With the 2008 Olympic games in Beijing, China, rapidly approaching,
attention is now turned to some of the medical and health challenges
facing the city. In particular, concerns have focused on some of
cardiovascular challenges facing China, challenges that will
continue to plague the country long after the athletes, coaches,
media, and visitors have left the historic city [1].

Dr John Cantwell (Emory University School of Medicine, Atlanta, GA),
who was involved in medical care in the 1996 Olympic games, recently
returned from a trip to China, where he shared his group's medical
experience with an international Red Cross symposium. On his trip,
Cantwell told heartwire, there were some surprises, some of which
have contributed to heart disease being the leading cause of death
of women and the second-leading cause of death in men.

"There are all kinds of cars in Beijing," he said. "The bicycles are
almost all gone. Anywhere we went in the city seemed to take about
an hour to get there."

Traffic is so bad, in fact, that city officials are vowing to cut
motor traffic in half during the Olympic games, mainly in order to
improve air quality and ease traffic flow [2]. The city is toying
with the idea of allowing vehicles on the road on alternate days,
with cars whose license plates end in an even number allowed to
travel one day, and odd numbers the next. Beijing has tried to
reduce pollution through an air-quality monitoring program known as
Blue Sky and has reported progress in doing so, but some have cast
doubt on the measurements and contend that air quality has not
improved in the past decade, according to the New York Times.

"Pollution is important because carbon monoxide bumps oxygen off the
hemoglobin, and so there is less oxygen to nourish the working
muscles," explained Cantwell. "This is a concern, particularly for
athletes in events where even a fraction of a second can be crucial."

Getting the US athletes ready for Beijing

Air quality, despite assurances from the Chinese Olympic committee,
remains a concern for US athletes heading over to Beijing this
summer. Some have even wondered, perhaps jokingly, if they should
run behind a bus to breath in the exhaust or maybe train along a
highway during rush hour, anything that would give them an edge,
according to the New York Times [3].

Luckily, exercise physiologists are steering these highly motivated
athletes in healthier directions. With pollution and smog a concern
for the team, Dr Randy Wilber (United States Olympic Training
Center, Colorado Springs, CO) is encouraging athletes to train in
other parts of Asia and arrive only just before their event. With
others he is trying to gain exemptions to use asthma inhalers. He is
also urging all athletes to wear a mask over their noses and mouths
while in Beijing.

"His multipronged strategy could give the United States team an
advantage over teams from less-prepared countries," writes New York
Times reporter Juliet Macur. "But the plan has a downside: it runs
the risk of offending the host country, creating political tension."

Cantwell told heartwire he is optimistic, however, that pollution
can be reduced, especially if the city shuts down factories
throughout the city as promised. However, he noted that while
pollution remains a concern for the athletes, cutting traffic is
important so as to be able to transport ailing spectators and
athletes through the congested city.

"This can be an issue when you have an emergency and need to
transport somebody from one site to another," said
Cantwell. "They'll need to work out ways to get them there, whether
by helicopter or special access lanes."

Fewer bikes, more cars, and much more fast food

During his trip to China, Cantwell said in addition to fewer
bicycles and more cars, he noticed an abundance of fast-food
restaurants. The Chinese diet, he said, appears to be adopting many
of the eating behaviors leading to coronary disease in the West.
Studies, in fact, estimate that 86 million Chinese are in need of
lifestyle changes--diet, exercise, blood-pressure control, and more--
because of hypercholesterolemia, and 35 million more qualify for
cholesterol-lowering medication on the basis of National Cholesterol
Education Panel Adult Treatment Panel III guidelines.

Cantwell noted that the top three cardiovascular risk factors in
China are hypertension, cigarette smoking, and physical inactivity.
China has more than 350 million smokers, and they consume
approximately 33% of world's total cigarettes. One previous study of
more 45 000 Chinese adults >35 years showed that 48% of men and 39%
of women were prehypertensive, while hypertension was observed in
37% of men and 39% of women.

With these changing risk factors, heart disease is one of the
leading causes of death in China. Heart disease, stroke, and cancer
account for 66% of all deaths among those >40 years old, compared
with just 16% 50 years ago. Stroke rates in China are also extremely
high, approximately seven times greater than those observed in the
US, notes Cantwell.

In his review, which outlines some of the major cardiovascular
problems facing China, published online December 17, 2007 in the
American Journal of Cardiology, Cantwell notes that only a small
percentage of Chinese have health insurance, as the government has
switched from "near-universal insurance coverage" to a private-payer
system. In light of this, he believes "more appropriate drug use
must be applied to the control of hypertension and
hypercholesterolemia," which should reduce the high stroke rates and
the incidence of coronary events.

To heartwire, Cantwell said he expects China to perform well,
especially as the country has continued to win more and more medals
at each of the Olympic games. Also a bit of a performer himself,
during his visit and presentation at the Red Cross symposium,
Cantwell lectured in Yao Ming's Houston Rockets jersey, making sure
he won over the hearts of his Chinese colleagues.

Cantwell JD. Cardiovascular disease and Olympic games in China. Am J
Cardiol 2008; DOI: 10.1016/j.amjcard.2007.09.105. Available at:
www.ajconline.org.
Yardley J. Smoggy Beijing plans to cut traffic by half for Olympics,
Paper Says. New York Times, January 24, 2008. Available at:
http://www.nytimes.com.
Macur J. Olympic teams vying to defeat Beijing's smog. New York
Times, January 24, 2008. Available at: http://www.nytimes.com.

A single-tablet combination of the new renin inhibitor aliskiren and
the diuretic hydrochlorothiazide (HCTZ) (Tekturna HCT, Novartis) has
been approved by the FDA for the second-line treatment of
hypertension.

The combination tablet is indicated for patients not controlled by
either drug alone but should not be used before other medications
have been tried first.

The prescribing information notes that the combination tablet may be
administered with other antihypertensive agents but that additive
effects with maximal doses of ACE inhibitors and beta blockers have
not been demonstrated.

Tekturna HCT will be available at wholesalers in early February 2008
in four strengths as tablets containing aliskiren and HCTZ: 150
mg/12.5 mg, 150 mg/25 mg, 300 mg/12.5 mg, and 300 mg/25 mg. No
specific prices are available yet, but Novartis says it will be
priced comparably to other branded hypertension medications.

The company notes that most hypertension patients require two or
more antihypertensive agents to reach their target blood pressure
and that single-tablet combinations simplify treatment by reducing
the number of pills people take daily. The US approval of Tekturna
HCT was based on clinical trials involving more than 2700 patients
that showed that the combination of aliskiren and HCTZ resulted in
significant additional blood-pressure reductions compared with
either drug alone, Novartis reports. In a study to evaluate rebound
hypertension, when the combination tablet was withdrawn, blood-
pressure reductions were maintained for up to four days after the
last dose, with blood pressure gradually returning toward baseline,
it adds.

The most common side effects experienced by patients taking the
combination included dizziness, flulike symptoms, diarrhea, cough,
and tiredness. Other less common side effects include skin rash.

More than 10 days since results of the ENHANCE trial were made
public in a press release issued by Merck/Schering-Plough
Pharmaceuticals, the makers of the ezetimibe and simvastatin
cholesterol-lowering combination (Vytorin), the drug remains in the
spotlight. This time, however, the companies, as well as the
American Heart Association (AHA) and the American College of
Cardiology (ACC), are in the sights of the media and government
oversight committees.

Yesterday, the US House Committee on Energy and Commerce sent
letters to the AHA, the ACC, and to Merck/Schering-Plough
Pharmaceuticals, asking about their financial arrangements. Both the
AHA and ACC have come under fire for statements issued in the wake
of the release of the ENHANCE study findings, statements that urged
patients not to panic about the findings and that clinical decisions
not be made based on the data of this surrogate-end-point trial.

"Conclusions should not be made until the three large clinical-
outcome trials are presented within the next two to three years,"
read the January 15, 2008 ACC press release. "The ACC recommends
that Zetia [ezetimibe] remain a reasonable option for patients who
are currently on a high-dose statin but have not reached their goal.
The ACC also notes that Zetia is a reasonable option for patients
who cannot tolerate statins or can tolerate only a low-dose statin."

The AHA issued a similar statement a day after ENHANCE was released,
telling the public the study was too limited and not designed to
draw conclusions about the drug's ability to reduce hard clinical
end points. The AHA advised patients not to stop the drug without
talking to their doctors.

Where the AHA and ACC have drawn fire is in the funding both receive
from industry. In their statement, the AHA failed to disclose that
it receives $2 million annually from Merck/Schering-Plough, the
joint venture that funded the study and currently markets the
ezetimibe/simvastatin combination. In addition, a link from the AHA
website to external sites did not make explicitly clear that these
external sites were sponsored by large contributions from
Merck/Schering-Plough and other drug companies. The AHA has since
changed the site to make the sponsorship of these companies clear.

Drawing the ire of the House

The Energy and Commerce Committee, according to documents obtained
by the Wall Street Journal, is interested in whether or not the ACC
urged Merck/Schering-Plough to release the ENHANCE results, an issue
that came to light when the company was criticized for not
presenting the results sooner [1]. The committee also wants to know
the names of the doctors responsible for drafting the ACC statement.

Both the AHA and ACC deny that funding from Merck/Schering-Plough
had anything to do with the press releases issued after the ENHANCE
data were made public. Dr Daniel Jones (University of Mississippi
Medical Center, Jackson), president of the AHA, told the New York
Times that the association does not list industry funding when
issuing statements for patients [2].

Last night, in a request from heartwire, the ACC issued a
statement: "The American College of Cardiology is in receipt of the
letters from the Senate Finance Committee and the House Committee on
Energy and Commerce regarding our January 15, 2008 statement on the
release of the ENHANCE trial results. The ACC appreciates the
committees' acknowledgement of the college's long-standing
reputation as being objective, impartial, and trusted by patients
and doctors alike. The ACC will comply with all congressional
requests for information related to the January 15 statement."

Goldstein J. Vytoringate! Senate boards bandwagon. Wall Street
Journal Health Blog, January 24, 2008. Available at:
http://www.wsj.com.
Saul S. Heart group backs drug made by ally. New York Times, January
24, 2008. Available at: http://www.nytimes.com.
Merck/Schering-Plough. Merck and Schering-Plough respond to issues
raised about ENHANCE clinical trial [press release]. January 25,
2008. Available at: http://www.sch-
plough.com/schering_plough/news/release.jsp?releaseID=1100091.
Merck/Schering-Plough. ENHANCE Chronology. January 25, 2008.
Available at: http://media.corporate-
ir.net/media_files/IROL/89/89839/ENHANCE_Chronology_012508.pdf.

Statin use is not associated with an increased or decreased risk of
breast cancer, according to a population-based, case-control study
published in the January 1st issue of Cancer.

"Findings that statins inhibited the proliferation of breast cancer
cells in vitro and in rodents have raised interest in whether the
use of statins might decrease a woman's risk of developing breast
cancer," Dr. Gaia Pocobelli, of the University of Washington,
Seattle, and colleagues write. Conversely, other studies in which
rodents were exposed to high doses of statins showed increases in
several types of cancer.

The researchers identified 4179 cases of incident invasive breast
cancer in women at least 50 years of age who were diagnosed between
January 1995 and May 2001. The women were randomly selected from
population-based cancer registries in Wisconsin, Massachusetts, and
New Hampshire.

A total of 4983 controls were also randomly selected in each state,
from lists of licensed drivers and Medicare beneficiaries.
Structured telephone interviews were conducted to obtain information
on the use of statins and breast cancer risk factors.

Overall, 7.0% of all the women ever used a statin, including 271
cases and 336 controls. The most commonly used statins included
lovastatin (2.8%) and simvastatin (2.4%). This was followed by
pravastatin (1.6%) and fluvastatin (1.0%).

Cases had a slightly greater mean cumulative duration of statin use
than controls (4.9 years and 4.5 years, respectively), but the
overall use of statins was not associated with breast cancer risk,
according to the authors. They also observed no relationship between
duration of use and cancer risk.

No association was observed between the use of lipophilic statins as
a group (simvastatin, lovastatin, fluvastatin) or the use of the
hydrophilic statin (pravastatin) and breast cancer risk.

Fluvastatin was associated with a small reduced risk of breast
cancer, but this relationship may have emerged by chance, the
researchers note.

Summing up, statin usage, either lipophilic or hydrophilic, was
unrelated to the risk of breast cancer in middle-age women, the
researchers conclude. However, given the extensive use of these
agents, they suggest that further investigation of individual
statins is warranted.

Cancer 2008;112:27-33.

Abstract
Increasing evidence points to insulin resistance as a primary
etiologic factor in the development of nonischemic heart failure
(HF). The myocardium normally responds to injury by altering
substrate metabolism to increase energy efficiency. Insulin
resistance prevents this adaptive response and can lead to further
injury by contributing to lipotoxicity, sympathetic up-regulation,
inflammation, oxidative stress, and fibrosis. Animal models have
repeatedly demonstrated the existence of an insulin-resistant
cardiomyopathy, one that is characterized by inefficient energy
metabolism and is reversible by improving energy use. Clinical
studies in humans strongly support the link between insulin
resistance and nonischemic HF. Insulin resistance is highly
prevalent in the nonischemic HF population, predates the development
of HF, independently defines a worse prognosis, and predicts
response to antiadrenergic therapy. Potential options for treatment
include metabolic-modulating agents and antidiabetic drugs. This
article reviews the basic science evidence, animal experiments, and
human clinical data supporting the existence of an "insulin-
resistant cardiomyopathy" and proposes specific potential
therapeutic approaches.

Introduction
Insulin resistance, often manifested clinically through the features
of the metabolic syndrome or type II diabetes mellitus, has reached
epidemic levels in the U.S. and many nations throughout the world.
[1,2] Heart failure (HF) will eventually affect 1 in 5 Americans and
is responsible for the consumption of an extraordinary proportion of
health care resources.[3-5] Although a relationship between these 2
diseases has been long-recognized, it has classically been
attributed to the increased prevalence of myocardial ischemia in
patients with insulin resistance and to the fact that HF itself
causes whole-body insulin resistance.[6,7] We propose a more
fundamental link between insulin resistance and HF, one independent
of coronary artery disease. The theories/evidence for this link as
well as potential treatment options will be reviewed in this article.

