Am J Cardiovasc Drugs 2006; 6 (6): 383-391 1175-3277/06/0006-0383/$39.95/0

ORIGINAL RESEARCH ARTICLE

© 2006 Adis Data Information BV. All rights reserved.

The A-SACT (Achievement in Singapore of Cholesterol Targets) Study in Patients with Coronary Heart Disease Kheng-Thye Ho,1 Khong-Whee Chin,2 Kheng-Siang Ng,1 Evo Alemao,3 Srinivasan Rajagopalan4 and Don Yin3 1 2 3 4

Tan Tock Seng Hospital, Singapore, Republic of Singapore Merck Research Laboratories, Rahway, New Jersey, USA Outcomes Research, Merck and Co., Inc., Whitehouse Station, New Jersey, USA Med Data Analytics Inc., Williamsville, New York, USA

Abstract

Background: Cardiovascular disease remains a leading cause of death worldwide, with hypercholesterolemia being a major risk factor. Evidence-based consensus guidelines have recommended consideration of increasingly stringent cholesterol-lowering goals, yet most patients do not meet these targets. Coronary heart disease (CHD) event and mortality rates and mean serum cholesterol levels have declined in Singapore in recent years; however, certain groups remain at elevated risk. Objective: To determine (i) proportions of patients with CHD in Singapore who achieved goals for serum low-density lipoprotein-cholesterol (LDL-C); and (ii) factors influencing goal attainment. Methods: A historical cohort study was conducted using records from the Singapore Cardiac Databank, a national registry of CHD patients. Serum LDL-C goal attainment was assessed in 5174 survivors of acute myocardial infarction or coronary revascularization (i.e. coronary artery bypass graft surgery or percutaneous coronary interventions), of whom 3811 (73.7%) were at very high risk. Results: At baseline, the mean patient age was 60.3 years, mean serum value of total cholesterol was 228 mg/dL, and mean LDL-C was 163 mg/dL. Of all CHD patients, approximately 70% did not achieve a serum LDL-C target of <100 mg/dL. Most patients receiving HMG-CoA reductase inhibitor (statin) regimens were treated initially with low- to medium-equipotency regimens and were never titrated to stronger regimens. The vast majority (~94%) of patients at very high risk did not achieve the stringent serum LDL-C target of <70 mg/dL. Patients receiving higher potency statins were significantly more likely to achieve LDL-C goals, whereas those with higher baseline LDL-C levels or Malaysian ethnicity were less likely to achieve LDL-C goals. Conclusions: Most CHD patients in the large group of Singapore residents with CHD in the present study did not achieve recommended LDL-C targets. A more effective disease-management approach, including patient education concerning lifestyle modification (e.g. diet, physical activity), efforts to enhance medication adherence, and more effective, well tolerated therapies such as high-equipotency or high-dose statins and statin combination regimens, may be needed to improve achievement of consensus cholesterol targets. This is the first study of cholesterol goal attainment in a large group of Southeast Asians and serves as a baseline for future evaluations in Asian populations.

Coronary heart disease (CHD) and stroke are leading causes of morbidity and mortality, and it is estimated that CHD will be the single largest cause of disease burden globally by the year 2020.[1]

Across the world, most deaths (32 million) each year are attributed to noncommunicable diseases, and more than half of these (16.7 million) result from cardiovascular disease.[2] Cardiovascular mor-

