http://www.medscape.

com/viewarticle/828967_print

Lower LDL Still Best: Very Low Levels of

LDL Linked With Reduced CV Events
Michael O'Riordan
July 28, 2014
AMSTERDAM, THE NETHERLANDS The question of how low LDL-cholesterol levels
should be in the present statin era, recently addressed with the new US clinical guidelines, is
once again questioned with the new publication of a patient-level meta-analysis of eight clinical
trials investigating statin therapy[1].
The new meta-analysis, published July 28, 2014 in the Journal of the American College of
Cardiology, suggests that lowering LDL-cholesterol levels to very low levels results in a
significant reduction in cardiovascular events. Individuals with LDL-cholesterol levels <50
mg/dL had a significantly lower risk of major cardiovascular events compared with individuals
who had higher LDL-cholesterol levels, including those with LDL levels 50 to <75 mg/dL and
75 to <100 mg/dL.
"No clinical-outcomes trial with statins has ever achieved a mean LDL-cholesterol level much
less than 70 [mg/dL]," senior investigator Dr John Kastelein (Academic Medical Center,
Amsterdam, the Netherlands) told heartwire . "That's why we thought it might be a good idea to
get all the individual patient data and see whether we could extend the line a little further down.
Of course, this is a nonrandomized, post hoc analysis, with all the caveats you should attach to it,
but I think the data are very convincing."
That "line" Kastelein refers to is the cardiovascular risk-reduction curve observed in clinical
trials that shows lowering LDL-cholesterol levels reduces major cardiovascular events. In 2010,
the Cholesterol Treatment Trialists' (CTT) collaboration showed there was a benefit of
lowering LDL cholesterol to around 50 mg/dL. The present meta-analysis extends those findings
by suggesting that even lower levels appear to reduce the risk of cardiovascular events further.
In November 2013, the US guidelines for the management of cholesterol elected to do away with
treatment goals, stating there was no evidence of cardiovascular benefit in treating to a specific
target. The recommendations were surprising, controversial, and in contrast to the previous
guidelines that suggested physicians treat high-risk patients to an LDL target of less than 100
mg/dL, with an option to treat patients to less than 70 mg/dL.
In an editorial[2], Dr Ori Ben-Yehuda (Cardiovascular Research Foundation, New York) and Dr
Anthony DeMaria (University of California, San Diego) are cautious in interpreting the data
from the meta-analysis, noting the new US guidelines recommend only measuring LDLcholesterol levels to assess adherence. Given the observational, post hoc nature of the data, the

editorialists do not believe the present study disproves the US guidelines writing committee's
contention that there was insufficient evidence to recommend treating to LDL targets. This is
problematic, they say.
"It is indeed regrettable that more than 25 years after the first [Adult Treatment Panel] ATP
guidelines, we still do not have clear-cut evidence on what the appropriate LDL-cholesterol
targets of therapy should be," write Ben-Yehuda and DeMaria. "The findings from the present
meta-analysis will hopefully further spur the design and implementation of lipid trials assessing
specific LDL-cholesterol targets rather than specific drug doses."
The Results From the Meta-analysis
The investigators, including first author Dr Matthijs Boekholdt (Academic Medical Center),
analyzed eight trials and 38 153 patients treated with statin therapy. The studies included some of
the landmark statin trials, including AFCAPS-TexCAPS , 4S , LIPID , SPARCL , TNT ,
IDEAL , and JUPITER .
The investigators observed a large degree of interindividual variability in the reductions of LDL
cholesterol, non-HDL cholesterol, and apolipoprotein B (apoB) levels with statin therapy. Among
those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDLcholesterol target of less than 70 mg/dL.
Compared with individuals with LDL-cholesterol levels >175 mg/dL, which served as the
reference group, individuals who achieved lower levels of LDL cholesterol had a significantly
lower risk of major cardiovascular events. For those with LDL-cholesterol levels <50 mg/dL, 50
to <75 mg/dL, and 75 to <100 mg/dL, the relative reduction in risk was 56%, 49%, and 44%,
respectively. Regarding the end point of major coronary events and cerebrovascular events, a
similar trend was observed with lower LDL cholesterol levels.
Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL)
Outcome
LDL <50
Major cardiovascular events 0.44 (0.35
0.55)

50 to <75
0.51 (0.42
0.62)

75 to <100
0.56 (0.46
0.67)

100 to <125
0.58 (0.48
0.69)

125 to <150
0.64 (0.53
0.79)

Similarly, the reduction in major cardiovascular, major coronary, and cerebrovascular events was
significantly reduced among individuals who achieved lower and lower non-HDL cholesterol
and apoB levels. Kastelein said a recent paper also suggested that non-HDL cholesterol was a
more powerful risk predictor, closely followed by apoB and LDL cholesterol.
"The role of non-HDL cholesterol is very often discussed in reviews," said Kastelein. "Many
people are slowly starting to believe it might be a better parameter to follow in patients treated
with statins and later on [proprotein convertase subtilisin-kexin type 9] PCSK9-inhibitor therapy,
especially if patients have higher triglycerides or have diabetes or the metabolic syndrome. In
these individuals, non-HDL cholesterol more accurately predicts residual risk."

150 to <
0.71 (0.5
0.89)

Going Low, Low, Low

This latest meta-analysis also showed that physicians can treat to very low levels of LDL
cholesterol without any risk, according to the researchers. In their analysis, Kastelein and
colleagues did not observe an increased risk of side effects among those who had LDL levels <50
mg/dL. This is positive news in the era of novel cholesterol-lowering drugs, said Kastelein.
The editorialists, however, point out that the risk of diabetes with statin therapy has been
documented in clinical studies. In addition, there are some patients who are simply unable to
tolerate high-dose statins. As result, Ben-Yehuda and DeMaria wonder what the future will hold
for patients treated with these other agents.
"Is it acceptable if a patient reaches a desired LDL-cholesterol level at a less than moderate- or
high-intensity statin dose, or is there an additional benefit to receiving a higher dose of a statin?"
they ask. "Also uncertain is whether a statin-sparing combination therapy would be as efficacious
as high-intensity agents."
Boekholdt reports consulting for Pfizer. Kastelein has received honoraria for serving on the
speakers' bureaus of AstraZeneca, Genzyme, Isis Pharma, Kowa, Merck Sharp & Dohme,
Novartis Pharmaceuticals, Pfizer, and Roche. Disclosures for the authors are listed in the
article. Ben-Yehuda and DeMaria report no conflicts of interest.
References
1. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoprotein
and the risk for cardiovascular events. J Am Coll Cardiol 2014;
DOI:10.1016.j.jacc.2014.02.615. Available at: http://content.onlinejacc.org/journal.aspx
2. Ben-Yehuda O, DeMaria AN. LDL-cholesterol after the ACC/AHA 2013 guidelines. J
Am Coll Cardiol 2014; DOI:10.1016.j.jacc.2014.05.020. Available at:
http://content.onlinejacc.org/journal.aspx

Heartwire 2014 Medscape, LLC

Cite this article: Lower LDL Still Best: Very Low Levels of LDL Linked With Reduced CV
Events. Medscape. Jul 28, 2014.

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SPARCL published: Statins should be a part

of preventive management in stroke patients
Shelley Wood
August 09, 2006
Boston, MA - Statin therapy should be initiated soon after stroke or transient ischemic attack
(TIA) to reduce the risk not only of stroke, but also coronary events, even in patients with no
prior cardiovascular disease (CVD), results from the Stroke Prevention by Aggressive
Reduction in Cholesterol Levels (SPARCL) trial show. The findings, first reported by heart
wire in May 2006 when they were presented at the 15th European Stroke Conference, are now
published in the August 10, 2006 issue of the New England Journal of Medicine [1].
I think that, in practice, physicians will start to call for adding statins in folks who are admitted to the hospital with a
stroke or TIA as part of the established preventive management of these patients.

With only a few months for the trial results to be absorbed by clinicians since the data were first
unveiled, primary investigator for the study, Dr Michael Welch (Rosalind Franklin University of
Medicine and Science, Chicago, IL), said it is too soon to know what their impact will be.
Already, however, "most of the vascular neurologists that I've talked to now believe that this will
become an established part of the way patients are managed after they've had a stroke or a TIA,
in addition, of course, to the rigorous control of blood pressure and the use of antiplatelet
medications," Welch told heart wire .
SPARCL: Main findings
SPARCL was the first trial to specifically look at the effect of a statinatorvastatinin
patients with a prior stroke or TIA but with no history of elevated cholesterol or coronary artery
disease. The study randomly assigned 4731 patients with a stroke or TIA within the past one to
six months to either atorvastatin 80 mg/day or placebo. The mean baseline LDL cholesterol in
SPARCL participants was 133 mg/dL (2.6 to 4.9 mmol/L) but dropped to a mean level of 73
mg/dL (1.9 mmol/L) in the atorvastatin-treated patients during the trial, a 37% reduction. LDL
levels fell by 7% during the study over the mean 4.9-year follow-up.
This appeared to translate into a significant reduction in the primary end point of nonfatal or fatal
stroke, which occurred in 11.2% of atorvastatin-treated patients and 13.1% of placebo-treated
patients, a five-year absolute reduction in risk of 2.2% and an adjusted hazard ratio of 0.84
(adjusted p=0.03). No significant differences were seen between the two groups in terms of
adverse events. The treated group also showed significant reductions in fatal stroke, ischemic
stroke, and a trend toward fewer nonfatal strokes, but a slight increase in hemorrhagic stroke,
with a hazard ratio of 1.66. Strikingly, given the lack of baseline CVD in the SPARCL cohort,
risk of major coronary events was also significantly reduced in the atorvastatin-treated patients,

at a rate of 3.4% vs 5.1% (p=0.003).

