Risk determination of dyslipidemia in populations characterized by low levels of high-density lipoprotein cholesterol

Prevention and Rehabilitation

Risk determination of dyslipidemia in populations characterized by low levels of high-density lipoprotein cholesterol Thomas P. Bersot, MD, PhD,a,b Guy M. Pe´pin,a and Robert W. Mahley, MD, PhDa,b San Francisco, Calif, and Istanbul, Turkey

Background Current guidelines for managing dyslipidemia qualify patients for treatment based on low-density lipoprotein cholesterol (LDL-C) levels and other risk factors for coronary heart disease (CHD). However, when LDL-C is the sole lipid criterion for initiating therapy, patients with levels below the treatment initiation threshold who are at high risk because of low levels (⬍40 mg/dL) of high-density lipoprotein cholesterol (HDL-C) might not be identified. Twenty percent of male patients with CHD in the United States fall into this category. The total cholesterol/HDL-C (TC/HDL-C) ratio predicts CHD risk regardless of the absolute LDL-C and HDL-C. Methods

We compared guidelines based on TC/HDL-C and LDL-C with those recommended by the National Cholesterol Education Program Adult Treatment Panel III (ATP III). Both sets of guidelines were applied to 9837 adults (⬎20 years of age) in the Turkish Heart Study, which has shown that 75% of men and 50% of women in Turkey have HDL-C ⬍40 mg/dL.

Results

ATP III guidelines identified 14% of Turkish adults, 20 years or older, as candidates for lifestyle treatment only and an additional 18% for drug treatment. In conjunction with ATP III LDL-C thresholds, the TC/HDL-C ratio (⬎3.5, patients with CHD; ⱖ6.0, 2⫹ risk factors, ⱖ7.0, 0 to 1 risk factor) assigned lifestyle therapy alone to 18% and drug treatment to an additional 36%. Among primary prevention subjects at high risk because of age (men ⱖ45 years; women ⱖ55 years), both sets of guidelines prescribed lifestyle therapy for only 5%; however, drug treatment was recommended for an additional 13% by ATP III guidelines and an additional 18% by TC/HDL-C and LDL-C.

Conclusions

In populations at risk for CHD caused by low HDL-C, qualification of subjects for treatment based on either the TC/HDL-C ratio or LDL-C thresholds identifies more high-risk subjects for treatment than LDL-C threshold values alone, and use of the ratio, instead of risk tables, simplifies the approach for physicians. (Am Heart J 2003;146: 1052⫺60.)

Current guidelines for dyslipidemia management were designed for populations that tend to have high levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and “normal” levels of highdensity lipoprotein cholesterol (HDL-C) (45 to 55 mg/ dL).1,2 Although HDL-C is a strong predictor of coronary heart disease (CHD) risk and is an independent risk factor for premature CHD,3 existing guideFrom the aGladstone Institute, American Hospital, Istanbul, Turkey, and the bGladstone Institute of Cardiovascular Disease, Cardiovascular Research Institute, and Departments of Medicine and Pathology, University of California, San Francisco, Calif. Supported in part by R01 grant HL71027 from the National Institutes of Health. Submitted April 12, 2002; accepted June 10, 2003. Reprint requests: Thomas P. Bersot, MD, PhD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100. E-mail: [email protected] © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(03)00516-7

lines do not give adequate consideration to subjects with very low HDL-C (⬍35 mg/dL) and low LDL-C. The inverse relation between HDL-C and CHD risk is continuous and has been documented in populations in many countries.4 –7 Furthermore, the relation of low HDL-C to CHD risk is at least as strong as that of LDL-C and is demonstrable irrespective of age.8 Among patients with established CHD, low HDL-C (values ⬍40 mg/dL) is the most common lipid risk factor.9,10 Patients with “desirable” TC (⬍200 mg/dL) and HDL-C ⬍40 mg/dL have as much CHD risk as those with categorically “high” TC (⬎240 mg/dL) and “normal” HDL-C.3 Data from recent clinical trials suggest that patients with near optimal (100 to 129 mg/dL) or even optimal LDL-C (⬍100 mg/dL) who also have low HDL-C benefit from drug treatment.11–14 These studies also demonstrate that it is unlikely that a single LDL-C target can be recommended, given the profound ef-

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Table I. Guidelines based on TC/HDL-C ratio for treatment of low HDL-C populations Goals

