A Multicentre, Open Study to Assess the Effect of Individualizing Starting Doses of Atorvastatin According to Baseline LDL-C Levels on Achieving Cholesterol Targets: the Achieve Cholesterol Targets Fast With Atorvastatin Stratified Titration (ACTFAST-2) S

By Farsang, C Athyros, V; Gaw, A; de Teresa, Eduardo; Et al

Key words: Atorvastatin – Cardiovascular diseases – Dyslipidaemia – HMG CoA reductase inhibitors – Risk factors – Statins ABSTRACT

Objectives: ACTFAST-2 was designed to match the starting dose of a statin to the baseline low density lipoprotein-cholesterol (LDL- C) value, to allow high-risk European subjects to achieve LDL-C targets within 12 weeks with the initial dose or one up-titration.

Research design and methods: This was a 1 2-week, prospective, open-label trial that enrolled 610 high-risk subjects from 8 European countries. Subjects with LDL-C > 2.6mmol/L (> 100 mg/dL), but

Results: At 12 weeks, 68.0% of subjects overall, including 73.5% of statin-free and 60.5% of statin-treated subjects, achieved LDL-C target (< 2.6 mmol/L (< 100 mg/dL). The total cholesterol/ high density lipoprotein-cholesterol (TC/HDL-C) ratio target was achieved by 75.2% of subjects overall, including 78.1% of statin-free and 71 .2% of statin-treated subjects. In the statin-free group, LDL-C decreased by a mean of 42%. In the statin-treated group, atorvastatin led to an additional 31% reduction in LDL-C over the statin used at baseline. Mean decreases in TC/HDL-C ratio were 30% and 20% in the statin-free and statin-treated groups, respectively. The incidence of AST/ALT greater than 3 times of upper limit of normal range in all patients was 0.8% and no rhabdomyolysls was reported.

Conclusion: This study confirms that use of a flexible starting dose of atorvastatin allows the large majority of high-risk subjects to achieve their LDL-C target safely within 12 weeks with an initial dose or just a single up-titration.

Introduction

Dyslipidaemia is an important cardiovascular risk factor that remains under treated. The European Action on Secondary Prevention by Intervention to Reduce Event (EUROASPIRE) I and II surveys demonstrated increases in the use of lipid lowering treatment and in achievement of lipid targets from the mid-1990s to 2000-2003(1-3). In these surveys the use of lipid lowering treatment doubled over a 5 year period, but treatment and goal attainment remained sub- optimal with only 49% of subjects reaching total cholesterol targets in the later survey3. Surveys in other European countries, including Greece, Hungary, Italy, Spain and Norway, have found that as many as 70-80% of subjects being treated with lipid lowering drugs remain above recommended cholesterol levels4-8.

The low rate of goal attainment in clinical practice may be due in part to ineffective use of statins3,6. Selection of an inappropriate starting dose can impact target achievement. It is common practice to initiate statin treatment at the lowest dose and frequently doses are not titrated up in order to reach the recommended low density lipoprotein-cholesterol (LDL-C) goal9,10.

The Joint European Societies recommend more aggressive lipid- lowering targets for subjects who are at high risk for cardiovascular events11. This makes targets even more difficult to attain in high-risk patient groups. Approaches to more aggressive therapy include starting with a more effective statin, or with a higher starting dose, which will likely achieve treatment goals in 50-80% of patients12.

Intensive lipid-lowering therapy with atorvastatin 80 mg/day provided significant clinical benefit compared with 10 mg/day, in patients with stable coronary heart disease (CHD)13. Atorvastatin can reduce LDL-C levels by 55-60% with the maximum dose of 80 mg and is well tolerated14,15. It has been shown to reduce the incidence of cardiovascular events in both primary and secondary prevention16- 19.

Several studies have shown that high-risk patients were more likely to achieve LDL-C goals safely and effectively with a higher starting dose of atorvastatin, whether or not they were stratified by baseline LDL-C level20,21. ACTFAST-1 suggested that individualizing the starting dose of atorvastatin, according to baseline LDL-C values, would allow a majority of high-risk subjects to achieve LDL-C targets22. ACTFAST-1 and ACTFAST-2 were conducted concurrently to provide data in widely varying patient populations. The patient population in ACTFAST-1 was predominantly Canadian (60%) and Western European, while in ACTFAST-2 the patients were mainly from Northern and Eastern European countries. EUROASPIRE II demonstrated that cardiovascular patients in different European countries are different in terms of the prevalence of cardiovascular risk factors and the use of lipid lowering medications’. For the most part, patients in the European countries included in ACTFAST-2 had a higher prevalence of smoking, obesity and elevated total cholesterol, than those included in ACTFAST-1. In addition, EUROASPIRE II suggested different genetic predispositions for CHD, with patients in the countries included in ACTFAST-2 having a greater prevalence of a family history of premature CHD. Dietary factors also vary substantially from country to country23. Adequate consumption of fruit and vegetables and a Mediterranean diet have been associated with a lower risk of CHD and mortality23,24.

There are also regional differences in the management of dyslipidaemia. In EUROASPIRE II, in general, fewer CHD patients were receiving lipid-lowering medications and were at treatment goal among those in the European countries included in ACTFAST-2 compared with those included in ACTFAST-1(1).