-SW
"Certainly the cardiologists love this study," Welch told heart wire , "because for them it's
actually a primary-prevention study. Here we have patients who have no known cardiovascular
disease who have had a stroke or TIA, and there was a 35% reduction in heart disease, which is
quite extraordinary. I think that, in practice, physicians will start to call for adding statins in folks
who are admitted to the hospital with a stroke or TIA as part of the established preventive
management of these patients."
Hemorrhage risk should be considered
As noted in previous heart wire coverage of the SPARCL trial, the apparent increased risk of
hemorrhagic stroke was included in the overall stroke analysis, suggesting a net benefit for statin
use. Commenting on the issue, Welch emphasized that the increased hemorrhagic stroke in
atorvastatin-treated patients, while small (2.3% in the atorvastatin arm vs 1.4% in the placebo
arm), has also been seen in other statin trials.
"It's a concern, enough for us to do further analyses to see whether we can identify those patients
who might be at risk so they can be managed in a different way," Welch told heart wire . "We
will certainly look at those conditions like age, male gender, and blood pressure before the event,
which are well-known to be associated with a risk of hemorrhage into the brain, and we'll see if
there's some kind of imbalance between the two groups that might have accounted for this."
At the same time, he cautioned, "The people who do have hemorrhage also are at risk for heart
disease and stroke: they all have hypertension, they all have problems with their lipids and
cholesterol, with obesity, etc, so they will need protection. And in the [SPARCL] study, the
benefits in preventing stroke and heart diseasewhich was remarkable since these folks had no
known heart disease to start withthose benefits far outweigh the small increased risk of
hemorrhage."
In the paper, the authors advise that the potential risk of recurrent hemorrhage "be considered
when one is deciding whether to administer a statin to patients who have had a hemorrhagic
stroke."
A question of timing
Welch also emphasized the "critical" importance of timing of statin treatment, noting that, in the
Heart Protection Study (HPS), which also included patients with previous stroke or TIA but no
established CVD, no benefit of statin treatment was seen in this group.
"If you have a stroke or a TIA your risk of having another one in the next five years is about
40%, but the HPS began to recruit patients about four years after their stroke or TIA. So our

feeling was that it would have been much tougher to show a difference when treating after four
years than within the first six months. And that's when you really want to treat these folks,
because the risk is so high within the next four years, not only for stroke but for death."
Statins, still debatable, but perhaps a place to start
In an editorial accompanying the SPARCL results, Dr David M Kent (Tufts-New England
Medical Center, Boston, MA) observes that while the SPARCL results are "roughly consistent"
with the stroke benefits seen in heart-disease trials, questions about the link between cholesterol
lowering and stroke prevention remain.
Stroke etiology is much more heterogeneous than heart attacks, he notes, and only a minority of
strokes are caused by large-vessel atherothrombosis. Yet, SPARCL enrolled patients with not
only ischemic strokes but also hemorrhagic, embolic, lacunar, and cryptogenic strokes/TIAs,
while patients with atrial fibrillation and other cardiac sources of emboli were excluded.
Cardioembolic strokes are less likely than other types of ischemic stroke to be responsive to
cholesterol-lowering agents, Kent points out.
"This raises the issue of whether the SPARCL results apply to the roughly one in five ischemic
strokes that are cardioembolic in origin," Kent writs. "The heterogeneity of the patients enrolled
in the trial, in terms of not only the cause of stroke but also vascular risk, is important to keep in
mind in the interpretation of the results, since the rate of fatal or nonfatal stroke was relatively
low and the absolute benefit of treatment with atorvastatin was relatively modest. A modest
overall benefit across a heterogeneous population often obscures a more dramatic treatment
effect in an influential subgroup among others that are highly unlikely to benefit."
It does not take recursive subgroup analyses to show that the greatest current risk to patients with ischemic stroke vis-
-vis statins remains gross undertreatment.

Kent also points out that 20% of SPARCL participants had diabetes, and while Framingham risk
scores were not provided in the paper, extrapolating from event rates in the placebo-treated
patients would suggest that the cohort as a whole likely had a 10-year CHD risk of roughly 10%.
Thus, according to the ATP III criteria for statin therapy, "even without any change in guidelines,
it is apparent that many of the patients enrolled would already qualify for statin therapy," Kent
writes.
All the same, he concludes, the SPARCL results will likely add to the mounting momentum
behind adding ischemic stroke as a CHD risk equivalent and the inclusion of statins in stroke
prevention guidelines and quality performance indicators.
"Those who might object to this collective-treatment approach to such a heterogeneous disease
should be reminded of our abysmal performance as individual doctors taking care of individual
patients. . . . Although we can all agree with the calls for careful science and although we await
the various SPARCL substudies to help clarify some controversies, it does not take recursive
subgroup analyses to show that the greatest current risk to patients with ischemic stroke vis--vis
statins remains gross undertreatment."

References
1. SPARCL investigators. High-dose atorvastatin after stroke or transient ischemic attack. N
Engl J Med 2006; 355:549-559.
2. Kent DM. Strokean equal opportunity for the initiation of statin therapy. N Engl J Med
2006; 355: 613-615.

Heartwire 2006
Cite this article: SPARCL published: Statins should be a part of preventive management in stroke
patients. Medscape. Aug 09, 2006.

http://www.medscape.com/viewarticle/787385_print

TNT: Intensive lipid lowering in stable CHD

patients reduces the risk of major
cardiovascular events
Michael O'Riordan
March 08, 2005
Orlando, FL - Lowering LDL cholesterol levels beyond the currently recommended guidelines
received another boost from a new study supporting the 'lower-is-better" premise. The findings,
from the Treating to New Targets (TNT) study, presented today during a late-breaking clinicaltrials session at the American College of Cardiology (ACC) 2005 Scientific Sessions and
published online in the New England Journal of Medicine, showed that lowering LDL
cholesterol levels in stable coronary heart disease (CHD) patients substantially below current
targets results in better clinical outcomes.[1]
In the TNT study, intensive lipid lowering with atorvastatin (Lipitor, Pfizer) 80 mg daily
provided greater protection from major cardiovascular events compared with low-dose
atorvastatin in stable CHD patients. High-dose atorvastatin reduced the primary composite end
point of death from CHD, nonfatal MI, resuscitation after cardiac arrest, and fatal or nonfatal
stroke 22% compared with patients treated with atorvastatin 10 mg, according to the results of a
new study.
"In summary, our findings demonstrate that the use of an 80-mg dose of atorvastatin to reduce
LDL cholesterol levels to 77 mg/dL provides additional clinical benefit in patients with stable
CHD that is perceived to be well controlled at an LDL level of approximately 100 mg/dL," write
Dr John C LaRosa (State University of New York Health Science Center, Brooklyn) and
colleagues. "These data confirm and extend the growing body of evidence indicating that
lowering LDL cholesterol levels well below currently recommended levels can have clinical
benefit."
Reduction of 22% in the primary end point
Last year at the ACC in New Orleans, LA, the Pravastatin or Atorvastatin Evaluation and
Infection Therapy (PROVE-IT) investigators, led by Dr Christopher Cannon (Brigham and
Women's Hospital, Boston, MA), showed that intensive lipid lowering with atorvastatin 80 mg
daily provided greater protection from death and cardiovascular events compared with
pravastatin (Pravachol, Bristol-Myers Squibb) 40 mg daily in patients recently hospitalized
with acute coronary syndromes (ACS).[2]

