The growing burden of cardiovascular disease (CVD), as shown by the increasing prevalence of coronary heart disease (CHD) and stroke, is a significant global health issue.1 Treatment targeting low-density lipoprotein cholesterol (LDL-C) has successfully reduced atherosclerosis and cardiovascular complications.2,3 The greater decrease in LDL-C achieved by the use of lipid-lowering drugs reflects proportionally on the reduction in cardiovascular events, irrespective of the risk levels of patients.4,5 The update of the Adult Treatment Panel III6 (ATP III) of the National Cholesterol Education Program recommends more rigorous LDL-C control, particularly for those patients at the highest risk with the most stringent goal for LDL-C of <70 mg/dL.
Despite the increasing awareness of the need for the management of CHD, more than half of high-risk patients do not attain the lipid levels recommended by the published guidelines.7–9 In Europe, the Centralized Pan-European Survey on the Under-treatment of Hypercholesterolaemia indicated that only 55% of patients receiving treatment attained the LDL-C targets set by the 2003 European guidelines.10 The Lipid Treatment Assessment Project 2 (L-TAP 2) study showed the proportions of patients attaining the LDL-C goals recommended by the ATP III, the 2003 European, or the Canadian guidelines ranged from 47% to 84% across countries, whereas only 30% of patients at very high risk attained optional LDL-C levels of <70 mg/dL.11 In spite of the growing availability of more effective lipid-lowering drugs, the failure of treatment commonly involves multiple factors.12,13 The rate of cardiovascular events was higher in patients not attaining the recommended LDL-C targets.14–16
It is of paramount importance to understand the determinants of successful LDL-C control with regards to the prevention of CVD. In Asia, the control rates of hypercholesterolemia largely vary between countries and registries.17,18 However, differences at the country level have not been analyzed in detail, and prognostic predictors have seldom been explored. This study, as part of the CEntralized Pan-Asian survey on tHE Under-treatment of hypercholeSterolemia (CEPHEUS-PA), investigated the major determinants for LDL-C goal attainment in Taiwan.
2.1. Study design
The CEPHEUS-PA study (ClinicalTrials.gov Identifier NCT00687492) was a prospective, cross-sectional survey of patients with hypercholesterolemia receiving pharmacological treatment. The study included patients from 405 sites across eight Asian countries; the Taiwan section of this study was conducted in eight hospitals in 2008.18 The protocol was approved by the local institutional review board of each hospital. Written informed consent was obtained from each participant before they were enrolled into the study.
Eligible patients were adults (≥18 years) who had at least two CHD risk factors defined by the ATP III update 2004 and who had been treated with lipid-lowering drugs for at least 3 months, without adjustment for at least 6 weeks before enrollment.
After patient consent had been obtained, data were collected on patient demographics, cardiovascular risk factors, history of CVD, the last available lipid concentrations before enrollment, and current lipid-lowering treatment and indications. The cardiovascular risk and the therapeutic LDL-C goal of each patient were stratified according to the recommendation of the ATP III update 2004.6,19 Blood was sampled for lipid measurements after overnight fasting and was analyzed at the local laboratory of the individual hospitals.
The objective of this analysis was to determine the proportion of patients treated with lipid-lowering drugs who were attaining the LDL-C goals set by the ATP III update 2004. The major determinants for successful control were also investigated.
Since 1995, Taiwan has instituted the National Health Insurance (NHI), a single-payer compulsory healthcare program that offers comprehensive medical coverage for more than 99% of the population. The reimbursement policy, which has to provide a balance between the control of health spending and the adoption of high-price treatments, has had an influence on the prescription of drugs, particularly statins.20Table 1 presents the differences between the recommendations of the ATP III update 2004 and those of the Taiwan NHI reimbursement policy.
Descriptive statistics included frequency distributions, means and standard deviations. Potential factors that may affect LDL-C goal attainment were investigated first in the univariate analysis by logistic model analysis. The estimated odds ratio (OR) and 95% confidence interval (CI) were calculated. Factors with p < 0.1 in the univariate model were further evaluated in the multivariate approach by the generalized linear mixed model using the NLMIXED procedure of the Statistics Analysis System statistical software (Cary, North Carolina, United States). The NLMIXED procedure fits a specified nonlinear mixed model by maximizing the approximation to the likelihood integrated over the random effects. The variables included in the model were chosen based on the p values of their effects in the model. Akaike's Information Criteria, F values and the number of nonmissing values were also referred to in addition to p values in the model selection. Variables were chosen and added to the model in the forward selection mode to finalize the analysis. A value of p < 0.05 was considered statistically significant.
From April 2008 to December 2008, 1072 participants were enrolled, of which 999 qualified for the full data set analysis.
3.1. Demographic profiles
Table 2 gives the baseline demographics and characteristics of the patients. With respect to CHD risk, hypertension and diabetes were the most common risk factors; 20% of patients had multiple risk factors with a 10-year risk >20%, and 69% had metabolic syndrome (MetS). The most common CVD (44%) was CHD, followed by carotid artery disease.