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tality is projected to double globally between 1990 and 2020, with developing countries shouldering approximately 80% of the increased disease burden.[3] At least 75–80% of new cases of CHD are explained by major risk factors, including hypercholesterolemia.[2] Epidemiologic studies and randomized controlled trials support the effectiveness of cholesterol lowering with 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) to lower CHD risk, CHD mortality, and all-cause mortality.[4-20] A recent meta-analysis by the Cholesterol Treatment Trialists demonstrated a 12% proportional reduction in all-cause mortality (19% reduction in coronary mortality) for each 1 mmol/L (38.7 mg/dL) decline in serum low-density lipoprotein-cholesterol (LDL-C).[21] A prior meta-analysis found a 15% decline in CHD mortality risk and an 11% decline in all-cause mortality risk for each 10-percentage-point lowering in serum levels of total cholesterol (TC).[22] Recognizing the benefits of intensive statin treatment in coronary prevention, consensus panels have recommended consideration of increasingly stringent LDL-C targets,[23-26] particularly in patients at very high risk. An update to the US consensus guidelines recommended consideration of an LDL-C target of <70 mg/ dL as a therapeutic option in patients at very high risk, including individuals with acute coronary syndromes, multiple risk factors (particularly diabetes mellitus), poorly controlled and severe risk factors (particularly continued smoking), and/or multiple risk factors of metabolic syndrome.[26] However, studies from around the world have shown that most patients at elevated CHD risk do not achieve even less stringent cholesterol goals.[27-31] The recent REALITY (Return on Expenditure Achieved for Lipid Therapy) study demonstrated that approximately 60% of Europeans did not achieve national cholesterol goals.[31] Singapore is a small tropical island state of approximately 700km2 with a population of 4.35 million that has a multiethnic (77% Chinese, 14% Malay, 8% Asian Indian) population and a rapidly developing economy.[32] Per capita gross national product is among the highest in the region, and the standard of living is comparable to standards in Western industrialized countries.[3] Like these societies, Singapore has witnessed an increasing life expectancy and median population age. Life expectancy at birth rose from 62 years in 1957 to 79.3 years in 2004.[3,33] The proportion of the population aged >65 years increased from 2.2% in 1970 to 8.0% in 2004 and is expected to reach 10% by 2012 and 20% by 2033.[3,34] With rapid economic and social development and an aging population, the burden of disease has shifted from infectious to © 2006 Adis Data Information BV. All rights reserved.

Ho et al.

chronic ‘lifestyle’ diseases (e.g. cardiovascular disease). By 1990, heart disease was the second leading cause of death after cancer in Singapore.[3,34] As of 1999, Singapore’s age-standardized CHD death rate (100/100 000) was comparable to those in the US (125/ 100 000) and Australia (97/100 000), and was among the highest of Southeast Asian nations (higher than in Japan [22/100 000] and Hong Kong [40/100 000]).[35-38] Certain ethnic groups in Singapore may be at increased CHD risk. With the advent of the 1991 National Health Policies Committee and improved primary prevention and medical care interventions (e.g. increased coronary revascularization procedures), CHD events and age-adjusted CHD case-fatality rates declined during the 1990s.[33,39,40] However, myocardial infarction (MI) event rates and age-standardized coronary mortality rates were more than twice as high in ethnic Malays and Asian Indians than in ethnic Chinese individuals.[40] The most recent Singapore National Health Survey found that the prevalence of hypercholesterolemia fell from 25.4% in 1998 to 18.7% in 2004, but was highest in ethnic Malays (22.8%).[41] To evaluate cholesterol goal achievement in Singapore and the effects of a number of variables on cholesterol goal achievement, we conducted a historical cohort study of a national registry of CHD patients: the A-SACT (Achievement in Singapore of Cholesterol Targets) study. Methods Study Design

We conducted a retrospective observational cohort study involving patients with CHD at three large public hospitals in Singapore (Alexandra Hospital, National University Hospital, and Tan Tock Seng Hospital). Records were derived from the Singapore Cardiac Databank, a national registry of CHD patients, and personal information was anonymized. This registry was established in 1987 to monitor MI trends. The procedures of the registry were adapted, with modifications, from the multinational WHO MONICA (WHO Monitoring of Trends and Determinants in Cardiovascular Disease Project) protocol. The methods adopted by the Singapore Cardiac Databank have been previously described.[42] Patients

