Author + information
- Masato Nakamura, MD, PhDa,∗ (, )
- Raisuke Iijima, MD, PhDa,
- Junya Ako, MD, PhDb,
- Toshiro Shinke, MD, PhDc,
- Hisayuki Okada, MD, PhDd,
- Yoshiaki Ito, MD, PhDe,
- Kenji Ando, MDf,
- Hitoshi Anzai, MD, PhDg,
- Hiroyuki Tanaka, MD, PhDh,
- Yasunori Ueda, MD, PhDi,
- Shin Takiuchi, MD, PhDj,
- Yasunori Nishida, MDk,
- Hiroshi Ohira, MDl,
- Katsuhiro Kawaguchi, MD, PhDm,
- Makoto Kadotani, MD, PhDn,
- Hiroyuki Niinuma, MD, PhDo,
- Kazuto Omiya, MD, PhDp,
- Takashi Morita, MD, PhDq,
- Kan Zen, MD, PhDr,
- Yoshinori Yasaka, MD, PhDs,
- Kenji Inoue, MD, PhDt,
- Sugao Ishiwata, MD, PhDu,
- Masahiko Ochiai, MD, PhDv,
- Toshimitsu Hamasaki, MSc, PhDw,
- Hiroyoshi Yokoi, MDx,
- NIPPON Investigators
- aDivision of Cardiovascular Medicine, Toho University Ohashi Medical Center, Tokyo, Japan
- bDepartment of Cardiovascular Medicine, Kitasato University Hospital, Sagamihara, Japan
- cDivision of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
- dDepartment of Cardiology, Seirei Hamamatsu General Hospital, Hamamatsu, Japan
- eDivision of Cardiology, Saiseikai Yokohama-City Eastern Hospital, Yokohama, Japan
- fDepartment of Cardiology, Kokura Memorial Hospital, Kitakyushu, Japan
- gCardiology Department, Ota Memorial Hospital, Ota, Japan
- hDepartment of Cardiology, Tokyo Metropolitan Tama Medical Center, Tokyo, Japan
- iCardiovascular Division, National Hospital Organization Osaka National Hospital, Osaka, Japan
- jDepartment of Cardiology, Higashi Takarazuka Satoh Hospital, Takarazuka, Japan
- kDepartment of Cardiovascular Medicine, Takai Hospital, Nara, Japan
- lDepartment of Cardiology, Edogawa Hospital, Tokyo, Japan
- mDepartment of Cardiology, Komaki City Hospital, Komaki, Japan
- nDepartment of Cardiology, Kakogawa Central City Hospital, Kakogawa, Japan
- oDepartment of Cardiology, St. Luke's International Hospital, Tokyo, Japan
- pDivision of Cardiology, St. Marianna University School of Medicine Yokohama City Seibu Hospital, Yokohama, Japan
- qDivision of Cardiology, Osaka General Medical Center, Osaka, Japan
- rDepartment of Cardiovascular Medicine, Omihachiman Community Medical Center, Omihachiman, Japan
- sDepartment of Cardiology, Hyogo Brain and Heart Center, Himeji, Japan
- tDepartment of Cardiology, Juntendo University Nerima Hospital, Tokyo, Japan
- uCardiovascular Center, Toranomon Hospital, Tokyo, Japan
- vDivision of Cardiology and Cardiac Catheterization Laboratories, Showa University Northern Yokohama Hospital, Yokohama, Japan
- wDepartment of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan
- xDepartment of Cardiovascular Medicine Center, Fukuoka Sanno Hospital, Fukuoka, Japan
- ↵∗Address for correspondence:
Dr. Masato Nakamura, Division of Cardiovascular Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
Objectives The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a multicenter randomized investigation of the noninferiority of short-term versus long-term dual antiplatelet therapy (DAPT) in patients with implantation of the Nobori drug-eluting stent (DES) (Terumo, Tokyo, Japan), which has a biodegradable abluminal coating.
Background The optimum duration of DAPT for patients with a biodegradable polymer-coated DES is unclear.
