The association between muscular strength and death from all causes
in men changed minimally after adjustment for cardiorespiratory
fitness (CRF), whereas the relation between muscular strength and
death from cardiovascular disease (CVD) was confirmed after
adjustment for all variables, including CRF.

Senior investigator Jonatan R. Ruiz, PhD, from the unit for
preventive nutrition at the department of biosciences and nutrition
at Novum, Karolinska Institutet, Huddinge, Sweden, presented his
findings here at the American College of Sports Medicine 55th Annual
Meeting. "These findings prove the benefits of having greater
muscular strength and thus require further research to confirm the
combined effects of strength and CRF."

The study consisted of 8762 men aged 20 to 82 years who were free of
known CVD and cancer. All participants underwent a medical
examination and completed muscular-strength and CRF testing between
1980 and 1989. Mortality surveillance was completed December 31,
2003.

Muscular strength was quantified by combining 1-repetition maximal
measures for leg and bench presses per body weight, and was
categorized as age-specific thirds of the combined strength
variable. CRF was tested using a maximal treadmill exercise and was
categorized as age-specific thirds of maximal test duration.
Covariables for muscular strength were age, current smoking,
physical activity level, body mass index, and family history of CVD.

"Men with low muscular strength had a 60% higher risk of CVD and a
higher mortality rate," stated Dr. Ruiz.

Whether the association between muscular strength and CVD mortality
risk is independent of typical confounders is worth investigating,
according to Dr. Ruiz.

"This study examines the association between muscular strength and
mortality. Other studies used a single measure of muscular strength,
but ours used 2 tests," he said. "Muscular strength and CRF combine
to provide protective effects against all-cause mortality in men."

I-Min Lee, MD, PhD, associate professor of medicine at Harvard
School of Public Health, in Boston, Massachusetts, who was not
involved in the study, noted that most of the studies she has seen
recently are based on physical activity and physical fitness, not on
muscular strength. "A study of muscular strength in relation to CVD
is very important, especially in this one, which led to a different
outcome and warrants further investigation."

American College of Sports Medicine (ACSM) 55th Annual Meeting:
Abstract 663. Presented May 28, 2008.

Six-month results from the CACTUS trial, comparing the crush
technique with provisional T-stenting in bifurcation lesions,
suggests that outcomes are similar, regardless of the technique
used, at least in "true" bifurcation lesions, where both the main
vessel and side branch have significant stenosis.

According to Dr Antonio Colombo (Columbus Hospital, Milan, Italy),
who presented the results during the recent EuroPCR 2008 meeting,
the results should be reassuring to physicians, who, he says, need
not be "afraid" of treating a bifurcation with a single
stent, "while being aware that, if another stent is needed, this
procedure can be safely performed."

"There is no advantage to routine double stenting and no
penalization for implantation of two stents," he concluded.

T-stenting is the classic provisional stenting technique. First the
main branch lesion is stented; then, if needed, a second stent can
be placed in the side branch by threading it through the stent
struts of the main branch stent, depending on the angle of the side
branch. The main drawback of the technique is providing enough stent
coverage at the ostium of the two vessels. By contrast, for the
crush technique, one stent is placed in the side branch, protruding
into the main branch, and then a second stent is inflated in the
main branch, crushing the tail of the side branch stent against the
wall of the main branch.

No Downside to Two Stents if Required

There have been very few randomized trials of bifurcation stenting
techniques, but the most well-known was the NORDIC trial, first
presented in 2006, which suggested that a single-stent approach was
better than a two-stent approach (including T-stenting or
the "crush" and "culotte" techniques). Commenting on the study for
heartwire, Dr John Ormiston (Mercy Angiography, Auckland, New
Zealand) explained that it was the NORDIC trial that first
established the rule of thumb that, where possible, operators should
avoid using two stents.

"And I agree with that absolutely, but it doesn't apply to all side
branches," he said. "For instance, if you have a large side branch,
with a lot of disease in it, then I don't think the results of
NORDIC apply. That's a situation where I would use two stents. And
in a way, we have to look beyond the simple bifurcations that were
in the NORDIC study and think of what happens if the side branch is
large or very badly diseased, because then I personally would go for
two stents, despite the NORDIC results. If the side branch is
diseased and large and supplies a large area of myocardium, I would
use two stents."

CACTUS Results

In CACTUS, as Colombo reported at EuroPCR, 177 patients were
randomized to a two-stent strategy using the crush technique, while
173 patients were randomized to provisional T-stenting. A full 92%
of patients were found to have type 1A, 2A, or 3A lesions, so-
called "true" bifurcation disease with significant stenosis in both
the main and side branches. At the time of the procedure, almost one-
third of patients randomized to provisional T-stenting crossed over
to be treated with two stents.

Six months after the procedure, rates of binary restenosis by
angiography (conducted in 86% of both groups) in both branches were
similar between the two stent techniques; rates of MI, target lesion
revascularization (TLR), target vessel revascularization (TVR),
stent thrombosis, and death were not statistically different. Of
note, however, almost one-third of patients randomized to
provisional T-stenting crossed over to be treated with two stents.

Commenting on the study to heartwire, Colombo emphasized the
crossover rate. "The findings of the CACTUS trial, which include the
need for crossover to two stents in 31% of the lesions, apply to
bifurcations where the side branch has focal stenosis. The crossover
rate would probably be much higher if patients had bifurcations with
longer lesions involving the side branch--I would guess the
crossover rate may approach 50%. In these types of more complex
lesions, the use of two stents may become more frequent and may not
allow a randomized trial due to the high crossover rate already
expected."

He also emphasized that patients with left main disease were not
included in the study. "Except in the setting of unprotected left
main coronary stenosis, most operators are now not afraid to treat
bifurcations with one stent, being aware that if another stent is
needed (about 30% of the time) this procedure can be safely
performed."

Ormiston agreed that the CACTUS results should be reassuring to
operators worried about disadvantages of "too much metal."

"NORDIC 1 was the big trial that changed practice. But NORDIC 1 had
deficiencies in that the side branches were small, patients probably
didn't have very long disease, and there may have been some issues
about following all the patients," Ormiston said. "So the CACTUS
trial does give us confidence that if, for example, we have a
patient with a big side branch with long disease, we're not going to
disadvantage the patient by putting two stents in from the very
outset."

Ormiston also pointed out that no single two-stent technique for
bifurcations has emerged as the clear winner--something the NORDIC 2
study attempted to address.

"My view is that crush is easier to perform than culotte, and you
have more control over the side branch throughout the procedure. I
myself prefer a minicrush technique where you have minimal amount of
strut protruding into the main branch, and the important thing is
that you do the postdilatation kissing balloons properly."

What appears to be the first-ever case of cardioversion of atrial
fibrillation to sinus rhythm after the delivery of a shock from a
Taser gun has been reported [1].

The report, published online May 27, 2008 in the Annals of Emergency
Medicine, is by a group led by Dr Kyle Richards (Hartford Hospital,
Hartford, CT).

They note that neuromuscular incapacitating devices, such as Taser
guns, are often used as a less-than-lethal alternative in attempts
to control an aggressive assailant and work by delivering a pulsed
electrical shock. While there have been several case reports linking
shocks from such devices to sudden cardiac death caused by induced
ventricular tachycardia or ventricular fibrillation, the authors say
they have never before heard of a beneficial effect of such an
experience.

They describe the case of a 28-year-old man with a medical history
of depression, anxiety, and bipolar disorder who had fled from
police and hidden in a lake. He was brought to the emergency
department because of concern about hypothermia, and initial
evaluation found him to have an irregular pulse rate of 120 to 150
bpm and a temperature of 32¢XC. Passive rewarming was started, and he
was given 5 mg of metoprolol tartrate intravenously to help control
his rapid pulse rate.

Subsequent evaluation by a cardiologist showed a rapid and irregular
pulse, and his ECG showed atrial fibrillation, with a rapid
ventricular response of 145 bpm. Atrial fibrillation was also
detected by palpation of the radial pulse and by bedside telemetry
monitor.

At the conclusion of the examination, the patient became
increasingly agitated and threatening, and the police officer who
had accompanied him to the hospital fired one shock from a Taser gun
(X26 model), which was delivered in drive-stun mode to the upper
left chest. His pulse was immediately checked, and he was found to
be in a rapid but regular rhythm. An ECG was performed immediately,
which showed the patient to be in sinus tachycardia, with a rate of
120 bpm. The interval between this ECG and the patient's last
confirmation of being in atrial fibrillation was approximately two
minutes.

Richards et al note that the Taser X26 model delivers 400 V in the
first pulse wave and that voltages lower than this have been shown
to cardiovert a patient out of atrial fibrillation. "With this
information, coupled with the patient's ECG recording results before
and after the neuromuscular incapacitating device shock, it is
plausible that our patient's cardioversion was related to his
neuromuscular incapacitating device discharge," they say. But they
add that such spontaneous cardioversion from atrial fibrillation
could have been the result of the beta-blocker treatment or even the
physical stress when the patient became combative.

Richards told the Wall Street Journal's Health Blog [2]: "The time
course is so close that it makes the Taser shock more likely as a
cause of his conversion." But he added that he can't be certain that
the Taser was the cause of normal sinus rhythm being restored. A
spokesperson for Taser (the manufacturer of the device) told the
Health Blog, "The timing could suggest that there were some effects
of the electric shock, but we just don't see that in any other
studies."

Richards KA, Kleuser LP, and Kluger J. Fortuitous Therapeutic Effect
of Taser Shock for a Patient in Atrial Fibrillation. Ann Emerg Med
2008; DOI:10.1016/j.annemergmed.2008.04.023. Available at:
http://www.annemergmed.com/webfiles/images/journals/ymem/Richards.pdf
.

Goldstein J. After Taser shot, fugitive¡¦s irregular heartbeat
becomes normal. Wall Street Journal Health Blog, May 27, 2008.
Available at: http://www.wsj.com.

The use of hormone replacement therapy (HRT) does not appear to
increase the short-term risk of coronary heart disease in women with
a favorable lipid profile, a new analysis of the Women's Health
Initiative (WHI) suggests [1].

The analysis, published in the June 1, 2008 issue of the American
Journal of Cardiology, was conducted by a group led by Dr Paul Bray
(Cardeza Foundation for Hematologic Research, Philadelphia, PA).

The National Heart, Lung, and Blood Institute (NHLBI)-sponsored WHI
consisted of two trials--one assessing the effect of conjugated
equine estrogen (CEE) alone in women without a uterus, and the other
examining CEE plus medroxyprogesterone acetate (MPA) in
postmenopausal women who had not undergone a hysterectomy. Overall
results showed that neither therapy protected against coronary
events, as had been suggested in earlier observational studies, and
that the combined therapy was actually associated with an increased
risk of CHD.

In the current case-control analysis, which was conducted only in
women without baseline cardiovascular disease, the researchers
examined whether levels of lipids and C-reactive protein (CRP) could
be useful for predicting HRT-mediated CHD risk. Lipid and CRP levels
at baseline and at one year were obtained from 271 patients who
suffered an initial CHD event during in the first four years of
follow-up of the study (cases) and from 707 controls matched for age
at screening, randomization date, and hysterectomy status. All
models were adjusted for age, year of randomization, history of
hypertension, body-mass index, current smoking, cholesterol-lowering
medication use, and diabetes.

Results showed that favorable lipid status at baseline tended to
predict better CHD outcomes when using CEE with or without MPA.
Several baseline lipid measurements, but especially the LDL/HDL-
cholesterol ratio, interacted with CEE with or without MPA to modify
the risk of CHD. Specifically, women with baseline LDL/HDL-
cholesterol ratios of more than 2.5 were at increased CHD risk from
hormone therapy, whereas there was no increased CHD risk from HRT
when the baseline LDL/HDL-cholesterol ratio was below 2.5.

Baseline CRP levels added little or no additional value beyond the
LDL/HDL-cholesterol biomarker for predicting CHD risk in women using
hormone therapy.

Bray et al comment: "Importantly, we found no clear evidence that
either form of hormone therapy posed a risk of coronary heart
disease events for women with baseline HDL cholesterol above 50
mg/dL or LDL cholesterol, total/HDL-cholesterol ratio, and LDL/HDL-
cholesterol ratio less than the median control value." They add that
the results "emphasize the potential coronary heart disease safety
of hormone therapy in women with a desirable 'healthy' lipid
profile."

Possible Mechanism

On the possible mechanism behind these observations, the authors
note that the cholesterol metabolite 27-hydroxycholesterol has been
shown to compete with estrogen for binding to vascular estrogen
receptors, blocking the beneficial effects of estrogen (nitric-oxide
production and endothelial cell migration) on murine vascular cells,
leading to the hypothesis that postmenopausal women with a poor
lipid profile have increased 27-hydroxycholesterol, which disables a
potential vascular benefit of estrogen. Conversely, the women with
favorable lipids might experience no harm or even benefit from
estrogen therapy if they have low 27-hydroxycholesterol, they add.

Bray et al point out that despite increasing information and
understanding of clinical benefits and risks of hormone therapy,
doctors are still challenged in making management choices for
individual postmenopausal women. They caution that this report
considered only risks and benefits associated with CHD outcomes, and
the decision to use HRT must consider the totality of health risks
and benefits, including stroke, thrombosis, and gallbladder disease.
They add that women considering the use of postmenopausal hormone
therapy should determine their overall cardiac risk and specifically
their lipid profile. Noting that a previous WHI analysis has
suggested that the absolute excess CHD risk is low or absent in
younger postmenopausal women who use CEE with or without MPA, they
conclude that the current analysis now suggests that this risk is
also low in women with a favorable lipid profile.

NHLBI: New Results Help Benefit-Risk Decision

Commenting on the current analysis for heartwire, Dr Michael Lauer
(director of the NHLBI division of prevention and population
sciences) warned that the results need to be interpreted carefully
because a case-control study is not as reliable as a randomized
trial. "These results do suggest that at least for a short period of
time, women with low cholesterol are not at increased risk of CHD
from taking hormones. But this does not change the primary results
of the WHI, which showed that neither form of hormone therapy
reduces the risk of heart disease in healthy, postmenopausal women,
and estrogen plus progestin increases the risk. In addition, both
estrogen plus progestin and estrogen alone increase the risk of
stroke and thromboembolism, serious cardiovascular conditions that
the new analysis does not address, and combination hormone therapy
also increases the risk of breast cancer," Lauer said.

He added: "These results can help women and their clinicians make
better informed decisions about whether the benefits of hormone
therapy outweigh the risks. I think we can say that short-term HRT
use is an option for a woman who is experiencing severe menopausal
symptoms, and if a woman has favorable cholesterol, we can now feel
more comfortable about that decision." But he added: "In general,
however, women should not take hormone therapy to prevent heart
disease, and women who choose to use hormone therapy for menopausal
symptoms should use the lowest possible dose for the shortest
duration."

Bray PF, Larson JC, LaCroix AZ, et al. Usefulness of baseline lipids
and C-reactive protein in women receiving menopausal hormone therapy
as predictors of treatment-related coronary events. Am J Cardiol
2008; 101:1599¡V1605. Abstract.

A polypill variant containing aspirin, a statin, and an ACE
inhibitor is ready to be tested in secondary-prevention studies
intended to show not efficacy, which has been all but settled, but
the product's pharmacodynamics and pharmacokinetics. Expected to be
completed in about two years, the studies are needed to satisfy
regulatory requirements that the three drugs, usually taken on
separate occasions, are as potent when they are ingested at the same
time, observed Dr Valentin Fuster (Mount Sinai Medical Center, NY),
at a press conference here at the World Congress of Cardiology (WCC)
2008 meeting.

This particular polypill--there are several varieties under
development around the world for primary and secondary prevention--
stems from a collaboration between the Spanish National Centre for
Cardiovascular Research, for which Fuster holds the position of
scientific president, and Ferrer Laboratories, a Barcelona, Spain
company, according to a statement from the World Heart Federation
(WHF) [1]. Fuster is the immediate past president of the Geneva,
Switzerland–based organization, which sponsors the biennial WCC
meeting and is a prominent backer of the three-agent pill.

At the press conference (conducted in Spanish, with English
translators provided by the WHF), Fuster demurred when asked to name
which specific statin and ACE inhibitor are being used in the pill.