A link between insulin resistance and HF has been noted for more
than a century. In 1881, Leyden[8] noted that HF is a "frequent and
noteworthy complication of diabetes mellitus," and Mayer[9,10]
speculated 7 years later that "heart disease in diabetes can be
traced to an abnormality in metabolism." In 1974, Kannel et al.[11]
found that men with cardiomyopathy were more than twice as likely as
matched control subjects to have diabetes mellitus, with women more
than 5 times as likely. Surprisingly, this link between diabetes and
HF actually grew stronger when patients with ischemic heart disease
were excluded. Other descriptions of a specific "diabetic
cardiomyopathy" continued to emerge in the 1970s.[12,13]

Subsequent studies have confirmed the existence, at the very least,
of a strong correlation between diabetes and nonischemic
cardiomyopathy, with a dramatically increased prevalence of diabetes
in the dilated cardiomyopathy population.[12,14-21] In newly
diagnosed patients with HF, this increase in prevalence might be up
to 4 times as high.[14] Each 1% increase in hemoglobin A1c is
associated with an 8% increased risk of HF, even after adjusting for
other factors, including coronary artery disease.[22] Importantly,
the increased prevalence of abnormal structure and frank HF is seen
with insulin resistance even when not accompanied by frank diabetes
mellitus.[18,21-23] Patients with nonischemic cardiomyopathy are not
only more insulin-resistant than a healthy control population but
also are more insulin-resistant than patients with coronary artery
disease.[24]

Abnormalities in diastolic function independent of ischemic heart
disease are very commonly observed in patients with insulin
resistance and diabetes mellitus and can be favorably impacted by
improved glycemic control.[25,26] Hypertension, left ventricular
hypertrophy, and left ventricular dysfunction are strongly
correlated with insulin resistance and the subsequent development of
HF.[17,18,27-29]

We have examined the prevalence of subclinical insulin resistance in
patients with nonischemic cardiomyopathy compared with a matched
control population, excluding patients with known pre-existing
diabetes. The cardiomyopathy population was not only significantly
more insulin resistant than matched control subjects (Fig. 2) but
also had a very high prevalence of frank glucose dysmetabolism when
challenged with an oral glucose load.[21] When patients with known
diabetes were included, 59% of cardiomyopathy patients had frank
glucose dysmetabolism,[21] even higher than another study examining
a mixed ischemic/nonischemic population, which found a prevalence of
43%.[19]

Epidemiological evidence suggests more than simply a correlation
between insulin resistance and HF, demonstrating that insulin
resistance precedes HF rather than occurring as a consequence of it.
A study of 1,187 Swedish patients without prior HF found that
insulin resistance predicts the subsequent development of HF,
independent of all established risk factors, including diabetes
mellitus itself.[18] Another study found higher proinsulin levels (a
surrogate marker for insulin resistance) in patients who
subsequently developed HF than in control patients 20 years before
their HF was diagnosed.[30]

Insulin resistance and diabetes portend a worse prognosis in HF. The
prognostic impact of insulin resistance is independent of other
variables, including peak oxygen consumption (VO2max) and left
ventricular ejection fraction (LVEF), implying that insulin
resistance is pathogenic rather than simply a marker for worsened HF.
[19,31]

The presence/absence of diabetes mellitus is more than 7 times as
potent a risk factor for mortality in the nonischemic cardiomyopathy
population as in the ischemic population.[4] Indeed, the highest-
risk subgroup from a recent study was the diabetic/nonischemic
population (relative risk [RR] 1.79 vs. the nondiabetic/nonischemic
population), as compared with the nondiabetic/ischemic population
(RR 1.07) or even the diabetic/ischemic population (RR 1.11).[4]

Preliminary evidence also suggests that the presence of insulin
resistance predicts response to therapy, especially antiadrenergic
therapy. The potent adrenergic-blocking medication carvedilol, the
only beta-blocker approved for HF that does not worsen insulin
resistance, is 3 times as likely to cause a dramatic improvement in
left ventricular function in the nonischemic cardiomyopathy
population as in the ischemic cardiomyopathy population.[32]
Intriguingly, this degree of response to antiadrenergic therapy can
be predicted by the severity of baseline abnormalities in myocardial
glucose uptake.[33]

NMT Medical announced today that it is halting MIST II, its US-based
trial evaluating the use of its patent foramen ovale (PFO)ˇVclosure
device to treat migraine with aura. According to the statement
released by NMT today, the company's decision to halt MIST II is due
in part to difficulties enrolling patients in the trial and in part
to the need to channel funding toward NMT's investigation of PFO
closure for stroke, in particular the company's pivotal CLOSURE I
trial. MIST II had been under way at 20 US centers, but out of more
than 1400 migraine patients screened for enrollment, "only a
handful" actually met requirements for randomization, the statement
reads.

"While NMT continues to believe in the relationship between PFO and
migraine, it has become clear that an acceptable enrollment dynamic
was not possible, and completing the study would require more time
and financial resources than we are willing to commit at this time,"
NMT president and CEO John E Ahern is quoted in the press release.

MIST trial program in the spotlight

NMT's MIST trial program has been under increased scrutiny since
October 2007, when the co-principal investigator for the trial, Dr
Peter Wilmshurst (Royal Shrewsbury Hospital, UK), told attendees of
a TCT 2007 session that he had concerns about how the MIST I data
were managed and reported. Wilmshurst and co-PI Dr Andrew Dowson
(Kings College Hospital, London, UK) first presented the MIST I
results publicly at the ACC 2006 Scientific Sessions, showing no
benefit to PFO closure for the primary end point of the trial--
headache cure--but promising secondary findings in terms of
reductions in headache days. But as reported by heartwire,
Wilmshurst now alleges that the study sponsor has misrepresented the
data, denied the existence of a review that questioned device
success in the trial, and repeatedly blocked access to the full data
set. NMT spokespeople, in response, have rejected Wilmshurst's
claims, saying he was never in fact a co-principal investigator for
the study and was dropped as a trial investigator for "protocol
violations."

As reported by heartwire, other experts have subsequently called for
an independent review of the MIST I data, although the company
insists that such a review cannot be performed without patient
consent. It has been almost two years since the MIST I results were
presented, yet the results have still not been published; NMT's
press release today asserts that the study is "expected" to be
published in Circulation early this year.



In its announcement today, NMT says it hopes to save approximately
$14 million over the next few years by redistributing funding that
had originally been budgeted for MIST II. Also quoted in the press
release, co-principal investigators for MIST II, Dr Stewart Tepper
(Yale University, New Haven, CT) and Dr Mark Reisman (Swedish
Medical Center, Seattle, WA), used words
like "difficult," "necessary," and "appropriate" to describe NMT's
decision. Reisman, a cardiologist, also emphasized that he is still
committed to evaluating the connection between migraine and PFO.

Commenting on the company's announcement for heartwire, Dr Roxana
Mehran (Columbia University, New York, NY) said that she
believes "absolutely" that PFO closure for migraine is worth further
investigation but appreciates that the company was in a tough
position.

"Frankly I'm not surprised by the decision. They have acted with
some sound judgment. Given the strict entry criteria for the trial,
they had to screen many, many patients, and if you have to screen
that many people to yield just a handful of eligible patients, you
risk ending up with trial results that may not be applicable to the
wide range of migraine patients."

She says the onus is back on scientists and researchers to come up
with the right trial design to investigate the link between PFO and
migraine, noting that at least two other companies have trials
investigating PFO closure for migraine. "I think the connection
between PFO and migraine is one that is very interesting and merits
further study. If you have a safe and effective device and a safe
procedure, you may be able to give quality of life back to millions
of migraine sufferers: I do believe there is a huge future here."

She rejected the suggestion that any problems with MIST I may be
behind the company's decision, saying that MIST I served the role of
being hypothesis-generating but perhaps was "too aggressive" in its
end points.

NMT's CLOSURE I trial, along with other pivotal trials by different
sponsors investigating PFO closure for stroke/transient ischemic
attack, has also struggled with sluggish patient enrollment. Today's
announcement by NMT, however, notes that CLOSURE I is now close to
finishing enrollment.

The debate surrounding the ENHANCE trial took a bit of a twist this
past week when attention turned to the LDL-cholesterol hypothesis,
with some experts arguing that lowering LDL cholesterol to prevent
clinical events is an unsophisticated premise and that other factors
beyond lowering LDL cholesterol are involved. Other reports openly
questioned whether this latest evidence suggests it might not be
important to reduce cholesterol levels.

"The idea that youˇ¦re just going to lower LDL and people are going
to get better, thatˇ¦s too simplistic, much too simplistic," Dr Eric
Topol (Scripps Translational Science Institute, La Jolla, CA) told
the New York Times last week [1].

Experts say, however, that this is not the dismissal of decades of
research, including numerous studies in the past few years adding
evidence to the "lower-is-better" cholesterol hypothesis. With many
of those trials, researchers used higher and higher doses of statins
to drive down cholesterol levels, all with the intention of further
reducing clinical events. Instead, some say that how cholesterol is
lowered is as important as how much.

"The message for me is not that lowering LDL cholesterol doesn't
work to prevent disease progression or to prevent clinical events,"
Dr Steven Nissen (Cleveland Clinic, OH) told heartwire. "The
important thing to remember is how the cholesterol levels are
lowered. Statins do a lot more than reduce LDL cholesterol. They
also increase HDL cholesterol, decrease triglycerides, and decrease
C-reactive protein levels. Ezetimibe doesnˇ¦t do any of these
things."

Is lowering LDL cholesterol important?

With the release of ENHANCE, a study showing that reductions in LDL
cholesterol did not translate into improvements in atherosclerosis
as measured by carotid IMT, as well as torcetrapib data published
last year, questions have been raised about whether or not it is
important to reduce LDL-cholesterol levels at all.

Some clinicians, in fact, are quite candid in their interpretation
of the newly presented data. Dr Rodney Hayward (University of
Michigan, Ann Arbor), for example, told BusinessWeek that
the "current evidence supports ignoring LDL cholesterol altogether.
[2]"

In case you've been under a rock . . .

The ENHANCE study captured the attention of clinical cardiology, the
business world, and the media this past week when the results of the
long-awaited and controversial ENHANCE study were presented.
Investigators presented data showing no benefit of the combination
of ezetimibe (Zetia, Merck/Schering-Plough Pharmaceuticals) and
simvastatin (sold together as Vytorin, Merck/Schering-Plough
Pharmaceuticals) over simvastatin alone.

ENHANCE, with lead investigator Dr John Kastelein (Academic Medical
Center, Amsterdam, the Netherlands), was conducted in 720 patients
with heterozygous familial hypercholesterolemia (FH) and showed no
significant difference in the primary end point--mean change in IMT
measured at three sites in the carotid arteries--between patients
treated with ezetimibe/simvastatin 10/80 mg and patients treated
with simvastatin 80 mg alone over a two-year period.

There was also no statistically significant difference between the
treatment groups for each of the components of the primary end
point, including the common carotid artery. Key secondary imaging
end points showed no statistical difference between treatment groups.

Commenting on the current climate following the release of the
ENHANCE data, Dr Patrick McBride (University of Wisconsin Medical
School, Madison) told heartwire that the LDL hypothesis is
irrefutable.

"Anytime you can lower LDL-cholesterol levels safely, you are going
to see reductions in the risk of clinical events," he said. "In any
of the previously published cholesterol studies, there is always a
decrease in cardiovascular risk with reductions in LDL cholesterol."

McBride stressed, however, the importance of safety. Two exceptions
to the LDL hypothesis are estrogen and torcetrapib; both reduced LDL-
cholesterol levels, but the reductions were offset with other side
effects, he said. Estrogen, for example, resulted in blood clotting
and posed a cancer risk, while torcetrapib increased blood pressure.
Ezetimibe, he said, is safe in that no known abnormalities have been
noted with the drug.

Nissen is skeptical, however, noting that much of the cholesterol
hypothesis is based on studies with statins. He is not sure, noting
the absence of data and the lack of imaging support, that adding
ezetimibe to simvastatin is the most effective means to reduce risk.
Moving the patient to a high-dose, highly potent statin, such as
atorvastatin (Lipitor, Pfizer) 80 mg, is supported by the evidence.

"There are many advocates out there who espouse lowering LDL
cholesterol by any means possible," said Nissen. "But let's be
clear: 95% of the studies that form the basis for the cholesterol
hypothesis are based on studies of statins. I think, then,
extrapolating from these statin trials to ezetimibe is a mistake."

Speaking with heartwire, most experts echoed the notion that it is
still too early to determine whether using ezetimibe to lower LDL
cholesterol is an effective means to reduce hard clinical events,
such as MI. They point out that the ENHANCE study was small,
enrolled difficult-to-treat FH patients, and was a surrogate-end-
point study. Although the imaging end points were nonsignificant, it
had been hoped that the ezetimibe and simvastatin combination, which
reduced LDL cholesterol 58% compared with a 41% reduction with
simvastatin alone, would lead to slower disease progression.

Dr Roger Blumenthal (Johns Hopkins University Medical Center,
Baltimore, MD) said that while it is certainly possible that not all
the methods of reducing LDL cholesterol will be equally beneficial,
he said that many statements made in the media have been alarmist.

"We are going to have a lot more data in the years to come, such as
the completion of the IMPROVE-IT study, and it is only then that
we're going to be able to know whether or not this particular method
of lowering LDL is clinically beneficial."

FH patients treated aggressively in the past

Commenting on the LDL hypothesis for heartwire, Dr Michael Blazing
(Duke Clinical Research Institute, Durham, NC), who is involved in
the IMPROVE-IT study, said that the ENHANCE study enrolled very-
difficult-to-treat patients, those with FH and LDL-cholesterol
levels exceeding 300 mg/dL. He stressed that the two-year change in
mean carotid IMT between the treatment arms was neutral, and not
doubled in the ezetimibe/simvastatin arm, as reported commonly in
the media.

"In the meantime, some people are really going out on a limb," said
Blazing. "At this point, we have data only from a surrogate-end-
point trial and have no way of knowing what type of clinical effect
the reductions in LDL will have. Moreover, we're extrapolating from
a difficult patient population who has been treated aggressively in
the past."

Dr Christie Ballantyne (Baylor College of Medicine, Houston, TX)
told heartwire that too much has been made of an unpublished study.
He agreed, however, that there are many questions that must be
answered, such as what is the most effective way to lower LDL
cholesterol after a high-dose statin failed to knock levels down low
enough.

"I still think ezetimibe is a good option," said Ballantyne. "What I
don't want people saying is that LDL is not important, although we
know that it's not everything. This is a complex disease, but we
want to avoid swinging too far, placing too much emphasis on an
unpublished study, and dismissing 20 years of published research."

In his video blog, Topol also pointed to the new BusinessWeek
article that questioned the value of statins, particularly the event
protection conferred by atorvastatin. In the lengthy article,
reporter John Carey crunches the numbers and shows that the number
needed to treat to prevent one MI is 100, not a very impressive
number. With reduction in strokes and longer-term follow-up, this
benefit might increase, but the vast majority of patients are not
really deriving protection from events, even though nearly all
patients have a reduction of LDL cholesterol, said Topol.

"We've seen punching of holes in this whole LDL story, on multiple
fronts," he said.

Berenson A. New questions on treating cholesterol. New York Times,
January 17, 2008. Available at: http://www.nytimes.com.
Carey J. Do cholesterol drugs do any good? BusinessWeek, January 17,
2008. Available at: http://www.businessweek.com.

New mortality data from the US Centers for Disease Control and
Prevention (CDC) show that, since 1999, death rates from coronary
heart disease and stroke have fallen by about 25%.

The latest figures, based on 2005 data, mean that the American Heart
Association's (AHA's) 2010 strategic goal for reducing deaths from
CHD has already been achieved, and the goal for reducing stroke
deaths has almost already been achieved, AHA president Dr Dan Jones
told heartwire. But he cautioned that the news was not all
good. "That's the 'cup-half-full' part of the story. But the 'cup-
half-empty' part is that we are not meeting goals for risk factors.
While cholesterol levels have shown a big improvement, the
statistics for hypertension, smoking, and physical activity are not
so good--they are going in the right direction but not fast enough.
And rates of obesity and diabetes are increasing," he noted.

"The mortality targets have been met by mainly by improved treatment
strategies--particularly of acute events, such as improved
reperfusion therapies for MI and more rapid and improved treatment
of acute stroke. We must keep this up but at the same time focus
efforts on prevention in years to come. We need to replicate the
success with statins on cholesterol in other areas of drug
treatment, but we also need to focus on changing lifestyles. That is
very difficult. There have been dramatic changes in lifestyles in
the US and Europe during the past few decades, but unfortunately
these have been in a negative direction," Jones added. "If this
trend continues, death rates could begin to rise again in years
ahead."

In 1999, the AHA set a goal of reducing the death rates from CHD and
stroke and reducing the risk factors for these diseases by 25% by
2010. The new CDC data show that the mortality figures are being
achieved but the goals for the risk factors are not, which means
that the victory could be short-lived.

Gender/ethnic differences

While CHD death rates for women are falling at a slightly greater
pace than for men, stroke death rates are showing the opposite trend-
-down by 23.7% for women vs 25.8% for men since 1999. Both CHD and
stroke death are falling more slowly in blacks than in whites. The
CHD death rate is down 23.8% in blacks vs 25.6% in whites, and
stroke deaths are down by 20.3% in blacks vs 25% in whites. "These
disparities are unacceptable," Jones said. "We are actively seeking
ways to better address these issues, so that we can ensure that
every person has the appropriate care they need to live a healthier,
longer life."

240 000 lives saved in 2008?

The reduction in the CHD and stroke death rates equates to
approximately 160 000 lives saved in 2005 (the most recent year for
which data are available) compared with the 1999 baseline data. If
the current mortality trends hold, the AHA projects that there may
be a 34% decline in CHD death rates and a 34% reduction in stroke
death rates in the 2008 data (in comparison with the 1999 data). The
population size in 2008 will also be larger, so it is projected that
the estimated lives saved in 2008 will be approximately 240 000.

