Changing lipid-lowering guidelines: whom to treat and how low to go

European Heart Journal Supplements (2005) 7 (Supplement A), A12 A19 doi:10.1093/eurheartj/sui003 Changing lipid-lowering guidelines: whom to treat and how low to go C.M. Ballantyne Section of Atherosclerosis, Baylor College of Medicine, 6565 Fannin Street, MS A601, Suite A656, Houston, TX 77030, USA KEYWORDS Statins; Low-density lipoprotein; Coronary heart disease; C-reactive protein; Adult Treatment Panel III guidelines Introduction The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for reducing coronary heart disease (CHD) risk published in 2001 contained a number of important changes from prior lipid-lowering guidelines. 1,2 These included an increased focus on global risk in risk assessment and in determining intensity of therapy; attention to risk factors other than low-density lipoprotein cholesterol (LDL-C), including non-high-density lipoprotein cholesterol (non-hdl-c) as a secondary target of therapy in individuals with elevated triglycerides; identification of the metabolic syndrome as Corresponding author. Tel: þ1 713 798 5034/790 5800; fax: þ1 713 798 3057. E-mail address: cmb@bcm.tmc.edu Results of recent lipid-lowering statin trials, including the Heart Protection Study (HPS), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER), Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL), and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT), have provided compelling evidence that both low-density lipoprotein cholesterol (LDL-C) cut-points for initiation of lipid-lowering treatment and LDL-C treatment goals in patients at high or moderately high risk of coronary heart disease have been set too high. This evidence has resulted in recent revisions to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, including recommendations for initiation of therapy in high risk patients with LDL-C 100 mg/dl (2.6 mmol/l); optional initiation of therapy in very high risk patients with LDL-C, 100 mg/dl, with an optional target of LDL-C, 70 mg/dl (1.8 mmol/l); and optional initiation of therapy in moderately high risk patients with LDL-C of 100 129 mg/dl (2.6 3.3 mmol/l), with an optional target of, 100 mg/dl. It is also recommended that lipid-lowering therapy in patients with high or moderately high risk be initiated at an intensity sufficient to produce a 30 40% reduction in LDL-C. Results of ongoing statin trials examining the effects of treatment to low LDL-C targets on clinical events will soon be available, and these will help to further refine optimal therapeutic goals. a secondary target of therapy; and a new definition of the highest risk category to include CHD risk equivalents, such as diabetes, other atherosclerotic disease, and a 10-year CHD risk. 20% conferred by the presence of multiple risk factors. This latter high-risk category was assigned a treatment goal of LDL-C, 100 mg/dl (2.6 mmol/l), representing a significant change from the prior goal of 100 mg/dl (Table 1 ). In essence, this change was an acknowledgement that simply reaching a level of 100 mg/dl was not enough, and that additional risk reduction was to be gained with further LDL-C reduction. Although there were no data available from clinical trials that directly addressed whether reductions to well below 100 mg/dl would be of additional benefit (indeed, there was little direct evidence that 100 mg/dl should be a target), there was substantial indirect support for such a target level. The authors of the ATP & The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Changing lipid-lowering guidelines A13 Table 1 NCEP ATP III LDL-C goals and cut-points for lipid-lowering drug therapy according to risk category 2001 guidelines Risk category Consider drug therapy 2001 guidelines LDL-C goal 2001 guidelines High risk: CHD or CHD risk equivalents, 10-year risk.20% 130 mg/dl (3.4 mmol/l),100 mg/dl (2.6 mmol/l) Drug optional at 100 129 mg/dl (2.6 3.3 mmol/l) Moderately high risk: 2þ risk factors, 10-year risk 10 20% 130 mg/dl (3.4 mmol/l),130 mg/dl (3.4 mmol/l) Moderate risk: 2þ risk factors, 10-year risk,10% 160 mg/dl (4.1 mmol/l),130 mg/dl (3.4 mmol/l) Lower risk: 0 1 risk factor 190 mg/dl (4.9 mmol/l),160 mg/dl (4.1 mmol/l) Drug optional at 160 189 mg/dl (4.1 4.8 mmol/l) Adapted from NCEP ATP III. 1 Figure 1 Major vascular event rate and event rate ratio for statin vs. placebo treatment in patients in the Heart Protection Study. Shown at bottom right is event rate ratio (95% confidence interval) and P value for comparison among all patients. (Adapted with permission from the Heart Protection Study Collaborative Group. 