Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study

Dyslipidemia and impaired glucose metabolism in diseases such as diabetes are known risk factors for cardiovascular disease; patients with both conditions are at even greater risk of cardiovascular (CV) events (1–3). Meta-analysis (4) has associated lower levels of LDL cholesterol (LDL-C) with reduced risk of CV events in patients with type 2 diabetes, and the risk of CV events increases further in patients with diabetic retinopathy (5,6). However, little evidence is currently available on the efficacy of lipid therapy specifically in these very high-risk patients.

The association of lower LDL-C and reduced risk of CV events has spurred interest in a treat-to-target approach, adjusting the drug dose to achieve a specific LDL-C target. However, at the time of this study, almost all large-scale lipid-lowering clinical studies with statins were either placebo controlled or compared treatment results based on statin type or dose (7). The authors of the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on lipid management (8) thus concluded that evidence was insufficient to prove the benefits of treat-to-target and did not include specific treat-to-target levels.

To explore the potential benefits of treat-to-target in very high-risk patients, we conducted a large-scale clinical study in patients with hypercholesterolemia and diabetic retinopathy (type 2 diabetes). Few prospective clinical studies have evaluated the efficacy of intensive lipid-lowering therapy specifically in primary prevention patients with diabetes, particularly for reducing risk through lipid-lowering intervention in hypercholesterolemic patients with diabetic retinopathy.

The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study examined whether intensive lipid-lowering therapy is superior to standard therapy in reducing the incidence of CV events in patients with hyperlipidemia and diabetic retinopathy but no history of coronary artery disease. Patients were divided into two groups targeting different LDL-C levels (<70 or ≥100 and <120 mg/dL). Statin therapy, regardless of statin type, was used to control LDL-C at the targeted level in each group. Safety and efficacy were compared between groups.

The EMPATHY study is the first to assess the benefits of intensive versus standard statin therapy for patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. The study also evaluates the appropriateness of treat-to-target, because all patients were treated to achieve specific LDL-C targets by titrating statin therapy.

The study used a multicenter, prospective, randomized, open-label, blinded end point (PROBE) design (9) and enrolled patients at hospitals and family practice clinics across Japan. The study was conducted under the Declaration of Helsinki and Japanese ethical guidelines for clinical studies. The protocol was reviewed and approved by the institutional review board of each participating center.

Patients who had elevated LDL-C and diabetic retinopathy without a history of coronary artery disease were eligible for participation (Supplementary Data). All patients were enrolled by the investigators and provided written informed consent.

A data center provided the computer-generated allocation sequence, stratified by sex, age, and baseline hemoglobin A_1c (HbA_1c). After patient eligibility was confirmed, the investigator contacted the data center for the allocated treatment. Staff who generated the allocation sequence were not involved in patient enrollment.

This study was designed to evaluate the treat-to-target approach, so investigators could not be blinded to statin types and doses. We thus selected a PROBE design rather than a double-blind design. To eliminate bias, defined end points were evaluated by a blinded end point committee.

As previously described (9), this PROBE study constituted a run-in period (4–8 weeks) and a treatment period (2–5.5 years). During run-in, patients received oral statin monotherapy targeting LDL-C between 100 and 120 mg/dL. Patients were then assessed for eligibility and randomly assigned (1:1) to oral intensive therapy (targeting LDL-C <70 mg/dL) or standard therapy (targeting LDL-C between 100 and 120 mg/dL). LDL-C levels were calculated from the Friedewald formula. LDL-C targets were based on guidelines in the U.S. and Japan when the study was designed (10,11). Each investigator independently selected a statin for the run-in and treatment periods for each patient. Statin dose escalation and switching to another statin were permitted in both groups. The investigators generally measured LDL-C once monthly for 6 months after study start to confirm that the treatment target had been reached. After that point, LDL-C was measured every 6 months if values remained within the treatment target, or more frequently at the discretion of the physician (for example, after LDL-C exceeded the target treatment range, to confirm that the treatment target had been reacquired) (9).