But no room for complacency

But the AHA warns that further reductions in mortality will not be
seen if risk factors are not improved more than is being done
currently. The data show some progress on the number of people with
uncontrolled hypertension (down 16%), the number of people with
raised cholesterol (down 19.2%), and in those who smoke (down
15.4%), but the rate of physical inactivity has declined only by
2.5%, and the prevalence rates for obesity and type 2 diabetes are
actually increasing and are appearing at earlier ages than ever
before, the organization points out.

"If we don't make a concerted effort to reduce these risks, we will
lose the momentum we celebrate today. We will see our children
developing heart disease earlier, experiencing early deaths, or
needing major medical care sooner," Jones stresses.

A novel treatment that triggers a nonspecific immune response
believed to attenuate inflammatory processes associated with heart
failure failed to improve survival or reduce heart failure
hospitalizations in a randomized placebo-controlled trial reported
in the January 19, 2008 issue of the Lancet [1].

Although the study was negative for its broad population of patients
with systolic heart failure, the immune-modulation therapy did
appear to benefit two prospectively defined subgroups: those with
NYHA class 2 disease (compared with NYHA class 3 or 4), and those
with no history of MI. Overall, the treatment appeared to improve
quality of life, a secondary end point, reported the authors, led by
Dr Guillermo Torre-Amione (Methodist Hospital, Houston, TX).

The results of the Advanced Chronic Heart Failure Clinical
Assessment of Immune Modulation Therapy (ACCLAIM) trial were
announced in 2006, in most detail at the European Society of
Cardiology/World Congress of Cardiology scientific sessions that
year, and were covered by heartwire at the time.

ACCLAIM randomized 2426 patients with NYHA class 3 or 4 systolic
heart failure on optimal standard medical therapy to receive either
the immune-modulation therapy or a sham version of the procedure in
a double-blind fashion.

The proprietary treatment (Celacade System, Vasogen) involves the ex
vivo exposure of the patient's own venous blood (10 mL) to
controlled oxidative stress in the form of an oxygen-ozone gas
mixture and ultraviolet light. The treated blood is then returned to
the patient by intragluteal injection. The procedure, which is
administered four times the first month and monthly thereafter, has
been shown to provoke a reduction in inflammatory cytokines and an
upregulation of anti-inflammatory cytokines.

Over a mean of 10 months, the adjusted hazard ratio for the primary
end point of all-cause mortality or cardiovascular hospitalization
in the active-therapy group, compared with controls, was 0.92 (95%
CI, 0.80-1.05; p=0.22). However, it was 0.74 (95% CI, 0.57-0.95;
p=0.02) for the 919 patients without a history of MI and 0.61 (95%
CI, 0.46-0.80; p=0.0003) for the 689 patients who had started out in
NYHA class 2. There was a slight but significant improvement
(p=0.04) in the Minnesota Living with Heart Failure Questionnaire
score among Celacade-treated patients.

That the treatment appeared to benefit patients with less-advanced
disease--that is, those "without a history of MI and those with a
history of MI who had not yet progressed to an increased symptomatic
or refractory stage of myocardial damage"-- is consistent with other
evidence indicating that immune modulation might work best in
cardiac disease when started before there is permanent cellular
damage, according to the authors.

According to an accompanying editorial [2], the entire concept of
immune-modulation therapy for heart failure has some limitations.
The involved cytokines, for example, can be produced by cells other
than immune cells and therefore might be beyond the treatment's
reach, observe Dr Karen Sliwa (University of the Witwatersrand,
Johannesburg, South Africa) and Dr Aftab A Ansari (Emory University,
Atlanta, GA). "Also, the chronic inflammatory process could be
beneficial in removing myocytes that are dying or dead for reasons
other than the immune response."

The treatment could have serious clinical consequences, as well,
according to Sliwa and Ansari. They could conceivably
include "susceptibility to opportunistic infections and failure to
respond to antigenic stimuli or to eliminate potentially malignant
cells," and the induction of autoimmune diseases.

There have been no indications of such hazards in ACCLAIM or
previous research on Celacade. But the study wasn't powered or long
enough to track such potential effects, they write, so "long-term
follow-up of patients receiving this type of therapy should be
mandatory."

Celacade is approved in the European Union but remains
investigational in the US. The US Food and Drug Administration has
given its blessing to an ACCLAIM-2 trial that will explore the
treatment's effectiveness in NYHA class 2 patients, according to a
Vasogen statement [3]. Dr James B Young (Cleveland Clinical
Foundation, OH) is the principal investigator and chairs the
steering committee.

The trial was funded by Vasogen. "All authors served on the steering
committee for the ACCLAIM study and each received an honorarium,
travel support, or both from the sponsor for this service."

Torre-Amione G, Anker S, Bourge RC, et al. Results of a nonspecific
immunomodulation therapy in chronic heart failure (ACCLAIM trial): A
placebo-controlled randomised trial. Lancet 2008; 371:228-236.

Sliwa K, Ansari AA. Immunosuppression as therapy for congestive
heart failure. Lancet 2008; 371:184-186.
The Lancet Publishes Vasogen's ACCLAIM Results. Vasogen press
release. January 18, 2008. Available at:
http://www.vasogen.com/sec/pr_1200616840.

A small meta-analysis published last week, which attempted to
address the inconsistencies in the data on fish-oil supplementation
in patients with implantable cardioverter defibrillators (ICDs),
suggests that there is significant heterogeneity in cardiac
patients' responses to the long-chain fatty acids. [1]

Published in the January 15, 2008 issue of the Canadian Medical
Association Journal, the researchers, led by Dr David Jenkins
(University of Toronto, ON), say the reasons for observed
differences in response are not clear, but conclude that "caution
should be used when prescribing fish-oil supplementation for
patients with ventricular tachycardia."

The meta-analysis included three trials presented and published in
the past few years, all reported by heartwire: the Study on Omega-3
Fatty Acids and Ventricular Arrhythmia (SOFA) [2], a trial showing
that supplementation with fish-oil capsules over one year did not
reduce the risk of ventricular tachycardia/ventricular fibrillation
(VT/VF) or death in patients with secondary-prevention ICDs; a study
by Dr Merritt Raitt (Oregon Health and Science University, Portland)
showing that the use of fish-oil supplements over two years failed
to protect against VT/VF in patients who had received an ICD because
of recent sustained ventricular arrhythmia [3]; and a study by Dr
Alexander Leaf (Harvard Medical School, Boston, MA) and colleagues
showing that regular ingestion of fish-oil fatty acids for 12 months
failed to reduce the risk of potentially fatal ventricular
arrhythmias in patients with secondary-prevention ICDs [4].

In the study by Leaf and colleagues, however, an "on-treatment"
analysis hinted that there was a longer time to first ICD event for
VT/VF or death from any cause among patients randomized to fish oil
than among those randomized to olive-oil placebo.

The meta-analysis of ICD discharge in the three studies of fish-oil
supplementation showed that the prescription of fish oil to these
patients failed to reduce arrhythmia. In a meta-analysis of all-
cause mortality, an outcome common to all three studies, the overall
relative risk was nonsignificant.

Jenkins and colleagues point out that two other meta-analyses failed
to "show a clear advantage of increased fish-oil consumption, either
for secondary prevention of coronary heart disease or restenosis
after angioplasty." They note, however, that fish oils have complex
and pleiotropic effects on the heart," including blocking cardiac
ion channels, reducing fibrosis in response to mechanical stress,
decreasing blood coagulation, reducing serum triglycerides, and
possibly altering immune function." Moreover, drug-nutrient
interactions, such as fish oil with antiarrhythmic medications,
might be partly responsible for the observed differences between
studies.

They conclude by stating that further research is needed, but, "at
present, the use of fish oils in patients with implantable
cardioverter defibrillators appears to warrant caution."

Jenkins DJ, Josse AR, Beyene J, et al. Fish-oil supplementation with
implantable cardioverter defibrillators: A meta-analysis. CMAJ 2008;
178:157-164. Abstract
Brouwer IA, Zock PL, Camm AJ, et al. Effect of fish oil on
ventricular tachyarrhythmia and death in patients with implantable
cardioverter defibrillators: The Study on Omega-3 Fatty Acids and
Ventricular Arrhythmia (SOFA) randomized trial. JAMA 2006; 295:2613-
2619. Abstract
Raitt MH, Connor WE, Morris C, et al. Fish oil supplementation and
risk of ventricular tachycardia and ventricular fibrillation in
patients with implantable defibrillators: A randomized controlled
trial. JAMA 2005; 293:2884-2891. Abstract
Leaf A, Albert CM, Josephson M, et al. Prevention of fatal
arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake.
Circulation 2005; 112:2762-2768. Abstract

Three new studies published online today in the Journal of the
American College of Cardiology attempt to replicate, in large
prospective studies, results published last year on a polymorphism
associated with heart disease, the gene for kinesin-like protein 6
(KIF6) [1, 2, 3]. Celera has funded the gene research, and the
company is planning to launch a diagnostic test to identify
individuals carrying the KIF6 variant. "These findings make a
compelling case for testing for KIF6 status to aid in the medical
assessment of the substantial number of Americans considered to be
at moderate risk of developing heart disease," says Kathy Ordonez,
president of Celera.

But not everyone is so enthusiastic. Dr Ali Marian (Center for
Cardiovascular Genetics, Texas Heart Institute, Houston), who has
written an editorial accompanying the 3 studies [4], told heartwire
that the original evidence for the association was "modest at best,
and a lot more work is required to validate this finding."

Dr Eric Topol (Scripps Translational Science Institute, La Jolla,
CA), who was not involved with this research, told heartwire
that "the KIF6 SNP [single nucleotide polymorphism] is a nice
contribution for its association with coronary artery disease and
statin response. It is disappointing that this SNP or the chromosome
6 locus that it is found in has not shown up in any of the genome-
wide association studies to date. Had this been the case, the
finding would carry more weight as an important commonly occurring
SNP. Independent studies (apart from Celera) of the KIF6 SNP variant
to show association and determine its functional effects are
required before one would think about using this SNP for predictive
(commercial) purposes."

KIF6 Allele Associated With CHD in WOSCOPS, CARE, and WHS

Two of the studies are led by Celera staff and examine the
association between KIF6 and heart disease in the CARE and WOSCOPS
studies [1] and in the Women's Health Study (WHS) [2].

In the CARE and WOSCOPS study, led by Dr Olga A Iakoubova, the
researchers looked at whether 35 genetic polymorphisms previously
associated with cardiovascular disease were associated with MI in
the two study populations. In both CARE and WOSCOPS, they found that
placebo-treated carriers of the KIF6 polymorphism (Trp719Arg) had an
increased risk of coronary events, with an adjusted hazard ratio
(HR) of 1.50 in CARE and 1.55 in WOSCOPS. They also found that among
carriers of the KIF6 allele, pravastatin treatment reduced that
risk.

"Of the 35 polymorphisms tested, only the KIF6719Arg allele was
associated with MI in the CARE trial and CHD in the WOSCOPS trial,"
the investigators note.

In the second study, led by Dov Shiffman [2], of 25 283 participants
in the WHS, whites who were carriers of KIF6 also had an increased
risk of coronary heart disease (adjusted HR, 1.24) and MI (adjusted
HR, 1.34) but not ischemic stroke. "This is the fourth prospective
study in which the KIF6719Arg allele has been associated with
increased risk of CHD," say Shiffman et al.

Can Statins Alleviate the Increased Risk?

The third study [3], also led by Iakoubova, goes one step further
and looks at the responses to statin therapy among acute coronary
syndrome patients with and without the KIF6 polymorphism in PROVE IT-
TIMI 22. The benefit from intensive statin therapy was significantly
greater in KIF6719Arg carriers (adjusted HR, 0.59) than in
noncarriers (adjusted HR, 0.94).

In a press release published today [5], Celera says the findings
show that statins can virtually alleviate the elevation in heart
disease risk conferred by the KIF6 genetic variant.

Quoted in the press release, Dr Frank M Sacks (Brigham and Women's
Hospital and Harvard Medical School, Boston, MA), who is a senior
author on the CARE and WOSCOPS paper, says: "These studies indicate
that carriers of the KIF6 gene variant are at higher risk of
coronary heart disease, and this risk is reduced by statin therapy."

"This is one of the first gene variants that has been associated
with the pharmacodynamics of statin therapy in multiple studies,
providing new genetic information that can assist physicians in
making personalized cardiovascular treatment decisions for their
patients. The important thing is that carriers are not only at
greater risk, but that statins lower the risk especially well
compared with non-carriers."

"Since reduction in LDL does not explain the KIF6 effect on
cardiovascular disease, a KIF6 test could give physicians new
information to identify patients in whom statins work particularly
well. This is really personalized medicine based on genetics for a
common condition."

Iakoubova et al say in their paper [3] that more work is needed to
try to determine how the benefits of statins are mediated in
carriers of KIF6. "The biological explanations for the observed
difference in treatment benefit should be provided by functional
studies of this kinesin motor protein . . .  that could, in turn,
generate novel targets for therapeutic intervention and lead to
better tailored therapy for patients," they note.

Are These Associations Robust and Solid?

In his editorial [4], Marian says that "these studies collectively
raise interest in KIF6 as a possible candidate gene in
susceptibility to myocardial infarction, coronary atherosclerosis,
and response to statins. They have considerable strengths, including
the relatively large sample size of the study populations, carefully
phenotyped participants, and concordant findings in separate
databases. Nonetheless, the results at best should be considered
provisional pending validation through experimentation."

"The fundamental question is, 'Are these associations that they have
shown--the risk of coronary artery disease--robust and solid?' The
answer is 'probably not','' he told heartwire. "And why not? Because
the hypothesis to test this gene was based on a previous study, also
done by Celera, which showed at best quite a modest association
[between KIF6 polymorphism and heart disease]."

"My argument is, where did this gene come from? How did they find
it? They didn't say how. There is no plausibility--we don't know how
this protein works, there is no known function for it. We don't even
know what this particular family of kinases does, so we really have
no clue about the function of the gene. It is not even expressed in
the vasculature. For their results to be meaningful, they will have
to be experimentally validated."

But Celera spokesperson Dr David P Speechly told heartwire that the
company takes issues with Marian's views. "The editorialist
expressed concern about the validation of this association. Yet no
common genetic variant has been more reproducibly validated in
prospective CHD studies than KIF6. Beyond the four studies described
in the three JACC manuscripts, this KIF6 SNP was also associated
with CHD in two other large prospective studies: ARIC [6] . . . and
CHS [7]."

Why Such Disagreement?

Softening a little, Marian told heartwire: "It doesn't mean they are
absolutely wrong--there are a lot of unknowns--but as I said, this
requires confirmation. This gene, if ever proven to be true, will
certainly open up a completely new pathway to understanding the
pathogenesis of ischemic heart disease. If proven to be true--and
that's the key."

"Unfortunately," Marian continues, "one of the trends today in the
society of genetic epidemiologists is to show an association and
move on, not to follow through to the how and the why. Even genome-
wide association studies, the way they are done, unless they are
followed-up to prove whether the variant is identified as a true
risk, become, if anything, harmful, because then 50 zillion people
try to replicate it and follow it. If we scientists fool society,
ultimately it degrades everyone."

Sacks explained to heartwire that the reason for the seemingly
completely divergent views of the editorialist and the study
authors "is that the field of gene-drug and gene-environmental
interactions does not enjoy consensus . . . . Some experts favor
classical candidate-gene research (such as Dr Marian) and others a
genome-wide approach. For some researchers, knowing the mechanism of
the association is paramount, whereas for others, the robustness of
the population's findings is key."

"It's regrettable that some of Dr Marian's skepticism stems from a
misunderstanding of two important facts on this work with KIF6: that
multiple KIF6 sites, not just one SNP, are associated with CHD and
its reduction by statins; and that the gene is in fact expressed by
vascular cells."

Dr James Shepherd (Glasgow Royal Infirmary, UK), a statin expert who
is a coauthor on the CARE and WOSCOPS study, told heartwire: "The
whole issue is, in my view, a storm in a teacup. We must all agree
that these three publications cannot be seen as the last word on the
subject. We still need to unravel how KIF6 manipulates that risk."

For the two Iakoubova papers, the genotyping and statistical
analysis were funded by Celera.