Methods The subjects were 3,773 patients with stable or acute coronary syndromes undergoing Nobori stent implantation. They were randomized 1:1 to receive DAPT for 6 or 18 months. The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (all-cause mortality, myocardial infarction, stroke, and major bleeding) from 6 to 18 months after stenting. Intention-to-treat analysis was performed in 3,307 patients who were followed for at least 6 months.
Results NACCE occurred in 34 patients (2.1%) receiving short-term DAPT and 24 patients (1.5%) receiving long-term DAPT (difference 0.6%, 95% confidence interval [CI]: 1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of −2%, noninferiority of short-term DAPT was confirmed. Mortality was 1.0% with short-term DAPT versus 0.4% with long-term DAPT, whereas myocardial infarction was 0.2% versus 0.1%, and major bleeding was 0.7% versus 0.7%, respectively. The estimated probability of NACCE was lower in the long-term DAPT group (hazard ratio: 1.44, 95% CI: 0.86 to 2.43).
Conclusions Six months of DAPT was not inferior to 18 months of DAPT following implantation of a DES with a biodegradable abluminal coating. However, this result needs to be interpreted with caution given the open-label design and wide noninferiority margin of the present study. (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227)
- biodegradable polymer
- drug-eluting stent(s)
- dual antiplatelet therapy
- net adverse clinical and cerebrovascular event(s)
- stent thrombosis
The indications for use of drug-eluting stents (DES) in patients with atherosclerotic coronary artery disease have been expanded due to the lower restenosis rates achieved with these stents. However, soon after the introduction of DES into real-world practice, the new clinical problem of “very late stent thrombosis” was discovered, and the association between the risk of stent thrombosis and cessation of dual antiplatelet therapy (DAPT) became a topic of discussion (1–3). It was initially reported that extending the duration of DAPT might increase the risk of bleeding complications without reducing cardiovascular events (4), leading to the strategy of performing short-term DAPT after DES implantation. Other studies were subsequently conducted to determine the optimal duration of DAPT after DES implantation (5–9). Although inconsistent and contradictory results were obtained, these studies also suggested that bleeding complications may be the major drawback of long-term DAPT. Therefore, although the optimal duration of DAPT after DES implantation remains unclear, the data obtained so far suggest that it is important to evaluate the net clinical benefit of DAPT by comparing the reduction of cardiovascular events with the risk of bleeding events. Recent advances in DES technology have included the introduction of stents that have a biodegradable polymer abluminal coating, and clinical trials have demonstrated a better safety profile of such second-generation DES compared with first-generation DES (10,11). The NIPPON (Nobori Dual Antiplatelet Therapy as Appropriate Duration) study was a prospective, multicenter, randomized controlled trial (RCT) that was designed to compare the net clinical benefit of short-term versus long-term DAPT on the basis of assessment of efficacy and safety. All patients in this trial received the Nobori stent (Terumo, Tokyo, Japan), a promising DES for reducing the long-term risk of stent thrombosis with a biodegradable abluminal coating. This was a RCT comparing different DAPT regimens after implantation of a stent with a biodegradable abluminal coating.
The NIPPON study was a prospective RCT that compared 6 months of DAPT (short-term DAPT) and 18 months of DAPT (long-term DAPT) after DES implantation in patients with coronary artery disease. It was performed from December 2011 to June 2015 at 130 Japanese institutions (Online Appendix). DAPT was aspirin (81 to 162 mg/day) combined with clopidogrel (75 mg/day) or ticlopidine (200 mg/day). During hospitalization for percutaneous coronary intervention (PCI), patients were assigned to 6 or 18 months of DAPT at a 1:1 ratio by central randomization using an interactive web-based system. This study was designed to approximate an all-comers trial with broad inclusion criteria to reflect the real-world clinical setting, and it enrolled patients with acute myocardial infarction (MI). The exclusion criteria were in-stent restenosis (bare-metal stent or DES) and index PCI for saphenous vein graft disease or unprotected left main trunk disease. The inclusion and exclusion criteria are detailed in the Online Appendix. A maximum of 4 analyses (3 blinded interim analyses and 1 final analysis) were prospectively planned. To control the Type I error, the maximum sample size was calculated to be 4,598 patients (2,299 patients per group) by a group-sequential method using the Lan-DeMets error-spending method (12) with the O’Brien-Fleming–type boundary, with the interim analyses being planned at equally spaced points during data accumulation (25%, 50%, and 75% of the total data). The first interim analysis was scheduled after follow-up of 1,500 patients for 18 months. This analysis showed substantially lower overall event rates in 1 treatment group and slower enrollment than anticipated, so the executive committee decided to terminate enrollment in June 2015. In addition, the DAPT trial demonstrated the advantages of long-term DAPT, especially in patients with acute coronary syndrome (9). Taken together, the choice of DAPT duration in this study was left up to the attending physician for the patients already enrolled.