Studies are also planned to test its effect on patient compliance
compared with taking the three components separately, Fuster said,
noting for reporters that compliance is notorious for diminishing
with an increase in the amount of pills that must be taken, a key
issue driving the polypill's development.

He said the secondary-prevention indication is related to a
requirement by the US FDA that each component of an approved
multidrug pill be clinically indicated for the target population. At
any rate, Fuster said through the interpreter, "I don't think I'd
give aspirin to someone who doesn't need it, or any other medication
that might have an antihypertensive effect. We want to make sure
that every individual receiving the drug needs each of the
medications contained in the polypill."

The pill's introduction, planned for Spain and Latin America before
it is made available elsewhere, is expected to cut the overall
prevalence of secondary cardiovascular events, according to Fuster,
because it should improve compliance and because a single medication
is easier and less costly to distribute than three. Also, it is
being developed at a greatly reduced cost compared with the usual
commercial channels for drugs intended to be money makers. And, he
said, the components are inexpensive, "so we will be able to go into
developing countries [that have] fewer resources."

The WHF statement puts the projected monthly cost of the pill at
somewhere less than $10. At the press conference, Fuster said it
could be as low as one or two dollars.

As previously recounted by heartwire, the polypill idea was
conceived by Drs Nicholas J Wald and Malcolm R Law (Wolfson
Institute of Preventive Medicine, London, UK) in a controversial
2003 article in BMJ [2]. Their thesis was that a polypill containing
six separate medications could reduce the prevalence of
cardiovascular events by 80% if it were taken by everyone older than
55. The hypothetical pill would contain standard doses of aspirin
and a statin; half doses of a thiazide, beta blocker, and ACE
inhibitor; and folic acid.

News outlets, primarily in the UK and British Commonwealth nations,
were reporting on and around May 4 that the first samples of a
polypill based on the formula of Wald and Law, minus the aspirin,
had been manufactured and are now ready to be tested clinically.

The London Sunday Times [3] quotes Wald: "Our mission is to make
this available to everyone over 55 at an affordable price. The
founders of our group would like this pill to be available to
everyone for about £1 a day." The pill, according to the story,
could be commercially available in the UK within two years; it will
be manufactured by Cipla, "one of India's largest pharmaceutical
companies," headquartered in Mumbai.

In January, 2007, heartwire reported that the Hyderabad, India drug
company Dr Reddy's Laboratories had just completed enrollment of 250
patients with a history of cardiovascular events for a secondary-
prevention trial of a polypill containing aspirin, lisinopril,
simvastatin, and atenolol. The company was also said to be planning
a larger international primary-prevention trial, of patients with
cardiovascular risk factors, of a similar polypill that substitutes
a thiazide diuretic for the beta blocker.

World Heart Federation. Polypill reaches clinical testing phase
[press release]. May 19, 2008. Available at:
www.worldheart.org/press/press-releases/news-
details/article/polypill-reaches-clinical-testing-phase-1/

Wald NJ and Law MR. A strategy to reduce cardiovascular disease by
more than 80%. BMJ 2003; 326:1419. Abstract

Templeton SK. Over 55s to get life-saving polypill. Sunday Times,
May 4, 2008. Available at:
www.timesonline.co.uk/tol/news/uk/health/article3867839.ece

There is a guidelines "evidence gap" regarding use of aldosterone
antagonists in patients with heart failure, in that the only two
relevant major randomized trials to explore the issue, ultimately
supporting their post-MI use and in NYHA class 3-4 disease,
respectively, essentially excluded patients in NYHA class 2. That
much was agreed by Dr Willem J Remme (Sticares Cardiovascular
Research Foundation, Rhoon, the Netherlands) and Dr José Luis López-
Sendón (Hospital Universitario La Paz, Madrid, Spain) at a debate
held during the World Congress of Cardiology 2008 scientific
meeting. Their point of contention: does it matter?

With López-Sendón advocating steadfast adherence to evidence-based
medicine and therefore not to use the drugs in NYHA class 2, Remme
produced a mountain of non–clinical-trial evidence to support the
contrary view.

The two trials, both placebo-controlled, were the Randomized
Aldactone Evaluation Study (RALES) [1], which tested spironolactone
on top of standard medical therapy in patients with chronic NYHA 3-4
heart failure and an LVEF <35%, and the Eplerenone Post-Acute
Myocardial Infarction Heart Failure Efficacy and Survival Study
(EPHESUS) [2], which explored the use of eplerenone in post-MI
patients with an LVEF <40--some of whom were in NYHA class 2 at
study entry. Aldosterone blockade was life-prolonging and reduced
morbidity in both trials, López-Sendón and Remme both noted.

"Impressionistic Medicine"

López-Sendón's first line of reasoning included a classic
observation about many heart-failure drug trials. "If you're a
gambler and you want to win, you should bet that a drug tested in
[heart-failure] clinical trials will be a loser," he said,
displaying a long list of drugs just like that, including xamoterol,
enoximone, milrinone, flosequinan, vesnarinone, epoprostenol,
sotalol, and others. Not that all those agents are worthless, he
said, simply that in heart failure, the right target population for
them or perhaps the right dosing has not been identified.

"So we are in great need of the evidence. But what sort of evidence
do we need?" Not anecdotal clinical experience ("worthless"),
surrogate end points ("terrible"), or observational registries or
case-control studies ("of poor value"), he said. Meta-analyses or a
large clinical trial ("getting better")? The evidence should be
sound, consistent with an evidence level of A in the guidelines--
that is, it should come from at least two appropriate clinical
trials. "The rest is so-called impressionistic medicine, where one
has the impression that a particular drug will of benefit to the
patient."

Acknowledging that there are, in fact, two trials supporting
aldosterone antagonism in heart failure, he pointed out that NYHA
class was not among the entry criteria of EPHESUS. Furthermore, many
heart-failure patients seen in clinical practice have ejection
fractions higher than the trial's 40% cutoff point. "So we don't
know the effects of blocking the aldosterone system in patients with
[higher] ejection fractions," López-Sendón said.

"Sorry, Guys . . . "

In return, Remme acknowledged that "the guidelines people" would
contend that there are inadequate data supporting the drugs in class
2. But he also noted that heart failure in patients with post-MI
systolic dysfunction will ultimately reach NYHA class 3 if nothing
major is done. "I'd say, sorry guys, but am I really going to stop
treating my EPHESUS-type patients [with aldosterone blockers], when
I've already started doing it, or should I wait until my patient in
class 2, who is definitely not very happy, gets really sick in class
3? Why shouldn't I treat all my class 2 patents?"

Remme presented a long list of aldosterone's deleterious physiologic
effects and then proceeded to cite evidence that blocking the
hormone would improve nearly all of them. Aldosterone promotes
myocardial fibrosis, increased ACE and catecholamine production,
hemodynamic deterioration, and rises in oxygen free radicals and
therefore vascular inflammation and injury--all of which are major
contributors to cardiovascular disease.

Myocardial collagen deposition occurs early in the development of
cardiomyopathy and heart failure and is common among patients in
NYHA class 2 patients, he observed. Preclinical studies support and
clinical studies show that treatment with spironolactone is
associated with significant reductions in myocardial collagen in
patients with "very mild heart failure, indicating that already at
this state, spironolactone does reduce myocardial fibrosis."

In a study from Japan, four months of spironolactone therapy led to
significant reductions in collagen formation, diastolic and systolic
volumes, and ventricular mass. "So the effect on fibrosis in these
patients has already translated into a very significant improvement
in remodeling," he said.

"But wait! There's more. Aldosterone antagonists are actually also a
very good ACE inhibitor, and you wouldn't, I think, want to wait
with an ACE inhibitor in class 2 heart failure, would you?"
Administration of either spironolactone or eplerenone can very
nearly completely suppress the production of angiotensin 2 from
angiotensin 1, while eplerenone has been shown to attenuate the rise
in ACE after an MI.

Remme went on to show further evidence that aldosterone inhibition
reduces levels of oxygen free radicals, restores diminished
endothelial nitric-oxide synthase production in heart failure,
thereby improving endothelial function, and stems atherogenesis in
various animal models. The antifibrosis effects are probably related
to reductions in ventricular arrhythmias and reduced risk of sudden
cardiac death in patients already on standard optimal medical
therapy, which was demonstrated in EPHESUS. Other evidence suggests
that spironolactone improves heart-rate variability and QT
dispersion.

"Now, with all these important effects of aldosterone antagonists,
all present in mild heart failure, are you going to deny all those
goodies to your patients because they are not yet NYHA class 3? Or
worse, would you stop treatment sometime after infarction?" Some
clinicians do stop aldosterone blockade before the patient reaches
class 2, he said, which is "the wrong interpretation of EPHESUS."

Trials of NYHA-2 on the Horizon

But using such drugs just because they are available, without
support from clinical trials, can be dangerous, López-Sendón
countered. "After the publication of RALES, with its superb benefit
of spironolactone in severe heart failure, there was an epidemic of
hyperkalemia in some patient registries," he said, referring to a
2004 observation of steep increases in spironolactone prescription
rates at the same time that hyperkalemia-related hospitalizations
and related in-hospital deaths were rising sharply in Ontario [3].

The evidence base is going to grow soon, he noted. A trial launched
in 2006, called EMPHASIS-HF, will enroll about 2500 patients with
NYHA class-2 chronic heart failure, randomizing them to eplerenone
or placebo, according to López-Sendón . Scheduled for completion in
2011, "this study will answer the question of whether or not we
should treat patients in NYHA class 2." Another trial in the works,
which will enroll a similar population, called AREA-IN-CHF, he said,
is looking at the effects of aldosterone antagonism on remodeling
end points.

For his final remarks, López-Sendón momentarily stepped outside his
debate persona as defender of the evidence-based approach and
offered a kind of conflict-of-interest disclosure. "I am not
participating in those aldosterone-blocker trials, and that is
because I use aldosterone blockers in all class 2 patients. But I am
afraid that is impressionistic medicine, and you have to be very
careful with that."

Patients in class 2 have the same disease as those in class 3, so
why wouldn't aldosterone antagonists work in both groups? Remme
asked rhetorically. "Guidelines or no guidelines, you're a doctor,
use your common sense! If you do that, you are not alone." He pulled
a finding from the Study on Heart Failure Awareness and Perception
in Europe (SHAPE) that demonstrates the point: 70% of surveyed
European cardiologists reported they do not primarily use the
guidelines to manage their patients with heart failure; rather, they
tend to follow "expert opinion," review articles, or other
information sources.

Then Remme gave his own twist on the position he had been assigned
to defend. "Guidelines aside, Dr López-Sendón argued that we need
data from a large, randomized, controlled trial for these patients,
and I agree. The proof is always in the pudding, and the pudding is
the EMPHASIS-HF study." Elaborating on the trial's design and
progress, he said the patients will be followed for the primary end
point of cardiovascular mortality or heart-failure hospitalization,
as well as some secondary clinical end points.

"Although I think you should give this medication to all class 2
heart failure patients, I am willing to wait for the results. After
all, I am the chairman of the events committee of EMPHASIS-HF and
committed to proof. Therefore, I think it will not be long before we
know the definitive answer," Remme said, smiling, "which of course
will be positive."

Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure.
Randomized Aldactone Evaluation Study Investigators. N Engl J Med.
1999; 34110:709-717. Abstract

Pitt B, Remme W, Zannad F, et al. Eplerenone Post-Acute Myocardial
Infarction Heart Failure Efficacy and Survival Study Investigators.
Eplerenone, a selective aldosterone blocker, in patients with left
ventricular dysfunction after myocardial infarction. N Eng J Med.
2003; 348:1309-1321. Abstract

Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after
publication of the Randomized Aldactone Evaluation Study. N Engl J
Med 2004; 351:543-551. Abstract

Patients with severe symptomatic carotid stenosis treated with
endovascular therapy (percutaneous transluminal angioplasty and
stenting) appear to have higher restenosis rates than their
counterparts treated with carotid endarterectomy.

However, the investigators note, the higher restenosis rates among
the endovascular group only held true for people treated with
angioplasty alone and did not apply to those who received stents.

Long-term follow-up results from the Carotid and Vertebral Artery
Transluminal Angioplasty Study (CAVATAS), presented here at the XVII
European Stroke Conference, showed that the cumulative risk for
carotid restenosis or occlusion in patients treated with
endovascular therapy or endarterectomy was 34% and 14%, respectively.

"Restenosis was significantly more frequent after angioplasty than
after endarterectomy." We did not detect a significantly higher risk
for restenosis among stented than among endarterectomy patients,
study investigator Leo H. Bonati, MD, from the University College of
London Institute of Neurology, in the United Kingdom, told
conference delegates.

Designed to compare the risks and benefits of endovascular therapy
with those of surgical intervention, CAVATAS randomized 504 patients
with carotid stenosis to either endovascular treatment ¡ª with or
without stenting ¡ª or carotid endarterectomy.

Little Change Over Time

The 1-year study results, which were published in the Lancet in 2001
(357:1729-1737), showed that the 2 treatments carried a similar risk
for disabling stroke or death at 30 days. However, at 1-year follow-
up, the investigators found that ipsilateral carotid stenosis was
more common after endovascular than after surgical treatment (14% vs
4%).

To determine whether the difference in restenosis persisted during
long-term follow-up, the investigators followed study subjects for
up to 8 years after randomization.

The researchers compared the cumulative risks for restenosis in both
treatments. They looked at the impact of the baseline degree of
carotid stenosis on restenosis (¡Ý70% and <70%).

Within the endovascular group, investigators examined whether stents
were more effective than angioplasty in preventing restenosis. The
investigators also looked at independent predictors of restenosis
and whether restenosis contributed to cerebrovascular events.

Patients with completed endovascular therapy or endarterectomy and
subsequent duplex ultrasound were included in the study.

Ultrasound follow-up was available in 196 patients in the
endovascular group and 217 patients in the endarterectomy group.
According to Dr. Bonati, there were no significant differences in
baseline characteristics between the 2 patient groups, including
age, sex, prevalence of diabetes, hypertension,
hypercholesterolemia, and smoking.

Stenting Comparable to Endarterectomy

In both groups, the mean degree of stenosis before treatment was
about 85% and the median duration of available ultrasound follow-up
was about 4 years.

A total of 54 patients in the endovascular therapy group went on to
develop restenosis during follow-up, compared with 19 patients in
the surgery group. Therefore, said Dr. Bonati, the cumulative risk
of developing restenosis was significantly higher in the
endovascular group than in the surgery group, with a hazard ratio of
3.6.

When researchers looked at the 2 endovascular subgroups, they found
that the majority of patients (146) were treated with angioplasty
alone and, of these individuals, 47 experienced restenosis. In
comparison, 50 patients received stents and, of these, 7 experienced
restenosis at 8-year follow-up.

"Compared with surgery, those who were treated with balloon
angioplasty alone had a significantly elevated risk of restenosis ¡ª
39% vs 17% for stenting," said Dr. Bonati.

He also pointed out that the restenosis rate among people who
received endovascular treatment with stents was comparable to the
rate (14%) of cumulative risk in the endarterectomy group.

Smoking Independent Restenosis Risk Factor

When the investigators looked at independent risk factors for
restenosis, they found that individuals who smoked at baseline or
who had smoked in the past had more than a 3-fold increased risk for
restenosis.

However, restenosis was not predicted by age, sex, the presence of
vascular risk factors, high blood pressure, peripheral artery
disease, coronary heart disease, or the degree of stenosis before
treatment.

The study had 2 primary end points. The first was a combined outcome
of ipsilateral stroke, transient ischemic attack, and amaurosis
fugax. There was also a single end point of ipsilateral stroke
alone.

A total of 52 patients in the study population had a diagnosis of
restenosis within the first year of treatment. Of these individuals,
10 went on to have the combined end point. In comparison, 27
patients in the study group who were free of restenosis within 1
year went on to have the combined end point.

There appeared to be no increased risk for ipsilateral stroke among
patients with first-year restenosis, compared with those who were
free of restenosis within the first year of treatment.

According to Dr. Bonati, carotid stenting has largely replaced
balloon angioplasty as the treatment of choice for symptomatic
carotid stenosis.

The study was supported by the British Heart Foundation, the NHS
Management Executive, and the Stroke Association.