Concomitant lipid-lowering therapy was prohibited with fibrates, ezetimibe, ethyl icosapentate, anion exchange resins, probucol, nicotinic acid derivatives, phytosterols, elastase, dextran sulfate sodium sulfur, pantethine, or polyenephosphatidylcholine.

Details of treatment for diabetes and hypertension were provided previously, along with medical histories, baseline findings, and changes during the treatment period in parameters such as body weight, blood pressure, blood chemistry, and electrocardiogram (9). Statin treatment adherence, concomitant use of other drugs, and adverse events (AEs) were investigated periodically throughout the study. The physician determined adherence by questioning each patient during each visit to the hospital and recording the patient’s answers. No situations arose during the study that required consideration of study discontinuation or suspension.

The primary and secondary outcomes of the EMPATHY study were previously described (9) (Supplementary Data). The primary outcome was the composite incidence of CV events, including cardiac, cerebral, renal, and vascular events, or CV-associated death. The secondary outcomes included death from any cause, individual incidence of study-defined CV events for the primary end point, incidence of stroke, change in laboratory variables related to chronic kidney disease (CKD), and safety. Items assessed for safety are listed in the Supplementary Data. Primary and secondary end points were adjudicated by an event evaluation committee whose members were unaware of the treatment allocation.

In the previous century, coronary artery disease and stroke were the primary end points in most large-scale clinical studies of statins. However, the relationship between CKD and arteriosclerosis began to be more widely accepted from about 2000. Today ischemic heart disease, cerebrovascular disease, peripheral vascular disease, and renal impairment are widely understood to be ischemic conditions, and a meta-analysis of randomized control and crossover studies has shown that statins inhibit proteinuria and progression of nephropathy (12). We thus selected a range of primary end points based on arteriosclerosis, including renal events.

Statistical methods for the EMPATHY study were previously described (9). The planned sample size was 5,000 patients, with 2,500 in each treatment group. This was considered sufficient to detect a hazard ratio (HR) of 0.65 for the superiority of intensive therapy with a power of 80% and a two-sided significance level of 5%. The incidence of CV events during the 3-year treatment period was estimated at 2.7% for intensive therapy and 4.1% for standard therapy, based on earlier reports in the literature (13–16). We used these estimates to calculate the sample size, assuming a withdrawal rate of 15% and a study period of 4.5 years. We estimated 179 occurrences of the primary end point by the end of the study.

The full analysis set (FAS) was selected as the main analysis set for efficacy. The primary and secondary end points were analyzed in the same way in the FAS and the per protocol set, and results for the two sets were examined for consistency. The FAS comprised all randomly allocated subjects for whom efficacy data were available. The per protocol set comprised all members of the FAS, except for subjects who did not qualify or were not treated and cases of protocol violation or noncompliance. All subjects who received the study treatment at least once and for whom safety information was available were included in the safety analysis set. In all analyses, each subject was included in the allocation group.

We compared the primary end point between the treatment groups by log-rank test, stratified by sex, age, and baseline HbA_1c, and used a stratified Cox proportional hazards model to estimate the HR and 95% CI.

Interim analysis was performed during the study at a prespecified time point, adjusted by the Lan-DeMets α spending function with O’Brien-Fleming boundaries. An independent data monitoring committee assessed the analysis results.

The software used was SAS version 9.2 (SAS Institute).

A total of 5,995 patients were enrolled between May 2010 and October 2013 (Supplementary Fig. 1) at 772 primary prevention sites (323 hospitals and 449 clinics) in Japan. Of these patients, 5,144 were randomized to intensive (2,571) or standard (2,573) statin therapy; 53 in intensive therapy and 49 in standard therapy were subsequently excluded from data analysis. Data were analyzed from 5,042 patients (2,518 in the intensive therapy group and 2,524 in the standard therapy group). Mean follow-up was 37 ± 13 months.