Risk category CHD or equivalent 2⫹ risk factors 0–1 risk factor

LDL-C (mg/dL) ⬍100 ⬍130 ⬍160

and and and

Lifestyle change initiated for

TC/HDL-C

LDL-C (mg/dL)

⬍3.5 ⬍4.5 ⬍5.5

ⱖ100 ⱖ130 ⱖ160

or or or

Drug therapy initiated for

TC/HDL-C

LDL-C (mg/dL)

ⱖ3.5 ⱖ4.5 ⱖ5.5

ⱖ100 ⱖ130 ⱖ160

TC/HDL-C or or or

ⱖ3.5 ⱖ6.0 ⱖ7.0

CHD, Coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol.

fects of HDL-C on CHD risk.11–13,15 However, two large secondary prevention trials of pravastatin failed to show a benefit among patients with baseline LDL-C ⬍125 mg/dL and HDL-C ⬍40 mg/dL.16 Thus, there has been a hesitancy to prescribe cholesterol-lowering therapy for patients with CHD who have near optimal or optimal LDL-C levels and low HDL-C.1 The current study was undertaken to compare the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines1 with guidelines based on the TC/HDL-C ratio and LDL-C levels (Table I) in Turks, a population characterized by low TC and LDL-C, extremely low HDL-C, and a high prevalence of CHD.17–23 The Turkish Heart Study has shown that the average LDL-C in this population is 119 mg/dL. In addition, the average HDL-C is 36 mg/dL in men and 42 mg/dL in women; 53% of men and 26% of women have HDL-C ⬍35 mg/dL, and approximately 75% of the men and 50% of the women have HDL-C ⬍40 mg/ dL.17 Many Turks, even those with CHD, do not meet ATP III thresholds to initiate therapy on the basis of LDL-C. Our goal was to identify high-risk subjects by using only routine lipid analyses (TC, LDL-C, HDL-C, and triglycerides) and medical history without using risk-prediction tables and without a total dependence on LDL-C. We applied both the ATP III guidelines and the alternate guidelines, based on TC/HDL-C and LDL-C, to the database of the Turkish Heart Study and compared the numbers of subjects identified for treatment. The database includes information on all the major risk factors used to guide therapy according to the current ATP III guidelines.1 In contrast to the ATP III guidelines, our risk factor criteria include obesity because it has been identified as a major risk factor for CHD.24 –29 The TC/ HDL-C ratio was used because it is the most sensitive plasma lipid predictor of CHD risk in clinical trials and in observational studies, including studies of the Turkish population.23,30 – 41

Methods The design of the Turkish Heart Study has been reported.17 The initial cohort of 9017 subjects was studied between 1990 and 1993 and was recruited from six regions of Turkey

selected for regional differences in diet, primarily the type of dietary fat. Between 1996 and 1999, 820 additional subjects who were residents of Istanbul were enrolled.42,43 All 9837 subjects (6495 men and 3342 women) were included in this analysis. All subjects were 20 years or older and, after giving informed consent, provided fasting blood samples for measurement of TC, triglycerides, and HDL-C. The study was approved by the Committee on Human Research of the University of California, San Francisco. The analytical techniques and the data collection process have been described.17 Briefly, HDL-C was measured after precipitation of apolipoprotein B-containing lipoproteins with phosphotungstic acid and magnesium. LDL-C values were calculated by the Friedewald formula.44 Blood glucose levels were not measured. Information on social, family, and medical history, including current medication use, was obtained by Turkish-speaking medical personnel. Anthropometric and demographic data were also obtained.

Risk assessment according to ATP III guidelines Each subject in the database was assessed on the basis of definitions of risk factors in the ATP III report.1 These risk factors are current cigarette smoking, hypertension (blood pressure ⱖ140/90 or use of an antihypertensive medication), HDL-C ⬍40 mg/dL (HDL-C ⱖ60 mg/dL is a negative risk factor), family history of CHD, and age ⱖ45 years for men or ⱖ55 years for women. For those subjects with 2 or more (2⫹) risk factors, the Framingham risk score was calculated and the 10-year risk of having a CHD event was assessed according to the Framingham risk tables.1 Coronary disease or equivalent status (“CHD or equivalent”) was defined by a history of any ischemic vascular disease syndrome (including use of nitrates for relief of angina pectoris), a history of diabetes mellitus or use of hypoglycemic drugs, or a Framingham risk score indicating ⱖ20% risk of having a CHD event over the next 10 years. Subjects with 2⫹ risk factors and ⬍20% risk were divided into two groups, based on subsequent 10-year CHD risk, either ⬍10% or ⱖ10% and ⬍20%. The group with lowest risk were those subjects with “0 to 1 risk factor.” Subjects qualified for lipidlowering therapy (either lifestyle or drugs) on the basis of threshold LDL-C for each of the risk categories, as described in the ATP III guidelines.1