Individuals aged ≥18 years who presented with acute MI or underwent coronary revascularization by percutaneous coronary intervention or coronary artery bypass graft surgery from 1 JanuaAm J Cardiovasc Drugs 2006; 6 (6)

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35 30 25 20

Table I. Patient characteristics Patient characteristics Mean age (y) [SD] Male (no.) [%]

Valuea (n = 5174) 60.29 [12.89] 3898 [75.3]

Ethnicity Chinese (no.) [%]

933 [18.0]

Asian Indian (no.) [%]

752 [14.5]

other (no.) [%]

124 [2.4]

Mean TC (mg/dL) [SD]

228 [69]

Mean LDL-C (mg/dL) [SD]

163 [64]

Mean TG (mg/dL) [SD]

52 [23] 178 [108]

With acute myocardial infarction (no.) [%]

3811 [73.7]

With revascularization (no.) [%]

2739 [52.9]

With diabetes mellitus (no.) [%]

2013 [38.9]

With hypertension (no.) [%]

3300 [63.8]

Current smokers (no.) [%]

1661 [32.1]

a

Some percentages do not total 100 because of rounding.

HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; TC = total cholesterol; TG = triglycerides. © 2006 Adis Data Information BV. All rights reserved.

os uv as ta tin Si m va st at in

va st at in Pr a

va st at in Lo

Fl

Statins

Fig. 1. Initial HMG-CoA reductase inhibitor (statin) therapy.

III of the National Cholesterol Education Program (NCEP), i.e. serum LDL-C level <100 mg/dL.[25] Logistic regression analyses were carried out to determine factors positively or negatively associated with cholesterol goal achievement. The full model included LDL-C level at study entry, risk category (very high risk or not), initial statin potency, and dummy variables for Malays and Indians; Chinese ethnicity was the base case. Head-to-head comparisons were made between one ethnic group and all the others combined. Results Of 7329 consecutive patients from three hospitals initially identified as potentially eligible for analysis, 1084 patients (14.8%) died within 28 days of hospitalization. An additional 1071 patients were excluded because they lacked baseline lipid measures. A total of 5174 surviving patients with available lipid data were included in the analysis. Of these patients, 3811 (73.7%) were considered to be at very high risk because of acute MI and/or CHD with concomitant diabetes mellitus.

3365 [65.0]

Malay (no.) [%]

Mean HDL-C (mg/dL) [SD]

R

Baseline patient data at the index CHD hospitalization were calculated as number (%) for categorical variables and mean (± SD) for continuous variables. Initial potencies of statin regimens were classified according to the formulation developed by Maron et al.[43] Lipids were measured in the three hospital laboratories at baseline and 14 months after hospital discharge. The maximum serum LDL-C level between the first CHD date (CHD event date) minus 60 days and first CHD date plus 60 days was used as the baseline LDL-C or study entry LDL-C levels. Most patients received a statin prescription on or about the CHD event date. The serum TC level measured on the same date as the serum LDL-C level was used as TC level at study entry. Only values >0 were included for all parameters. The primary outcome measure was the proportion of patients achieving cholesterol goal at the final follow-up laboratory assessment visit. This LDL-C target was consistent with cut-off points for patients with CHD as established by the Adult Treatment Panel

At or

Statistical Methods

uv as ta tin

15 10 5 0 va st at in

Percentage

ry 2000 through 31 December 2002, and who received a lipidlowering therapy prescription, were eligible for inclusion. Patients who died within 28 days of hospitalization or lacked baseline or follow-up lipid measures or data on lipid-lowering therapy were excluded.