These differences in patient populations and management strategies have a clinical impact as evidenced by the rates of achievement of lipid targets. Surveys in 2 of the European countries that were included in ACTFAST-2 reported that only 21% of high-risk patients in Hungary4 and 22% in Greece5 achieved LDL-C targets, in contrast to 51-64% of high-risk patients achieving targets in Canadian surveys25,26. Therefore, it is important to assess new approaches for the management of dyslipidaemia in a wide variety of patient populations, before the strategy can be accepted as generally efficacious.

A wide variety of patient population and treatment practices exist in European countries. Risk factor prevalence differs and treatment targets may vary from country to country, making it important to assess the value of a flexible starting dose strategy in these different populations3. The objective of ACTFAST-2 was to assess whether a starting dose of atorvastatin matched to the baseline LDL-C value would allow high-risk European subjects to achieve LDL-C targets within 12 weeks with the initial dose or one uptitration.

Methods

Patient population

ACTFAST-2 is a 12-week, multicentre, prospective, open-label trial assessing the effectiveness of using starting doses of atorvastatin that are selected according to the baseline LDL-C value and on the required LDL-C reduction to reach target. Adults, at least 18 years old, were eligible for inclusion if they had been diagnosed with dyslipidaemia defined as LDL-C of > 2.6mmol/L (100mg/ dL) and 20% as per the Framingham tables27. Subjects could be either statin-free or statin-treated at baseline. Subjects had to be willing to follow the National Cholesterol Education Program (NCEP) III multifaceted lifestyle approach (or local equivalent)27.

Subjects were ineligible for the study if they were receiving higher than ‘usual maintenance’ doses of statins defined as 10-40 mg for simvastatin and 20-40 mg for fluvastatin, pravastatin and lovastatin, or were taking atorvastatin, fibrates, niacin or resins that could not be discontinued a minimum of 2 months prior to enrolment. Subjects were excluded if they had suffered from specific systemic diseases including impaired hepatic (defined as aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) >/= 2 times the upper limit of normal) or renal function (creatinine >/= 181 [mu]mol/L), elevation of creatine kinase (CK) level (defined as > 3 times the upper limit of normal), uncontrolled diabetes (haemoglobin A1c, HbA^sub 1c^ > 10%), uncontrolled hypertension (> 160/100 mm Hg) or uncontrolled primary hypothyroidism.

The following medications were prohibited for the duration of the study: all other lipid-lowering medications, psyllium (> 2 tablespoons/day), orlistat, fish oils, terfenadine, strong cytochrome (CYP) 3A4 inhibitors such as macrolide antibiotics, systemic azole antifungals and cyclosporine.

Treatment

Subjects were assigned to 6 weeks of open-label treatment with atorvastatin 10, 20, 40 or 80 mg according to their LDL-C level and prior statin use at baseline, followed by an additional 6-week open- label treatment during which subjects who had not reached target LDL- C levels were titrated to the next highest dose of atorvastatin, according to a predefined titration algorithm, except for those allocated to 80 mg (Table 1). Subjects initially allocated to atorvastatin 80 mg who did not reach LDL-C targets were continued at that dose and a more intense therapeutic lifestyle intervention (NCEP II step 2 diet or equivalent) was recommended27. One week after the screening visit, subjects who had not received statin therapy within 2 months of screening (i.e. statin-free) were allocated to an atorvastatin dose according to their baseline LDL-C level (Table 1). LDL-C concentration in mg/dL was used to determine initial dose assignment and for decision-making regarding dose titration at Week 6. Subjects who had received prior statin therapy (excluding atorvastatin) but whose LDL-C remained above target values (i.e. statin-treated) received double the atorvastatin dose for the same baseline LDL-C level as compared with their untreated counterparts, without any washout period. Subjects with LDL-C between 4.5 and 5.7 mmol/L (170-220 mg/dL) all received the 80 mg dose, regardless of their use or not of a statin at baseline.

Blood samples were obtained at screening, Week 6 and Week 12 for the measurement of 12-h fasting serum lipid profiles, and routine haematology and chemistry measurements that were part of the safety assessment. All cholesterol assays were performed by a central laboratory and direct LDL-C measurement was performed. Subjects received dietary counselling at all visits. The relevant institutional review boards approved the protocol and informed consent was obtained from all subjects. This study was conducted in compliance with the ethical principles of the Declaration of Helsinki28.

Efficacy and safety parameters

The primary efficacy outcome was the proportion of subjects achieving LDL-C levels of < 2.6 mmol/L (< 100 mg/dL) after 12 weeks of treatment (last observation carried forward [LOCF]). Secondary efficacy parameters included the proportion of subjects achieving total cholesterol < 5 mmol/L (< 190 mg/dL), total cholesterol/high density lipoprotein-cholesterol (TC/HDL-C) ratio target (< 4.0) at 6 and 12 weeks and mean percentage change from baseline in TC, LDL-C, HDL-C, TC/HDL-C ratio, non-HDL-C, triglycerides and apo-B at 6 and 1 2 weeks.

Table 1. Study design and initial dose assignment according to baseline LDL-C levels for statin-free and statin-treated subjects

Safety variables included treatment-emergent adverse events defined as any adverse event reported after administration of at least one dose of study medication or that worsened in intensity or frequency after therapy began. Serious adverse events were defined as death or events that were life-threatening, or that required prolonged hospitalization that resulted in persistent or significant disability or congenital anomalies.

