Lipids

Centralized Pan-Middle East Survey on the Undertreatment of Hypercholesterolemia: Results From the CEPHEUS Study in Arabian Gulf Countries

Angiology 2014, Vol. 65(10) 919-926 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319713512414 ang.sagepub.com

Mohamed Arafah, MD1, Ali T. Al-Hinai, MD2, Wael Al Mahmeed, MD3, Khalid Al-Rasadi, MD4, Omer Al Tamimi, MD5, Shorook Al Herz, MD6, Faisal Al Anazi, MD7, Khalid Al Nemer, MD8, Othman Metwally, MD9, Akram Alkhadra, MD10, Mohammed Fakhry, MD10, Hossam Elghetany, MD11, Abdel Razak Medani, MD12, Afzal Hussein Yusufali, MD12, Obaid Al Jassim, MD12, Omar Al Hallaq, MD13, Fahad Omar Ahmed S. Baslaib, MD14, Mahmoud Alawadhi, MD15, Haitham Amin, MD16, Khamis Al-Hashmi2, and Abdullah Shehab, MD17

Abstract The Centralized pan-Middle East Survey on the undertreatment of hypercholesterolemia (CEPHEUS) survey evaluated the attainment of low-density lipoprotein cholesterol (LDL-C) goals among patients on lipid-lowering drugs (LLDs) according to the updated National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP-III) guideline. The survey was conducted in 6 Arabian Gulf countries. Patients aged 18 years on LLDs for at least 3 months (stable medication for 6 weeks) were recruited. Fasting blood samples were collected at a single visit. In this survey, 5276 (58.2% male) patients were included in the final analysis. The LDL-C goal was attained in 91.1% of low-risk, 52.7% of high-risk, and 32.0% in very-high-risk categories. Goal attainment was directly related to female gender, age 25 and >30 kg/m2, respectively, and metabolic syndrome (MetS) defined according to harmonized MetS definition.13 Physical examination included measurement of height, weight, waist circumference, and blood pressure.

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Table 1. Patient Demographics and Clinical Characteristics. Surveyed Number Cohort Male Race (GCC) Age (mean þ SD), years SBP (mean þ SD), mm Hg DBP (mean þ SD), mm Hg Body weight (mean þ SD), kg Waist circumference (mean þ SD), cm BMI (mean þ SD) History of CHD History of PAD History of cerebrovascular disease Current smoker Diabetes Metabolic syndrome Arterial hypertension Family history of premature CVD Single LLD Statins Fibrates Other Combination LLD Type of statin Atorvastatin Simvastatin Rosuvastatin

5261 5276 5276 5268 5268 5271 5133

3060 3916

Values (%) 58.2 74.2 55.6 132.0 78.7 82.1 103.3

(11.3) (18.2) (10.3) (17.4) (13.9)

5260 5272 5272 5272 5276 5276 5244 5276 5276

1616 149 192 627 3350 1945 2607 1086

31.4 (6.9) 30.7 2.8 3.6 11.9 63.5 37.1 66.6 20.6

5272 5272 5272 5272

4926 46 27 273

93.4 0.9 0.5 5.2

5551 5551 5551

2263 2216 657

40.8 39.9 11.8

Abbreviations: GCC, Gulf Cooperation Council; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; DBP, diastolic blood pressure; LLD, lipid-lowering therapy; SBP, systolic blood pressure; SD, standard deviation; PAD, peripheral arterial disease.

Laboratory Tests A fasting blood sample was taken from each patient for measurement of total cholesterol (TC), high-density lipoprotein (HDL-C), LDL-C, triglyceride (TG), ApoA1, ApoB, glucose, and glycated hemoglobin A1c (HbA1c). Blood samples were collected in 3 tubes (5 mL in a gel tube, 2 mL in a fluoride tube, and 2 mL in an EDTA tube). The blood samples were shipped by air courier and the tests were performed at the King Faisal Specialist Hospital and Research Centre (Riyadh, KSA). All the laboratory tests underwent internal and external quality control checks.