Risk assessment according to proposed guidelines for patients with low HDL-C In addition to the risk factors defined in the ATP III guidelines (see above), we included obesity (defined as body mass

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1054 Bersot, Pe´ pin, and Mahley

Table II. Mean values of plasma lipid levels, TC/HDL-C ratio, and BMI according to CHD risk factor status (Turkish Heart Study, 1990–1999) Mean lipid levels No. (%)

CHD or equivalent* 2⫹ risk factors 0–1 risk factor P values CHD versus 2⫹ risk factors CHD versus 0–1 risk factor 2⫹ versus 0–1 risk factor

TC

LDL-C

Men

Women

Men

Women

Men

Women

368 (5.7) 4382 (67.5) 1745 (26.9)

279 (8.3) 1461 (43.7) 1602 (47.9)

194 ⫾ 39 186 ⫾ 43 179 ⫾ 42

190 ⫾ 41 182 ⫾ 42 168 ⫾ 37

129 ⫾ 37 123 ⫾ 39 117 ⫾ 39

124 ⫾ 37 120 ⫾ 38 106 ⫾ 33

.0006 ⬍.0001 ⬍.0001

.0049 ⬍.0001 ⬍.0001

.0027 ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

BMI, Body mass index. *CHD or equivalent is defined as self-reported diagnosis of any ischemic vascular disease, diabetes mellitus, or use of hypoglycemic drugs.

Table III. Distribution of LDL-C, HDL-C, and TC/HDL-C ratio according to risk factor status* LDL-C (mg/dL)

Men (%) CHD or equivalent† 2⫹ risk factors 0–1 risk factor Women (%) CHD or equivalent† 2⫹ risk factors 0–1 risk factor

HDL-C (mg/dL)

TC/HDL-C ratio

No.

>100

>130

>160

<30

<35

<40

>5

>6

>7

368 4382 1745

288 (78) 3075 (70) 1106 (63)

180 (50) 1707 (39) 548 (31)

73 (20) 715 (16) 239 (14)

63 (17) 814 (19) 95 (5)

184 (50) 2385 (54) 381 (22)

283 (77) 3764 (86) 674 (39)

241 (66) 2539 (58) 519 (30)

134 (36) 1413 (32) 211 (12)

65 (18) 659 (15) 76 (4)

279 1461 1602

209 (76) 1009 (69) 850 (53)

112 (40) 529 (36) 315 (20)

47 (17) 181 (12) 104 (7)

22 (8) 103 (7) 33 (2)

68 (24) 466 (32) 150 (16)

134 (48) 993 (70) 355 (22)

118 (42) 600 (41) 175 (11)

50 (18) 246 (17) 59 (4)

15 (5) 102 (7) 13 (1)

*Data are presented as number of subjects (% of population) with these characteristics. †CHD or equivalent is defined as self-reported diagnosis of any ischemic vascular disease, diabetes mellitus, or use of hypoglycemic drugs.

index [BMI] ⱖ30 kg/m2) as a risk factor. Framingham risk scores were not calculated for inclusion of those with 2⫹ risk factors into the CHD or equivalent group. Assignment of treatment status (lifestyle only or lifestyle and drugs) was based on threshold values of either LDL-C or the TC/HDL-C ratio (Table I).

Analysis of all subjects All subjects in the database were evaluated according to both sets of guidelines to assess the number of patients eligible for each of the following treatment categories: no treatment, lifestyle treatment only, or drug treatment.

Age-adjusted analysis For analysis by age, the number of patients in each of the risk factor categories in the Turkish Heart Study database was adjusted to reflect the population distribution of Turkey according to 1998 census data. By decade starting at age 20, the number of men (and women) according to 1998 census data was divided by the number of men (and women) in the database. This factor, when multiplied by the number of men (and women) in the database, yielded an “adjusted number” representing the population distribution according to census data. After this adjustment, the prevalence of risk factors of

study participants was assumed to be representative of that of the entire adult Turkish population. The data were entered into a Microsoft Excel 5 spreadsheet, and the subjects were segregated into risk categories. Values are reported as mean ⫾ SD. Statistical differences between mean values were determined by 2-sample t tests.