On the basis of PROVE-IT and data from the Heart Protection Study (HPS), the National
Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) updated the
guidelines for cholesterol management, with significant changes in the treatment of high-risk and
moderate-risk patients. The panel also introduced a more aggressive, but optional, LDL
cholesterol goal of <70 mg/dL for patients at very high risk for CHD, even if baseline LDL
cholesterol was <100 mg/dL.
Still, there was no definitive evidence that intensive statin therapywith a goal of reducing LDL
cholesterol levels to <70 mg/dLwas associated with better outcomes than moderate LDL
cholesterol treatment targets of approximately 100 mg/dL in a population of stable CHD patients.
The primary hypothesis of the TNT study was that an incremental reduction in risk could be
achieved by lowering LDL cholesterol levels beyond the currently recommended minimum
targets.
The TNT trial is a parallel-group study randomizing 10 001 patients from 14 countries to a
double-blind treatment with either atorvastatin 10 mg or 80 mg. Patients included were men and
women aged 35 years to 75 years with clinically evident CHD, defined as previous myocardial
infarction (MI), previous or present angina with evidence of atherosclerotic CHD, or having
undergone a coronary revascularization procedure. All patients entered an eight-week period of
open-label treatment with atorvastatin 10 mg to reduce LDL cholesterol levels to <130 mg/dL
before randomization.
After a median follow-up of 4.9 years, treatment with atorvastatin 80 mg resulted in greater
reductions in LDL cholesterol, reducing LDL levels to 77 mg/dL, whereas those treated with
atorvastatin 10 mg had an average LDL cholesterol level of 101 mg/dL. This greater reduction in
LDL cholesterol levels in patients treated with atorvastatin 80 mg was associated with a 22%
relative reduction in the risk of major cardiovascular events. Individually, the risk of myocardial
infarction was reduced 22% and the risk of nonfatal or fatal stroke 25%.
TNT: Baseline and final LDL cholesterol levels

LDL cholesterol level

Mean baseline LDL cholesterol levels (mg/dL)
Final LDL cholesterol levels (mg/dL)
TNT: Primary efficacy outcomes

Outcome
Total major cardiovascular events (%)
Death from coronary heart disease (%
Nonfatal MI (%)
Resuscitation after cardiac arrest (%)
Fatal or nonfatal stroke (%)

"Our findings indicate that the quantitative relationship between reduced LDL cholesterol and
reduced CHD risk demonstrated in prior secondary-prevention trials of statins holds true even at
very low levels of LDL cholesterol," write the TNT investigators in their paper. "If these results
were extrapolated to clinical practice, the use of an 80-mg dose of atorvastatin to reduce LDL
cholesterol levels from a baseline of 101 mg/dL to 77 mg/dL in 1000 patients with stable CHD
would prevent 34 major cardiovascular events over a period of five years; in other words,
approximately 30 patients would need to be treated to prevent one event."
A total of 60 patients treated with high-dose atorvastatin had a persistent elevation in alanine
aminotransferase, aspartate aminotransferase, or both, compared with nine patients receiving
atorvastatin 10 mg. (1.2% vs 0.2%, p<0.001). There were no persistent elevations in creatine
kinase.
Caution still urged
In an editorial accompanying the published study, Dr Bertram Pitt (University of Michigan
School of Medicine, Ann Arbor) writes that clinicians will need to look critically at the TNT data
to determine whether the results are sufficient to alter clinical practice.[3] Specifically, Pitt notes
that although the study was not adequately powered to observe differences in overall mortality,
there were no differences in this end point between the two therapies and even an increase in the
number of deaths from noncardiovascular causes in those treated with atorvastatin 80 mg.
We need further reassurance as to the safety of this approach before we can advocate a major shift in our current goals
for LDL cholesterol levels in patients with stable CHD.

He notes that while the number of deaths from CHD was reduced by 26 among patients assigned
to high-dose atorvastatin, the number of deaths from noncardiovascular causes increased by 31,
despite no significant increase in the number of deaths due to cancer, accidents, or any other type
of death. If there is an increase in the risk of death from noncardiovascular causes associated
with the 80-mg dose in stable CHD patients, further efforts will be needed to select the subgroup
of patients who are at an increased risk for adverse cardiovascular events to preserve the benefits
of the dose on MI and stroke, he writes. While this increase in noncardiovascular events may be
due to chance, it is still a matter of concern, notes the editorialist.
"We need further reassurance as to the safety of this approach before we can advocate a major
shift in our current goals for LDL cholesterol levels in patients with stable CHD," writes Pitt.
A remaining question, Pitt notes, is whether the effects of the 80-mg dose are due entirely to a
reduction in LDL cholesterol levels or to the pleiotropic effects of high-dose atorvastatin. If the
results are due to reductions in LDL cholesterol, there might be other means of achieving LDL
cholesterol levels of 70 mg/dL that would be equally beneficial with respect to cardiovascular
events but possibly safer, especially in light of the lack of an effect of the 80-mg dose of
atorvastatin on overall mortality, he suggests. Pitt notes that other strategies, including ezetimibe,
nicotinic-acid derivatives, fibrates, and inhibitors of cholesterol ester transfer protein (CETP),
used in combination with a low-dose statin, are potential alternatives to high-dose lipid-lowering

therapy, but all need to be tested and compared with the safety and efficacy of the 80-mg dose of
atorvastatin.
The TNT study was sponsored by Pfizer. LaRosa has received lecture fees from Pfizer, as well as research grants
References
1. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in
patients with stable coronary disease. N Engl J Med 2005; available at:
http://www.nejm.org.
2. Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate
lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;
350:1495-504.
3. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart diseaseis
it time to shift our goals? N Engl J Med 2005; available at: http://www.nejm.org.

Heartwire 2005
Cite this article: TNT: Intensive lipid lowering in stable CHD patients reduces the risk of major
cardiovascular events. Medscape. Mar 08, 2005.

http://www.medscape.com/viewarticle/789379_print

IDEAL: High levels of HDL cholesterol a

poor marker of cardioprotection when
adjusted for apoA-1 and apoB
Michael O'Riordan
June 13, 2007
Helsinki, Finland - An analysis of the Incremental Decrease in Endpoints through
Aggressive Lipid Lowering (IDEAL) study suggests that high levels of HDL cholesterol, when
adjusted for apolipoprotein A1 (apoA-1) and other lipoprotein variables, might be an adverse risk
factor for cardiovascular disease and a poor marker of cardioprotection [1].
Presenting the findings from the analysis at the European Atherosclerosis Society (EAS) 76th
Congress in Helsinki, Finland, investigators showed that increased levels of HDL cholesterol,
when adjusted for apoB and apoA-1, were associated with an increased risk of major cardiac
events, particularly at levels greater than 70 mg/dL.
"Epidemiologic data suggest that HDL cholesterol is an independent, inverse predictor of
coronary heart disease risk," lead investigator Dr Ingar Holme (Ullevl University Hospital,
Oslo, Norway) explained during the late-breaking plenary session. "But recent findings from the
torcetrapib trials have suggested that high HDL-cholesterol levels might have an adverse effect
on CHD risk. On this basis, we looked at the relationship between high HDL-cholesterol levels
and coronary-event rates."
Legacy of torcetrapib spurs analysis
As previously reported by heart wire , torcetrapib was a high-profile cholesteryl-ester-transfer
protein (CETP) inhibitor designed to increase HDL cholesterol and decrease, to a small degree,
LDL-cholesterol levels, a typically antiatherogenic profile. The much-anticipated and heavily
hyped drug was stopped in development in early 2007 when investigators showed it increased
the risk of death and cardiovascular events.
With these concerns in mind, that high levels of HDL cholesterol might actually be harmful, the
IDEAL investigators performed a post hoc analysis of their data to assess the relationship
between HDL-cholesterol levels and coronary heart disease events. Special emphasis was placed
on HDL-cholesterol levels >70 mg/dL, especially when apoA-1 and apoB were kept constant.
The group also wanted to evaluate the predictive ability of increased apoA-1 on major cardiacevent risk, again when HDL cholesterol and apoB were constant.
IDEAL, in a nutshell

The IDEAL study, previously reported by heartwire , was a prospective, randomized, openlabel, blinded-end-point evaluation trial conducted in 8888 patients aged 80 years or younger
with a history of acute MI. The primary end point of coronary death, acute MI, or cardiac arrest
with resuscitation occurred in 463 patients (10.4%) in the simvastatin group and in 411 patients
(9.3%) in the atorvastatin group and was not statistically significantly different between the two
study arms. The composite secondary end point of a major cardiovascular event, defined as
major coronary events and stroke, was significantly reduced in patients treated with atorvastatin.
Similarly, there were reductions in the risk of nonfatal MI, any CHD event, and any
cardiovascular event.
As presented earlier at the EAS meeting, Holme noted that the incidence of major cardiovascular
events in the IDEAL study declined with increasing HDL-cholesterol levels. However, he said
that there was wide variation in the highest quintile, including patients with an HDL-cholesterol
level >54.1 mg/dL, and investigators were interested in the relationship with coronary events at
this high level. After adjustment for various lipoproteins, the risk of major cardiac events was
shown to increase with increasing levels of HDL cholesterol.
Relationship of HDL cholesterol to major cardiac events
Adjustment variable
None
LDL cholesterol
ApoA-1
ApoA-1, LDL cholesterol
ApoA-1, apoB
ApoA-1, LDL cholesterol, apoB
One standard-deviation increase in HDL cholesterol=12 mg/dL

Relationship of apoA-1 to risk of major cardiac events

Adjustment variable
None
HDL cholesterol
HDL cholesterol, apoB
One standard-deviation increase in apoA-1=0.22 g/L