XVII European Stroke Conference. Presented May 15, 2008

The US governmental body in charge of civil aviation safety--the
Federal Aviation Administration (FAA)--announced yesterday that
pilots and air-traffic controllers are no longer permitted to take
the smoking-cessation drug varenicline (Chantix, Pfizer). The move
follows an FDA public-health advisory, issued earlier this year,
warning of a suicide risk, aggressive or erratic behavior, and other
serious psychiatric symptoms in people taking the drug.

FAA spokesperson Les Dorr told heartwire that the organization had
previously permitted pilots and air-traffic controllers to take the
drug; by their estimate, about 150 pilots and 30 air-traffic
controllers were taking varenicline at the time of the group's
decision. They have now been told to stop taking it and to stay away
from work for 72 hours, Dorr said.

Dorr explained that the FAA had made the decision in response to a
recent report issued by the Institute for Safe Medication Practices
(ISMP) [1] and based on adverse-event reports collected by the FDA.
According to the ISMP report, there were 227 domestic reports of
suicidal acts, thoughts, or behaviors; 397 cases of possible
psychosis; and 525 reports of hostility or aggression in people
taking varenicline. Included in these totals were 28 suicides,
41 "mentions of homicidal ideation," 60 cases of paranoia, and 55
cases of hallucination. Moreover, the report also cites "other kinds
of serious harm for which no warnings now exist," either from the
company or the FDA. These include accidents and injuries (173
events); vision disturbances (148 events); heart-rhythm disturbances
(224 events); seizures and muscle spasms/movements (458 cases); skin
reactions (338 cases); and diabetes (544 cases).

Authors of the report, led by ISMP senior scientist Thomas J Moore,
conclude: "We have immediate safety concerns about the use of
varenicline among persons operating aircraft, trains, buses, and
other vehicles or in other settings where a lapse in alertness or
motor control could lead to massive, serious injury."

According to Dorr, it was a member of the press that alerted the FAA
to the ISMP's report and, after taking a day to review the findings
and consulting with the FAA¡¦s Civil Aerospace Medical Institute, in
Oklahoma City, OK, the federal air surgeon recommended that the FAA
ban the use of the drug by pilots and controllers. It has also
contacted other aviation groups to "spread the word" about the
decision.

"Obviously, we are always open to new data," Dorr said, adding that
the administration would continue to consider any new data. That
said, he added, "if we're going to err, we're going to err on the
side of caution."

In response, Pfizer has issued a statement, quoted in the New York
Times [2], pointing out that the labeling for its product includes
warnings about its potential to trigger psychiatric problems and to
impair driving. The company also highlights the health benefits of
quitting smoking and suggests that these must be weighed against the
drug's risks.

Institute for Safe Medication Practices. Strong safety signal seen
for new varenicline risks. Accessed May 23, 2008. Available at:
www.ismp.org/docs/vareniclineStudy.asp.

Saul S. FAA Bans antismoking drug, citing side effects. New York
Times, May 22, 2008. Available here.

A new imaging substudy of the recently published Ongoing Telmisartan
Alone and in Combination with Ramipril Global Endpoint trial
(ONTARGET) has shown no difference between the ACE inhibitor
ramipril, the angiotensin-receptor blocker telmisartan (Micardis,
Boehringer Ingelheim), or the combination in the reduction of left
ventricular mass. The MRI study, say investigators, parallels the
main findings from ONTARGET, showing no clear advantage to
combination therapy with ramipril and telmisartan.

"We know that making hearts smaller is good for you, but we wanted
to know if we could make them smaller still with the combination
therapy," lead investigator Dr Brett Cowan (University of Auckland,
New Zealand) told heartwire. "This study showed that there was no
additional benefit of combining the ACE inhibitor with the
angiotensin-receptor blocker to reduce left ventricular mass. These
findings fit nicely with the main data showing no additional benefit
of combining the medications."

The results of the MRI substudy were presented here last week at the
American Society of Hypertension 2008 Annual Meeting.

ONTARGET Presented at the ACC

The results of ONTARGET were presented earlier this year at the
American College of Cardiology 2008 Scientific Sessions and
published simultaneously online in the New England Journal of
Medicine [1]. As previously reported by heartwire, telmisartan
was "noninferior" to the ACE inhibitor ramipril in patients with
vascular disease or high-risk diabetes, but the combination of the
two drugs was associated with more adverse events without an
increase in benefit.

The ONTARGET investigators enrolled 25 620 patients with coronary
heart disease or diabetes plus additional risk factors who were over
the age of 55 years of age but did not have evidence of heart
failure. Patients were randomized to receive ramipril 10 mg per day,
telmisartan 80 mg a day, or the combination of the two. The mean
duration of follow-up of the study was 55 months.

In this new substudy, investigators reported data on 330 subjects
who underwent MRI at baseline and 287 patients who had a follow-up
MRI at two years. Investigators report no differences in left
ventricular mass in the different treatment arms and no
statistically differences in other variables, including end-systolic
volume, end-diastolic volume, stroke volume, or ejection fraction,
by treatment.

During the presentation, Cowan noted that ventricular mass decreased
8% in the largest hearts but was unchanged in smaller hearts. The
key determinants of left ventricular mass reduction were baseline
left ventricular mass, history of hypertension, and extent of blood-
pressure lowering.

Dr Michael Weber (SUNY Downstate College of Medicine in Brooklyn,
New York), who presented the ONTARGET results during a review of
late-breaking trials, told the media that these were well-treated
patients, so it was unlikely that there would be an observed
reduction in left ventricular mass.

"There wasn't much of a change in left ventricular hypertrophy, and
people might say, 'Isn't that odd, considering that ACE inhibitors
and angiotensin-receptor blockers are supposed to be very good for
causing regression of left ventricular hypertrophy?' " said
Weber. "But remember, in this trial we were using experienced
investigators who had already been using ACE inhibitors and
angiotensin-receptor blockers in most of their patients before they
even got into this study. The patients had already had the benefit
of that therapy. How much smaller do you want to make the heart? You
don't want the heart to disappear altogether."

Boehringer Ingelheim sponsored the ONTARGET study.

Yusuf S, Teo KK, Pogue J, et al for the ONTARGET investigators.
Telmisartan, ramipril, or both in patients at high risk for vascular
events. N Engl J Med 2008: 358:1547-1559. Abstract

It's an old trick: make a task fun and people will be more likely to
do it. It could even work for the conventional cardiac-
rehabilitation program, which tends to be underused and dogged by
poor patient compliance. In a two-year observational study, a formal
rehab regimen that substituted dance routines based on familiar
ballroom and night-club dances for more conventional exercises
allowed participants to safely achieve comparable exercise levels
and muscle-training effects and left them wanting to come back for
more [1].

Patients in the program, who had ischemic or valvular heart disease,
chronic heart failure, or congenital heart disease, were taught
dance routines developed in a non–rehab population for their
measured effects on blood pressure and heart rate, according to Dr
Paula V Quiroga (National Institute of Cardiology Ignacio Chavez,
Mexico City, Mexico). Fitted with monitors that transmitted the
readings to a physical therapist at a central control station,
patients performed different dance steps that varied by target
levels of exertion, she told heartwire through a translator. They
danced to the blues for warm-ups and low-intensity exercise, to rock
and roll or to distinctly Cuban danzón rhythms for intermediate
levels of exercise, and to vigorous salsa steps for the highest
exertion levels.

Quiroga reported on the 560-patient experience with the unusual
cardiac-rehab program here at the World Congress of Cardiology 2008.
Over two years, the participants developed no serious arrhythmias,
angina, or other important complications while dancing, and some
showed only occasional runs of ventricular ectopia. Overall, the
group experienced few complications, even with 70% of them
considered at high clinical risk, according to Quiroga.

The dance routines help overcome the high rate of noncompliance
associated with conventional rehab programs, she said; although she
has no data to show it, compliance with the novel program appears
much greater. Part of that success comes from the enriched social
life most participants enjoy as they learn to use the routines
recreationally out on the dance floor. "It's a great alternative to
the conventional rehabilitation program," she said, "and helps them
avoid a sedentary lifestyle."

The observations are consistent with other studies of dance-based
rehab in patients with heart failure, according to Dr Mauricio
Wajngarten (University of São Paolo, Brazil), who moderated the
session that featured Quiroga's report. "They showed more adherence
to the program and a similar gain in physical capacity--so it's a
good strategy. I wouldn't expect there to be complications or
arrhythmias, [however,] because [the exercise] is low-intensity,
submaximal. Complications are more likely to be musculoskeletal than
cardiac."

The participants, the majority in their 40s, 50s, and 60s but some
as old as 80 and as young as four, were each assigned to one of four
groups based on their capacities and degree of cardiovascular risk,
according to Quiroga. Each group's routines included a variety of
tempos, but those at lowest cardiovascular risk, for example, would
be assigned more salsa, and those at highest risk would get
predominantly blues or danzón, the intensities adjusted according to
heart rate.

After four weeks of twice-weekly training sessions, mean exercise
tolerance increased by 1.7 METS at stress testing; the mean heart
rate during maximal exercise in the routines rose 17% (p<0.001),
indicating a training effect. No arrhythmias were ever documented in
three-fourths of the group; 18% had occasional runs of ventricular
ectopia, and in 7% they were frequent. Ischemic ECG changes were
observed in about one-fifth of the population. But there were no
instances of angina, acute coronary syndromes, sustained VT or VF,
or any cases of sudden death.

The dance routines had been carefully designed to achieve varying
heart-rate targets based on monitoring data from healthy volunteers,
according to Quiroga. But the original idea to incorporate dance
into a formal rehab program, which Quiroga designed with coauthors
Drs Mariola Rius Suárez and Hermes Ilarraza-Lomelí (National
Institute of Cardiology Ignacio Chavez), came from one of their
patients--a dance teacher.

Quiroga PV, Ruis-Suarez MD, Ilarraza-Lomell H, et al. Dance-hall
dancing in patients with cardiovascular disease: Experience of 2
years. World Congress of Cardiology 2008; May 20, 2008; Buenos
Aires, Argentina. Abstract 131.

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

Erectile Dysfunction in Diabetics Predictive of Coronary Artery
Disease
Journal of the American College of Cardiology, May 21, 2008, as
reported by WebMD

Erectile dysfunction (ED) is a "powerful" predictor of coronary
heart disease/cardiovascular disease events, including death, in
type 2 diabetics, reports WebMD. In the first of 2 separate studies,
Italian investigators showed that among 291 type 2 diabetic men with
angiographically proven asymptomatic coronary artery disease, the
presence of ED was associated with a doubling of risk for a major
cardiac adverse event over 4 years. Statins and 5-phosphodiesterase
inhibitors appeared to lower the risk, but not eliminate it. In the
second study, researchers in Hong Kong looked at 2306 men with type
2 diabetes and found that ED was an independent predictor for
coronary heart events (hazard ratio, 1.58; 95% confidence interval,
1.08 ¡V 2.30; P = .018) after adjustment for other covariates.

Asthma May Increase Adult Suicide Risk
Annals of Allergy, Asthma & Immunology, May 2008, as reported by
WebMD

Adults with asthma are at increased risk for suicidal ideation with
suicide attempts, WebMD tells readers. Using survey data on 5692
adults, investigators found that women, current smokers, and those
who were depressed, anxious, alcohol abusers, or nicotine dependent
were more likely to have suicidal ideation with attempts. Asthma was
significantly associated with suicidal ideation with attempts, but
not ideation without attempts (P < .001). The authors found that
significant amounts of the association between asthma and suicidal
ideation with attempts may be independently attributable to smoking
and concurrent mental health issues and that "modification of
smoking behaviors and effective treatment of depression, anxiety,
alcohol abuse, and possibly asthma are important suicide prevention
strategies."

Aprotinin Link to Deaths in High-Risk CABG Patients Affirmed
New England Journal of Medicine, published online May 14, 2008, as
reported by the New York Times

Results of the Blood Conservation Using Antifibrinolytics in a
Randomized Trial (BART) study, halted last year, may signal the
death knell for aprotinin (Trasylol, Bayer Healthcare
Pharmaceuticals), says the New York Times. In the trial, aprotinin,
an antifibrinolytic agent designed to reduce major bleeding during
coronary artery bypass graft (CABG), significantly increased the
risk for death compared with either of 2 lysine analogues,
tranexamic acid or aminocaproic acid. The trial's data safety and
monitoring board halted the study last October after identifying the
increased deaths. "Despite the possibility of a modest reduction in
the risk for massive bleeding, the strong and consistent negative
mortality trend associated with aprotinin, as compared with the
lysine analogues, precludes its use in high-risk cardiac surgery,"
the BART investigators wrote.

Mammography Plus Ultrasound Ups Detection and False-Positive Rates
Journal of the American Medical Association, May 14, 2008, as
reported by WebMD

Adding 1 ultrasound screening to mammography can yield an additional
1.1 to 7.2 cancers for every 1000 high-risk women screened, but it
will also significantly increase the number of false positives,
reports WebMD. In a study of 2809 women screened at 21 sites, the
diagnostic yield for mammography was 7.6 per 1000 women screened,
which increased to 11.8 per 1000 women when ultrasound was also
performed, for a supplemental yield of 4.2 per 1000 women screened.
Ultrasound increased the diagnostic accuracy for mammography from
0.78 to 0.91, but the positive predictive value of biopsy
recommendation after full diagnostic workup was 22.6% for
mammography alone, 8.9% for ultrasound alone, and 11.2% for the
combined procedures.

Shingles Risk Linked to Family History of Herpes Zoster
Archives of Dermatology, May 2008, as reported by Bloomberg

Add family history of zoster to age and immunosuppression as a risk
factor for herpes zoster, Bloomberg reports. The case-control study
compared 504 patients with herpes zoster, also known as shingles,
with 523 matched controls (nonimmunocompromised patients with skin
diseases other than zoster). The cases had an 11% greater likelihood
of having a blood relative with a history of zoster compared with
controls (P < .001). The risk was 13-fold higher when more than 1
blood relative had zoster and 4.5-fold higher when a single relative
had shingles.

Childhood cancer survivors are at increased risk of developing
premature cardiovascular disease, and hence need to be closely
monitored after their treatment and followed appropriately as they
age, concludes the largest and longest study of this population.

The findings are scheduled to be presented June 3 at the American
Society of Clinical Oncology (ASCO) 2008 Annual Meeting, and were
unveiled last week during a preview presscast organized by the
society.

The study followed 14,358 survivors of various childhood cancers and
compared them with 3,899 siblings. The diagnoses included childhood
leukemia, central nervous system tumors, Hodgkin's and non-Hodgkin's
lymphomas, renal tumors, neuroblastomas, soft-tissue sarcomas, and
bone cancers. The average age of study participants at diagnosis was
7.8 years and the mean age at follow-up was 27.5 years, so the mean
follow-up period was nearly 20 years.

The risk for cardiovascular disease was significantly greater in
survivors than in siblings. The risk for atherosclerosis was 10
times greater, for congestive heart failure was 5.7 greater, for
myocardial infarction was 4.9 times greater, for pericardial disease
was 6.3 times greater, and for valvular disease was 4.8 times
greater.

"This study shows that childhood cancer survivors in their 20s are
developing the kinds of heart disease we typically see in older
adults," commented lead investigator Daniel Mulrooney. MD, from the
University of Minnesota, in Minneapolis. The risk for cardiovascular
disease increased with time, and some of these problems appear quite
late, he continued.

"Cardiovascular monitoring of childhood cancer survivors should
begin early and should be life-long," Dr. Mulrooney stated. He
estimated that there are currently 270,000 childhood cancer
survivors in the United States.

Long-Term Consequences of Cancer Treatment

Studies of childhood cancer survivors have identified long-term
problems that can unfold as children grow into adulthood. In
addition to cardiovascular problems, these include an increased risk
for secondary cancers, infertility, lung scarring, thyroid problems,
and psychological problems such as depression and anxiety, commented
Julie Gralow, MD, from the University of Washington, in Seattle, who
moderated the presscast.

"Being a cancer survivor is a very special diagnosis in many ways,"
Dr. Gralow commented, "and brings with it a responsibility to
understand the long-term consequences of cancer treatment and to
monitor these patients appropriately for any problems they may
develop."

