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Readers are encouraged to respond to George Lundberg, MD, Editor of MedGenMed,
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Purpose
The relationships of various lipids with risks for coronary heart disease
(CHD) are well documented in basic research, clinical studies, retrospective
and prospective epidemiologic studies, and numerous randomized trials. In
randomized trials, statins produce large reductions in total cholesterol,
low-density lipoprotein (LDL) cholesterol, and triglycerides as well as raise
high-density lipoprotein (HDL) cholesterol -- each of which increases the
risks for CHD. Randomized trials of statins in secondary and primary
prevention and their meta-analyses have demonstrated statistically significant
and clinically important reductions in myocardial infarction (MI), stroke, and
cardiovascular disease (CVD) death (each by about one third) as well as total
mortality (by about one fifth). An overview of 16 randomized trials showed
that statins reduced total cholesterol by 22%, LDL by 30%, stroke by 30%, CVD
death by 30%, and total mortality by 22%.[1]
The early landmark trials of statins, including the Scandinavian Simvastatin
Survival Study (4S), Long-Term Intervention with Pravastatin in Ischemic
Disease (LIPID), and Cholesterol and Recurrent Events (CARE), led to a large
expansion of the number of patients who are eligible for treatment as
recommended by the National Cholesterol Education Program (NCEP) {*filter*}
Treatment Panel (ATP) III in 2001. High risk was defined as secondary
prevention patients with prior MI, stroke, or peripheral vascular disease as
well as primary prevention patients with the 10-year risk for a first CHD
event of ? 20% and all patients with diabetes. Moderate risk was defined as
primary prevention patients with a 10-year risk of 10% to 19% and low risk of
less than 10%. These clinical management guidelines recommended LDL goals of <
100 mg/dL for high-risk patients, < 130 mg/dL for moderate-risk patients, and
< 160 mg/dL for low-risk patients with pharmacologic agents as well as
therapeutic lifestyle changes to achieve these goals.[2] More recently, the
NCEP ATP III guidelines were modified to include the therapeutic option of
reducing LDL goals to < 70 for very high-risk patients and < 100 for
moderately high-risk patients.[3]
Methods
We conducted a literature search of randomized trials of statin therapy whose
results were published since May 15, 2001. After review of each published
trial, we extracted the overall trial results and data on adverse events, when
available.
Results
Our review revealed 7 published, landmark, randomized trials of statins, some
of which contributed to the recent addendum to the NCEP ATP III guidelines,
which suggested therapeutic options for reducing LDL goals to < 70 mg/dL for
very high-risk patients and < 100 mg/dL for moderately high-risk patients.[4]
The 7 published, landmark trials of statins reviewed below include the Heart
Protection Study (HPS), PROspective Study of Pravastatin in the Elderly at
Risk (PROSPER), Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (lipid-lowering trial component, ALLHAT-LLT), Anglo-Scandinavian
Cardiac Outcomes Trial (ASCOT), Reversal of Atherosclerosis with Aggressive
Lipid Lowering (REVERSAL), Pravastatin or Atorvastatin Evaluation and
Infection Therapy (PROVE-IT) trial, and Collaborative Atorvastatin Diabetes
Study (CARDS).
The HPS
The HPS was a randomized, 2 x 2 factorial trial of lipid lowering and
antioxidant vitamins, after a prerandomization run-in of several months on
active drug, of 20,536 high-risk patients, defined as those who had at least 1
of the following: (1) coronary disease, (2) occlusive disease of the
noncoronary arteries, or (3) diabetes mellitus. Subjects were randomized to
simvastatin 40 mg or placebo and followed for a mean duration of 5 years.