Baseline Characteristics

Table I summarizes patient characteristics. Most patients were ethnic Chinese (65.0%), followed by Malays (18.0%) and Asian Indians (14.5%). The mean age was 60.3 years, and most patients (75.3%) were men. The mean serum LDL-C level at hospitalization was 163 mg/dL, including 172 mg/dL in Malays, 162 mg/dL in Asian Indians, and 160 mg/dL in ethnic Chinese persons. At hospitalization, 13.3% of Chinese patients, 8.5% of ethnic Malays, and 12.2% of Asian Indians were at their LDL-C goals. Treatment Patterns

At discharge, 4344 of 5174 patients (84.0%) received statins, mainly simvastatin, lovastatin, or pravastatin (figure 1). As shown in table II, 2650 (70.1%) of 3778 patients who received at least two Am J Cardiovasc Drugs 2006; 6 (6)

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Ho et al.

Table II. Changes in initial lipid-lowering therapya Initial potency

Final potency potency 1

Potency 1 (n = 154)

potency 2

potency 4

potency 5

18 (11.7%)

2 (1.3%)

111 (4.4%)

1655 (66.3%)b

602 (24.1%)

124 (5.0%)

Potency 3 (n = 910)c

16 (1.8%)

139 (15.3%)

645 (70.9%)b

105 (11.5%)

5 (0.6%)

210)c

5 (2.4%)

15 (7.1%)

41 (19.5%)

142 (67.6%)b

7 (3.3%)

Potency 5 (n = 8)

0

45 (29.2%)

potency 3

Potency 2 (n = 2496)

Potency 4 (n =

89

(57.8%)b

0

1 (12.5%)

3 (37.5%)

0 4 (0.2%)

4 (50.0%)b

a

Among 3778 patients who received at least two prescriptions for a statin and had available data, using the Maron formulation,[43] i. e. potency 1 = pravastatin 20 mg/day or equipotent; potency 2 = simvastatin 20 mg/day or equipotent; potency 3 = simvastatin 40 mg/day or atorvastatin 20 mg/ day or equipotent; potency 4 = simvastatin 80 mg/day or atorvastatin 40 mg/day or equipotent; potency 5 = atorvastatin 80 mg/day.

b

No. (%) of patients having the same regimen potency at the final follow-up visit as at the baseline visit.

c

Percentages in rows 3 and 4 do not add to 100% because of rounding.

prescriptions for a statin and had available data were treated with low- or very low-equipotency statin regimens (i.e. atorvastatin ≤10 mg/day or simvastatin ≤20 mg/day). Table II also shows that <6% of patients received initial treatment with a high- or very high-equipotency (potency 4–5) statin. Figure 2 depicts data for 4344 patients receiving a statin at discharge. Among this group, 58.4% of patients received low- or very low-equipotency statin regimens. Over the 14-month observation period, statin dosages were titrated in a minority of patients. As shown in table II, statin dosages remained at their initial equipotency from baseline to post-discharge month 14 in 67.1% (2535/3778) of patients. Less than 1% (16/3778) of patients initially receiving statins in potency categories 1–4 were receiving treatment with very high-equipotency statin regimens (potency 5; atorvastatin 80 mg/day) at the follow-up lipid measurement. Reduction in Low-Density Lipoprotein-Cholesterol and

goals, whereas 7.7% of patients achieved the LDL-C target with medium- to high-equipotency-dose statins. A total of 189 patients achieved goal but did not have data on initial statin potency. The mean statin dose among 2704 patients not achieving goal was simvastatin 15.4 mg/day or equipotent. Approximately two-thirds (65.6%) of patients who did not achieve LDL-C goal were receiving low- to medium-equipotency (potency ≤3) statins at the 14-month follow-up lipid evaluation (figure 4). A total of 24.7% of patients who did not achieve goal had received upward adjustments in dose at any time during follow-up. Logistic Regression Analyses

Table III shows that the likelihood of achieving cholesterol goal increased significantly with initial post-CHD statin dose and decreased significantly as a function of baseline LDL-C (odds ratio [OR] 0.747; 95% CI 0.704, 0.793; p < 0.05) or very high-risk status (OR 0.799; 95% CI 0.642, 0.995; p < 0.05). High initial

Goal Achievement

Treatment Patterns and Goal Attainment

A total of 840 (18.8%) of 4479 patients whose initial regimens were equipotency <3 (very low to low) achieved their LDL-C © 2006 Adis Data Information BV. All rights reserved.