Iakoubova OA, Tong CH, Rowland CM, et al. Association of the
Trp719Arg polymorphism in kinesin-like protein 6 with myocardial
infarction and cohronary heart disease in two prospective trials:
The CARE and WOSCOPS trials. J Am Coll Cardiol 2008; 51:435-443.
Shiffman D, Chasman DJ, Zee RY, et al. A kinesin family member 6
variant is associated with coronary heart disease in the Women's
Health Study. J Am Coll Cardiol 2008; 51:444-448.
Iakoubova OA, Sabatine MS, Rowland CM, et al. Polymorphism in KIF6
gene and benefit from statins after acute coronary syndromes:
Results from the PROVE IT-TIMI 22 study. J Am Coll Cardiol 2008;
51:449-455.
Marin AJ. Surprises of the genome and personalized medicine. J Am
Coll Cardiol 2008; 51:456-458.
Celera publishes three papers confirming carriers of a KIF6 gene
variant are at elevated risk of coronary heart disease and that this
elevated risk is virtually alleviated by statin therapy. Celera
press release. January 21, 2008. Available at
http://www.celera.com/celera/pr_1200945773.
Bare LA, Morrison AC, Rowland CM, et al. Five common genetic
variants identify elevated genetic risk factors for coronary heart
disease. Genet Med 2007; 9:682-689. Abstract
Shiffman D, O'Meara ES, Bare LA, et al. Association of gene variants
with incident myocardial infarction in the Cardiovascular Health
Study. Arterioscler Thromb Vasc Biol 2007; 28:173-179. Abstract

The ENHANCE study, showing no difference between simvastatin plus
ezetimibe (Zetia/Vytorin, Merck and Schering-Plough) compared with
simvastatin alone on the progression of carotid atherosclerosis in
patients with familial hypercholesterolemia, has been a major
talking point over the past few days.

The study results have attracted intense media coverage, which was
inevitable given the controversy surrounding the study in the past
few weeks. It was the lead item on many US television news programs
on Monday, and sales of ezetimibe--which have been running at around
$5 billion worldwide--are now bound to fall. Indeed, in a poll on
theheart.org, 60% of respondents said they would now be less likely
to prescribe the drug.

However, many experts are urging that not too much weight be
attached to this one imaging study, a view echoed by the American
College of Cardiology (ACC). But Dr Steven Nissen (Cleveland Clinic,
OH) is sticking to his guns and insists that, in the absence of any
evidence of health benefits, the drug should not be used.

Califf: "I'm still taking it"

Dr Robert Califf (Duke Clinical Research Institute, Durham, NC), who
is coordinating one of the large clinical outcome trials with
ezetimibe (IMPROVE-IT), is also taking the drug himself and says
that while it is disappointing that no benefit was seen in ENHANCE,
he is not going to stop taking ezetimibe based on this one study. He
says he cannot take high doses of statins because of side effects
but can obtain the same degree of LDL lowering with ezetimibe and a
low-dose statin, without the adverse affects. "I don't see any
signal of toxicity from this trial, so that is reassuring. There's
no indication that it's working, either, but that was also the case
before ENHANCE came out. For me, the fact it lowers LDL and does not
appear to have side effects is enough until definitive outcome data
become available," he told heartwire.

Califf gave similar comments to the Wall Street Journal when the
ENHANCE results were first released, adding: "Until that point, I'm
only losing money." The newspaper reports that a 30-day supply of
ezetimibe 10 mg costs around $93 and Vytorin (10 mg ezetimibe and 80
mg simvastatin) $100, vs just $32 for generic simvastatin 80 mg.

Contributors to the Wall Street Journal Health Blog did not seem to
take too kindly to Califf's comments, pointing out that as a
prominent cardiologist, he can probably afford ezetimibe, but many
others can't, and that Schering-Plough contributes heavily to the
Duke Clinical Research Institute. Califf told heartwire that this
was a "fair comment."

"People need to interpret my comments any way they will. Yes, we do
a lot of work with Schering-Plough, but we also work with about 80
other companies, and unfortunately you can't conduct large trials
without involvement with the industry. But I don't think I would
actually be taking a drug just because I am doing a trial for the
company that makes it."

A "botched" trial?

Califf said he thought ENHANCE was a "botched" trial. "They took 18
months to get the results out after the trial was completed. I am
not aware of any reason why it could take that long unless the
database had been messed up. We will find out more about that with
the Congressional investigation, but these things sometimes happen.
We all have screwed up trials--it happens."

But Califf believes that at the end of the day, the neutral result
of ENHANCE is definitely not the end of the world. "This is just an
imaging trial, and imaging is just another biomarker. They are by no
means proof of anything. There are lots of problems with imaging
trials, such as missing data, and we don't know how many of these
studies are actually published. HRT was actually shown beneficial in
[intima media thickness] IMT studies. No biomarker can be 100%
predictive of clinical outcome. In my book, LDL reduction is a much
more solid biomarker than an IMT study, but I wouldn't want to
depend on either of them," he commented.

Several other experts contacted by heartwire took a view similar to
Califf's. Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles,
CA) commented: "Embracing a therapeutic intervention as a resounding
success or rejecting it as a disappointing failure simply on the
basis of an imaging outcome study is rather short-sighted and
betrays a higher confidence in surrogacy than is otherwise warranted
by the existing body of evidence. Bottom line, surrogate end points
are a slippery slope. We need to await the results of clinical-
outcome studies before drawing any firm conclusions."

Power limited

Dr Harvey White (Green Lane Hospital, Auckland, New Zealand), who is
also an investigator in IMPROVE-IT, pointed out that the changes in
carotid IMT in the ENHANCE trial were minimal, so that the study had
no statistical power to detect differences between the two
groups. "This will not change my practice; I think we need to treat
to guideline goals with statins, and if that fails we should lower
the LDL further with ezetimibe. Large clinical-outcome trials such
as IMPROVE IT will help define lower treatment goals with ezetimibe
added to simvastatin, as well as safety and efficacy."

And the ACC issued a statement saying that patients should not panic
about the ENHANCE results and that major clinical decisions should
not be made on the basis of this study alone. "Conclusions should
not be made until the three large clinical-outcome trials are
presented within the next two to three years. The ACC recommends
that Zetia remain a reasonable option for patients who are currently
on a high-dose statin but have not reached their goal. The ACC also
notes that Zetia is a reasonable option for patients who cannot
tolerate statins or can tolerate only a low-dose statin," the
statement says.

Nissen not reassured

But Nissen is still not convinced by all these reassurances. "If the
ENHANCE trial had shown regression of atherosclerosis or slowed
progression, both the company and advocates of ezetimibe would be
trumpeting the results as a landmark study. Now that the trial has
failed, they describe ENHANCE as a small and unimportant imaging
study. You can't have it both ways," he commented to heartwire.
Contrary to Califf's assertion that it was "botched," Nissen says
ENHANCE was well designed and well executed, and the sponsors had an
understanding with the FDA that a positive result would potentially
yield a label claim.

"The main problem is that after six years on the market, there are
no data for ezetimibe demonstrating any health outcome benefit.
Statins do much more than lower LDL. They increase HDL, lower
triglycerides, and reduce inflammation. In the absence of any
demonstrable effect beyond LDL lowering, nearly one million
prescriptions per week are written for ezetimibe. Is this rational?"
Nissen asked.

He cited another imaging study, ASAP, which was published in the
Lancet in 2001 by the same lead investigator as ENHANCE (Dr John
Kastelein [Academic Medical Center, Amsterdam, the Netherlands]) and
studied simvastatin and atorvastatin in the same familial-
hypercholesterolemia population as ENHANCE [1]. "ASAP showed a 9%
additional lowering of LDL with atorvastatin, which resulted in a
highly significant difference in CIMT progression. In fact, the
intensive-statin group actually regressed. In contrast, ENHANCE had
a 17% lower LDL in the ezetimibe-simvastatin group, but the
progression rates showed no benefit and actually trended in the
wrong direction," Nissen added.

Smilde TJ, van Wissen S, Wollersheim H, et al. Effect of aggressive
versus conventional lipid lowering on atherosclerosis progression in
familial hypercholesterolaemia (ASAP): a prospective, randomised,
double-blind trial. Lancet 2001; 357:577-81. Abstract

A new study has shown that calcium supplementation might increase
vascular events in elderly women [1]. The findings are somewhat
unexpected, because previous trials have shown that calcium improves
blood cholesterol levels, senior author Dr Ian R Reid (University of
Auckland, New Zealand) told heartwire.

Dr Mark J Bolland (University of Auckland, New Zealand) and
colleagues published the findings online in BMJ January 15, 2008.

"This is quite controversial, given that the worldwide calcium-
supplement market is worth $3 billion a year," says Reid. "The trial
was primarily looking at what calcium supplements do to bone
density, but we had a secondary hypothesis right from the outset
that calcium might actually prevent heart attack. What we found, to
our surprise, was that we didn't see a decrease but an increase, and
the findings appear to be quite robust." Reid added, however, that
there have been some clues from three other recent studies,
including one from Women's Health Initiative (WHI) in the US
[2]: "these three did not find significant increases in the number
of heart attacks [with calcium], but they have found upward trends."

Dr Erin D Michos (Johns Hopkins University, Baltimore, MD), who was
not involved with this new study but cowrote an editorial
accompanying the publication of the WHI study on vitamin-D/calcium
supplements last year [3], told heartwire: "This is a thought-
provoking study, although not definitive, but further work should be
done."

Others warned that it is premature to make any treatment decisions
on the basis of this new study. British Heart Foundation
spokesperson Judy O'Sullivan said more rigorous research was needed
before any firm conclusions could be drawn. "Anyone who has been
advised by their doctor to take calcium supplements to protect their
bones should not stop doing so in light of this study alone without
medical advice," she said.

Findings equivocal

The New Zealand team randomized 1471 postmenopausal women (average
age 74 years) to either calcium supplementation (1 g/day calcium
citrate) or placebo. As well as bone density, they looked at adverse
cardiovascular events over five years: death, sudden death, MI,
angina, other chest pain, stroke, transient ischemic attack, and a
composite end point of MI, stroke, or sudden death.

Reid says the study collected data on MIs and strokes "in a much
more careful way" than any other previous studies have done. "We got
cardiologists and other people involved and audited all those things
and went back to patients' hospital records and so on."

MI was more commonly reported in the calcium group than in the
placebo group (45 events in 31 women vs 19 events in 14 women,
p=0.01), and the composite end point was also reached more often in
the calcium group (101 events in 69 women vs 54 events in 42 women,
p=0.008). Even after adjudication, MI remained more common in the
calcium group, as did the composite end point.

But when unreported events were added from the national database of
hospital admissions in New Zealand, the relative risk of MI was 1.49
in those taking calcium compared with placebo recipients (p=0.16)
and that of the composite end point 1.21 in those taking calcium
compared with those on placebo (p=0.32).

"Thus, the present study does not unequivocally show an adverse
cardiovascular event of calcium but suggests that this matter needs
to be considered carefully before calcium supplementation can be
broadly advocated," the researchers note.

Michos told heartwire the results are somewhat difficult to
interpret, because there appear to be some imbalances between the
calcium and placebo arms at baseline, "which may have influenced the
higher outcomes seen in the calcium arm."

Also, the New Zealand team did not report serum vitamin-D levels,
except to say they excluded those with very severe vitamin-D
deficiency, she notes. "While I still believe vitamin D is important
and beneficial for cardiovascular health, supplementation with
calcium alone (without vitamin D) may not be beneficial for CV
health."

Age may play a role

Reid says that "there is a possibility that this was a chance
finding, but what makes us believe that this is not the explanation
is that there have been three other recent studies--one from the UK,
one from the US, and one from Australia--that have found upward
trends in the numbers of heart attacks with calcium, so we are
showing the same sorts of trends."

"Taken together, these four studies raise major concerns about the
cardiovascular safety of calcium supplementation, particularly with
respect to MI in older postmenopausal women," say the researchers in
their paper.

Reid says it is important to consider age. The women in the New
Zealand study were quite old, those in the Australian study were
similarly elderly, but those in the US--the WHI study--were more
than 10 years younger, as were the ones studied in the UK.

"Most of the trials have been done in women in their 50s and 60s,
and the signal hasn't come through as strongly in those younger
women, so it's probably okay [to use calcium] in those younger
women."

High calcium uptake might accelerate calcification of arteries?

The findings from his study may also be stronger, Reid said, because
they used quite a high dose, 1 g per day, and a more soluble calcium
preparation than others have done, which probably resulted in better
compliance. "And our study is a bit longer than some of the others,
so that may also explain why we've got a more powerful effect.

"The other thing that makes us think that this is not a chance
finding is that it is now pretty well established that patients on
dialysis using calcium supplementation are at increased risk of
heart attack and death.

"What we think is happening is that the higher calcium intake--and
particularly the bolus of calcium that supplementation provides--is
somehow accelerating the laying down of calcium in the artery walls
of the heart," he notes.

"The way I interpret this is that if you have preexisting heart
disease--which probably most of our participants did, although they
probably weren't aware of it--then the extra calcium appears to be
bad. But if, on the other hand, you are 54 and you have nice clean
arteries to your heart, then probably calcium is not going to cause
you any major problems. That's my take on it. But I don't know if it
can be proven."

He added that the advice they have been providing to women in New
Zealand in the past few months, since they became aware of these
findings, "is that if you are in the older age group and are known
to have heart disease, it's probably not sensible for you to take a
calcium supplement. In younger people, calcium supplements look
reasonable, but it may be sensible to aim for a smaller dose, say
500 mg/day."

He noted that the study also showed--"in a more clear-cut way than
any other"--that calcium substantially slows bone loss, "so going
down to 500 mg/day is not going to achieve the same bone benefit,
although it is probably a safer balance."

But for patients who really have major problems with
osteoporosis, "it's much more sensible to focus on using specific
osteoporosis drugs," he said. "If you've got osteoporosis, take
other things, don't just rely on extra calcium."

What's next?

Reid says his team has a number of plans to look at this issue going
forward. "We are going to try to access the radiographs from women
in the study and see if we can quantify calcification in them." They
also have another study that has just finished, this time in a few
hundred men, in which they are looking at coronary artery
calcium. "In the men's study, they are younger, and there is an
adverse trend, but it's much smaller," he noted.

And he hopes to coordinate a meta-analysis of the UK, US, and
Australian studies and his own "to see if we can use all the
available evidence to determine whether there really is something
solid here."

Reid has received research support from and acted as a consultant
for Fonterra and Mission Pharmacal.

Bolland MJ, Barber AP, Doughty RN, et al. Vascular events in healthy
older women receiving calcium supplementation: randomized controlled
trial. BMJ 2008; DOI:10.1136/bmj.39440.525752.BE. Available at:
http://www.bmj.com.
Hsia J, Heiss G, Ren H, et al. Calcium/vitamin D supplements and
cardiovascular events. Circulation 2007; 115:846-854. Abstract
Michos ED, Blumenthal RS. Vitamin D supplementation and
cardiovascular disease risk. Circulation 2007;115:827-828. Abstract

In a new study, published online January 13, 2008 in Nature
Medicine, scientists showed that the dream of growing new human
hearts to replace damaged ones is not simply in the realm of a too-
distant future, as the group reported they were successful in
creating a beating rat heart in a laboratory [1].

Using a process known as perfusion decellularization, the
scientists, among them senior investigator Dr Doris Taylor
(University of Minnesota, MN), created a functional scaffold of the
rat heart and then, after injecting it with cardiac cells from other
rats, were able to get the heart beating again.

"In my opinion, the biggest advance with this study is that this is
the first time we were able to generate tissue with early function
within a 3D anatomical framework," Taylor told heartwire. "With the
scaffold, we preserved the extracellular matrix and produced a
vascular architecture complete with patent valves and vascular
conduits. This was not just about trying to make the tissues beat in
a dish. We already know we can do that."

White, opaque, and beautiful

In the decellularization process, Taylor and colleagues, including
lead investigator Dr Harald Ott (Harvard Medical School, Boston,
MA), removed all the cells from a rat heart. To do this, the heart
is hung by the vasculature and perfused with a detergent to lyse
cells and wash cellular debris from the vascular network. The
process is repeated until only the extracellular matrix is left, a
process that leaves the heart looking "white and opaque."
This "beautiful" structure retains all the architecture of the
original organ, said Taylor.

