Ichiro Matsumoto, MD; Yuichi Miyake, MD; Mizuki Mizukawa, MD; Yuichiro Takagi, MD

Transcription

1 Circulation Journal Official Journal of the Japanese Circulation Society ORIGINAL ARTICLE Ischemic Heart Disease Impact of Low-Density Lipoprotein Cholesterol/ High-Density Lipoprotein Cholesterol Ratio on Long-Term Outcome in Patients Undergoing Percutaneous Coronary Intervention Ichiro Matsumoto, MD; Yuichi Miyake, MD; Mizuki Mizukawa, MD; Yuichiro Takagi, MD Background: Several studies have demonstrated that the low-density lipoprotein cholesterol/high-denisty lipoprotein-cholesterol (LDL-C/HDL-C) ratio is an excellent predictor of cardiovascular disease. The aim of the present study was to determine whether the LDL-C/HDL-C ratio would affect outcome in patients after percutaneous coronary intervention (PCI). Methods and Results: Six-hundred-eighty-seven participants who underwent successful PCI for acute coronary syndromes or stable angina were enrolled. They were divided into 3 groups on the basis of the LDL-C/HDL-C ratio recorded 6 months after PCI: those with LDL-C/HDL-C 1.5 (n=125); 1.5< LDL-C/HDL-C 2.0 (n=205); LDL-C/HDL-C >2 (n=357). In the 3 groups, the incidence of major adverse cardiac events (MACE) was measured during the 5 years after baseline evaluation. MACE was defined as cardiac death, non-fatal myocardial infarction, new lesions, and restenosis. The median follow-up duration was 33 months. Kaplan Meier analysis demonstrated that patients with LDL-C/HDL-C 1.5 had a significantly lower incidence of MACE after PCI than patients with 1.5< LDL-C/HDL-C 2.0 (P=0.014) or with LDL-C/HDL-C >2.0 (P<0.001). In addition, Cox proportional hazards analysis indicated that the LDL-C/HDL-C ratio was correlated with the incidence of MACE (HR =1.39, 95% confidence interval: , P<0.001). Conclusions: The LDL-C/HDL-C ratio had an impact on long-term outcome in patients undergoing PCI. (Circ J 2011; 75: ) Key Words: LDL-cholesterol/HDL-cholesterol ratio; Percutaneous coronary intervention; Secondary prevention Although very few epidemiological studies have been made to investigate the incidence of coronary artery disease (CAD), it is assumed that the incidence of CAD in Japan has been increasing since a more Westernized lifestyle has been adapted. 1 Low-density lipoprotein cholesterol (LDL-C) lowering therapy is one of the most important strategies to prevent the development of CAD, established by abundant clinical evidence. 2 5 Likewise, the importance of controlling the level of high-density lipoprotein cholesterol (HDL-C) to prevent CAD has been generally accepted, as several previous studies reported that the risk of CAD was reduced with an escalation of HDL-C level. 6 8 Taking these evidence into account, the guidelines for secondary prevention of CAD in Japan have proposed to control the level of LDL-C less than 100 mg/dl and the level of HDL-C exceeding 40 mg/dl in patients with a history of cardiovascular disease. 9,10 In the USA, the stricter level of LDL-C for secondary prevention has been set less than 70 mg/dl in a major guidelines or consensus statement. 11,12 The LDL-C to HDL-C (LDL-C/HDL-C) ratio, which simultaneously reflects both, has been increasingly recognized as a stronger prognostic factor of CAD than the individual level of LDL-C and HDL-C both in primary and secondary prevention, reported by several epidemiological and clinical studies In Japan, subanalysis of the MEGA Study has shown that lowering the LDL-C/HDL-C at 2.0 or lower is beneficial to reduce the risk of cardiac events for primary prevention. 16 Furthermore, the results of pooled analysis based on 4 randomized trials using intravascular ultrasound (IVUS) have shown that lowering the LDL-C/HDL-C ratio less than 1.5 results in atheroma regression in the patients with cardiovascular diseases. 17 However, there have been few studies to Received March 16, 2010; revised manuscript received November 26, 2010; accepted December 7, 2010; released online February 11, 2011 Time for primary review: 21 days Cardiovascular Center, KKR Takamatsu Hospital, Takamatsu, Japan Name of grant: None. Mailing address: Ichiro Matsumoto, MD, Cardiovascular Center, KKR Takamatsu Hospital, 4-18 Tenjinmae, Takamatsu , Japan. ichiroh@kkr-ta-hp.gr.jp ISSN doi: /circj.CJ All rights are reserved to the Japanese Circulation Society. For permissions, please cj@j-circ.or.jp