"Many patients, as they continue with their lives, tend to transfer
their medical care to primary care physicians and to discontinue
relationships with their oncologists, or maintain them very
infrequently, as would be appropriate for someone who is...cured of
their cancer," she continued. "But it then becomes incumbent on
patients and their primary care physicians to be aware of their
cancer history and their cancer treatment, and the potential
consequences of that treatment."

"ASCO is working very hard to develop a template for a cancer-
survivor care plan," Dr. Gralow noted. It will contain details of
the cancer that the patient had, the treatment received, and the
potential consequences. The patient will have this document and will
be able to present it to any doctor who becomes involved in his or
her care.

Risk is Increased, But Overall Risk is Low

The highest risk for cardiovascular disease was seen in survivors
who had undergone treatment with either anthracyclines (doses above
250 mg/m2) or radiation to the heart area (doses above 3500 Gy).
These individuals had a two- to five-fold increased risk for
cardiovascular disease, compared with survivors who underwent other
types of treatment.

Anthracyclines are already known for their cardiotoxic effects, Dr.
Mulrooney commented; previous studies have shown a risk for dilated
myopathy and congestive heart failure, and this seems to be
progressive over time. The mechanism is thought to involve iron
deposited in the heart, but more work needs to be done on this, he
said. The damage from radiation seems to be inflicted on the
pericardium and the epithelial lining of blood vessels, and the
vessel disease seen in these young adult cancer survivors is
different from what you would see in an older population with
cardiovascular disease, he commented.

"Typically, in these older patients on a coronary angiogram, you
would see diffuse disease and lipid deposits that have occurred over
time; in cancer survivors who have received chest radiation, you
typically see injury to the coronary artery and deposits that are
very proximal to the heart. Why this is the case is not clear at the
current time," he said.

Children in this study were treated between 1970 and 1986, and
therapy has changed since then, Dr. Mulrooney commented. "We now
have more targeted therapies and new...ways to give radiation
therapy that give off less scatter, hopefully less scatter to the
heart itself. And we have different ways of administering drugs, for
example continuous infusions instead of bolus doses," he
commented. "We don't know yet what the long-term results will be
with these new modalities. But hopefully they will maintain the
efficacy that we have seen while reducing the long-term adverse
effects."

Dr. Mulrooney emphasized that although the risk for heart disease is
significantly increased in survivors, the overall risk of developing
cardiovascular problems is low. Thirty years after a diagnosis of
childhood cancer, 2% of survivors had atherosclerosis, 4% had
congestive heart failure, 1% had myocardial infarction, 3% developed
pericardial disease, and 4% had valvular heart disease.

An analysis of baseline data from an ongoing study assessing the
value of transcranial Doppler (TCD) in predicting stroke risk among
patients with asymptomatic carotid stenosis shows a negative
association between the presence of embolic signals and antiplatelet
and statin therapy.

"The baseline results show associations between drug therapy and
asymptomatic embolization, with antiplatelet therapy associated with
fewer embolic signals, and statin therapy associated with fewer
embolic signals as well, possibly reflecting plaque stabilization,"
Raffi Topakian, MD, from the Academic Teaching Hospital Wagner-
Jauregg, in Linz, Austria, told delegates here at the 17th European
Stroke Conference.

The analysis, from the ongoing Asymptomatic Carotid Emboli Study
(ACES), was presented here at the 17th European Stroke Conference.

Predicting the Risk for Asymptomatic Stenoses

The risk for stroke in asymptomatic carotid stenosis is relatively
low, about 2% per annum, Dr. Topakian said. "Operating on all
patients with tight stenosis has small benefits," he said. "For
every 85 people operated on in clinical studies, about 1 stroke is
prevented per year. For ever 32 operations, 1 disabling stroke is
prevented over 5 years."

Better selection of high-risk patients with asymptomatic carotid
stenosis might improve risk-benefit ratios and identify those who
would preferentially benefit from carotid endarterectomy. One
potential tool to identify high-risk patients is the detection of
carotid embolic signals using TCD. Detection of embolic signals has
been shown to predict stroke risk in symptomatic carotid stenosis,
but studies of its use in asymptomatic patients have produced
conflicting results, Dr. Topakian said.

ACES is a large, multicenter, international study, funded by the
British Heart Foundation, that aims to answer this question of
whether the presence of embolic signals can predict the risk for
stroke or transient ischemic attack in patients with asymptomatic
carotid stenosis.

Patients enrolled in the trial had to have carotid stenosis of 70%
to 99% and must have been asymptomatic for at least 2 years. They
also had to be asymptomatic in the contralateral carotid or
vertebrobasilar territory, again for at least 2 years, or if
contralateral surgery or stenting had been performed, patients were
eligible after 1 year as long as they had been asymptomatic in the
interim. Patients were eligible whether they were taking
antiplatelet or anticoagulant therapy, he noted.

The primary aim of ACES is to determine whether the presence of
embolic signals on either of two 1-hour recordings at study entry
predict ipsilateral transient ischemic attack or stroke risk during
the following 2 years, Dr. Topakian said. The secondary endpoint is
whether embolic signals on a single 1-hour recording predict
ipsilateral transient ischemic attack or stroke risk during the
subsequent 6-month period.

Power calculations for the ACES study were done based on interim
blinded data from the first 132 subjects enrolled because previous
data on this topic were "very sparse," he said. Of the enrolled
patients, 12.1% had embolic signals on the first of 2 entry
recordings, and 21.2% had embolic signals on either of the 2 entry
recordings. The 3-year combined ipsilateral stroke and transient
ischemic attack rate was 6.6%. On this basis, and assuming that the
risk for stroke or transient ischemic attack in embolic signal¡V
positive (ES+) patients would be 3 times higher than in embolic
signal¡Vnegative (ES-) patients, they calculated a sample size of
480 for the primary endpoint, and 340 patients for the secondary
endpoint.

After the 2 baseline TCD recordings at entry, done 1 week apart,
patients are being followed up every 6 months, up to 24 months.
Recruitment was completed in October of 2007, with 482 patients
enrolled from 26 centers in 17 countries in Europe, Asia, and the
United States. All TCD recordings are reviewed at a coordinating
center by a human observer blinded to clinical information. Embolic
signals are defined using an intensity threshold of more than 70
dBs. TCD recordings are considered ES+ if any embolic signal was
detected on either of the 2 baseline recordings, and ES- if no such
signals were detected.

At the meeting here, Dr. Topakian presented the baseline data,
showing that the mean age of patients is about 71.5 years, 25% are
women, 90% have hypertension, and 20% have diabetes. Some 15% are
current smokers, and 20% have contralateral carotid occlusive
disease of 70% or greater. The majority of patients, 88%, were
taking antiplatelet agents at baseline, and 66% were taking lipid-
lowering therapy, almost exclusively statins, he noted.

All baseline recordings have now been analyzed, a total of 1748
hours, and from these, 366 embolic signals have been detected. A
total of 149 of these hours, or 8.5% were ES+, he said.

When they compared baseline characteristics among those who were ES-
and ES+, they found 2 factors, antiplatelet therapy and lipid-
lowering agents, were significantly associated with the absence of
embolic signals on TCD.

Final follow-up of the ACES trial is expected to be completed in
October of 2009, he concluded.

The ACES study is funded by the British Heart Foundation.

17th European Stroke Conference: Large Clinical Trials II. Presented
Friday, May 16, 2008.

For the first time, several research findings have been released to
the media ahead of the American Society of Clinical Oncology (ASCO)
2008 Annual Meeting presentations. The meeting starts May 30, but 6
abstracts were discussed in a presscast on May 15. The featured
abstracts covered breast and lung cancer, Ewing's sarcoma, and
continuing cardiovascular problems in childhood cancer survivors.

The hottest news item ¡X picked up by media worldwide ¡X was the
finding that vitamin D deficiency at the time of breast cancer
diagnosis is associated with a worse outcome. The results come from
an analysis of 512 women treated at university hospitals in Toronto,
Ontario.

Many of the women had low levels of vitamin D at the time they were
diagnosed with breast cancer ¡X 37.5% had levels classified
as "deficient," and only 24% had levels that were "sufficient."

After a median follow-up of 11.6 years, the researchers found that,
compared with women who had normal levels of vitamin D at diagnosis,
the women with vitamin D deficiency were 94% more likely to
experience metastasis and 73% more likely to die.

"We were concerned to find that vitamin D deficiency is so common in
women diagnosed with breast cancer and that very low vitamin D
levels adversely affect patient outcome," said lead researcher
Pamela Goodwin, MD, from the University of Toronto and Mount Sinai
Hospital. She emphasized, however, that these results need to be
replicated and that although the data show an association, "we can't
say at this time if it is causal."

Another finding in the breast cancer field highlighted in the
preview was the increase in women undergoing mastectomies. These
data come from the Mayo Clinic in Rochester, New York, where 5464
women had surgery for early breast cancer between 1997 and 2006.

The percentage of these women who opted for mastectomy declined from
45% in 1997 to 30% in 2003 but then rose to 43% in 2006.

The researchers speculate that the increase in preoperative breast
magnetic resonance imaging (MRI) could be responsible for the
pattern that was observed. They note that the percentage of women
who had breast MRI doubled, from 11% in 2003 to 22% in 2006, and
that women who received breast MRI before surgery were more likely
to undergo mastectomy than those who did not.

However, there are other factors that might be responsible for this
shift, commented presenting author Matthew Goetz, MD, assistant
professor of oncology at the Mayo Clinic. The past few years have
seen an increase in genetic testing and improvements in breast-
reconstruction techniques, and these might influence a woman's
decision about whether or not to opt for a mastectomy.

Progress in Non¡VSmall-Cell Lung Cancer

Two of the highlighted findings related to non¡Vsmall-cell lung
cancer (NSCLC). A phase 3 clinical trial of 663 patients, all of
whom received platinum-based induction therapy, showed that those
who received maintenance therapy with pemetrexed (Alimta, Lilly) had
twice the time to progression as those who received placebo.

"This is the first study to show that lung cancer patients can
benefit from maintenance therapy," said lead investigator Tudor
Eliade Ciuleanu, MD, PhD, from Iuliu Hatieganu University, in Cluj-
Napoca, Romania. "The fact that this approach significantly
increases the amount of time that patients have before their cancer
progresses, without increases in additional side effects, is
particularly significant," he added.

However, the data on overall survival from this study are
preliminary, Dr. Ciuleanu cautioned, and more time is needed before
the impact of this therapy on the overall outcome can be determined.

"Not all patients benefit from chemotherapy," Ming Tsao, MD, from
the University of Toronto, pointed out. His team presented details
of a 15-gene expression signature that appears to identify patients
with more aggressive disease, who stand to gain the most benefit
from chemotherapy. They maintain that this test is an independent
prognostic marker in early-stage NSCLC; it identifies patients who
are likely to benefit from postoperative chemotherapy more
selectively than disease stage.

Outcomes in Childhood Cancers

In Ewing's sarcoma, administering chemotherapy every 2 weeks rather
than every 3 weeks improves outcome, said Richard Wormley, MD, from
the Children's Hospital of Philadelphia and University of
Pennsylvania School of Medicine. He was reporting results from a
randomized comparison of the 2 different administration schedules, a
study of 568 patients treated at 160 institutions.

All patients received a total of 14 cycles of chemotherapy, which
comprised vincristine, doxorubicin, cyclophosphamide, ifosfamide,
and etoposide. After a median follow-up of 3 years, the group of
patients who received chemotherapy every 2 weeks showed better event-
free survival than the group treated every 3 weeks (76% vs 65%);
adverse effects were similar in both groups.

"These findings are convincing enough to change the standard of care
for patients with localized Ewing's sarcoma," Dr. Wormer commented.

Finally, the largest study to date of childhood cancer survivors has
confirmed that that as these children grow into adulthood, they
continue to be plagued with cardiovascular problems. This latest
analysis, involving more than 14,000 patients, shows that survivors
are 5 to 10 times more likely than their healthy siblings to develop
heart disease in early adulthood. Those who were at greatest risk
had received chemotherapy with anthracyclines or radiation directed
near the heart as part of their treatment.

"Our findings emphasize the need to educate patients, their
families, and other healthcare providers about the risk of delayed
cardiovascular side effects of these otherwise life-saving cancer
treatments, so that patients can be closely monitored after
treatment and appropriately followed as they age," commented lead
author Daniel Mulrooney, MD, from the Masonic Cancer Center,
University of Minnesota, in Minneapolis.

The research team presenting the findings on pemetrexed for NSCLC
report various financial arrangements with Eli Lilly, including
consulting and honoraria, and some authors are employees. The team
presenting the 15-gene expression signature for NSCLC reported
receiving honoraria from Pierre Fabre. None of the other researchers
disclosed any relevant financial relationships.

American Society of Clinical Oncology 2008 Annual Meeting: Abstracts
511, 509, 8011, 7510, 10504, 9509. Preview presscast, May 15, 2008.

Long-term results from 2 large European trials suggest that carotid
artery stenting (CAS) is as effective as carotid endarterectomy
(CEA) in preventing recurrent ischemic stroke in patients with
severe, symptomatic carotid stenosis.

Presented here at the 17th European Stroke Conference (ESC), results
from both the Endarterectomy Versus Angioplasty in Patients with
Symptomatic Severe Carotid Stenosis (EVA-S3) and the Stent-Protected
Percutaneous Angioplasty of the Carotid Artery vs Endarterectomy
(SPACE) studies reported strikingly similar results in terms of the
long-term efficacy of the 2 procedures, despite the fact that in
both studies, stenting had failed to meet noninferiority criteria vs
endarterectomy in their primary analyses.

"The conclusion from the SPACE trial is exactly the same as the EVA-
S3 study. That is, if a patient has been treated successfully
without any complications, the [long-term] risk of a secondary
stroke is very small and very comparable between these 2
modalities," Peter A. Ringleb, MD, from Ruprecht-Karls-University,
in Heidelberg, Germany, principal investigator of the SPACE study,
told reporters attending an ESC press conference.

SPACE Results

Launched in 2001, the SPACE study is a randomized noninferiority
trial that included 1214 patients from 37 centers in Germany,
Switzerland, and Austria.

The goal of the study was to determine whether safety and efficacy
of treatment for symptomatic carotid stenosis with CAS was
equivalent to the standard approach of CEA.

The 30-day outcome results, which were published in 2006, failed to
demonstrate noninferiority of the stenting procedure vs
endarterectomy.

Here at the ESC, where the 2-year follow-up results were presented
for the first time, the investigators found the rate of any
periprocedural stroke or death, plus ipsilateral ischemic stroke
within 2 years, was very similar, at 8.49% in the CEA group and
9.22% in the CAS group.

Furthermore, the investigators reported the absolute number of
recurrent ischemic events after the periprocedural period at 2-year
follow-up was low — 10 events after CEA (1.7%) and 12 after CAS
(2.0%).

Need for Improvement

The EVA-S3 trial was also a randomized noninferiority study that was
conducted at 30 centers in France and included 527 subjects.
Launched in 2000, the study was stopped by the safety committee in
2005 due to a higher 30-day risk of stroke or death associated with
stenting.

In 2006, within a week of the SPACE investigators publishing their
findings, the EVA-3S researchers reported that the 30-day risk of
any stroke was significantly greater for stenting — 9.6% for CAS vs
3.9% CEA. For disabling stroke, the rate at 30 days was 3.4% for
stenting compared with 1.5% for endarterectomy.

However, the investigators continued to follow study subjects and
found the rates of ipsilateral stroke from 31 days to 4 years were
very low in both groups — 11.1% for CAS and 6.2% for CEA — a
difference that was not statistically significant, said the study's
principal investigator, Jean-Louis Mas, MD, from the Hôpital Sainte-
Anne, in Paris, France.

"Carotid stenting is as effective as carotid endarterectomy in
preventing further ischemic stroke, but we need to improve the
safety of the technique before it can become a widespread
alternative to carotid endarterectomy in patients with symptomatic
carotid stenosis," said Dr. Mas.

17th European Stroke Conference: Abstracts 4 and 5. Presented May
14, 2008.

Physicians at this year's EuroPCR meeting had the chance to glimpse
some of the first randomized clinical data on so-called "active"
stents that promote vessel healing while reducing the risk of
antiproliferative reactions, without carrying polymers or drugs that
have been blamed for an increased risk of stent thrombosis.