Results Plasma lipids and TC/HDL-C The mean plasma lipid levels, TC/HDL-C ratio, and BMI for all subjects are shown in Table II, according to risk factor status. The distributions of LDL-C, HDL-C, and the TC/HDL-C ratio by risk factor status are shown in Table III. In the CHD or equivalent group, the TC was 190 to 194 mg/dL, and the HDL-C was low (men, 36 ⫾ 8 mg/ dL; women, 41 ⫾ 8 mg/dL). Approximately 75% of men and 50% of women had HDL-C ⬍40 mg/dL. Approximately 50% of men and 60% of women had LDL-C ⬍130 mg/dL, and approximately 25% had levels ⬍100 mg/dL; the mean was ⬍130 mg/dL. The mean triglyceride level was 143 ⫾ 84 mg/dL in men and 127

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(mg/dL ⴞ SD) HDL-C Men 36 ⫾ 8 35 ⫾ 6 41 ⫾ 8 .0001 ⬍.0001 ⬍.0001

Triglycerides Women

Men

41 ⫾ 8 38 ⫾ 7 45 ⫾ 8

143 ⫾ 84 141 ⫾ 79 107 ⫾ 62

⬍.0001 ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

BMI (kg/m2)

TC/HDL-C ratio

Women

Men

Women

Men

Women

127 ⫾ 70 117 ⫾ 63 84 ⫾ 47

5.6 ⫾ 1.6 5.5 ⫾ 1.5 4.5 ⫾ 1.3

4.9 ⫾ 1.4 4.9 ⫾ 1.4 3.8 ⫾ 1.0

26.0 ⫾ 3.9 26.0 ⫾ 3.8 24.5 ⫾ 2.8

28.0 ⫾ 6.1 28.0 ⫾ 5.6 23.8 ⫾ 3.6

.0191 ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

Table IV. Use of NCEP and low HDL-C guidelines to predict lifestyle or drug therapy in Turkish Heart Study subjects (9837 men and women) NCEP guidelines*

2ⴙ risk factors, n (%)

0–1 risk factor, n (%)

647 (7) – 56 (9) 591 (91)

5843 (59) 1691 (29) 1539 (26) 2613 (45)

3347 (34) 2789 (83) 189 (6) 369 (11)

0.6 6.0

15.6 26.6

1.9 3.8

⬍160 –

⬍100 & ⬍3.5

⬍130 & ⬍4.5

⬍160 & ⬍5.5

ⱖ130 –

ⱖ160 –

ⱖ100 or ⬎3.5

ⱖ130 or ⱖ4.5

ⱖ160 or ⱖ5.5

ⱖ130 (or ⱖ160)** –

ⱖ190 –

⬎100 or ⬎3.5

ⱖ130 or ⱖ6.0

ⱖ160 or ⱖ7.0

2ⴙ risk factors, n (%)

0–1 risk factor, n (%)

1259 (13) 215 (17) 320 (25) 724 (58)

4960 (50) 3247 (65) 763 (15) 950 (19)

3618 (37) 3255 (90) 254 (7) 109 (3)

3.3 7.4

7.8 9.7

2.6 1.1

⬍100 –

⬍130 –

ⱖ100 – ⱖ130 –

CHD or equivalent,‡ n (%) All subjects㛳 No treatment# Lifestyle treatment# Drug treatment# Percent of all subjects Total lifestyle treatment (%) Total drug treatment (%) Goal LDL-C (mg/dL) TC/HDL-C Lifestyle LDL-C (mg/dL) TC/HDL-C Drug LDL-C (mg/dL) TC/HDL-C

Low HDL-C guidelines†

Total %

13.7 18.2

CHD or equivalent,§ n (%)

Total %

18.1 36.4

NCEP, National Cholesterol Education Program Adult Treatment Panel III. *See reference 1 for the 2001 NCEP guidelines used to define the treatment categories. †Uses guidelines shown in Table I. ‡Equivalent includes those estimated to have ⱖ20% CHD risk over 10 years, patients with diabetes, and participants reporting non-CHD vascular disease. §Equivalent includes only patients with diabetes and participants reporting non-CHD vascular disease. 㛳Percentages are of all subjects. #Percentages are of subjects in each risk category. **Threshold value depends on 10-year Framingham risk score.