Approximately 28% (n = 5806) of the subjects included were composed of persons
aged 70 years or older at entry. Regardless of the entry levels of LDL
cholesterol or total cholesterol (including those who presented with LDL
cholesterol below 116 mg/dL or total cholesterol below 193 mg/dL), treatment
with simvastatin resulted in the lowering of LDL cholesterol, and showed that
bringing LDL levels from 116 mg/dL to below 77 mg/dL results in significant
reductions in vascular events. Specifically, all-cause mortality was
significantly reduced by 12.9% for those assigned simvastatin vs 14.7% for
those assigned placebo (P = .0003) primarily due to a highly significant 18%
reduction in coronary death (5.7% vs 6.9%, respectively; P = .0005) and a
marginally significant reduction in other vascular deaths (1.9% vs 2.2%,
respectively; P = .07). The first-event rates for nonfatal MI or coronary
death (8.7% vs 11.8%, P < .0001), for nonfatal or fatal stroke (4.3% vs 5.7%,
P < .0001), and for coronary or noncoronary revascularization (9.1% vs 11.7%,
P < .0001) were reduced significantly for those assigned to atorvastatin as
compared with placebo.[4]
In regard to adverse events, there were no significant differences between
treatment groups with respect to the number of subjects hospitalized for any
reason or for the number of subjects who dropped out. Specifically, there was
no difference between treatment groups with respect to the number of subjects
whose study treatment was stopped because of elevated liver enzymes (0.5% in
the simvastatin group, 0.3% in the placebo group). Moreover, in this
randomized, double-blind, placebo-controlled trial, the reporting of
muscle-related symptoms was virtually identical among the 2 treatment groups
(32.9% in the simvastatin group, 33.2% in the placebo group). Table 1 shows
the liver or muscle enzyme data recorded during follow-up.[4]
PROSPER
PROSPER was a randomized controlled trial of elderly patients (aged 70-82)
with either a history of, or risk factors for, CVD and stroke. A total of 5804
patients (2804 men, 3000 women) were randomly assigned to either pravastatin
40 mg daily (n = 2891) or placebo (n = 2913), and followed for a mean of 3.2
years. At 3-month follow-up, LDL cholesterol was 34% lower, HDL cholesterol 5%
higher, and triglycerides 13% lower in the compliant pravastatin group; the
rates for all pravastatin patients included a 32% decrease in LDL, 5% increase
in HDL, and 12% decrease in triglycerides. At 2-year follow-up, compliant
patients who were assigned pravastatin experienced a reduction in LDL
cholesterol of 33% (27% in all patients assigned pravastatin). Pravastatin
significantly lowered the risk for a primary endpoint (a composite of definite
or suspect death from CHD, nonfatal MI, and fatal or nonfatal stroke) by 15%
(P = .014), and the risk for a secondary endpoint, CHD death, or nonfatal MI
by 19% (P = .006). Pravastatin also significantly reduced other outcomes,
including the risk for all cardiovascular events (including primary endpoint
or coronary artery bypass graft, percutaneous transluminal coronary
angioplasty or peripheral arterial surgery, or angioplasty) by 15% (P = .012)
and risk for death from CHD by 24% (P = .043).[5]
Reports of adverse events were similar in both treatment groups. Specifically,
56% of patients who were assigned to pravastatin reported 1 or more adverse
events compared with 55% of those assigned to placebo. Liver function muscle
enzyme abnormalities were very infrequent and virtually equal in both
treatment groups. One unexpected finding that is likely due to chance was that
patients in the pravastatin group experienced a 25% higher rate of reporting
newly diagnosed cancers. The sample size was small, however, and the
observation is inconsistent with findings from a meta-analysis conducted by
PROSPER investigators of previous randomized trials of pravastatin lasting 3
years or more. Specifically, pravastatin (hazard ratio, 1.06; 95% confidence
interval [CI], 0.96-1.17; P = .20) or all statins (hazard ratio, 1.02; 95% CI,
0.96-1.09; P = .32) conferred no significant, increased risk for newly
diagnosed cancers ( Table 2 ).[5]
ALLHAT-LLT
ALLHAT-LLT was a multicenter, randomized, nonblinded trial conducted from 1994
through 2002 in a subset of 10,355 patients, aged 55 years and older with LDL
cholesterol of 120-189 mg/dL (100-129 mg/dL if known CHD), from ALLHAT.
