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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
Corresponding author. Tel: +1 713 798 5034/790 5800; fax: +1 713 798 3057. E-mail address: cmb{at}bcm.tmc.edu
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Abstract
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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.
Key Words: Statins • Low-density lipoprotein • Coronary heart disease • C-reactive protein • Adult Treatment Panel III guidelines
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Introduction
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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 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 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.
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Table 1 NCEP ATP III LDL-C goals and cut-points for lipid-lowering drug therapy according to risk category—2001 guidelines
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Recent clinical trial evidence: do lower LDL-C levels provide better outcomes?
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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.
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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)
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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 lipid-lowering 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
(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=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=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=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 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 –0.4% in the atorvastatin group, suggesting a non-significant trend toward regression, vs. 2.7% in the pravastatin group, indicating statistically significant disease progression (P=0.02 for the difference between groups; 502 patients with follow-up).
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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)
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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. all-cause
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=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=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.
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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)
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Modifications to ATP III guidelines
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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 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.
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Table 2 Recommended revision to NCEP ATP III LDL-C goals and cut-points for lipid-lowering drug therapy according to risk category (changes in update shown in italics)
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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.
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Achieving recommended lipid levels
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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 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.
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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)
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Other potential targets of lipid-lowering treatment
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Future lipid-lowering guidelines may also focus more attention
on other lipid and non-lipid parameters, 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 well-documented 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 8 weeks and at 20 mg
for a further 8 weeks. As shown in
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.
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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)
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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 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 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.
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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)
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Conclusion
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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.
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Discussion
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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 high-risk 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 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 levels got to 50 mg/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.
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Abstract
Introduction