3 ) III guidelines were aware that a number of trials were under way that would provide more direct evidence on the question of treatment targets. Some of these trials have been completed and have indeed contributed to the recognition that optimal LDL-C levels are likely well below 100 mg/dl in high risk patients. Precisely how low the LDL-C target, or other atherogenic lipid targets, should be set in both high risk and lower risk patients remains to be determined. Recent clinical trial evidence: do lower LDL-C levels provide better outcomes? The results of the Heart Protection Study (HPS) 3 were reported months after the publication of the ATP III guidelines and, in the opinion of many, immediately rendered some parts of those guidelines obsolete. This trial enrolled patients aged 40 80 years with increased risk for CHD death due to prior disease (myocardial infarction [MI] or other CHD, occlusive disease of non-coronary arteries, diabetes, or treated hypertension) who had total cholesterol.135 mg/dl (3.5 mmol/l) and in whom statin therapy was not considered clearly indicated or contraindicated by the patient s physician. The trial included many patients who had initial LDL-C levels below 100 mg/dl i.e. patients who would be considered to be already at high risk target levels and thus would not be considered candidates for lipid-lowering therapy. However, as shown in Figure 1, treatment with simvastatin 40 mg resulted in significant benefit vs. placebo in preventing major vascular events among patients with initial LDL-C levels,100 mg/dl. This preventive benefit was similar to that observed in patients with higher initial LDL-C levels. Consistent results were obtained from the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA), 4 which indicated that patients with more moderate risk who would not necessarily be considered candidates for lipid-lowering therapy derived significant protective benefit from statin treatment. In the lipidlowering arm, 10 305 hypertensive patients who had three or more other cardiovascular risk factors and total cholesterol 250 mg/dl (6.5 mmol/l) received atorvastatin 10 mg or placebo. The mean LDL-C at baseline was 133 mg/dl (3.4 mmol/l) in both treatment groups, just above the ATP III target levels for therapy in both moderately high risk and moderate risk patients (,130 mg/dl [3.4 mmol/l]), just above the threshold for initiating drug therapy in patients with moderately high risk (130 mg/dl [3.4 mmol/l]), and well below the threshold for initiating drug therapy in those with moderate risk (160 mg/dl [4.1 mmol/l]). Thus, many of the patients in this trial also would not have been considered candidates for statin or other lipid-lowering therapy. The trial was designed for an average follow-up of 5 years but was stopped early, at a median follow-up of 3.3 years, because a significant difference in rates of CHD events

A14 C.M. Ballantyne (CHD death or non-fatal MI, including silent MI) clearly favored the atorvastatin group (1.9 vs. 3.0% in the placebo group, 36% reduction, P ¼ 0.0005), with a 35% decrease in LDL-C vs. placebo. The event rate in the placebo patients suggests a 10-year CHD risk similar to that in the ATP III moderate-risk category. These findings thus raise questions about whether the LDL-C cut-points for initiating therapy and the therapeutic targets for the moderately high risk and moderate-risk categories were also set too high in the ATP III guidelines. Other recent studies have also indicated the benefits of treating patients to below ATP III LDL-C targets, with each of these comparing two statin regimens: pravastatin 40 mg, which was supposed to have superior pleiotropic effects, and atorvastatin 80 mg, designed to provide maximal LDL-C lowering. Two of these trials, Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) and Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL), used surrogate endpoints to assess effects of statin treatment. In ARBITER, 5 161 