAPT is not inferior to 12 months of DAPT. Thus, we expected non-inferiority at the initial stage, but we did not expect superiority for 1 month of DAPT over 12 months of DAPT. Perhaps significant bleeding inhibition with only 1 month of DAPT is a part of the reason for this outcome, but we were not able to predict this outcome due to lack of evidence with single clopidogrel treatment.

Q: In this study, both groups demonstrated significantly lower event rates as compared to other non-Japanese studies. Do you believe that the outcome is only applicable to intervention as practiced in Japan?
Dr. Watanabe: In fact, we have received many questions since we presented at the late-breaking clinical trial session at the ACC 2019 meeting. The utilization rate of intracoronary imaging devices (include IVUS/OCT) in the present study was 97.3%. Current practice in Japan uses intracoronary imaging devices in most PCIs.

The use of intracoronary imaging devices is much lower in Europe and U.S. counterparts. Imaging devices are mostly used in university hospital or research centers in Western countries due to cost and time consumption. Intracoronary imaging devices are not reimbursed in many of their countries. However, event rates in previous studies comparing IVUS-guided and Angiography-guided PCI (e.g., IVUS-XPL and ULTIMATE) are not much different from STOPDAPT-2.

On the other hand, patient characteristics are slightly different between allocated and not allocated in the present study. Overall, 6,504 patients were eligible for the study and 3,045 patients were randomized at 90 centers in Japan; 3,459 eligible patients were not enrolled in the study, mainly because of the judgment of attending physician or patient refusal. Excluding 36 patients who withdrew consent, 3,009 patients were included in the main analysis. Thus, a certain number of high-risk patients were possibly excluded during the screening process. Patients with STEMI, those who received first-generation DES, or patients who suffered from CKD were more common in the patient group not allocated to the study, but the actual difference was small in the current study.

We also should consider differences between Japanese and the Western patients. For example, the average age and BMI of Japanese patients who undergo PCI is 69 and 24, whereas those of Western nations are 64 and 28 respectively. We strongly believe that age and body weight affect bleeding and ischemic events. I am not sure that this outcome applies to DESs other than CoCr-EES. Antiplatelet effect of fluoropolymer coating which is peculiar to CoCr-EES may or may not affect the outcomes, so we cannot assert this unless demonstrated by appropriate studies. Event rates of restenosis and stent thrombosis in current available DESs are considerably low and many of them have demonstrated non-inferiority as compared CoCr-EES. Thus, we can expect that DESs other than CoCr-EES may show the equivalent outcomes to the present study.

Q: The outcomes of this study modified the Japanese guidelines. How does the present study affect your clinical practice?
Dr. Watanabe: When we initiated the study, we were concerned about a potential increase in stent thrombosis with only 1 month of DAPT. However, as study progressed, we were assured that single clopidogrel treatment after 1 month of DAPT did not increase stent thrombosis; rather it is safer than 12 months of DAPT.

As the result of the current study, 1 month of DAPT will become standard practice in Japan. Today, I stop DAPT at one month without hesitation. However, the present study was not powered for patients who suffer from ACS or complex lesions. We need further evidence before discontinuing DAPT for these complex patients.

This interview was conducted in July 2019 by TCROSS NEWS, Tokyo, Japan