⫾ 70 mg/dL in women. Sixty-six percent of the men and 42% of the women had a TC/HDL-C ratio ⬎5. Subjects with 2⫹ risk factors represent the largest proportion of patients eligible for treatment. Their TC and LDL-C levels were 4 to 8 mg/dL lower than those in the CHD or equivalent group, but their HDL-C levels were similar, and neither the TC/HDL-C ratio nor BMI differed significantly between the groups. The HDL-C was ⬍40 mg/dL in 86% of men and 70% of women.

Only 16% of men and 12% of women had LDL-C ⬎160 mg/dL. About one third of the men and 17% of the women had a very high-risk TC/HDL-C ratio (⬎6.0). Subjects with 0 to 1 risk factor had TC and LDL-C levels that were 15 to 20 mg/dL lower than those in the CHD or equivalent group and approximately 5 to 15 mg/dL lower than those in the 2⫹ risk factor group. Their HDL-C was substantially higher (men, 41 ⫾ 8; women, 45 ⫾ 8 mg/dL), and their mean TC/

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Table V. Mean values of plasma lipid levels (mg/dL ⫾ SD), TC/HDL-C ratio, and BMI according to CHD risk factor status among men ⱖ45 years and women ⱖ55 years of age No.

CHD or equivalent 2⫹ risk factors 0–1 risk factor P values CHD versus 2⫹ risk factors CHD versus 0–1 risk factor 2⫹ versus 0–1 risk factor

TC

LDL-C

Men

Women

Men

Women

Men

Women

281 1564 153

156 500 86

195 ⫾ 38 198 ⫾ 44 198 ⫾ 42

197 ⫾ 39 195 ⫾ 44 190 ⫾ 37

131 ⫾ 36 133 ⫾ 39 131 ⫾ 39

130 ⫾ 36 130 ⫾ 40 122 ⫾ 34

NS NS NS

NS NS NS

NS NS NS

NS NS NS

HDL-C ratio was substantially lower (men, 4.5 ⫾ 1.3 versus 5.5 ⫾ 1.5; women, 3.8 ⫾ 1.0 versus 4.9 ⫾ 1.4). The average triglyceride values were 30 to 35 mg/dL lower than those in the higher-risk categories. Only approximately 10% of the lowest-risk subjects had LDL-C ⬎160 mg/dL. The TC/HDL-C ratio was ⬎6.0 in ⬃8% and ⬎7.0 in ⬃3%.

Comparison of ATP III and proposed low HDL-C guidelines The ATP III criteria and the low HDL-C guidelines (Table I) were applied to the Turkish Heart Study database. The results for men and women combined are shown in Table IV. The ATP III criteria, including ⱖ20% CHD risk over 10 years as calculated from the Framingham risk tables, identified almost twice as many CHD or equivalent patients as the low HDL-C guidelines, using the TC/HDL-C ratio and LDL-C but not the Framingham risk scoring system [1259 (13%) versus 647 (7%)]. Ninety-nine percent of 612 CHD or equivalent additional patients (1259 minus 647) identified by the ATP III guidelines were assigned to the 2⫹ risk factor group by the low HDL-C guidelines. Despite identifying so many additional high-risk subjects, the ATP III criteria mandated drug treatment for only 58% of them (7.4% of the entire cohort) (Table IV). The low HDL-C guidelines, however, assigned 91% of CHD or equivalent subjects (6% of the entire cohort) to drug treatment. An analysis of the 612 subjects not identified as CHD or equivalent by the proposed low HDL-C guidelines indicates that 462 (75%) were considered candidates for drug treatment, based on these guidelines. Although it is clear that the ATP III guidelines identify significantly more high-risk patients with the Framingham risk tables, 42% of the CHD or equivalent patients identified did not qualify for drug therapy on the basis of LDL-C threshold alone. As discussed below, it is reasonable to ask whether the time and effort required for physicians to use the risk tables to identify more