patients who met the ATP II criteria for lipid-lowering therapy (46% had known cardiovascular disease) were randomized to pravastatin 40 mg or atorvastatin 80 mg for 1 year and were assessed for changes in carotid intima media thickness (IMT) using B-mode ultrasound. Baseline LDL-C levels were 155 mg/ dl in the pravastatin group and 148 mg/dl in the atorvastatin group; at 12 months, these had been reduced to 76 mg/dl (2.0 mmol/l; 48.5% reduction) in the atorvastatin 80 mg group and 110 mg/dl (2.8 mmol/l; 27.2% reduction) in the pravastatin group (P, 0.001). The inflammatory marker C-reactive protein (CRP) was also found to be reduced more by atorvastatin treatment from 4.3 to 2.1 mg/l, compared with a reduction from 4.0 to 3.6 mg/l with pravastatin (P ¼ 0.005). At 12 months, mean IMT had increased by 0.025 + 0.017 mm in the pravastatin group and decreased by 0.034 + 0.021 mm in the atorvastatin group (P ¼ 0.03). Although these changes in IMT are small, carotid ultrasound studies have indicated that changes of this order of magnitude can be accompanied by significant reductions in cardiovascular events. 6 In REVERSAL, 7 intravascular ultrasound (IVUS) was used to quantify atheroma volume in 654 CHD patients randomized to receive pravastatin 40 mg or atorvastatin 80 mg over 18 months. LDL-C was reduced from a mean of 150 mg/dl (3.89 mmol/l) in both groups to 110 mg/dl (2.85 mmol/l; 25.2% decrease) in the pravastatin group and to 79 mg/dl (2.05 mmol/l, 46.3% decrease) in the atorvastatin group (P, 0.001) (Figure 2 ); CRP was also Figure 2 Changes in lipids (A) and in measures of atheroma burden (B) at 18 months among patients receiving pravastatin 40 mg or atorvastatin 80 mg in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. (Adapted with permission from Nissen et al. 7 )

Changing lipid-lowering guidelines A15 reduced significantly more in the atorvastatin group (36.4 vs. 5.2%, P, 0.001). For the primary study endpoint (Figure 2 ), percentage change in atheroma volume at 18 months was 20.4% in the atorvastatin group, suggesting a non-significant trend toward regression, vs. 2.7% in the pravastatin group, indicating statistically significant disease progression (P ¼ 0.02 for the difference between groups; 502 patients with follow-up). The Pravastatin or Atorvastatin Evaluation and Infection Therapy trial (PROVE IT) was a cardiovascular event endpoint study demonstrating that reduction of LDL-C to levels well below 100 mg/dl with atorvastatin 80 mg was associated with significant benefit in preventing death or major cardiovascular events compared with pravastatin 40 mg, even though the mean LDL-C level in the pravastatin 40 mg group was reduced to within the ATP III treatment target range. 8 In this trial, 4162 patients who had been hospitalized for an acute coronary syndrome within the past 10 days received atorvastatin or pravastatin and were followed up for 18 to 36 months (mean, 24 months) for the composite primary endpoint of death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization (performed 30 days after randomization), or stroke. This patient population (recent acute coronary syndrome) differs from that included in other major statin clinical event endpoint trials; in addition, the primary endpoint in this trial was broader (i.e. allcause mortality and major cardiovascular events) than that used in other trials to assess CHD-preventive effects for example, the use of a primary endpoint of total mortality in the Scandinavian Simvastatin Survival Study (4S). Median LDL-C levels were reduced from 106 mg/dl (2.74 mmol/l) in both groups to 95 mg/dl (2.46 mmol/l) in the pravastatin group and 62 mg/dl (1.60 mmol/l) in the atorvastatin group (P, 0.001), with the latter being the lowest LDL-C level achieved in a clinical trial group thus far. Median CRP levels were reduced from 12.3 mg/l early after acute coronary syndrome in both groups to 2.1 mg/l in the pravastatin group and 1.3 mg/l in the atorvastatin group at a mean 24-month follow-up (P, 0.001). Kaplan Meier estimates of primary endpoint rates at 2 years were 26.3% in the pravastatin group vs. 22.4% in the atorvastatin group, representing a 16% reduction in hazard ratio for the endpoint with atorvastatin treatment (P ¼ 0.005, 95% confidence interval 5 26%) (Figure 3 ). The