Statistical analysis

Based on the results of New Atorvastatin Starting Doses A Comparison (NASDAC)20 where 69% of high-risk subjects achieved LDL- C target, the dose assignment table of ACTFAST-2 was expected to allow 70% of subjects to reach target. With a sample size of 559 patients, a two-sided 95% confidence interval for a single proportion using the large sample normal approximation will extend 3.8% from the observed proportion for an expected proportion of 70%. Based on an estimated 6% dropout rate, the planned total sample size was 595 subjects. This sample size adequately addressed the study hypothesis that atorvastatin treatment would enable subjects to achieve their LDL-C target with either no or just a single titration step.

The intention-to-treat (ITT) population was the primary population for assessing treatment efficacy. If data for a given visit were missing, this was resolved by carrying forward the most recent non-missing on-treatment data (LOCF). The ITT population consisted of all subjects who were assigned a starting dose, took at least one dose of study medication and who had at least one subsequent assessment. The per-protocol population consisted of those subjects who completed the study as per protocol, were exempt from major protocol violations and who were compliant with study treatment. The safety population consisted of all subjects who took at least one dose of study medication.

Categorical efficacy variables are presented as counts and percentages. Continuous variables are summarized as mean, standard deviation and 95% confidence intervals for the mean. No inferential statistical tests were performed. Although allocation of doses was not randomized, data were summarized by initial dose allocation, as well as for all doses combined, where appropriate. Safety parameters were summarized overall and by initial dose allocation. The Steering Committee designed the trial in collaboration with the sponsor, oversaw the conduct of the trial and led the preparation of the manuscript.

Results

Between January 2003 and February 2004, 775 subjects were screened from 50 sites in Greece, Hungary, Ireland, Poland, Portugal, Russia, Slovakia and Switzerland, 610 patients were assigned to the study drug and 579 completed the study. Consequently, the safety population comprised 610 subjects and 600 subjects (98.4%) were included in the ITT population (144 on 10mg [24%], 198 on 20mg [33%], 68 on 40mg [11.3%] and 190 on 80mg [31.7%]). Dosing stratification is summarized in Table 1. A high proportion of patients completed the study: 97%, 94%, 91% and 95% for the 10, 20, 40 and 80 mg doses, respectively.

Subjects included 61% males, with a mean age of 61.2 years and 40% of the study population was over age 65 years. Overall, 22.7% were current smokers, 32.7% had diabetes and 67% had prior CHD (Table 2). There was a lower prevalence of diabetes and smoking and a higher prevalence of CHD in the statin-treated group. The most common concomitant medications used at baseline were beta-blockers and angiotensin converting enzyme (ACE) inhibitors. As expected from the dose assignment scheme based on LDL-C and status of statin use at baseline, the mean baseline TC and LDL-C were significantly lower in the statintreated compared with the statin-free group (Table 3).

Efficacy

Using the LOCF analysis, the primary efficacy parameter, the proportion of subjects achieving LDL-C targets of < 2.6 mmol/L (100 mg/dL) after 12 weeks of treatment, was 68.0% (95%CI 64.3%, 71.7%) overall, and 73.5% (95%CI 68.6, 78.1) and 60.5% (95%CI 54.5, 66.5) for statin-free and statin-treated subjects, respectively (Figure 1). Figure 1 shows the proportion of subjects achieving the LDL-C target according to initial dose and all doses for both the statin- free and statin-treated groups (ITT, LOCF analysis). The proportions of subjects achieving targets in the per protocol population were similar.

Among subjects who achieved target (N = 408), 391 (96%) achieved their LDL-C target with the initial dose by Week 6. Within each treatment group, there were no considerable differences in the proportions of subjects reaching target at Week 6 and Week 12 (Table 4).

The proportions of patients achieving a TC/ HDL-C target of < 4.0 after 12 weeks (LOCF) were 75.2% (95%CI 71.7, 78.6) overall, including 78.1% (95%CI 73.8, 82.5) for statin-free and 71.2% (95%CI 65.7, 77.0) for statin-treated subjects (Figure 2). The proportion of subjects achieving either LDL-C < 2.5 mmol/L (< 96 mg/dL) or TC/ HDL-C < 4.0 after 12 weeks (LOCF) was 82.2% (95%CI 79.1, 85.2) overall, including 85.6% (95%CI 81.9, 89.3) for statin-free and 77.5% (95%CI 72.3, 82.6) for statin-treated subjects. The proportions of subjects achieving both these targets after 12 weeks (LOCF) were 57.0% (95%CI 53.07, 61.0) including 63.1% (95%CI 58.0, 68.2) for statin-free and 48.6% (95%CI 42.5, 54.8) for statin- treated subjects.