Patients were randomized to pravastatin 40 mg or to usual care, and were
followed for 8 years (mean follow-up, 4.8 years). With respect to these older
patients with well-controlled hypertension and moderately elevated LDL
cholesterol, all-cause mortality, the primary outcome, or CHD, a secondary
outcome, were not reduced significantly by pravastatin when compared with
usual care. Specifically, all-cause mortality was similar for the 2 groups:
14.9% for the pravastatin group as compared with 15.3% for the usual care
group (P = .88). Additionally, CHD event rates were 9.3% and 10.4%,
respectively (P = .16).[6] This apparent null result, however, should be
interpreted as uninformative rather than null due to the small sample size
achieved and the poor compliance in both randomized groups. Specifically, the
statistical power of a trial is proportional to the square of the difference
in compliance between the 2 groups. Because 70% of the treated group and 30%
of the usual care group took statins, the statistical power of ALLHAT-LLT is
(0.7-0.4)2 or about 9% to detect the most plausible small-to-moderate
treatment effect. If ALLHAT-LLT had design features similar to those in
ASCOT-LLA, it is likely that a statistically significant benefit would have
emerged.[7]
In ALLHAT-LLT, less than 1% (0.4%, n = 21) of patients in the pravastatin
group had elevations of alanine aminotransferase (ALT) greater than 3 times
the upper limit of normal.[6]
ASCOT-LLT
ASCOT was a randomized, double-blind, placebo-controlled, 2 x 2 factorial
primary prevention trial of {*filter*} pressure lowering and lipid lowering.
Nine{*filter*} thousand three hundred forty-two hypertensive patients (aged 40-70
years with at least 3 other cardiovascular risk factors) were randomized to 1
of 2 antihypertensive regimens. A total of 10,297 European patients with
nonfasting total cholesterol concentrations of < 250 mg/dL or less were
randomly assigned to an additional 10 mg of atorvastatin, comprising the
lipid-lowering arm of the trial (ASCOT-LLT). Atorvastatin reduced LDL
cholesterol by 35% and total cholesterol by 24% after 1 year of follow-up.
ASCOT-LLT was terminated early after about 3 years by the independent Data and
Safety Monitoring Board (DSMB) due to the emergence of a statistically extreme
36% reduction in the primary outcome of CHD events (P = .0005). At that time,
there was also a statistically significant 27% reduction in the secondary
outcome of fatal and nonfatal stroke (P = .0236); a statistically significant
21% reduction in total cardiovascular events, including revascularization
procedures (P = .0005); and a statistically extreme 29% reduction in total
coronary events (P = .0005).[8]
There were no differences between treatment groups with respect to serious
adverse events, including liver enzyme abnormalities. One subject with a very
high {*filter*} intake and a recent febrile illness in the atorvastatin group
developed a nonfatal case of rhabdomyolysis.[8]
REVERSAL
REVERSAL was a randomized trial of 502 patients with positive intravascular
ultrasound (IVUS) at baseline who were randomized to atorvastatin 80 mg or
pravastatin 40 mg. By 18 months, patients randomized to high-dose atorvastatin
achieved average LDL cholesterol of 79 mg/dL, average decreases in C-reactive
protein of 36.4%, and no progression in atherosclerosis based on IVUS
imaging -- the primary endpoint. In contrast, pravastatin patients achieved
LDL cholesterol of 110 mg/dL, average decreases in C-reactive protein of 5.2%,
and had mild progression -- a difference that was statistically
significant.[9]
In this trial of small sample size, there were no significant excesses of
liver function abnormalities of drug discontinuations ( Table 3 ).[9]
PROVE-IT
The PROVE-IT trial randomized 4162 postacute coronary syndrome patients to
atorvastatin 80 mg or pravastatin 40 mg with a mean follow-up of 2 years.
Patients randomized to high-dose atorvastatin achieved an average LDL
cholesterol of 62 mg/dL, and those assigned pravastatin achieved an average
LDL cholesterol of 95 mg/L (P < .001). In regard to the secondary endpoint,
those who were assigned high-dose atorvastatin had significant reductions in
subsequent CHD events, including a 25% reduction in death due to CHD, MI, or
revascularization (P < .001), as compared with those who were assigned to
standard-dose pravastatin who experienced a 14% reduction in these events (P =
.029). In regard to the individual components of the primary endpoint,
high-dose atorvastatin was more beneficial than standard-dose pravastatin.