50 Percentage

From baseline to month 14, serum levels of LDL-C declined by 13.5%, TC by 10.4%, and triglycerides by 3.0%. Serum levels of high-density lipoprotein-cholesterol (HDL-C) also decreased marginally (by 0.6%). Of 4479 patients with at least one follow-up LDL-C evaluation 14 months after discharge, 1372 (30.6%) attained an LDL-C goal of <100 mg/dL (figure 3). This included 33.5% of ethnic Chinese patients, 21.6% of Malays, and 29.2% of Asian Indians.

60

40 30 20 10 0 Potency 1 Potency 2 Potency 3 Potency 4

Potency 5

Fig. 2. Initial statin potency (among 4344 patients receiving a statin at discharge). Potency 1 = pravastatin 20 mg/day or equipotent; potency 2 = simvastatin 20 mg/day or equipotent; potency 3 = simvastatin 40 mg/day or atorvastatin 20 mg/day or equipotent; potency 4 = simvastatin 80 mg/day or atorvastatin 40 mg/day or equipotent; potency 5 = atorvastatin 80 mg/ day. Am J Cardiovasc Drugs 2006; 6 (6)

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40

Goal not attained Goal attained

35

Percentage

30 25 20 15 10 5 0 Potency 1

Potency 2

Potency 3

Potency 4

Potency 5

Fig. 3. Achievement of low-density lipoprotein-cholesterol goal <100 mg/dL 14 months after admission, by initial regimen potency. Some patients who achieved cholesterol goals did not have data on initial regimen potency. For potency designations, see table II or figure 2.

statin potency increased the likelihood of achieving goal (OR 1.014; 95% CI 1.004, 1.024; p = 0.0040). In addition, ethnic Chinese patients were significantly more likely to achieve LDL-C <100 mg/dL compared with all other groups (OR 1.460; 95% CI 1.231, 1.731; p < 0.0001). On the other hand, ethnic Malays were significantly less likely to achieve this LDL-C goal compared with all other groups (OR 0.577; 95% CI 0.461, 0.722; p < 0.0001). Discussion Cholesterol goal attainment is a multifactorial process, with a range of potentially operative factors including initial serum LDL-C levels, starting doses of statins, dose titration, treatment adherence, and lifestyle modification. In the A-SACT study, a retrospective analysis of patients with CHD in Singapore, most

patients (~70%) did not achieve the consensus LDL-C goal of <100 mg/dL. If one were to apply the more stringent standard of <70 mg/dL as suggested by a US panel,[26] an even smaller minority of patients would achieve this goal: 273 (6.1%) of 4479 with final LDL-C evaluations (figure 5). There is a relative paucity of data on cholesterol goal achievement in Asian populations compared with other societies, and the A-SACT study is thus important, as it establishes a baseline for further investigations. During the interval when the present study was conducted (2000–2) and soon thereafter, consensus panels adopted increasingly stringent cholesterol targets, particularly for patients at highest cardiovascular risk including those with CHD or CHD risk equivalents.[23-25] On the other hand, at about the midpoint of the A-SACT study, the HMG-CoA reductase inhibitor cerivastatin was voluntarily withdrawn from the market by its manufacturer after a high number of reports of rhabdomyolysis among patients taking this drug, particularly when combined with gemfibrozil. The net effect of these countervailing influences on prescribers during the present study is not clear, although the practice of low-dose statin therapy may gradually be giving way to the use of more aggressive regimens in high-risk patients. Given these dynamic factors, it might be of interest to repeat the A-SACT study in Singapore patients with CHD after another 5 years. Given that attainment of LDL-C targets is suboptimal in North American, Western European, and Australasian populations, findings from the A-SACT are not surprising. In a recent crosssectional survey conducted in Japan, another industrialized Asian nation with ‘Western lifestyle’ influences, >70% of patients with CHD did not achieve the Japanese Atherosclerosis Society LDL-C target of <100 mg/dL.[44] The goal attainment rate was higher