Whether such stents end up competing directly with blockbuster drug-
eluting stents (DES) or end up as niche products in people who
cannot take dual antiplatelet therapy remains to be seen, experts
say.

The Genous stent is an antibody-coated bare-metal stent designed to
capture a patient's own endothelial progenitor cells (EPCs) to
accelerate the natural healing process after stent placement and to
modulate smooth-muscle-cell growth. Stent developers believe the
stent would be particularly attractive to patients who cannot take
extended dual antiplatelet therapy or who may be at particularly
high risk for stent thrombosis.

Investigators for the e-Healing multicenter first-in-human registry
of the Genous stent (OrbusNeich) and for the TRIAS-HR randomized
pilot study comparing the Genous stent with the Taxus stent
presented new data here at the meeting. The e-Healing registry, led
by Dr Sigmund Silber (Dr Müller Hospital, Munich, Germany) and Dr
Robbert de Winter (Academic Medical Center, Amsterdam, the
Netherlands) had, as of late March 2008, enrolled almost 5000
patients at 144 sites. In an interim analysis of 1640 patients who
have completed 12-month follow-up, investigators report that rates
of cardiac death, MI, and target lesion revascularization (TLR) are
low and comparable with rates seen in the early Taxus registry
studies. Importantly, a low rate of stent thrombosis was seen
despite patients taking just one month of dual antiplatelet therapy.

de Winter also presented 12-month results from the randomized TRIAS-
HR pilot study, a single-center randomized controlled trial
comparing the Genous with the Taxus stent in high-risk patients
(long lesions, small vessels, chronic total occlusions, or any
lesion in a diabetic patient). As he explained to heartwire, TRIAS-
HR had been designed to enroll a larger patient population but was
closed after one year in order to switch to the larger multicenter
study.

In all, 98 patients were randomized to the Genous stent, followed by
one month of dual antiplatelet therapy, and 95 patients randomized
to the Taxus, with at least six months of dual antiplatelet therapy.
At 12 months, the rate of MI was numerically higher in Taxus-treated
patients (n=5 vs 1) but TLR rates were higher in Genous-treated
patients (n=11 vs 8).

Intriguing Trends

In an interview with heartwire, de Winter emphasized that the trial
was not powered to detect differences in clinical events, but there
are at least early signs that while the Genous may not be as
effective at reducing restenosis, it may be associated with less
stent thrombosis--the likely cause of the MIs in the Taxus-treated
patients. "And of the infarctions in the Taxus-treated patients,
four of these were large infarcts, likely due to stent thrombosis,"
he said.

Whether these trends, in a small trial, will prove important in a
larger study group is unknown, he continued.

"It's not something we can determine from this study, because this
pilot study was clearly underpowered, but if you look at the risk of
repeat revascularization for clinical restenosis in most instances,
these are very low-risk procedures," de Winter explained. "And even
if you have an incidence of periprocedural MI in the redo
procedures, those are small infarcts compared with the generally big
infarcts that are associated with stent thrombosis. So I think this
trade-off will translate, in the end, into clinical benefit or
clinical equality."

The original TRIAS-HR study has now been extended and will be part
of the TRIAS-High-Risk (HR) multicenter study with an intended
enrollment of 1200 patients comparing the Genous with a market-
approved DES (so far the Cypher or the Taxus, although investigators
are considering inclusion of the Xience V). A second TRIAS-Low-Risk
(LR) study has also been launched, also with a target enrollment of
1200 patients, comparing the Genous with a bare-metal stent in low-
risk patients.

The big question is whether the Genous will end up being a niche
device, used primarily in patients where an as-yet-unproven,
minimally increased risk of revascularization may be a reasonable
trade-off for reduced stent thrombosis in higher-risk patients or in
patients who cannot take clopidogrel, for a range of reasons. In e-
Healing, de Winter noted, one of the top enrolling countries was
Malaysia, where patients seem to suffer from a higher rate of
gastrointestinal bleeding on dual antiplatelet therapy.

"The niche is probably going to be much larger than just the
occasional patient with a clopidogrel allergy," he told
heartwire. "But it depends on what comes out of the randomized
study. If we are able, in 1200 patients, to repeat the findings we
saw in the pilot study, namely a slight increase in TLR but also a
much lower risk of stent thrombosis, then we may have a safer stent
that is more or less equally effective." If that's the case, he
said, "I think this is going to be a competitor with DES, depending
on type of lesion and types of patients."

Commenting on the study for heartwire, Dr Roxana Mehran (Columbia
University, NY) also underscored the need for the large randomized
clinical trial results, but she hinted that the efficacy benchmark
set by DES may be tough to match.

"I think this product will be interesting for those patients in whom
antiplatelet therapy will be an issue," she said. "More data are
absolutely needed to prove the efficacy and safety of this stent."

According to de Winter, over 500 patients have already been enrolled
in the TRIAS-HR/LR trial, and investigators expect to complete trial
enrollment by the end of the year. The study is designed with one-
year target lesion failure as the primary end point, with an
angiographic substudy at 13 months.

In a separate presentation, Salim Yusuf, MD, from McMaster
University, Hamilton, Ontario, Canada, presented results of the
telmisartan vs placebo comparison.

Previous studies such as the Heart Outcomes Prevention Evaluation
(HOPE) and Protection against Recurrent Stroke Study (PROGRESS)
trials had shown a benefit associated with using an angiotensin-
converting enzyme inhibitor initiated late after stroke, with or
without a large reduction in blood pressure. No previous trials have
looked at treatment early after a stroke, again using a blocker of
the renin angiotensin system, telmisartan.

In this trial, though, the primary results for recurrent stroke
showed no statistically significant benefit with treatment over
placebo.

The curves showed a somewhat higher rate of strokes in the first 6
months in the telmisartan group that was not significant, "but then
the curves start to diverge out after about a year and towards the
end of the trial, this continues to be striking," he said. Time-
dependent analyses showed a significant difference in results from
the first 6 months, where there was no difference between groups,
and after 6 months, where there were fewer events with
telmisartan, "suggesting but not proving that the effect of
telmisartan varies by time," Dr. Yusuf noted.

Similar findings were seen for the secondary end point of the
composite of stroke, MI, and vascular death, where there was no
significant difference overall, but a similar pattern emerged when
the endpoint was analyzed before and after 6 months of treatment.
There were also trends to lower rates of intracerebral hemorrhage
and diabetes mellitus in patients receiving telmisartan, Dr. Yusuf
said.

He speculated that with only 2.5 years of follow-up, the trial may
have been too short to realize any potential benefit of treatment,
since the previous HOPE trial for example, had followed up patients
for 4 years. In addition, suboptimal adherence in the treatment
group as well as competing use of other blood pressure¡Vlowering
agents had reduced the blood pressure differential between the
groups, "which hurt our power," he said.

"What we need are longer trials, but large trials, with greater
blood pressure lowering," Dr. Yusuf concluded.

Neuroprotective Effects?

Finally, Hans-Christof Diener, MD, from the University Duisburg-
Essen, Essen, Germany, reported the results of an analysis looking
for any potential neuroprotective effects of any of these agents
among those who had a recurrent stroke during the study.

Previous preclinical data had suggested neuroprotective properties
for dipyridamole, aspirin (although at very high doses), and for
angiotensin receptor blockers in models of cerebral ischemia. The
problem with previous neuroprotective trials ¡X all of some 90 of
which have failed to date ¡X has been among other things, the
challenge of how to get the agent on board at the time of the
stroke, Dr. Diener said.

To look for signals of neuroprotection with these agents in the
PROFESS trial, they used the modified Rankin scale and the Barthel
Index 3 months after the stroke occurred to compare functional
outcomes after any recurrent stroke while patients were receiving
study treatments.

"The result unfortunately was that there was no difference," Dr.
Diener stated here at the press conference. There was no significant
difference in functional outcomes on either scale for the comparison
of aspirin plus extended-release dipyridamole vs clopidogrel (which
has not been thought to have any neuroprotective effect) or
comparing telmisartan vs placebo.

They also looked at cognitive impairment between groups using the
Mini-Mental State Examination (MMSE), and again, found no difference
between the groups in terms of how many patients were cognitively
impaired after a recurrent stroke.

"There are 2 possible explanations," for these findings, Dr. Diener
said. "The most likely explanation is there is no effect. The other
possible explanation is that the observation at 2.5 years is not
long enough. Perhaps you have to have treatment and observation
times of 10 years or more to see a difference," he speculated.

Drs. Sacco, Diener, and Yusuf were co-chairs of the PROFESS steering
committee.

Clopidogrel Superior?

During the question period after the 3 presentations, a member of
the audience asked the investigators whether, given the high dropout
rate due to adverse effects and the higher bleeding risk with the
combination of aspirin and extended-release dipyridamole, "can we
conclude that only clopidogrel would be the first choice for
secondary prevention of stroke compared to aspirin and
dipyridamole?"

Declining to answer, they directed him to a planned symposium where
the PROFESS trial was to be discussed by those not involved in the
trial. The questioner though, pressed for some conclusion.

"Like anything, guidelines are written by numerous groups, and I
think until we can really digest all this data, it would be
premature for us to make a conclusion," Dr. Sacco replied
finally. "We are still working on the papers, we are still going
through analyses, and then the guideline committees that are set up
in Europe and the Americas will have to review the data and make
decisions."

"I can answer that," Dr. Yusuf added wryly. "There is a range of
reasonable conclusions and yours is one of that range, with wide
confidence limits."

Dr. Sacco told Medscape Neurology & Neurosurgery that his own
interpretation is that the 2 treatments are similar. "My current
take is that we still have choices, these choices are up to us to
decide, and if anything now we have direct comparisons showing equal
efficacy between these agents."

The decision of which agent to use in individual cases, he said,
will depend on factors such as cost, tolerance of adverse effects ¡X
for example to the increased risk for headache with the
combination ¡X concomitant cardiovascular risk, since clopidogrel
has been shown to be effective in those who also have unstable
angina or postangioplasty, and the individual physician's
familiarity with the agents.

The PROFESS study was funded by Boehringer Ingelheim. Dr. Sacco has
disclosed that he has received honoraria from Boehringer Ingelheim
as a consultant.

European Stroke Conference 2008: Large Clinical Trials I. Presented
Wednesday, May 14, 2008.

The PROFESS trial used a factorial design to address several
questions in a large population of 20,332 patients from 695 sites in
35 countries. The patients included all had a noncardioembolic
ischemic stroke within the previous 120 days and were randomized to
receive aspirin (25 mg) plus extended-release dipyridamole (200 mg)
twice daily, or clopidogrel (75 mg) once daily. At the same time,
patients were randomized to receive either 80 mg/day of telmisartan
or placebo.

In the first presentation here, Ralph Sacco, MD, from the University
of Miami School of Medicine in Miami, Florida, reported results for
the comparison of aspirin and extended-release dipyridamole vs
clopidogrel.

Current guidelines in Europe and the United States recommend that
for antiplatelet therapy after a stroke, aspirin, aspirin plus
dipyridamole and clopidogrel are options for prevention of stroke
recurrence, but there are no direct comparisons of the latter agents
available to guide choices, Dr. Sacco said. The European and
Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT)
and European Stroke Prevention Study 2 (ESPS2) trials had previously
compared aspirin vs aspirin and dipyridamole and shown the
combination to be more effective than aspirin alone.

The analysis used for this comparison was noninferiority first, then
superiority, he explained, and the margin chosen for noninferiority
was 1.075, or a 7.5% noninferiority difference.

In the end, the primary endpoint of recurrent stroke was not
statistically significantly different between the groups, but they
were not able to conclude that the combination was noninferior to
clopidogrel. "The upper boundary of the effect estimate crossed our
noninferiority margin (of 1.075), and therefore the trial could not
conclude, statistically, noninferiority," Dr. Sacco said.

Treatment with the combination was associated with a reduction of 25
ischemic strokes over clopidogrel, but with an increase of 38
hemorrhagic strokes, and 4 strokes of unknown etiology, for a net
excess of 17 strokes, although the difference was not statistically
significant between the 2 groups.

The secondary outcome of combined stroke, myocardial infarction
(MI), and vascular death was "nearly identical" between groups;
other endpoints including deaths and MIs were not statistically
different with the exception of new or worsening congestive heart
failure, which was significantly less frequent in the combination
group.

Major hemorrhagic events were increased with the aspirin plus
extended-release dipyridamole combination vs clopidogrel, Dr. Sacco
noted, but life-threatening hemorrhages were not different between
groups.

Despite this increase in bleeds, when they combined stroke
recurrence and major hemorrhage into 1 endpoint reflecting a benefit-
risk relationship, there was no statistical difference between the
groups.

As expected, headache was more frequent with aspirin and extended-
release dipyridamole, but did not lead as often to permanent
discontinuation as seen in other studies of this agent, Dr. Sacco
noted. Headache led to discontinuation in 5.9% of the combination
group vs 0.9% with clopidogrel. Dizziness, fainting, and migraine
during the first 6 months of the study were also more frequent with
the combination.

"In conclusion, for the antiplatelet part of this large trial, we
were not able to meet our prespecified noninferiority criteria for
the combination vs clopidogrel," Dr. Sacco said. The agents had
similar rates of recurrent stroke and the composite of stroke, MI,
or vascular death he noted. Major hemorrhagic events including
intracranial bleeds were more frequent in the combination
group, "however, the absolute risks were low and partially offset by
fewer ischemic events, primary outcomes," he concluded. "The net
benefits and risks were similar with the 2 agents."

When confronted with what the FDA terms a "recall" of their
implantable cardioverter defibrillator (ICD) or pacemaker, most
patients would be willing to go along with the course of action
recommended by their physicians. On the other hand, about one in 20
would insist that the device be explanted and replaced, regardless
of whether a far less invasive measure is all that's needed. But
only half that many would insist on a device change-out if the
regulatory action were called a "safety advisory."

That's according to a survey of 165 randomly chosen device
recipients at a major referral center, in which most also showed
undue confidence that they wouldn't themselves be subject to such a
recall or safety advisory [1].

Regardless of which term is used, patients who would demand a device
change-out are "clearly outliers" compared with the majority who
would trust their doctors' decision, observed Dr Christina M Murray
(University of Oklahoma, Oklahoma City) for heartwire. But
replacement of implanted devices, and especially their leads,
entails well-recognized risks of infection and other complications,
she noted, many of which could apparently be prevented if device
recalls were always referred to as advisories.

Murray reported the survey results here today at the Heart Rhythm
Society [HRS] 2008 Scientific Sessions. They support several years
of so-far-unsuccessful effort by the organization to convince the
FDA to change the terminology it uses to inform doctors and patients
about device failures and advise them on how to respond, especially
the word recall.

Recall vs Advisory: The HRS and FDA Collide

In a Town Hall Meeting conducted at the HRS sessions two years ago,
heartwire then reported, Dr Mark D Carlson (Case Western Reserve
University, Cleveland, OH) described what the society was asking
federal regulators to do about the word in a broad and far-reaching
set of guidelines for the oversight of ICD and pacemaker performance
[2]. "The FDA should eliminate the term recall and use in its place
terms such as advisory notice or safety notice," he had said.

The FDA's position at that time, as stated by agency spokesperson Dr
Bram Zuckerman, was that the word is "currently an important part of
FDA regulations and operations and cannot be changed quickly due to
broad policy ramifications. The FDA is currently committed to more
clearly explaining and communicating the current terminology and
system to the public and physician community."

At a similar Town Hall Meeting at this year's sessions, Dr Dwight W
Reynolds (University of Oklahoma), HRS immediate past president and
a coauthor of Murray's analysis, said that the society formally
resubmitted the recommendation to the FDA in February 2008.

"We advised the FDA-regulated manufacturers and the FDA to use
identical terminology when classifying device malfunctions," he
said, and "We reiterated that we recommend to the FDA that they
eliminate the term recall for all public communications regarding
implanted devices, and once again we recommended that they change
the word to advisory notice or safety alert."

Added HRS president-elect Dr NA Mark Estes III (Tufts University-New
England Medical Center, Boston, MA), "The word recall to a patient
means something very different from what it does to a regulator." In
general, he said, industry and the FDA have done well at adopting
the recommendations in the society's 2006 document. "But this word
recall is still there." To FDA representatives who were also at the
Town Hall Meeting, Estes said, "What's it going to take to have the
regulatory agencies understand the major impact it has on our
patients?"