Patients randomized to the two treatment groups had similar baseline characteristics (Table 1). Atorvastatin, rosuvastatin, and pitavastatin users accounted for 54.8% of all patients in the intensive group and 54.4% in the standard group at baseline. The other patients used pravastatin, fluvastatin, or simvastatin. At the end of the study, the proportion of patients using atorvastatin, rosuvastatin, and pitavastatin increased (95.6%) in the intensive group but remained nearly unchanged (53.4%) in the standard group. For all statin types, dose at baseline was nearly identical between the intensive and standard groups. By the last visit, statin dose had increased for all statin types in the intensive group; the mean doses for the standard group remained essentially unchanged over the course of the study (Supplementary Table 1). It should be noted that the statin dose for “intensive” therapy in Japan is lower than in the U.S. and Europe; at the last visit in this study, the dose in the intensive group would be considered “moderate to low-intensity” statin therapy under ACC/AHA guidelines.

The mean level of LDL-C for the patients in the intensive group was 106.2 ± 26.7 mg/dL (median 105.0 mg/dL) at the start of treatment. That level decreased to 85.6 ± 24.3 mg/dL (83.0 mg/dL) after 6 months of treatment and continued to gradually decline over time, reaching 76.5 ± 21.6 mg/dL (73.0 mg/dL) at 36 months of treatment. For patients treated with standard statin therapy, mean LDL-C was 106.1 ± 25.9 mg/dL (105.0 mg/dL) at the start of treatment and remained at or near that level throughout the treatment period. The difference between the two groups was 23.6 mg/dL at 1 year and 27.7 mg/dL at 3 years. The difference was significant from 6 to 60 months after the start of treatment (Supplementary Fig. 2).

Changes in other lipid parameters are shown in Supplementary Table 2. Total cholesterol and triglycerides were lower in the intensive than the standard group. HDL-C values differed very little between the two groups.

Blood pressure, HbA_1c, serum creatinine, creatine kinase, and hs-CRP are summarized in Supplementary Fig. 3. Overall findings for each treatment group differed little over time, including these parameters or hematological results, or liver and renal function test results. After treatment for 1 year and thereafter, mean hs-CRP was significantly lower in the intensive group than the standard group.

The primary outcome, combined incidence of CV events or deaths associated with CV events, was lower in the intensive group (LDL-C target <70 mg/dL, 129 patients) than the standard group (LDL-C target ≥100 and <120 mg/dL, 153 patients), but that difference was not statistically significant (HR 0.84 [95% CI 0.67–1.07]; P = 0.15) (Fig. 1). Calculated values for the primary and secondary outcomes are listed in Supplementary Table 3.

The incidence of deaths from any cause did not differ significantly between the two groups (HR 1.21 [95% CI 0.77–1.91]) (Fig. 2). The incidence of cerebral events (cerebral infarction or cerebral revascularization) decreased significantly in the intensive group (HR 0.52 [95% CI 0.31–0.88]) (Fig. 1), as did the incidence of cerebral infarction (HR 0.54 [95% CI 0.32–0.90]) (Fig. 2). The incidence of stroke (cerebral infarction, cerebral hemorrhage, and subarachnoid hemorrhage), cerebral hemorrhage, and subarachnoid hemorrhage did not differ between the groups (HR 0.64 [95% CI 0.40–1.01], HR 1.34 [95% CI 0.46–3.86], and HR NA [not applicable], respectively). No other significant differences were noted. The HR for cardiac events was 0.93 (95% CI 0.65–1.33), for renal events 1.07 (95% CI 0.72–1.58), and for vascular events 1.00 (95% CI 0.38–2.67) (Supplementary Table 3).

Change and percent change from baseline to 36 months in the parameters for CKD were evaluated as a secondary end point. Estimated glomerular filtration rate decreased by 5.9 mL/min/1.73 m² (7.8%) in the intensive group and 6.5 mL/min/1.73 m² (8.3%) in the standard group. Urine albumin increased by 85.3 mg/g creatinine (343.2%) and 86.5 mg/g creatinine (300.8%), and urine protein increased 10.7 mg/dL (1,503.1%) and 11.0 mg/dL (236.1%) in the intensive and standard groups, respectively. None of these parameters differed significantly between the intensive and standard groups (Supplementary Table 4).