benefit of the intensive atorvastatin regimen was evident after 30 days and was consistent thereafter. With regard to some of the secondary endpoints, significant preventive effects for atorvastatin treatment were observed for risk of CHD death, MI, or revascularization (19.7 vs. 22.3%, 14% reduction, P ¼ 0.029) and risk of all-cause death, MI, or urgent revascularization (25% reduction, P, 0.001). There was a consistent pattern of benefit for atorvastatin treatment for the individual components of the composite primary endpoint, although not all comparisons reached significance. Modifications to ATP III guidelines On the basis of evidence provided by the above trials and other clinical trial data, the NCEP has proposed changes to the ATP III guidelines (Table 2 ). 9 For patients at very high risk, based on risk assessment, an LDL-C goal of,70 mg/dl (1.8 mmol/l) is considered a therapeutic option. Patients with very high risk can be considered to be those with established atherosclerotic cardiovascular disease who have multiple risk factors (especially diabetes), severe and poorly controlled risk factors (e.g. ongoing cigarette smoking), or acute coronary syndromes. In high-risk patients, initiation of drug therapy is recommended at LDL-C levels 100 mg/dl (2.6 mmol/l); initiation of drug treatment at an initial LDL-C of,100 mg/dl with a target of,70 mg/dl is Figure 3 Risk of primary endpoint (death or major cardiovascular event) among patients receiving pravastatin 40 mg or atorvastatin 80 mg in the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) trial. (Adapted with permission from Cannon et al. 8 )

A16 C.M. Ballantyne Table 2 Recommended revision to NCEPATP III LDL-C goals and cut-points for lipid-lowering drug therapy according to risk category (changes in update shown in italics) Risk category Consider drug therapy 2004 update LDL-C goal 2004 update High risk: CHD or CHD risk equivalents, 10-year risk.20% 100 mg/dl (2.6 mmol/l),100 mg/dl (2.6 mmol/l),100 mg/dl (2.6 mmol/l) optional in very high risk,70 mg/dl (1.8 mmol/l) optional in very high risk Moderately high risk: 2þ risk factors, 10-year risk 10 20% 130 mg/dl (3.4 mmol/l),130 mg/dl (3.4 mmol/l) also considered an option in patients at very high risk. For patients at moderately high risk (two or more risk factors conferring a 10 20% 10-year risk), LDL-C, 100 mg/dl is considered an optional treatment goal, and initiation of drug treatment at LDL-C levels of 100 129 mg/dl is now considered an option. It should be noted that the ATP III non-hdl-c goals in patients with elevated triglycerides after achieving target LDL-C, set at 30 mg/dl above the LDL-C target, are maintained; thus, in a patient with elevated triglycerides and a target LDL-C of,70 mg/dl, the target non-hdl-c is,100 mg/dl. The guideline modifications also recommend that when lipid-lowering therapy is to be employed in high risk or moderately high risk patients, intensity of therapy should be sufficient to achieve at least a 30 40% reduction in LDL-C. Results of additional trials addressing the question of optimal LDL-C reductions are expected soon. These include the Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL) trial (publication expected in 2005), the Treating to New Targets (TNT) trial (late 2005), and the Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine (SEARCH) (2005 or later). Findings from these trials are likely to result in additional modifications of current guidelines. Achieving recommended lipid levels With the renewed and continued focus on achieving lower LDL-C levels in at-risk patients, the ability of currently available lipid-lowering agents to provide the needed reductions becomes an important issue. The NCEP committee reporting the modifications to the ATP III guidelines provides a table showing estimated doses of available statins required to achieve a 30 40% reduction in LDL-C, based on package inserts for each drug, as follows 9 : lovastatin 40 mg, 31% reduction; pravastatin 40 mg, 34% reduction; simvastatin 20 40 mg, 35 41% reduction; fluvastatin 40 80 mg, 25 35% reduction; atorvastatin 10 mg, 39% reduction; and rosuvastatin 5 10 mg, 39 45% reduction (the starting Drug optional at 100 129 mg/dl (2.6 3.3 mmol/l),100 mg/dl (2.6 mmol/l) optional Moderate risk: 2þ risk factors, 