Specifically, there was a 14% decrease in the need for revascularization (P =
.04) and a 29% decrease in the risk for recurrent unstable angina (P = .02),
with possible but nonsignificant reductions in rates of death from any cause
or MI.[10]
Few adverse events were recorded during the PROVE-IT trial. There was an
increase in ALT of 3 or more times the upper limit of normal in 3.3% in the
atorvastatin group and 1.1% in the pravastatin group (P < .001). Reports of
myalgias or elevations in creatine kinase levels led investigators to withdraw
3.3% of patients in the atorvastatin group and 2.7% of patients in the
pravastatin group (P = .23). Finally, rhabdomyolysis did not occur in either
group ( Table 4 ).[10]
CARDS
CARDS was a randomized, placebo-controlled trial of diabetics without a
documented previous history of CVD. CARDS, which randomized 2838 patients to
10 mg of atorvastatin or placebo, was terminated early after about 3 years by
the independent DSMB due to the emergence of a statistically extreme benefit
of 37% on the primary endpoint of fatal and nonfatal CHD (P = .001). In regard
to individual components of the primary endpoint, acute CHD events were
reduced by 36%, coronary revascularizations by 31%, and risk for stroke by
48%.[11]
In this trial, no difference in adverse events was found between treatment
groups. Specifically, rhabdomyolysis was absent in both groups; myopathy was
equally present in both groups (0.1%); creatine kinase was greater than 10
times the upper limit of normal, with and without symptoms, and was more
present in the placebo vs treatment group; an increase in ALT of 3 or more
times the upper limit of normal occurred in 1% of both groups; and a rise in
aspartate aminotransferase (AST) of 3 or more times the upper limit of normal
occurred slightly more often, yet infrequently, in the atorvastatin patients
as compared with the placebo patients ( Table 5 ).[11]
Conclusions
In 2004, the NCEP ATP III guidelines were updated on the basis of the clinical
importance and public health relevance of recently published randomized trials
of statins. These revised guidelines include therapeutic options for LDL goals
of 70 mg/dL for high-risk patients and 100 mg/dL for moderate-risk patients.
Accordingly, primary healthcare providers need to consider statins for many
more patients. For high-risk patients who have survived a prior occlusive
event or who have a 20% or greater 10-year risk for a first CHD event, the
optional LDL goal is now < 70 mg/dL ( Table 6 ). For all of these high-risk
patients, although the primary goal is LDL reduction, it is also important to
lower triglycerides and raise HDL, and statins remain the first-line choice
for drug therapy. For moderate-risk patients, those currently free of CVD who
are likely to require statin therapy are patients with metabolic syndrome,
which affects about 40% of {*filter*}s over age 40, as well as patients with
diabetes. Metabolic syndrome patients have an average 10-year risk for a first
CHD event of 16% to 18%, and patients with diabetes should be treated as
aggressively as patients who have survived an MI or stroke.
With respect to adverse events, for all marketed statins 2.5% to 6% of
patients have reported myalgia; 0.03% have reported myopathy, and less than
0.1% have reported rhabdomyolysis. Furthermore, in regard to fatal
rhabdomyolysis, the rate is 0.15 deaths per million prescriptions. This is a
weighted average of 0.18 for lovastatin and simvastatin, 0.06 for atorvastatin
and pravastatin, and 0.00 for fluvastatin and rosuvastatin. With respect to
renal issues, patients with proteinuria are at higher risk for CVD than their
counterparts without proteinuria. In general, statins do not increase the risk
for proteinuria. The highest marketed dose of rosuvastatin of 40 mg was found
to double the rate of proteinuria, but long-term data were reassuring.
Specifically, over 96 weeks of treatment and follow-up, it was found that the
proteinuria was transient and reversible and creatinine clearance
improved.[12] Moreover, a meta-analysis of data from large-scale randomized
trials of statins, which include high doses used for long durations, is
reassuring. Among over 90,000 patients treated and followed for 5 years, there
were 15 cases of rhabdomyolysis -- 9 among the statin takers and 6 among the
placebo group. Thus, the 5-year excess risk for rhabdomyolysis is 0.01% (P =
.4).[13] In fact, in the randomized, double-blind, placebo-controlled trials,
the rates of muscle-related and/or liver enzyme abnormalities attributable to
the statins have been low or nonexistent. Nonetheless, media reports have been
alarming to patients and their healthcare providers despite a totality of
evidence that suggests that statins may have avoided over 1 million premature
deaths while causing only about 350 cases of fatal rhabdomyolysis. Thus,
evidence-based medicine strongly favors the use of statins in both secondary
and primary prevention in patients whose risk for CVD outweighs the low risk
for side effects of these {*filter*}. The NCEP ATP III guidelines and their recent
revisions provide a rational basis for clinicians to use in diagnosis and
treatment. Nonetheless, less than about one third of eligible patients are
reaching the goals. There is a clinical and public health challenge for the
more widespread use of statins, which should be used as an adjunct not
alternative to favorable lifestyle modifications and pharmacologic
interventions on other risk factors for CVD.