As part of an exploratory analysis, we performed subgroup analysis of the primary end point for both treatment groups based on various demographic factors (Supplementary Fig. 4). No significant heterogeneity of treatment effects was seen in any of the factors examined.

Overall, a similar percentage of patients in both groups experienced AEs (intensive 75.3%; standard 75.2%) and serious AEs (intensive 21.3%; standard 22.0%) (Table 2). A significantly higher proportion of patients experienced adverse drug reactions (ADRs) in the intensive group (10.1%) than the standard group (6.7%) (P < 0.001), but most of those ADRs were mild. The proportion of serious ADRs was similar between groups (1.3% vs. 0.9%; P = 0.22).

The EMPATHY study assessed the benefits of intensive statin monotherapy for lipid management in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. The study also evaluated the appropriateness of the treat-to-target approach in this patient population. Results indicated that lipid-lowering therapy targeting LDL-C <70 mg/dL had no more beneficial effect on the primary end point than therapy targeting LDL-C of 100–120 mg/dL. In exploratory findings, the secondary end points of cerebral events and cerebral infarction were reduced significantly in the intensive group. No major safety concerns were noted.

The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (17) demonstrated the usefulness of intensive lipid therapy for the secondary prevention of CV events, using statin and ezetimibe to achieve LDL-C as low as 50 mg/dL. Our study focused on primary prevention to expand the evidence regarding intensive lipid management using statin monotherapy. However, our results differed from those previous studies using statins.

Why did our study fail to show superior results for intensive therapy? EMPATHY included some soft end points that required subjective assessment, such as revascularization, and renal events that were attributable to arteriosclerosis. To evaluate these effects on the study results, we compared the groups using three-point major CV events (CV death, nonfatal myocardial infarction, and nonfatal stroke) and the primary end point after excluding renal events. We found no significant differences (HR 0.82 [95% CI 0.58–1.14] and HR 0.76 [95% CI 0.57–1.01], respectively) (Supplementary Fig. 5), suggesting that our study findings were unaffected by either soft end points or renal events.

Primary end point incidence was 20.41/1,000 person-years in the standard group and 17.27/1,000 person-years in the intensive group. The cumulative incidence at 3 years was 5.8% and 5.4%, respectively, exceeding our earlier estimates of 4.1% and 2.7%. The statistical power of the study was thus sufficient to detect significant differences in CV events between the two groups.

We believe that this study failed to find a significant reduction in the primary end point because of the smaller-than-predicted difference in LDL-C between the two treatment groups. Our planned between-group difference in LDL-C was ∼40 mg/dL (<70 mg/dL for the intensive group vs. ∼110 mg/dL for the standard group), and the HR was predicted to be 0.65. However, after 3 years of treatment, the actual LDL-C difference was 27.7 mg/dL (76.5 vs. 104.1 mg/dL).

In exploratory findings, we compared our results to the Cholesterol Treatment Trialists’ (CTT) meta-analysis (18) and three primary prevention studies in patients with diabetes (13–15). We graphed the relationship between changes in LDL-C and proportional reduction in event rate (major CV events including major coronary events [coronary death or nonfatal myocardial infarction], stroke of any type, and coronary revascularization [angioplasty or bypass grafting]). Interestingly, the slope of the line for the diabetes studies seems to be steeper than the original CTT line (Supplementary Fig. 6). Next, we plotted the findings of the EMPATHY study. In our study, the predicted between-group difference in LDL-C of ∼40 mg/dL should have provided a reduction of ∼30% in major CV events, close to this data line and to the originally predicted primary event reduction rate (HR 0.65). The observed 20% reduction in major CV events (HR 0.80 [95% CI 0.59–1.07]) is quite similar to the reduction that would be predicted by Supplementary Fig. 6, given the observed 23.6 mg/dL reduction in LDL-C (after 1 year). In other words, the primary results of the EMPATHY study, despite not being significant, are consistent with previous findings. We hypothesize that if we had achieved the predicted difference of 40 mg/dL LDL-C between two treatment groups, the primary end point would have reached statistical significance. This suggests that aggressive LDL-C management may further reduce risk in patients with conditions such as hyperlipidemia and diabetic retinopathy.