CHD or equivalent patients may be offset by undertreatment, especially of patients with low HDL-C, resulting from the use of LDL-C threshold values only. Among subjects with 2⫹ risk factors, the low HDL-C guidelines included 9% more of the sample population than the ATP III guidelines (5843 versus 4960) (Table IV). This increase primarily reflects the number of patients assigned to the CHD or equivalent group on the basis of their Framingham risk assessment scores, by the ATP III criteria that now are assigned to the 2⫹ risk factor group based on the low HDL-C guidelines. In the 2⫹ risk factor group, the ATP III guidelines assigned 65% to no treatment, 15% to therapeutic lifestyle change, and only 19% to drug treatment. The low HDL-C guidelines, however, assigned substantially fewer patients to no treatment (29%) and substantially more to lifestyle change (26%) and drug treatment (45%). Considering the 2⫹ risk factor group as a percentage of the entire sample population, the ATP III guidelines assigned 9.7% and the low HDL-C guidelines 26.6% to drug therapy. Among subjects with 0 to 1 risk factor, most (80% to 90%) did not qualify for treatment, and only ⬃2% to 3% qualified for therapeutic lifestyle change under both sets of guidelines (Table IV). The low HDL-C guidelines, however, assigned a substantially higher percentage of these patients to drug therapy (11% versus 3%). In summary, the ATP III guidelines identified 13.7% of 9837 subjects in the Turkish Heart Study database for therapeutic lifestyle change and 18.2% for drug treatment. According to the proposed low HDL-C guidelines, however, 18.1% qualified for lifestyle change and 36.4% for drug treatment.

Analysis of subjects at risk because of age Although it might be optimal to treat all adults at risk for CHD because of low HDL-C, few countries can afford to recommend that one third of the adult population receive chronic cholesterol-lowering drug ther-

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HDL-C

Triglycerides

BMI (kg/m2)

TC/HDL-C ratio

Men

Women

Men

Women

Men

Women

Men

Women

36 ⫾ 8 36 ⫾ 7 47 ⫾ 8

40 ⫾ 8 41 ⫾ 8 49 ⫾ 8

140 ⫾ 75 142 ⫾ 80 96 ⫾ 45

133 ⫾ 71 122 ⫾ 63 94 ⫾ 41

5.7 ⫾ 1.5 5.6 ⫾ 1.6 4.2 ⫾ 1.0

5.1 ⫾ 1.4 5.0 ⫾ 1.4 3.9 ⫾ 0.9

26.2 ⫾ 4 26.3 ⫾ 3.8 24.5 ⫾ 2.7

28.4 ⫾ 6.0 27.5 ⫾ 5.5 23.3 ⫾ 3.5

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

apy. Accordingly, we performed an additional analysis of subjects at increased risk because of age (men ⱖ45 and women ⱖ55 years of age). The mean plasma lipid levels, TC/HDL-C ratio, and BMI of these subjects are shown according to risk factor status in Table V. The TC and LDL-C levels were similar in all three groups. However, the HDL-C levels were ⬃10 mg/dL higher in subjects with 0 to 1 risk factor. As a result, the mean TC/HDL-C ratio was substantially lower in these subjects than in those with CHD or equivalent or 2⫹ risk factors (men, 4.2 versus ⬃5.6; women, 3.9 versus ⬃5.0). Triglyceride levels and BMI were also substantially lower in subjects with 0 to 1 risk factor. Before applying the two sets of guidelines to men ⱖ45 years and women ⱖ55 years of age, we adjusted the population distribution of the database to reflect that of the Turkish population according to 1998 census data. After this age adjustment in the population distribution and the restriction of drug treatment of primary prevention patients by age (men ⱖ45 years; women ⱖ55 years), the ATP III guidelines identified 13% of all adult subjects in the Turkish Heart Study for drug therapy, whereas the low HDL-C guidelines identified 18%. Through the use of this age-restricted approach, 5% of adults (18% versus 13%) who otherwise qualified for drug treatment according to ATP III were precluded from treatment. The effect of age restriction on treatment based on the proposed low HDL-C guidelines was greater. Only 18% of adults qualified for drug treatment when the age criteria were applied compared with 36% (Table IV) of all adults who qualified without the age restriction. Both sets of guidelines recommended lifestyle therapy for 5% of all adults above the age cut-points.