The study protocol was approved by the institutional review board at each participating center. Written informed consent was obtained from all patients. This study was conducted in accordance with the Declaration of Helsinki and was registered at ClinicalTrials.gov (Nobori Dual Antiplatelet Therapy as Appropriate Duration [NIPPON]; NCT01514227).
Study procedures and follow-up
All interventions for coronary revascularization were performed in the real-world clinical setting in accordance with the current Japanese guidelines, and were selected at the discretion of the interventional cardiologist. Clinical follow-up was scheduled at 1, 3, 6, 12, 18, and 36 months after DES implantation, but angiographic follow-up was not mandatory. Discontinuation of thienopyridine therapy for at least 2 weeks was defined as withdrawal.
The primary endpoint was net adverse clinical and cerebrovascular events (NACCE) (defined as all cause death, Q-wave or non–Q-wave MI, cerebrovascular events, and major bleeding events) from 6 to 18 months after DES implantation. Major bleeding was defined by a modification of the criteria used in the REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2) study, and included intracranial bleeding, intraocular bleeding, retroperitoneal bleeding, clinically evident bleeding causing a decrease of hemoglobin by >3 g/dl, all bleeding causing a decrease of hemoglobin by >4 g/dl, and bleeding leading to transfusion of packed red blood cells or ≥2 U of whole blood (13). Major bleeding was also evaluated by the Bleeding Academic Research Consortium (BARC) criteria for type 3 and 5 bleeding (14). The main secondary endpoints were: 1) NACCE during the entire follow-up period (0 to 18 months); 2) the incidence of definite or probable stent thrombosis according to the Academic Research Consortium definition (15) from 6 to 18 months after implantation; 3) the incidence of death, MI, and cerebrovascular events from 6 to 18 months after DES implantation; and 4) the incidence of major bleeding events at 18 months. More detailed definitions of the endpoints are provided in the Online Appendix.
The steering committee, data safety monitoring board, and clinical event committee are listed in the Online Appendix.
This study was designed to demonstrate noninferiority of short-term DAPT versus long-term DAPT with a power of 90% and a significance of 2.5% for the 1-sided, chi-square test. The incidence of the primary endpoint (NACCE from 6 months to 18 months) was assumed to be 4.5% in both the long-term and short-term DAPT groups, with the noninferiority margin being set at 2.0%. Analyses were primarily performed on an intention-to-treat (ITT) basis. For assessment of noninferiority, the 95% confidence interval (CI) of the difference in the event rate (determined by subtracting the rate in the short-term DAPT group from that in the long-term DAPT group) was calculated by using the Newcombe-Wilson method, and noninferiority was accepted if the lower limit of the 95% CI was more than −2.0. An “as-treated” analysis was also conducted to evaluate the robustness of the results obtained by ITT analysis. Event rates with 95% CIs were calculated. Kaplan-Meier survival analysis was also conducted, and survival event curves were compared by using the log-rank test. Categorical variables were described as numbers and proportions. Analysis of categorical variables was performed using the chi-square test or Fisher exact test, whereas continuous variables were analyzed with the Student t test or Wilcoxon rank test. The Cox proportional hazard (PH) model was used to calculate the hazard ratio (HR) and 95% CI. The treatment-by-subgroup interaction was assessed for all subgroups, either by calculating HRs between subgroups or by using the interaction terms in the Cox PH model. All p values were 2-sided, and p < 0.05 was considered to indicate statistical significance. All statistical analyses were performed with SAS version 9.3 for Windows (SAS Institute, Cary, North Carolina).