10-year risk,10% 160 mg/dl (4.1 mmol/l),130 mg/dl (3.4 mmol/l) Lower risk: 0 1 risk factor 190 mg/dl (4.9 mmol/l),160 mg/dl (4.1 mmol/l) Drug optional at 160 189 mg/dl (4.1 4.8 mmol/l) Adapted from Grundy et al. 9 Figure 4 LDL-C reductions from baseline after 6 weeks by dose of rosuvastatin, atorvastatin, simvastatin, and pravastatin in the Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. (Adapted with permission from Jones et al. 10 ) rosuvastatin dose is 10 mg). The relative efficacy of widely used statins across their dose ranges is indicated by results of the comparative Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin (STELLAR) trial. 10 In this study, 2431 patients with LDL-C 160 and,250 mg/dl and triglycerides,400 mg/dl were randomized to receive rosuvastatin, atorvastatin, simvastatin, or pravastatin across their dose ranges for 6 weeks. As shown in Figure 4, the 46% reduction in LDL-C achieved with rosuvastatin 10 mg was similar to the reductions achieved with atorvastatin 20 mg (43%) and 40 mg (48%) and with simvastatin 80 mg (46%), and it was significantly greater than the reductions achieved with atorvastatin 10 mg; simvastatin 10, 20, or 40 mg; and pravastatin 10, 20, or 40 mg. Other potential targets of lipid-lowering treatment Future lipid-lowering guidelines may also focus more attention on other lipid and non-lipid parameters,

Changing lipid-lowering guidelines A17 Figure 5 Effects of rosuvastatin or atorvastatin 10 mg (8 weeks) and 20 mg (16 weeks) on LDL-C and CRP in A randomized, Double-blind, double-dummy, multicentre phase IIIb parallel group study to compare the efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atorvastatin (10 Mg and 20 mg) in subjects with type II DiAbetes mellitus (ANDROMEDA) trial. (Data are from Betteridge et al. 12 ) particularly inflammation-related risk factors for CHD. The role of inflammation in atherosclerosis has been the subject of increasing research. 11 The inflammatory marker CRP has been identified as a predictor of cardiovascular disease, and there has been considerable interest in ascertaining whether reductions in CRP are associated with reduced CHD risk. Part of the rationale underlying the PROVE IT trial was that the welldocumented pleiotropic effects of pravastatin would outweigh the clinical benefit of additional LDL-C reduction achieved with high-dose atorvastatin; however, the results indicated that the superior LDL-C-lowering regimen was superior in preventing clinical disease. Although the anti-inflammatory effects of pravastatin might have been expected to provide greater reductions in CRP levels, atorvastatin produced significantly greater CRP reductions than pravastatin in PROVE IT, ARBITER, and REVERSAL. The recently reported A randomised, Double-blind, double-dummy, multicentre phase IIIb parallel group study to compare the efficacy and safety of Rosuvastatin (10 mg and 20 mg) and atorvastatin (10 Mg and 20 mg) in subjects with type II DiAbetes mellitus (ANDROMEDA) 12 compared the effects of rosuvastatin and atorvastatin in reducing LDL-C, other lipid measures, CRP, and other inflammatory markers in 509 patients with diabetes and triglycerides 531 mg/dl (6.0 mmol/l). Patients received each drug at 10 mg for 8weeksandat20mgforafurther8weeks.Asshownin Figure 5, rosuvastatin reduced LDL-C significantly more than atorvastatin at both time points. Rosuvastatin also reduced CRP more than atorvastatin at both time points, although the differences between treatments were not statistically significant; however, the CRP reductions mirrored those in LDL-C, with an apparent dose response relationship. Additional investigation of the role of CRP as a target of therapy and as a potential causative factor in atherosclerotic disease is needed. Other potential risk factors and targets of therapy that are receiving increasing attention are apolipoprotein B (apo B) and non-hdl-c. Many patients at risk for CHD Table 3 Therapeutic goals for LDL-C and potential goals for non-hdl-c and total apo B a NCEP ATP III risk category Goal (mg/dl) LDL-C Non-HDL-C Total apo B High risk,100,130,90,70 optional,100 optional Moderately,130,160,110 high risk,100 optional Moderate risk,130,160,110 Lower risk,160,190,130 a LDL-C goals are those currently recommended by ATP III. Non- HDL-C