Discussion This study shows that, in populations at risk for CHD caused by low HDL-C levels, use of the proposed guidelines based on the TC/HDL-C ratio and LDL-C val-

NS ⬍.0001 ⬍.0001

NS ⬍.0001 ⬍.0001

ues identifies more high-risk subjects for treatment than LDL-C threshold values alone. In Turkish men and women with a CHD or equivalent diagnosis, the average TC values (194 and 190 mg/dL, respectively) (Table II) were substantially below those (ⱖ200 mg/dL) in several studies of American men with CHD.10,45–52 In the largest of these studies,10 the average TC of 2905 white men was 213 mg/dL, the average HDL-C was 38 mg/dL, and the average LDL-C was 139 mg/dL. However, in the study of American men,10 41% had LDL-C ⬍130 mg/dL and would not be considered candidates for mandatory drug therapy according to current NCEP guidelines. Among Turkish men in the CHD or equivalent category with lower average LDL-C (129 mg/dL) and similar HDL-C (36 mg/dL), 50% would not be mandated to receive drug therapy (Tables II and III). Assuming that there is a treatment benefit for the 40% to 50% of patients with CHD who do not meet NCEP LDL-C threshold values for initiating drug therapy, another criterion that identifies patients for drug therapy should be considered. Observational and intervention studies indicate that risk is lowest when the TC/HDL-C ratio is ⬍3.5.23,30 –34,36 – 40,53 We therefore suggest that this criterion should be the desired TC/ HDL-C ratio and that drug treatment should be recommended for CHD or equivalent patients with LDL-C ⬎100 mg/dL or a TC/HDL-C ratio ⬎3.5 (Table I). Among Turkish CHD or equivalent subjects, ⬎90% would be candidates for drug therapy according to the proposed criteria compared with only 58% according to the NCEP guidelines (Table IV). When assigning participants in the Turkish Heart Study database to CHD or equivalent status according to the proposed low HDL-C guidelines, we did not calculate the 10-year risk of CHD. We chose this approach to eliminate the need to consult risk tables and to enhance the utility of the proposed guidelines. Compliance by healthcare providers with the previous NCEP guidelines,54 which lacked the additional step of calculating the 10-year risk recommended by the cur-

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rent guidelines, was less than optimal.55–57 Without the 10-year risk calculation, the low HDL-C guidelines identified ⬃7% of the cohort as CHD or equivalent patients (Table IV). When the 10-year CHD risk was calculated, ⬃13% of the cohort was identified as CHD or equivalent. However, most of these additional patients did not qualify for drug treatment on the basis of LDL-C thresholds alone. Consequently, nearly equal proportions of CHD or equivalent patients in the cohort, 7.4% (ATP III guidelines) and 6% (low HDL-C guidelines), were identified to receive drug treatment. Virtually all the subjects (6.3%) identified by ATP III but not by the low HDL-C guidelines as CHD or equivalent were included among the group with 2⫹ risk factors according to the low HDL-C guidelines (Table IV). Most of the subjects who were included in the 2⫹ risk factor group were mandated for drug treatment. According to the proposed low HDL-C guidelines, by using a high-risk TC/HDL-C threshold ratio ⱖ6.0 and an LDL-C threshold ⱖ130 mg/dL, drug treatment was recommended for 26.6% of subjects with 2⫹ risk factors, whereas the NCEP guidelines identified only 9.7% as candidates for drug treatment (Table IV). Thus, the low HDL-C guidelines identified almost twice as many CHD or equivalent and 2⫹ risk factor participants for drug treatment as the NCEP guidelines (32.6% versus 17.1%). Studies that examined the use of the TC/ HDL-C ratio indicated that a value ⬎6.0 identifies substantially more persons at risk than LDL-C thresholds.31 After inclusion of the subjects with 0 to 1 risk factor identified as drug treatment candidates, the ATP III guidelines recommended that 18.2% of all adults receive drug therapy as opposed to 36.4% according to the low HDL-C guidelines. Observational studies in the United States and western Europe show that persons without CHD whose HDL-C levels are 10 to 15 mg/dL lower than the population mean are at increased risk. However, primary prevention trial data demonstrating that it is efficacious to treat patients with low HDL-C and normal LDL-C are available only for those who are also at risk because of age.11 For that reason and to reduce the cost if 36% of the adult population were to receive drug therapy according to the low HDL-C guidelines, we restricted drug therapy to men ⱖ45 years and women ⱖ55 years of age. After adjustment of our database to reflect the age distribution according to 1998 Turkish census data, drug treatment was recommended for 13% of all adults by the ATP III guidelines and 18% by the low HDL-C guidelines (Table IV). Clinical trial data support the treatment of persons with average LDL-C who are free of CHD but are at increased risk because of age and low HDL-C.11 In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), baseline mean lipid values were LDL-C, 156 mg/dL, and HDL-C, 36 mg/dL, for