Table III. Results of logistic regression analyses for cholesterol goal achievementa Variable

Full modelb (n = 3080) [OR (95% CI)]

Chinese vs all others (n = 3162) [OR (95% CI)]

Indians vs all others (n = 3162) [OR (95% CI)]

Ethnic Chinese

–

1.460 (1.231, 1.731)c

–

–

Ethnic Indians

0.832 (0.661, 1.046)

–

0.937 (0.748, 1.174)

–

Ethnic Malays

0.554 (0.441, 0.696)c

–

–

0.577 (0.461, 0.722)c

1.468)c

1.253 (1.068, 1.469)c

1.249 (1.063,

Very high risk

0.799 (0.642, 0.995)c

0.780 (0.628, 0.969)c

0.758 (0.611, 0.941)c

0.785 (0.632, 0.976)c

0.793)c

0.784)c

0.781)c

0.741 (0.699, 0.786)c

1.013 (1.003, 1.022)c

1.013 (1.004, 1.023)c

0.747 (0.704,

Initial statin potency after CHD

1.014 (1.004, 1.024)c

a

Goal serum LDL-C level <100 mg/dL.

b

Base case is ethnic Chinese.

c

Significant at p < 0.05 vs comparator.

0.739 (0.697,

1.014 (1.004, 1.023)c

1.276 (1.089,

1.496)c

Current smoker

Study entry LDL-C

1.258 (1.073,

1.476)c

Malays vs all others (n = 3162) [OR (95% CI)]

0.737 (0.694,

CHD = coronary heart disease; LDL-C = low-density lipoprotein-cholesterol OR = odds ratio. © 2006 Adis Data Information BV. All rights reserved.

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was less than half the percent reduction needed by the average patient to achieve the LDL-C goal of <100 mg/dL (39%).

25 20 15 10 5 0 Potency 1 Potency 2 Potency 3 Potency 4 Potency 5

Fig. 4. Final statin potency distribution for patients not at goal (low-density lipoprotein-cholesterol <100 mg/dL). For potency designations see table II or figure 2.

among CHD patients who received a statin (41%) compared with those who did not receive a statin (23%; p < 0.001).[44] The finding that most CHD patients in the A-SACT study did not achieve LDL-C goals extends prior data in other populations showing that CHD patients and those with higher LDL-C are less likely than lower risk patients to achieve cholesterol goals. An even larger majority (~94%) of patients considered to be at very high coronary risk in the A-SACT study did not achieve the more stringent goal of LDL-C <70 mg/dL. Goal attainment was directly related to initial post-CHD statin dose and inversely related to initial serum LDL-C level. Approximately two-thirds (65.6%) of patients who did not achieve the LDL-C goal of <100 mg/dL within 14 months after hospital discharge were receiving low- to medium-equipotency statins. Most patients remained at their initial statin dose at the 14-month post-discharge visit. In the A-SACT study, patients with very high coronary risk sustained an acute MI between 2000 and 2002, before the LDL-C target of <70 mg/dL was proposed for consideration. However, given the baseline mean serum LDL-C value of 163 mg/dL, achieving this more stringent LDL-C target would have required an average reduction in LDL-C of 57% from baseline, which would have been unlikely given the difficulty of attaining even an LDL-C goal of <100 mg/dL (figure 3), the predominance of lowto medium-equipotency statins among initial regimens (table II), and the failure to upwardly adjust statin dosages in most patients (table II). These data give some idea as to the size and scope of the task involved in populations such as Singapore’s if the LDL-C target is reduced to <70 mg/dL in very high-risk populations. Although the average CHD patient in this study (mean serum LDL-C level of 163 mg/dL) needed an LDL-C reduction of approximately 39% to reach the consensus target of LDL-C <100 mg/dL, <6% of patients received high- or very high-equipotency statin regimens initially, and <1% of patients were treated with very high-equipotency statin regimens. The observed mean proportionate LDL-C reduction on treatment in this study (13.5%) © 2006 Adis Data Information BV. All rights reserved.