After successfully removing all of the cells from the rat heart,
researchers then reseeded the "scaffold" with progenitor cells taken
from neonatal or newborn rat hearts. The investigators focused the
reseeding on the left ventricular freewall, all with the hope of
generating cardiac function in the new heart. After four days,
contractions were observed, and by day 8 the hearts were able to
pump a small amount of blood.

"We had hoped that it would work, we thought that it should,
especially the way we put the pieces back together again, but things
like this are never straightforward in science," said Taylor. "That
being said, we were obviously thrilled when it did work."

Taylor told heartwire that the next steps will
involve "understanding the science" and moving toward an application
of the science to clinical therapy as quickly as possible. In terms
of the science, understanding how the cells interact with the matrix
or how they interact with a damaged matrix is important, she said.
In addition, scientists will want to learn what type of cells work
best, especially as it pertains to using stem cells as the source of
reseeding the decellularized matrix. She is confident, however, that
within five to 10 years the science can be applied to engineering
bioartificial hearts as replacements for patients awaiting a donor
heart.

"There are going to be inestimable hurdles, but with this study, we
went from the idea to the beating heart within one year," said
Taylor.

Ott HC, Matthiesen TS, Goh SK, et al. Perfusion-decellularized
matrix: using nature's platform to engineer a bioartificial heart.
Nat Med 2008; DOI: 10.1038/nm1684. Abstract

The authors of a Perspective on drug-eluting stent (DES) safety and
efficacy appearing in the Annals of Internal Medicine next month and
published online December 17, 2007 say they believe the message
about the relative safety of DES as compared with bare-metal stents
is not getting out beyond the interventional community [1].

"I think interventional cardiologists have followed the story and
are quite well-informed, but the general cardiologists may not, at
this point, be up to date," Dr Allen Jeremias (Stony Brook
University Medical Center, NY) told heartwire. "The truth is, the
pendulum has swung radically. When we first wrote this article, it
was the height of the DES mania. What we tried to do was familiarize
ourselves with the data and try to provide a more unbiased and
scientific type of review. And what we found was that when you
looked at the data objectively, in balance, DES are more favorable
than harmful."

In the interim, between writing the Perspective and its publication,
the pendulum has swung back to more strongly favor DES, he adds. "If
we were to write the same article again today, I think we'd be even
stronger in our conclusions, because now there is a lot of evidence
that they do save lives as compared with bare-metal stents. The
pendulum has really swung toward them being not only efficacious but
also safer and better than bare-metal stents."

The Perspective summarizes much of the information published on DES
safety and efficacy until mid-2007, in aggregate suggesting that a
net clinical benefit of DES outweighs the risks associated with an
increase in stent thrombosis. Jeremias and coauthor Dr Ajay Kirtane
(Columbia University, New York) also emphasize that premature
discontinuation of antiplatelet therapy "is an important trigger"
for stent thrombosis and that patients undergoing PCI and stenting
must clearly be candidates for long-term, uninterrupted antiplatelet
therapy.

"If you forget stent thrombosis as a semisurrogate end point for a
minute and focus really on death and MI, which are really the only
hard end points we should look at, they are reduced at four years,"
Jeremias said. "You could argue that we should wait 10 years, but if
you look at the data emerging, there is more and more evidence that
those devices are not only safe but also more beneficial than we
anticipated."

Bad news travels further

None of this is new news to interventional cardiologists who have
followed the turbulent history of drug-eluting stents minute by
minute, but Jeremias maintains that while the bad-news DES story was
trumpeted from the hilltops, stories about the more reassuring
results for the devices have been muffled. The result:
noninterventionalists and the public remain concerned.

"We really wanted to publish this in a general medical journal
rather than a cardiology journal, because this message really needs
to come out to the general medicine practitioner and to general
cardiologists as well," he says. "From the media's perspective, it's
always more interesting to report alarming news, and more people
will hear that or read that than they will news that is more in
favor of these devices, because it makes a more interesting story.
Now, I think it's very hard to get the message out that after repeat
analysis, the devices appear to be safer than anticipated a year ago
and in fact might be of benefit to patients."

Jeremias emphasized that he is by no means playing down the now-
accepted increased risk of late stent thrombosis. "Stent thrombosis
with DES is a problem and can certainly be improved upon. However,
if you look at the balance at the end of the day, in terms of hard
outcomes, death and MI, they are reduced with DES."

Jeremias is on the speaker's bureau for Novartis and Medtronic.
Kirtane discloses, in the paper, consulting for Medtronic Vascular
and receiving honoraria from Boston Scientific.

Jeremias A, Kirtane A. Balancing efficacy and safety of drug-eluting
stents in patients undergoing percutaneous coronary interventions.
Ann Intern Med 2008; published online December 17, 2007. Abstract

Proponents of cardiac CT angiography (CTA) are, in the words of one
clinician, "in uproar and panic" over a proposed national coverage
determination (NCD) by the US Centers for Medicare & Medicaid
Services (CMS). Far from establishing national Medicare coverage for
patients undergoing CTA--something that all 50 individual states
already provide under local coverage determinations--the federal
policy decision would limit Medicare coverage of a diagnostic CT to
just two indications and only in cases where the patient was
enrolled in a clinical trial of cardiac CT.

"Usually when you hear 'national coverage determination,' that
connotes good, it means the modality or therapy will be covered
nationally," Dr Michael Poon, president of the Society of
Cardiovascular Computed Tomography (SCCT), one of the organizations
protesting the proposed NCD, lamented to heartwire. "But
unfortunately this time, they've added another acronym, CED--
coverage with evidence development--which is a totally different
ball of wax. What it means is CTA will be covered only if the
patient is enrolled in some kind of clinical trial."

No preexisting national Medicare policy deals specifically with
coronary CT angiography; until now, Medicare reimbursement has been
governed by local coverage determinations at a state level, where
local contractors variously opted to cover CTA between 2005 and
2006. CMS spokesperson Don McLeod confirmed to heartwire that a
national policy would trump all locally established determinations.

The proposed NCD was drafted in December 2007 and is open for a
second round of public comment until January 13, 2008. If adopted,
the determination would take effect in mid-March 2008 and would
limit Medicare coverage of CTA for the diagnosis of CAD in
symptomatic patients enrolled in a clinical trial presenting with
either "chronic stable angina at intermediate risk of CAD or with
unstable angina at low risk of short-term death and intermediate
risk of CAD."

According to Dr Pamela Woodard, president of the North American
Society for Cardiovascular Imaging, which is also objecting
vociferously to the draft NCD, the actual indications suggested
represent only two of the "useful" patient populations.

"However, there are others," she noted. "For example, patients who
may have abnormal stress tests in low- or intermediate-risk
populations who might otherwise go on to cardiac caths. But the CMS
is basically only including patients at intermediate risk."

In the face of evidence

The CMS Coverage and Analysis Group responsible for the draft NCD,
led by Dr Steve E Phurrough, asserts that there is not enough
evidence to support Medicare coverage of CTA.

But proponents of CTA who spoke with heartwire say that the proposed
NCD does not take into account many CTA studies that have been
published or presented since the CMS first announced it was looking
into CTA reimbursement, back in the summer of 2007.

"We knew that the CMS was coming out with a proposal; we didn't know
it was going to be an NCD," Woodard told heartwire. "The opinion of
the societies is that the CMS ignored a lot of literature that is
already out there in its NCD proposal. We know that there are about
20 to 24 articles that are not cited. One of the concerns was the
lack of multicenter trials; however, there were two multicenter
trials that have been presented at the AHA and RSNA
[meetings]. . . . That information was also not considered."

McLeod, however, speaking for the CMS, insists that "this is a
science-based process," adding that the CMS decision takes into
account evidence it finds on its own and any submitted through the
open public comment. Whether that includes the most recent clinical
data presented or published is unclear, something many imaging
experts allege has not taken place in this case, given the fast-
paced accumulation of data supporting a role for CTA. But Dr Barry
Straube, the CMS chief medical officer and director of its office of
clinical standards and quality, rejected this concern, telling
heartwire, "The charge that evidence published in the last year was
not used is incorrect. CMS will review all public comment and decide
whether the proposed decision memo should be modified or not."

Turning back the train

Dr Armin Zadeh is one of nine imaging experts at Johns Hopkins
University who have signed onto a letter to Phurrough, inviting him
to visit their cardiac imaging lab to better understand the benefits
of cardiac CT angiography. He believes the cardiac imaging societies
duly provided feedback during the initial public comment period but
did not "take seriously" the CMS threats that an NCD was in the
works.

"We really didn't think they'd go through with this, so that's why
everybody was shocked when they came out a few weeks back and said
that they are ready to implement this. If you read it, it already
sounds like a final decision. It's open for discussion, but the
chance that they'll actually revoke it is pretty slim."

Zadeh notes that, in the past, the CMS has rarely gone back and
rejiggered a proposed or finalized NCD for cardiac imaging, even
after evidence supporting a benefit of the technology on hard
outcomes is in. "A similar thing happened with PET scanning, which
has never really gotten reimbursement," he told heartwire.

Poon, likewise, is concerned it may be too late to turn the train
around. "Unfortunately, this is an election year, and politicians
have bigger fish to fry than worry about cardiac CT," he said
ruefully. "I don't think politicians are interested in saving a
modality when there is so much discussion about cost containment and
the Deficit Reduction Act and so on."

Radiation risks

In recent months, risks associated with CT angiography--particularly
the amount of radiation it delivers--have been under increased
scrutiny. At last year's AHA meeting, Dr Michael Lauer (National
Heart, Lung, and Blood Institute) delivered a stinging rebuke to the
field as a whole, calling for a moratorium on cardiac CT until proof
of safety and benefit was in. Contacted by heartwire, Lauer's office
said he "would not be commenting" on the proposed CMS coverage
decision.

"Obviously there are concerns regarding radiation, which are
legitimate, and I don't think we should be using CT in everybody,"
Zadeh told heartwire. "But for the appropriate indications, these
scans actually save lives by the mere fact that if, based on the CT
scan, you don't do a cardiac catheterization you will inevitably
save lives. The complication rate from cardiac catheterization is
very well-documented. There is no doubt that people die during
diagnostic catheterizations every year."

Zadeh acknowledges that the CED-portion of the proposed NCD may be
to encourage clinical studies. In this case, however, "CT studies
are just exploding everywhere," he said. "There is not a lack of
data, it's just that many of these outcome studies take time. They
are all in the planning phases or have already started. But there's
no lack of willingness and interest in conducting studies."

Societies comment, then wait

A range of other cardiac and imaging societies have expressed their
concern about the draft NCD, among them the American College of
Cardiology, the American College of Radiology, the American Society
of Nuclear Cardiology, and the Society for Cardiovascular
Angiography and Interventions. A "Comment" button on the CMS website
where the draft proposed decision memo has been posted allows
physicians and other concerned parties to comment on the NCD until
January 13, 2008.

In recent weeks, society presidents, including Poon and Woodard,
having been trying to get the word out to their members to voice
their opinions while there is still time.

"This is a very unfortunate, backward, and draconian move on the
part of the CMS," Poon told heartwire. "What this means is that many
Medicare beneficiaries will have to go back along the traditional
pathway, which is, if you have an equivocal stress test, you get
cathed. If you have atypical symptoms, or are unable to exercise,
you get cathed. Right now we have CTA as the gatekeeper, so that
many of the unnecessary caths can be avoided."

He notes that registry results suggest that as many as 40% of
diagnostic catheterizations are unnecessary; other patients who
undergo diagnostic catheterizations end up getting interventions
for "quasi-indicated lesions" because they're already prepped and on
the table, he adds. "Every state in the union accepted this
technology as efficacious and beneficial before the CMS turned an
about-face, without any legitimate reason and without looking at all
the published evidence. I think that is wrong, and I don't think
it's fair to the Medicare beneficiaries."

The results of the long-awaited and controversial ENHANCE trial,
finally announced today, have shown no benefit of the combination of
ezetimibe (Zetia, Merck/Schering-Plough Pharmaceuticals) and
simvastatin (sold together as Vytorin, Merck/Schering-Plough
Pharmaceuticals) over simvastatin alone.

The trial, which has been dogged with controversy in recent months,
was conducted in 720 patients with heterozygous familial
hypercholesterolemia and showed no significant difference in the
primary end point--mean change in the intima media thickness (IMT)
measured at three sites in the carotid arteries--between patients
treated with ezetimibe/simvastatin 10/80 mg vs patients treated with
simvastatin 80 mg alone over a two-year period.

At baseline, the mean carotid IMT measurement for the
ezetimibe/simvastatin group was 0.68 mm and for the simvastatin-80-
mg group was 0.69 mm. There was also no statistically significant
difference between the treatment groups for each of the components
of the primary end point, including the common carotid artery. Key
secondary imaging end points showed no statistical difference
between treatment groups.

Huge disappointment

These results will be a huge disappointment to Merck and Schering-
Plough. Ezetimibe, which has a complementary action to the statins,
preventing the intestinal absorption of cholesterol and generally
adding an extra 20% LDL reduction to that seen with statins alone,
is a relative newcomer to the cholesterol market but is already
generating blockbuster sales, said to be in the region of $5
billion. That is despite the fact there have been no outcome data
available on the drug.

The ENHANCE trial is the first major study to be conducted with
ezetimibe, which is why the results were so eagerly anticipated.
Although it is not a clinical-outcome study, carotid ultrasound
studies monitoring the effects of drug therapy on atherosclerotic
plaque are seen as reliable surrogates and normally predict whether
a drug will be effective in lowering cardiac events. The results
were originally expected to be reported about a year ago, and this
had led to much speculation in recent months that they were being
delayed as they were negative, although this was denied by the
companies and the lead investigator.

More details

Further results from the ENHANCE trial show that the overall
incidence rates of treatment-related adverse events, serious adverse
events, or adverse events leading to discontinuation were generally
similar between treatment groups. There were no cases of
rhabdomyolysis. Both medicines were generally well tolerated.

Cardiovascular events similar

And there were no differences in cardiovascular events between the
two groups in the trial, which was not powered to assess
cardiovascular clinical-event outcomes.

There were no noncardiovascular deaths or incidents of resuscitated
cardiac arrests in the ENHANCE trial.

Larger outcome trials under way

Merck/Schering-Plough are stressing that this was a surrogate-end-
point trial, and they are currently conducting three large outcomes
trials with ezetimibe/simvastatin that involve more than 20 000 high-
risk patients, including the more-than-10 000-patient IMPROVE-IT
trial. No incremental benefit of ezetimibe/simvastatin on
cardiovascular morbidity and mortality over and above that
demonstrated for simvastatin has been established, they note.

The ENHANCE trial used digitized single-frame ultrasound technology
for imaging purposes. There were 357 patients randomized to
ezetimibe/simvastatin and 363 to simvastatin. The study collected
more than 30 000 carotid artery and 10 000 femoral artery images
from these patients. Single-frame ultrasound images were analyzed
from the right and left carotid arteries at three sites (the common
carotid, the internal carotid, and the carotid bulb) and at numerous
time points (baseline and six, 12, 18, and 24 months). Images from
the right and left common femoral arteries were analyzed at these
same time points as well.

Consuming sweets and chewing gum with sugar substitutes may help the
weight-conscious slash calories, but excessive use of the sweetener
sorbitol can cause extreme weight loss and other problems, according
to a new report.

In this week's BMJ, Juergen Bauditz, MD, of the University of
Berlin, and colleagues describe two patients with a sorbitol habit
who had dramatic, unexplained weight loss until their excessive use
of the sweetener was discovered.

Sugar-Free Sweeteners and Side Effects: Case Histories

One patient, a 21-year-old woman, had unexplained diarrhea and
abdominal pain for eight months. She reported an unintended weight
loss of 24 pounds, weighing in at about 90 pounds.

After she was asked about diet, she said she chewed sugar-free gum
with sorbitol daily, taking in about 18 to 20 grams a day. One stick
typically has 1.25 grams.

Once she eliminated sorbitol from her diet, the gastrointestinal
problems stopped and she gained back more than 15 pounds.

The second patient, a 46-year-old man, had been hospitalized because
of diarrhea and a weight loss of more than 48 pounds during the
previous year. His blood work and other exams came back normal, but
when asked about diet, he, too, reported excessive consumption of
sorbitol. He chewed 20 sticks of sugar-free gum daily and also ate
about 7 ounces of sweets daily, totaling about 30 grams of sorbitol.

