Addition of Ezetimibe to Intensive Lipid-Lowering Therapy Is Associated With a Lower Incidence of Heart Failure in Patients With Acute Coronary Syndrome.

BACKGROUND: This study investigated whether intensive lipid-lowering therapy with pitavastatin and ezetimibe lowers the incidence of heart failure (HF) events in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: In the HIJ-PROPER study, 1,734 patients with ACS were randomly assigned to either pitavastatin plus ezetimibe therapy (n=864) or pitavastatin monotherapy (n=857). We examined the incidence of HF between these 2 groups over a 3.9-year period after ACS. The primary endpoint of the study was hospitalization for HF. The mean low-density lipoprotein cholesterol levels during the follow-up period were 65.1 mg/dL in the pitavastatin plus ezetimibe group and 84.6 mg/dL in the pitavastatin monotherapy group. The incidence of HF hospitalization was significantly lower in the pitavastatin plus ezetimibe group than in the pitavastatin monotherapy group (19 [2.2%] vs. 40 [4.7%] patients; hazard ratio 0.47, 95% confidence interval 0.27-0.81; P<0.005). This trend was consistent after multivariable analysis using multiple models. CONCLUSIONS: Intensive lipid-lowering therapy with pitavastatin and ezetimibe is associated with a lower incidence of hospitalization for HF in patients with ACS.

Low-density lipoprotein cholesterol targeting with pitavastatin + ezetimibe for patients with acute coronary syndrome and dyslipidaemia: the HIJ-PROPER study, a prospective, open-label, randomized trial.

AIMS: To elucidate the effects of intensive LDL-C lowering treatment with a standard dose of statin and ezetimibe in patients with dyslipidaemia and high risk of coronary events, targeting LDL-C less than 70 mg/dL (1.8 mmol/L), compared with standard LDL-C lowering lipid monotherapy targeting less than 100 mg/dL (2.6 mmol/L). METHODS AND RESULTS: The HIJ-PROPER study is a prospective, randomized, open-label trial to assess whether intensive LDL-C lowering with standard-dose pitavastatin plus ezetimibe reduces cardiovascular events more than standard LDL-C lowering with pitavastatin monotherapy in patients with acute coronary syndrome (ACS) and dyslipidaemia. Patients were randomized to intensive lowering (target LDL-C < 70 mg/dL [1.8 mmol/L]; pitavastatin plus ezetimibe) or standard lowering (target LDL-C 90 mg/dL to 100 mg/dL [2.3-2.6 mmol/L]; pitavastatin monotherapy). The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischaemia-driven revascularization. Between January 2010 and April 2013, 1734 patients were enroled at 19 hospitals in Japan. Patients were followed for at least 36 months. Median follow-up was 3.86 years. Mean follow-up LDL-C was 65.1 mg/dL (1.68 mmol/L) for pitavastatin plus ezetimibe and 84.6 mg/dL (2.19 mmol/L) for pitavastatin monotherapy. LDL-C lowering with statin plus ezetimibe did not reduce primary endpoint occurrence in comparison with standard statin monotherapy (283/864, 32.8% vs. 316/857, 36.9%; HR 0.89, 95% CI 0.76-1.04, P = 0.152). In, ACS patients with higher cholesterol absorption, represented by elevated pre-treatment sitosterol, was associated with significantly lower incidence of the primary endpoint in the statin plus ezetimibe group (HR 0.71, 95% CI 0.56-0.91). CONCLUSION: Although intensive lowering with standard pitavastatin plus ezetimibe showed no more cardiovascular benefit than standard pitavastatin monotherapy in ACS patients with dyslipidaemia, statin plus ezetimibe may be more effective than statin monotherapy in patients with higher cholesterol absorption; further confirmation is needed. TRIAL NO: UMIN000002742, registered as an International Standard Randomized Controlled Trial.

Prognostic impact of disseminated intravascular coagulation score in acute heart failure patients referred to a cardiac intensive care unit: a retrospective cohort study.