Study Objectives The primary objective was to establish the proportion of patients on LLDs achieving LDL-C goals according to the updated (2004) NCEP-ATP-III guidelines.6 The secondary objectives included the following: the proportion of patients on LLDs achieving LDL-C goals according to the Third JETF guidelines4 and the proportion of patients in primary prevention, secondary prevention, and MetS achieving LDL-C goals according to both updated NCEP-ATP-III and Third JETF guidelines.4 Furthermore, the study aimed to

identify patient and physician determinants for attainment of the LDL-C goals according to TJETF and NCEP guidelines

Statistical Analysis All statistical analyses were descriptive in nature and generated by Statistical Analysis System (SAS) software. Continuous data are described by their mean and standard deviation (SD), minimum and maximum. Categorical data are described by the number and percentage of patients in each category. Multivariate logistic regression analysis was used to determine the prognostic factors of achieving the LDL-C goals, according to the 3 guidelines, with patients at the first level and physicians at the second level. The main data analysis on the primary and secondary variables was performed on the full analysis set (FAS) population. Due to the noninterventional nature of this survey, no safety analyses were performed.

Results Patient Characteristics In total, 5457 patients participated in the survey. Laboratory data were missing for 158 patients, 6 patients were underage, and 17 patients were missing the risk-level data. Therefore, the FAS comprised 5276 patients Patient demographics and clinical characteristics are shown in Table 1. The mean age was 55.6 years, and 41.8% of the patients were female. The most frequent reason for having LLDs prescribed were primary prevention (71.5%; n ¼ 3773); other reasons were secondary prevention (27.3%; n ¼ 1438) and familial hypercholesterolemia (1.2%; n ¼ 63). The majority of patients (93.4%; n ¼ 4926) received statins as a monotherapy, followed by fibrates (0.87%; n ¼ 46), while 27 (0.51%) patients were treated with other LLDs. Among the statins used as monotherapy, atorvastatin was the most frequently used (40.8%; n ¼ 2263), followed by simvastatin (39.9%; n ¼ 2216) and rosuvastatin (11.8%; n ¼ 657). Laboratory data were available for 5276 patients and the results of the analysis are shown in Table 2.

Investigator Questionnaire In total, 177 investigators participated in this survey. The mean age was 43.9 + 8.8 years. Among the investigators 70.9% (n ¼ 124) were male, 42.0% (n ¼ 71) were general practitioners/primary care providers, 31.4% (n ¼ 53) were cardiologists, and 29.9% (n ¼ 53) were other medical specialists. The investigators indicated that they set individual target cholesterol levels for 70% of their patients targeting the LDL-C levels in 89.8% (n ¼ 158), often in combination with the other lipid parameters such as TC, HDL-C, and TG. Most investigators (n ¼ 155; 87.6%) used guidelines to establish individual target cholesterol levels, the NCEP-ATP-III guidelines being the most frequently used (34.7%; n ¼ 58). Other guidelines used were National guidelines (n ¼ 27; 18.8%), the TJETF guideline (14.6%; n ¼ 21), local health care authority guidelines (9.0%; n ¼ 13), and individual practice guidelines

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Angiology 65(10)

Table 2. Lipid Profile at the Time of the Survey: Laboratory Results.a Unit Total cholesterol High-density lipoprotein (HDL) Low-density lipoprotein cholesterol (LDL-C) Triglycerides Glucose ApoA1 ApoB ApoB–ApoA ratio HbA1c

mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL mmol/L mg/dL g/L g/L

N

5276 5276 5276 5276 5276 5276 5274 5276 5175 5175 5262 5261 5261 Percentage 5249

Mean (+ SD) 4.4 (1.1) 169 (42) 1.2 (0.3) 46 (13) 2.6 (0.9) 100 (36) 1.7 (1.2) 152 (109) 7.4 (3.5) 133 (63) 1.5 (0.27) 0.92 (0.27) 0.63 (0.22) 8 (3)

Figure 1. Proportion of patients attaining their 2004 updated National Cholesterol Educational Program Adult Treatment Panel III– recommended low-density lipoprotein cholesterol (LDL-C) goals, according to the risk category.