After stratification by cardiovascular risk and the updated ATP III recommendations, 25% and 50% of the patients were classified into high- and very high risk categories with targeted LDL-C levels of <100 mg/dL and <70 mg/dL, respectively. The duration of treatment with lipid-lowering drugs was 4 ± 4 years and 66% of their use was indicated for secondary prevention. The most common regimens included rosuvastatin (39%) and atorvastatin (30%). Some statin users (36%) received higher therapeutic doses (atorvastatin ≥20 mg, pravastatin ≥40 mg, rosuvastatin ≥10 mg, and simvastatin ≥20 mg).
Based on the last-known lipid profiles available before treatment began (baseline lipid levels), the concentrations of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglyceride were 230 ± 46 mg/dL (n = 826), 147 ± 39 mg/dL (n = 583), 45 ± 12 mg/dL (n = 634), and 220 ± 229 mg/dL (n = 826), respectively. The lipid concentrations measured in the survey were 168 ± 39 mg/dL for total cholesterol, 93 ± 31 mg/dL for LDL-C, 47 ± 13 mg/dL for HDL-C and 152 ± 90 mg/dL for triglyceride.
3.2. LDL-C goal attainment and determinants
Overall, 50% of patients achieved the therapeutic LDL-C targets set by the ATP III update 2004. Fig. 1 shows goal attainment rates in the subgroups stratified by cardiovascular risk and indications. Comorbid metabolic conditions and high CHD risk predisposed to unfavorable LDL-C control rates (53% vs. 46%, p = 0.021 for patients without diabetes vs. those with diabetes; 66% vs. 43%, p < 0.001 for patients without MetS vs. those with MetS; 53% vs. 37%, p < 0.001 for patients with CHD risk ≤20% vs. patients with CHD risk >20%). Goal attainment was inadequate in patients in the higher risk categories (87% in the low/moderate risk patients, 69% in high-risk patients, 22% in very high risk patients, p < 0.001). For therapeutic indications, patients treated for primary prevention had a significantly greater proportion of control success (58%), followed by those treated for familial hypercholesterolemia (46%) and those treated for secondary prevention (46%); in particular, only 39% of patients with CHD attained their goals for LDL-C. In addition, treatment with statins was associated with a higher rate of goal attainment than treatment with nonstatins (51% vs. 32%, p = 0.004).
Table 3 presents the univariate predictors for LDL-C goal attainment. Male gender, abdominal obesity, established risk factors, CHD, and longer treatment times correlated with less likelihood of achieving targeted LDL-C. Higher LDL-C targets, lower baseline total cholesterol and higher HDL-C were positively related to goal attainment. Patients treated for secondary prevention had a significantly smaller probability of attaining their goals than patients treated for primary prevention. Moreover, patients treated with nonstatins were less likely to attain their goals (OR 0.45, 95% CI 0.26–0.78, p = 0.004). In the multivariate model, higher LDL-C targets, treatment with statins, and lower baseline LDL-C were major determinants for goal attainment.
3.3. Determinants for treatment with statins
Treatment with statins was the major determinant for LDL-C control and nearly 94% of the patients had been prescribed statins. Table 3 shows the results of the univariate analysis for allocation to treatment with statins. Patients with advanced age, a family history of premature CHD, established CHD, higher baseline LDL-C and HDL-C, and indication for secondary prevention were more likely to receive statins. In contrast, a higher body mass index, the presence of diabetes and the presence of MetS were associated with a lower likelihood of treatment with statins.
Fig. 2 shows the use of statins in subgroups stratified by metabolic conditions and the components of MetS. Among the components of MetS, impaired fasting glucose (OR 0.21, 95% CI 0.10–0.47, p < 0.001), low HDL-C (OR 0.54, 95% CI 0.32–0.90, p = 0.019) and increased triglyceride (OR 0.11, 95% CI 0.05–0.25, p < 0.001) were significantly associated with a lower probability of treatment with statins, whereas patients with abdominal obesity (OR 0.54, 95% CI 0.28–1.03, p = 0.062) had a trend towards a lower likelihood of treatment with statins. In the multivariate model, increased triglyceride, established CHD and baseline LDL-C were major determinants for treatment with statins.
Our analysis showed that half of the patients indicated for lipid-lowering drugs did not attain the recommended LDL-C targets, with higher rates of nonattainment in the populations at higher risk. This unsatisfactory result was directly related to LDL-C concentrations before treatment as well as the drugs selected for treatment. It was also found that statins were underused in patients with metabolic conditions such as diabetes and MetS.