To further clarify the reasons for the failure to demonstrate the efficacy of intensive therapy, we performed post hoc analysis, classifying patient data into four subcategories (mean LDL-C <70, 70 to <100, 100 to <120, and ≥120 mg/dL during the study). Our exploratory findings tended to show event prevention at lower LDL-C values in both the intensive and standard groups (Supplementary Fig. 7). We plan additional exploratory analysis of between-group comparison, limited to patients in each group with LDL-C levels within the targeted range. We obtained preliminary results showing that the event rate for the primary end point was significantly lower in the intensive group than in the standard group. Our findings from that subanalysis will be published separately.

In an intervention study where the control group also receives statin therapy, the duration of follow-up is of considerable importance. Non-Japanese studies with a relative difference in LDL-C of 40–50% between two groups required 2 years to show significance in incidence between groups (19,20). EMPATHY follow-up time was 3 years, but the between-group difference in LDL-C was lower than anticipated; longer follow-up might have shown greater between-group difference.

Our study data indicated that intensive therapy favorably affected cerebral events, particularly cerebral infarction. An inference of significant reduction cannot be supported given the lack of a statistically significant difference in the primary end point. However, we note that in the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study (21), statin therapy effectively reduced cerebrovascular events when LDL-C was lowered to 70 mg/dL, whereas in the Japan Statin Treatment Against Recurrent Stroke (J-STARS) study (22), where LDL-C levels were reduced only to 100 mg/dL, no such efficacy was detected. Exploratory results from EMPATHY were similar to those from SPARCL in that LDL-C reached 70 mg/dL and may confirm that a decrease in LDL-C contributes to reducing the event risk for cerebral infarction.

Of further interest, the Japan Diabetes Complications Study (JDCS) (2) reported that the incidences of coronary heart disease and stroke were 9.59/1,000 and 7.45/1,000 person-years, respectively, in Japanese patients with type 2 diabetes. In EMPATHY, the incidences of cardiac events and stroke were 8.13/1,000 and 6.14/1,000 person-years, respectively, in the standard group. The incidences of cardiac events and ischemic stroke were surprisingly similar between the JDCS and EMPATHY. This is noteworthy because the EMPATHY study targeted patients who were already under statin therapy, and the LDL-C baseline in the standard group (106 mg/dL) was substantially lower than in the JDCS patients (120 vs. 135 mg/dL). These findings suggest that Japanese patients with diabetic retinopathy may be at particularly high risk for CV events.

No major AE or severe ADR increases were associated with statin monotherapy targeting LDL-C <70 mg/dL, and rhabdomyolysis occurred at a similar rate in both groups. This suggested low potential risk for excessive LDL-C reduction by statin monotherapy. Aggressive LDL-C lowering might be associated with increased levels of cerebral hemorrhage, since cerebral hemorrhage increased with intensive therapy in the SPARCL study (21). However, subsequent investigation of SPARCL showed that on-treatment LDL-C did not predict cerebral hemorrhage (23). EMPATHY findings showed no intergroup differences in cerebral hemorrhage, potentially eliminating concerns of increased cerebral hemorrhage risk due to intensive statin therapy. Although concerns have been raised over worsening of HbA_1c due to statin therapy (24,25), no such effects were noted in this study.

Key strengths of this study were implementation of the first-ever assessment of benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in primary prevention; suitability assessment of a treat-to-target approach for LDL-C management by titrating statin therapy; and inclusion of clinics as over half the participating sites so that patient management was closer to routine clinical practice, which is advantageous for assessing real-world effects of lipid-lowering therapy.