Abbreviations: Apo, apolipoprotein; HbA1c, glycated hemoglobin A1C; SD, standard deviation. a Data based on the full analysis set.

(6.3%; n ¼ 9). In all, 89 (53.3%) investigators were unable to name the precise guideline used. For reviewing the cholesterol levels, 44.5% (n ¼ 69) of the investigators reported to schedule a visit every 3 months, 40.0% (n ¼ 62) indicated to program a visit every 6 months, and 11.6% (n ¼ 18) once per year. According to the investigators, the LLDs most frequently recommended to patients were statins (85.4% + 0.20%), followed by fibrates, 10.4% + 0.10% and other drugs, 2.86% + 0.05%.

Guideline Target Attainment Target Attainment According to the 2004 Updated NCEP-ATP-III Guidelines. Patient risk categorization, their respective LDL-C goals, and target attainment according to 2004 updated NCEP-ATP-III are listed in Figure 1. Overall only 52.0% of the study population reached the 2004 updated NCEP-ATP-III goal. Among the very high 2004 updated NCEP-ATP-III risk category, 31.9% had succeeded the LDL-C goal and 52.7% among the high but not very high CVD risk. The percentage of patients reaching the LDL-C goal per subgroup, according to the 2004 updated NCEP-ATP-III guidelines, is shown in Figure 2. The proportion of patients attaining the 2004 updated NCEP-ATP-III guidelines stratified by the LLDs is shown in Figure 3. A lower percentage of patients attaining the LDL-C goal was observed among patients having CHD (33.4%; n ¼ 540), peripheral arterial disease. (24.8%; n ¼ 37), cerebrovascular disease (27.6%; n ¼ 53), hypertension (50.1%; n ¼ 1751), a family history of premature CVD (48.4%; n ¼ 526), or being a smoker (45.9%; n ¼ 288). Target Attainment According to the TJETF Guidelines. In total, only 59.7% of the study population reached the TJETF-

Figure 2. Attainment of low-density lipoprotein cholesterol (LDL-C) goals in the overall cohort, and in patients with primary (1 ) and secondary (2 ) prevention, metabolic syndrome (MetS), familial hypercholesterolemia (FH), and peripheral arterial disease (PAD).

Figure 3. Proportion of patients attaining the 2004 updated National Cholesterol Educational Program Adult Treatment Panel III (NCEPATP-III) goals stratified by the lipid-lowering treatments. *Ezetimibe, bile acid sequestrant (BAS), nicotinic acid, lipid-lowering drugs (LLD).

recommended LDL-C goal. The percentage of the study population with the highest CVD risk, who succeeded the LDL-C goal, was 58.3% among the high TJETF risk category.

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Figure 4. Positive predictors for achievement of low-density lipoprotein cholesterol (LDL-C) goals according to 2004 updated National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP-III) and Third Joint European Task Force (TJETF) guidelines. OR indicates odds ratio; CI, confidence interval; CVD, cardiovascular disease.

A higher percentage of achieving patients were also observed among normal weight (64.1%; n ¼ 456) than the other BMI categories. The percentage of LDL-C goal achievers was higher in patients with CHD (71.0%; n ¼ 1147) than patients without CHD (54.7%; n ¼ 2000) and patients with cerebrovascular disease (61.5%; n ¼ 118) than those without the disease (59.6%; n ¼ 3029). Diabetes, hypertension, and family history of premature CVD had minimal effects on the percentage of patients reaching the LDL-C goals. Patients with MetS (as defined by the NCEP-ATP-III; 54.3%; n ¼ 1057) had less achievement than those without MetS (62.8%; n ¼ 2070). Primary prevention patients had a lower achievement (55.5%; n ¼ 2095) than secondary prevention (71.5%; n ¼ 1028) but were lowest among patients with familial hypercholesterolaemia (38.1%; n ¼ 24). Patient and Physician Determinants for Attainment of the LDL-C Goals According to TJETF and NCEP Guidelines. Among all the patient and physician factors assessed by the questionnaires in this study, LDL-C goal attainment was significantly related to female gender, age