The findings that a minority of patients received dose titration, were treated with medium- to high-equipotency statins, or achieved cholesterol goals extend recent observations from the REALITY[31] and L-TAP (Lipid Treatment Assessment Project)[27] studies. Even in patients who received medium- or higher equipotency regimens initially or were up-titrated to these stronger regimens in the A-SACT study, <10% achieved the LDL-C goal of <100 mg/dL. Among patients not achieving goal, approximately 25% had received dose titrations. These findings underscore the need for more effective disease-management strategies for patients with CHD, including patient education concerning lifestyle modification (diet, physical activity), efforts to enhance medication adherence, and/or the use of higher potency or higher equipotencydose statins, increased rigorousness in up-titrating statin dosages, as well as the use of statin combination regimens, to enhance goal achievement beyond that attainable with statin monotherapy at low- to medium-equipotency doses. The finding that ethnic Malays were significantly less likely than other ethnic groups to achieve LDL-C goals may be related to complex environmental and biologic factors. Significantly reduced cholesterol goal achievement among Malays may be related in part to the lower average socioeconomic status in this ethnic group,[3] which may present barriers to optimal use of healthcare and prevention resources. In addition, the ethnic Malay diet in Singapore is known to be high in cholesterol and saturated fats from sources such as eggs and coconut-based products.[35] Compared with other Chinese populations (e.g. Hong Kong Chinese), ethnic Chinese in Singapore have higher dietary ratios of saturated 56

Goal not attained Goal attained

46 36 Percentage

Percentage

35 30

26 16 6 −4

Potency 1

Potency 2

Potency 3

Potency 4

Potency 5

Fig. 5. Achievement of low-density lipoprotein-cholesterol goal <70 mg/dL by patients at very high risk 14 months after admission, by initial regimen potency. Some patients who achieved cholesterol goals did not have data on initial regimen potency. For potency designations, see table II or figure 2. Am J Cardiovasc Drugs 2006; 6 (6)

Cholesterol Goal Achievement in Singapore

to unsaturated fats.[45] Malays also have shown relatively high prevalences of smoking, obesity (particularly in women), and physical inactivity, as well as a propensity to hypertensive heart disease with higher BP values.[35,46,47] They may also be at elevated CHD risk because of a higher frequency of APOE gene polymorphisms (i.e. ε4 allele) compared with ethnic Chinese and Indians.[46] Limitations of the A-SACT study include the observational, retrospective nature of the analysis. Statin prescriptions as derived from hospital pharmacies do not equate to actual medicationcompliance behaviors such as filling prescriptions, refilling prescriptions, and taking medicines. In addition, <5% of patients in the current study received higher potency statins (e.g. atorvastatin, rosuvastatin) and statin combination regimens as their initial therapy. In the Japanese cross-sectional survey cited above,[44] a multiple logistic regression analysis revealed that treatment with atorvastatin or simvastatin significantly contributed to the achievement of the LDL-C target (<100 mg/dL) in a secondary-prevention population. Consistent with the fact that the A-SACT study was conducted in 2000–2, very few patients (<1%) received the higher equipotency HMG-CoA reductase inhibitor rosuvastatin or the intestinal cholesterol absorption inhibitor ezetimibe. There is evidence in other populations that treatment using either of these preparations may significantly increase cholesterol goal attainment compared with other forms of statin monotherapy.[48-52] As a result of the ethno-racial composition of the population (65% Chinese, 18% Malays, 14.5% Asian Indians), ethnic Chinese were somewhat under-represented and Malays slightly over-represented in this study compared with the overall Singapore population.[32] Because of these differences, the A-SACT analysis may have slightly underestimated LDL-C goal achievement in the overall population because Malays were significantly less likely than other ethnic groups to achieve goals. The A-SACT analysis also centered on statins and LDL-C goal achievement and did not take into account cardioprotective benefits of other therapies that increase serum HDL-C levels to a greater extent, including niacin and fibric acid derivatives. Finally, it should be noted that, despite the suboptimal cholesterol goal attainment in the present study, coronary mortality rates in Singapore have been falling in recent years. Clearly, larger societal trends affecting risk factors other than hypercholesterolemia impact the long-term outcomes of coronary prevention in Singapore. For instance, the prevalence of smoking in Singapore declined from 20% in 1984 to 15% in 1998.[53] Consistent with data in a number of Western societies, certain populations of © 2006 Adis Data Information BV. All rights reserved.