With her response in 2008 echoing Zuckerman's in 2006, Megan
Moynahan of the FDA's Center for Devices and Radiological Health
said, "We've heard that message loud and clear. . . . But it's also
important to remember that one reason we get worked up about the
word recall is because many physicians equate the word with
explantation. And we really want the message to get out
that 'recall' does not mean explantation."

From the audience, Dr G Frank O Tyers (University of British
Columbia, Vancouver) offered other reasons to keep the current
terminology. "I don't think we should get rid of recall. Something
like that could be [seen as] attempting to whitewash the problem.
Recall is used across all industries, and recall means to me that
the manufacturer actually went out and took the product back from
the field, [ones] that hadn't been implanted. It's not such a bad
word," he said. "I think the critical issue is that this still
requires physician judgment. Not every recalled device should be
explanted."

Whereupon audience member Dr Peter N Smith (Marshfield Clinic, WI)
said, "The word recall has different connotations in different
industries. Recall is why I have never bought a set of tires for my
truck. I've gotten free tires twice. Recall to a patient with an ICD
evokes all kinds of anxiety."

Show Me the Data

According to Murray, the survey goes a long way toward giving the
HRS efforts some teeth--that is, hard evidence that the word recall
has an adverse effect on patients and that using safety advisory
instead might have measurable clinical benefits.

The 45 patients with conventional pacemakers, one with a
resynchronization pacemaker, and 119 with ICDs were asked a number
of questions, including, "If you were told there was a safety
advisory on your device, what would you want?" Of the patients, 2.5%
responded they "would want the device removed no matter what." But
5% (p=0.01) gave that answer to the same question with recall
substituted for safety advisory, Murray said.

In an analysis of how the 2.5% difference in the number of patients
insisting on change-outs would have played out hypothetically last
year, when--as covered at the time by heartwire --Medtronic issued a
recall of its popular Sprint Fidelis ICD leads due to what it saw as
an increased failure risk, calling it a "safety advisory" would have
prevented about 300 major change-out-related complications and about
26 deaths, Murray said. "We think these are powerful data, actually,
to support a change in terminology."

Survey responses also showed that 77% of the group understood that
their generator might fail and need replacing; 71% understood that
about their leads. But when they were asked what they believed their
chances were of experiencing a safety advisory or a recall, 30.6%
responded 1 in 100 000, the same percentage said 1 in 10 000, 14.3%
said 1 in 1000, and 17.7% said 1 in 100. So just over 75%
had "clearly very unrealistic expectations of device performance,"
Murray said, adding that the true risk is "somewhere between 1 in 10
and 1 in 100."

The finding suggests that physicians need to educate their patients
better on the risks of implanted devices, she said. Indeed, asked
whether they had received enough education on the risk that their
device would malfunction, 67% of the patients replied yes; 58%
replied yes when asked if they'd had adequate education on the risk
of a "recall" or "safety advisory."

Murray CM, Germany RE, Bright BC, et al. Device "recall"
terminology: Results of a patient survey. Heart Rhythm Society 2008
Scientific Sessions; May 15, 2008; San Francisco, CA. Abstract AB22-
3.
Heart Rhythm Society. Draft recommendations report by the Heart
Rhythm Society task force on device performance policies and
guidelines. April 26, 2006. Available at:
www.hrsonline.org/uploadDocs/HRS_Device-Performance-Recommendations-
Apr06.pdf.

Long-distance follow-up of patients with pacemakers using an
internet-based remote monitoring system is more likely to catch
events that may be clinically important, and catch them sooner, than
standard transtelephonic ECG evaluation, according to a randomized
trial reported here at the Heart Rhythm Society 2008 Scientific
Sessions [1].

Although the Pacemaker Remote Follow-up Evaluation and Review
(PREFER) trial wasn't designed to show whether patients fare better
clinically when their devices are remotely interrogated on a regular
basis, compared with conventional transtelephonic monitoring (TTM),
it shows that the strategy "has the potential to improve outcomes by
reducing the time between onset and detection of clinical pathology
and the indicated therapeutic options," the trial's lead
investigator, Dr Bruce L Wilkoff (Cleveland Clinic Foundation,
Ohio), said when presenting its results. The older TTM, he said, may
be of limited value by comparison, its clinical usefulness in
pacemaker follow-up perhaps restricted to detecting battery
depletion.

Wilkoff noted that remote monitoring systems have already proven
their value in following patients with implantable defibrillators,
which, like today's pacemakers, collect copious data not available
from rhythm strips. But the strategy had yet to be tested in a
randomized fashion in patients with conventional pacemakers, he
said.

PREVENT randomized 897 patients at 50 US centers, who had been
implanted with single- or dual-chamber pacemakers from Medtronic
compatible with the company's CareLink Network, to be followed
either that way or using standard TTM. Two patients were randomized
to remote monitoring for every one assigned to the older method; the
two groups were similar with respect to demographics, drug therapy,
presence of bradycardia, LVEF, and mean pacemaker age.

Remote interrogations were conducted every three months until month
12, when patients went to the clinic to be evaluated in person. In
the TTM group, transmissions were scheduled for every two months up
to one year, when patients went to the clinic; patients with dual-
chamber pacemakers, however, were evaluated at the clinic, in
person, in place of a TTM transmission.

Over an average of 375 days, the identification of at least
one "clinically actionable event" (CAE) was significantly more
common among the 602 remotely monitored patients than the 295
followed with TTM; the rates of this primary end point were 45% and
37.6%, respectively (p<0.0001).

As described by Wilkoff, CAEs were prospectively defined events of
potential clinical importance that clinicians could do something
about and included nonsustained ventricular tachycardia (VT) of at
least five beats, new-onset atrial tachycardia (AT) or atrial
fibrillation (AF), device loss-of-capture, AT or AF lasting at least
48 hours, an increase in ventricular pacing, a heart rate exceeding
100 bpm during AF, significant changes in lead impedance, or a jump
in the pacing voltage threshold.

In fact, Wilkoff reported, only three CAEs, or 2% of all that
occurred over 12 months in the TTM group (as confirmed by device
interrogation in the clinic), were picked up by TTM; that is, TTM
missed 98% of events. Remote monitoring disclosed 446 CAEs, or 66%
of those that occurred in the remote-monitoring group. "So, a very
low yield for transtelephonic monitoring," he said.

In an analysis of CAE detection by individual events, significantly
better detection by remote monitoring seemed driven by two CAEs in
particular: new-onset AT or AF and heart-rate increase during AT or
AF; rate differences for the other CAEs didn't reach significance.

"This is potentially very important," Wilkoff said, "as this earlier
detection of AT/AF [could] have implied the need to give these
patients Coumadin and may have prevented strokes."

On the other hand, Wilkoff said, rates at which clinicians actually
responded to individual CAEs didn't differ significantly between the
two monitoring group--although, he observed, such rates trended
higher in the remote-monitoring group for several of the CAEs: 24%
of new-onset AT/AF events, for example, vs only 5% in the TTM group,
or 10% of increases in ventricular pacing, compared with 5% in the
TTM group.

The next step after PREVENT, Wilkoff said, would be a trial that
determines whether earlier event detection with remote monitoring
compared with TTM actually cuts mortality or improves other clinical
outcomes.

PREVENT was sponsored by Medtronic. Wilkoff reports being a
consultant for and receiving research support from and/or having
lectured on behalf of Medtronic, Boston Scientific, St Jude Medical,
Biotronik, Sorin, Spectranetics, Inner Pulse, Cook, and Lifewatch.

Wilkoff BL. Pacemaker Remote Follow-up Evaluation and Review:
Results of the PREFER trial. Late-breaking clinical trials session.
Heart Rhythm Society 2008 Scientific Sessions; May 15, 2008; San
Francisco, CA.

In men with and without cardiovascular disease, the addition of
several biomarkers of cardiovascular and renal dysfunction
significantly improves risk stratification for death from
cardiovascular causes, according to the results of a new study [1].
The addition of these biomarkers substantially improves risk
stratification beyond other models based only on established
cardiovascular risk factors, report the authors.

"In this community-based sample of elderly men, the incorporation of
a combination of biomarkers that reflect myocardial cell damage,
ventricular function, renal function, and inflammation to a model
with established risk factors improved risk stratification for death
from cardiovascular causes," write Dr Björn Zethelius (Uppsala
University, Sweden) and colleagues in the May 15, 2008 issue of the
New England Journal of Medicine. The results, they add, were
consistent when they applied the model to participants who did not
have apparent cardiovascular disease at baseline.

In an editorial accompanying the published study [2], Drs James de
Lemos (University of Texas Southwestern Medical Center, Dallas) and
Donald Lloyd-Jones (Northwestern University, Chicago, IL) write that
the study shows that combining biomarkers of cardiovascular and
renal disease does appear to improve risk assessment, at least in
this cohort of elderly men.

"These findings need to be validated in younger cohorts of men and
women that include only patients who are free from cardiovascular
disease and should be updated iteratively as newer, and better,
biomarkers emerge from discovery research programs," write the
editorialists. "Then, the hard work begins in determining what
should be done differently on the basis of test results and in what
format this complex information should be presented to clinicians."

The Search for Risk Stratification Strategies . . .

In their paper, the Swedish investigators note that the use of
established risk factors does not fully explain the development of
cardiovascular disease in the community. Some of the existing tools
based on these risk factors, such as the Framingham Risk Score,
perform well at the population level but often fall short when
applied to individual patients. Because of these limitations, there
is a constant push to improve on established risk factors for the
prediction of cardiovascular disease.

Zethelius and colleagues hypothesized that a "multimarker approach"
could improve on the shortcomings of existing algorithms. In their
study, they chose biomarkers that reflected myocardial cell damage,
left ventricular dysfunction, renal failure, and inflammation,
investigating whether or not troponin I, N-terminal pro-brain
natriuretic peptide (NT-proBNP), cystatin C, and high-sensitivity C-
reactive protein (hs-CRP) in a model with established risk factors
could improve the prediction of death from cardiovascular causes.

The group analyzed data from the Uppsala Longitudinal Study of Adult
Men (ULSAM), a community-based cohort of elderly men (mean age 71
years). In total, 1135 subjects, including 661 without prevalent
cardiovascular disease at baseline, had valid measurements of the
investigational biomarkers, as well as traditional risk factors.

The novel biomarkers--troponin I, NT-proBNP, cystatin C, and hs-CRP--
predicted death from cardiovascular causes and from all causes in
multivariable analysis in the whole cohort and in participants who
did not have cardiovascular disease. The risk of death among
subjects with elevated levels of any two of the biomarkers increased
threefold compared with established risk factors. This risk was
increased sevenfold in subjects with elevation in three biomarkers
and increased more than 16-fold in subjects who had elevations of
all four biomarkers.

In the whole cohort, as well as in subjects without cardiovascular
disease at baseline, the C statistic--used to determine how well the
model can discriminate between persons in whom the disease will
develop and those who will remain healthy--for the prediction of
death from cardiovascular causes increased when the four biomarkers
were incorporated into a model with the established risk factors.
The C statistic increased regardless of how elevations in the
biomarkers were measured, in this case, when cutoff points
established in the literature were used or cutoff points identified
and used to achieve optimal discrimination.

The investigators point out, as do the editorialists, that there is
a discrepancy between these findings and previous studies. In past
research, the addition of multiple biomarkers has yielded only small
increases in the C statistic that did not achieve statistical
significance. The Swedish investigators note that subjects in their
study are more than 10 years older than previous studies. However,
the reason for their positive findings, they suggest, might be the
biomarkers used. These four biomarkers have not been studied
previously but have all been shown to be closely associated with
cardiovascular and renal damage.

"Thus, one reason that the addition of these biomarkers contributed
to the prediction of death from cardiovascular causes in people who
did not have apparent cardiovascular disease may be that they better
identify those who have structural and functional abnormalities in
the cardiovascular system that have not yet led to overt
cardiovascular disease," write Zethelius and colleagues. They add
that if their data are validated, the biomarkers can be incorporated
rather quickly into clinical practice, as the measurement of these
biomarkers is already well established for diagnostic use.

Role in Primary Prevention Most Important

In their editorial, de Lemos and Lloyd-Jones write that much of the
debate over new biomarkers surrounds how much incremental value they
add to existing biomarkers. In assessing why this model performed
better than previous models, they agree that these biomarkers are
better than those measured in other studies. Also important,
however, is the restriction of the cohort to lean white men who were
all the same age at study entry.

"This restriction mitigates the powerful influence of age in the
established risk-factor model; moreover, some established risk
factors are less predictive of events from cardiovascular disease
among older people," write de Lemos and Lloyd-Jones.

In addition, the inclusion of patients with prevalent cardiovascular
disease distinguishes this study from a "pure evaluation of
population screening," note the editorialists. "The data for those
without prevalent cardiovascular disease in this study are of
greatest interest for biomarker screening, since secondary
approaches to prevention should be implemented aggressively among
people with established cardiovascular disease regardless of
biomarker levels."

Zethelius and Lloyd-Jones report no conflicts of interest. De Lemos
reports receiving grant support from Biosite/Inverness and
consulting fees from Biosite/Inverness and Roche Diagnostics.

Zethelius B, Berglund L, Sundström J, et al. Use of multiple
biomarkers to improve the prediction of death from cardiovascular
causes. N Engl J Med 2008; 358:2107-2116.

De Lemos JA, Lloyd-Jones DM. Multiple biomarker panels for
cardiovascular risk assessment. N Engl J Med 2008; 358:2172-2174.

A Quiet Breakthrough Beneath All the Controversy

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The US FDA has approved less ominous and restrictive language for
the labeling of the echocardiographic contrast agents perflutren
lipid microspheres injectable suspension (Definity, Lantheus Medical
Imaging) and perflutren protein-type A microspheres for injection
(Optison, General Electric). The changes come after the agency added
new warnings and contraindications to the labeling late last year.

The latest wording addresses concerns raised with the FDA by the
cardiology community after the agency, in October 2007, added
warnings and contraindications to the labeling that may not have
been justified. As subsequently reported by heartwire, the new
language warned users of "serious cardiopulmonary reactions
occurring within 30 minutes of product administration" and noted
that the products are "contraindicated in patients with unstable
cardiopulmonary status, including those with unstable angina, acute
MI, respiratory failure, and recent worsening of congestive heart
failure."

Experts weighing in on the new wording vehemently disagreed with the
agency's interpretation of the evidence, heartwire reported, and
lamented that it would prevent the contrast agents' use in the very
patients who would most benefit from them.

After receiving feedback from thought leaders in the field, the FDA
reconsidered.

A press release issued today by Lantheus Medical Imaging [1], which
described the new, less restrictive wording as it pertains to the
product, says, "The decision by the FDA to revisit the changes it
initially made to the Definity label last fall came after
extraordinary advocacy by the global community of contrast
ultrasound and echocardiography practitioners." It further notes
that "Educational outreach by the echocardiography community to the
FDA was instrumental in achieving this class label change."

The company's statement also states that similar changes are being
made to the labeling of "all perflutren-containing microsphere
contrast agents." Lantheus Medical Imaging is the company that
evolved from the purchase of Bristol-Myers Squibb Medical Imaging,
the previous owner of Definity, by an investment group earlier this
year.

Definity's labeling, Lantheus says, now reads, "Do not administer
Definity to patients with known or suspected right-to-left,
bidirectional, or transient right-to-left cardiac shunts, or
hypersensitivity to perflutren. Do not administer Definity by intra-
arterial injection." It also says that "All other contraindications
have been removed."

According to Lantheus, "The boxed 'warning' and 'warnings' sections
have been revised to reflect monitoring only in patients with
pulmonary hypertension or unstable cardiopulmonary conditions, as
compared with the previous label, which included language regarding
monitoring in all patients."

Lantheus Medical Imaging. Lantheus Medical Imaging updates Definity
label to modify benefit/risk assessment of the product [press
release]. May 13, 2008. Available at:
http://www.lantheus.com/News.html.