Table 2. Baseline characteristics (ITT)

Table 3. Baseline laboratory values (ITT), mean (95%CI)

Table 4. Proportion of subjects achieving LDL-C target at Weeks 6 and 12, in statin-free and statin-treated groups (ITT), mean (95%CI)

Mean percentage changes in LDL-C were significant versus baseline for all doses in both statin-free and statin-treated subjects. Similarly, significant changes from baseline in TC, TC/HDL-C ratio, triglycerides, non-HDL-C and apo-B were observed with all doses in both statin-free and statin-treated subjects (Table 5). The significant reductions in triglyceride levels increased with increasing atorvastatin dose in the statin-free subjects, from 9.9% with 10 mg to 21.9% with 80 mg. In the statin-treated subjects the reductions in triglycerides were not significant in the 20 mg group (3.8%), but were significant in the 40 mg and 80 mg groups, with little difference between the latter two (19.9% and 19.5%, respectively). Overall, changes in HDL-C were minor. However, it is important to note that among subjects with low HDL-C (< 1.03 mmol/ L, < 40 mg/dL) at baseline mean HDL-C level increased by 16.6% (95%CI -14.7, 86.2), 8.9% (95%CI -13.9, 37.1), 10.2% (95%CI -16.2, 22.2), 3.0% (95%CI -22.9, 31.8) in the statin-free 10, 20, 40 and 80 mg groups, respectively and by 4.5% (95%CI -18.4, 30.8), 24.9% (95%CI 8.3, 54.5) and 11.6% (95%CI -8.8, 44.7) in the statin- treated 20, 40 and 80 mg groups, respectively, at study end.

Figure 1. Mean proportion of subjects reaching LDL-C target of < 2.6mmol/L (100 mg/dL) according to starting dose in the statin-free and statin-treated groups (intention to treat (N = 600); hst observation carried forward) at 12 weeks

Figure 2. Mean proportion of subjects reaching TC/HDL-C target of < 4.0 according to starting dose in the statin-free and statin- treated groups (intention to treat [N = 60O]; last observation carried forward) at 12 weeks

The proportion of subjects achieving LDL-C target according to the most common major cardiovascular risk factors at baseline was also analysed (Figure 3). The most common cardiovascular risk factor at baseline was hypertension (N = 435), followed by metabolic syndrome (N= 269) and diabetes (N = 196). In the analysis of statin- free and statin-treated subjects combined, there were no significant differences in the proportion of patients achieving LDL-C target for each of the cardiovascular risk factors (47.8-78.8%), and this was not significantly different from the proportion in the overall group (68.0%). However, fewer patients with hypertension or cerebrovascular disease achieved LDL-C targets in the statin- treated group (60.5% [95%CI 53.6, 67.5] and 54.8% [95%CI 37.3, 72.4], respectively) compared with the statin-free group (74.7% [95%CI 69.3, 80.1] and 92.6% [95%CI 82.1, 97.9], respectively) (Figure 3). The proportion of subjects with diabetes (N= 196) or metabolic syndrome (N = 269) who achieved LDL-C targets (70.9% and 66.9%, respectively) were similar to those without diabetes (N = 404) or metabolic syndrome (N = 328) (66.6% and 68.9%, respectively) and to the proportion in the overall group (68.0%). Safety

Of the 610 subjects who received at least one dose of atorvastatin, 36 (5.9%) experienced at least one treatment-related adverse event (Table 6). The most common treatment-related events with a global incidence >/= 0.5% were: diarrhoea (n = 3, 0.5%), nausea (n = 3, 0.5%), hepatic enzyme increase (n = 5, 0.8%) and myalgia (n = 4, 0.7%). The majority of events were of mild to moderate intensity. Severe adverse events were reported in only four (0.7%) subjects. Overall, only 12 subjects discontinued atorvastatin due to treatment-related adverse events or laboratory abnormalities (n = 10, 1.6% and n = 2, 0.3%, respectively). The most frequently reported adverse events leading to discontinuation of atorvastatin were liver/biliary complaint, headache and laboratory abnormality. Treatment-related adverse events involving the musculoskeletal system occurred in only six (1.0%) subjects, with no case of rhabdomyolysis being reported.

Table 5. Percentage reduction from baseline in lipid parameters at the end of a 12-week study (ITT, LOCF), mean (95%CI)

The incidence of any rise in AST/ ALT > 3 times the upper limit of normal, regardless of causality, was low at 0.8% (n = 5). No cases of creatine kinase > 10 times the upper limit of normal were reported.

Only one treatment-related serious adverse event was reported in a patient on the 80 mg dose. A 69 year old female experienced an increase in hepatic enzymes that was classified as moderate and resolved on discontinuation of atorvastatin therapy. One subject in the 10 mg group died during the study of suspected coronary syndrome, which was deemed, by the investigator, not to be treatment- related.

Discussion

The results of ACTFAST-2 confirm those of ACTFAST-1(22). They show that an appropriate starting dose of atorvastatin, selected according to baseline LDL-C concentration allowed the large majority of high-risk European subjects to achieve their LDL-C target of < 2.6 mmol/L (< 100 mg/dL) safely at initial dose or with a single up- titration. This approach differs from standard practice where statin therapy is initiated at the lowest dose and titrated up over time, without considering the magnitude of LDL-C reduction required for the patient to reach target levels.