Thrombosis within the vascular system in relation to inflammation and stasis is potentially associated with poor prognosis in patients with heart failure. The aim of this study was to clarify the association between disseminated intravascular coagulation (DIC) score, a scoring system for microvascular thrombosis and multiple organ dysfunction, and outcome in hospitalized patients with acute heart failure (AHF). We retrospectively evaluated 160 AHF patients referred to a cardiac intensive care unit who had their DIC score measured according to the Japanese Association for Acute Medicine (JAAM) DIC scoring system on admission. Platelet count, prothrombin time ratio, fibrin/fibrinogen degradation products, and the criteria for systemic inflammatory response syndrome were measured. Using the JAAM DIC score, the prevalence of DIC (score ≥4) in AHF patients was 5.0% (8 of 160 patients). The risk of death for patients grouped according to the DIC score was 27.8%, 46.2%, and 87.5% for DIC scores 0-1, 2-3, and ≥4, respectively (median follow-up 460 days). In multivariate analysis adjusted for various markers of disease severity, a DIC score ≥2 was independently associated with a higher all-cause death rate (adjusted hazard ratio 2.45; P = 0.005) and a higher rate of reaching the combined endpoint of all-cause death and readmission for AHF (adjusted hazard ratio 2.10; P = 0.006) after admission for AHF. In an intensive care setting, measurement of DIC score on admission could help risk stratification in hospitalized patients with AHF.

Effect of Hemodialysis on 7-Year Clinical Outcomes After Sirolimus-Eluting Stent Implantation.

BACKGROUND: Hemodialysis (HD) patients are reported to show poor clinical outcomes after percutaneous coronary intervention (PCI) with sirolimus-eluting stent (SES) compared with non-HD patients and their long-term prognosis remains unclear. METHODS AND RESULTS: We prospectively enrolled 489 consecutive patients undergoing PCI with SES and performed a retrospective analysis focusing on HD patients. Median follow-up was 7.0 years (interquartile range, 4.2-7.9) and the follow-up rate was 100%. At the 7-year follow-up, the cumulative incidences of all-cause death, target lesion revascularization (TLR) and major adverse cardiac events (MACE) were significantly higher in HD patients than in non-HD patients (HD vs. non-HD=34.7% vs. 9.6%, 42.6% vs. 10.2% and 75.3% vs. 24.4%, respectively; log-rank P<0.001). Cox-proportional hazard analysis revealed that independent predictors of all-cause death were HD (hazard ratio [HR] 2.88, 95% confidence interval [CI]: 1.39-6.00), insulin-treated diabetes mellitus (HR 2.19, 95% CI: 1.17-4.11), heart failure (HR 2.58, 95% CI: 1.25-5.32) and older age (HR 1.06/1-age, 95% CI: 1.02-1.10). Moreover, HD was an independent predictor of TLR (HR 3.63, 95% CI: 1.85-7.11) and MACE (HR 3.54, 95% CI: 2.19-5.73). CONCLUSIONS: In the present study, Japanese HD patients undergoing PCI with SES showed poorer long-term clinical outcomes than non-HD patients. HD was a strong predictor of long-term adverse events after SES implantation.

Baseline low-density lipoprotein cholesterol predicts the benefit of adding ezetimibe on statin in statin-naïve acute coronary syndrome.

We aimed to evaluate the effect of baseline low-density lipoprotein cholesterol (LDL-C) on the outcomes of patients with the acute coronary syndrome (ACS) receiving pitavastatin monotherapy or the combination of pitavastatin + ezetimibe. In the HIJ-PROPER study, 1734 ACS patients with dyslipidemia were randomly assigned to receive pitavastatin or pitavastatin + ezetimibe therapy. Statin-naïve participants (n = 1429) were divided into two groups based on the median LDL-C level (131 mg/dL) at enrollment. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. The median follow-up was 3.2 years. In the < 131 mg/dL group (n = 686), LDL-C changes were - 34.0% and - 49.8% in the pitavastatin monotherapy and pitavastatin + ezetimibe-treated groups (P < 0.0001), respectively; in the ≥ 131 mg/dL group (n = 743), LDL-C changes were - 42.9% and - 56.4% (P < 0.0001, respectively. Kaplan-Meier analyses revealed that the primary endpoint was not significantly different between the treatment groups for the < 131 mg/dL group, however, it was significantly lower in patients treated with pitavastatin + ezetimibe in the ≥ 131 mg/dL group (Hazard ratio = 0.72, 95% confidence interval = 0.56-0.91, P = 0.007, P value for interaction = 0.012). Statin-naïve ACS patients with baseline LDL-C < 131 mg/dL did not clinically benefit from pitavastatin + ezetimibe, while patients with baseline LDL-C ≥ 131 mg/dL treated with pitavastatin + ezetimibe showed better clinical results than those treated with pitavastatin monotherapy.Clinical Trial Registration: Original HIJ PROPER study; URL: http://www.umin.ac.jp/ctr . Unique Identifier; UMIN000002742, registered as an International Standard Randomized Controlled Trial.