men and 40 mg/dL for women.58 Eighty-three percent of participants had baseline LDL-C below threshold levels for initiating drug therapy according to ATP III guidelines. Similarly, the guidelines based on global risk assessment recently proposed by the Second Joint Task Force of European and Other Societies on Coronary Prevention also failed to identify for treatment approximately 80% of AFCAPS/TexCAPS subjects.11,54,59,60 Baseline TC/HDL-C but not LDL-C predicted subsequent risk, suggesting that for a cohort with average LDL-C, the LDL-C is not predictive unless considered in conjunction with the HDL-C.30 In the AFCAPS/TexCAPS trial, the benefit of treatment was restricted to the two thirds of the cohort with baseline HDL-C ⬍40 mg/dL.11 In this subgroup, only 38 subjects required treatment to prevent one end point event compared with 50 for the entire cohort.11,59 Cost-consequences analysis of the entire AFCAPS/TexCAPS cohort demonstrated that the economic benefits were comparable to the proven benefits of treating hypertension in the United States.59 Predictably, however, the economic benefits were not as striking as those in higher-risk subjects with a history of CHD.61,62 Consequently, it may be more economically feasible in some countries to reserve cholesterollowering therapy for adults who qualify for treatment according to the low HDL-C guidelines and who are also at risk because of age (men ⱖ45 years; women ⱖ55 years). Thus, we conclude that the proposed low HDL-C guidelines, which do not rely on the use of risk tables and rely only on lipid values and the identification of routine risk factors, may increase compliance. The use of LDL-C plus TC/HDL-C may simplify treatment guidelines for physicians and yet accomplish the major goal of treating the most high-risk patients. We are indebted to our associates at the American Hospital, Istanbul, especially Dr Erhan Palaogˇlu, and to Sibel Tanir in the Gladstone Research Laboratory (Istanbul). We thank Sylvia Richmond and Catharine Evans for manuscript preparation and Stephen Ordway and Gary Howard for editorial assistance. We acknowledge the generous support of the American Hospital, especially George Rountree, and the J. David Gladstone Institutes.

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The following article is an AHJ Online Exclusive. Full text of this article is available at no charge at our website: www.mosby.com/ahj. Increased levels of pregnancy-associated plasma protein-A in patients with hypercholesterolemia: The effect of atorvastatin treatment ˇtulc, MD,a Ivan Malbohan, MD, PhD,b Jan Malı´k, MD, PhD,a Lenka Fialova´, MD, PhD,b Jirˇina Soukupova´, PhD,b and Toma´ ˇs S ˇ esˇka, MD, PhDa Prague, Czech Republic Richard C

Background

Serum levels of pregnancy-associated plasma pro-

Results

In untreated hypercholesterolemic subjects, PAPP-A levels

tein-A (PAPP-A) have recently been linked to plaque instability and are in-

were significantly higher than in control subjects (8.02 ⫾ 1.86 mU/L vs

creased in acute coronary syndromes. The relation between PAPP-A levels

6.50 ⫾ 2.54 mU/L, P ⫽ .018). There was no correlation between PAPP-A

and coronary risk factors, namely blood lipids, has not been studied to

levels and serum lipid levels. Atorvastatin treatment reduced total and LDL-

date. We have therefore investigated whether serum PAPP-A levels are

cholesterol by 31% and 40%, respectively. Despite this profound lipid

increased in asymptomatic hypercholesterolemic subjects and whether

lowering, there was no significant change in the serum PAPP-A levels.

PAPP-A levels are influenced by atorvastatin therapy.

Conclusions

PAPP-A levels are elevated in hypercholesterolemic

subjects without clinical signs of atherosclerosis. PAPP-A may therefore not

Methods

We examined 27 subjects with isolated hypercholesterol-

emia free of manifest vascular disease and 29 age-matched healthy con-

only reflect plaque instability but also serve as a marker of total atherosclerotic burden in asymptomatic subjects with hyperlipidemia. However,

trol subjects. Patients were examined at baseline and after 10 weeks of

PAPP-A levels are not influenced by atorvastatin treatment. (Am Heart J

atorvastatin treatment (20 mg/d).

2003;146:e21.)