ACTFAST-2 was conducted in a European population, while ACTFAST- 1 included mainly Canadians (60%). The demographic and baseline characteristics of the study population of ACTFAST-2 were similar to the population of ACTFAST-1. However, differences in choice of therapy and how aggressively European and North American physicians treat dyslipidaemia may have influenced the composition of patients in ACTFAST-1 and ACTFAST-2, beyond what we can observe from mere demographics. Baseline total cholesterol and LDL-C levels were somewhat higher in ACTFAST-2 compared with ACTFAST-1 (TC 6.1 vs. 5.7 and LDL-C 4.0 vs. 3.7 mmol/L). This may reflect the less frequent use of lipid lowering therapy and the lower rates of lipid target achievement observed in Europe1-3 compared with those seen in Canada. In EUROASPIRE II, the use of lipid lowering medications in high risk patients was about 35-40% in the European countries included in ACTFAST-2, compared with 78% in Canada25. Epidemiological surveys have reported that LDL-C targets were achieved by only 21% of high risk patients in Hungary4 and 22% in Greece5 compared with 51-64% in Canada25,26.

Figure 3. Mean proportion of subjects reaching LDL-C target of < 2.6 mmol/L (100 mg/dL) according to major cardiovascular risk factors at baseline in the statin-free and statin-treated groups (intention to treat; last observation carried forward) at 12 weeks. CHD; coronary heart disease; CVD: cerebrovascular disease; Met. syndrome: metabolic syndrome

Table 6. Overview of safety

A dosing regimen that allows for a larger number of subjects to reach LDL-C target would be expected to significantly improve cardiovascular outcomes, as demonstrated in clinical trials that compared aggressive treatment with atorvastatin to usual care-based regimens17,19. Given the issues with inadequate up-titration of statin doses by physicians, initiating treatment at a higher dose can shorten the time between treatment initiation and achievement of the LDL-C target. Studies demonstrate that for subjects with CHD or acute coronary syndromes, treatment with high-dose statins can result in better clinical outcomes than with usual low doses29. Therefore, the NCEP ATP III recommends more aggressive therapies with more effective or higher doses of statins29, an approach that if adopted, is likely to achieve treatment goals in 50-80% of patients12. Atorvastatin is approved at flexible starting doses ranging from 10 to 40 mg, with titration to 80 mg, if required. Subjects with CHD or CHD-equivalent have the lowest LDL-C target and may require higher doses. Therefore, it is logical to initiate therapy using a dose of atorvastatin that is appropriate for the required LDL-C reduction.

Subjects at high cardiovascular risk have a greater chance of achieving lipid targets with higher doses of atorvastatin. Approximately 32-59% of subjects with CHD or diabetes will achieve lipid targets with a starting dose of atorvastatin of 10 mg20,30- 33, but another 29-51% will go on to achieve targets when atorvastatin is titrated to higher doses30-33. ACTFAST-2 showed that by initiating therapy at doses selected according to baseline LDL-C levels, 68.0% of all subjects, whether statin-free (73.5%) or statin- treated (60.5%), achieved a target LDL-C of < 2.6mmol/L (100 mg/dL) as early as 6-12 weeks. The study population also included 33% of subjects with diabetes and 45% with metabolic syndrome, of which 70.9% and 66.9%, respectively, achieved LDL-C targets. The proportion of subjects achieving the LDL-C target was similar to the 72.0% of subjects in ACTFAST-1(22). This suggests that the lower rate of target achievement in European compared with North American populations (20% vs. 50-60%) does not reflect a more resistant dyslipidaemia, but rather a failure to initiate lipid lowering therapy in those who need treatment and a failure to adequately dose those who are receiving treatment.

The New Atorvastatin Starting Doses A Comparison (NASDAC) was a randomized, double-blind study that included US patients with different CHD risk levels and different LDL-C targets20. The study had an 8-week washout period so all patients were statin-free. Only 63.5% of subjects had CHD or CHD-equivalents compared with 100% in ACTFAST-2. Subjects in NASDAC were randomized to their starting dose without consideration for baseline LDL-C value or degree of LDL-C reduction required, and unlike ACTFAST-2, no up-titration was performed. Despite this, NASDAC also demonstrated the benefits of a higher starting dose in high-risk subjects. There was a greater likelihood of subjects with CHD or CHD-equivalents to reach targets with higher starting doses (over 80% with 40-80 mg) than with lower starting doses (46.5% with 10mg, 66.2% with 20mg)20.

The design of the Atorvastatin Goal Achievement Across Risk Levels (ATGOAL) study was similar to that of the ACTFAST studies21. Both trials were open-label studies in which patients were assigned to an appropriate starting dose of atorvastatin according to their cardiovascular risk and the level of LDL-C reduction required. However, ATGOAL included US patients at various CAD risk level (54% were at high risk vs. 100% in ACTFAST-2) and had an 8-week washout period (so all patients were statin-free). As in ACTFAST-2, up- titration was allowed but study duration was 8 weeks compared with 12 weeks in ACTFAST-2. In ATGOAL, 84.8% of subjects overall, and 81.1% of high-risk subjects achieved the LDL-C targets by Week 8(21). The majority of subjects (84.2%) achieved goals with the starting dose without the need for titration. In ACTFAST-2, 66.2% of subjects achieved LDL-C goals at 6 weeks with the starting dose, including 77% of statin-free and 52% of statin-treated subjects. Few additional patients achieved goal after dose titration in the ACTFAST-2 study, which may be related to the high proportion of uncontrolled statin-treated subjects at baseline in this population.