Targeting high-sensitivity C-reactive protein levels in acute coronary syndrome patients undergoing contemporary lipid-lowering therapy: a sub-analysis of the HIJ-PROPER trial.

BACKGROUND: The effects of high-sensitivity C-reactive protein (hs-CRP) levels on clinical outcomes in chronic-phase acute coronary syndrome (ACS) patients undergoing aggressive lipid-lowering therapy remain unclear. We examined the effects of hs-CRP levels on the prognosis of ACS patients who underwent aggressive lipid-lowering therapy and determined treatment targets for hs-CRP value. METHODS: This post-hoc sub-analysis of a prospective randomized control trial (HIJ-PROPER) included 1734 ACS patients with dyslipidemia, who were divided into hs-CRP quartiles after 3 months of treatment. Primary endpoints were combined all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. Secondary endpoint was all-cause death. RESULTS: The median follow-up period was 3.7 years. Overall, 1415 patients were evaluated retrospectively. No significant among-group differences were noted in low-density lipoprotein cholesterol (LDL-C) levels over time (p = 0.44). Kaplan-Meier analyses revealed that the incidence of the primary and secondary endpoints was significantly higher in the highest hs-CRP group than in the other groups [hazard ratio (HR) = 1.52, 95% confidence interval (CI) = 1.16-2.00, p < 0.01; HR = 5.30, 95% CI = 2.47-11.32, p < 0.01, respectively]. The cut-off hs-CRP level to predict all-cause death was 0.74 mg/L (receiver operating characteristic curve: sensitivity: 68%, specificity: 62%). Multivariate analyses revealed that hs-CRP ≥0.74 mg/L　at 3 months was correlated with an increased risk of all-cause death (adjusted HR = 3.68, 95% CI = 2.22-6.10, p < 0.01). CONCLUSION: Elevated hs-CRP levels independently predicted a worse prognosis, regardless of LDL-C levels, suggesting that interventions against elevated inflammatory responses plus intensive lipid-lowering therapy and coronary revascularization are encouraging options for secondary prevention in ACS patients. TRIAL REGISTRATION: This trial is registered with the UMIN Clinical Trials Registry number UMIN000002742. Trial name: Proper level of lipid lowering with pitavastatin and ezetimibe in acute coronary syndrome (HIJ-PROPER) URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr-view.cgi?recptno=R000003334.

Effect of Ezetimibe + Pitavastatin on Cardiovascular Outcomes in Patients with ST-Segment Elevation Myocardial Infarction (from the HIJ-PROPER Study).

Lipid-lowering therapy is necessary to reduce cardiovascular event rates in patients with ST-segment elevation myocardial infarction (STEMI). This study aimed to evaluate the effect of intensive lipid-lowering therapy, which comprised pitavastatin and ezetimibe, on patients with STEMI. We therefore undertook a post hoc subanalysis of the HIJ-PROPER study's data that examined the clinical outcomes of the patients with dyslipidemia and STEMI (n = 880) who received pitavastatin and ezetimibe therapy (intensive lipid-lowering therapy group) or pitavastatin monotherapy (standard lipid-lowering therapy group), and we evaluated their cardiovascular events. The primary end point was a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina, and ischemia-driven revascularization. During the median 3.4-year follow-up period, the cumulative rates of the primary end point were 31.9% and 39.7% in the intensive lipid-lowering therapy and standard lipid-lowering therapy groups, respectively (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62 to 0.97; p = 0.02). Compared with the standard lipid-lowering therapy group, the intensive lipid-lowering therapy group had significantly lower all-cause death (6.9% vs 3.2%; HR, 0.45; 95% CI, 0.23 to 1.84; p = 0.01) and nonfatal stroke (2.9% vs 1.6%; HR, 0.77; 95% CI, 0.62 to 0.97; p = 0.02) rates. Patients with pitavastatin and ezetimibe therapy, as compared with pitavastatin monotherapy, had a lower cardiovascular event in STEMI patients. In conclusion, adding ezetimibe to statin therapy may be beneficial for patients with dyslipidemia and STEMI.

The Effects of Lipid-Lowering Therapy on Serum Eicosapentaenoic Acid to Arachidonic Acid Ratio: An HIJ-PROPER Sub-Analysis.

