ATGOAL Poster presented at
EAS (European Atherosclerosis Society)
15 January 2004 in Seville, Spain

James McKenney¹, Michael Davidson², Joseph Saponaro³, Paul Thompson⁴, and Harold Bays⁵ prepared this poster for the ATGOAL investigators.
¹National Clinical Research Inc, Richmond, VA, USA, ²Rush-Presbyterian-St Luke's Medical Center, Chicago, IL, USA, ³Drug Study Institute, Jupiter, FL, USA, ⁴Hartford Hospital, Hartford, CT, USA, ⁵Louisville Metabolic and Atherosclerosis Research Center, Louisville, KT

INTRODUCTION
In their latest guidelines, the Joint European Societies and the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III recommend more aggressive low density lipoprotein cholesterol (LDL-C) treatment goals in certain patient groups than previously endorsed.^1,2 This trend for target goals for LDL-C to move progressively downward with the accumulation of convincing clinical data, creates a genuine concern that the gap between theory and clinical practice will widen and that the under-treatment of hypercholesterolemia in CHD patients and those at risk of developing CHD will become even more prevalent. Evidence suggests that a major underlying reason that many hyperlipidemic patients do not achieve LDL-C treatment goals is the failure of Physicians to select the appropriate starting dose of statin medication or to aggressively titrate upwards. In patients who require large reductions in LDL-C, attainment of target levels is particularly poor. The NCEP ATP III guidelines advise that in those individuals requiring large reductions in LDL-C, rather than administering a statin at its usual starting dose, therapy should be initiated at higher doses commonly used in clinical trials.¹ In 2002, the US Food and Drug Administration (FDA) approved a label change for atorvastatin-the current recommended starting doses are 10 mg or 20 mg once daily, while patients who require a larger reduction in LDL-C (>45%) may be started at 40 mg once daily.³ If necessary, starting doses can be titrated up to 80 mg to achieve the LDL-C target. The Atorvastatin Goal Achievement Across Risk Levels (ATGOAL) Study was designed to determine whether the attainment of LDL-C goals can be improved by initiating atorvastatin at a dose selected according to a patient's cardiovascular risk and the level of LDL-C reduction required.

METHODS

Study design
ATGOAL was an eight-week, multicenter, open-label, single-step titration trial. Study subjects were male and female (postmenopausal, surgically sterilized, or using a reliable method of birth control) subjects, aged 18 to 80 years. To qualify for randomization, participants had to have a diagnosis of dyslipidemia and be candidates for lipid-lowering therapy according to NCEP ATP III criteria. In addition it was required that LDL-C (?220 mg/dL (5.6 mmol/L) and triglycerides (TG) (?600 mg/dL (6.8 mmol/L), at baseline. After an eight-week washout period, eligible patients were assigned to four weeks of open-label treatment with atorvastatin 10, 20, 40 or 80 mg via a predefined treatment algorithm which depended on baseline LDL-C value and LDL-C reduction needed to achieve goal according to cardiovascular risk category (Table 1). Further analysis showed that 75.8% of all patients had achieved the LDL-C target level at Week 2. In the low-, medium- and high-risk groups LDL-C goal attainment after two weeks was 88.3%, 80.2% and 68.4%, respectively. The effects of atorvastatin on lipid parameters are presented in Table 3. As expected from the more frequent use of higher doses, the mean percent changes in LDL-C, TC and TG were greater in the high-risk group than in the medium- and low-risk groups. Changes from baseline in HDL-C were small in all groups.

Safety
Atorvastatin was well tolerated across all risk categories. The majority of adverse events (AEs) were considered to be of mild or moderate intensity by investigators. Serious AEs were experienced by 22 patients — two (0.6%) in the low-risk group, three (1.2%) in the medium-risk group and 17 (2.4%) in the high-risk group. None of these serious AEs were considered to be treatment related. Discontinuations due to treatment-related AEs were low (3.2%). Clinically meaningful elevations (>3xULN) in liver transaminases were infrequent (AST, 0.4%; ALT, 0.7%). No clinically meaningful elevations (>10xULN) in CPK were reported.