"If we adjust for LDL cholesterol, not much happens," said Holme. "However, once we start to
adjust for apoA-1, this benefit is turned in the direction of risk. If we also adjust for LDL
cholesterol and apoB, a better predictor of risk than LDL cholesterol, then the risk of major

cardiac events starts to become significant." He said that by adjusting for apoA-1 statistically and
increasing HDL cholesterol, the analysis reflects the effects of increasing HDL particle size.
Increased levels of apoA-1, on the other hand, whether or not adjustments were made for HDL
cholesterol and apoB, were associated with decreased risk, said Holme.
"When adjusting for apoA-1 and other lipoprotein variables, a high level of HDL cholesterol
might be a poor marker of cardioprotection," said Holme. "In contrast, apoA-1 may be associated
with decreased major cardiac events across the whole range, whether or not adjustments for HDL
cholesterol and apoB are made."
Holme noted that there are limitations with the analysis, the post hoc nature of the study being
one of them. Adjustments for lifestyle, concomitant medications, or other considerations were
not made either, he noted, adding that these are observational findings from the combined
treatment groups and not from the randomized comparisons.
Why no clinical benefit with the CETP inhibitor?
A second study, by Dr Wim van der Steeg (Academic Medical Center, Amsterdam, the
Netherlands), also suggests that very large HDL particles do not confer protection against
cardiovascular disease, at least when levels of apoA-1 and apoB are kept constant [2].
Presenting the results during the same late-breaking plenary session, van der Steeg, who works
with lipid expert Dr John Kastelein (Academic Medical Center), said the hypothesis of the
present study was that an increase in HDL particle size, induced by CETP inhibitors like
torcetrapib, might affect its antiatherogenic capacity and might result in less functional and
possibly even dysfunctional HDL cholesterol.
In this case-control study, investigators studied 858 cases of fatal and nonfatal MI in the
European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Population
Study and 1491 matched controls. HDL particle size was measured by nuclear magnetic
resonance spectroscopy. The focus of the analysis was the relationship between HDL particle
size and cardiovascular events, particularly with very large HDL particles.
After adjustment for classical cardiovascular risk factors, as well as for apoA-1 and apoB, very
large HDL particles, those >9.5 nm, were associated with an increased cardiovascular risk. Very
high levels of HDL cholesterol also showed a trend toward increased cardiovascular risk. Very
high levels of apoA-1, following an adjustment for classic cardiovascular risk factors as well as
HDL cholesterol and apoB, were not associated with an increased risk, the group found.
References
1. Holme I, Kastelein JJ, Faergeman O, et al. High HDL-C and CHD risk in statin-treated
CHD patients: Analysis of the Incremental Decrease in Endpoints Through Aggressive

Lipid-Lowering (IDEAL) trial. European Atherosclerosis Society 76th Congress; June

12, 2007; Helsinki, Finland.
2. van der Steeg, Holme I, Boekholdt SM, et al. Relationship between high-density
lipoprotein particle size and coronary artery disease risk in the EPIC-Norfolk Prospective
Study. European Atherosclerosis Society 76th Congress; June 12, 2007; Helsinki,
Finland.

Heartwire 2007
Cite this article: IDEAL: High levels of HDL cholesterol a poor marker of cardioprotection when
adjusted for apoA-1 and apoB. Medscape. Jun 13, 2007.

http://www.medscape.com/viewarticle/583269_print

AHA 2008: JUPITER Hits New Orleans:

Landmark Study Shows Statins Benefit
Healthy Individuals With High CRP Levels
Michael O'Riordan
November 09, 2008
November 9, 2008 (New Orleans, Louisiana) The Justification for the Use of Statins in
Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) started the
American Heart Association (AHA) 2008 Scientific Sessions here today with a bang, shaking
up the field of primary prevention with new data showing that the treatment of apparently
healthy patients with a statin cuts their risk of cardiovascular disease morbidity and mortality by
almost half [1].
In a study of individuals with low LDL cholesterol but elevated C-reactive-protein (CRP) levels,
investigators showed that rosuvastatin (Crestor, AstraZeneca) 20 mg significantly reduced the
primary end point--a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable
angina, revascularization, and confirmed death from cardiovascular causes--by 44% compared
with individuals treated with placebo.
Presented by Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) during the latebreaking clinical-trials session and published online in the New England Journal of Medicine to
coincide with the AHA presentation, investigators showed that the benefits extended to all
subgroups, including "robust reductions in cardiovascular events with statin therapy in women
and black and Hispanic populations, for which data on primary prevention are limited," write the
JUPITER investigators.
Calling JUPITER "one of the most important clinical trials in the long history of statin studies,"
Dr Steven Nissen (Cleveland Clinic, OH) told heartwire that such large reductions in clinical
events in less than two years among patients considered healthy by conventional definitions is
likely to change the guidelines.
"Ideally, if a patient comes to me with normal LDL-cholesterol levels--in JUPITER, the median
LDL-cholesterol level was 108 mg/dL--I tell him to keep doing what he's doing and to go about
his business," said Nissen. "Now, what happens when that same patient arrives in my office and I
know his CRP is elevated? I know that treating him with intensive statin therapy, despite what
the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half."

Dr James Stein (University of Wisconsin Medical School, Madison) echoed the sentiments of
others when he said that the findings are going to pose challenges, particularly as clinicians
grapple with changing how they think about and treat seemingly low-risk patients.
"It is a true landmark in preventive cardiology, not only for its findings, but even more so for the
challenges it raises to our current strategies for use of cholesterol-lowering medications and to
our risk-assessment paradigms," said Stein.
Stopped After 1.9 Years of Study
JUPITER was designed as a four-year study but was stopped by AstraZeneca after just 1.9 years
based on recommendations from an independent data monitoring board and the JUPITER
steering committee. When the study was stopped on March 29, 2008, as reported by heartwire at
that time, the company reported unequivocal evidence of a reduction in cardiovascular morbidity
and mortality among patients treated with rosuvastatin compared with those treated with placebo.
Despite the benefits, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA)
questioned why it was stopped so early, "especially when we have no idea about the long-term
safety of very low LDL levels as achieved in this trial."
Reductions in Cardiovascular Events Line Up in JUPITER
JUPITER is a large, multinational, long-term, double-blind, placebo-controlled, randomized
clinical trial that included 17 802 healthy men and women assigned to rosuvastatin 20 mg or
placebo. The study was designed to assess whether statin therapy should be given to apparently
healthy individuals with normal LDL cholesterols but elevated C-reactive protein levels (CRP
>2.0 mg/L).
Among patients treated with rosuvastatin, LDL-cholesterol levels were cut in half, decreasing
from a median 108 mg/dL at baseline to 55 mg/dL at 12 months. CRP levels were also
significantly reduced, declining from 4.2 mg/L at baseline to 2.2 mg/L at 12 months. Triglyceride
levels were reduced 17% from baseline among those treated with statin therapy. These effects
persisted over the course of the study.
Baseline and Change in LDL Cholesterol and CRP Levels During Study Period
Measure

Baseline

12 mo

24 mo

36 mo

48 mo

Rosuvastatin 20 mg

108

55

54

53

55

Placebo

108

110

108

106

109

Rosuvastatin 20 mg

4.2

2.2

2.2

2.0

1.8

Placebo

4.3

3.5

3.5

3.5

3.3

LDL cholesterol (mg/dL)

High-sensitivity CRP (mg/L)

p<0.001 for all between-group comparisons

After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary
composite end point 44% compared with placebo. This reduction was observed among nearly all
of the individual end points, including a 55% reduction in nonfatal MI, a 48% reduction in the
risk of nonfatal stroke, and a 47% reduction in the risk of hard cardiac events (a composite of
MI, stroke, and death from cardiovascular causes).
In terms of absolute benefits, the proportion of patients who had an MI, stroke, revascularization,
or hospitalization for unstable angina or died from cardiovascular causes was 1.6% in the
rosuvastatin arm and 2.8% in the placebo arm, an absolute risk reduction of 1.2%. Similarly, the
proportion of patients with hard cardiac events--cardiovascular death, MI, and stroke--was
reduced from 1.8% in the placebo arm to 0.9% in the rosuvastatin arm, an absolute reduction of
0.9%.
JUPITER: Outcomes According to Study Group
End point

Patients with event,

Patients with event, Hazard
rosuvastatin (n=8901), placebo (n=8901), n ratio (95%
n
CI)

Primary end point*

142

251

0.56 (0.46
0.69)

Nonfatal MI

22

62

0.35 (0.22
0.58)

Any MI

31

68

0.46 (0.30
0.70)

Nonfatal stroke

30

58

0.52 (0.33
0.80)

Any stroke

33

64

0.52 (0.34
0.79)

Revascularization

71

131

0.54 (0.41
0.72)

Hospitalization for unstable

angina

16

27

0.59 (0.32
1.10)

Revascularization or
hospitalization for unstable
angina

76

143

0.53 (0.40
0.70)