After the release of the revisions to the NCEP ATP III guidelines, the
Treatment to New Targets (TNT) trial, was completed and published. TNT was a
randomized, double-blind, placebo-controlled trial in 14 countries, and
randomized 10,003 patients with CHD to either atorvastatin 10 mg or 80 mg. The
goal was for patients in the low-dose group to reach LDL levels of
approximately 100 mg/dL on average, and for the high-dose group to reach LDL
levels of approximately 75 mg/dL on average. TNT had a 5-year follow-up (or
750 events defined as CHD death, nonfatal MI, resuscitated cardiac arrest, or
stroke). When compared with patients randomized to 10 mg of atorvastatin,
those assigned to 80 mg of atorvastatin had a statistically significant and
clinically important 22% reduction in the aforementioned primary endpoint. In
addition, they also experienced a 25% reduction in stroke. The large size and
long duration of this trial of non-acute coronary syndrome patients provided
crucial data in regard to whether clinical and public health benefits are
important in maintaining LDL cholesterol levels at approximately 75 mg/dL.
Ongoing and future statin trials will address the most clinically useful doses
for statins in secondary and primary prevention. At present, the totality of
evidence may lead to even more rigorous guidelines for LDL cholesterol
management. In the meantime, the clinical and public health challenges to
primary healthcare providers are clear for the more widespread and appropriate
use of statins in the treatment and prevention of CVD.
Table 1. Adverse Events in the HPS
HPS Adverse Events Simvastatin 40-mg Group% (n) Placebo Group% (n)
CK elevation 4-10 x ULN 0.19% (19) 0.13% (13)
CK elevation > 10 x ULN 0.11% (11) 0.06% (6)
ALT 2-4 x ULN 1.35% (139) 1.28% (131)
ALT ? 4 x ULN 0.42% (43) 0.31% (32)
No rhabdomyolysis 0.05% (5) 0.01% (1)
Rhabdomyolysis 0.05% (5) 0.03% (3)
HPS = Heart Protection Study; CK = creatine kinase; ULN = upper limit of
normal; ALT = alanine aminotransferase
Table 2. Adverse Events in PROSPER
PROSPER Adverse Events Pravastatin 40-mg Group% (n) Placebo Group% (n)
CK ? 10 ULN 0.0% (0) 0.3% (10)
ALT ? 3 ULN 0.03% (1) 0.03% (1)
AST ? 3 ULN 0.03% (1) 0.03% (1)
Rhabdomyolysis 0.0% (0) 0.0% (0)
Myalgia 1.2% (36) 1.1% (32)
PROSPER = PROspective Study of Pravastatin in the Elderly at Risk; CK =
creatine kinase; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; ULN = upper limit of normal
Table 3. Adverse Events in REVERSAL
REVERSAL Adverse Events Atorvastatin 80-mg Group% (n) Pravastatin
40-mg Group% (n)
CK elevation > 10 x ULN 0% (0) 0% (0)
ALT ? 3 x ULN 2.3% (7) 1.6% (5)
AST > 3 x ULN 0.6% (2) 0.6% (2)
Drug discontinued for increase AST or ALT < 3 x ULN 0.0% (0) 1.2% (4)
Drug discontinued for myalgia 2.8% (9) 3.4% (12)
Drug discontinued for abdominal complaint 1.5% (5) 0.9% (3)
Drug discontinued for cancer 0.6% (2) 0.0% (0)
Drug discontinued for chest pain 0.6% (2) 0.0% (0)
REVERSAL = Reversal of Atherosclerosis with Aggressive Lipid Lowering; CK =
creatine kinase; ALT = alanine aminotransferase; AST = aspartate
aminotransferase; ULN = upper limit of normal
Table 4. Adverse Events in PROVE-IT
PROVE-IT Adverse Events Atorvastatin 80-mg Group% (n) Pravastatin
40-mg Group% (n)
CK elevation 1.5% (31) 1.1% (23)
ALT ? 3 ULN 3.3% (69) 1.1% (23)
Drug discontinued for myalgia/CK elevations 3.3% (69) 2.7% (56)