When he cut out the sorbitol, he gained back 11 pounds within six
months and his diarrhea problems disappeared.

The message for doctors, the authors conclude, is to inquire about
dietary habits when a patient has unexplained weight loss.

Sugar-Free Sweeteners and Side Effects: A Food Scientist's View

Reports of side effects such as abdominal pain and diarrhea with
high amounts of sorbitol consumption are nothing new, says Roger
Clemens, DrPH, a spokesman for the Institute of Food Technologists
and professor of pharmacology and pharmaceutical sciences at the
University of Southern California, Los Angeles.

"The laxative effect is very well documented," Clemens tells
WebMD. "It could be these individuals [in the case histories] were
particularly sensitive." And they did consume excessive amounts, he
notes. "We would not expect the average consumer to consume upwards
of 20 sticks of gum a day."

"Sorbitol is not well absorbed," Clemens says. As a result, excess
water enters the gastrointestinal tract and diarrhea can occur.
Those who rely on artificially sweetened products to help manage
their diabetes or to reduce overall calories, he says, should use a
variety of such products and consume them in moderation. Sorbitol is
found in toothpastes as well as chewing gum and sweets.

What's a 'Safe' Amount of Sorbitol?

The FDA requires a warning label on a product with sorbitol if the
manufacturer thinks the consumption would exceed 50 grams a day,
according to an FDA spokesperson.

But levels under 50 grams of sorbitol daily may cause problems for
some people, says Patti Truant, a spokeswoman for the Center for
Science in the Public Interest in Washington, D.C. In 1999, the
center petitioned the FDA to require a better label on sorbitol-
containing products, noting that problems such as diarrhea can occur
with as few as 10 grams a day of the sweetener.

Sorbitol Manufacturers Respond

The cases reported in BMJ involved excesses, says Chris Perille, a
spokesman for the William Wrigley Jr. Company, which makes chewing
gum containing sorbitol (including its brands Extra, Orbit,
Freedent, and Eclipse).

"To reach the threshold of excessive consumption of sorbitol through
use of gum alone [at levels set by the FDA], someone would have to
chew close to 50 sticks or 100 pellets of gum daily," he says. In
the U.S., he adds, the average per capita gum consumption is just
one stick every other day.

The ingredient is safe and effective "when used as directed," adds
Tonia Elrod, a spokeswoman for Procter & Gamble, the manufacturer of
Crest toothpaste, which contains sorbitol.

Ethanol intake is well known as a potential cause of hypoglycemia in
diabetic patients and now new findings from an animal study shed
light on the mechanisms involved, according to a report in the
January issue of Endocrinology.

The findings show that alcohol produces "a massive redistribution of
blood flow within the pancreas," lead author Dr. Ake Sjoholm, from
the Karolinska Institute in Stockholm, told Reuters Health.

Using various techniques, Dr. Sjoholm along with Dr. Zhen Huang,
also from the Karolinska Institute, showed that pancreatic islet
blood flow is increased by about fourfold in rats after an injection
of ethanol. Whole pancreatic blood flow, by contrast, was not
affected.

"The magnitude of the alcohol effect on islet blood flow surprised
us," Dr. Sjoholm said. Ethanol injection also amplified insulin
secretion and resulted in hypoglycemia.

Further experiments showed that these effects were prevented by a
nitric oxide synthase inhibitor and by atropine.

Summing up, the investigators write: "Our findings demonstrate that
ethanol acutely exerts substantial influences on pancreatic
microcirculation by evoking a massive redistribution of pancreatic
blood flow from the exocrine into the endocrine part via mechanisms
mediated by nitric oxide and vagal stimuli."

The take-home message for clinicians? "They should advise their
diabetic patients (or patients with liver problems) to be very
careful with alcohol, especially if they are also treated with
hypoglycemic sulfonylureas since these drugs may potentiate the
alcohol effect," Dr. Sjoholm emphasized.

Endocrinology 2008;149:232-236.

Take a look at the following studies, recently in the news, that
your patients may ask you about.

Vaccine Preservative Not Linked to Risk for Autism
Archives of General Psychiatry, January 2008, as reported in the New
York Times

The incidence of autism in California continued to rise even after
the mercury-based preservative thimerosal was removed from routine
childhood vaccine formulations, reports the New York Times in a
story from the Associated Press. Investigators from California's
Public Health Department found that although thimerosal was removed
from nearly all pediatric vaccines administered in California
beginning in 2001, autism rates rose steadily from 1995 to 2007. The
study authors note that the findings further bolster evidence that
thimerosal-based vaccines are unlikely to be a cause of autism
spectrum disorders.

Anxiety Boosts MI Risk by Up to 40%
Journal of the American College of Cardiology, January 15, 2008, as
reported by Bloomberg News

Anxiety may increase the risk of acute myocardial infarction (AMI)
in men by up to 40%, even after controlling for risk factors such as
age, education, marital status, fasting glucose levels, body mass
index, high-density lipoprotein cholesterol levels, and systolic
blood pressure in proportional hazards models, report University of
Southern California researchers and quoted by Bloomberg News. An
analysis of data on 735 men enrolled in the Normative Aging Study
and followed for a mean of 12 years showed that the relationships
between anxiety and AMI risk remained significant even after further
adjustments for health behaviors (drinking, smoking, and caloric
intake), hypertension medications, high cholesterol, diabetes during
follow-up, and psychologic variables including depression, type A
behavior, hostility, anger, and negative emotions.

Breast-Feeding May Lower Allergy Risk
Pediatrics, January 2008, as reported by WebMD

Infants who are breast-fed exclusively for the first 4 months of
life have a significantly lower risk for atopic diseases ˇX atopic
dermatitis, asthma, and food allergy ˇX during the first 2 months of
life compared with children reared on cows' milkˇVbased formula,
notes WebMD, reporting on an American Academy of Pediatrics (AAP)
updated policy statement. The statement from the AAP's Committee on
Nutrition and Section on Allergy and Immunology also notes that "in
studies of infants at high risk of atopy and who are not exclusively
breastfed for 4 to 6 months, there is modest evidence that the onset
of atopic disease may be delayed or prevented by the use of
hydrolyzed formulas compared with formula made with intact cow milk
protein, particularly for atopic dermatitis." There is little
evidence to suggest that delaying introduction of solid foods beyond
4 to 6 months offers any atopy-prevention benefits, however.

FDA Studies Pain in Osteoporosis Drugs
US Food and Drug Administration, January 7, 2008, as reported by
Business Week

The US Food and Drug Administration (FDA) has issued an alert that
some patients may experience severe and possibly incapacitating
musculoskeletal pain while taking bisphosphonates, notes Business
Week, carrying an Associated Press wire story. "Although severe
musculoskeletal pain is included in the prescribing information for
all bisphosphonates, the association between bisphosphonates and
severe musculoskeletal pain may be overlooked by healthcare
professionals, delaying diagnosis, prolonging pain and/or
impairment, and necessitating the use of analgesics," the FDA says
in a statement on its Web site. The pain is separate from the acute-
phase response experienced by some patients following initial
administration of the drugs, the agency noted. "Healthcare
professionals should consider whether bisphosphonate use might be
responsible for severe musculoskeletal pain in patients who present
with these symptoms and consider temporary or permanent
discontinuation of the drug," the FDA cautions.

Vitamin D Deficiency May Hurt the Heart
Circulation (Rapid Access edition), January 7, 2008, as reported by
WebMD

Vitamin D deficiency appears to be a risk factor for cardiovascular
disease in adults with hypertension, reports WebMD in a news story
about an analysis of data from the Framingham Offspring Study. Among
1739 adults with a mean age of 59 years and no prior cardiovascular
disease, there were 120 incident cardiovascular events (myocardial
infarction, stroke, chest pain, heart failure, and peripheral
claudication). Those with low 25-dihydroxyvitamin D levels (<15
mg/mL) had a 62% higher cardiovascular disease risk in a
multivariate adjusted analysis. The risk in this observational study
appeared to be inversely related to vitamin D levels and could not
be explained by risk factors such as C-reactive protein levels,
physical activity, or vitamin supplementation.




Related Links
Online CME
Anxiety Boosts MI Risk, Independent of Other Psychosocial Factors
Guidelines Issued for Nutritional Options for Early Life May Affect
Development of Atopic Disease
Vitamin D Deficiency: A Risk Factor for Heart Disease?


Resource Centers
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Autism Spectrum Disorders Resource Center
Mental Health and Psychiatric Nursing Resource Center
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Osteoporosis Resource Center


External Links
Medscape Alert: Bisphosphonate Therapy Linked to Risk for Severe
Musculoskeletal Pain

A new study shows that acute-stress responses to the terrorist
attacks of 9/11/2001 were associated with a 53% increased incidence
of cardiovascular ailments over the following three years [1]. And
the people who were particularly at risk were those who had an acute-
stress response and cited ongoing concerns about terrorism--these
individuals had a more than threefold increased risk of physician-
diagnosed heart problems three years after the event.

Dr E Alison Holman (University of California, Irvine) and colleagues
report their findings in the January 2008 issue of the Archives of
General Psychiatry. Holman, a nurse practitioner, told
heartwire: "Most doctors and cardiologists know that acute stress
can trigger problems with the heart--we all know about broken-heart
syndrome--but those are people who have experienced a highly
stressful event themselves; they were directly affected. What makes
our findings unique is that the majority of the people in our study
watched the news of 9/11 on TV--they saw the second tower get hit
live on TV, or they watched it afterward. The fact that these folks
for the most part had not directly experienced anything is what
makes this stand out."

The other important factor in this study is that the majority of the
sample did not have preexisting cardiovascular problems, Holman
notes. "There have been some small studies done in New York that
show that, post-9/11 compared with pre-9/11, there were more heart
problems, but those were particular to people who had preexisting
heart disease. This shows that in a sample of people who were
exposed indirectly and for the most part did not have preexisting
cardiovascular disease, over the course of three years there is an
increased risk of the development of some kind of cardiovascular
ailment if they had the high acute-stress type of reaction and that
these effects were exacerbated by ongoing worry about terrorism."

A message for doctors

"What this means for cardiologists, for doctors, is that we have to
find a way to make time for issues of stress," she explains. "When
we know our patients have been exposed in some way to a highly
stressful event, we need to take seriously the risk that this may
pose to them, and we can't minimize it and say, 'Oh well, it didn't
happen to you.' "

Holman does acknowledge, however, that 9/11 was unique: "The US had
not been hit with this kind of attack in more than 50 years, since
Pearl Harbor, and to the American public, this was a major event, a
collective trauma. I have no idea whether individual exposure to
lesser events would create the same kind of problem."

Acute-stress response increases risk of heart problems threefold

Holman and colleagues used health data collected from a sample of
just over 2500 people before 9/11 and therefore had baseline data.
They then asked the same people to complete a web-based assessment
of acute-stress responses approximately 9 to 14 days after the
terrorist attacks. Individuals who met Diagnostic and Statistical
Manual of Mental Disorders, 4th ed (DSM-IV)--described by Holmes
as "the bible of psychiatrists"--criteria B, C, and D for acute-
stress disorder were deemed to have had an acute-stress response.
Holmes noted that most participants were not deemed to have acute-
stress disorder, because direct exposure is one of the criteria for
this diagnosis (there was a very small group who were directly
linked--ie, they lost a loved one or were at the site of the attacks
and got out). She also points out that her study recorded a direct
response, collected right after 9/11, and therefore it was not a
retrospective analysis.

Follow-up health surveys, which were self-reported, assessed
physician-diagnosed cardiovascular ailments one (n=1923), two
(n=1576), and three years (n=1950) after the attacks. These asked
people whether they had ever had or had ever been told by a doctor
that they had had hypertension, stroke, or heart problems in the
generic sense. Holmes said that participants had to have reported at
least two of these three to be deemed at increased risk.

Around 12% of the sample was deemed to have had an acute-stress
response to 9/11. Acute-stress responses were associated with a 53%
increased incidence of cardiovascular ailments over the subsequent
three years.

Even after adjustment for pre-9/11 cardiovascular and mental-health
status, degree of exposure to the attacks, cardiovascular risk
factors, total number of physical-health ailments, somatization, and
demographics, individuals reporting high levels of stress
immediately following the attacks reported around a threefold
increased incidence of heart problems (relative risk ratio 2.98 at
one year and 3.12 at two years) compared with individuals who did
not record high levels of stress following 9/11.

Ongoing worry about terrorism exacerbates effects

Each annual 9/11-related survey also included two questions designed
to assess continuing concerns about terrorism. Items were scored on
a five-point Likert scale and combined as an index of ongoing worry.

Holman explains: "We found that for the first two years post-9/11
there was a direct impact of acute stress. It didn't matter if you
were worrying about terrorism or not. But then starting at two
years, when you look at the people who had high levels of acute
stress and also had high levels of ongoing worry about terrorism,
then we see an almost fivefold increased risk for new-onset
cardiovascular ailments compared with those who had neither acute
stress nor ongoing concerns about attacks."

"The people who had ongoing worry who are at risk are the people who
had acute stress," she points out. "If they had ongoing worry but
did not have acute stress, they did not appear to be at risk.

"To have a reaction within the first two to three weeks following
9/11 that, somehow, three years later, is predicting that something
more serious is going on is pretty amazing," she says.

She explains that extremely stressful events may precipitate
biological processes that increase an individual's risk of
developing cardiovascular ailments. "While acute stress may trigger
immediate potentially lethal cardiovascular responses, acute,
subacute, and chronic stress can gradually increase cardiovascular
risk through neurohormonal arousal. This physiologic reactivity may
be easily rekindled by trauma reminders, leaving individuals
vulnerable to the detrimental effects of arousal over time.

"What this means," Holman continues, "is that we need to think about
how we use terror alerts for the public. We need to think about the
impact. How can we best alert the public so people can take the
action they need to take but not put them at risk for other
problems? That's a challenging question that there is not enough
research, right now, to answer."

Holman EA, Cohen Silver R, Poulin M, et al. Terrorism, acute stress,
and cardiovascular health. A 3-year national study following the
September 11th attacks. Arch Gen Psychiatry 2008; 65: 73-80.

The sequence variant on chromosome 9p21 that increases the risk of
MI and was last year hailed as one of the most significant genetic
risk factors for heart attack identified to date has now been
associated with increased risk of abdominal aortic aneurysm (AAA)
and intracranial aneurysm (IA) [1]. The study, led by deCODE
genetics scientist Dr Anna Helgadottir, has been published online
January 6, 2008 in Nature Genetics.

Senior author and deCODE CEO Dr Kari Stefansson told
heartwire: "This is the first demonstration of an association of any
sequence variant in the human genome and aneurysm, so for this
reason alone it is interesting." But he added that the finding has
even greater implications regarding insight into the mechanisms of
these diseases. "Both heart attack and AAA are associated with
atherosclerosis," he explained, "but IA is not. This means that this
variant confers a tendency or risk of some sort for a structural
defect that leads to IA and that attracts atherosclerosis outside of
the cranium. It could be that this latest discovery indicates a new
mechanism behind the risk of heart attack."

Dr Eric Topol (Scripps Translational Science Institute, La Jolla,
CA) commented to heartwire: "This is a big step forward on 9p21,
since now the phenotypes that the genomic marker is associated with
go beyond MI and coronary artery disease to AAA and IA. Since IA is
not an atherosclerotic process, it does indeed implicate a vessel-
wall story." But he added, "We still don't have a good clue of how
9p21 exerts its effects, but at least we now know that its
importance extends through many vascular phenotypes."

Dr Daniel Judge (Johns Hopkins University, Baltimore, MD)
said: "This is a remarkable finding, validating additional disease
associations with 9p21 genotypes. This is the first highly prevalent
genomic variant identified as a risk factor for either disease [AAA
or IA]."

Variant confers equal risk for all three diseases

In May last year, deCODE scientists, together with another group
from Canada, first reported in Science that a region on chromosome 9
was thought to account for 20% of the incidence of MI in populations
of European origin and a third of cases of early-onset MI. At the
time, this was hailed as a major discovery, and the findings were
later confirmed in two large cohorts in the UK and Germany.