BACKGROUND: Controversy remains regarding the influence of lipid-lowering therapy on the eicosapentaenoic acid/arachidonic acid ratio. OBJECTIVE: This study aimed to clarify the effects of lipid-lowering therapy on the eicosapentaenoic acid/arachidonic acid ratio in patients with acute coronary syndrome (ACS). METHODS: This was a post hoc sub-analysis of the Heart Institute of Japan-PRoper level of lipid-lowering with pitavastatin and ezetimibe in ACS study. We compared the eicosapentaenoic acid/arachidonic acid ratio changes from baseline to the 3-month follow-up after contemporary lipid-lowering therapy with pitavastatin + ezetimibe therapy and pitavastatin mono-therapy. RESULTS: Among patients with ACS and dyslipidemia, the eicosapentaenoic acid/arachidonic acid increased significantly in the pitavastatin mono-therapy group (0.40 ± 0.26 to 0.46 ± 0.34, P < .0001) but did not increase in the pitavastatin + ezetimibe group (0.37 ± 0.22 to 0.38 ± 0.27, P = .18). When the analysis was limited to patients who received 2 mg/day of pitavastatin during the follow-up period, these trends in changes of the eicosapentaenoic acid/arachidonic acid ratio remained unchanged. Multivariate analysis showed that ezetimibe use (P = .005; ß = 0.09), ST-elevation myocardial infarction (P = .04; ß = -0.01), and baseline low-density lipoprotein cholesterol (LDL-C) level (P = .0003; ß = 0.12) were independent predictors of the percentage change in the eicosapentaenoic acid/arachidonic acid ratio. These trends were similar even when the analysis was limited to patients who did not take statins at enrollment. CONCLUSION: Standard lipid-lowering therapy with pitavastatin mono-therapy improved the eicosapentaenoic acid/arachidonic acid ratio for patients with ACS. Intensive lipid-lowering therapy with pitavastatin + ezetimibe did not improve the eicosapentaenoic acid/arachidonic acid ratio, although LDL-C decreased significantly. Inhibition of the improvement in the eicosapentaenoic acid/arachidonic acid ratio by adding ezetimibe may affect cardiovascular disease prognosis.

Impact of age on clinical outcomes of antihypertensive therapy in patients with hypertension and coronary artery disease: A sub-analysis of the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Artery Disease.

This study aimed to determine whether different systolic blood pressure (SBP) measurements achieved with antihypertensive therapy impact clinical outcomes by age in patients with hypertension and coronary artery disease (CAD). This post hoc analysis from the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in Coronary Heart Disease (HIJ-CREATE) trial included 2048 patients with hypertension and angiographically documented CAD. Participants were divided into three groups based on age at enrollment: middle-aged (<60 years, n = 570), pre-elderly (≥60-<70 years, n = 730), and elderly (≥70 years, n = 748). Among the 2,048 patients, 1695 (82.7%) underwent percutaneous coronary intervention. The primary end point was the time to first occurrence of a major adverse cardiac event (MACE). During a median follow-up of 4.2 years, the MACE rate was 19.8%, 28.1%, and 31.1% in the middle-aged, pre-elderly, and elderly groups, respectively. Achieved BP was defined as the mean BP during scheduled visits. Patients with higher achieved SBP had a higher occurrence of MACE in all age groups. An unadjusted quadratic proportional hazard model was used to evaluate the relationship between achieved BP during follow-up and risk for MACE. In each age group, participants were divided into quartiles based on the achieved BP during follow-up. The relationship between achieved SBP and the incidence of MACE did not follow a J-shaped curve in any age group. In conclusion, in the contemporary era of aggressive coronary revascularization, a lower SBP target may be appropriate even in elderly patients with hypertension and CAD.

Effect of Aggressive Lipid-Lowering Therapy in Single-Vessel vs. Multivessel Coronary Artery Disease Patients With Acute Coronary Syndrome　- Heart Institute of Japan-Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome (HIJ-PROPER) Substudy.