Rhabdomyolysis 0% (0) 0% (0)
PROVE-IT = Pravastatin or Atorvastatin Evaluation and Infection Therapy; ALT
= alanine aminotransferase; ULN = upper limit of normal
Table 5. Adverse Events in CARDS
CARDS Adverse Events Atorvastatin 10-mg Group% (n) Placebo Group% (n)
CK ? 10 ULN 0.1% (2) 0.7% (10)
CK ? 10 ULN + symptoms 0% (0) 0.1% (1)
ALT ? 3 ULN 1% (17) 1% (14)
AST ? 3 ULN 0.4% (6) 0.3% (4)
Rhabdomyolysis 0% (0) 0% (0)
Myopathy 0.1% (1) 0.1% (1)
CARDS = Collaborative Atorvastatin Diabetes Study; CK = creatine kinase; ALT
= alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper
limit of normal
Table 6. NCEP ATP III Guidelines
Patient LDL Goal
2001* 2004?
High-risk < 100 < 70
Moderate-risk < 130 < 100
Low-risk < 160 < 160
NCEP ATP III = National Cholesterol Education Program {*filter*} Treatment Panel
III; LDL = low-density lipoprotein
*From: Expert Panel on Detection, Evaluation, and Treatment of High {*filter*}
Cholesterol in {*filter*}s. Executive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,
And Treatment of High {*filter*} Cholesterol In {*filter*}s ({*filter*} Treatment Panel III).
JAMA. 2001;285:2486-2497.
?From: Grundy SM, Cleeman JI, Merz CN, et al. National Heart, Lung, and
{*filter*} Institute; American College of Cardiology Foundation; American Heart
Association. Implications of recent clinical trials for the National
Cholesterol Education Program {*filter*} Treatment Panel III guidelines.
Circulation. 2004;110:227-239.
References
1.. Hebert PR, Gaziano JM, Chan KS, Hennekens CH. Cholesterol lowering with
statin {*filter*}, risk of stroke, and total mortality. An overview of randomized
trials. JAMA. 1997;278:313-321. Abstract
2.. Expert Panel on Detection, Evaluation, and Treatment of High {*filter*}
Cholesterol in {*filter*}s. Executive Summary of The Third Report of The National
Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,
And Treatment of High {*filter*} Cholesterol In {*filter*}s ({*filter*} Treatment Panel III).
JAMA. 2001;285:2486-2497. Abstract
3.. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and {*filter*}
Institute; American College of Cardiology Foundation; American Heart
Association. Implications of recent clinical trials for the National
Cholesterol Education Program {*filter*} Treatment Panel III guidelines.
Circulation. 2004;110:227-239. Abstract
4.. 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.
Abstract
5.. Shepherd J, Blauw GJ, Murphy MB, et al; PROSPER study group. PROspective
Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly
individuals at risk of vascular disease (PROSPER): a randomised controlled
trial. Lancet. 2002;360:1623-1630. Abstract
6.. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive
patients randomized to pravastatin vs usual care: the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA.
2002;288:2998-3007. Abstract
7.. Hennekens CH; The ALLHAT-LLT and ASCOT-LLA Trials. Are the discrepancies
more apparent than real? Curr Atherosclerosis Rep. 2004;6:9-11.
8.. Sever PS, Dahlof B, Poulter NR, et al; ASCOT investigators. 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. Abstract
9.. Nissen SE, Tuzcu EM, Schoenhagen P, et al; REVERSAL Investigators.
Effect of intensive compared with moderate lipid-lowering therapy on
progression of coronary atherosclerosis: a randomized controlled trial. JAMA.