goals are those currently recommended as secondary targets in patients with triglycerides of 200 500 mg/dl. (Adapted from Grundy et al. 13 ) have elevated levels of small, dense LDL particles, which may not be accurately reflected in LDL-C level, and increased levels of triglyceride-rich remnant lipoproteins, including very low density lipoprotein (VLDL) remnants and intermediate-density lipoprotein (IDL) particles. Apo B level provides a measure of all atherogenic particles. Non-HDL-C, which serves as a measure of all apo B-100-containing lipoproteins, may be calculated from measurements already available in the standard lipid panel (total cholesterol level minus HDL-C level) and correlates well with specific measurement of apo B, which is not yet widely available in clinical practice. Because they include all atherogenic lipoproteins, apo B and/or non-hdl-c levels might provide useful primary goals of lipid-lowering therapy. Corresponding levels of the current primary target of LDL-C, the secondary target of non-hdl-c for patients with high triglycerides, and proposed apo B targets are shown in Table 3. 13 There is some evidence that achieving apo B targets is even more difficult than achieving LDL-C

A18 C.M. Ballantyne Figure 6 Final LDL-C and apolipoprotein B-100 levels on treatment in patients receiving pravastatin 40 mg or atorvastatin 80 mg in the REVERSAL trial. (Adapted with permission from Nissen et al. 7 ) goals. For example, in REVERSAL, the mean apo B level remained above the goal of 90 mg/dl despite the reduction in mean LDL-C to 79 mg/dl (Figure 6 ). Reductions in apo B and non-hdl-c with statin therapy, like those in LDL-C, are dose dependent; therefore, additional intensification of lipid-lowering treatment is necessary in some patients to ensure that apo B or non-hdl-c levels are also within optimal ranges once target LDL-C levels are achieved. Conclusion As clinical endpoint trials of lipid-lowering therapy examine the effects of reducing LDL-C to increasingly lower levels, incremental benefits of additional reductions continue to be revealed. Data from trials completed since the publication of the ATP III guidelines in 2001 have already resulted in modification of those guidelines, including the introduction of an optional treatment goal of LDL-C, 70 mg/l in very high risk patients, an optional goal of LDL-C, 100 mg/dl in moderately high risk patients, and optional thresholds for instituting lipid-lowering therapy that are below prior initiation levels in moderate- and high-risk patients. Also new is the recommendation that the intensity of lipid-lowering therapy in such patients be sufficient to achieve a 30 40% reduction in LDL-C. Ongoing trials are examining the issue of optimal reductions in LDL-C, and these results will likely also have an impact on future recommendations for treatment. In addition to refining LDL-C targets, ongoing studies are examining the roles of other lipids and apolipoproteins as targets of treatment. Future guidelines may include recommendations regarding apo B and non-hdl-c levels as targets of lipid-lowering therapy. The role of CRP both as a risk marker and as a potential target of lipid-lowering therapy is also under investigation. Discussion Audience Question: Do you know what the number needed to treat [to prevent a cardiovascular event] is when patients were treated down to LDL-C of 70 mg/dl? Dr Ballantyne: Of course, that depends on the event rate. I am not sure what the number needed to treat was in PROVE IT. But the question can really be asked as compared with what? We are going to treat these high-risk patients anyway. If the question is compared with pravastatin? and the issue is cost, then it is good to recognize that, at least in the United States, pravastatin is more expensive than both atorvastatin and rosuvastatin, which provide much better LDL-C reductions. Why would we use therapies that are both more expensive and provide less LDL-C reduction? Audience Question: Could you discuss the potential benefits of, say, an intensive statin regimen compared with a more moderate statin regimen plus another agent that produces the same magnitude of LDL-C reduction would risk reduction be the same? Dr Ballantyne: That is a very good question, and we will need a study to answer