The author of a commentary published in Catheterizations and
Cardiovascular Interventions (CCI) online March 26, 2008 is urging
regulatory authorities to investigate the Migraine Intervention with
STARflex Technology (MIST) I trial and ask for an independent review
of the echocardiogram data [1]. Dr Jonathan Tobis (University of
California, Los Angeles), who also raised questions about the study
when follow-up data were presented at the TCT meeting last year,
says the FDA, as well as the Multicentre Research Ethics Committee
(MREC) and Medicines and Healthcare Products Regulatory Agency
(MHRA) in the UK, should help lift the "mist of confusion" over this
trial.

As it is now, says Tobis, the MIST trial "provides an excellent case
example where interests of researchers, business entities, and
government supervising agencies are openly in conflict and reveal
the forces that shape the current scientific environment of industry-
sponsored clinical research."

But contacted by heartwire, at least one of the regulatory bodies,
MHRA, says that it has reviewed the "available evidence" and has
found nothing to suggest that there is a problem with the
performance or safety of the closure device used in the MIST I trial.

Lifting the MIST

As previously reported by heartwire, co-PI for the MIST I study, Dr
Peter Wilmshurst (Royal Shrewsbury Hospital, UK), has alleged that,
at NMT's behest, he himself conducted a review of the MIST I
echocardiography data suggesting that roughly one-third of patients
appeared to have residual shunting following PFO closure. He has
also alleged that the trial monitor, Dr Luc Missault (St Jan
Hospital, Bruges, Belgium), also reviewed the bulk of the MIST I
echocardiograms. In interviews with heartwire, however, both the
trial sponsor, NMT Medical, as well as Wilmshurst's co-PI Dr Andrew
Dowson (Kings College Hospital, London, UK) have said that no such
review ever took place. The trial protocol stipulated that the
implanting physician would check that the device had effectively
closed the PFO, with no core lab reviewing the results. The MIST
results have since been published in Circulation, where the authors
report a residual-shunt rate of just 6% and make no mention of an
after-the-fact review of the echocardiograms [2]. Wilmshurst, now
embroiled in a legal battle with NMT, is not listed as an author or
as a member of the steering committee.

Tobis's article is part of a planned series of papers in CCI
examining the validity and generalizability of randomized clinical
trials; in the case of MIST, he argues, physicians should be wary of
accepting the trial's conclusion--PFO closure does not cure migraine-
-at face value, without also considering the methodology and results.

To heartwire, Tobis points out that the MIST I example has
implications for other ongoing clinical trials of PFO closure for
migraine--both AGA and St Jude Medical have trials under way; Tobis
is on the steering committee for the AGA trial and a consultant to
that company. NMT's own phase 2 study, MIST II, has since been
canceled, reputedly due to slow enrollment and the need to
concentrate finances on the company's CLOSURE trial for cryptogenic
stroke. Tobis believes MIST I's failure, as well as the halting of
MIST II, has already had a chilling effect on the other PFO/migraine
studies.

"The other trials are still going ahead, but they are going slower
than expected," he said. "I think MIST I has affected the neurology
community and may have made them believe less in the possibility
that this hypothesis is correct."

Tobis is not alone in his concerns about MIST's implications for
ongoing research. In an editorial that accompanied the MIST I paper
[3], Dr John Carroll (University of Colorado, Aurora) points out
that other trials of PFO closure for migraine were designed with the
seemingly positive secondary results in mind. He, like Tobis, called
for clarification of the results. "The controversies surrounding
MIST must be appropriately addressed and resolved," Carroll writes
in his editorial.

Why MIST Failed

In his article, Tobis argues that there are two possible reasons why
MIST did not succeed: one, the patient population was not the same
as the patients in whom the migraine-PFO link was first described;
or two, the right-to-left shunt was not effectively closed in MIST
I. To heartwire, Tobis said that he believes both hypotheses are
probably true to some degree, but with the lingering disagreement
over the "real" residual-shunt results, it is impossible to know for
sure.

"Only an independent review of the six-month follow-up
echocardiographic data can provide a reliable and trustworthy
interpretation of the incidence of residual shunts," he writes.

"I believe it's really an FDA issue and also an issue for the
regulatory council in England that supervises these things," Tobis
told heartwire. "They really need to get involved and say show us
the data."

He says he himself has written to the FDA but received no response.
Contacted by heartwire, an FDA spokesperson refused to comment
specifically on the Starflex device or the MIST I trial, falling
back on a stock response: "As with all products, the FDA carefully
evaluates all available information submitted in support of a US
investigation or marketing application," she said.

In the UK, by contrast, an MHRA spokesperson explained that the
agency will take action only if there is a question of a device not
performing as intended or claimed or if it is associated with any
unexpected adverse events."

"In the case of the Starflex device, the MHRA has looked at all the
available evidence in relation to this product and believes that
there isn't any scientific evidence to suggest there is an issue
either with the performance or safety of this product," MHRA
spokesperson Stephen Hallworth told heartwire. "Indeed, our adverse-
incident database reveals no reported adverse events."

The Company's Position

NMT president and chief executive officer John E Ahern, asked to
comment, refutes the statement by Tobis in his article that "NMT
knows something about MIST trial results that we don't."

"There is nothing more to deduct from the published, peer-reviewed
manuscript where 15 investigators and nine other study contributors
reviewed all study data, and all agreed with the results as
reported," Ahern said in a statement. "It is unfortunate that
individuals who had no involvement in the study must criticize their
efforts. Certainly if there were more to report from the study data,
these highly regarded scientific investigators would have included
it in the results as reported in Circulation."

Tobis is on the steering committee for AGA's PREMIER trial of PFO
closure for migraine, is a consultant for AGA, and is also an
implanting physician at UCLA for AGA's RESPECT trial, examining PFO
closure for stroke.

Tobis J. Management of patients with refractory migraine and PFO: Is
MIST I relevant? Catheter Cardiovasc Interv 2008; 10.1002/ccd.21504.
Abstract
Dowson A, Mullen MJ, Peatfield R, et al. Migraine Intervention With
STARFlex Technology (MIST) trial: a prospective, multicenter, double-
blind, sham-controlled trial to evaluate the effectiveness of patent
foramen ovale closure with STARFlex septal repair implant to resolve
refractory migraine headache. Circulation 2008; 117:1397-404.
Abstract
Carroll JD. Migraine intervention with STARFlex technology trial. A
controversial trial of migraine and patent foramen ovale closure.
Circulation 2008; 117:1358-1360. Abstract

A generic version of clopidogrel is expected to be available soon in
Germany, according to an announcement from Swiss pharmaceutical
company Schweizerhall.

The company says that its generic subsidiary, Cimex, has
successfully completed the decentralized approval procedure in
Germany for its generic version of clopidogrel. "We expect shortly a
positive ruling from the German authorization agency for medicines,
and we plan to launch clopidogrel throughout the European Union in
cooperation with marketing partners. A first license agreement with
a major generics company was already concluded, and the signing of a
contract with another generics provider is imminent. We expect first
sales already in the current quarter," said Luzi A von Bidder, chair
of Schweizerhall, in a press release [1].

Schweizerhall adds that clopidogrel could also obtain approval in
Luxembourg within the second quarter of 2008. Applications for
approval in additional European countries are in preparation. The
European market for clopidogrel is currently about CHF 3.2 billion
(£á2 billion, $3.09 billion), of which Germany accounts for CHF 600
million, it says.

Another Patent Battle Ahead

Clopidogrel is currently sold by Sanofi-Aventis and Bristol-Myers
Squibb as Plavix or Iscover. Sanofi-Aventis said the drug is
protected by patents until 2013 in Europe and 2011 in the US.

But von Bidder told heartwire that Schweizerhall is not infringing
Sanofi's patent. "We are not patent infringing, but I have no
further comments on this matter," he said. Analysts are suggesting
that Schweizerhall has formulated a slightly different chemical
version of the drug to get around the patent.

Not Going for US Market

Von Bidder told heartwire that Schweizerhall was not going for the
US market at this time. "We are just interested in the European
market for the time being. The patent in Europe is slightly
different from that in the US," he commented.

Plavix had worldwide sales last year of $7.3 billion, making it the
world's second-largest-selling drug. Sanofi-Aventis said in a
statement that it would "vigorously defend its intellectual property
rights" in Europe. Sanofi and Bristol-Myers Squibb MS won a patent
battle on clopidogrel in the US in 2007, after Apotex started
selling a generic version of the drug. A US court ruled that Apotex
had to stop selling its drug until the US patent on Plavix expired
in 2011.

Schweizerhall. Impending approval of clopidogrel from Cimex in
Germany. May 8, 2008. Available at:
http://www.schweizerhall.com/html/uploads/media/080508_PressRel_Clopi
do_E.pdf

A high-tech procedure that delivers radiation deep within the brain
relieved symptoms in half of patients with obsessive-compulsive
disorder who got no help from medication or talk therapy, a small
study shows.

The procedure uses a gamma knife to target brain circuits that work
overtime in people with obsessive-compulsive disorder (OCD), says
Antonio Lopes, MD, PhD, of the University of Sao Paulo in Brazil.

"In people with OCD, the network of areas that communicate is always
working, working, working. Medication and behavioral therapy can
lower the activity of this brain circuitry. But some people don't
respond, and we use the gamma knife to try to cut the connection,"
Lopes tells WebMD.

Not really a knife at all, the gamma knife is a machine that emits
powerful, highly focused gamma radiation beams. This helps the
doctors target a specific area of the brain while sparing healthy
surrounding tissue. It's used to treat people with brain tumors,
Parkinson's disease, and other neurological disorders.

Gamma Knife Relieves OCD Symptoms

At the annual meeting of the American Psychiatric Association, Lopes
presented early results of a study that pits the gamma knife against
a sham procedure in 48 patients.

Two years after undergoing the procedure, two of four patients
continue to have significant relief from symptoms, he says. Their
memory has improved. And they are better able to pay attention to
tasks at hand.

In contrast, there has been no improvement among patients who got
the sham procedure.

The procedure was relatively safe, with transient headaches and
dizziness among the most common side effects.

However, one patient suffered a manic episode about three months
after the procedure, which was followed by a bout of hallucinations
and delusions a few months after that.

"There are some complications, so this is not for everyone," Lopes
says. "This is for people who fail to respond to other treatments."

But for such patients, the procedure can mean the difference between
being homebound and functioning "moderately well," says David Baron,
DO, professor and chairman of psychiatry at Temple University in
Philadelphia.

"These are patients who have failed every single drug and are
essentially nonfunctioning, so even a little improvement is a big
deal," he says.

Baron tells WebMD that in the U.S., "surgery [for OCD] is an old
idea that is coming back because of the gamma knife. It allows you
to be much more selective and precise with less adverse effects."

Inflammatory markers are independent predictors of congestive heart
failure (CHF) and likely reflect the link between obesity and CHF, a
new study suggests [1]. In a new analysis of the Multi-Ethnic Study
of Atherosclerosis (MESA), researchers led by Dr Hossein Bahrami
(Johns Hopkins, Baltimore, MD) report that serum interleukin-6 (IL-
6), C-reactive protein (CRP), and albuminuria all predicted the
development of CHF over four years, independent of obesity or other
established risk factors.

"Our results suggest that inflammation might be involved, directly
or as a marker of other underlying conditions, in the pathologic
pathways that link obesity to left ventricular [LV] dysfunction and
ultimately CHF," Bahrami et al write.

The study appears in the May 6, 2008 issue of the Journal of the
American College of Cardiology.

Authors of the study calculated the hazard ratios (HRs) linking
baseline metabolic syndrome, inflammatory markers, insulin
resistance, and albuminuria with incidence CHF in the MESA
population, after taking into account standard risk factors, interim
myocardial infarction (MI), and left ventricular structure and
function. MESA enrolled 6814 participants from multiple ethnic
backgrounds; median follow-up for the current analysis was four
years.

Baharmi and colleagues report that 79 patients developed CHF during
follow-up: while obesity was significantly associated with
subsequent CHF, the association lost statistical significance after
inflammatory markers were included in the model. Obese patients,
however were found to have much higher levels of interleukin 6, CRP,
and fibrinogen.

According to Baharmi, the findings suggest a mechanistic link
between obesity, inflammation, and CHF.

"The implication may be that greater control of obesity may reduce
the risk of heart failure and down the road, maybe targeting
inflammatory markers may reduce the risk of heart failure related to
obesity," he told heartwire.

Inflammation may also help explain the link between the metabolic
syndrome and CHF risk: inflammation is a known characteristic of the
metabolic syndrome, and metabolic syndrome is associated with a
higher risk of developing CHF, the authors note.

The National Heart, Lung, and Blood Institute supported this study.

Source

Bahrami H, Bluemke DA, Kronmal R, et al. Novel metabolic risk
factors for incident heart failure and their relationship with
obesity. The Multi-Ethnic Study of Atherosclerosis Study. J Am Coll
Cardiol. 2008;51:1775-1783.

Carotid bruits detected by auscultation might serve as markers for
heart disease, rather than detect carotid lesions and the subsequent
risk of stroke, and could help select patients who would benefit
from an aggressive treatment strategy for cardiovascular risk,
according to the results of new study [1]. Investigators report that
those with carotid bruits have twice the risk of MI and
cardiovascular death than those without carotid bruits.

"Our study has shown that the presence of a carotid bruit
significantly increased the likelihood of a cardiovascular death or
myocardial infarction," write lead investigator Dr Christopher
Pickett (Walter Reed Army Medical Center, Washington, DC) and
colleagues in the May 10, 2008 issue of the Lancet. "Our findings
accord with the notion that these atherosclerotic changes might be
indicative of systemwide vascular pathological change to include the
coronary bed."

According to the authors, since auscultation of the carotid is a
quick and inexpensive test, it could be used to aid clinicians in
the assessment of coronary heart disease risk in certain patients.
The group points out that the prognostic implications of a carotid
bruit have focused primarily on the risk of cerebrovascular events,
but carotid bruits are a weak predictor of cerebrovascular events in
asymptomatic individuals. For those with symptoms, including
nondisabling stroke or transient ischemia in the ipsilateral
carotid, prognosis depends more of the severity of stenosis than the
presence of a carotid bruit, they write.

Because of these uncertainties, the United States Preventive
Services Task Force and the Canadian Task Force recommend against
routine auscultation of carotid bruits. However, as Pickett and
colleagues note, the turbulent flow in the lumen might serve as a
better marker for generalized atherosclerosis and, to test this
hypothesis, performed a meta-analysis to assess whether carotid
bruits could be used as a prognostic tool in determining in
cardiovascular risk.

Risk of MI and Cardiovascular Death Doubled

Overall, 22 studies, with 17 295 patients followed for a median of
four years, were included in the meta-analysis. The rate of MI in
patients with carotid bruits was 3.69 per 100 patient-years,
compared with 1.86 per 100 patient-years in those without carotid
bruits. Four studies directly compared the risk of MI in patients
with and without carotid bruits and showed that the risk was doubled
in patients with detectable carotid turbulence.

In 16 studies, the rate of cardiovascular death in patients with
carotid bruits was 2.85 per 100 patient-years, greater than the 1.11
per 100 patient-years observed in four studies assessing risk in
patients without bruits. In studies directly comparing the risk of
cardiovascular death among those with and without carotid bruits,
the risk was more than doubled for those with bruits.

The group notes that a 65-year-old male smoker with uncontrolled
hypertension or LDL-cholesterol levels >190 mg/dL would have a
similar 10-year risk of coronary events to that conveyed by the
presence of a carotid bruit. In addition, the analysis shows that
the presence of a carotid bruit meets the definition of a coronary
risk equivalent, with a 3.7% risk per year (or 37% risk over 10
years) of cardiac events when the abnormality is detected.

"Risk stratification for future coronary events is a large focus of
cardiovascular care for outpatients, and thus our findings for the
predictive power of a carotid bruit can be useful," write Pickett et
al.

Shifting Away From Physical Examinations

In an editorial accompanying the study [2], Drs Victor Aboyans and
Phillipe Lacroix (Dupuytren University Hospital, Limoges, France)
note that the physical exam has lost some of its original value,
particularly because other noninvasive methods have become
available. "The higher accuracy of these noninvasive methods along
with the dominant image culture shifted our diagnostic approach from
physical examination toward an increasing need for imaging methods,"
they write.