Three months ago, deCODE genetics launched the first genetic test
for MI based on its findings, deCODE MI; it detects the variations
in two single nucleotide polymorphisms (SNPs) on chromosome 9p21
that have been associated with increased risk of MI.

Stefansson told heartwire that once his team had identified the
variants on chromosome 9p21 that conferred increased risk of
MI, "the next question was, what is the mechanism whereby this
sequence variant confers risk? To address this question we looked at
a very large number of people with AAA, IA, and peripheral arterial
disease [PAD] from around the world, and the people with AAA and IA
had this variant much more often than the controls."

He explains that the variant confers almost equal risk for all three
diseases--MI, AAA, and IA--"indicating that it confers the risk of a
fundamental lesion that can develop in all three directions." He
added that he did not find it surprising that they did not find a
link between the variant and PAD, "because it's a different disease
from the others. For example, if you take type 2 diabetes mellitus
(DM), PAD is found very commonly in these people. But AAA is found
more rarely in people with DM than it is in the population in
general."

The new paper "ranks very high among the papers I have participated
in. I find it enormously satisfying to be able to take this story
and develop it to the next chapter," he said.

deCODE MI will now include risks for AAA and IA

Stefansson said the risks for AAA and IA will now be incorporated
into the deCODE MI diagnostic test. "What this means is that if you
turn out to be homozygous for this variant, you not only have the
risk of heart attack but these other diseases, too. You would need
to be screened not only for MI but for lesions in the abdominal
aorta, and you would need a magnetic resonance imaging scan of the
brain."

Judge commented: "Since clinical tests for these risk alleles are
now available [from deCODE], additional disease associations are
likely to increase their use.

"However," he cautions, "healthcare practitioners should recognize
the limitations and appropriate application of this novel risk
factor when applying these population studies to individuals and
families. For instance, in a family with dominantly segregating
aortic or intracranial aneurysm, absence of the 9p21 high-risk
genotype in a proband makes its utility in progeny questionable in
the assessment of these aneurysms, as other genomic factors may
exert greater influence."

Disclosures for the authors are available in the paper.

Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same
sequence variant on 9p21 associated with myocardial infarction,
abdominal aortic aneurysm and intracranial aneurysm. Nat Genet 2008;
DOI: 10.1038/ng.72. Available at: http://www.nature.com/ng. Abstract

An abnormal electrocardiogram (ECG) in a young, highly trained
athlete might be the first expression of underlying cardiomyopathy,
a new study suggests, and might not simply be the benign expression
of cardiac remodeling associated with athletic conditioning [1]. As
the underlying cardiomyopathy might not show itself until many years
later and may be associated with adverse outcomes, athletes with
abnormal ECGs merit continued clinical surveillance, say
investigators.

"Contrary to previous reports describing such ECG patterns as
innocent manifestations of 'athlete's heart,' without adverse
clinical consequences, the present study shows that these abnormal
ECGs may represent the initial expression of genetic cardiac
disease, preceding by many years phenotypic expression and adverse
clinical outcomes," according to lead investigator Dr Antonio
Pelliccia (Institute of Sports Medicine and Science, Rome, Italy)
and colleagues.

Publishing their report in the January 10, 2008 issue of the New
England Journal of Medicine, the Italian authors, along with Dr
Barry Maron (Minneapolis Heart Institute Foundation, MN), note that
12-lead ECGs often show a range of alterations in young, trained
athletes, most commonly of the type suggesting left ventricular
hypertrophy. These repolarization abnormalities are usually thought
to be the result of exercise training, but the group writes that a
small subgroup of athletes without evidence of structural heart
disease might have "diffusely and deeply inverted T waves,
suggestive of an underlying cardiac disorder."

Screening for all athletes in Italy

Italy is one of the few countries to legally require those
participating in competitive sports to undergo preparticipation ECG
screening to rule out cardiovascular disease. Because of this,
Pelliccia and colleagues were able to evaluate the clinical outcomes
associated with abnormal ECGs, characterized by these distinctive
repolarization patterns, in trained athletes. From the database of
more than 12 000 athletes, the group identified 81 athletes with
repolarization abnormalities--inverted T waves >2 mm in at least
three leads--but who had no apparent cardiac disease.

Of the 81 athletes with abnormal ECGs, five later proved to have
cardiomyopathies, including one who died at age 24 from undetected
arrhythmogenic right ventricular cardiomyopathy. The clinical and
phenotypic features of hypertrophic cardiomyopathy developed in
three subjects after approximately 12 years, and one of these
subjects had an aborted cardiac arrest. The fifth athlete had
dilated cardiomyopathy after nine years of follow-up. Comparisons
between 229 matched control athletes with normal ECGs from the same
database revealed that none of those athletes had a cardiac event or
were diagnosed with cardiomyopathy more than nine years after their
initial evaluation.

"These observations underscore the importance of greater diagnostic
scrutiny and continued clinical surveillance of trained athletes who
present with such distinctly abnormal ECGs," write the authors.

Commenting on the findings for heartwire, Dr Benjamin Levine
(University of Texas Southwestern Medical Center, Dallas) noted that
the most feared of the cardiomyopathies of the left and right
ventricles are associated with sudden death in competitive
athletics. Regarding the Italian cohort, he pointed out that nearly
one-third of the athletes were part of a select population, referred
to the authors because of bizarre ECG screening, rather than
detected on routine screening.

"Therefore, the authors carefully and appropriately avoid raising
any implications of their findings for the 'hot' issue of ECG
screening of competitive athletes," noted Levine. "In my opinion,
these data provide no further evidence that can inform this debate--
mass screening of any population, regardless of the method, is
likely to identify a fraction of 1%, probably 0.2% to 0.5%, of
individuals who may have an underlying inherited cardiomyopathy that
is at some point in its clinical expression."

The frequency of previously undiagnosed cardiomyopathies was a small
but important fraction of the total of athletes with abnormal ECG
patterns. He noted that if 24 athletes with documented
cardiomyopathy, picked up at the initial ECG screening but excluded
from subsequent analysis, were added to the five subjects in whom
cardiomyopathy was later detected, the overall prevalence of
clinically meaningful cardiomyopathy in the population was
0.23%, "remarkably similar to the prevalence of hypertrophic
cardiomyopathy that has been reported in the general population."

In addition, Levine noted that the study highlights the finding that
a normal ECG is strongly predictive of a benign short-term,
approximately 10 years, clinical course.

Pelliccia A, Di Paolo FM, Quattrini FM, et al. Outcomes in athletes
with marked ECG repolarization abnormalities. N Engl J Med 2008;
358:152-61.

Compared with paclitaxel-eluting stents (PES), sirolimus-eluting
stents (SES) appear to decrease the risk of in-stent late luminal
loss in diabetics with coronary artery disease, new research shows.

The optimal drug-eluting stents for diabetic patients has been
unclear, lead author Dr. Fabrizio Tomai, from the European Hospital
in Rome, and colleagues note in the January issue of Diabetes Care.

Comparing PES with SES has been difficult since there are so many
individual variables that contribute to neointimal hyperplasia. In
the present study, the researchers addressed this problem by
comparing PES and SES directly in the same diabetic patient.

The study enrolled 60 patients with two or more significant de novo
angiographic stenoses in different coronary segments. Overall, 60
lesions were successfully treated with PES and 60 with SES, the
report shows. (Another 26 coronary lesions were treated with bare
metal stents and were not included in the analysis.)

The main outcome measure was the occurrence of angiographic in-stent
late luminal loss at 8-month follow-up. This was lower with the SES
(0.26 mm) than with the PES (0.50 mm), a significant difference (p =
0.01).

On multivariate analysis, the type of drug-eluting stent was the
only independent predictor of in-stent late luminal loss.
Specifically, in-stent late luminal loss was 2.3-times more likely
when a PES rather than a SES was used (p = 0.03).

Further research is needed to determine if the better angiographic
results achieved with SES actually translate into long-term clinical
benefits, the authors conclude.

Diabetes Care 2008;31:15-19.

The American Association of Clinical Endocrinologists (AACE) has
released a statement on hormone replacement therapy (HRT) and
cardiovascular risk, emphasizing that HRT does not appear harmful in
younger women in early menopause and may indeed be beneficial in
this group [1]. "With this in mind, and given the powerful effects
of estrogen therapy in relieving menopausal symptoms, we believe
that physicians may safely counsel women to use estrogen for the
relief of menopausal symptoms. Each patient should be evaluated for
the severity of her symptoms, her age, and specific risk factors
that might impact on her use of hormonal therapy," the statement
concludes.

One of the authors of the statement, past AACE president Dr Rhoda
Cobin (Mount Sinai School of Medicine, New York), told heartwire
that a review of all the available evidence suggests that younger
women who are close to menopause have less to fear from HRT than
older women in terms of cardiovascular risk. "We think the data
offer some reassurance to women close to the menopause, with the
suggestion that estrogen supplementation may even protect against
heart disease in these younger women. And even if it is not
protective, it doesn't appear to be harmful so can probably be used
safely to treat menopausal symptoms. There does appear to be a
window of opportunity for use of estrogen."

She added: "After all the negative publicity from the HRT trials,
physicians are now fearful of prescribing estrogen at all. But we
believe there are advantages and disadvantages to such treatment and
that cardiovascular risk in particular is not the same for everyone.
Each woman should be considered individually, and many factors
should be taken into account when thinking about prescribing HRT.
These include age, time from menopause, other cardiovascular and
thrombotic risks, and menopausal symptoms.

"The evidence is particularly reassuring for estrogen-only therapy,
which has not been associated with increases of either
cardiovascular disease or breast cancer in younger women. So for
women who have had an early hysterectomy and therefore do not have
to have progesterone, they should not be deprived of estrogen
replacement therapy," Cobin commented.

The AACE statement notes that in animal studies, estrogen is
effective in inhibiting progression of early-stage atherosclerosis
but it is much less effective in inhibiting progression of more
advanced atherosclerosis in older animals. After these observations,
data from the major HRT studies were reexamined to determine the
effect of treatment on cardiovascular risk when stratified by age or
time from menopause.

The reevaluation of the Nurses' Health Study found that women
beginning hormone therapy near menopause had a significantly reduced
risk of CHD (RR=0.66 for estrogen alone; RR=0.72 for estrogen with
progestin). A recent meta-analysis of 23 trials of HRT that compared
results in younger women (younger than 60 or less than 10 years
since menopause) vs older women showed that HRT significantly
reduced CHD events in the former (OR 0.68) but not in the latter (OR
1.03). And in the Womenˇ¦s Health Initiative (WHI) trial, when
stratified by time since menopause, the hazard ratios for CHD were
0.76 in the women fewer than 10 years from the onset of menopause,
1.1 in those 10 to 19 years from onset of menopause, and 1.28 in
those women more than 20 years from onset of menopause. By age, the
hazard ratios for cardiovascular disease were 0.93 for ages 50 to
59, 0.98 for ages 60 to 69, and 1.26 for ages 70 to 79.

The AACE statement notes that further data on HRT in younger women
will come from the Kronos Early Estrogen Prevention Study (KEEPS),
which is evaluating five years of HRT vs placebo in 720 women aged
42 to 58 years within 36 months of final menstrual period. The end
points will include prevention of progression of carotid intimal
medial thickness and accrual of coronary calcium, but results will
not be available for several years.

American Association of Clinical Endocrinologists. AACE Analysis
shows no excess cardiovascular risk from hormone replacement therapy
for most patients [press release]. January 2, 2008. Available at:
http://www.aace.com/newsroom/press/2008/index.php?r=20080102-1.

Obese, relatively young women with polycystic ovary syndrome (PCOS)
are at increased risk for early subclinical coronary atherosclerosis,
independent of the presence of traditional cardiovascular risk
factors and novel inflammatory risk markers, a study shows.

"These findings underscore the need to screen and aggressively
counsel and treat these women to prevent symptomatic cardiovascular
disease," Dr. Rupal Shroff and colleagues from the University of
Iowa, Iowa City, conclude in the December issue of the Journal of
Clinical Endocrinology and Metabolism.

The researchers conducted a prospective study involving 24 women,
between 21 and 50 years of age, with PCOS and a BMI of 30 or higher,
and 24 weight- and age-matched controls without PCOS. The team
detected coronary artery calcium, a marker of early-onset
atherosclerosis in 8 of 24 PCOS subjects (33%) and 2 of 24 controls
(8%).

This translated to an adjusted odds ratio of 5.5 (p < 0.03), the
investigators note.

Moreover, they found that the majority of women with detectable
coronary artery calcium did not have traditional cardiovascular risk
factors "and the presence of PCOS status per se appeared to
contribute to this increased risk of coronary artery calcium."

"Longitudinal studies to document the progression of coronary artery
calcium in this population are urgently needed," Dr. Shroff and
colleagues say.

J Clin Endocrinol Metab 2007;92:4609-4614.

In what is likely the most rigorous evaluation to date of surrogate
end points in modern-day stent trials, researchers report that late-
loss (LL) and percent-diameter stenoses (%DS) are both "suitable"
surrogates for efficacy. The analysis, appearing in the January 1/8,
2008 issue of the Journal of the American College of Cardiology [1],
combines data from 11 pivotal drug-eluting-stent trials, and many of
the investigators for these trials are coauthors on the current
paper.

Lead author on the study, Dr Stuart J Pocock (London School of
Hygiene and Tropical Medicine, UK), told heartwire that he believes
the analysis represents an important consensus on the role and
validity of these angiographic surrogates at a time when it is
becoming increasingly complicated to compare the antirestenotic
effects of two drug-eluting stents.

"I think this is really the most systematic evaluation of the issue
of these surrogate end points," he said. "It's taken a lot of the
noise out of the system where people have explored these things in
smaller databases. Also, it's a more rigorous study, because we have
used all the established statistical criteria for surrogacy that
other methodologists, in other fields, have developed over the
years. It sounds self-important to say itˇ¦s the definitive study of
surrogacy in this field, but it's getting closer."

LL and %DS Equally Predictive of TLR

The study found that LL and %DS, both in-stent and in-segment,
strongly predicted the risk of target lesion revascularization
(TLR). Of the four angiographic surrogates, in-segment %DS was the
most highly predictive. The authors also point out that although LL
has been the more widely accepted surrogate in the past, %DS might
be a more attractive surrogate moving forward because it is not
dependent on vessel size and entails a single angiogram at follow-
up, making it easier to use, clinically. In contrast, LL is derived
from two different angiograms, at different times, and therefore
potentially subject to more measurement error.

Pocock points out that the two pioneers of angiographic surrogates,
Drs Laura Mauri (Harvard University, Boston, MA) and Rick Kuntz, now
at Medtronic, were "very much in favor of late loss." In this
paper, "I think we steered a sensible middle course, showing in
effect that both LL and %DS are essentially equally good and, given
that you'll end up measuring both, you should use both in reporting
the results."

Although the analysis supports a role for both in-stent and in-
segment measurements, Pocock told heartwire that the pendulum is
swinging in favor of in-segment measurements. "There's still a
difference of opinion, but the way I see it, in-stent is the pure
efficacy of the device, just in the tiny bit of the artery that is
covered by the stent, whereas in-segment is real patient efficacy,
because it's looking at the picture just beyond the stent as well. I
think there's a move toward accepting in-segment [as the superior
surrogate], but people do vary."

Going Forward

Pocock and colleagues argue that their analysis supports a new
approach for DES clinical-trial programs. As he explained to
heartwire, the tight correlation demonstrated in their paper between
LL and/or %DS and TLR supports relatively small phase 2 efficacy
trials, "with hundreds rather than thousands of patients." According
to calculations provided by the authors, future trials comparing DES
on the basis of angiographic surrogates could enroll approximately
71% fewer subjects than trials that use TLR as the efficacy measure.

According to Pocock, "if you pass the efficacy test you then need to
make sure you have in place much larger but simpler safety trials."
In recent years, next-generation drug-eluting stents have gone
before FDA advisory panels with surrogate end points featured
prominently, as opposed to the clinical outcomes that were used in
the original DES trials. The FDA panels have, in response, urged
regulators to require large long-term studies to establish safety,
but there has been little consensus as to whether registry studies
are adequate, or whether randomized clinical studies would be
necessary.