it. Professor Kastelein: As guidelines evolve more rapidly, a question that sometimes comes up for all of us is whether we have the drug armamentarium to keep up with the changes. Dr Ballantyne: We know that with the more potent LDL- C-lowering statins, such as rosuvastatin and atorvastatin, we can get large reductions in LDL-C; in one trial, the MERCURY II trial, there is an analysis comparing rosuvastatin regimens with other statin regimens with regard to achievement of the optional goal of LDL-C, 70 mg/dl. In addition, there is another trial under way combining rosuvastatin with ezetimibe, and it will be of interest to see what types of LDL-C reductions are achievable with that combination. Professor Kastelein: I know this is speculation, but are we going to continue to go ever lower in terms of LDL-C goals? Are we going to reach the biologic threshold are we going to find levels at which there is no further benefit in terms of risk reduction? Dr Ballantyne: You know, I am sure that many of us run into a related question in the clinic. When the target in the highrisk patients was 100 mg/dl in the US, I would back off treatment when the LDL-C got down to 70 mg/dl or so. In

Changing lipid-lowering guidelines A19 some of the studies we have talked about, patients were down to levels of 40 or 45 mg/dl. In some of our recent large trials, the procedure was to back-titrate when levelsgotto50mg/dl or lower. In a very recent trial, I was somewhat shocked that we decided to back off treatment if the level got below 35 mg/dl; it is amazing how rapidly the clinical trial protocols have evolved in this way. In my own practice, if a patient gets down to somewhere between 40 and 50 mg/dl, I leave it at that; I do not feel we need to go any lower right now. I do get one more measurement, however, to be sure of the level, since it is not uncommon to see some fluctuation. Professor Kastelein: There was a question from the audience about the safety data from the ANDROMEDA trial in terms of creatine kinase and liver enzyme levels. Dr Ballantyne: Thus far, the study reports are only in abstract form. The study was a short-term study, and I do not believe there were any safety concerns with rosuvastatin or atorvastatin. Professor Kastelein: If the question is about safety concerns with rosuvastatin, maybe I can add to that. Currently, about 9 million rosuvastatin prescriptions have been written. When there were 9 million prescriptions of Baycol (cerivastatin), there had already been 30 deaths from rhabdomyolysis. There have been none reported with rosuvastatin. Looking at this bigger picture, I think it looks very reassuring. References 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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 III). JAMA 2001;285:2486 2497. 2. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 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. Circulation 2002;106: 3143 3421. 3. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7 22. 4. Sever PS, Dahlof B, Poulter NR 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 1158. 5. Taylor AJ, Kent SM, Flaherty PJ et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation 2002;106: 2055 2060. 6. Furberg CD, Adams HP Jr, Applegate WB et al., for the Asymptomatic Carotid Artery Progression Study (ACAPS) Research Group. Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994;90:1679 1687. 7. Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: randomized controlled trial. JAMA 2004; 291:1071 1080. 8. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495 1504. 9. Grundy SM, Cleeman JI, Merz CN et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227 239. 10. Jones PH, Davidson MH, Stein EA et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92: 152 160. 11. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135 1143. 12. Betteridge J, Gibson M, on behalf of the ANDROMEDA study investigators. Effect of rosuvastatin and atorvastatin on LDL-C and CRP levels in patients with type 2 diabetes: results of the ANDROMEDA study. Poster presentation at: the 74th European Atherosclerosis Society Congress; April 17 21, 2004; Seville, Spain. 13. Grundy SM. Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein B as targets of lipid-lowering therapy. Circulation 2002;106:2526 2529.