The editorialists note that radiography, ultrasound, and other
methods introduced to aid in diagnosis are used as prognostic
markers, and the last gap to complete this circle would be to
determine whether physical signs first used in diagnosis could also
aid in determining a patient's prognosis. They point out that many
of these other validated cardiovascular risk markers, such as
coronary artery calcium screening, are often out of reach in the
physician's office and are expensive. In developing countries, high-
tech imaging is not available now or in the foreseeable future for
aiding in disease prognosis.

Regarding the study by Pickett and colleagues, Aboyans and Lacroix
write that one-third of patients had existing cardiovascular
disease, raising questions about how the detection of a carotid
bruit would alter secondary prevention. In addition, the prognostic
value of a carotid bruit was not compared with risk scores for
cardiovascular disease, and therefore the incremental value is
unknown. Moreover, the presence of carotid bruit is low in subjects
45 years of age and older, about 4%, and while it increases with
age, other clinical signs exist that could be of similar prognostic
significance.

What is needed, they write, is a comparison between various clinical
signs, like neck and groin auscultation, and vascular markers, such
as heart rate, pulse pressure, or blood pressure, and these studies
could be used to "narrow the indications of cardiovascular imaging
techniques and make them more cost-effective in developed countries."

Pickett CA, Jackson JL, Hemann BA, Atwood JE. Carotid bruit as a
prognostic indicator of cardiovascular death and myocardial
infarction: a meta-analysis. Lancet 2008; 371:1587-1594.
Aboyans V, Lacroix P. Carotid bruit: good for silent cardiovascular
disease? Lancet 2008; 371:1554-1556.

Discrepancies in current recommendations on the use of various
antithrombotics in the European and US guidelines for the treatment
of acute coronary syndromes is causing confusion, some clinicians
have suggested [1].

The editorial, published in the May 10, 2008 issue of the Lancet, is
written by Drs John Eikelboom (Hamilton General Hospital, ON),
Gordon Guyatt (CLARITY Research Group, Hamilton, ON), and Jack Hirsh
(Henderson Research Centre, Hamilton, ON). They say that
discrepancies on recommendations regarding enoxaparin and
fondaparinux between US and European guidelines undermines
confidence in the integrity of guideline development, and they
suggest that in the future such discrepancies may be avoided if both
committees met and debated differences between their recommendations
and if they included nonconflicted methodologists to ensure that
criteria for evidence quality were applied consistently.

They write: "The disagreements in the recommendations for enoxaparin
and fondaparinux seem to stem from differences in both the
interpretation of the trial data and from differences in the
application of nearly identical criteria that were used by both
committees to classify the evidence. Without an opportunity to
review the reasoning behind each recommendation, it is difficult for
readers to decide which recommendations to follow."

Eikelboom et al note that the American College of Cardiology
(ACC)/American Heart Association (AHA) and the European Society of
Cardiology (ESC) both updated their ACS guidelines last year
[2,3]. "The committees reviewed the same research and used nearly
identical criteria to rate the strength of the recommendations and
to grade the quality of the evidence, but they interpreted the
evidence for acute anticoagulant use differently and so reached
different conclusions. Therefore, physicians who read
recommendations from both the US and European societies might be
confused."

They point out that the ACC/AHA gave enoxaparin and fondaparinux a
class 1 rating for conservatively and invasively managed patients,
implying that there is evidence or general agreement that the
treatments are useful or effective. By contrast, the ESC gave
enoxaparin a class 2 rating for conservatively and invasively
managed patients, implying that there is conflicting evidence or
divergence of opinion about the usefulness of enoxaparin, and did
not recommend fondaparinux for patients undergoing urgent invasive
procedures. "For clinicians, this is the most important area of
disagreement between the guidelines, because it directly affects the
choice of anticoagulant; unfortunately, it is also the hardest to
explain," the authors state.

They suggest that the ACC/AHA must have placed greater weight than
the ESC on the results of a meta-analysis that showed that
enoxaparin compared with heparin reduced MI and did not increase
bleeding. In contrast, the ESC seemed to place greater weight on the
results of the SYNERGY trial (which showed that enoxaparin was as
effective as heparin but was associated with more bleeding in
invasively treated patients) and the OASIS-5 trial (which found that
enoxaparin was as effective as fondaparinux but caused more bleeding
and was associated with excess strokes and deaths at day 30).

Eikelboom et al note that the divergent recommendations for
fondaparinux probably also reflect differences in the interpretation
of the OASIS-5 trial, which showed an excess of catheter thrombosis
in patients treated with fondaparinux undergoing PCI. This, they
suggest, led the ESC not to recommend fondaparinux in invasively
managed patients, "but the strong recommendation by the ACC/AHA for
fondaparinux in invasively managed patients implies that they did
not think the risk of catheter thrombosis to be an important issue,
provided that a bolus dose of heparin is used at the time of the
invasive procedure."

Clarifying the US Position

Chair of the AHC/AHA guidelines committee, Dr Jeffery Anderson
(University of Utah, Salt Lake City), told heartwire that the Lancet
editorial had somewhat misread the recommendations. He pointed out
that although the ESC doesn't recommend fondaparinux for patients
getting urgent revascularization, it has given the drug a 1A
recommendation for delayed invasive therapy within three days. He
added that the ACC/AHA recommendation for fondaparinux was for an
invasive strategy within 48 hours, not an urgent strategy, and gives
it a 1B, not a 1A, and it also specifies giving it with heparin.

"Thus, one could interpret the ACC/AHA guideline as being more
conservative, not more liberal, for fondaparinux. The difference is
the way 'early invasive' is defined. Reading the text carefully
reveals similar concerns about catheter thrombosis by both
societies, and neither advances fondaparinux particularly for
invasive patients. So the editorial obviously doesn't fairly assess
the very close overall agreement in the sense of both guidelines
that is included in the text. However, OASIS-5 was a very large and
well-done study that indicates fondaparinux as being successful for
the overall efficacy and safety end points, regardless of strategy,
despite the small excess of catheter thrombosis," Anderson
commented.

Different Focuses on Benefit/Risk?

Dr Sanjay Kaul (Cedar Sinai Medical Center, Los Angeles) suggests
that one reason for the discordant recommendations between the
ACC/AHA and ESC guidelines is that the benefit/risk trade-off
focuses only on efficacy outcomes in US guidelines but on both
efficacy and safety in the European guidelines. "Thus, while
enoxaparin gets a class 1A recommendation in the ACC/AHA guidelines
(based only on equivalent efficacy with heparin), it is downgraded
in the ESC guidelines (based on both equivalent efficacy but
increased bleeding compared with heparin or fondaparinux)," he
commented to heartwire.

"Ideally, guidelines must be written in a manner that communicates a
clear, rational, and practical balance between clinically important
magnitude of benefits and harms, not just statistically significant
benefits," Kaul said. He adds: "Rigorous standardized analytical
methodology that focuses on benefit/risk (and cost) assessment might
also improve the quality of adjudication of evidence in guideline
development."

In a recent discussion on theheart.org on differences between the US
and European guidelines (sponsored by Sanofi-Aventis and Bristol-
Myers Squibb), speakers noted that although enoxaparin and
fondaparinux were not given such strong recommendations in the
European guidelines, they were both used more extensively in Europe
than they were in the US [4].

Dr Keith Fox (University of Edinburg, Scotland) said that
fondaparinux was favored by some clinicians in the UK because it
showed a mortality advantage over enoxaparin in OASIS-5; as it is
not sufficient to be used alone in the cath lab, many centers use
unfractionated heparin in the cath lab if patients have been
pretreated with fondaparinux. But enoxaparin was still the most
widely used agent in his center, Fox added.

Dr Charles Pollack (University of Pennsylvania School of Medicine,
Philadelphia) said he was happy to use either enoxaparin or
unfractionated heparin, both of which have class 1A recommendations
in the US. He pointed out that there was very little use of
fondaparinux in the US at present, probably because it was not yet
approved for the ACS indication there. "Fondaparinux is attractive,
but there is very little experience of this drug in the US, and we
don't like the idea of having to give extra unfractionated heparin
on top of it in the lab," he said.

Dr Giles Montalescot (Hospital La Pitie Salpetriere, Paris, France)
concurred in this point. "We have moved away from using
unfractionated heparin, and we put almost everyone on enoxaparin, as
it covers all situations. If we use fondaparinux, we would have to
bring back unfractionated heparin, but we don't use it anymore," he
said. He added that his center does use fondaparinux in patients who
it is known will not be going to the cath lab.

On the other option of bivalirudin, Pollack noted that it was not
used much in the US to treat ACS patients and had not been approved
yet for use outside the cath lab, although there were signs that it
was now starting to move into the upstream setting.



Eikelboom has received honoraria from and has worked on studies with
GlaxoSmithKline, Sanofi-Aventis, and the Medicines Company. Hirsh
has received an honorarium from GlaxoSmithKline for attending an
advisory meeting.

Eikelboom J, Guyatt G and Hirsh J. Guidelines for anticoagulant use
in acute coronary syndromes. Lancet 2008; 371: 1559-1561.
Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for
the management of patients with unstable angina/non-ST-Elevation
myocardial infarction: a report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2007; 50: e1¡V157. Abstract
Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the
diagnosis and treatment of non-ST-segment elevation acute coronary
syndromes: the task force for the diagnosis and treatment of non-ST-
segment elevation acute coronary syndromes of the European Society
of Cardiology. Eur Heart J 2007; 28: 1598¡V1660. Abstract
Lost in translation: US and European guidelines for the
pharmacologic management of ACS. theheart.org. [CME programs >
Clinical cardiology]; April 10, 2008. Available at
http://www.theheart.org/article/846579.do.

Results of a randomized pilot trial suggest that cilostazol (Pletal,
Otsuka Pharmaceuticals), a phosphodiesterase 3 (PDE3) inhibitor, is
as effective as aspirin in preventing recurrent stroke, with
significantly lower rates of bleeding.

There was a trend toward fewer recurrent strokes with cilostazol in
this study, carried out in China, than with aspirin, but this did
not reach statistical significance.

"The lower rates of ischemic and hemorrhagic stroke in the
cilostazol group suggest that cilostazol might be a more effective
and safer alternative to aspirin for Chinese patients with ischemic
stroke; however, a larger phase 3 trial is required to confirm
this," the researchers, with first author Yining Huang, MD, from
Peking University First Hospital, in Beijing, China, conclude.

The study, supported by the National Health Ministry of the People's
Republic of China and Otsuka Pharmaceuticals, was released online
May 5 in advance of publication in the June issue of Lancet
Neurology.

Pilot Findings

Most patients are treated with aspirin after a stroke, the authors
write, but "aspirin-related cerebral hemorrhage is a complication
that is of concern, particularly in China, where there is a high
incidence of cerebral hemorrhage in secondary-prevention programs
and within the community."

Cilostazol is already approved in the US for the treatment of
symptoms of intermittent claudication associated with peripheral
vascular disease. It acts by preventing inactivation of the
intracellular second messenger cyclic AMP and irreversibly inhibits
platelet aggregation and vasodilation, the authors write. It also
has been shown to delay the onset of atherosclerosis, protect
endothelium, and inhibit the proliferation of arterial smooth-muscle
cells, they note.

A previous study in a Japanese population showed efficacy for
cilostazol in the prevention of ischemic stroke, they note. "We
report the results of a trial to assess the efficacy and safety of
cilostazol compared with aspirin in the prevention of secondary
stroke in a small sample of patients, which could be a pilot study
for a large phase 3 trial," Dr. Huang and colleagues write.

Called the Cilostazol vs Aspirin for Secondary Ischemic Stroke
Prevention (CASISP) trial, the multicenter, double-blind study
enrolled 720 consecutive patients within 1 to 6 months of an
ischemic stroke. Patients were treated for 12 to 18 months and
imaged at the beginning and the end of the study with T1 magnetic
resonance imaging (MRI), T2 MRI, diffusion-weighted imaging, T2
fluid-attenuated inversion recovery (FLAIR), and T2 gradient echo
imaging. The primary end point was any recurrence of stroke,
including ischemic and hemorrhagic stroke, or subarachnoid
hemorrhage.

A primary end-point event occurred in 12 patients in the cilostazol
group and 20 in the aspirin group. The estimated hazard ratio,
calculated with Kaplan-Meier curves (risk of primary end point in
the cilostazol group vs the aspirin group) was 0.62 (95% CI, 0.30 ¡V
1.26; P = 0.185).

During the first 6 months of treatment, the curves were close, but
with aspirin more effective than cilostazol during this period, they
note. However, after 6 months, the curves crossed and thereafter
favored cilostazol. At the end of the study, there was a 38.1%
reduction in the relative risk of the primary end point in the
cilostazol group vs the aspirin group. "However, this did not reach
statistical significance, which, we feel, is due to the small sample
size and the short follow-up period," they write.

In addition, the difference in symptomatic hemorrhage, they write,
is "an important distinction between the treatments." Asymptomatic
cerebral hematoma was found in 4 patients in the aspirin group vs 1
in the cilostazol group. In all, brain bleeding events occurred in 7
patients treated with aspirin vs 1 on cilostazol (the same patient
who had a symptomatic hemorrhage), a significant difference (P
= .034).

There was no significant difference between the groups in the
combined end point, including recurrent stroke, new myocardial
infarction, transient ischemic attack, or a vascular event such as
pulmonary embolism. The estimated hazard ratio was 0.70 (95% CI,
0.40 ¡V 1.21; P = .200).

Major adverse effects were generally not different between the
groups, they report, but mild adverse events, including headache,
dizziness, and tachycardia, as well as palpitations, were more
common with cilostazol.

They note that all 6 patients with symptomatic hemorrhage were found
to have microbleeds on imaging in the area where the hematoma was
located.

"To reduce drug-related cerebral hemorrhage, screening for cerebral
microbleeds might be helpful before long-term antiplatelet therapy
is started, and aspirin should be selected cautiously, particularly
in patients with microbleeds at many sites," they
conclude. "Phosphodiesterase inhibitors such as dipyridamole and
cilostazol can be thought of as candidate drugs to supplement or
replace aspirin in these high-risk patients."

Hope for a Safer Antiplatelet Drug

In a Reflection and Reaction article accompanying the paper, Graeme
J. Hankey, MD, from Royal Perth Hospital, in Western Australia,
writes that the finding on the primary end point in this study was
as expected but points out that the confidence intervals
were "extremely wide," owing to the small number of patients
randomized, their moderate risk profile, and the short follow-
up. "Unfortunately the trial design did not include the more robust
outcome event ¡X the composite of stroke, myocardial infarction, or
vascular death," he writes.

Although the authors are "understandably excited" about the smaller
number of symptomatic intracerebral hemorrhages with cilostazol and
the possibility that microbleeds might help identify those at risk
for hemorrhage, Dr. Hankey urges caution on interpretation of these
results, again based on the small number of events seen in this
trial.

"The implications of these results for clinicians are that they
offer hope for a safer antiplatelet drug that is at least as
effective as aspirin for use in patients with ischemic stroke," Dr.
Hankey concludes. "The implications of these results for researchers
are the need to explore the external validity of these pilot study
results in a phase 3 randomized trial that compares cilostazol with
aspirin (or with the new gold standard of antiplatelet therapy,
pending the results of the [Prevention Regimen for Effectively
Avoiding Second Strokes] PROFESS trial) in a large number of high-
risk patients with recent ischemic stroke from a wide range of
nations and ethnic groups."

The PROFESS trial is an ongoing randomized trial comparing 2
antithrombotic regimens, a fixed-dose combination of extended-
release dipyridamole plus aspirin with clopidogrel, and telmisartan
vs placebo in a factorial design in patients with strokes. It will
be presented May 14, 2008 at the upcoming European Stroke Conference
in Nice, France and will be reported by Medscape Neurology &
Neurosurgery at that time.

The study was supported by the National Health Ministry of the
People's Republic of China and Otsuka Pharmaceuticals. Dr. Huang has
received lecture fees from Otsuka. Disclosure information for
coauthors appears in the paper. Dr. Hankey reports that he has
received honoraria from Sanofi-Aventis, Bristol-Myers Squibb,
Boehringer Ingelheim, and Pfizer for serving on advisory boards and
speaking at sponsored scientific symposia.

Lancet Neurol. Published online May 5, 2008.