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smokers in Singapore have less healthy lifestyles, including higher cholesterol intake and less physical activity, compared with nonsmokers.[54] In addition, a sharp increase in cardiac procedures in Singapore during the 1990s may also have contributed to the decline in the coronary mortality rate in this country.[39] Among its strengths, the A-SACT analysis was the first study of cholesterol goal attainment in a large group of Southeast Asians. In addition, the findings represent real-world clinical results, in contrast to data from randomized controlled trials. Finally, the A-SACT study involved a large number of patients from each segment of Singapore’s multiethnic culture. Conclusion The A-SACT study demonstrated that a large majority of CHD patients in Singapore did not achieve consensus LDL-C goals. These findings of low cholesterol goal attainment are consistent with data on patients with CHD in the US[27] and Europe,[31] as well as, most recently, women with CHD in Scandinavia.[55] These data serve as a baseline for subsequent studies in Asian populations to determine the efficacies of different approaches to enhancing cholesterol control. These include more effective diseasemanagement strategies for patients with CHD, which might consist of patient education concerning lifestyle modification, measures to enhance medication adherence, and/or the use of higher equipotency or higher dose statins or statin combination regimens. Acknowledgments Assistance in manuscript preparation was provided by Stephen W. Gutkin, Rete Biomedical Communications Corp. (Ridgewood, NJ, USA). Med Data Analytics Inc. had access to the database on which this study report was based. Dr Binayak Deb assisted in acquiring, analyzing, and interpreting data. Author contributions: Study concept: Kheng-Thye Ho; Study design: Dr Ho and all other authors; Acquisition of data: Dr Ho, Khong-Whee Chin, and Kheng-Siang Ng; Analysis and interpretation of data; all authors; Drafting of the manuscript: Dr Ho with editorial assistance from Stephen W. Gutkin; Critical revision of the manuscript for important intellectual content: all authors; Statistical analysis: Srinivasan Rajagopalan; Obtained funding: Dr Ho; Administrative, technical, and material support: Evo Alemao; Study supervision: Dr Ho. Financial support for the study was provided by a grant from MSP (Merck/Schering-Plough) Singapore Company, LLC. Conflicts of interest are as follows: Khong-Whee Chin is an employee of Merck Research Laboratories, Merck and Co., Inc. Evo Alemao and Don Yin are employees of Merck and Co., Inc., and are Merck shareholders (stocks and stock options). Srinivasan Rajagopalan and Stephen W. Gutkin are paid consultants to Merck. Neither Kheng-Thye Ho nor Kheng-Siang Ng has any affiliation with the sponsor or any financial interests in this report. Am J Cardiovasc Drugs 2006; 6 (6)

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Correspondence and offprints: Dr Kheng-Thye Ho, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Republic of Singapore. E-mail: [email protected]

Am J Cardiovasc Drugs 2006; 6 (6)