2004;291:1071-1080. Abstract
10.. Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin
Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22
Investigators. Intensive versus moderate lipid lowering with statins after
acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. Abstract
11.. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators.
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;364:685-696. Abstract
12.. Zipes DP, Pfeffer MA, Zvaifler NJ, et al. Analysis of the efficacy and
safety of rosuvastatin. MedGenMed. In press.
13.. Baigent C, Keech A, Kearney PM, et al; Cholesterol Treatment Trialists'
(CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment:
prospective meta-analysis of data from 90,056 participants in 14 randomised
trials of statins. Lancet. 2005;366:1267-1278. Abstract
Charles H. Hennekens, MD, Voluntary Professor of Medicine & Epidemiology and
Public Health, Miller School of Medicine, University of Miami, Miami, Florida;
Research Professor of Biomedical Science, Center of Excellence, Florida
Atlantic University, Boca Raton, Florida; Director of Research, Agatston
Danielle Hollar, PhD, Voluntary Assistant Professor of Medicine, Miller School
of Medicine, University of Miami, Miami, Florida; Research Assistant,
Professor of Biomedical Science, Center of Excellence, Florida Atlantic
University, Boca Raton, Florida; Deputy Director of Research, Agatston
Research Institute, Miami Beach, Florida
Rachel S. Eidelman, MD, Florida Cardiology Group, PA, Atlantis, Florida;
Agatston Research Institute, Miami Beach, Florida
Arthur S. Agatston, MD, FACC, Associate Professor of Medicine, Miller School
of Medicine, University of Miami, Miami, Florida; President, Agatston Research
Institute, Miami Beach, Florida
Disclosure: Charles H. Hennekens, MD, has disclosed that he has been funded by
the Department of Biomedical Science and Center of Excellence at Florida
Atlantic University (FAU), Boca Raton, Florida. He is the principal
investigator or co-principal investigator on 2 investigator-initiated research
grants funded to FAU by Bayer, testing the effects of aspirin doses on
platelet biomarkers, inflammatory markers, nitric oxide formation, and
endothelial function. Dr. Hennekens has also disclosed that he has served as a
consultant to, including as a chair or member of, the data and safety
monitoring boards for Agatston Research Institute (ARI), Amgen, AstraZeneca,
Bayer, Bristol-Myers Squibb, Chattem, Delaco, US cooking.net">food and Drug Administration,
GlaxoSmithKline, Keryx, McNeil, Merck, National Institutes of Health,
Novartis, Pfizer, Reliant, TAP, United BioSource Corporation, and UpToDate;
that he has served on the speaker's bureaus for AstraZeneca, concerning lipids
and heart failure, and Bristol-Myers Squibb, Reliant, and Pfizer, concerning
lipids; that he has received royalties for authorship or editorship of 3
textbooks; and that he has received royalties as co-inventor on patents
concerning inflammatory markers and cardiovascular disease, which are held by
Brigham and Women's Hospital, Boston, Massachusetts. He also has an investment
management relationship with Sun Trust Bank who has sole discretionary
investment authority.
Disclosure: Danielle Hollar, PhD, has disclosed that she has received funding
for research and teaching from the Department of Biomedical Science and the
Center of Excellence at Florida Atlantic University, Boca Raton, Florida. Dr.
Hollar has also disclosed that she has served as the project director on 2
investigator-initiated research grants funded by Bayer HealthCare to Florida
Atlantic University, and has served as a consultant to the Agatston Research
Institute, Miami Beach.
Disclosure: Rachel S. Eidelman, MD, has disclosed no relevant financial
relationships. At the time of manuscript writing, Dr. Eidelman's affiliation
was also with Agatston Research Institute, Miami Beach, Florida.
Disclosure: Arthur S. Agatston, MD, FACC, has disclosed that he has received
royalties for authorship of several books, including The South Beach Diet, The
South Beach Diet Cookbook, and others; and has received royalties resulting
from a partnership with Kraft Foods, as well as other activities associated
with SBD Trademark Limited Partnership. He has a private cardiology practice:
Arthur Agatston, M.D.P.A.
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Update for Primary Healthcare Providers: Recent Statin Trials and Revised National Cholesterol Education Program III Guidelines