Although some of the questions about surrogates of efficacy have
been put to rest by Pocock et al's paper, these questions about
safety and how to establish it remain. In an editorial accompanying
the Pocock analysis [2], Drs Robert A Harrington, Vic Hasselblad,
and Robert M Califf (Duke Clinical Research Institute, Durham, NC)
note that although they agree with "some" of the suggestions Pocock
et al offer for future trial design, they caution against the
oversimplification of safety studies. "Observational registries can
be helpful in assessing how a therapy is adopted into routine
practice, but an adequate and appropriate comparison of a new
therapy against another therapy requires randomization," they
write. "Even detailed statistical adjustments of the data from
registries are insufficient to allow a proper assessment of one
therapy compared with another."

Pocock disclosed serving as a consultant to Abbott for its XIENCE V
FDA premarket application and has served on data safety and
monitoring boards for "a number" of DES trials.

Pocock SJ, Lansky AJ, Mehran RM, et al. Angiographic surrogate end
points in drug-eluting stent trials. A systematic evaluation based
on individual patient data from 11 randomized, controlled trials. J
Am Coll Cardiol 2008; 51:23-32.
Harrington RA, Hasselblad V, Califf RM. Defining and utilizing
surrogates in the evaluation of coronary stents. What do we really
want and need to know? J Am Coll Cardiol 2008; 51: 33-36.

A pair of articles in the January 1, 2008 Annals of Internal
Medicine brings together the existing literature to address issues
that have persisted since the introduction of angiotensin-receptor
blockers (ARBs): namely, when and how these drugs might be
advantageous in conditions long served by ACE inhibitors.

A meticulous survey of studies found that the two drug classes are
about equally safe and effective at managing high blood pressure and
have similar effects on other risk factors and clinical outcomes in
patients with essential hypertension [1]. It also confirmed that
ARBs are less likely to cause coughing, but suggested that the side
effect might be less common with ACE inhibitors than randomized
trials indicate.

In the setting of chronic kidney disease (CKD), concludes the other
study, which is a meta-analysis, ACE inhibitor and ARB monotherapy
are similarly effective at reducing proteinuria, but a combination
of the two angiotensin-2-suppressing drugs works better than either
agent individually [2]. But a blanket recommendation to combine them
would be premature, according to the authors, because there is
little evidence that the combination would improve clinical outcomes
over monotherapy, and the safety of such combination therapy is
largely undefined.

The authors of both analyses acknowledge that they have major
limitations, particularly the heterogeneity of the combined studies,
their limited follow-up times, and spotty data on adverse effects.

"The most important contribution of these systematic reviews is that
they tell us what we do not know," notes an accompanying editorial
[3]. They suggest that the two drug classes are comparably effective
as antihypertensive and antiproteinuric agents, writes Dr Patrick S
Parfrey (Memorial University of Newfoundland, St Johnˇ¦s), but "we
know far too little about their long-term safety, especially with
combination therapy of ACE inhibitors plus ARBs in stage 3 or 4
chronic kidney disease."

No "Clinically Meaningful Difference" in Hypertension

"With the exception of rates of cough, the available evidence does
not strongly support the hypothesis that ACE inhibitors and ARBs
have clinically meaningful differences in benefits or harms for
individuals with essential hypertension," according to the report's
authors, led by Dr David B Matchar (Duke Center for Clinical Health
Policy Research, Durham, NC).

He and his colleagues analyzed 69 reports based on 61 randomized and
observational studies that lasted at least three months and directly
compared an ACE inhibitor and an ARB in adults with essential
hypertension, and which evaluated meaningful end points like blood
pressure control, treatment compliance, and adverse events.

The strength of evidence was considered high for the observation
that the two drug classes are similarly effective at controlling
blood pressure. They were comparable in 37 of the 50 studies
evaluated for that outcome; 47 of those 50 studies were randomized
controlled trials (RCTs).

Also similar were the associated rates of death and CV events,
quality-of-life measures, successful use of the ACE inhibitor or ARB
as the only antihypertensive agent, effects on lipid levels and LV
mass, and risk of dysglycemia or renal dysfunction.

Mortality and CV-event outcomes were available for only nine
studies, most of which excluded patients with clinically significant
CV disease or comorbidities, the group reported. Few of the studies
followed patients for even as long as a year, and "there were really
very limited data about major events, such as heart attack and
stroke," Matchar told heartwire.

The two drug classes showed similar risks of headache and dizziness,
but ACE inhibitors were about three times more likely to have cough
as a side effect, regardless of whether the study was cohort-based
or an RCT. But the rates of cough were "dramatically higher" in the
RCTs, probably because in RCTs, in contrast to cohort-based studies,
patients are more likely to be queried specifically for that side
effect, Matchar said.

Other evidence suggested that patients are more likely to stick with
ARBs than with ACE inhibitors when each were given as initial
therapy, but "the magnitude of this difference is difficult to
quantify," according to the report.

Although any differences in efficacy between the two drug classes
are likely to be small, according to Matchar et al, pinning down
such small differences might be worth the challenge of mounting a
large long-term randomized study, given that small changes in blood
pressure are known to have a substantial outcomes effect.

To heartwire Matchar said, "if there really is a marginal benefit to
be had from, say, greater tolerability of ARBs compared with ACE
inhibitors, then we really do need some [more definitive] head-to-
head studies to show it."

"Encouraging" Support for Combination Therapy in CKD

The other reported study provided "high-quality evidence" that
monotherapy with ACE inhibitors or ARBs reduces proteinuria to
comparable degrees in patients with CKD, regardless of the
underlying cause of renal dysfunction. And, write the authors, led
by Dr Regina Kunz (University Hospital, Basel,
Switzerland), "evidence is encouraging that the combination of the
two drugs is more effective, at usual doses, than either drug alone."

The group analyzed 49 RCTs that compared ARBs with ACE inhibitors, a
combination of the two drug classes, placebo, or calcium-channel
blockers, and tracked microalbuminuria and proteinuria over at least
four weeks in patients with CKD.

ARBs and ACE inhibitors were similarly effective at lowering
proteinuria, ARBs were more effective than calcium-channel blockers,
and a combination of ARBs and ACE inhibitors was more effective than
either agent alone.

Only one third of the reports included details on how adverse drug
effects were assessed in the studies; according to the authors,
few "presented adverse drug reactions in a structured manner that
allowed us to make causal inferences," and 45 of the 49
studies "lacked quantitative data even on more common but less
severe adverse drug reactions, prohibiting a reliable estimate of
their incidence."

According to Parfrey, the editorialist, the findings from Kunz et
al, along with those of the recent IMPROVE trial [4], suggest
that "monotherapy with inhibitors of the reninˇVangiotensin system
is sufficient for patients with early-stage renal disease and
relatively low albumin excretion, and that combination therapy is
effective for patients with heavier proteinuria." However, he
cautions, "for combination therapy, we have no safety data in
chronic kidney disease, and we do not know the rates of progression
of chronic kidney disease. . . . We need a large-scale, long-term,
head-to-head, three-group RCT comparing monotherapy with ARBs or ACE
inhibitors, and with combination therapy involving both ARBs and ACE
inhibitors."

The report by Matchar et al notes that coauthor Dr Douglas C McCrory
(Duke Center for Clinical Health Policy Research) has received
honoraria from AstraZeneca and coauthor Dr Gregory P Samsa (Duke
Center for Clinical Health Policy Research) holds Pfizer stock or
stock options. The article by Kunz et al says that "meetings,
literature search, and statistical analysis were supported in part
by Novartis," and that coauthor Dr Johannes F E Mann (Munich General
Hospital, Germany) has received honoraria from Boehringer-Ingelheim,
Novartis, and Aventis and grants from Aventis and Novartis.

Matchar DB, McCrory DC, Orlando LA, et al. Systematic review:
Comparative effectiveness of angiotensin-converting enzyme
inhibitors and angiotensin II receptor blockers for treating
essential hypertension. Ann Intern Med 2008; 148:16-29. Abstract
Kunz R, Friedrich C, Wolbers M, Mann JFE. Meta-analysis: Effect of
monotherapy and combination therapy with inhibitors of the renin
angiotensin system on proteinuria in renal disease. Ann Intern Med
2008; 148:30-48. Abstract
Parfrey PS. Inhibitors of the renin angiotensin system: Proven
benefits, unproven safety. Ann Intern Med 2008; 148:76-77. Abstract
Bakris GL, Ruilope L, Locatelli F, et al. Treatment of
microalbuminuria in hypertensive subjects with elevated
cardiovascular risk: results of the IMPROVE trial. Kidney Int 2007;
72:879-885. Abstract

In elderly patients with documented coronary heart disease (CHD),
statins reduce all-cause mortality, as well as CHD mortality,
nonfatal myocardial infarction, the need for revascularization, and
stroke, a new review has shown [1]. Investigators say that the
magnitude of benefit, with statins reducing all-cause mortality 22%,
is larger than previously estimated.

"Despite having as many positive statin trials as we do, concerns
have been raised about a lack of hard evidence with statins in
elderly patients, mainly because there have been limited data
showing a reduction in all-cause mortality," said lead investigator
Dr Jonathan Afilalo (McGill University, Montreal, QC). "We hope that
this study will reawaken an awareness in clinicians that this is a
proven therapy that is being significantly underutilized in our
highest-risk patients."

The results of the study are published in the January 1, 2008 issue
of the Journal of the American College of Cardiology.

Some Doubt About the Benefits of Statins in Elderly

Speaking with heartwire, Afilalo said that despite the
recommendations of the National Cholesterol Education Program Adult
Treatment Program (NCEP ATP III) to lower LDL cholesterol levels in
elderly CHD patients, the use of statins in these patients remains
low, hovering between 40% and 60%.

"As much as statins have garnered a good reputation in cardiology,
we still see in the literature that the prescription rates, even
among elderly patients who have had a recent myocardial infarction,
are low," said Afilalo. "We're talking about half of these high-risk
patients with active coronary heart disease not receiving statins."

The underutilization, he said, stems from inconsistencies in the
data showing the effectiveness of statins to reduce mortality in
elderly patients. Specifically, concerns were raised after the
publication of the Prospective Study of Pravastatin in the Elderly
at Risk (PROSPER) trial, a study that failed to show an effect of
statin therapy on all-cause mortality in patients 70 to 82 years old
with cardiovascular risk factors or documented cardiovascular
disease. The published PROSPER data, however, did not present
results stratified by the primary and secondary cohorts, leaving
questions about the possible benefits of statins in the secondary-
prevention patients.

With these inconsistencies in mind, the investigators performed a
meta-analysis to determine if statins reduce all-cause mortality in
elderly CHD patients, and to quantify the treatment effect. The
group included nine studies, consisting of 19 569 patients between
65 and 82 years of age. In addition to studies publishing data on
elderly subgroups, including the 4S, CARE, LIPID, and HPS studies,
the investigators obtained unpublished data on elderly subgroups and
on the secondary-prevention subgroup in the PROSPER trial.

Overall, the review showed that the use of statins for secondary
prevention in elderly patients with documented CHD reduced all-cause
mortality 22% and reduced CHD mortality 30%. Nonfatal myocardial
infarction was reduced 26%, the need for revascularization 30%, and
stroke 25%.

Afilalo said the benefit is larger than expected, mainly because two
meta-analyses of young and elderly patients showed that the number
needed to treat to save one patient was 56 and 61, respectively. In
this meta-analysis focused on elderly patients, the number needed to
treat to save one patient was 28.

The investigators did not pool rates of adverse events in their meta-
analysis, mainly because the different studies used different
definitions of adverse events and reported these events differently.
Afilalo told heartwire, however, that elderly patients do not
experience higher rates of serious adverse events than younger
patients. There are higher rates of myalgia typically reported in
the elderly, both in the placebo and statin arms, partly because the
elderly have more aches and pains, he noted.

Evidence-Based Reimbursement

In an editorial accompanying the published study [2], Drs George
Diamond and Sanjay Kaul (University of California Los Angeles) write
that two practical problems continue to plague statin therapy in
clinical practice: long-term adherence remains poor; and the
treatment gap, especially among the elderly, remains large.

"Meanwhile, the use of PCI continues to increase despite the lack of
equivalent evidence of outcomes benefit," write the
editorialists. "Current reimbursement policy actually encourages
such misuse. Once drugs and devices are approved for marketing,
physicians often use them in unapproved ways, and payers reimburse
such 'off-label' use to the same degree as 'on-label' use. Fine
tuning these financial incentives might help to close the treatment
gap and increase adherence to statin therapy."

Diamond and Kaul propose that the Centers for Medicare and Medicaid
discount a drug's price not by some fixed amount, but rather in
direct proportion to its proven therapeutic benefit. With various
incentives in place, the patient could receive better access to
proven drugs at more affordable prices. They even suggest empowering
the US Food and Drug Administration advisory panels with additional
authority to discount the drug's cost on the basis of the scientific
evidence they are already reviewing.

The statin treatment gap, Diamond and Kaul argue, is an example of
the disconnect between what the providers of care should do,
according to the evidence, and what they are paid to do, according
to reimbursement policies.

"This situation will not change unless and until we realign the
financial and scientific incentives and begin rewarding caregivers,
not for the prodigal provision of products and services, but for the
enlightened provision of therapeutic benefit," they write. "Evidence-
based reimbursement can be the bridge to [a] 'far, far better
thing'."

Afilalo J, Duque G, Steele R, et al. Statins for secondary
prevention in elderly patients. J Am Coll Cardiol 2008; 51:37-45.
Diamond GA, Kaul S. Prevention and treatment: a tale of two
strategies. J Am Coll Cardiol 2008; 51:46-48

Restless legs syndrome (RLS) has been associated with a
significantly increased risk for cerebrovascular or cardiovascular
disease, a new study has shown.

Investigators at Harvard Medical School in Boston, Massachusetts,
found that, compared with individuals without RLS, those with the
condition were more than twice as likely to have heart disease or
stroke; this association was stronger in subjects with greater
frequency or severity of RLS symptoms.

"The association of RLS with heart disease and stroke was strongest
in those people who had RLS symptoms at least 16 times per month.
There was also an increased risk among people who said their RLS
symptoms were severe compared to those with less bothersome
symptoms," study investigator John Winkelman, MD, PhD, said in a
release from the American Academy of Neurology.

The study was published in the January 1 issue of Neurology.

Community-Based Study

According to the paper, 2 previous epidemiologic studies reported a
link between cardiovascular disease and RLS. However, that research
did not use currently accepted criteria for RLS diagnosis and only 1
of them included male subjects.

The current cross-sectional observational study evaluated 3433
individuals participating in the Sleep Heart Health Study, a
community-based prospective study investigating the consequences of
sleep-disordered breathing.

RLS was identified by means of responses to a series of questions
based on National Institutes of Health diagnostic criteria.
Furthermore, duration, frequency, and severity of symptoms were also
evaluated.

Prevalent coronary artery disease (CAD) was defined as a self-
reported history of doctor-diagnosed angina, myocardial infarction,
or coronary revascularization procedures. Cardiovascular disease was
defined as CAD or a history of physician-diagnosed stroke or heart
failure.

Of the total study group, 6.8% of women and 3.3% of men had RLS.
After controlling for age, sex, race, body mass index, systolic
blood pressure, antihypertensive medication use, diabetes,
cholesterol levels, smoking history, and sleep apnea, researchers
found a 2-fold increased risk for RLS and prevalent CAD and
cardiovascular disease.

Possible Mechanisms

According to the authors, RLS might increase cardiovascular risk
through a number of potential mechanisms. Among them is the
possibility that the periodic leg movements of sleep, a hallmark of
RLS, result in significant elevations in blood pressure and heart
rate.

"In particular, most people with RLS have as many as 200 to 300
periodic leg movements per night of sleep, and these leg movements
are associated with substantial acute increases in blood pressure
and heart rate, which may, over the long term, produce
cardiovascular or cerebrovascular disease," said Dr. Winkelman.

It is also possible that poor sleep quality or quantity associated
with RLS influences cardiovascular risk. "Sleep disturbance is the
primary clinical complaint in those with RLS, and over 60% of
patients with clinically significant RLS report at least 3
awakenings per night and a sleep latency greater than 30 minutes on
nights with RLS. Recent epidemiologic studies demonstrate that sleep
duration is associated with both cross-sectional as well as incident
cardiovascular disease," the authors write.

Neurology. 2008; 70:35-42. Abstract