Background: The effects of aggressive lipid-lowering therapy according to the number of diseased coronary arteries in acute coronary syndrome (ACS) are still controversial. This study investigated the efficacy of this therapy in ACS patients with multivessel disease (MVD) and single-vessel disease (SVD). Methods and Results: The subjects were derived from the HIJ-PROPER study, in which ACS patients with dyslipidemia were randomized to receive either pitavastatin+ezetimibe (targeting low-density lipoprotein cholesterol [LDL-C] <70 mg/dL) or pitavastatin monotherapy (targeting LDL-C <90 mg/dL). In this study, treatment efficacy was compared between patients with MVD and SVD. The primary endpoint was a composite of major advanced cardiovascular events (MACE; all-cause death, non-fatal myocardial infarction, non-fatal stroke, and ischemia-driven revascularization). We identified 1,702 eligible patients (MVD, n=869; SVD, n=833; mean age, 65.6 years; male, 75.6%; acute revascularization, 96.2%). MACE incidence was significantly higher in the MVD group than in the SVD group (43.7% vs. 25.9%, HR, 1.95; 95% CI: 1.65-2.31, P<0.001). In the SVD group, pitavastatin+ezetimibe had significantly fewer MACE than pitavastatin monotherapy (34.6% vs. 47.4%, HR, 0.72; 95% CI: 0.55-0.94, P=0.02). Conclusions: The benefits of aggressive lipid-lowering therapy, with the addition of ezetimibe to statins, were enhanced in ACS patients with SVD, but not with MVD, in the early invasive strategy era.

Clinical characteristics of hospitalized heart failure patients with preserved, mid-range, and reduced ejection fractions in Japan.

AIMS: There are regional differences in the patient characteristics, management, and outcomes of hospitalized patients with heart failure (HF). The aim of this study was to evaluate the clinical characteristics and outcomes of Japanese patients who are hospitalized with HF on the basis of the left ventricular ejection fraction (LVEF) stratum. METHODS AND RESULTS: We retrospectively conducted a multicentre cohort study of 1245 hospitalized patients with decompensated HF between 2013 and 2014. Of these patients, 36% had an LVEF < 40% [HF with reduced ejection fraction (HFrEF), median age 72 years, 71% male], 21% had an LVEF 40-49% [HF with mid-range EF (HFmrEF), 77 years, 56% male], and 43% had an LVEF ≥ 50% [HF with preserved EF (HFpEF), 81 years, 44% male]. The primary outcome was death from any cause, and the secondary outcomes were cardiac death and re-hospitalization due to worsened HF after hospital discharge. There were high proportions of non-ischaemic cardiomyopathy (32%) in HFrEF patients, coronary artery disease (44%) in HFmrEF patients, and valvular disease (39%) in HFpEF patients. The frequencies of intravenous diuretic and natriuretic peptide administration during hospitalization were 66% and 30%, respectively. The median hospital stay for the overall population was 19 days, and the length of stay was >7 days for >90% of patients. In-hospital mortality was 7%, but was not different among the LVEF groups (HFrEF 7%, HFmrEF 6%, and HFpEF 8%). After a median follow-up of 19 months (range, 3-26 months), 192 (17%) of the 1156 patients who were discharged alive died, and 534 (46%) were re-hospitalized after hospital discharge. There were no significant differences in mortality after hospital discharge among the three LVEF groups (HFrEF 18%, HFmrEF 16%, and HFpEF 16%). There were no differences in cardiac death or re-hospitalization due to worsened HF after hospital discharge among the LVEF groups (cardiac death: HFrEF 8%, HFmrEF 7%, and HFpEF 7%; re-hospitalization due to worsened HF: HFrEF 19%, HFmrEF 16%, and HFpEF 17%). Multivariable-adjusted analyses showed that the HFmrEF and HFrEF groups, compared with the HFpEF group, were not associated with an increased risk for in-hospital death or death after hospital discharge. Non-cardiac causes of death and re-hospitalization after hospital discharge accounted for 35% and 38%, respectively. CONCLUSIONS: Our results revealed different clinical characteristics but similar mortality rates in the HFrEF, HFmrEF, and HFpEF groups. The most common cause of death and re-hospitalization after hospital discharge was HF, but non-cardiac causes also contributed to their prognosis. Integrated management approaches will be required for HF patients.

Polyunsaturated Fatty Acid Impact on Clinical Outcomes in Acute Coronary Syndrome Patients With Dyslipidemia: Subanalysis of HIJ-PROPER.