MI, stroke, or death from

cardiovascular causes

83

157

0.53 (0.40
0.69)

Death on any known date

190

235

0.81 (0.67
0.98)

Any death

198

247

0.80 (0.67
0.97)

*Primary end point: composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from
cardiovascular causes

A subgroup analysis revealed no heterogeneity in any of the results, including an analysis of

subgroups based on age, race, or ethnic group, as well as baseline LDL-cholesterol and CRP
levels. The investigators report that even patients considered to be at very low risk--those who
did not smoke, were not overweight, did not have metabolic syndrome, or had a Framingham
risk score of 10% or less--benefited from statin therapy.
Of note, among the 6801 women included in JUPITER, rosuvastatin significantly reduced the
primary composite end point by 46%. "These are our most impressive data in women in the
primary-prevention setting," Dr Roger Blumenthal (Johns Hopkins Medical Institute,
Baltimore, MD) told heartwire .
In terms of side effects, significantly more patients in the rosuvastatin arm developed new
diabetes, and they also had significantly higher glycated hemoglobin levels, report investigators.
Any reported serious adverse events were similar between the placebo and statin-therapy arms.
Lulled Into a False Sense of Security With "Normal" LDL Cholesterol Levels
To heartwire , Stein said the results, despite the significant risk reduction in apparently healthy
individuals, are not surprising. He praised the JUPITER investigators and the study sponsor for
exposing the current LDL-cholesterol thresholds for lipid-lowering therapy as arbitrary, but more
important, as a poor indicator of cardiovascular risk.
"Many patients with heart attacks have normal LDL-cholesterol values," said Stein. "Thus,
doctors and patients are lulled into a false sense of security when their LDL cholesterol is
'normal' and then are surprised when they have a heart attack. JUPITER illustrates this point
perfectly. If you look at the median values--age 66 years, body-mass index 28.3 kg/m2, systolic
blood pressure 134 mm Hg, and 41% with metabolic syndrome--you know these people are
going to have heart attacks and strokes and die. Indeed, in the placebo arm, the event rate was
1.36% per year. But current guidelines say not to treat them."
Nissen pointed out that there has been a lot of recent pushback against the cholesterol hypothesis,
with many speculating that lowering LDL-cholesterol levels had no impact on the reduction of
cardiovascular risk. Patients in the JUPITER study, he pointed out to heartwire , had a
significant 50% reduction in LDL-cholesterol levels, coupled with the significant 37% reduction
in CRP levels, and this suggests that LDL cholesterol remains an important end point clinicians
should treat.
"Reducing LDL cholesterol while at the same time treating inflammation is one of the reasons
why this treatment was so successful," said Nissen. Two other studies, analyses of the PROVEIT and REVERSAL trials, by Ridker and Nissen, respectively, previously showed that lower

CRP levels are associated with fewer cardiovascular events independent of LDL-cholesterol
levels [2,3]. Stein said he thinks LDL-cholesterol levels of 100 mg/dL are still too high if the
patient has other markers of risk, such as increased age, obesity, and hypertension.
Should Every Patient Undergo CRP Testing?
In an editorial accompanying the published study, Dr Mark Hlatky (Stanford University School
of Medicine, CA) agreed that guidelines are likely to be revisited, although he is cautious on just
how big an impact the findings will have on clinical practice [4].
JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even
among persons who would not currently be considered for pharmacotherapy.

"JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing
cardiovascular risk, even among persons who would not currently be considered for
pharmacotherapy," writes Hlatky. "Guidelines for primary prevention will surely be reassessed
on the basis of the JUPITER results, but the appropriate size of the orbit of statin therapy
depends on the balance between the benefits of treatment and its long-term safety and cost."
To heartwire , Kaul said he is not quite as bullish on the findings as others, noting that nearly
one out of every five patients screened was enrolled, which has implications about the
generalizability for clinical practice, as very few patients have elevated CRP without traditional
risk factors. Moreover, clinicians and health-policy experts should focus on the absolute risk
reductions, he said.
"The absolute risk differences are less impressive than the relative differences and, together with
cost and long-term safety considerations, will serve to temper the conclusions of the study," said
Kaul.
In his editorial, Hlatky calculated that 120 patients need to be treated for 1.9 years to prevent one
death from cardiovascular causes, MI, or stroke, and this benefit needs to be balanced against
concerns about significantly higher glycated hemoglobin levels and increased diabetes incidence
observed in the rosuvastatin arm. The JUPITER investigators, on the other hand, calculated the
number needed to treat (NNT) based on the primary-end-point event and report that the NNT
with rosuvastatin for two years to prevent one primary end point is 95 and just 31 need to be
treated for four years to prevent one primary-end-point event.
In his editorial, Hlatky said the design of JUPITER provides only limited information about the
role of CRP testing in clinical practice, since investigators did not compare subjects with and
without CRP measurements and did not compare the use of CRP with the use of other markers of
cardiovascular risk.
"At this point, the current guidelines for measurement of high-sensitivity CRP remain
reasonable," writes Hlatky. Measurements of CRP may be obtained in asymptomatic individuals
who have an intermediate level of risk, based on standard clinical risk markers, and in whom

treatment might change depending on the high-sensitivity CRP level. Blumenthal said most
doctors use CRP as a "tie-breaker" to make a decision about which men >50 years and women
>60 years would benefit from statins.
Stein told heartwire that the use of more widespread screening of CRP values needs more
investigation. The test has high variability and is elevated with infections and injuries, so
abnormally high CRP levels do not always reflect arterial injury or cardiovascular-disease risk.
"However, I suspect we should start using it more often," he said. "For starters, it makes
communication easier. It summarizes a myriad of metabolic problems that individually are not
bad enough to treat but collectively indicate increased risk. Increased CRP tells you that. It is
one number, and explaining and implementing it may be easier for physicians and patients than
trying to explain why 'borderline' high blood pressure and being 'a little overweight' are bad.
They damage and inflame blood vessels, and high CRP shows it."
AstraZeneca sponsored the JUPITER study.
1. Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in
men and women with elevated C-reactive protein. New Engl J Med 2008; DOI:
10.1056/NEJMoa0807646. Available at: http://www.nejm.org.
2. Ridker PM, Cannon CP, Morrow D et al. C-reactive protein levels and outcomes after
statin therapy. New Engl J Med 2005; 352:20-8. Abstract
3. Nissen SE, Tuzcu EM, Schoenhagen P et al. Statin therapy, LDL cholesterol, C-reactive
protein, and coronary artery disease. N Engl J Med 2005l 352: 29-38. Abstract
4. Hlatky M. Expanding the orbit of primary prevention--moving beyond JUPITER. New
Engl J Med 2008; 359: published online before print November 9, 2008. DOI:
10.1056/NEJMe0806320. Available at: http://www.nejm.org.

Heartwire 2008 Medscape

Cite this article: Michael O'Riordan. AHA 2008: JUPITER Hits New Orleans: Landmark Study
Shows Statins Benefit Healthy Individuals With High CRP Levels. Medscape. Nov 09, 2008.

http://www.medscape.com/viewarticle/814152_print

New Cholesterol Guidelines Abandon LDL

Targets
Michael O'Riordan
November 14, 2013
WASHINGTON, DC It's been more than a decade since the Adult Treatment Panel (ATP)
issued the third report for the detection, evaluation, and treatment of elevated cholesterol and
nine years since those recommendations were updated, but new guidelines from the American
College of Cardiology (ACC) and American Heart Association (AHA), developed in
conjunction with the National Heart, Lung, and Blood Institute (NHLBI), are now available
online in both the Journal of the American College of Cardiology and Circulation [1].
And they contain some substantial changes from ATP 3.
Gone are the recommended LDL- and non-HDLcholesterol targets, specifically those that ask
physicians to treat patients with cardiovascular disease to less than 100 mg/dL or the optional
goal of less than 70 mg/dL. According to the expert panel, there is simply no evidence from
randomized, controlled clinical trials to support treatment to a specific target. As a result, the new
guidelines make no recommendations for specific LDL-cholesterol or non-HDL targets for the
primary and secondary prevention of atherosclerotic cardiovascular disease.
Instead, the new guidelines identify four groups of primary- and secondary-prevention patients in
whom physicians should focus their efforts to reduce cardiovascular disease events. And in these
four patient groups, the new guidelines make recommendations regarding the appropriate
"intensity" of statin therapy in order to achieve relative reductions in LDL cholesterol.
No Evidence for Treating to Specific Targets
Dr Neil Stone (Northwestern University Feinberg School of Medicine, Chicago, IL), the chair of
the expert panel who wrote the guidelines, spoke with the media during a conference call and
said there were some problems with treating to goal, specifically in patients who were treated
close but not exactly to target.
"In secondary prevention, what if your patient is on high-intensity statin therapy and gets an
LDL-cholesterol level of 78 [mg/dL] and is adhering to an excellent lifestyle?" said Stone. "From
our point of view, there is a large body of evidence that says he's actually doing as good a job as
he can possibly do. If he has to get to an optional goal of under 70 [mg/dL] as some would
advocate, it means adding on medicines for which there is not proven benefit."