2 906 MATSUMOTO I et al. evaluate the impact of the LDL-C/HDL-C ratio on long-term outcome in secondary prevention of CAD after percutaneous coronary intervention (PCI) in Japanese population. Therefore, we conducted a post hoc analysis based on the clinical data in patients who underwent successful PCI after coronary events in our hospital to investigate whether the LDL-C/HDL- C ratio would affect outcome in patients after PCI. Methods Study Population The present study used clinical records of consecutive 687 patients who underwent successful PCI after acute coronary syndrome or stable angina pectoris between January 2002 and September Patients with residual stenosis in main coronary arteries by coronary angiography (CAG) after PCI, or residual heart failure of more than New York Heart Association class 3 in 6 months after PCI were excluded from the study. Also, those with a past history of coronary artery bypass grafting or malignant tumor were excluded. Furthermore, patients who had coronary artery events within 3 months after PCI were also excluded to avoid the influence of PCI procedure or subacute thrombosis. The ethics committee of our hospital approved the study protocol, and all patients prior to entry gave written informed consent. Study Design After PCI, the follow-up and drug treatment were initiated at the outpatient clinic. The patients were followed-up carefully with inquiry and examination every 2 months and blood tests every 6 months. Also, routine CAG was performed 6 8, 12 18, and months after PCI, and exercise tests were performed every 12 months. During the follow-up, if symptoms appeared, or abnormalities were noted on an exercise test, CAG was performed when considered necessary. Concerning antiplatelet therapy after PCI, 100 mg of aspirin and 75 mg of clopidogrel or 200 mg of ticlopidine were used in combination for 6 months, in principle, and at least aspirin was continued thereafter. Also, the use of antidyslipidemic drugs was left to the judgment of the attending physician by setting no particular restriction, but we made efforts to effectuate their optimal lipid level during 6 months after PCI. The baseline evaluation was performed 6 months after PCI. Based on the baseline LDL-C/HDL-C, the patients were divided into 3 groups, ie, LDL-C/HDL-C 1.5, 1.5< LDL-C/ HDL-C 2.0, and LDL-C/HDL-C >2.0. This range of the ratio was decided referred to the reports of Nicholls et al. 17 Demographic data including the age, gender, body mass index (BMI), coronary risk factors (hypertension, diabetes, and smoking history), blood test (LDL-C, HDL-C, triglycerides (TG), HbA1c, C-reactive protein (CRP)), estimated glomerular filtration rate (egfr) calculated using the Schwartz formula, medication use were retrospectively collected in the database in our institution. Moreover, primary disease (acute coronary syndrome or stable angina), characteristics of coronary artery stenosis, the number of diseased vessels and the usage rate of drug-eluting stents (DES) were checked. Blood samples were obtained early in the morning after an overnight fast. Hypertension was defined as being prescribed oral antihypertensive drugs or blood pressures at an outpatient visit of 140/90 mmhg or higher. Diabetes was defined as being prescribed oral antidiabetic drugs or an HbA1c level of 6.5 or higher. Furtermore, the incidence of major adverse cardiac events (MACE) after baseline evaluation was compared among the 3 groups. In this study, MACE was defined as cardiovascular death, non-fatal myocardial infarction, a new lesion of coronary stenosis, and restenosis of a treated site. Coronary stenosis was defined as 50% or greater narrowing detected by quantitative CAG and restenosis was defined as stenosis within both sides 5 mm of PCI site. Furthermore, the correlations between the incidence of MACE and various risk factors were evaluated by multivariate analysis. Follow-up was conducted for up to 5 years after PCI and endpoint was defined as the occurrence of MACE. During follow-up periods, the patients who died of the causes except cardiovascular trouble were censored. Also, the