CONCLUSIONS
The ATGOAL study has shown that majority of subjects, when treated with an appropriate starting dose of atorvastatin based on risk category and baseline LDL-C, achieved the LDL-C target level by Week 4. Atorvastatin was safe and well tolerated across all risk groups. Levels of LDL-C goal attainment observed in the ATGOAL study are markedly higher than those reported in surveys of current clinical practice in both Europe and the U.S., 4,5 particularly among patients at highest risk of future cardiovascular events. Our data suggest that tailoring an individual's treatment to the most appropriate starting dose of atorvastatin may allow rapid and more widespread attainment of LDL-C goals without additional risk.

REFERENCES

1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. NIH Publication No. 02-5215. September, 2002.
2. De Backer G, Ambrosioni E, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on cardiovascular disease prevention in clinical practice. Eur J Cardiovasc Prev Rehabil 2003; 10(Suppl 1): S1-S78.
3. Pfizer Inc. Lipitor United States Product Insert. Available at: http://www.pfizer.com/hml/pi's/lipitorpi.pdf. Accessed March 23, 2004.
4. EUROASPIRE II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II Euro Heart Survey Programme. Eur Heart J 2001; 22: 554-572.
5. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP). A multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000; 160: 459-467.<.li>

Baseline LDL-C Cardiovascular Risk Category (number of risk factors, 10-year risk)
LOW MEDIUM HIGH
(0-1, NA) (2+, <10%) (2+, 10-20%) (CHD, >20%)
100-129 mg/dL
(2.6-3.4 mmol/L) NA NA NA 10
130-139 mg/dL
(3.4-3.6 mmol/L) NA NA 10 10
140-149 mg/dL
(3.6-3.9 mmol/L) NA NA 10 10
150-159 mg/dL
(3.9-4.1 mmol/L) NA NA 10 20
160-169 mg/dL
(4.1-4.4 mmol/L) 10 10 10 40
170-179 mg/dL
(4.4-4.6 mmol/L) 10 10 10 80
180-189 mg/dL
(4.7-4.9 mmol/L) 10 10 20 80
190-220 mg/dL
(4.9-5.7 mmol/L) 10 20 20 80

Target LDL-C <160 mg/dL <130 mg/dL <130 mg/dL <100 mg/dL
(<4.1 mmol/L) (<3.4 mmol/L) (<3.4 mmol/L) (<2.6 mmol/L)
NA = Not applicable Table 1: Treatment algorithm giving starting dose of atorvastatin (in mg) according to cardiovascular risk category and baseline LDL-C level
Overall Risk Groups
92%
88%
79%
n/N
1049/12,446
At LDL-C goal
Not at LDL-C goal
Medium
n/N
212/242
High
n/N
532/672
Low
n/N
305/332
84%
Figure 1: Percentage of subjects attaining LDL-C goal at Week 4

Demographic/Baseline Risk Category
Characteristic
Low Medium High Total
(N = 338) (N=252) (N=705) (N=1295)
Mean age, years (SD) 55.1 (11.0) 58.8 (10.4) 61.6 (10.3) 59.4 (10.8)
Gender, n (%)
Male 119 (35.2) 190 (75.4) 437 (62.0) 746 (57.6)
Female 219 (64.8) 62 (24.6) 268 (38.0) 549 (42.4)
Race, n (%)
White 289 (85.5) 224 (88.9) 582 (82.6) 1095 (84.6)
Black 23 (6.8) 16 (6.3) 50 (7.1) 89 (6.9)
Hispanic 18 (5.3) 8 (3.2) 62 (8.8) 88 (6.8)
Asian 8 (2.4) 2 (0.8) 6 (0.9) 16 (1.2)
Other 0 2 (0.8) 5 (0.9) 7 (0.5)