The phenomenon of the under-treatment of hypercholesterolemia has been consistently reported throughout the last century.16,21 As landmark studies indicated the advantages of more aggressive lipid-lowering drugs, LDL-C targets stratified by CHD risk were further lowered for patients at very high risk.6,22 LDL-C goal attainment rates have been encouraging, but are still suboptimal.10,11 The overall LDL-C control in Asia has been reported across studies as inadequate compared with the results presented in Western countries.17,18 Taiwan and Korea were both included in recent surveys involving Asian countries. The general LDL-C control rates were 66% in Taiwan and 84% in Korea in the L-TAP 2 study, 24% and 42%, respectively, in the Return on Expenditure Achieved for Lipid Therapy in Asia (REALITY-Asia) study, and 50% and 51%, respectively, in CEPHEUS-PA. The discrepancies across registries were related mainly to differences in study populations and designs. It is noteworthy that the majority of patients enrolled in CEPHEUS-PA were at very high cardiovascular risk and the therapeutic LDL-C target set by the most stringent guideline was <70 mg/dL. By using the more updated recommendation for patients at very high risk in the L-TAP 2 study, the success rate was reduced to 30%, in contrast with 73% based on the LDL-C goal set at <100 mg/dL. However, it still represents a substantial improvement since both the L-TAP 2 study and the REALITY-Asia study were conducted in 2006.
There was agreement in these studies that the goal attainment rate was higher in patients with relatively lower CHD risk. It was further found that LDL-C targets were achieved in only 46% of patients indicated for secondary prevention, which was similar to data reported in other Asian countries.15,23 In both the L-TAP 2 and the REALITY-Asia studies, LDL-C control was comparably insufficient in the higher risk groups with the LDL-C target of <100 mg/dL set by the ATP III. In our study, the LDL-C goal attainment rate of 43% in patients with MetS was far from satisfactory. This is partially attributed to the fact that MetS, with low HDL-C as one of its components, is not included in the risk assessment for atherosclerosis management and LDL-C targets in the Taiwan NHI reimbursement policy.
The nonattainment of LDL-C goals was directly related to the cardiovascular risk of patients, which also determined the therapeutic target of the given patient. Other major determinants included treatment with statins and LDL-C levels before treatment with lipid-lowering drugs.
In our analysis, the presence of CHD and its risk and the indication for secondary prevention increased the probability of treatment with statins. However, those concomitant conditions were negative predictors of LDL-C goal attainment. This could be in part explained by the lower equipotency doses used in clinical practice.24,25 A similar result was observed in the REALITY-Asia study, in which <10% of the participants received higher potency treatment.17 Moreover, our study further suggested that an increase in treatment duration was inversely related to LDL-C goal attainment (OR 0.94 per year, 95% CI 0.91–0.98, p = 0.002). This finding also echoed the results of a previous study showing that most of the patients at the therapeutic targets achieved their LDL-C goals within the first 3 months of treatment.17 In addition, the NHI reimbursement policy mandates the reduction of lipid-lowering drugs once therapeutic goals are achieved. The down-titration of treatment may contribute to this “reverse epidemiology” phenomenon with regard to lipid-lowering drugs. As longer treatment did not necessarily translate into goal attainment, more effective treatment and a follow-up strategy are required.
As MetS is not recognized in the risk evaluation in the NHI reimbursement policy, decreased HDL-C and increased triglyceride as components of MetS were attributable to a lower likelihood of treatment with statins, which are more efficacious in the reduction of LDL-C. The treatment bias also led to a lower LDL-C goal attainment rate in patients with MetS. Patients with diabetes were also less likely to receive statins in our analysis. This underuse of statin treatment in such subgroups of patients at high- or even very high risk is common in other diseases and societies.26–29
Finally, the concerns about the long-term safety of treatment with statins might lead to under-prescription or noncompliance, which compromises the favorable risk–benefit profiles of statins.30,31 Recent analyses have provided reassurance that the benefits of lowering LDL-C using statins outweigh the risk of incident diabetes, particularly in the population at highest risk of CHD.32,33 The acknowledgement of the gaps between guideline recommendations and clinical practice and the need for more intensive treatment in patients with hypercholesterolemia are important steps in delivering the comprehensive management of CVD.
There are several limitations to this study that need to be addressed. Firstly, the CEPHEUS-PA was cross-sectional and observational in nature. The implications of under-treatment with regard to long-term outcomes cannot be extrapolated. Secondly, baseline lipid concentrations were not available from medical records for every patient. Finally, this part of the analysis focused on Taiwanese patients, who may not be representative of a larger population receiving lipid-lowering drugs.
In conclusion, the overall management of patients with hypercholesterolemia is unsatisfactory and there is a need for the better utilization of more effective treatment, particularly in higher risk populations. Our findings emphasize the urgent need to address the high number of patients who do not attain their LDL-C goals, as this would narrow the gaps currently seen between the benefits demonstrated in clinical trials and those seen in real-world practice. Finally, the focus in secondary prevention for CHD should center not only on treating hypercholesterolemia per se, but also on treating patients with the aim of attaining the recommended targets referenced by the practice guidelines to maximize the benefits to patients.
This study was supported in part by grants from the Department of Health (DOH99-TD-B-111-008) and intramural grants from Taipei Veterans General Hospital (V102B-028; V102C-002) and was financially supported and monitored by AstraZeneca (as part of the CEPHEUS Pan-Asian Survey). The authors take sole responsibility for any opinions, conclusions, and interpretation of data.
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