Limitations of this study were the use of PROBE rather than double-blind comparison of the two treatment methods; inclusion of soft end points (although those end points were assessed by a blinded independent committee to ensure objectivity); unexpectedly high patient discontinuation from data loss during a major earthquake, which may have reduced study power even though discontinuations were well balanced between the two groups; and failure to control LDL-C within the target range in some patients in both groups, resulting in a smaller-than-planned intergroup difference in LDL-C that possibly affected study power. Median LDL-C level at 6 months in the intensive group was 83.0 mg/dL, indicating failure to reach the protocol-stipulated target LDL-C level of <70 mg/dL. In real-world clinical practice, many Japanese physicians who are not lipid management experts worry about adverse effects such as intracranial hemorrhage from intensive LDL-C lowering, and may have been somehow affected by these concerns even when the protocol stipulated the aggressive target of <70 mg/dL.

In conclusion, the intensive therapy targeting LDL-C <70 mg/dL did not reduce the incidence of composite CV events more significantly than the standard therapy targeting LDL-C ≥100 and <120 mg/dL. However, based on previous studies in patients with diabetes in a primary prevention setting, the event reduction rate in this study is consistent with expectations regarding the LDL-C difference that was achieved and might be clinically meaningful. Exploratory results suggest that intensive therapy reduces cerebral events, especially cerebral infarction, with no increase in AEs in this population.

Acknowledgments. EDIT, Inc. (Tokyo, Japan) provided medical writing and editing.