ACTFAST-2 builds on the data of NASDAC and ATGOAL by including subjects that were statin-treated at baseline, a situation that more closely reflects clinical practice. The dose decision algorithm used in ACTFAST-2 provides a useful tool for physicians to appropriately select the starting dose of atorvastatin that will allow high-risk subjects (either statin-free or statin-treated) to achieve targets with an initial dose or with just one titration step. Studies have shown that these high-risk subjects benefit from aggressive lipid lowering19,34,35 and that they are too frequently under-treated1- 3,25. In addition, ACTFAST-2 has now demonstrated the efficacy of this decision algorithm for dosing atorvastatin in European subjects as opposed to only Americans as in NASDAC or ATGOAL.

Significant reductions in LDL-C can also be obtained with strategies using rosuvastatin or ezetimibe in combination with a statin. In the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial the proportion of patients achieving LDL-C targets at 6 weeks with fixed doses of rosuvastatin 10, 20 or 40 mg were 82%, 89% and 89% and with atorvastatin 10, 20, 40 or 80 mg were 69%, 75%, 85% and 83%, respectively36. In a 6-week trial the proportion of patients achieving LDL-C targets at 6 weeks with fixed dose combination ezetimibe/simvastatin 10/10, 10/20, 10/40 or 10/80 mg were 78%, 82%, 90% and 91%, and with atorvastatin 10, 20, 40 or 80 mg were 47%, 66%, 78% and 85%37. In both of these trials there was a wash-out period so these patients were statin-free at baseline. Whether there would be a benefit of a targeted flexible starting dose strategy with rosuvastatin, ezetimibe/ simvastatin combination or other statins has not yet been investigated. Currently, using higher doses of rosuvastatin is restricted to subjects not responding to lower doses, in many countries. In addition, there would be a cost concern when considering the targeted starting dose strategy if treatment was to be initiated with combined therapy as in the case of ezetimibe/simvastatin therapy. Morbidity and mortality trials with rosuvastatin and ezetimibe are still ongoing. In ACTFAST-2, additional LDL-C reductions of 2540% were observed when subjects treated with another statin at baseline were switched to an atorvastatin dose selected according to their LDL-C level. The flexible start dose regimen of atorvastatin also led to reductions in TC, TC/HDL ratio, triglyceride and apo-B in statin-free subjects, and additional reductions over what was achieved with the prior statin in statin-treated subjects. Reductions generally increased with increasing atorvastatin doses; however, the differences between the 40 mg and 80 mg dose were minor, which may be related to the low patient numbers in the 40 mg groups (n = 39 and 29 in the statin- free and statin-treated groups, respectively).

Elevated triglycerides are a significant risk factor for CHD, with the relative risk of CHD increasing from < 1.0 to > 2.0 as the level of triglycerides increases from 0.6 to 4.5 mmol/L38,39. In addition, the Helsinki Heart Study showed that the combination of high triglycerides and low HDL-C was associated with a very high risk of cardiovascular events. In this study, atorvastatin was associated with significant reductions in triglyceride levels with all doses in the statin-free patients and in additional reductions over prior statin therapy with doses of 40 mg and 80 mg in previously treated subjects. Overall, changes in HDL-C concentrations were small and similar to those observed in other studies16.18,21. However, atorvastatin was associated with increases in HDL-C in all dosing groups among subjects with low HDL-C at baseline (< 1.03 mmol/L, < 40mg/dL), patients who would be at greater risk. In addition, the TC/HDL-C ratio was significantly decreased in all patient groups. Therefore, as well as rapidly lowering LDL-C to target, this atorvastatin dosing strategy may help to correct the very high risk dyslipidaemic profile of high triglycerides and low HDL-C.

In the European guidelines total cholesterol and the ratio of TC/ HDL-C are also used to estimate cardiovascular risk and to define treatment targets11. The dose assignment approach tested in ACTFAST- 2 allowed 75.2% of subjects, whether statin-free or statin-treated, to achieve a target TC/HDL-C ratio of <4.0.

A recent analysis of pooled results from 49 clinical trials of atorvastatin in 14236 subjects found no significant differences in the rate of adverse events and laboratory abnormalities between the 10 mg and 80 mg doses40. In this meta-analysis, withdrawals due to treatment-related adverse events were observed in 2.4%, 1.8% and 1.2% of patients in the atorvastatin 10mg, atorvastatin 80mg and placebo groups, respectively. This is similar to the 1.9% (12 subjects) reported with all doses of atorvastatin in this study. Thus, in accordance with other studies, ACTFAST-2 confirms that atorvastatin 80 mg can be safely used as a starting dose in subjects at high risk for CHD and with a baseline LDL-C between 4.5 and 5.7 mmol/L (175-220 mg/dL)22,34,41,42.

The incidence of AST or ALT levels greater than 3 times the upper limit of normal in ACTFAST-2 was 0.8%, which is comparable to the rates seen in ACTFAST-1 (1.2%), the NASDAC trial (0.7%) and the meta- analysis (0.96%)20,22,43. No cases of an elevation of CK greater than 10 times the upper limit of normal occurred in ACTFAST-2, compared with one case in 2150 subjects in ACTFAST-1, two cases in 919 subjects in NASDAC and no cases in 1295 subjects in ATGOAL20- 22.