Medical History, n (%)
Previous MI 0 0 145 (20.6) 145 (11.2)
Angioplasty 0 0 137 (19.4) 74 (32.0)
CABG 0 0 97 (13.8) 97 (7.5)
Type 2 diabetes 0 0 309 (43.8) 309 (23.9)
Hypertension 84 (24.9) 150 (59.5) 507 (71.9) 741 (57.2)
Mean lipid levels, mg/dL (mmol/L)
LDL-cholesterol 187 (4.8) 176 (4.6) 160 (4.1) 170 (4.4)
Total cholesterol 263 (6.8) 251 (6.5) 236 (6.1) 246 (6.4)
HDL-cholesterol 52 (1.3) 43 (1.1) 43 (1.1) 45 (1.2)
Triglycerides 176 (2.0) 207 (2.3) 201 (2.3) 195 (2.2)
LDL-cholesterol/HDL-cholesterol* 3.8 4.3 4.0 4.0
* The LDL-cholesterol/HDL-cholesterol ratio has no units
SD, standard deviation; MI, myocardial infarction; CABG, coronary artery bypass graft; LDL, low density lipoprotein; HDL, high density lipoprotein
Table 2: Demographic and baseline characteristics
Risk Category
Low Medium High Total
(N=332) (N=242) (N=672) (N=1246)
LDL-cholesterol -38.2 -37.3 -44.2 -41.2
Total cholesterol -29.2 -29.4 -35.4 -32.6
HDL-cholesterol -1.9 +1.9 -3.0 -1.7
Triglycerides -16.5 -19.3 -26.0 -22.2
LDL, low density lipoprotein; HDL, high density lipoprotein
Table 3: Mean percentage change in lipid parameters from baseline to Week 4
Subjects who attained their target LDL-C by Week 4 remained on their starting dose for the duration of the study. Subjects who had not attained their target LDL-C by Week 4 received the next highest dose for the final 4 weeks of treatment, with the exception of subjects initially assigned to take 80 mg/day, who remained on that dose.

Evaluation of Efficacy and Safety

• For the purpose of analysis, risk categories were defined as:
• Low: ?1 CHD risk factor or ?2 risk factors with 10-year CHD risk <10%
• Medium: ?2 risk factors with 10-year CHD risk 10-20%
• High: Existing CHD or CHD equivalent or ?2 risk factors with 10-year CHD risk >20%.
• Efficacy analyses were performed on an intent-to-treat (ITT) population, which consisted of all subjects who had at least one post-baseline measurement and who were not at the LDL-C goal at baseline. The primary efficacy parameter was the percentage of patients achieving LDL-C goal after 8 weeks of treatment. Secondary efficacy parameters included:
• Percentage of subjects achieving LDL-C goal after 2 and 4 weeks of treatment
• Mean percent changes from baseline in LDL-C, TC, TG, high density lipoprotein cholesterol (HDL-C), non-HDL-C and LDL-C/HDL-C ratio after 2, 4 and 8 weeks of treatment. The safety of each dose of atorvastatin was assessed in all randomized subjects who received at least one dose of study medication.

RESULTS

Study disposition
• A total of 1298 subjects at 68 sites in the US were enrolled in the study with 1295 subjects receiving study medication (Low risk, n=338; Medium risk, n=252; High risk, n=705). Of the 1295 subjects that received atorvastatin, 1206 (93.1%) completed the study and 89 (6.9%) discontinued prematurely. Overall, 54 subjects discontinued due to an adverse event (AE); in 42 of these individuals the AE was considered to be related to treatment. The ITT population consisted of 1283 individuals (Low risk, n=335; Medium risk, n=249; High risk, n=699). Efficacy data after four weeks was obtained from 1246 subjects (Low risk, n=332; Medium risk, n=242; High risk, n=672). All 1295 subjects that received atorvastatin were evaluated for safety.

Demographic and Baseline Characteristics
• Demographic and baseline characteristics of the study participants are shown in Table 2. Predictably, mean age increased with escalating risk across groups, and again not surprisingly, there were more males than females in the high- and medium-risk groups, by risk definition. Mean baseline LDL-C and TC levels decreased with increasing risk across groups, while mean baseline HDL-C levels, were higher in the low-risk group than in the medium- and high-risk groups.

Efficacy
• For the purposes of this poster, four-week efficacy data are presented. After four weeks, 1049/1246 (84.2%) subjects had reached the NCEP III LDL-C target. Corresponding values for the low-, medium- and high-risk groups were 305/332 (91.9%), 212/242 (87.6%) and 532/672 (79.2%), respectively (Figure 1). Although not presented here, these levels of LDL-C goal attainment were sustained at Week Eight.