Figure 1 shows a flowchart of the trial. Of the 3,773 patients enrolled, 3,307 patients were followed for at least 6 months and were analyzed for the primary endpoint. Seventeen patients in the long-term DAPT group and 13 patients in the short-term DAPT group were excluded from the “as treated” analysis because they did not receive DAPT. The profile of the subjects who were followed up for 6 to 18 months is shown in Table 1. There were no significant differences of baseline characteristics between the short-term and long-term DAPT groups. Mean age was 67.2 ± 9.9 years in the long-term DAPT group and 67.4 ± 9.6 years in the short-term DAPT group. The prevalence of diabetes was approximately 40% in both groups. Index PCI was performed for acute coronary syndrome in 33.5% of the long-term DAPT group and 31.9% of the short-term DAPT group. Procedural and angiographic characteristics of the 2 groups are displayed in Table 2. There were no significant differences of procedural characteristics, including the number of stents, stent length, and stent size. The left anterior descending coronary artery was the target vessel for revascularization in 52.4% and 51.8% of patients, respectively. Adherence to DAPT in each group is summarized in Figure 2. The demographic and angiographic findings of the patients who received allocated treatment and those enrolled in the “as treated” analysis are listed in the Online Tables S1 to S4.
Primary and secondary endpoints
The median follow-up period was 435 days (quartile 1 to quartile 3: 365 to 540 days) in the long-term DAPT group and 430 days (quartile 1 to quartile 3: 361 to 540 days) in the short-term DAPT group. The primary endpoint was reached by 24 patients in the long-term DAPT group (1.5%) and 34 patients in the short-term DAPT group (2.1%) (Table 3), with a 0.6% difference in the primary endpoint rate between the 2 groups (95% CI: −1.5 to 0.3). Because the lower limit of the 95% CI was inside the specified margin of −2%, noninferiority of short-term DAPT was confirmed. This finding was also confirmed in as treated analysis (Online Table S5). Kaplan-Meier survival curves of both groups for the primary endpoint are depicted in Figure 3. The curves of the 2 groups diverged during the follow-up period, and the estimated probability of events was numerically higher in the short-term DAPT group (HR: 1.44, 95% CI: 0.86 to 2.43). Occurrence rates for the individual components of the primary endpoint are displayed in Table 3 and Figure 4. The Kaplan-Meier mortality curve showed higher mortality in the short-term DAPT group (HR: 2.25, 95% CI: 0.93 to 5.43; p = 0.05). Definite or probable stent thrombosis occurred in 0.1% of each group from 6 to 18 months. Identical outcomes were revealed by “as-treated” analysis (Online Table S5, Online Figure S1). The incidence of NACCE and the individual components of NACCE from 0 to 18 months are depicted in Online Table S5 and Online Figures S2 and S3.
From 6 to 18 months after stenting, major bleeding events occurred in 12 patients (0.7%) from the long-term DAPT group and 11 patients (0.7%) from the short-term DAPT group. Table 4 shows the bleeding events categorized according to the modified REPLACE-2 criteria, BARC criteria, and cause.
Interactions with the primary endpoint
When potential interactions with NACCE were analyzed in pre-specified subgroups (Figure 5), consistent outcomes were obtained among various clinical subsets. However, a marginal interaction was observed in relation to the number of stents, because multiple stenting was associated with a higher rate of NACCE in the short-term DAPT group. All of these results were confirmed by “as treated” analysis (Online Figure S4).