patients that we could not observe because of removal were censored, too. However, the patients who had unscheduled CAG but who did not have either new stenosis or restenosis were continued observation. Statistical Analysis Continuous variables were expressed as the mean ± standard deviation and were compared using one-way ANOVA with Tukey post hoc and chi-square analyses. Cardiac event-free survival was analyzed using Kaplan Meier estimation with the log-rank test. Multivariate Cox proportional-hazards regression adjusted for age, gender, BMI, smoking habit, the LDL-C/HDL-C ratio, TG, HbA1c, CRP, egfr, and statin use determined risks for the occurrence of MACE. In this analysis, the LDL-C/HDL-C ratio was used as continuous variables. A P-value of <0.05 was considered significant. All data were analyzed using SAS software, version (SAS institute Inc, NC, USA). Results The mean LDL-C/HDL-C ratio of all 687 patients was 2.19±0.81, and the percentage of patients whose LDL-C/ HDL-C 1.5 in 18.2% (n=125), 1.5< LDL-C/HDL-C 2.0 in 29.8% (n=205), and LDL-C/HDL-C >2.0 in 52.0% (n=357). Regarding the characteristics of the patients, the percentage of males was higher (P<0.001), and the BMI was also higher (P<0.001), in the LDL-C/HDL-C >2.0 group, but no difference was noted in the percentage of hypertensive or diabetic patients or smokers among the 3 groups. Naturally, the LDL- C level was significantly lower (P<0.001), and the HDL-C level was significantly higher (P<0.001), in the LDL-C/HDL- C 1.5 group. The TG level was significantly higher in the LDL-C/HDL-C >2.0 group (P<0.001). Concerning the data of other blood tests, the high sensitivity CRP level was high in the LDL-C/HDL-C >2.0 group (P=0.026), but no difference was noted in the HbA1c level or egfr among the 3 groups. In terms of oral medications, the percentage of patients taking antihypertensive drugs or antidiabetic drugs showed no difference among the 3 groups, but the percentage of those taking a statin was lower in the LDL-C/HDL-C >2.0 group (P=0.002). Also, there were no significant differences in terms of primary diseases, the characteristics of coronary artery stenosis, the number of diseased vessels and the usage rate of DES (Table 1). The median follow-up duration was 33 months. During the follow-up period, 3 patients and 1 patient died of severe infection and leukemia, respectively. In addition, 6 patients changed their residences. These 13 patients, including 3 other patients, we could not follow-up and were therefore censored. The incidence of MACE was compared in patients with these characteristics among the 3 groups based on the LDL-C/HDL- C ratio. At first, MACE did not occurr between 3 and 6 months after PCI. On the first CAG, restenosis was detected in 5

3 LDL-C/HDL-C Ratio as a Risk Factor of CVD 907 Table 1. Baseline Characteristics L/H < 1.5 (n=125) 1.5< L/H < 2.0 (n=205) L/H >2.0 (n=357) P value Mean age (years) 68.6± ± ±10.2, M/F 80/45 148/57 309/48, <0.001 BMI (kg/mm 2 ) 23.3± ± ±3.2, <0.001 Hypertension 69 (55.2%) 121 (59.0%) 224 (62.7%) Diabetes 47 (37.6%) 67 (32.7%) 133 (37.2%) Smoking 14 (11.2%) 40 (19.5%) 63 (17.6%) LDL-C (mg/dl) 78.0± ± ±24.1, <0.001 HDL-C (mg/dl) 67.1± ± ±8.9, <0.001 TG (mg/dl) 131.6± ± ±108.7, <0.001 HbA1c (%) 5.92± ± ± CRP (mg/l) 1.21± ± ± GFR (ml m m 2 ) 65.2± ± ± ARB/ACEI 73 (60.3%) 135 (65.9%) 267 (62.5%) CCB 47 (37.0%) 91 (44.4%) 154 (43.1%) Statin 89 (71.2%) 140 (68.3%) 201 (56.3%), ACS 31 (24.8%) 49 (23.9%) 82 (23.0%) Mean no. of diseased vessels DES use 68 (54.4%) 121 (59.0%) 222 (62.2%) Data are expressed as mean ± standard deviation or number (%). P<0.05 vs. L/H < 1.5 group, P<0.05 vs. 1.5< L/H < 2.0 group. L/H, low-denisty lipoprotein-cholesterol (LDL-C)/high-denisty lipoprotein-cholesterol (HDL-C) ratio; BMI, body mass index; TG, triglyceride; CRP, C-reactive protein; GFR, estimated glomerular filtration rate; ARB/ACEI, angiotensin receptor blocker/angiotensin converting enzyme inhibiter; CCB, calcium channel blocker; ACS, acute coronary syndrome; DES, drug-eluting stent. Figure. Comparison of cumulative incidence of MACE. MACE, major adverse cardiac events; L/H, low-denisty lipoproteincholesterol/high-denisty lipoprotein-cholesterol ratio; PCI, percutaneous coronary intervention.