In addition, the panel said that the use of LDL-cholesterol targets might result in the
overtreatment of patients with nonstatin drugs. These other agents have not been shown to reduce
the risk of atherosclerotic cardiovascular disease.
Dr Donald Lloyd-Jones (Northwestern University Feinberg School of Medicine), the cochair of
the guidelines on the assessment of cardiovascular risk, which were also released today along
with guidelines for the management and treatment of obesity and guidelines for lifestyle
management, said the evidence for treating to target simply isn't there, but that doesn't mean
repeated measurements of LDL cholesterol won't be needed.
"There have been no clinical trials in which they've taken an approach where they've titrated
medication dosing to achieve a certain LDL level," said Lloyd-Jones. "We just haven't had those
trials designed or performed yet. So we just couldn't endorse that kind of approach. And yet,
we're not abandoning the measurement of LDL cholesterol, because it's perhaps our best marker
of understanding whether patients are going to achieve as much benefit as they can for the dose
of statin they can tolerate. For the clinician, it's also a very important marker of adherence."
Stone acknowledged that the old targets might be part of the "mind-set" of physicians but said
the new recommendations actually simplify treatment in that doctors won't have to fuss around
with additional means to lower LDL cholesterol if the patient has been treated with an
appropriate dose of statin therapy.
The Four Major Statin Groups
The four major primary- and secondary-prevention patient groups who should be treated with
statins were identified on the basis of randomized, controlled clinical trials showing that the
benefit of treatment outweighed the risk of adverse events. The four treatment groups include:

Individuals with clinical atherosclerotic cardiovascular disease.

Individuals with LDL-cholesterol levels >190 mg/dL, such as those with familial
hypercholesterolemia.

Individuals with diabetes aged 40 to 75 years old with LDL-cholesterol levels between 70
and 189 mg/dL and without evidence of atherosclerotic cardiovascular disease.

Individuals without evidence of cardiovascular disease or diabetes but who have LDLcholesterol levels between 70 and 189 mg/dL and a 10-year risk of atherosclerotic
cardiovascular disease >7.5%.

In those with atherosclerotic cardiovascular disease, high-intensity statin therapysuch as

rosuvastatin (Crestor, AstraZeneca) 20 to 40 mg or atorvastatin 80 mgshould be used to
achieve at least a 50% reduction in LDL cholesterol unless otherwise contraindicated or when
statin-associated adverse events are present. In that case, doctors should use a moderate-intensity
statin. Similarly, for those with LDL cholesterol levels >190 mg/dL, a high-intensity statin
should be used with the goal of achieving at least a 50% reduction in LDL-cholesterol levels.

For those with diabetes aged 40 to 75 years of age, a moderate-intensity statin, defined as a drug
that lowers LDL cholesterol 30% to 49%, should be used, whereas a high-intensity statin is a
reasonable choice if the patient also has a 10-year risk of atherosclerotic cardiovascular disease
exceeding 7.5%.
For the individual aged 40 to 75 years without cardiovascular disease or diabetes but who has a
10-year risk of clinical events >7.5% and an LDL-cholesterol level anywhere from 70 to 189
mg/dL, the panel recommends treatment with a moderate- or high-intensity statin.
"In the primary-prevention-therapy decisions, we insisted that the patient and the physician have
a discussion to determine what the benefits and risks are specifically for that patient," said Stone.
This discussion should focus on the patient's characteristics and preferences to determine the best
therapy.
To assess the patient's degree of risk, a new global risk assessment tool was developed by the
expert panel. The new cardiovascular risk score is designed to assess the risk of an initial
cardiovascular event and includes participants from racially and geographically diverse cohorts
such as the Framingham Heart Study (FHS), the Atherosclerosis Risk in Communities
(ARIC) study, the Coronary Artery Risk Development in Young Adults (CARDIA), and the
Cardiovascular Health Study (CHS). The new pooled cohort equations predict the future risk
of cardiovascular disease and also stroke.
New Risk Score Raises Eyebrows
To heartwire , Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD), who
was not part of the writing committee, said he agreed with 90% of the information in the new
guidelines. "To put that in perspective, I probably only agree with my wife 85% of the time," he
said.
I don't even agree with my wife 100% of the time.

Namely, he is a little troubled by the new atherosclerotic risk score. Derived from FHS, ARIC,
CARDIA, and CHS, it hasn't performed all that well when applied to other cohorts, such as the
Multiethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial
Differences in Stroke (REGARDS) study, he said. The risk score does not take into account
family history of premature cardiovascular disease, triglycerides, waist circumference, bodymass index, lifestyle habits, and smoking history.
"In my mind, we're putting a lot of faith in this risk score," said Blumenthal. "We're probably
going to be treating many more people, especially many more ethnic minorities, who get above
this 7.5% threshold."
Dr Brendan Everett (Brigham and Women's Hospital, Boston, MA) told heartwire that the
expert panel is going "out on a limb" a little with regard to the new risk score. He said that while
a risk-prediction algorithm was used in the ATP III guidelines, a number of large statin trials

have been published to date, and none of these studies used a risk score to identify patients for
inclusion.
"If the model performs poorly, of course, then it's unlikely to do a good job separating patients at
a higher rather than lower 10-year atherosclerotic cardiovascular disease risk, and it will thus
lead to misallocation of statins," commented Everett. "Even if it does perform well, using a risk
score to identify individuals who will benefit from statin therapy, regardless of the etiology of
their elevated risk, is not an approach that has been tested in any clinical trial."
Will There Be Any Controversy?
The aspect of the new guidelines that will likely receive the most pushback from physicians is
treating individuals with LDL-cholesterol levels ranging from 70 to 100 mg/dL, the so-called
"normal" levels, simply because their risk score exceeds 7.5%. The risk score, argues
Blumenthal, is dominated largely by chronological age, blood pressure, and smoking status.
"Patients could have a completely normal lipid profile, with normal triglycerides, HDL
cholesterol, and LDL cholesterol, but because of what your birth certificate says, or because your
blood pressure is 145 [mm Hg], the guidelines will now recommend treatment," Blumenthal told
heartwire . "I think this is going to be problematic for a lot of physicians and patients because
just last week you would have said their LDL-cholesterol levels of 80 or 90 [mg/dL] is optimal."
Dr Steven Nissen (Cleveland Clinic, OH) said the guidelines are a "radical change" from ATP
III, but he agrees with moving away from the traditional targets. "Those goals, of less than 70 or
less than 100 [mg/dL], were never based on any kind of careful scientific study," said Nissen.
"They were helpful to physicians and patients because they were a target. The guideline writers
threw out those goals and are working very hard to identify patients in whom statins provide
benefit."
Nissen also said treating patients with a calculated risk exceeding 7.5% is a lower threshold for
treatment than previous guidelines and likely expands the use of statins to millions of patients
who would not have otherwise been treated under the ATP III guidelines. What will help is that
the drugs are so cheap, now that all the statins, with the exception of rosuvastatin, are available
as generic medications.
"I think it makes sense," said Nissen. "Statins have had a profound impact on the risk of morbid
and mortal events for heart disease. They are generally very safe. The old guidelines previously
emphasized the treatment of patients in older age groups. Now it's easier to look at people in
their 40s or 50s and have them reach a 7.5% risk. In many ways, that's good, because if you wait
until people are older to treat them, they'll already have vascular disease by the time you begin
treatment. The point of treatment is to prevent disease."
Blumenthal said another limitation to the guidelines is in selecting 70 mg/dL as the threshold for
treatment if their 10-year risk exceeds 7.5%. There would likely be less resistance to change if
the guideline writers selected 100 mg/dL as the lower threshold for treatment in this group, he
suggested. He agreed that physicians who don't advocate statin therapy in patients who have not