The NIPPON trial was a multicenter RCT that was performed to evaluate the optimal duration of DAPT after implantation of DES with a biodegradable abluminal coating. On the basis of current knowledge, the combination of short-term DAPT and a second-generation DES with a biodegradable abluminal coating should simultaneously minimize the incidence of thrombotic events and bleeding complications. Therefore, we hypothesized that a short duration of DAPT (6 months) might be acceptable with this new type of stent. Although the present findings seem to support the strategy of short-term DAPT after deployment of a newer DES, interpretation of the data in relation to daily practice may be difficult, and we should be cautious about drawing conclusions. First, the incidence of the primary endpoint was lower than expected in both groups. Therefore, the statistical power of our study may not have been adequate to fully assess the risk of the primary endpoint, and this point deserves emphasis. It may be reasonable to consider that the enrollment of relatively low-risk patients resulted in the present outcome. In fact, the total stent length was about 20 mm, and 66% of the stents were >3 mm in size. In this study, the duration of long-term DAPT was set at 18 months. Other recent RCTs have investigated different durations of DAPT after deployment of DES, ranging from 3 months up to 30 months. Therefore, it is difficult to compare these studies directly in order to elucidate the optimal duration of DAPT after DES implantation. Moreover, the reported outcomes have been inconsistent. We hypothesized that the findings of the present study were likely to be consistent with the results of previous studies demonstrating the noninferiority of short-term DAPT (5–7). A comparison with these previous RCTs revealed several important similarities among them, including lower event rates than anticipated and slow enrollment resulting in early termination. Although there were some differences with regard to the duration of DAPT, the cumulative event rate was similar in our study and in the recent ISAR-SAFE (Intracoronary Stenting and Antithrombotic Regimen: Safety and Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting) (5) and ITALICplus (Is There a Life for DES After Discontinuation of Clopidogrel) (6) studies. These findings, together with slow enrollment, might reflect selection bias in all of the studies. Thus, selection bias favoring lower-risk patients may be a common feature of trials assessing DAPT (5–8). Furthermore, early termination of DAPT in some patients and switching of others to prolonged DAPT (adherence to protocol) could make it difficult to assess the clinical advantages of different DAPT durations after DES implantation. This type of error is also likely to be common in these studies. For example, 33.8% of patients assigned to the 6-month group in the SECURITY (Second Generation Drug-Eluting Stent Implantation Followed by Six- Versus Twelve-Month Dual Antiplatelet Therapy) study were still receiving treatment at 12 months (7), whereas 353 patients (19%) discontinued treatment prematurely or received it for longer than specified in the ITALICplus study (6).
This study was based on the hypothesis that using a DES with biodegradable abluminal polymer coating may reduce the risk of future events including stent thrombosis. The safety of DES coated with biodegradable polymers has been confirmed by previous RCTs (16,17). However, absorption of the polymer coating of the Nobori stent takes longer than 6 months (16), suggesting that mismatch between the polymer degradation time and the duration of DAPT may have resulted in adverse outcomes in the short-term DAPT group. An on-going trial using a DES with an abluminal polymer coating that shows more rapid degradation than that of the Nobori stent may enhance understanding of the importance of the polymer degradation time (18). Another possible explanation is that this outcome simply reflected different risks of cardiovascular events in the 2 groups. In fact, the noncardiovascular death rate after 6 months was also higher in the short-term DAPT group.
The outcomes of our sensitivity analyses were consistent with the main findings, although the marginal interaction between the number of stents and NACCE may be meaningful. An influence of the number of stents deployed is consistent with a recent meta-analysis, which showed that procedural complexity is an important factor when considering prolonged DAPT (19). Taken together, it seems reasonable to conclude that our findings strengthen the recent emphasis on the importance of personalized DAPT to avoid bleeding and thrombotic events.
Major bleeding complications were not different in the 2 groups. This finding is also consistent with the outcomes of previous RCTs demonstrating noninferiority of short DAPT (5,6). However, it is not in agreement with the results of the DAPT trial or with the findings of meta-analysis (9,20). There may be several reasons why long-term DAPT was not associated with a higher rate of bleeding. First, our study may not have been adequately powered to calculate the risk of individual cardiovascular events, such as major bleeding. Second, initiation of DAPT is an important risk factor for bleeding events (21), so performing analysis after 6 months provides data on outcomes in patients who have tolerated DAPT. Actually, more than 50% of the major bleeding events occurred within 6 months of starting DAPT in the present study, with the subsequent bleeding event rate being <1% in both groups. Third, the lower-than-anticipated event rate suggests that our subjects also had a lower risk of bleeding, because these risks frequently coexist and are difficult to discriminate from each other (22). Finally, a low frequency of gastrointestinal bleeding may have been a factor in the present cohort because proton pump inhibitors or histamine 2 blockers were prescribed for more than 70% of patients in both groups, whereas the prescription rate of proton pump inhibitors was only around 30% in the ISAR-SAFE study (5). A large-scale registry study has shown that approximately 60% of bleeding originates from the gastrointestinal tract (23), and the protective effect of proton pump inhibitors against bleeding due to nonsteroidal anti-inflammatory drugs has been thoroughly demonstrated (24,25). Physicians should be cautious about the risk of gastrointestinal bleeding in both patients receiving DAPT and those on antiplatelet monotherapy. On the other hand, it should be kept in mind that BARC 5 bleeding was only observed in the 18-month DAPT group.