Background This study aimed to examine the impact of baseline eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio on clinical outcomes of patients with acute coronary syndrome. Methods and Results In the HIJ-PROPER (Heart Institute of Japan Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome) study, 1734 patients with acute coronary syndrome and dyslipidemia were randomly assigned to pitavastatin+ezetimibe therapy or pitavastatin monotherapy. We divided the patients into 2 groups based on EPA/AA ratio on admission (cutoff 0.34 µg/mL as median of baseline EPA/AA ratio) and examined their clinical outcomes. The primary end point comprised all-cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina pectoris, or ischemia-driven revascularization. Percentage reduction of low-density lipoprotein cholesterol and triglyceride from baseline to follow-up was similar regardless of baseline EPA/AA ratio. Despite the mean low-density lipoprotein cholesterol level during follow-up being similar between the low- and high-EPA/AA groups, the mean triglyceride levels during follow-up were significantly higher in the low- than in the high-EPA/AA group. After 3 years of follow-up, the cumulative incidence of the primary end point in patients with low EPA/AA was 27.2% in the pitavastatin+ezetimibe group compared with 36.6% in the pitavastatin-monotherapy group (hazard ratio 0.69; 95% CI, 0.52-0.93; P=0.015). However, there was no effect of pitavastatin+ezetimibe therapy on the primary end point in patients with high EPA/AA (hazard ratio 0.92; 95% CI, 0.70-1.20; P=0.52). Conclusions Among acute coronary syndrome patients who have dyslipidemia and low EPA/AA ratio, adding ezetimibe to statin decreases the risk of cardiovascular events compared with statin monotherapy. Clinical Trial Registration URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000002742.

Predictive Value of Baseline High-Sensitivity C-Reactive Protein Level and Renal Function for Patients With Acute Coronary Syndrome Undergoing Aggressive Lipid-Lowering Therapy: A Subanalysis of HIJ-PROPER.

The systematic inflammatory response might confound renal impairment, and both have been reported to affect clinical outcomes after acute coronary syndrome. We examined the impacts of the high-sensitivity C-reactive protein (hsCRP) level and estimated glomerular filtration rate level on the prognosis for acute coronary syndrome patients who underwent aggressive lipid-lowering therapy in contemporary practice. This was a subanalysis of the HIJ-PROPER study, and 1,734 patients were enrolled. Patients were divided into 4 groups using an hsCRP value of 10mg/L and an estimated glomerular filtration rate value of 60 ml/min/1.73 m2 as the cut-off points. Groups were defined as follows: group A, low hsCRP and normal or mild renal impairment; group B, low hsCRP and renal impairment; group C, high hsCRP and normal or mild renal impairment; and group D, high hsCRP and renal impairment. The primary end point was defined as the composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina or coronary revascularizations. The median follow-up period was 3.9years, and the follow-up rate was 99%. Compared with group A, the 2 higher hsCRP groups (groups C and D) showed a significantly higher incidence of primary end points (hazard ratio 1.36, 95% confidence interval 1.12 to 1.65, p = 0.002; and hazard ratio 1.40, 95% CI 1.10 to 1.80, p = 0.008). Such a difference was not found compared with group B. In conclusion, patients with higher hsCRP levels had worse prognoses regardless of renal impairment and aggressive lipid-lowering therapy.

Baseline serum sitosterol level as predictor of adverse clinical events in acute coronary syndrome patients with dyslipidaemia: A sub-analysis of HIJ-PROPER.

BACKGROUND AND AIMS: We aimed to examine the effect of serum sitosterol, a cholesterol absorption marker, on clinical outcomes in acute coronary syndrome patients with dyslipidaemia. METHODS: This is a sub-analysis of the HIJ-PROPER trial that assesses the effect of aggressive low-density lipoprotein cholesterol (LDL-C) lowering treatment with pitavastatin + ezetimibe in 1734 acute coronary syndrome (ACS) patients with dyslipidaemia. Patients were divided into two groups based on sitosterol level at enrolment (cut-off value was 2.2 µg/mL; a median of baseline sitosterol level), and clinical outcomes were examined. RESULTS: The mean LDL-C level after 3 years in the low sitosterol group was 84.8 ± 20.1 mg/dL with pitavastatin-monotherapy and 64.6 ± 20.3 mg/dL with pitavastatin + ezetimibe, while corresponding values in the high sitosterol group were 91.0 ± 22.9 mg/dL and 71.1 ± 23.3 mg/dL, respectively. In the high sitosterol group, the Kaplan-Meier event rate for the primary endpoint at 3 years was 26.0% in the pitavastatin + ezetimibe group, as compared with 34.3% in the pitavastatin-monotherapy group (hazard ratio, 0.71; 95% confidence interval, 0.56-0.91; p = 0.006, p-value for interaction = 0.010). However, in the low sitosterol group, there was no significant reduction of the primary endpoint by pitavastatin + ezetimibe therapy. CONCLUSIONS: Aggressive lipid-lowering treatment with ezetimibe had a positive effect on clinical outcomes in the high sitosterol subset of ACS patients with dyslipidaemia, but not in the low sitosterol subset. This effect was independent of LDL-C reduction and suggests that sitosterol measurement on admission in ACS patients might contribute to a "personalised" lipid-lowering approach.