yet had a cardiovascular event, the primary-prevention cohort, might be upset that more
Americans are going to be treated with the lipid-lowering drugs.
Fire and Forget
Overall, nearly every expert consulted agreed with the shift away from specific LDL-cholesterol
treatment targets given the lack of evidence and with the emphasis on using maximum tolerated
statin intensity. As Everett said, "there are really no other good data in this broad population that
anything works as well as a statin." He noted the previous guidelines left more room for doctors
to use nonstatin agents, but none of them have been shown to reduce hard clinical end points.
Nissen told heartwire the new recommendations should generally help make treatment easier for
aware physicians, in that there is a decision to treat followed by a decision on dose. He used a
military term to describe the approach, "fire and forget," in that physicians won't have to titrate to
goal but instead choose a statin known to achieve a given relative reduction in LDL-cholesterol
levels. He adds there is the possibility of confusion among some doctors given the switch away
from targets, and this might lead to treatment inertia.
Dr Michael Miller (University of Maryland, Baltimore, MD) agreed about the increased ease of
use with the new guidelines. "In a way, the guidelines are easier because it's either moderate or
high dose, and it knocks out other medications like fibrates, niacin, and ezetimibe unless
patients are statin intolerant or they can't get the desired LDL lowering," he told heartwire . "It
does bring a bit more focus in on simplifying the regimen until we get new data."
He added he was not surprised by the shift away from specific targets, adding that writing
committee largely "got it right based on what we know today." The Pravastatin or Atorvastatin
Evaluation and Infection Therapy (PROVE-IT) trial, for example, was a secondary-prevention
study that led the way for "lower is better" in acute coronary syndrome patients, but that trial
tested a moderate-intensity statin vs a high-intensity statin. It did not compare outcomes based on
specific treatment targets.
"The problem I foresee now is what to do with patients we've been taking care of for a period of
time," said Miller. "I have patients I've been taking care of for 20 years, and they've been doing
fine on a moderate statin. Am I now going to push the envelope?"
The strongest recommendation, he believes, will be to institute moderate or intensive statin
therapy in patients coming into the clinic now or for the statin-naive patient. For the patient who
has not yet been maximized on an intensive statin but who has had a coronary event years ago,
there is insufficient evidence to make changes, said Miller.
Other Recommendations
In addition to identifying the four statin groups, the focus on intensity rather than goals, and the
new global risk assessment equations for primary prevention, the new cholesterol guidelines also
make recommendations on safety and provide guidance on the role of biomarkers and other
noninvasive tests.

In the new guidelines, the ACC/AHA state that in selected individuals who don't fit into any of
the four groups, additional factors can be considered if the decision to start statin therapy is
unclear. The factors include family history of premature atherosclerotic cardiovascular disease in
a first-degree relative, high-sensitivity C-reactive protein (CRP) >2 mg/L, the presence of
calcification on a coronary artery calcium (CAC) scan, and an ankle-brachial index <0.9.
The writing committee also states that the new guidelines are not intended to provide a
comprehensive approach to managing lipids and that many unanswered questions remain. These
future questions, such the use of non-HDL cholesterol in decision-making, the role for treating
high triglycerides, and whether treating markers such as apolipoprotein B or LDL particles is
useful, will hopefully be examined in future randomized trials and incorporated in future
guidelines.
Stone and Lloyd-Jones report no conflicts of interest. Disclosures for the coauthors are listed in
the paper. Blumenthal reports no conflicts of interest. Everett reports grant support from Roche
Diagnostics, the NHLBI, and Novartis. Nissen reports consulting for all the major
pharmaceutical companies, including AstraZeneca, the makers of Crestor, but does not accept
financial compensation. Miller reports consulting for Amarin and GlaxoSmithKline and receives
research funding from Amgen, Eli Lilly, Merck, Roche, and Takeda Pharmaceuticals.
References
1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment
of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the
American College of Cardiology/American Heart Association. J Am Coll Cardiol 2013.
Article. Circulation 2013. Article.

Heartwire 2013
Cite this article: Michael O'Riordan. New Cholesterol Guidelines Abandon LDL
Targets. Medscape. Nov 12, 2013.

Related links
1. [HeartWire > News; Jun 03, 2003]
2. [HeartWire > News; Jul 4, 2002]

Heartwire 2004
Cite this article: Ten-year follow-up from 4S study shows survival benefits of simvastatin
endure. Medscape. Aug 27, 2004.

http://www.medscape.org/viewarticle/834329?
nlid=71507_2802&src=cmemp
News Author: Pauline Anderson
CME Author: Charles P. Vega, MD

Stroke is the fourth leading cause of death in the United States, and the authors of
the current guidelines provide a review of the epidemiology of stroke. During the
past 40 years, the prevalence of stroke has declined by more than 40% in
developed countries, but it has more than doubled in low-income and middleincome countries. In general, the risk for stroke increases as adults age -approximately 9% per year among men and 10% per year among women.
Stroke is often not fatal but still results in a substantial rate of disability.
Approximately one-quarter of adults 65 years or older are dependent in their
activities of daily living 6 months after a stroke, and nearly half experience longterm cognitive deficits.
Just 10 potentially modifiable risk factors account for approximately 90% of strokes,
meaning that patients and clinicians can dramatically reduce the morbidity and
mortality of stroke. The current comprehensive guidelines by Meschia and
colleagues focus on the primary prevention of stroke.
Study Synopsis and Perspective
New oral anticoagulants in patients with atrial fibrillation (AF), home blood pressure
monitoring in patients with hypertension, smoking cessation, nonestrogen oral
contraceptives for women experiencing migraine with aura, and the healthy
Mediterranean diet for all patients.
These are among the new recommendations for primary prevention of stroke
released by the American Heart Association (AHA)/American Stroke Association. The
updated guideline was published online October 28 in Stroke.
Through the years, there have been numerous advances in preventing stroke,
including medications to control blood pressure and lipids, anticoagulants for at-risk
patients with AF, revascularization, smoking cessation programs, and changes in
diet and physical activity level, write the guideline authors, led by James F. Meschia,
MD, FAHA, professor and chair, neurology, Mayo Clinic, Jacksonville, Florida.
"With so many interventions, optimization of stroke prevention for individuals
requires systems of care that identify risk factors as they emerge and that gain
control of emerging risk factors safely, expeditiously, and cost-effectively."

The latest iteration of the guideline, which summarizes the evidence for established
and emerging stroke risk factors, is an update of the last AHA statement, published
in 2011. Targets for stroke prevention in the new document have been "reordered"
to align with the AHA's "Life's Simple" public health campaign for cardiovascular
health, the authors write.
Atrial Fibrillation
One of the most important changes, Dr Meschia said, is the expansion of the
recommendation for oral anticoagulants to include agents other than warfarin for
patients with nonvalvular AF who are at acceptably low risk for hemorrhagic
complications (options now include dabigatran, apixaban, and rivaroxaban as well
as warfarin).
"We are now recognizing the important role of the novel oral anticoagulants as an
alternative to warfarin," he told Medscape Medical News. "Not that they are
superior, but we recognize that there is sufficient evidence to recommend them as
an alternative for stroke prevention."
He stressed that "by no means are we saying that everyone needs to stop their
warfarin and switch; what we're basically saying is that people now have options,
and legitimate options."
Some patients with AF are "very reluctant" to take warfarin because of "the rigors"
involved with frequent monitoring, he added.
Although public awareness is growing, gaps in the field include the underuse of
anticoagulants by suitable patients with AF, particularly those who are elderly, the
authors note.
Home BP Monitoring
The committee added several new recommendations pertaining to hypertension.
One is self-monitoring of blood pressure.
"There's now a more explicit acknowledgement that home blood pressure
monitoring is useful," said Dr Meschia. "This is important for a lot of reasons,"
including that it "empowers patients" and can lead to better blood pressure control,
he said.
"It's an acknowledgment that the automated cuffs are getting better and are more
reliable, and that with advancing technology, there are going to be greater and
greater opportunities to monitor health variables, and fitness variables," he added.
Importantly, the committee decided to retain the target systolic blood pressure of
140 mm Hg, regardless of age. "That's a little controversial," said Dr Meschia.

"Some folks had recommended perhaps that in older individuals, that goal could be
liberalized."
Other recommendations relating to hypertension are regular blood pressure
screening and appropriate treatment of patients with hypertension, including
lifestyle modification and pharmacologic therapy, and annual blood pressure
screening and health-promoting lifestyle modification for patients with
prehypertension.
Successful reduction of blood pressure is more important in reducing stroke risk
than is the choice of a specific agent, and treatment should be individualized on the
basis of other patient characteristics and medication tolerance, the authors
stressed.
Women With Migraine
The updated document has new recommendations on migraine. The experts
recommended smoking cessation in women with migraine headaches with aura and
that these women use alternatives to oral contraceptives, especially those
containing estrogen.
The guideline committee also focused on risk assessment tools, such as the AHA
and American College of Cardiology Risk Calculator. These tools, the committee
said, may be useful in uncovering stroke risks, but treatment decisions should be
considered in the context of a patient's overall risk profile.
According to the committee, all such tools have limitations. For example, newer risk
factors, such as obstructive sleep apnea, that were not collected in older studies
need to be considered.
"Risk assessment tools should be used with care because they do not include all the
factors that contribute to disease risk. Some potential for harm exists from
unnecessary application of interventions that may result from inappropriate use of
risk assessment tools or from the use of poorly adjudicated tools."
They also stressed that risk assessment tools need to be validated across age,
gender, and race/ethnic groups.
Another new recommendation advocates for following a Mediterranean diet that is
supplemented with nuts. Other dietary recommendations are to reduce intake of
sodium and increase intake of potassium, and to follow the DASH-style (Dietary
Approaches to Stop Hypertension) diet, which emphasizes fruits, vegetables, low-fat
dairy products, and reduced saturated fat.
Overweight and Obesity