In addition to the points mentioned in the preceding text, several important limitations need to be taken into consideration. First, this was not a double-blind trial. As a result, early termination of DAPT and switching to prolonged DAPT occurred in a substantial number of subjects. The low thrombotic event rate in the present study could be partly explained by the meticulous stent deployment procedure that was used. However, the observed events rate was lower than anticipated, making this study underpowered relative to the initial calculations. Therefore, interpretation of our findings should be done with caution, especially with regard to the interactions between outcomes. Furthermore, antiplatelet therapy was mainly provided with clopidogrel in the present study, so use of more potent antiplatelet agents may have led to different outcomes. Additionally, generalization of our results to high-risk patients may require caution. Finally, the follow-up period may not have been long enough to determine the optimum duration of DAPT after DES implantation, because the DAPT trial has demonstrated the benefit of continuing DAPT for 30 months (9). Thus, a further long-term study may be warranted in the future.
In this study, 6 months of DAPT showed noninferiority to 18 months of DAPT in terms of NACCE after implantation of DES with a biodegradable abluminal coating. However, the results need to be interpreted with caution due to premature termination of enrollment and the open-label design with a wide noninferiority margin.
WHAT IS KNOWN? The optimal duration of DAPT after DES implantation remains unclear, so evaluation of the net clinical benefit of DAPT (balance between bleeding complications and reduction of cardiovascular events) is crucial. Recent advances in DES technology have improved the safety profile compared with first-generation DES.
WHAT IS NEW? After biodegradable polymer DES deployment, short-term DAPT is not inferior to long-term DAPT in relatively low-risk patients. Our findings support the recent emphasis on the importance of personalized DAPT to avoid bleeding and thrombotic events.
WHAT IS NEXT? Further studies are needed to establish ideal risk stratification schemes for patients undergoing deployment of contemporary DES.
For an expanded Methods section, list of investigators, and supplemental tables and figures, please see the online version of this article.
Funded by the Association for Establishment of Evidence in Interventions. Dr. Nakamura has received research grant support and honoraria from Terumo Corporation, Sanofi, and Daiichi-Sankyo. Dr. Iijima has received honoraria from Terumo, Daiichi-Sankyo, Sanofi, and Bayer Yakuhin. Dr. Shinke has received research grant support from Terumo Corporation; and honoraria from Terumo Corporation, Daiichi-Sankyo, and Sanofi. Dr. Ueda has received honoraria for lectures from Daiichi-Sankyo, Novartis, AstraZeneca, MSD, Goodman, Sanofi, Abbott Vascular, Eisai, Toaeiyo, Mochida, Takeda, Boehringer Ingelheim, Bristol-Myers Squibb, Kowa, Sumitomo Dainippon Pharma, Teijin, Boston Scientific, Astellas, and Amgen Astellas BioPharma; and has received research grants from Abbott Vascular, Pfizer, Sanofi, Bayer, Ono Pharmaceutical, Nihon Kohden, and Novartis. Dr. Morita has received honoraria from Terumo Corporation, Daiichi-Sankyo, and Sanofi. Dr. Ochiai has been an expert witness for Terumo Corporation. Dr. Kawaguchi has received honoraria from Terumo Corporation. Dr. Yokoi has received honoraria from Terumo Corporation and Daiichi-Sankyo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Bleeding Academic Research Consortium
- confidential interval
- dual antiplatelet therapy
- drug-eluting stent(s)
- hazard ratio
- intention to treat
- myocardial infarction
- net adverse clinical and cerebrovascular event(s)
- percutaneous coronary intervention
- proportional hazard
- randomized controlled trial
- Received April 3, 2017.
- Accepted April 6, 2017.
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