4 908 MATSUMOTO I et al. Table 2. Incidence and Details of MACE L/H < 1.5 (n=125) 1.5< L/H < 2.0 (n=205) L/H >2.0 (n=357) No-MACE Cardiac death Myocardial infarction New lesions Restenosis Total MACE 14 (11.2%) 47 (22.9%) 168 (46.9%), Data are expressed as number (%). P<0.05 vs. L/H < 1.5 group, P<0.05 vs. 1.5< L/H < 2.0 group. MACE, major adverse cardiac events; L/H, LDL-C/HDL-C ratio. Table 3. Proportional Hazards Cox Regression Model: Incidence of MACE Hazard ratio 95%CI P value Age Male BMI Smoking LDL-C <0.001 HDL-C <0.001 L/H ratio <0.001 Triglyceride HbA1c CRP GFR Statin DES use CI, confidence interval. Other abbreviations see in Tables 1,2. patients (4.0%) with LDL-C/HDL-C 1.5, 20 patients (9.8%) with 1.5< LDL-C/HDL-C 2.0, and 48 patients (13.4%) with LDL-C/HDL-C >2.0. Conclusively, total MACE was observed in 14 patients (11.2%) in the LDL-C/HDL-C 1.5 group, 47 patients (22.9%) in the 1.5< LDL-C/HDL-C 2.0 group, and 168 patients (46.9%) in the LDL-C/HDL-C >2.0 group. Most of the MACE was new lesions or restenosis for 5 years (Table 2). Next, we analyzed the incidences of MACE in the 3 groups by the Kaplan Meier analysis. The incidence of MACE in the LDL-C/HDL-C 1.5 group was significantly lower than that not only in the LDL-C/HDL-C >2.0 (P<0.001) but also in the 1.5< LDL-C/HDL-C 2.0 group (P=0.014) (Figure). Moreover, when the relationships of the incidence of MACE with various risk factors (age, gender, BMI, smoking history, LDL-C, HDL-C, LDL-C/HDL-C ratio, TG, HbA1c, CRP, egfr, statin use, and DES use) were evaluated using Cox proportional hazard model, the incidence of MACE after PCI was significantly correlated with the LDL-C/HDL- C ratio (hazard ratio=1.39, 95% confidence interval (CI): , P<0.001). The hazard ratio for LDL-C was 1.02 (95%CI: , P<0.001), and the ratio for HDL-C was 0.97 (95%CI: , P<0.001). Meanwhile, the use of statin and DES was not correlated with the occurrence of MACE (Table 3). In addition, the hazard ratio of each L/H ratio category was (95%CI: , P<0.001) in the LDL-C/HDL-C >2.0 group and (95%CI: , P=0.021) in the 1.5< LDL-C/HDL-C 2.0 group compared with the LDL-C/HDL-C 1.5 group. Discussion The present study demonstrated that the relationship between the LDL-C/HDL-C ratio and the incidence of MACE in patients who underwent PCI and had no cardiac events within 6 months after PCI. According to a subanalysis of the MEGA Study, which focused on primary prevention of cardiovascular events in a Japanese population, the incidence of cardiovascular events was significantly lower in those with an LDL-C/HDL-C ratio of 2.0 or lower than in those with an LDL-C/HDL-C ratio exceeding 2.0 regardless of the value of the HDL-C level. 16 Therefore, it is suggested that the LDL-C/HDL-C ratio should be controlled at 2.0 or lower for primary prevention of CAD. In terms of secondary prevention of CAD, little is available on the relationship between the LDL-C/HDL-C ratio and the incidence of cardiovascular events. However, according to the report from von Birgelen et al, which determined the relationship between the predicted risk of cardiovascular events and plaque progression measured by IVUS, the greatest plaque progression was observed in patients with the highest predicted risk, and a positive linear relationship was observed between the risk score and plaque progression. That is, this report suggested that coronary events could be prevented by inducing the regression of atherosclerosis. 18 In addition, recent studies, such as ASTEROID, 19 ESTABLISH, 20 JAPAN-ACS, 21 and a study conducted by Toi et al, 22 have showed the regression of coronary plaques as a result of lowering LDL-C by statins. Moreover, Brown et al demonstrated that regression by 1% in atherosclerosis induced the marked reduction of the incidence of cardiovascular events. 