Funding and Duality of Interest. This work was supported by Shionogi & Co., Ltd. H.I. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corp., Shionogi & Co., Ltd., and Taisho Toyama Pharmaceutical Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., Kyowa Hakko Kirin Co., Ltd., Teijin Pharma Ltd., Mochida Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and Eli Lilly and Company Japan K.K., and personal fees from Nipro Corp. and SBI Pharmaceuticals Co., Ltd. outside the submitted work. I.K. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. and grants from MSD K.K., Shionogi & Co., Ltd., GlaxoSmithKline K.K., Sanofi K.K., Genzyme Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corp., and Bristol-Myers Squibb outside the submitted work. M.T. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study. T.A. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from St. Jude Medical Japan Co., Ltd., Terumo Corp., Daiichi Sankyo Co., Ltd., and Abbott Vascular Japan Co., Ltd., grants from Goodman Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Bayer Yakuhin, Ltd., and Boston Scientific Corp., and personal fees from Nippon Boehringer Ingelheim Co., Ltd. outside the submitted work. H.D. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study, and grants and personal fees from AstraZeneca K.K., Astellas Pharma Inc., Abbott Vascular Japan Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kaken Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Kowa Pharmaceutical Company Ltd., Sanofi K.K., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Terumo Corp., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., Philips Respironics GK, Bristol-Myers Squibb, Sanwa Kagaku Kenkyusho Co., Ltd., Mitsubishi Tanabe Pharma Corp., MSD K.K., and GlaxoSmithKline K.K., grants from Eisai Co., Ltd., Teijin Pharma Ltd., Nippon Shinyaku Co., Ltd., VitalAire Japan K.K., Fujifilm RI Pharma Co., Ltd., Boston Scientific Corp., Fuji Chemical Industries Co., Ltd., Fukuda Denshi Co., Ltd., and Actelion Pharmaceuticals Japan Ltd., and personal fees from ASKA Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Toa Eiyo Ltd., Ono Pharmaceutical Co., Ltd., Medtronic Japan Co., Ltd., and Mochida Pharmaceutical Co., Ltd. outside the submitted work. Y.E. reports nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. H.F. reports other fees (consultant) from Mehergen Group Holdings, Inc. outside the submitted work. J.H. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Astellas Pharma Inc., Nippon Boehringer Ingelheim Co., Ltd., Mochida Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., MSD K.K., Teijin Pharma Ltd., Actelion Pharmaceuticals Japan Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., and Sanwa Kagaku Kenkyusho Co., Ltd. outside the submitted work. K.-i.H. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Daiichi Sankyo Co., Ltd. and Mochida Pharmaceutical Co., Ltd., grants from Actelion Pharmaceuticals Japan Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., Sysmex Corp., Medtronic Japan Co., Ltd., and St. Jude Medical Japan Co., Ltd., and personal fees from Kowa Pharmaceutical Co., Ltd. outside the submitted work. S.Is. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Amgen Astellas BioPharma K.K., Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Eli Lilly and Company Japan K.K., Kowa Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Corp., Ono Pharmaceutical Co. Ltd., Sanofi K.K., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and Teijin Pharma Ltd., grants from Fujifilm Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., and Kyowa Hakko Kirin Co., Ltd., and personal fees from AstraZeneca K.K., Bayer Yakuhin, Ltd., Novo Nordisk Pharma Ltd., Pfizer Japan Inc., and Sanwa Kagaku Kenkyusho Co., Ltd. outside the submitted work. T.I. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., and Daiichi Sankyo Co., Ltd., grants from Takeda Pharmaceutical Co., Ltd. and Mitsubishi Tanabe Pharma Corp., and personal fees from Astellas Pharma Inc., AstraZeneca K.K., and MSD K.K. outside the submitted work. S.It. reports grants, personal fees, and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. A.K. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study and personal fees from Astellas Pharma Inc., Sunstar Group Ltd., Eli Lilly and Company Japan K.K., Sanofi K.K., AstraZeneca K.K., Takeda Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Kowa Pharmaceutical Co., Ltd., and Sanwa Kagaku Kenkyusho Co., Ltd. outside the submitted work. S.K. reports grants from Shionogi & Co., Ltd. during the conducting of the study. K.K. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study. M.Ki. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Astellas Pharma Inc., Sanofi K.K., Pfizer Japan Inc., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Mitsubishi Tanabe Pharma Corp., Kyowa Hakko Kirin Co., Ltd., Abbott Japan Co., Ltd., and Otsuka Pharmaceutical Co., Ltd., grants from the Japanese government, Japan Heart Foundation, Japan Cardiovascular Research Foundation, Calpis Co., Ltd., and Nihon Kohden Corp., and personal fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin Ltd., Nippon Boehringer Ingelheim Co., Ltd., Kowa Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Sawai Pharmaceutical Co., Ltd., MSD K.K., Shionogi & Co., Ltd., AstraZeneca K.K., Asahi Kasei Medical Co., Ltd., Novo Nordisk Pharma Ltd., Fujifilm RI Pharma Co., Ltd., and Japan Medical Data outside the submitted work. T.K. reports grants and personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Daiichi Sankyo Co., Ltd. and Bayer Yakuhin Ltd. and grants from MSD K.K., Novartis Pharma K.K., Astellas Pharma Inc., and Pfizer Japan Inc. outside the submitted work. M.Ku. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Shionogi & Co., Ltd. outside the submitted work. K.M. reports other (meeting attendance fee) from Shionogi & Co., Ltd. during the conducting of the study. T.Mura. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study. T.Muro. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Daiichi Sankyo Co., Ltd., Pfizer Japan Inc., Kowa Pharmaceutical Co., Ltd., MSD K.K., and Mitsubishi Tanabe Pharma Corp. and personal fees from AstraZeneca K.K. outside the submitted work. K.No. reports nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. S.O. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. Y.Sa. reports grants, personal fees, and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study and grants, personal fees, and other (advisory boards) from MSD K.K., Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Pfizer Japan Inc., and Novartis Pharma K.K., grants and personal fees from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Astellas Pharma Inc., and Takeda Pharmaceutical Co., Ltd., and grants from Baxter Ltd., Kyowa Hakko Kirin Co., Ltd., Teijin Pharma Ltd., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Nihon Medi-Physics Co., Ltd., Chugai Pharmaceutical Co., Ltd., Genzyme Japan K.K., and Medtronic Japan Co., Ltd. outside the submitted work. Y.Se. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Otsuka Pharmaceutical Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd. and grants from Mitsubishi Tanabe Pharma Corp., Fujifilm RI Pharma Co., Ltd., Roche Diagnostics K.K., MSD K.K., Pfizer Japan Inc., Bayer Yakuhin, Ltd., and Shionogi & Co., Ltd. outside the submitted work. T.S. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. S.Sh. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. M.S. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. S.Su. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants from the Ministry of Education, Culture, Sports, Science and Technology in Japan outside the submitted work. Y.T. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Astellas Pharma Inc., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company Japan K.K., Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., Novo Nordisk Pharma Ltd., Ono Pharmaceutical Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Shionogi & Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. and personal fees from Novartis Pharma K.K. outside the submitted work. H.T. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study and grants and personal fees from Daiichi Sankyo Co., Ltd. and Takeda Pharmaceutical Co., Ltd., grants from Novartis Pharma K.K. and Astellas Pharma Inc., and personal fees from MSD K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Mitsubishi Tanabe Pharma Corp., Teijin Pharma Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., and Bristol-Myers Squibb outside the submitted work. K.Ue. reports other (contracted work) from Shionogi & Co., Ltd. during the conducting of the study and personal fees from Shionogi & Co., Ltd. outside the submitted work. K.Ut. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study and grants from Sanofi K.K., MSD K.K., Taisho Toyama Pharmaceutical Co., Ltd., Nippon Boehringer lngelheim Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Company Japan K.K., and Novo Nordisk Pharma Ltd. outside the submitted work. M.Ya. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and other (donation) from Shionogi & Co., Ltd. outside the submitted work. T.Y. reports other (lecture fee) from Shionogi & Co., Ltd. during the conducting of the study. S.Y. reports other (contracted work) from Shionogi & Co., Ltd. during the conducting of the study. K.Yok. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and grants, personal fees, and nonfinancial support from MSD K.K., grants and personal fees from Astellas Pharma Inc., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Boehringer lngelheim Co., Ltd., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Shionogi & Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Ltd., and Mitsubishi Tanabe Pharma Corp., grants from Bristol-Myers Squibb, Eli Lilly and Company Japan K.K., Teijin Pharma Ltd., and Toyama Chemical Co., Ltd., and personal fees from AstraZeneca K.K., Eisai Co., Ltd., Kowa Company, Ltd., Kowa Pharmaceutical Co., Ltd., Sanofi K.K., and Sanwa Kagaku Kenkyusho Co., Ltd. outside the submitted work. K.Yos. reports personal fees and nonfinancial support from Shionogi & Co., Ltd. during the conducting of the study. M.Yo. reports grants and personal fees from Shionogi & Co., Ltd. outside the submitted work. N.Y. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and personal fees from Shionogi & Co., Ltd. outside the submitted work. K.Na. reports other (contracted) work from Shionogi & Co., Ltd. during the conducting of the study and grants from Takeda Pharmaceutical Co., Ltd. and Fujifilm Pharma Co., Ltd. outside the submitted work. R.N. reports personal fees from Shionogi & Co., Ltd. during the conducting of the study and personal fees from Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., MSD K.K., Ono Pharmaceutical Co. Ltd., Kowa Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Nippon Boehringer Ingelheim Co., Ltd., Toa Eiyo Ltd., Eisai Co., Ltd., and Nippon Chemiphar Co., Ltd. outside the submitted work. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. H.I., I.K., H.F., T.Muro., and T.Y. designed the study, collected and interpreted data, and contributed to the writing. M.T. collected and analyzed data and contributed to the writing. T.A., J.H., T.I., A.K., M.Ki., T.K., M.Ku., K.No., S.O., Y.Sa., Y.Se., T.S., S.Sh., and S.Y. interpreted data. H.D. and K.Ut. designed the study and collected and interpreted data. Y.E. collected data. K.-i.H., S.It., S.Su., K.Yok., and K.Na. designed the study and interpreted data. S.Is., K.K., Y.T., and M.Ya. collected and interpreted data and contributed to the writing. S.K. designed the study, collected data, and contributed to the writing. K.M. designed the study and collected data. T.Mura. designed the study. M.S. collected data and contributed to the writing. H.T. and N.Y. interpreted data and contributed to the writing. K.Ue. and R.N. designed the study, interpreted data, and contributed to the writing. K.Yos. and M.Yo. collected and interpreted data. All authors read the drafted manuscript, provided feedback, and approved the final version of the manuscript. H.I. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation. This study was presented at the European Society of Cardiology Congress 2017 Hot Line session, Barcelona, Spain, 29 August 2017.