Conclusions

Subjects with CHD or CHD-equivalent risk have the lowest LDL-C target (< 2.6 mmol/L, 100 mg/dL) and are likely to require higher doses of statins in order to achieve goal. This study confirms that use of a flexible starting dose of atorvastatin allows the majority of high-risk subjects to achieve their LDL-C target safely within 6- 12 weeks at initial dose or with just a single up-titration. Thus, tailoring the starting dose of atorvastatin according to the required level of LDL-C reduction and status of statin use at baseline provides clinicians with a simple strategy to manage dyslipidaemia and help decrease CHD risk faster and more effectively in high-risk subjects.

Acknowledgements

Declaration of Interest: This study was funded by Pfizer Inc. The authors would like to thank Pauline Lavigne, MSc (CMED, Toronto, Ontario, Canada), for editorial assistance in preparing this manuscript.

Previously presented at: the 75th European Atherosclerosis Society Congress, 23-26 April 2005, Prague, Czech Republic and the Mediterranean Meeting on Hypertension and Atherosclerosis. 14-18 April 2004, Antalya, Turkey.

Joint Steering Committee of ACTFAST 1 & 2 Eduardo de Teresa, Spain; Csaba Farsang, Hungary Allan Gaw, UK; GianFranco Gensini, Italy Anatoly Langer, Canada (Chair); Lawrence A Leiter, Canada; Pierre Martineau, Canada (Pfizer, clinical lead).

ACTFAST 2 investigators: Greece: Athyros VG, Thessaloniki; Elisaf MS, Ioannina; Fousas S, Pireaus; Kolovou G, Athens. Hungary: Gurzo M, Kecskemet; Jozan-Jilling M, Szekszard; Dudas; M, Gyula; Toth K, Budapest; Hajos P, Budapest; Zamolyi K, Budapest; Hankoczy J, Budapest; Polgar P, Nyiregyhaza; Karpati P, Budapest; Rodics K, Budapest; Poor F, Mosonmagyarovar. Ireland: O’Doherty B, Wexford; Fennell W, Cork; Mulcahy DA, Dublin; Shiels P, Offaly; Foley D, Dublin; Crean P, Dublin, Feely J, Dublin; Crowley J, Galway; Baron J, Galway; Maher V, Dublin. Poland: Ruzyllo W, Warszawa; Banasiak W, Wroclaw; Dluzniewski M, Warszawa; Siminiak T, Poznan; Kardaszewicz P, Czestochowa; Kalarus Z, Zabrze; Szwed H, Warszawa. Portugal: Matos MC, Cascais; Goncalves JB, Lisboa; Mendonca C, Vila Franca de Xira; Juliao S, Aveiro; Araujo P, Porto. Russian federation: Kukharchuk W, Moscow; Gratsianski NA, Moscow; Naumov VG, Moscow; Ahmedzhanov NM, Moscow; Shestakova MV, Moscow. Slovakia: Gajdos M, Bratislava; Hricak V, Bratislava; Tkac I, Kosice; Uhliar R, Bratislava. Switzerland: Noll G, Zurich; Mach F, Genave; Allemann Y, Bern; Pagnamenta A, Locamo.

* Clinical trial identification number: NCT00442325 (www.clinicaltrials.gov)

References

1. Anon. 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;22:554-72

2. EUROASPIRE. A European Society of Cardiology survey of secondary prevention of coronary heart disease: principal results [EUROASPIRE Study Group]. European Action on Secondary Prevention through Intervention to Reduce Events. Eur Heart J 1997;18:1569-82

3. Anon. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. EUROASPIRE I and II Group. European Action on Secondary Prevention by Intervention to Reduce Events. Lancet 2001;357:995-1001

4. Mark L, Zamolyi K, Pados G, et al. Achieving the target lipid levels in Hungary, 2004. Orv Hetil 2005;146:147-52

5. Athyros VG, Elisaf M, Mikhailidis DP. Undertreatment of dyslipidaemia in Greece. Atherosclerosis 2004; 177: 215-6

6. Di Martino M, Degli Esposti L, Ruffo P, et al. Underuse of lipid-lowering drugs and factors associated with poor adherence: a real practice analysis in Italy. Eur J Clin Pharmacol 2005;61: 225- 30

7. Garcia Ruiz FJ, Marin Ibanez A, Perez-Jimenez F, et al. Current lipid management and low cholesterol goal attainment in common daily practice in Spain [The REALITY Study], Pharmacoeconomics 2004;22(Suppl 3): 1-12

8. Ose L, Skjeldestad FE, Bakken IJ, et al. Lipid management and cholesterol goal attainment in Norway. Am J Cardiovasc Drugs 2006;6:121-8

9. Marcelino J, Feingold K. Inadequate treatment with HMG-CoA reductase inhibitors by health care providers. Am J Med 1996;100:605- 10

10. Monkman D. Treating dyslipidaemia in primary care. The gap between policy and reality is large in the UK. Br Med J 2000;321:1299-300

11. 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 Heart J 2003;24:1601-10

12. McKenney JM. Pharmacologic options for aggressive low- density lipoprotein cholesterol lowering: benefits versus risks. Am J Cardiol 2005;96:60E-66E

13. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New Engl J Med 2005;352:1425-35

14. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J 2003;326:1423

15. LIPITOR* (atorvastatin calcium) Prescribing Information. Pfizer Inc., March 2007. Available at: www.pfizer.com/hml/pi’s/ lipitorpi.pdf [accessed 29 May 2007] 16. Sever P, Dahlof B, Poulter N, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial – Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003;361:1149-58

17. Koren MJ, Hunninghake DB. Clinical outcomes in managedcare patients with coronary heart disease treated aggressively in lipid- lowering disease management clinics: the Alliance study. J Am Coll Cardiol 2004;44:1772-9

18. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685- 96

19. Athyros V, Papageorgiou A, Mercouris B, et al. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus ‘usual’ care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Curr Med Res Opin 2002;18:220-8

20. Jones PH, McKenney JM, Karalis DG, Downey J. Comparison of the efficacy and safety of atorvastatin initiated at different starting doses in patients with dyslipidemia. Am Heart J 2005;149:e1

21. McKenney JM, Davidson MH, Saponaro J, et al. Use of a treatment algorithm to achieve NCEP ATP III goals with atorvastatin. J Cardiovasc Pharmacol 2005;46:594-9

22. Martineau P, Gaw A, de Teresa E, et al. Effect of individualizing starting doses of a statin according to baseline LDL- cholesterol levels on achieving cholesterol targets: the Achieve Cholesterol Targets Fast with Atorvastatin Stratified Titration (ACTFAST) study. Atherosclerosis 2006;191:135-46

23. Lock K, Pomerleau J, Causer L, et al. The global burden of disease attributable to low consumption of fruit and vegetables: implications for the global strategy on diet. Bull World Health Organ 2005;83:100-8

24. Knoops KT, de Groot LC, Kromhout D, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. J Am Med Assoc 2004;292:1433-9

25. Yan AT, Yan RT, Tan M, et al. Contemporary management of dyslipidemia in high-risk patients: targets still not met. Am J Med 2006;119:676-83

26. Bourgault C, Davignon J, Fodor G, et al. Statin therapy in Canadian patients with hypercholesterolemia: the Canadian Lipid Study – Observational (CALIPSO). Can J Cardiol 2005;21:1187-93

27. NCEP. Executive summary of the 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 IH]. J Am Med Assoc 2001;285:2486-97

28. World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Med Assoc 2000;284:3043-5

29. Grundy S, Cleeman J, Merz C, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: 227-39

30. Brown A, Bakker-Arkema R, Yellen L, et al. Treating patients with documented atherosclerosis to National Cholesterol Education Program-recommended low-density-lipoprotein cholesterol goals with atorvastatin, fluvastatin, lovastatin and simvastatin. J Am Coll Cardiol 1998;32:665-72

31. Andrews T, Ballantyne C, Hsia J, Kramer J. Achieving and maintaining National Cholesterol Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med 2001;111:185-91

32. Aguilar-Salinas C, Gomez-Perez F, Posadas-Romero C, et al. Efficacy and safety of atorvastatin in hyperlipidemic, type 2 diabetic patients. A 34-week, multicenter, open-label study. Atherosclerosis 2000;152:489-96

33. McPherson R, Angus C, Murray P, Genest J. Efficacy of atorvastatin in achieving National Cholesterol Education Program low- density lipoprotein targets in women with severe dyslipidemia and cardiovascular disease or risk factors for cardiovascular disease: the Women’s Atorvastatin Trial on Cholesterol (WATCH). Am Heart J 2001;141: 949-56

34. Nissen S, Tuzcu E, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. J Am Med Assoc 2004;291:1071-80

35. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. J Am Med Assoc 2005;294: 2437-45

36. Jones P, Davidson M, Stein E, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003;92:152-60

37. Ballantyne CM, Abate N, Yuan Z, et al. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J 2005;149:464-73

38. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol 1992;70:3H-9H

39. Onat A, Sari I, Yazici M, et al. Plasma triglycerides, an independent predictor of cardiovascular disease in men: a prospective study based on a population with prevalent metabolic syndrome. Int J Cardiol 2006;108:89-95

40. Newman C, Tsai J, Szarek M, et al. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14236 patients. Am J Cardiol 2006;97: 61-7

41. Cannon C, Braunwald E, McCabe C, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. New Engl J Med 2004;350:1495-504

42. Kinlay S, Schwartz G, Olsson A, et al. High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003;108:1560-6

43. Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of atorvastatin derived from analysis of 44 completed trials in 9416 patients. Am J Cardiol 2003;92:670-6

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-3980_3, Accepted for publication: 20 June 2007

Published Online: 11 July 2007

doi:10.1185/030079907X223242

C. Farsang(a), V. Athyros(b), A. Gaw(c); on behalf of the ACTFAST- 2 investigatorst and Steering Committee members

a First Department of Medicine, Semmelweis University, Budapest, Hungary

b Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece

c University of Glasgow, Glasgow, UK

Address for correspondence: Csaba Farsang MD, DSc, 1st Department of Internal Medicine, Semmelweis University, Budapest VIII, Koranyi S. u. 2/a, H-1083, Hungary. Tel.: +36 1 210 0279; Fax: +36 1 313 0250; e-mail: farsang@bell.sote.hu

[dagger] See acknowledgments for complete list of investigators

Copyright Librapharm Aug 2007

(c) 2007 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.