Rationale, design features, and baseline characteristics: The Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome (HIJ-PROPER).

BACKGROUND: In contrast to current guidelines in Western countries, moderate reduction of low-density lipoprotein cholesterol (LDL-C) is recommended for Japanese patients with atherosclerotic cardiovascular disease and dyslipidemia even in secondary prevention. HIJ-PROPER (Heart Institute of Japan-PRoper level of lipid lOwering with Pitavastatin and Ezetimibe in acute coRonary syndrome) is a prospective, randomized, open-label, blinded endpoint multicenter trial designed to assess whether closely controlled LDL-C lowering with a standard statin dose plus ezetimibe, targeting LDL-C of <70mg/dL, would reduce cardiovascular events more than standard statin monotherapy targeting LDL-C of <100mg/dL as per the Japan Atherosclerotic Society guideline in patients with acute coronary syndrome (ACS) and dyslipidemia. METHODS: We recruited patients with ACS and dyslipidemia who had undergone coronary angiography. Participants are randomly allocated to either intensive LDL-C lowering treatment (target LDL-C of <70mg/dL; pitavastatin plus ezetimibe) or standard LDL-C lowering treatment (target LDL-C of 90-100mg/dL; pitavastatin monotherapy). The primary endpoint is a composite of total death, non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina, and any ischemia-driven revascularization. Patients will be followed for a minimum of 3 years. RESULTS: Between January 2010 and April 2013, 1734 patients were enrolled from 19 hospitals in Japan with a mean age of 65.6 years; 75.5% were men and 83.3% were statin-naïve. The qualifying ACS was an acute MI in 61.5%. This study is expected to report its findings in August 2016. CONCLUSION: HIJ-PROPER will determine whether targeting LDL-C of <70mg/dL with pitavastatin plus ezetimibe can improve cardiovascular outcomes in Japanese patients with ACS and dyslipidemia in comparison to targeting LDL-C of 90-100mg/dL with standard pitavastatin monotherapy. TRIAL REGISTRATION: UMIN000002742.

Effects of Statin versus the Combination of Ezetimibe plus Statin on Serum Lipid Absorption Markers in Patients with Acute Coronary Syndrome.

Background. The use of statins is essential for aggressive lipid-lowering treatment in acute coronary syndrome (ACS) patients with dyslipidemia. Recently, elevation of sitosterol, a lipid absorption marker, was reported to be associated with premature atherosclerosis. The purpose of the present study was to examine the impact of ezetimibe, a selective intestinal cholesterol transporter inhibitor, in ACS patients. Methods. A total of 197 ACS patients were randomized to pitavastatin + ezetimibe (n = 100) or pitavastatin (n = 97). Low-density lipoprotein cholesterol (LDL-C) and sitosterol levels were evaluated on admission and after 12 weeks. Results. After 12 weeks, the pitavastatin + ezetimibe group showed a significantly greater decrease of sitosterol (baseline versus after 12 weeks; 2.9 ± 2.5 versus 1.7 ± 1.0 ng/mL, P < 0.001) than the pitavastatin group (2.7 ± 1.5 versus 3.0 ± 1.4 ng/mL). The baseline sitosterol level was significantly higher in patients with achieved LDL-C levels ≥ 70 mg/dL than in patients with levels < 70 mg/dL (3.2 ± 2.5 versus 2.4 ± 1.3 ng/mL, P = 0.006). Conclusions. Ezetimibe plus statin therapy in ACS patients with dyslipidemia decreased LDL-C and sitosterol levels more than statin therapy solo. Sitosterol Elevation was a predictor of poor response to aggressive lipid-lowering treatment in ACS patients.

Impact of visit-to-visit variability and systolic blood pressure control on subsequent outcomes in hypertensive patients with coronary artery disease (from the HIJ-CREATE substudy).