The new guideline defines overweight and obesity on the basis of body mass index
(BMI). The committee recommended weight reduction to lower blood pressure in
patients who are overweight (BMI of 25 - 29 kg/m2) and obese (BMI >30 kg/m2).
In the category of cigarette smoking, the committee deemed that community-wide
or statewide bans of smoking in public spaces is reasonable for reducing the risk for
stroke. The authors noted, however, a lack of data showing that participating in
smoking cessation programs leads to a long-term reduction in stroke.
Because of its association with stroke risk, the committee recommended screening
for sleep apnea through a detailed history, including physical examination;
polysomnography where indicated; and structured questionnaires, this latest being
a new element, said Dr Meschia. The committee noted, however, that although
treating sleep apnea is reasonable, its effectiveness in preventing stroke is
unknown.
Another new aspect of the updated guideline is that patients with asymptomatic
carotid stenosis are encouraged to take daily aspirin and a statin. The previous
guideline did not explicitly state this except in the perioperative and postoperative
context.
Specific Circumstances
In the category of genetic factors, pharmacogenetic dosing of vitamin K antagonists
should now be considered when therapy is initiated. The committee also slightly
updated recommendations for prevention of stroke in a variety of other specific
circumstances, including sickle cell disease.
According to background information in the guideline paper, approximately 795,000
people in the United States sustain a stroke each year, roughly 610,000 of them for
the first time. This results in 6.8 million adult stroke survivors.
Stroke is a leading cause of functional impairment. Six months after a stroke, 26%
of those 65 years and older are dependent on others for their activities of daily
living and 46% have cognitive deficits.
Effective primary prevention is the best approach for reducing the burden of stroke,
said the authors. "Primary prevention is particularly important because >76% of
strokes are first events," they write. "Fortunately, there are enormous opportunities
for preventing stroke."
The authors cited an international case-control study of 6000 individuals that found
10 potentially modifiable risk factors explained 90% of the risk for stroke.
"[S]troke-prone individuals can readily be identified and targeted for effective
interventions," they said.

The American Academy of Neurology affirms the value of these guidelines as an

educational tool for neurologists. The guideline is endorsed by the American
Association of Neurological Surgeons, the Congress of Neurological Surgeons, and
the Preventive Cardiovascular Nurses Association.
Stroke. Published online October 28, 2014. Abstract
Study Highlights
Risk calculators, such as that endorsed by the AHA and the American College of
Cardiology, can be useful in assessing patients risk for stroke in a holistic context.
However, these tools should not absolutely dictate treatment decisions for each
individual patient.
Not all strokes are ischemic. Clinicians should consider noninvasive screening of
the cerebral vasculature for patients with at least 2 first-degree relatives with a
history of subarachnoid hemorrhage or intracranial aneurysms.
The minimal amount of exercise recommended to prevent stroke is 40 minutes
per day at 3 to 4 days per week.
Statins should be first-line agents for stroke prevention among patients who meet
the 10-year risk criteria for use of these drugs.
Niacin can raise high-density lipoprotein cholesterol levels, but it is unproven in
preventing stroke. Similarly, fibric acid derivatives may not actually prevent stroke.
Hypertension should be treated to a goal blood pressure of less than 140/90 mm
Hg to prevent stroke. Achieving target blood pressure is, in itself, more important
than the types of medications used to treat hypertension.
However, evidence exists that reducing systolic blood pressure to a target of less
than 130 mm Hg may prevent more strokes.
Self-measured blood pressure monitoring helps to reduce overall blood pressure
values and is recommended.
A graded positive relationship appears to exist between the degree of obesity and
the risk for stroke, regardless of other cardiovascular risk factors. Weight loss
reduces blood pressure and blood glucose levels and has been demonstrated to
reduce the risk for stroke in long-term research protocols.
Comorbid diabetes should not alter blood pressure targets to prevent stroke, but
these patients should preferentially receive a statin. The 10-year overall
cardiovascular risk profile should be used to decide on aspirin prophylaxis for these
patients; the presence of diabetes alone is less appropriate as an indication for
aspirin therapy.

Dabigatran has been associated with lower risks for stroke and embolic events
compared with warfarin, as well as a lower risk for intracranial hemorrhage, among
patients with AF. However, dabigatran was associated with a higher risk of
gastrointestinal bleeding vs warfarin. Dabigatran may also slightly increase the risk
for myocardial infarction.
Rivaroxaban is more similar to warfarin in risk reduction for stroke or embolism
among patients with AF, with a lower risk of serious bleeding.
Similarly, the benefit of apixaban vs warfarin in cases of AF is more marked for
intracranial hemorrhage vs stroke prevention.
Economic analyses of the 3 new oral anticoagulants have generally been
favorable.
The 3 new anticoagulants and warfarin can be considered for patients with AF
and a CHA2DS2-VASc score of 2 or more. Treatment choice should be individualized
based on patients' risks of bleeding, tolerability, cost, and patient preference.
Patients with AF and a CHA2DS2-VASc score of 0 should not receive anticoagulant
or aspirin therapy, and treatment may also be withheld among patients with a score
of 1.
Patients with mitral stenosis and a previous embolic event should receive
anticoagulant therapy. Even severe mitral stenosis with left atrial enlargement
might serve as an indication for anticoagulants.
For patients who receive an aortic or mitral bioprosthesis, aspirin is sufficient in
stroke prevention.
Patients with asymptomatic carotid stenosis should receive aspirin and a statin.
Carotid endarterectomy may be considered if the level of stenosis exceeds 70% and
the risk for serious perioperative morbidity and mortality is less than 3%, but the
efficacy of endarterectomy vs modern medical therapy is not well established.
Risk stratification using transcranial Doppler ultrasound screening should be
initiated at age 2 years for patients with sickle cell disease, and these patients
should receive annual screening through age 16 years.
Migraine with aura has been associated with a higher risk for stroke among
women. Women with migraine should be urged not to smoke and should consider
other methods of contraception besides oral contraceptives.
Chronic inflammatory diseases, such as rheumatoid arthritis, should be
considered risk factors for stroke.
Annual influenza vaccination may reduce the risk for stroke among high-risk
adults.

Aspirin at a dose of 81 mg per day or 100 mg every other day remains

recommended for patients at high risk for stroke, including those with chronic
kidney disease. Aspirin should not be used to prevent stroke among patients whose
sole risk factor is diabetes or asymptomatic peripheral artery disease.

Clinical Implications
According to the new guidelines on primary stroke prevention, aspirin at a dose of
81 mg per day or 100 mg every other day remains recommended for patients at
high risk for stroke, including those with chronic kidney disease. Aspirin should not
be used to prevent stroke among patients whose sole risk factor is diabetes or
asymptomatic peripheral artery disease.
The new guidelines on primary stroke prevention state that warfarin, dabigatran,
rivaroxaban, and apixaban may be recommended to prevent stroke among high-risk
patients with AF. The main benefit of newer agents compared with warfarin is a
reduction in the risk for intracranial hemorrhage.
*****

http://www.medscape.com/viewarticle/783224_print

Ten-year follow-up from 4S study shows

survival benefits of simvastatin endure
Shelley Wood
August 27, 2004 Fri, 27 Aug 2004 20:30:00
Helsinki, Finland - More than 16 years after the first patient was enrolled in the Scandinavian
Simvastatin Survival Study (4S), the study drug has been shown unequivocally to improve
survival over time, without producing an increase in cancer, when compared with placebo. By
extending patient follow-up an additional five years, the 4S investigators, led by Dr Timo E
Strandberg (University of Helsinki, Finland), have provided the longest follow-up data to date
from a placebo-controlled statin study.
"The main finding of this 10-year follow-up study of the participants of 4S was that the survival
benefit of patients allocated simvastatin compared with those allocated placebo that accrued
during the double-blind trial period persisted during follow-up," the authors observe.
The 10-year results appear in the August 28, 2004 issue of the Lancet. The original 4S results
appeared in the Lancet in 1994.
Enduring benefits
The original 4S results saw simvastatin reducing lipid fractions and cholesterol concentrations as
well as cardiovascular mortality over a five-year period, when compared with placebo. After an
additional five years of follow-up, the investigators report that the 2221 patients who have
remained on simvastatincompared with patients who switched from placebo to statin at the fiveyear markhave enjoyed at 17% reduction in CV mortality and a 24% reduction in coronary
deaths.
4S: Relative risk reduction with simvastatin at five and 10 years

Outcome

Relative risk: Trial conclusio

0.70*
0.64*

0.83*
0.91
*Statistically significant compared with patients taking placebo or originally randomized to placebo

Despite earlier risks that statins might increase cancer risk, the new data show long-term statin
users to have a slightly reduced cancer risk, although this was not statistically significant.
"These findings are reassuring and in accordance with the negative findings on the risk of cancer
in the Heart Protection Study," the authors note.
Indeed, they add, there have been biological and animal studies that have hinted at mechanisms
through which statins might have anticancer effects, but only time will tell what further effects
statins may have beyond the 10-year mark.