23 Therefore, it is reasonable to say that the regression of arthrosclerosis along with falling the LDL-C/HDL-C ratio can lead to reduction of cardiovascular event risk. It is important to review several studies from this viewpoint. A retrospective analysis of the PROSPER trial showed that the LDL-C/HDL- C ratio was the strongest predictor of cardiovascular events among conventional lipid markers in patients with a history of cardiovascular disease or high risk of CAD including hypertension, diabetes, and smoking habit. 15 Nicholls et al performed pooled analysis by integrating the data of 4 prospective randomized trials using IVUS to assess plaque regression as a result of LDL-C lowering therapy for secondary prevention of CAD and demonstrated that plaques were regressed by controlling the LDL-C/HDL-C ratio at 1.5 or lower. 17 Moreover, in COSMOS, an interventional study using rosuvastatin for patients with stable CAD in Japan, even stable plaques were reduced 5.6% in their volume by lowering the LDL-C/HDL-C ratio to In the present study, the outcome after PCI was more favorable in the LDL-C/HDL-C 1.5 group than that not only in the LDL-C/HDL-C >2.0 group but also in the 1.5< LDL- C/HDL-C 2.0 group. Also, the occurrence of cardiac death, non-fatal myocardial infarction, restenosis of the treated sites, and development of new lesions were significantly lower in the LDL-C/HDL-C 1.5 group in spite of the number of diseased vessels, the characteristics of coronary artery stenosis and the usage of DES. It is reasonable to say that in secondary prevention of CAD, the LDL-C/HDL-C ratio at 1.5 or lower appears to be beneficial to reduce the incidence of CAD. In addition, it was also observed that the use of statins was not correlated with the incidence of MACE. This is considered to be caused primarily by insufficient control

5 LDL-C/HDL-C Ratio as a Risk Factor of CVD 909 of LDL-C/HDL-C ratio despite the use of statins. As the effect of statins on improving lipids profiles has been established, the appropriate use of statins by paying attention to the LDL-C/HDL-C ratio would be necessary for secondary prevention following PCI. Study Limitations The greatest limitation was the insufficient number of patients, which resulted in unevenness in the number of patients and their characteristics such as gender, age, BMI, TG, and CRP among the groups. However, because the LDL-C/HDL-C ratio showed a close correlation with the incidence of MACE after PCI on multivariate analysis, there was little doubt that it was one of the most important factors in the follow-up after PCI. Also, as there were differences in the percentage of patients using statins in the present study, further interventional researches using statins were awaited. Furthermore, various clinical test items were evaluated 6 months after PCI in the present study. Although changing antidyslipidemic drugs was prohibited in principle, the LDL-C/HDL-C ratio might be affected by subsequent changes such as the diet, exercise habit, the addition or discontinuation of antidiabetic drugs, which would affect lipid metabolism, and antihypertensive drugs. However, the patients in the present study underwent sufficient overall cardiac rehabilitation immediately after PCI, and the treatments and life guidance of 6 months after PCI were maintained thereafter, resulting in no marked change in the LDL-C/HDL-C ratio. Therefore, the effects of these factors on the outcome are considered to have been small. Conclusions The present study demonstrates that the LDL-C/HDL-C ratio has an impact on long-term outcome in patients who undergo PCI and have no cardiac events within 6 months after PCI. 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