Although visit-to-visit variability in systolic blood pressure (BP) is a strong predictor of stroke, the impact on subsequent major adverse cardiac events (MACEs) in patients with coronary artery disease (CAD) in terms of secondary prevention remains unclear. The aim of this study was to clarify the prognostic significance of visit-to-visit variability in systolic BP on subsequent MACE in hypertensive patients with CAD. In the Heart Institute of Japan Candesartan Randomised Trial for Evaluation in Coronary Artery Disease, a total of 2,049 hypertensive patients with CAD were enrolled. Incidence of MACEs in addition to biochemistry tests and office BP were determined during follow-up. Achieved BP was defined as the mean value of systolic BP in patients who did not experience MACE and the mean value of systolic BP before MACE in those who experienced MACE during follow-up. In the present study, 1,734 patients had multiple follow-up visits (≥3 times) until their final follow-up. During a median follow-up of 4.2 years, the primary outcome occurred in 317 patients (18.3%). Visit-to-visit variability of systolic BP was defined as the SD. Participants were divided into equal quartiles based on the mean systolic BP during follow-up and visit-to-visit variability of systolic BP, respectively. Although there was no relation between visit-to-visit variability of systolic BP and the incidence of MACE, the highest quartile based on mean systolic BP showed a significant relation with subsequent MACE. In conclusion, in hypertensive patients with CAD, inadequate BP control is a strong predictor of subsequent MACE, whereas visit-to-visit variability of systolic BP is not.

Chronic kidney disease and long-term outcomes of myocardial infarction.

BACKGROUND: Although chronic kidney disease (CKD) is a risk factor for cardiovascular disease, information about myocardial infarction (MI) with CKD is limited in the acute revascularization era. METHODS: To clarify the relationship between CKD and long-term outcomes of MI, consecutive 4550 patients with acute MI treated at 17 participating hospitals were analyzed. The primary study outcome was death from any cause, and a secondary endpoint was the first appearance major adverse cardiovascular events. RESULTS: Acute revascularization therapies were performed in 75.2% of the patients and the mean left ventricular ejection fraction (LVEF) was 53%. The median follow-up was 4.1 years (follow-up rate, 95.2%). Patients were divided into four categories (<45.0, 45.0 to 59.9, 60.0 to 74.9, and ≥ 75.0 mL/min per 1.73 m(2) of body-surface area) according to the glomerular filtration rate (GFR) estimated by the Modification of Diet in Renal Disease equation. A total of 1941 (42.7%) patients had an estimated GFR of <60.0 mL/min per 1.73 m(2). Mortality rates increased with declining estimated GFR. Unadjusted hazard ratios for total and cardiovascular death in the group with an estimated GFR of 45.0 to 59.9 mL/min per 1.73 m(2) using the group with an estimated GFR of ≥ 75.0 mL/min per 1.73 m(2) as the reference were 1.63 (95% CI, 1.28 to 2.07) and 2.09 (95% CI, 1.45 to 3.01), respectively. CONCLUSIONS: Even early-stage CKD should be considered a powerful risk factor for long-term cardiovascular death after acute MI with preserved LVEF in the acute revascularization era.

Efficacy of the combination of amlodipine and candesartan in hypertensive patients with coronary artery disease: a subanalysis of the HIJ-CREATE study.

BACKGROUND: The effects of the combination of angiotensin II receptor blocker (ARB) plus dihydropyridine calcium channel blockers (DHP-CCBs), which is known as a potent antihypertensive drug regimen, on cardiovascular events remain unclear. OBJECTIVE: The purpose of this post hoc subgroup analysis was to compare the incidence of major adverse cardiovascular events (MACE) of patients treated with candesartan and amlodipine with that of those with candesartan and non-amlodipine CCBs in hypertensive patients with coronary artery disease (CAD). METHODS: HIJ-CREATE was a multicenter, prospective, randomized, controlled study that compared the effects of candesartan-based with those of non-ARB-based standard therapy on MACE in 2049 hypertensive patients with CAD. In the candesartan group, a total of 335 patients were treated with DHP-CCBs (amlodipine: 170 and non-amlodipine-CCBs: 165) at the baseline. In this sub-analysis, we compared, among the participants allocated to candesartan regimen, the long-term effects of amlodipine and non-amlodipine CCBs that were concomitantly given with ARB, although the choice of CCB was not randomized. RESULTS: The median follow-up was 3.9 years. Treatment using amlodipine with candesartan reduced the risk of MACE by 38% (hazard ratio, 0.62; 95% confidence interval, 0.41-0.94, p=0.025), as compared to patients treated with non-amlodipine-CCBs and candesartan. In a multivariate analysis, combination therapy of candesartan with amlodipine was an independent predictor of reduced risk of MACE. CONCLUSIONS: The results suggest that the combination of amlodipine and candesartan is more beneficial in reducing MACE in hypertensive patients with CAD compared to non-amlodipine-DHP-CCBs in combination therapy with candesartan. Further investigation in larger-scale prospective randomized studies is required to reach any conclusion as to the superiority of combination therapy of candesartan with amlodipine.